Hypercoagulable Syndromes and New Anticoagulant Therapies ...€¦ · Hypercoagulable Syndromes. and New Anticoagulant Therapies (Hypercoagulability in the Era of. Direct Oral Anticoagulants)
69
Hypercoagulable Syndromes and New Anticoagulant Therapies (Hypercoagulability in the Era of Direct Oral Anticoagulants) Kenneth A. Bauer, MD [email protected]
Hypercoagulable Syndromesand New Anticoagulant Therapies
(Hypercoagulability in the Era ofDirect Oral Anticoagulants)
Kenneth A Bauer MD
kbauerbidmcharvardedu
Janssen ndash rivaroxaban
Disclosures
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral AnticoagulantsReversal
Risk Factors for VTE
bull Surgerybull Trauma (major trauma or
lower-extremity injury)bull Acute medical illnessbull Immobilizationbull Estrogen-containing
contraceptives or hormone replacement therapy
bull Pregnancypuerperiumbull Central venous catheters
bull Prolonged air travel (operationally manage as idiopathic)
Adapted from Weiler H Factor V Leiden (Arg506Gln) Va resistant to inactivation by APC
Prothrombin Gene MutationG rArr A Mutation at Position 20210 in 3acute- UT Region
GENOTYPE PROTHROMBIN RANGE20210 AG 132 95-17820210 GG 105 55-156
From Poort et al Blood 1996
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Initial Treatment of DVTPEbull Parenteral AC followed by VKA or DOAC (ldquo2 drug approachrdquo)
bull UFH (IV with PTT monitoring)LMWH or Fondaparinux (SC without coagulation monitoring) overlapping with warfarin for at least 5 days until INR gt2 for 1-2 days
bull Start warfarin on day 1 to achieve INR of 2-3 treat for 3-6 months clinical utility of pharmacogenomic testing for 2Cy9 and VKORC1 polymorphisms not established
bull Dabigatran 150 mg bid or Edoxaban 60 mg qd bull Oral factor Xa inhibition (ldquoone drug approachrdquo)
bull Start rivaroxaban on day 1 at 15 mg bid x 3 weeks followed by 20 mg daily with food treat for 3-6 months
bull Start apixaban on day 1 at 10 mg bid x 1 week followed by 5 mg bid daily treat for 3-6 months
bull No laboratory monitoring required
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Janssen ndash rivaroxaban
Disclosures
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral AnticoagulantsReversal
Risk Factors for VTE
bull Surgerybull Trauma (major trauma or
lower-extremity injury)bull Acute medical illnessbull Immobilizationbull Estrogen-containing
contraceptives or hormone replacement therapy
bull Pregnancypuerperiumbull Central venous catheters
bull Prolonged air travel (operationally manage as idiopathic)
Adapted from Weiler H Factor V Leiden (Arg506Gln) Va resistant to inactivation by APC
Prothrombin Gene MutationG rArr A Mutation at Position 20210 in 3acute- UT Region
GENOTYPE PROTHROMBIN RANGE20210 AG 132 95-17820210 GG 105 55-156
From Poort et al Blood 1996
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Initial Treatment of DVTPEbull Parenteral AC followed by VKA or DOAC (ldquo2 drug approachrdquo)
bull UFH (IV with PTT monitoring)LMWH or Fondaparinux (SC without coagulation monitoring) overlapping with warfarin for at least 5 days until INR gt2 for 1-2 days
bull Start warfarin on day 1 to achieve INR of 2-3 treat for 3-6 months clinical utility of pharmacogenomic testing for 2Cy9 and VKORC1 polymorphisms not established
bull Dabigatran 150 mg bid or Edoxaban 60 mg qd bull Oral factor Xa inhibition (ldquoone drug approachrdquo)
bull Start rivaroxaban on day 1 at 15 mg bid x 3 weeks followed by 20 mg daily with food treat for 3-6 months
bull Start apixaban on day 1 at 10 mg bid x 1 week followed by 5 mg bid daily treat for 3-6 months
bull No laboratory monitoring required
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral AnticoagulantsReversal
Risk Factors for VTE
bull Surgerybull Trauma (major trauma or
lower-extremity injury)bull Acute medical illnessbull Immobilizationbull Estrogen-containing
contraceptives or hormone replacement therapy
bull Pregnancypuerperiumbull Central venous catheters
bull Prolonged air travel (operationally manage as idiopathic)
Adapted from Weiler H Factor V Leiden (Arg506Gln) Va resistant to inactivation by APC
Prothrombin Gene MutationG rArr A Mutation at Position 20210 in 3acute- UT Region
GENOTYPE PROTHROMBIN RANGE20210 AG 132 95-17820210 GG 105 55-156
From Poort et al Blood 1996
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Initial Treatment of DVTPEbull Parenteral AC followed by VKA or DOAC (ldquo2 drug approachrdquo)
bull UFH (IV with PTT monitoring)LMWH or Fondaparinux (SC without coagulation monitoring) overlapping with warfarin for at least 5 days until INR gt2 for 1-2 days
bull Start warfarin on day 1 to achieve INR of 2-3 treat for 3-6 months clinical utility of pharmacogenomic testing for 2Cy9 and VKORC1 polymorphisms not established
bull Dabigatran 150 mg bid or Edoxaban 60 mg qd bull Oral factor Xa inhibition (ldquoone drug approachrdquo)
bull Start rivaroxaban on day 1 at 15 mg bid x 3 weeks followed by 20 mg daily with food treat for 3-6 months
bull Start apixaban on day 1 at 10 mg bid x 1 week followed by 5 mg bid daily treat for 3-6 months
bull No laboratory monitoring required
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Risk Factors for VTE
bull Surgerybull Trauma (major trauma or
lower-extremity injury)bull Acute medical illnessbull Immobilizationbull Estrogen-containing
contraceptives or hormone replacement therapy
bull Pregnancypuerperiumbull Central venous catheters
bull Prolonged air travel (operationally manage as idiopathic)
Adapted from Weiler H Factor V Leiden (Arg506Gln) Va resistant to inactivation by APC
Prothrombin Gene MutationG rArr A Mutation at Position 20210 in 3acute- UT Region
GENOTYPE PROTHROMBIN RANGE20210 AG 132 95-17820210 GG 105 55-156
From Poort et al Blood 1996
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Initial Treatment of DVTPEbull Parenteral AC followed by VKA or DOAC (ldquo2 drug approachrdquo)
bull UFH (IV with PTT monitoring)LMWH or Fondaparinux (SC without coagulation monitoring) overlapping with warfarin for at least 5 days until INR gt2 for 1-2 days
bull Start warfarin on day 1 to achieve INR of 2-3 treat for 3-6 months clinical utility of pharmacogenomic testing for 2Cy9 and VKORC1 polymorphisms not established
bull Dabigatran 150 mg bid or Edoxaban 60 mg qd bull Oral factor Xa inhibition (ldquoone drug approachrdquo)
bull Start rivaroxaban on day 1 at 15 mg bid x 3 weeks followed by 20 mg daily with food treat for 3-6 months
bull Start apixaban on day 1 at 10 mg bid x 1 week followed by 5 mg bid daily treat for 3-6 months
bull No laboratory monitoring required
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
VTE Risk Factor Model
Intrinsic Thrombosis
Risk
Acquired Risk FactorsGenes ++
VTE
Triggering Factors
Prophylaxis+
ndash
Thrombosis Threshold
bull Anticoagulant deficienciesAntithrombin 20-fold uArr RRProtein S 10-fold uArrProtein C 10-fold uArr
bull Prothrombin 3-fold uArrbull Factor V Leiden 3-8 fold uArr
Adapted from Weiler H Factor V Leiden (Arg506Gln) Va resistant to inactivation by APC
Prothrombin Gene MutationG rArr A Mutation at Position 20210 in 3acute- UT Region
GENOTYPE PROTHROMBIN RANGE20210 AG 132 95-17820210 GG 105 55-156
From Poort et al Blood 1996
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Initial Treatment of DVTPEbull Parenteral AC followed by VKA or DOAC (ldquo2 drug approachrdquo)
bull UFH (IV with PTT monitoring)LMWH or Fondaparinux (SC without coagulation monitoring) overlapping with warfarin for at least 5 days until INR gt2 for 1-2 days
bull Start warfarin on day 1 to achieve INR of 2-3 treat for 3-6 months clinical utility of pharmacogenomic testing for 2Cy9 and VKORC1 polymorphisms not established
bull Dabigatran 150 mg bid or Edoxaban 60 mg qd bull Oral factor Xa inhibition (ldquoone drug approachrdquo)
bull Start rivaroxaban on day 1 at 15 mg bid x 3 weeks followed by 20 mg daily with food treat for 3-6 months
bull Start apixaban on day 1 at 10 mg bid x 1 week followed by 5 mg bid daily treat for 3-6 months
bull No laboratory monitoring required
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Activated Protein CMechanism of Action
Thrombin
Thrombomodulin
PC APC
Anticoagulant
PSVa
VIIIa
Adapted from Weiler H Factor V Leiden (Arg506Gln) Va resistant to inactivation by APC
Prothrombin Gene MutationG rArr A Mutation at Position 20210 in 3acute- UT Region
GENOTYPE PROTHROMBIN RANGE20210 AG 132 95-17820210 GG 105 55-156
From Poort et al Blood 1996
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Initial Treatment of DVTPEbull Parenteral AC followed by VKA or DOAC (ldquo2 drug approachrdquo)
bull UFH (IV with PTT monitoring)LMWH or Fondaparinux (SC without coagulation monitoring) overlapping with warfarin for at least 5 days until INR gt2 for 1-2 days
bull Start warfarin on day 1 to achieve INR of 2-3 treat for 3-6 months clinical utility of pharmacogenomic testing for 2Cy9 and VKORC1 polymorphisms not established
bull Dabigatran 150 mg bid or Edoxaban 60 mg qd bull Oral factor Xa inhibition (ldquoone drug approachrdquo)
bull Start rivaroxaban on day 1 at 15 mg bid x 3 weeks followed by 20 mg daily with food treat for 3-6 months
bull Start apixaban on day 1 at 10 mg bid x 1 week followed by 5 mg bid daily treat for 3-6 months
bull No laboratory monitoring required
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Prothrombin Gene MutationG rArr A Mutation at Position 20210 in 3acute- UT Region
GENOTYPE PROTHROMBIN RANGE20210 AG 132 95-17820210 GG 105 55-156
From Poort et al Blood 1996
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Initial Treatment of DVTPEbull Parenteral AC followed by VKA or DOAC (ldquo2 drug approachrdquo)
bull UFH (IV with PTT monitoring)LMWH or Fondaparinux (SC without coagulation monitoring) overlapping with warfarin for at least 5 days until INR gt2 for 1-2 days
bull Start warfarin on day 1 to achieve INR of 2-3 treat for 3-6 months clinical utility of pharmacogenomic testing for 2Cy9 and VKORC1 polymorphisms not established
bull Dabigatran 150 mg bid or Edoxaban 60 mg qd bull Oral factor Xa inhibition (ldquoone drug approachrdquo)
bull Start rivaroxaban on day 1 at 15 mg bid x 3 weeks followed by 20 mg daily with food treat for 3-6 months
bull Start apixaban on day 1 at 10 mg bid x 1 week followed by 5 mg bid daily treat for 3-6 months
bull No laboratory monitoring required
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Initial Treatment of DVTPEbull Parenteral AC followed by VKA or DOAC (ldquo2 drug approachrdquo)
bull UFH (IV with PTT monitoring)LMWH or Fondaparinux (SC without coagulation monitoring) overlapping with warfarin for at least 5 days until INR gt2 for 1-2 days
bull Start warfarin on day 1 to achieve INR of 2-3 treat for 3-6 months clinical utility of pharmacogenomic testing for 2Cy9 and VKORC1 polymorphisms not established
bull Dabigatran 150 mg bid or Edoxaban 60 mg qd bull Oral factor Xa inhibition (ldquoone drug approachrdquo)
bull Start rivaroxaban on day 1 at 15 mg bid x 3 weeks followed by 20 mg daily with food treat for 3-6 months
bull Start apixaban on day 1 at 10 mg bid x 1 week followed by 5 mg bid daily treat for 3-6 months
bull No laboratory monitoring required
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Initial Treatment of DVTPEbull Parenteral AC followed by VKA or DOAC (ldquo2 drug approachrdquo)
bull UFH (IV with PTT monitoring)LMWH or Fondaparinux (SC without coagulation monitoring) overlapping with warfarin for at least 5 days until INR gt2 for 1-2 days
bull Start warfarin on day 1 to achieve INR of 2-3 treat for 3-6 months clinical utility of pharmacogenomic testing for 2Cy9 and VKORC1 polymorphisms not established
bull Dabigatran 150 mg bid or Edoxaban 60 mg qd bull Oral factor Xa inhibition (ldquoone drug approachrdquo)
bull Start rivaroxaban on day 1 at 15 mg bid x 3 weeks followed by 20 mg daily with food treat for 3-6 months
bull Start apixaban on day 1 at 10 mg bid x 1 week followed by 5 mg bid daily treat for 3-6 months
bull No laboratory monitoring required
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Pregnancy-associated VTE or post-partum if breast feeding
Massive PE (hemodynamically unstable) or DVT (phlegmasia cerulea dolens) where thrombolysis is a consideration
Very obese patients ( weight gt120 kg) with severe DVTPE
Patients with altered GI anatomy (gastric bypass procedures)
Highly rdquothrombosis-pronerdquo patients (recurrent DVT or PE on therapeutic anticoagulation)
Important to ensure that patients adhere to therapy with medication (behavioral insurance and cost issues)
Question Now that DOACs are an oral option for initial VTE treatment when should we use it
Wouldnrsquot use (or be cautious) in
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patients
Prandoni P et al Haematologica 2007
10 per year
3 per yearIdiopathic
Secondary
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
VTE rates after different durations of anticoagulation for unprovoked VTE
0
5
10
15
20
25
30
0 5 10 15 20 25 30
Series1
Months of Anticoagulation
Rec
urre
nce
VTE
per
Yea
r (
) LevineBTS
DURAC 1
PiniPrandoniLAFIT
0 63 12 24
WODIT 1WODIT 2DOTAVK
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Chart1
91
47
163
118
174
124
61
121
111
86
86
101
105
74
72
246
102
103
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
1
3
1
3
3
15
6
3
3
3
6
3
12
3
12
3
27
6
Sheet1
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
1
91
3
47
1
163
3
118
3
174
15
124
6
61
3
121
3
111
3
86
6
86
3
101
12
105
3
74
12
72
3
246
27
102
6
103
Sheet1
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Sheet2
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Sheet3
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Duration of anticoagulant treatment Summary3 months is equivalent to 6 months Extending anticoagulation is
highly effective in eliminating recurrences (gt90 relative risk reduction) but only as long as treatment is continued
Unprovoked DVTPE is associated with a high recurrence risk after the discontinuation of anticoagulation which is greatest during the first 2 years
2016 ACCP Guidelinesbull For VTE without cancer we suggest DOACs instead of VKA
for the first 3 months and beyond (2B)bull In patients with recurrent VTE on oral anticoagulation we
suggest switching to LMWH at least temporarily (2C)In VTE associated with strong transient risk factors (surgery
trauma) extended treatment beyond 3-6 months not required nor is testing for thrombophilia (from lsquoASH Choosing Wiselyrsquo)
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Agenda
bull Risk Factors and Pathophysiologybull Initial Rx and Prognosis of VTEbull Acquired and Inherited Thrombophiliasbull Duration of AnticoagulationRisk Stratificationbull Direct Oral Anticoagulants
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
The Homocysteine Story
Epidemiologic studies done 20-30 years ago found that mild hyperhomocysteinemia was both prothrombotic and proatherogenic
Multiple controlled randomized trials of B vitamin supplementation reduced homocysteine levels but did not reduce the risk of thrombosis
Recent studies suggest that the association between mild hyperhomocysteinemia and vascular disease (particularly VTE) may have been due to unmeasured confounding factors (Ospina-Romero M et al Am J Epidemiol 2018)
rArr No reason to measure homocysteine levelsrArr Never test for MTHFR polymorphisms (C677T A1298C)
Also never test for PAI-1 promoter (4G5G) or Factor XIII polymorphisms
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
(high titer gt40 GPLMPL or gt99th percentile)ndash β2-glycoprotein I antibodies (IgG or IgM) (gt99th percentile)
2 or more occasions gt12 wks apart
Antiphospholipid Antibody Syndrome (APLS)
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Antiphospholipid Antibody Syndrome
Lupus Anticoagulant
THROMBOSIS
ACAAnti-β2GPI
APLS is associated with SLE cancer infections drugs often idiopathic
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Antiphospholipid Antibody Syndrome (APLS)bull A clinically heterogeneous autoimmune disorder
associated with thrombosis in any vascular bed most patients present with venous thrombosis ischemic stroke or recurrent fetal loss
bull Literature suggests that a 1st unprovoked venous thrombotic event in association with persistent LA (review Blood 2013 122817) rArr high recurrence risk rArr need for long-term anticoagulation
bull Two randomized trials showed that an INR of 2-3 was effective in venous thrombosis and APLS
bull Rivaroxaban vs Warfarin in high-risk APLS (TRAPS) Stopped after 120 patients enrolled due to high event rate (19) with rivaroxaban vs 3 with warfarin (Blood 2018 in press)
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
How to approach DOAC use in patients with APLSbull Experience with warfarin and TRAPS trial makes it drug of choice in high risk APLS patients (triple positive arterial clots) ASTRO-APS trial ongoing using apixaban
bull Is there any APLS patient (ie those at lower recurrence risk) in which a DOAC can be considered
bull Vignette 68 year old male diagnosed with unprovoked bilateral PE and successfully treated with rivaroxaban for 6 months Baseline PTPTT wnl LA testing not done as he was continuously on anticoagulation Cardiolipin and B2GPI IgM antibodies persistently gt40 Patient is resistant to going on warfarinCONSIDER LEAVING ON DOAC AT FULL DOSE AFTER COUNSELING (DOCUMENT DISCUSSION)
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Venous Thromboembolism in Cancer
Common (~20 of all patients with VTE)
Increased risk of recurrent VTE on VKACan occur with a therapeutic INR (ldquowarfarin failurerdquo)
2016 ACCP GuidelinesChronic low molecular weight heparin suggested over
warfarin (Grade 2B) or DOACs (Grade 2C)In patients with recurrent VTE on long term LMWH
we suggest increasing dose of LMWH by one quarter to one third (2C)
Observational studies of rivaroxaban and apixaban showed favorable outcomes with respect to efficacy and safety
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
In patients with active cancer and acute VTE chronic LMWH treatment as compared to LMWH followed by a vitamin K antagonist for 6 months
bull Reduced the cumulative risk of recurrent VTE at 6 months (CLOTCATCH) from 120105 for VKA to 6072 for LMWH (HR 047065)
bull Similar rates of major bleeding
bull Warfarin is difficult to manage in cancer patients Time that INR was in Therapeutic Range (TTR) in CLOTCATCH were 4647 20 of 53 recurrent thrombotic events in CLOT occurred with an INR lt 2
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Treatment for up to 12 months (at least 6 months)
Efficacy and safety data collected during the entire 12 month study period
Independent blind adjudication of all suspected outcomes
Severity of major bleeding at presentation also adjudicated
N ~1000
Objectively Confirmed VTEbull Stratified randomization for
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Major bleeding 33 (63) 17 (32) + 31 (05 57)Fatal 0 2Intracranial 2 4 GI upper 17 3 GI lower 3 3
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Severity of Major Bleeding Edoxaban Dalteparin
Severity (33 major bleeds) (17 major bleeds)
1 0 0
2 21 (64) 5 (29)
3 12 (36) 11 (65)
4 0 1 (6)
3 or 4 12 of 522 (23) 12 of 524 (23)
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Event-free SurvivalFreedom from Recurrent VTE Major Bleeding and Death
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Conclusionsbull Oral edoxaban noninferior to subcutaneous dalteparin for primary outcome of recurrent VTE or major bleedingbull Lower rate of recurrent VTE observed with edoxaban offset by similar increase in risk of major bleedingbull More upper GI bleeding with edoxaban mainly in patients with GI cancer at entrybull Major bleeding less severe with edoxabanbull Rate of severe major bleeding similarbull Survival free of recurrent VTE or major bleeding similar
bull Similar findings in SELECT-D Pilot Trial using rivaroxaban as monotherapy vs LMWH for treatment of cancer-associated VTE (Young AM et al J Clin Oncol 2018)
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
LMWH followed by edoxaban is an alternative to chronic LMWH with the following caveats
Absence of drug interactions with edoxaban No expected fluctuation in renal status Avoid use in patients with upper GI tract tumors Avoid in those at high risk for bleeding
Monotherapy with rivaroxaban or apixaban for acute VTE (trials ongoing including Caravaggio)
DOAC Use in Cancer Patients
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Data after 1st 3-6 months of treatment are limited for type of anticoagulant as well as duration of therapy
General consensus is to continue anticoagulation in the setting of activepersistent cancer and treatment which can be years for some patients
Must individualize based on severity of initial thrombotic event initialongoing risk factors quality of life considerations and patient preference
Cancer-Associated Thrombosis Duration of Treatment
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performed
Carrier M New Eng J Med 2015
Evaluation for occult malignancy in the patient presenting with unprovoked VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Sites of Thrombosis
ABNORMALITY ARTERIAL VENOUS
Factor V Leiden - +Prothrombin 20210A - +AT Deficiency - +Protein C Deficiency - +Protein S Deficiency - +
Lupus Anticoagulant + +
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Factor V Leiden (FVL) 12-40Prothrombin Gene Mutation (PGM) 6-18Deficiencies of AT Protein C Protein S 5-15Antiphospholipid Antibody Syndrome ~5Unknown 20-70
Several variants have been found by candidate and genome-wide screens ndash all common and weak (OR lt 15) (Smith NL JAMA 2007 Bezemer ID JAMA 2008 Li Y JTH 2009
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Significantly increased risk for second and third trimester fetal loss (~3-fold uarr)
No association with preeclampsia IUGR Role of LMWH to prevent recurrent fetal
loss One positive trial in thrombophilic women Multiple negative trials in women with
recurrent losses before 20 weeks including thrombophilic women (TIPPS Lancet 2014)
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
The ldquoHypercoagulable Workuprdquo
Genetic test for Factor V Leiden mutation Genetic test for Prothrombin G20210A mutation Functional assay of Antithrombin Functional assay of Protein C Functional assay of Protein S
Free Protein S Antigen (ldquobestrdquo protein S measurement) Total Protein S Antigen
Tests for Antiphospholipid Antibody Syndrome Lupus anticoagulant Cardiolipinβ2-glycoprotein I antibodies
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Assay Measurements in Deficiencies of Antithrombin Protein C or Protein S
TYPE ANTIGEN ACTIVITYI Low LowII Normal Low
Free protein S antigen is the best assay for diagnosing protein S deficiency Protein S levels and the risk of venous thrombosis results from the Mega
Study ndash a population-based case-control study (Blood 2013)N=5317 protein S deficient if protein S level lt 25th percentile of controls
Total protein S lt 68 UdL (Odds ratio 090 95th CI 062-131)Free protein S lt 53 UdL (Odds ratio 082 95th CI 056-121)Using a lower cut-off for free protein S (lt010th percentile)
Free protein S lt 33 UdL (OR 54 95th CI 061-488)Conclusion Low protein S levels were not associated with VTE in this study In
the absence of a family history hereditary protein S deficiency as a risk factor for VTE is rare
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Acquired Deficiencies in AntithrombinProtein C or Protein S
ANTITHROMBIN PROTEIN C PROTEIN SPregnancy PregnancyLiver Disease Liver Disease Liver DiseaseDIC DIC DICNephrotic syndromeMajor surgery InflammationAcute thrombosis Acute thrombosis Acute thrombosis
Caveats1 Donrsquot draw these tests when patients present acutely with VTE or are receiving
anticoagulants DOACs can result in erroneous results in some functional assays (eg oral factor Xa inhibitors in testing for antithrombin deficiency)
2 Abnormal results drawn at presentation with VTE must be confirmed Draw protein C and S levels after discontinuing warfarin for a minimum of 1 week
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Risk of Recurrent Venous Thrombosis in Patients with Inherited Thrombophilia
bull Heterozygosity for Factor V Leiden (FVL) or Prothrombin G20210A do not substantially increase recurrence risk
bull Retrospective data indicate that risk is not even higher in homozygotes with FVL and heterozygotes with both FVL and PT G20210A (Lijfering WM Circulation 2010)
bull Antithrombin Protein C Protein S Deficiencybull High in selected kindreds with strong clinical
penetrance (retrospective studies)bull Less data in unselected patients
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
How do DOACs compare to standard therapy (LMWHwarfarin) in patients with hereditary
thrombophilia
bull We donrsquot know ndash patients entering trials were not routinely screened for hereditary thrombophilia (review in J Thromb Thrombolysis 2017 4324-30)
bull But no a priori mechanistic reason to believe that DOACs will not be as effective and as safe as LWMHwarfarin in patients with common thrombophilias (1 copy of Factor V Leiden or Prothrombin G20210A mutations) Mechanistically DOACs might be preferable to heparinLMWH in AT deficiency or warfarin in protein C deficiency
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
What do the ACCP guidelines say about the presence of hereditary thrombophilia with respect to the duration of anticoagulation
The presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation for VTE in these guidelines because evidence from prospective studies suggests that these factors are not major determinants of the risk of recurrence
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
42
Any patient with spontaneous VTE
Younger patient with VTE + family history
Any patientwith VTE
General population
Younger patient with VTE
ConservativeLiberal
Nobody
Who Should Be Tested
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and Inherited Thrombophilias Duration of AnticoagulationRisk
Stratification Direct Oral AnticoagulantsReversal
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
ACCP Evidenced-Based Clinical Practice Guidelines
IndicationProximal DVTPE
secondary to a transient risk factor
1st isolated unprovoked distal DVT
Idiopathic proximal DVT or PE
2nd Unprovoked DVT or PE
Duration of Anticoagulation
3 months
3-6 months or indefinite
Long-term
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Duration of anticoagulant treatment What do the ACCP guidelines say2008 We recommend that patients
with a first idiopathic VTE be evaluated for long-term treatment If no contra-indication we recommend long-term treatment (Grade 1A)Values and preferences This recommendation
attaches a relatively high value to prevention of recurrent VTE and a lower value to the burden of long-term anticoagulant therapy
2012 2016 In patients with a first VTE that is an unprovoked proximal DVT of the leg and who have a low or moderate bleeding risk we suggest extended anticoagulant therapy over 3 months of therapy (Grade 2B)
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Extension of warfarin treatment beyond 3 to 6 months in 1st unprovokedidiopathic VTE
Death byPE recurrence80 VTE recurrencesCase-fatality rate 4-123 to 10 deaths
Death bymajor bleed20 to 60 bleedsCase-fatality rate 102 to 6 deaths
In year 1 following cessation of anticoagulationfor 1000 patient-years
NO MORTALITY BENEFIT FROM LONG-TERM ANTICOAGULATION WITH VITAMIN K-ANTAGONISTS (WARFARIN)
rArr A recurrent VTE rate of lt5 per year has been considered rdquoacceptablerdquo (risk of anticoagulation gt benefit)
Douketis JD et al Ann Intern Med 2007147766-774Linkins LA et al Ann Intern Med 2003 139893-900
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
Other elements that increase the risk of recurrence after stopping anticoagulant treatment includebull Persistently elevated D-dimer levels off anticoagulantsbull Male genderbull Residual thrombus on ultrasound (conflicting data difficult to
standardize)Clinical Prediction Models
bull Vienna Prediction Model (gender type of VTE D-dimer on VKA)bull HERDOO (Hyperpigmentation edemaleg redness D-dimer
BMI patient age)bull DASH (D-dimer post-VKA age gender hormonal therapy)
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
D-dimer to select patients with a first unprovoked VTE who have anticoagulants stopped at 3-7 months a multicentre management study (D-Dimer Optimal Duration Study DODS)
410 patients enrolled (mean age 51) 319 patients with negative D-dimer on VKA (lt 500) and 4 weeks later off VKA
Recurrent VTE 95 CIEntire Cohort (n=318) 66 per year 48-90Men (n=180) 97 per year 67-137Women (no estrogens=81) 54 per year 25-102Women (estrogens=58) 0 per year 00-30
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Caveats about Using D-dimer forVTE Risk Stratification
1) Only applies to patients with a 1st unprovoked VTE (OCP-related events included)
2) Most useful for risk stratification in women lt age 75 All men have a higher recurrence risk (~10 or greater in 1st
year after discontinuing anticoagulation)
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
5 Primary efficacy endpoint in AMPLIFY-EXT was recurrent VTE and all-cause death in other
trials was recurrent VTE and VTE-related death
Plt00001 (for superiority)
20 mg QDHR (95 CI)
018 (009ndash039)
n=42
n=8
Placebo(N=594)
Rivaroxaban(N=602)
NoninferiorHR (95 CI)
144 (078ndash264)
n=18n=26
Warfarin(N=1426)
Dabigatran(N=1430)
Plt00001(for superiority)HR (95 CI)
008 (002ndash025)
n=37
n=3Placebo(N=662)
Dabigatran(N=681)
EINSTEIN-EXT RE-MEDYRE-SONATEAMPLIFY-EXT
Placebo(N=829)
n=73
n=14
n=34
Apixaban25 mg
(N=840)
Apixaban5 mg
(N=813)
25 mg BIDRR (95 CI)
019 (011 ndash 033)5 mg BID
RR (95 CI)020 (011 ndash 034)
Plt00001 (for superiority)
n=14
Patie
nts
With
Prim
ary
Effic
acy
Even
t (
)
1318
04
56
13
71
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Chart1
Placebo (N=594)
Rivaroxaban (N=602)
71
13
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Recurrent VTE
Recurrent VTE
Sheet1
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Recurrent VTE
Placebo (N=594)
71
Rivaroxaban (N=602)
13
To resize chart data range drag lower right corner of range
Chart1
Warfarin (N=1426)
Dabigatran (N=1430)
13
18
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Recurrent VTE orRelated Death
Recurrent VTE orRelated Death
Sheet1
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Recurrent VTE orRelated Death
DVT
PE
Warfarin (N=1426)
13
09
04
Dabigatran (N=1430)
18
12
07
To resize chart data range drag lower right corner of range
Chart1
Placebo (N=662)
Dabigatran (N=681)
56
04
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Recurrent VTE or Related Death
Recurrent VTE or Related Death
Sheet1
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or Related Death
DVT
PE
Placebo (N=662)
56
33
21
Dabigatran (N=681)
04
03
01
To resize chart data range drag lower right corner of range
Chart1
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
88
88
17
17
88
17
17
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Recurrent VTE or VTE-Related Death
Sheet1
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Placebo (N=829)
Apixaban 25 mg (N=840)
Apixaban 5 mg (N=813)
Recurrent VTE or VTE-Related Death
88
17
17
To resize chart data range drag lower right corner of range
Among patients with unprovoked VTE aspirin was associated with recurrent VTE rate of 56 vs 18 in 20mg rivaroxaban vs 15 in 10mg rivaroxaban
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st
unprovoked VTE with extended therapy
ldquoGreater net clinical benefit with DOACs than VKAsrdquo
DVTPE recurrence5 to 15 per year
Major bleeds~05 per year
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Other Considerations Site of thrombosis
PE more likely to recur as PE DVT as DVT Severity of Thrombosis (favor indefinite anticoagulation)
Massive PE Ilio-femoral DVT Severe post-thrombotic syndrome
Pharmacomechanical Catheter-Directed Thrombolysis for DVT No reduction in post-thrombotic syndrome at 6-24 months 27 reduction in percent of patients with moderate-severe
PTS compared to anticoagulation (18 vs 24) SubmassiveMassive PE (PERT Teams ndash EKOS catheters low-
dose lytic therapy no RCT data showing improved outcomes) IVC filters (many retrievable filters never retrieved)
uArr risk of recurrent DVT especially if VTE unprovoked No benefit shown in a randomized trial in proximal DVT
Mismetti P JAMA 2015
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Agenda
Risk Factors and Pathophysiology Initial Rx and Prognosis of VTE Acquired and inherited thrombophilias Duration of anticoagulationRisk Stratification Direct Oral AnticoagulantsReversal
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Fibrin Clot
XII
VIIVIII
IX
XI
II
V
X
I
Unfractionated Heparin
WarfarinLow Molecular
Weight Heparin
Direct Oral Anticoagulants (DOACs)
Direct Thrombin (IIa) Inhibitors
Dabigatran etexilate
Direct Factor Xa Inhibitors
RivaroxabanApixabanEdoxaban
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
DabigatranEtexilate
Rivaroxaban Apixaban Edoxaban
Bioavailability6-7 ~80 ~66 ~60
T (max) 2 h 2-4 h 3 h 1-2 h
Half-life 12-14 h 7-13 h 8-13 h 9-11 h
ProteinBinding
35 90 87 55
Dosing Twice (or once) daily
Once (or twice) daily Twice daily Once daily
Elimination 80 renal 67 renal (12 active)33 fecal
25 renal 75 fecal
35 renal65 fecal
Potential Drug Interactions
Potent P-gpinhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 and P-gp inhibitors
Potent CYP 3A4 (lt4)
and P-gp inhibitors
Comparative Properties of DOACs
Inhibitors ketoconazole ritonavir Inducers rifampin phenytoin carbamazepine St Johnrsquos wort
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Direct Oral AnticoagulantsApproval Status in United States
Betrixaban approved in 617 for prophylaxis of VTE (for 35-42 days) in patients hospitalized for acute medical illness with moderatesevere
restricted mobility and other risk factors for VTEDOACs should never be used in patients with prosthetic heart valves
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Summary Trials of DOACs vs Warfarin
DOACs at least as effectivesafe as warfarin in AF as well as VTE and can be given without monitoring
Lower stroke risks with dabigatranapixaban in AF
Less major bleeding with apixaban and edoxaban
Slight increase in myocardial infarction rates with dabigatran in AF
Increase in gastrointestinal bleeding with dabigatran rivaroxaban and edoxaban in AF
In comparison with warfarin direct oral anticoagulants reduced major bleeding by 28 and intracranial and fatal hemorrhage by ~50
Connolly SJ et al NEJM 2009 Alexander J et al NEJM 2011 Mahaffey K et al NEJM 2011
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Assessing Presence or Levels of DOACs
Clinical applicability PTINR for rivaroxabanedoxaban is variable depending on PT reagent Apixaban has minimal effect in many PT assays even at supratherapeutic concentrations Quantitative assays are not yet FDA-approved or widely available Rapid point-of-care assays would be required to make decisions in bleeding emergencies
Oral Factor Xa Inhibtors Dabigatran
Drug Present(Qualitative test)
PT (for rivaroxaban)
PT more sensitive than PTT
Thrombin time highly sensitive
PTT more sensitive than PT
Quantitative Assay Chromogenic anti-factor Xa Dilute thrombin time or Ecarin Clotting Time
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Dabigatran
Idarucizumab
bull Humanized Fab fragmentbull Binds with high-affinity to dabigatranmetabolites
bull Primarily renal excretion
bull Terminal tfrac12 103 hours bull No interaction with other drugs
bull Dose 5 grams over 15 minutes
bull Leads to immediate complete and sustained reversal of dabigatran activity as measured by dilute thrombin time and ecarin clotting time
Idarucizumab A specific reversal agentfor the anticoagulant activity of dabigatran
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Pollack et al NEJM 2017
Idarucizumab Pivotal Study Findings
bull 503 patients with either serious bleeding (301) or need for urgent procedure (202) Most were elderly with atrial fibrillation (median age 78) 13 of serious bleeds were intracranial bleeding
bull Median time to bleeding cessation (ie when assessed to have stopped) was 25 hours ldquoNormal hemostasisrdquo as judged by surgeoninterventionalist (procedure group) achieved in 934 of patients
bull Thrombotic events in 68 and 19 died at 90 days (related to index event and comorbidities)
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Andexanet - a decoy protein for factor Xa inhibitorsretained
bull 41 kD recombinant human Factor Xa moleculebull Catalytic activity eliminated by substitution of active site
serine by alaninebull Gla domain removed to eliminate membrane binding
and incorporation into prothrombinase complexbull Oral Factor Xa inhibitors as well as
heparinsLMWHfondaparinux (bound to AT) reversibly bind to active site of andexanet inhibiting their ability to bind to Factor Xa
bull Higher dose of andexanet required for rivaroxaban than for apixaban
bull Half-life (tfrac12) ~1 hour ndash administered as an intravenous bolus followed immediately by a constant infusion over 2 hours
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Antifactor Xa Activity Before and After Andexanet
bull Anti-Xa levels reduced
bull Apixaban Andexanet vs placebo (94 vs 21 Plt001) bolus
bull Rivaroxaban Andexanet vs placebo (92 vs 18 Plt001) bolus
bull Apixaban Andexanet vs placebo (92 vs 33 Plt001) infusion
bull Rivaroxaban Andexanet vs placebo (97 vs 45 Plt001) infusion
NEJM 2015Non-neutralizing antibodies developed in 17 of patients 15-30 days after administration
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Andexanet in Acute Major BleedingANNEXA-4 Trial
bull Andexanet was administered to 228 patients 61 had intracranial bleeds
bull 88 of 132 adjudicated patients had anti-factor Xa levels le 75 ngmL after andexanet Clinical hemostasis was excellent or good in 83 12 hours after drug
bull Thrombotic events occurred in 11 and death in 12 at 30 days (related to index event and comorbidities)
bull Time from ED presentation to administration of andexanet bolus (mean 48 plusmn 18 hours) in initial 67 patients
bull Limited availability until 2019 Very expensive (25-50K)
Connolly et al NEJM 2016 and ACC Abstract 2018
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Discontinuehold anticoagulant
Supportive Care (IV fluids packed RBCs)
Activated charcoal (if ingested in last 2 hours)
Localizationmanagement of bleeding site (if possible)
If taking dabigatran administer idarucizumab
In life-threatening or uncontrolled bleedingFor emergency surgeryurgent procedures (if judged to have clinically significant plasma levels of dabigatran)
If taking an oral FXa inhibitor administer andexanet (if available) in life-threatening or uncontrolled bleeding otherwise consider administration of PCCs
Management of Major Bleeding in Patientson DOACs
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Calculated CrCl mLmin Half-life h
Timing of Last Dose Before Surgery
Standard Risk of BleedingA
High Risk of BleedingN
Dabigatrangt80 13 (11-22) 24 h 2 dgt50-le80 15 (12-34) 24 h 2 dgt30-le50 18 (13-23) 2 d 4 dle30 27 (22-35) 4 d 6 dRivaroxabangt30 12 (11-13) 24 h 2 dle30 Unknown 2 d 4 dApixaban
24 h 48 hA Examples cardiac catheterization ablation therapy colonoscopy without removal of large polyps
uncomplicated laparoscopic proceduresB Examples major cardiaccancerurologicvascular surgery insertion of pacemakersdefibrillators
neurosurgery large hernia surgery
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Question 1A 25-year-old woman has completed 6 months of warfarin
for pulmonary emboli which occurred 2 months after starting an oral contraceptive which was discontinued upon diagnosis Family history is negative for thrombosis but she is found to be heterozygous for the prothrombin G20210A mutation What do you recommend for this patient
A Discontinue warfarin and discuss contraceptive options (eg IUD with progestational agent mini-pill)
B Continue warfarin at a target INR of 2-3 indefinitelyC Switch to rivaroxaban 10 mg qd indefinitelyD Switch to apixaban 25 mg bid indefinitelyE Switch to aspirin 325 mg daily
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
Slide Number 68
Slide Number 69
Question 2A 58 year old woman with recurrent ovarian cancer
develops pulmonary emboli She was treated with 7 days of LMWH at therapeutic doses The patient dislikes LMWH injections Based on currently available evidence what anticoagulant option would be most effective in preventing recurrent VTE
A Continued therapy with LMWH for 6 monthsB Switch to the oral FXa inhibitor edoxaban 60 mg dailyC Switch to the oral FXa inhibitor rivaroxaban 20 mg dailyD IVC filter placement followed by warfarin (INR 2-3) with
ldquobridgingrdquoE Transition to warfarin (INR 2-3) with ldquobridgingrdquo
Slide Number 1
Slide Number 2
Agenda
Risk Factors for VTE
Slide Number 5
Activated Protein CMechanism of Action
Prothrombin Gene MutationG A Mutation at Position 20210 in 3acute- UT Region
Slide Number 8
Agenda
Initial Treatment of DVTPE
Slide Number 11
Risk of recurrent VTE after discontinung anticoagulation in a cohort of 1626 patientsPrandoni P et al Haematologica 2007
VTE rates after different durations of anticoagulation for unprovoked VTE
Duration of anticoagulant treatment Summary
Agenda
The Homocysteine Story
Slide Number 17
Antiphospholipid Antibody Syndrome
Antiphospholipid Antibody Syndrome (APLS)
How to approach DOAC use in patients with APLS
Venous Thromboembolism in Cancer
Conclusions ndash CLOT (Dalteparin) and CATCH (Tinzaparin) Trials of LMWH vs VKA in Cancer-Associated Thrombosis
Edoxaban vs LMWH (Dalteparin) in Cancer-Associated VTERaskob et al NEJM 2018
Patient Characteristics and Treatment Duration
Primary OutcomeFirst Recurrent VTE or Major Bleeding Event
First recurrent VTE or Major bleeding event
Severity of Major Bleeding
Slide Number 28
Slide Number 29
Slide Number 30
Slide Number 31
Available data do not support an extensive search for occult malignancy (ie CT scans) it is however important to pursue symptoms or signs which suggest an underlying malignancy and to ensure that age-appropriate screening tests have been performedCarrier M New Eng J Med 2015
Sites of Thrombosis
Prevalence of Defects in Caucasian Patients with Venous Thrombosis
Duration of anticoagulant treatmentAdditional determinants of the risk of recurrence
D-Dimer for VTE Risk StratificationKearon C et al Ann Intern Med 2015
Caveats about Using D-dimer forVTE Risk Stratification
Recurrent VTEVTE-Related Death in DOAC Extended Treatment Trials
Slide Number 52
The Reality The superior safety profile of oral factor Xa inhibitors is leading to the treatment of more patients with a 1st unprovoked VTE with extended therapy ldquoGreater net clinical benefit with DOACs than VKAsrdquo
Other Considerations
Agenda
Slide Number 56
Slide Number 57
Direct Oral AnticoagulantsApproval Status in United States
Summary Trials of DOACs vs Warfarin
Assessing Presence or Levels of DOACs
Slide Number 61
Idarucizumab Pivotal Study Findings
Andexanet - a decoy protein for factor Xa inhibitors
Slide Number 64
Andexanet in Acute Major BleedingANNEXA-4 Trial
Slide Number 66
Periprocedural Management of DOACsTiming of Interruption of DOACs Before SurgeryInvasive Procedures
