new oral anticoagulants: breakthrough or just another bleeding mess?
TRANSCRIPT
New Oral Anticoagulants:
Breakthrough or Just Another
Bleeding Mess?
Debate between Dr. Marc Carrier
and Dr. Jafna Cox at
#FMF2013
November 8, 2013
The following slides were presented as part of a debate
at the Family Medicine Forum 2013 in Vancouver,
British Columbia.
• Dr. Cox and Dr. Carrier served as expert clinical advisors on
CADTH’s Preventing Stroke in Patients with Atrial Fibrillation
project that focused on the clinical and cost-effectiveness of
warfarin, the new oral anticoagulants (NOACs), and
antiplatelets in the prevention of stroke in Afib.
• We enjoyed their lively debates during the project and felt that
they needed to be heard by a larger audience — especially
family physicians faced with decisions of which agent to
choose for their patients.
New Oral Anticoagulants: Breakthrough or
Just another Bleeding Mess?
Marc Carrier MD MSc FRCPC
Thrombosis Program
Ottawa Hospital Research Institute
Objectives
• Is evidence for the new oral anticoagulants (NOACs)
impressive, or is it hype?
• More effective for all patients?
• Safe?
» Major bleeding?
» Other complications?
• How relevant are clinical practice guidelines that
disregard cost (and evidence)?
• How difficult is it to treat a bleed with the new drugs?
Warfarin the underdog!
• Is NOT rat poison
– Rats have evolved (and so
should you…)
• Advantages of warfarin – Active by the oral route
– Once daily dosing
– Can be monitored
• Surgeries
• Bleeding episodes
• Recurrent events
• Adherence
– Rapidly-acting antidote available
– Low cost
Is evidence for the NOACs impressive, or
is it hype?
Efficacy data
Warfarin is highly effective for the
prevention of stroke in patients with atrial
fibrillation
Hart et al Ann Intern Med. 2007;146:857-867
Drug Brand name
Target Peak (h)
Half-life (h)
Bio Renal excr. (%)
Drug interactions
Dabigatran Pradaxa® Factor IIa
1.5 14 - 17 8% > 80% P-glycoprotein
Rivaroxaban Xarelto® Factor Xa
2 - 3 7 - 11 80% 33% CYP3A4
P-glycoprotein
Apixaban Eliquis ® Factor Xa
3 8 – 14 66% 25% CYP3A4
P-glycoprotein
Edoxaban Lixiana ® Factor Xa
4 8 - 11 45% 35% CYP3A4
P-glycoprotein
NOACs
RE-LY ROCKET AF ARISTOTLE
Sample size 18,113 14,264 18,201
Population Non-valvular A fib
CHADS ≥ 1
Non-valvular A fib
CHADS ≥ 2
Non-valvular A fib
CHADS ≥ 1
NOACs Dabigatran 110 mg or
150 mg BID Rivaroxaban 20 mg OD Apixaban 5 mg BID
Design
Open RCT with two
doses of double-blind
dabigatran
Double-blind Double-blind
1. Patel MR et al, 2011; 2. Connolly SJ et al, 2009; 3. Lopes RD et al, 2010; 4.Granger CB et al, 2011.
Trials Comparing NOACs vs. Warfarin
Are NOACs really more effective?
Wallentin L. Lancet. 2010 Sep 18;376(9745):975-83.
Are NOACs good anticoagulants? Other high risk populations
• Mechanical heart valves
• Trial terminated early after
enrolling 252 patients
– Dabigatran 150, 220 or 300
mg PO BID
– Warfarin
• Increased rates of
thromboembolic and
bleeding complications
with NOACs
Eikelboom JW et al N Engl J Med. 2013 Sep 26;369(13):1206-14.
Are NOACs good anticoagulants? Other high risk populations
• Secondary prevention of VTE
Castellucci L et al BMJ. 2013 Aug 30;347:f5133.
Is evidence for the new oral
anticoagulants impressive, or is it hype?
Safety data
Are NOACs really safer?
Wallentin L. Lancet. 2010 Sep 18;376(9745):975-83.
New or unknown side effects? MI or ACS
Uchino K et al. Arch Intern Med 2012;172(5):397-402.
Need more real world data! • Carefully selected patients enrolled in Phase III clinical
trials are not fully representative of real-world patients
• Especially for adherence!
– Need for studies assessing adherance over time and in different
clinical settings
– Schulman S. J Thromb Haemost 2013;11:1295-9.
• Current phase 4 data registries only include highly
selected patient population
• Low risk of MI, low risk of bleeding, etc.
• Southworth MR, et al. N Engl J Med 2013;368:14; 1272-74.
• Connolly SJ et al. Circulation 2013 Jul 16;128(3):237-43.
• Larsen TB et al. J Am Coll Cardiol 2013;61:2264-73.
Need more real world data!
• More phase IV clinical studies are needed to provide
more generalizable data. Until then patient selection is
important
How relevant are clinical practice
guidelines that disregard cost (and
evidence)?
Oral anticoagulation is not candy!
CHADS2 = 0
*Aspirin is a reasonable
alternative in some as
indicated by risk/benefit
CHADS2 = 1 CHADS2 ≥ 2
No anti-
thrombotic
Assess Thromboembolic Risk (CHADS2)
No
additional
risk factors
for stroke
Increasing stroke risk
ASA OAC* OAC* OAC
Either
female
sex or
vascular
disease
Age ≥ 65 yrs or combination of female sex and vascular
disease
Skanes AC, et al. Can J Cardiol 2012;28:125-136.
How relevant are clinical practice
guidelines that disregard cost/evidence
• What is the evidence for CHADS 0?
• Unknown benefit (unknown risk/benefit)
• But known cost!!
– Annual cost of NOACs from $1,147.53 to $1,289.44 (for life!)
• Changing practice based on absence of data…
– Hard to actually do trials once the practice has changed
– $$ for industry without known benefit
• What is the evidence for rivaroxaban in CHADS1?
No blood monitoring is an advantage of
NOACs but it is also a major
disadvantage…
Ms MT
• Ms. MT is on dabigatran 150 mg po bid. Her CrCl is 35 cc/min. She is fell and presented to ER with left hip fracture
• Basic coagulation parameters 1. Thrombin time > 60 s
2. INR normal
3. PTT 45 s
• When can the surgery be done? Keep in mind that morbidity/mortality is increased if delayed by > 48 hours
• Does it manner if the anesthesiologist want to do a spinal?
Ms MT • Ms. MT is on rivaroxaban 20 mg po daily. Her CrCl is 45
cc/min. She presented to ER with new acute stroke symptoms. Investigations showed that she would be a candidate for thrombolytics.
• Last dose of rivaroxaban was 12 hours ago.
• Basic coagulation parameters 1. Thrombin time normal
2. INR normal
3. PTT normal
4. Anti-Xa is 0.4
• Can she receive thrombolytics?
How difficult is it to treat a bleed with the
new drugs?
What is the evidence that it controls
bleeding?
What is the evidence that it controls
bleeding?
• Rabbit data
• Pragst I et al. J Thromb Haemost 2012 10: 1841–1848
• RCT of 10 non-bleeding healthy volunteers receiving
prothrombin complex (Octoplex/beriplex)
• FII, FVII, FIX, FX - 50 IU/kg
• Eerenberg ES et al. Circulation. 2011 Oct 4;124(14):1573-9.
• “Spiked” serum analyses with FEIBA
• FII, FVIIa, FIX, FX – 25 to 50 IU/Kg
• Marlu R et al. Thromb Haemost 2012 Aug;108(2):217-24.
What is the evidence that it controls
bleeding?
• Hooray!! Some bleeding patients data
– Level 1 ;) Case series of 4 bleeding patients who received FEIBA
• Industry has done RCT enrolling over 50,000 patients to
receiving NOAC without any data antidote or reversal
• We need to tailor our practice using data of a case series
involving 4 patients!!!
Conclusions
• NOACs not more effective or safe than warfarin if good
time in therapeutic range
• Phase III clinical trials are not fully representative of real-
world patients
• Many questions remain around bleeding and
perioperative management of NOACs
• More research on adherence is needed
Conclusions
• Good old warfarin might still be the number #1 drug of
choice...especially for long-term treatment
Jafna L. Cox, MD, FRCPC, FACC
Heart and Stroke Foundation of Nova Scotia Endowed Chair in Cardiovascular Outcomes Research
Professor of Medicine and of Community Health and Epidemiology, CDHA/Dalhousie University
Past ACC Governor, Atlantic Provinces
New Oral Anticoagulants: Breakthrough or Just Another Bleeding Mess?
Disclosure
• Dr Cox
– Has served on advisory boards for AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Pfizer, and Sanofi-Aventis
– Has participated in research funded by Bayer, Merck, Pfizer and Sanofi-Aventis
– Has served as/is a consultant to the Nova Scotia Department of Health, the New Brunswick Department of Health, the Public Health Agency of Canada, and the Canadian Agency for Drugs and Technologies in Health
– Is a member of the Canadian Cardiovascular Society’s Atrial Fibrillation Guidelines Panel and Chair of its Atrial Fibrillation Quality Indicator Subcommittee
Antiplatelet drugs vs. Placebo
Warfarin vs. Placebo/Control
100% 50% 0 - 50%
6 Trials n = 2,900
8 Trials n = 4,876
Treatment Better
Treatment Worse
Hart RG et al. Ann Intern Med 2007; 146: 857
RRR 64%
RRR 19%
Antithrombotic Therapy for AF: Efficacy of Existing Stroke Risk Reduction Therapy
Warfarin vs. Aspirin: RRR 39%
• Warfarin is highly effective for stroke prevention in AF –reduces risk by 64% – but its use is problematic
– Associated with significant increase in intracranial and other haemorrhage, especially in the elderly
– Only about 1 in 4 patients are optimally treated
• Registries show that only 50-60% of eligible patients receive warfarin
• In clinical trials, time in therapeutic range (TTR) is 60-68%; in general practice, TTR is typically <50%
Warfarin for Stroke Prevention in AF
Hart Ann Int Med 2007;146:857; Hylek Stroke 2006;37:1075; Singer Chest 2008;133:546S; Gladstone Stroke 2009;40:235; CCS guidelines 2004; Matchar Am J Med 2002;113:42; Bungard Pharmacotherapy 2000;20:1060
60
35 34
55
64
51 49 54
34
67
59
45 43
0
20
40
60
80
100
Warf
arin U
se (
%)
Underuse of Oral Anticoagulation in AF: Results from Recent Studies
2005-06 1999-2000 2007-10
Go Ann Intern Med 1999;131:927 Nieuwlaat Eur Heart J 2006;27:3018 Friberg Eur Heart J 2006;27:1954 Glazer Arch Intern Med 2007:167 Samsa Arch Intern Med 2000;160:967 Hylek Stroke 2006;37:1075 Monte Eur Heart J 2006;27:2217 Walker Heart Rhythm 2008;5:1365 Gage Stroke 2000;31:822 Hylek Stroke 2006;37:1075 Boulanger Int J Clin Pract 2006;60:258 Zimetbaum Am J Med 2010;123:446 Waldo J Am Coll Cardiol 2005;46:1729 Birman-Deych Stroke 2006;37:1070
Use of Oral Anticoagulation in AF: Results from a Global Registry
Healey et al. ESC 2011
Appropriate use of OAC continues to remain low. When OAC is used, INR control is suboptimal.
65.1
44.8
63.5
38.7
55.8
36.9 39.9
10.5
43.6
0
20
40
60
80
100
%
OAC Use in CHADS2 ≥2
53.5
43.5
66.9
59.1
46.8 39.5
33.9 36.1 38.4
0
20
40
60
80
100
%
Time in Therapeutic Range*
*based on 3 most recent INR values
Based on 15,174 patients presenting to an Emergency Department with AF/AFL between Jan. 2008 and Apr. 2011
Adding Insult to Injury: Patient Persistence With Warfarin for Atrial Fibrillation
Gomes T, et al. Arch Intern Med 2012; 172: 1-3
43% stop in 2 years, 61% stop in 5 years (median 2.9 years)
Ontario patients > 66 years of age, 1997-2008 (N= 125,195)
Warfarin and ASA/Antiplatelets are Commonly Associated With Adverse Events
Drug Annual Estimate of
Hospitalizations % ED Visits Resulting in
Hospitalization
Oral hypoglycemics 10,656 (10.7%) 51.8%
Warfarin 33,171 (33.3%) 46.2%
Oral antiplatelets 13,263 (13.3%) 41.5%
Insulins 13,854 (13.9%) 40.6%
ED=emergency department
Budnitz DS et al. N Engl J Med 2011; 365: 2012-12
Annual US National Estimates of Hospitalizations and ED Visits Resulting in Hospitalization in Adults ≥65 Years of Age (2007-2009)
Key Factors in Physician Underutilization Of VKAs in AF
• Lifestyle issues
– Need for regular monitoring, lifestyle restrictions, compliance and other patient factors
• Resource challenges
– Lack of availability of a coordinated anticoagulant outpatient monitoring process or clinic
• Perceived bleeding risk
– Concern about risk of hemorrhage, not always appropriately balanced against risk of stroke
Go AS, et al. Ann Intern Med 1999; 131: 927–934
Age (years)
35.4 44.3
57.3 60.7 58.1
0
20
40
60
80
100
War
fari
n U
se (
%)
<55 55-64 65-74 75-84 >85
Rate of Warfarin Use Within 3 Months of Diagnosis of AF
An Age-Related Risk-Treatment Paradox With Warfarin Use in SPAF
• Risk of stroke in AF patients increases with age
– 1.5% per year in 50-59 year olds
– 23.5% in 80-89 year olds
Anticoagulation and Risk of Falls in the Elderly – Putting Matters in Perspective
• A patient with a 5% annual stroke risk from AF would need to fall 295 times in a year for the calculated risk of subdural hematoma from falling to outweigh the stroke reduction benefit of warfarin
Arch Intern Med 1999; 159:677-685
Stroke Prevention in the Elderly With AF Remains A Challenge – Fear of Bleeding
Hylek EM, et al. Circulation 2007; 115: 2689-2696
Major Hemorrhage on Warfarin in First Year of Therapy Among Elderly Patients with AF
New Oral Anticoagulants for SPAF
• Direct Thrombin Inhibitors
– Dabigatran
• Factor Xa Inhibitors
– Rivaroxaban
• Phase III data published Aug. 2011
– Apixaban
• Phase III data published Aug. 2011
– Edoxaban
• Phase III data expected Nov. 2013
http://www.clinicaltrials.gov/ct2/search Adapted from Turpie Eur Heart J 2008; 29:155
Xa
IIa
TF/VIIa
X IX
IXa VIIIa
Va
II
Fibrin Fibrinogen
Rivaroxaban
Apixaban
Edoxaban
TTP889
Warfarin sites of action
Dabigatran
Prevention of Stroke
Connolly N Engl J Med 2010; 363: 1876; Patel N Engl J Med 2011; 365: 883; Granger N Engl J Med 2011; 365: 981
0.50 0.75 1.00 1.25 1.50
Dabigatran 110 mg BID
Dabigatran 150 mg BID
HR (95% CI)
Warfarin better Comparator better
Rivaroxaban 20 mg QD
Apixaban 5 mg BID
0.29
<0.001
0.12
0.01
Stroke or Systemic Embolism
Ischemic Stroke
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Rivaroxaban 20 mg QD
Apixaban 5 mg BID
0.35
0.03
0.59
0.42
Superiority p-value
Reducing the Bleeding Risk
HR (95% CI)
Warfarin better Comparator better
0.50 0.75 1.00 1.25 0.25
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Rivaroxaban 20 mg QD
Apixaban 5 mg BID
Intracranial Haemorrhage
ISTH Major Bleeding
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Rivaroxaban 20 mg QD
Apixaban 5 mg BID
Superiority p-value
<0.001
<0.001
0.02
<0.001
0.003
0.31
0.58
<0.001
Connolly N Engl J Med 2010; 363: 1876; Patel N Engl J Med 2011; 365: 883; Granger N Engl J Med 2011; 365: 981
Sensitivity Analysis – Major Bleeding
Apixaban 5 mg BID versus Adjusted Dose
Warfarin
Dabigatran 110 mg BID versus Adjusted Dose
Warfarin
Dabigatran 150 mg BID versus Adjusted Dose
Warfarin
Rivaroxaban 20 mg OD versus Adjusted Dose
Warfarin
No treatment/Placebo versus Adjusted Dose
Warfarin
Low Dose Aspirin (≤ 100 mg OD) versus
Adjusted Dose Warfarin
Medium Dose Aspirin (> 100 mg and ≤ 300 mg
OD)versus Adjusted Dose Warfarin
Clopidogrel 75 mg OD & Low dose Aspirin (≤ 100
mg OD) versus Adjusted Dose Warfarin
0.69(0.6,0.8)
0.71(0.61,0.81)
0.8(0.69,0.93)
0.8(0.69,0.93)
0.93(0.8,1.08)
0.93(0.81,1.08)
1.03(0.89,1.19)
1.03(0.89,1.19)
0.33(0.08,1.08)
0.21(0.06,0.62)
1.05(0.6,1.86)
0.77(0.57,1.04)
1.78(0.62,5.59)
0.73(0.48,1.11)
1.1(0.83,1.46)
1.19(0.92,1.54)
Mortality
0.50 0.75 1.00 1.25 1.50
Dabigatran 110 mg BID
Dabigatran 150 mg BID
HR (95% CI)
Warfarin better Comparator better
Rivaroxaban 20 mg QD
Apixaban 5 mg BID
Superiority p-value
0.13
0.051
0.073
0.047
All-Cause Mortality
Cardiovascular Mortality
Dabigatran 110 mg BID
Dabigatran 150 mg BID
Rivaroxaban 20 mg QD
Apixaban 5 mg BID
0.21
0.04
0.29
NR
NR: Not Reported
Connolly N Engl J Med 2010; 363: 1876; Patel N Engl J Med 2011; 365: 883; Granger N Engl J Med 2011; 365: 981
Major Clinical Recommendations for Antithrombotic Management in AF
Risk of stroke Canadian Guidelines
CCS
American Guidelines
ACCP
European Guidelines
ECS
Low
(CHADS2 = 0)
Higher risk* = OAC Dabigatran, rivaroxaban, apixaban
recommended over warfarin.†
Lower risk* = ASA
Lowest risk* = No therapy
No therapy Higher risk* = OAC
Lowest risk* = No therapy
Intermediate
(CHADS2 = 1)
OAC Dabigatran, rivaroxaban, apixaban
recommended over warfarin.†
OAC Dabigatran recommended over
warfarin.‡
OAC Dabigatran, rivaroxaban, apixaban
recommended over warfarin.
High
(CHADS2 ≥2)
OAC Dabigatran, rivaroxaban, apixaban
recommended over warfarin.†
OAC Dabigatran recommended over
warfarin.‡
OAC Dabigatran, rivaroxaban, apixaban
recommended over warfarin.
ASA = acetylsalicylic acid; OAC = oral anticoagulants; VKA = vitamin K antagonist.
* Based on the consideration of other risk factors (age 65-74 years, female sex and presence of vascular disease). † Preference for newer agents less clear in patients under warfarin with stable INR and no bleeding complications. ‡ At the time the American Guidelines were published (2012), only dabigatran received regulatory approval for use in AF and therefore, the Guidelines do not make recommendations for apixaban and rivaroxaban.
Persistence Among Patients with Non-Valvular AF Beginning Dabigatran or Warfarin
0
10
20
30
40
50
60
70
80
90
100
6 months 12 months
Dabigatran Warfarin
% o
f p
atie
nts
per
sist
ent
on
th
erap
y
Zalesak M, et al. Higher persistence in newly diagnosed nonvalvular atrial fibrillation patients treated with dabigatran versus warfarin. Circ Cardiovasc Qual Outcomes 2010; 3: 624-631.
Assembled into propensity-score matched pairs (each N=1745)
• At 6 months:
- 72 % of patients still persistent with dabigatran treatment
- 53% of patients still persistent with warfarin treatment
• At 12 months:
- 63% of patients still persistent with dabigatran treatment
- 39% of patients still persistent with warfarin treatment
Newly diagnosed AF patients: 1,775 on warfarin and 3,370 on dabigatran (identified from US Department of Defense claims database)
Mean Time to Switch or Discontinue From Original Prescription
131 149
168
0
30
60
90
120
150
180
Warfarin Dabigatran(110&150mg)
Rivaroxaban (20mg)
Day
s o
n in
itia
l th
erap
y
Initial drug therapy
Evers et al, Real life treatment persistence with newer oral anticoagulants and potential strokes avoided in patients with atrial fibrillation [abstract]. Eur Heart J 2013; 34S
Anticoagulants and Antidotes
• There is no antidote for any of the new oral anticoagulants
However, there is also no immediate antidote for warfarin!
– Vitamin K takes time to work (12 or more hours), far too long if the patient is presenting with an intracranial haemorrhage
• By 12-24 hours of stopping a NOAC, hemostasis will have normalized
– PCC therapy rapidly corrects INR in most patients on warfarin, yet with debatable prognostic impact
– Antidotes for the Factor Xa inhibitors are in development
• Benefit shown in mice with apixaban, betrixaban, rivaroxaban
• Phase 2 studies in humans have begun
Pandit TN, et al. Am J Hematol 2012; 87: S56-62; Dowlatshahi. Stroke 2012; 43: 1812; Lu et al. Nat Med 2013; 19: 446-452
Warfarin-Associated ICH: Poor Prognosis Despite Anticoagulation Reversal
Dowlatshahi. Stroke 2012; 43: 1812
Canadian PCC (prothrombin complex concentrate) Registry: • N=141 anticoagulation associated intracerebral hemorrhages • 72% with INR < 1.5 within < 1h; yet 42% mortality (50% of cases)
• Warfarin is an effective agent that has long served as our foundation for anticoagulation in AF
• Warfarin has important limitations that contribute to underutilization and poor INR control – 3 of 4 patients with AF are unprotected or poorly protected
against stroke
• New agents offer important safety and efficacy advantages over warfarin
• Warfarin will continue to play an important role: – For other indications (e.g., prosthetic valves) – In patients with renal impairment (i.e., CrCl < 15 ml/min)
A Cardiologist’s Perspective: On The Shifting Role of Warfarin
• Compared with warfarin, each of the 3 new agents: – Are at least as effective in preventing stroke/systemic embolism – Are associated with less intracranial bleeding – Are associated with similar or less major bleeding – Offer greater ease of use
• Many patients will benefit from the advantages offered by these drugs that ideally should be started by primary care or emergency department physicians rather than cardiologists
A Cardiologist's Perspective: On The Evolving Treatment Paradigm for SPAF
• It’s just too bad that • You wouldn’t necessarily get there on time • Comfort would be a significant problem • Forget about “hands free” anything • And who needs seat belts, automatic transmission,
parking/lane change/braking assist, etc., anyway?
If the only cars available were from the 1950s you’d still get to where you needed to be; well, maybe 2/3 of the time…
Why Bother To Innovate?
Why Bother To Innovate?
• If you are unlucky enough to crash you will probably survive • And while you are unlikely ever to be able to replace any broken
parts, well… just get someone else to drive you the next time
Safety and convenience are overrated and not worth the money; you’ll still get from point A to point B… Maybe...
• Imagine if the novel anticoagulants had been established therapy for some 6 decades and a new drug appeared that: – Was unpredictable in terms of patient therapeutic response – Had slow therapeutic onset and offset – Had a narrow therapeutic window – Required close monitoring via frequent blood tests – Required frequent dose adjustment – Was plagued by drug-drug and drug-food interactions – Was associated with more intracranial haemorrhage – Resulted in a 10% increase in mortality
Would anyone in their right mind think it had a chance of getting to market and, if it did, would anyone prescribe it?
Some Final Insane Musings
Thank You
Choice of Anticoagulant Based on Patient Characteristics
Adapted/modified from Weitz & Gross, Hematology 2012:536-40
Characteristic Drug Choice Rationale
Mechanical or valvular AF Warfarin New agents not studied
Liver dysfunction with elevated INR
Warfarin New agents require hepatic metabolism
Poor compliance Warfarin or nothing Missed doses of greater consequence with shorter acting agents
Stable on warfarin Warfarin Consider switching at patient request
CrCl < 30 mL/min Warfarin Such patients were excluded from trials with new agents
CrCl of 30-50 mL/min Rivaroxaban or Apixaban
Oral Xa inhibitors are less affected by impaired renal function than dabigatran
Dyspepsia or upper GI complaints
Rivaroxaban or Apixaban
Dyspepsia in up to 10% given dabigatran
Recent GI bleed Apixaban More GI bleeding with dabigatran (150 mg BID) or rivaroxaban than with warfarin
Recent ischemic stroke on Warfarin
Dabigatran Dabigatran (150 mg BID) associated with lowest risk of ischemic stroke vs warfarin
Recent acute coronary syndrome Rivaroxaban or Apixaban
Small MI signal with dabigatran
Poor compliance with BID regimen or desire for once daily
Rivaroxaban Only oral agent that is currently once a day
NOACs and Poor Kidney Function
CrCl (mL/min)
Age Range (years)
0% 20% 40% 60% 80% 100%
20-39
40-59
60-69
≥70
≥90
60-89
30-59
15-29
Kidney Function Declines With Advancing Age
The Risk Factors for CKD are Commonly Found in Patients with AF
Risk Factor for Stroke in AF
(CHA2DS2-Vasc)
Congestive Heart Failure
Hypertension
Age ≥ 75
Diabetes Mellitus
Stroke/TIA/Thromboembolism
Vascular Disease
Age 65-74
Female
Risk Factors (CKD)
Heart Disease
Hypertension
Age ≥ 65
Diabetes Mellitus
Smoking
Obesity
Family history of kidney disease
High cholesterol
African-American, Native-American or Asian-American
race
Haroun et al. J Am Soc Nephrol 14: 2934–2941, 2003; http://www.mayoclinic.com/health/kidney-failure/DS00682/DSECTION=risk-factors; Lip, GY, et al. Stroke 2010; 46: 2731
The Risk of Stroke and Bleeding Increases with Declining Renal Function – Real World Data
Olesen et al. N Engl J Med 2012; 367: 625-35
Data from 132,372 patients with a diagnosis of non-valvular atrial fibrillation using Danish national registries
Stroke/thromboembolism Bleeding
Eve
nt
rate
/10
0 p
ers
on
ye
ars
No Renal Disease
Non end-stage CKD
10
8
6
4
2
0
Measuring and Monitoring Renal Function with NOAC Anticoagulants
• NOAC studies used creatinine clearance (CrCl) to assess renal function
• For prescribing and monitoring patients on NOAC, use CrCl not creatinine
• With NOAC, check kidney function:
• Every 6 months for most patients
• Every 3 months for those who have CrCl < 50
• With every acute, especially dehydrating, illness
• Important: for fragile patients calculate CrCl and not GFR (they can be very different in older patients)
Pharmacologic properties
Rivaroxaban (Xarelto®)
Dabigatran (Pradaxa®)
Apixaban (Eliquis®)
Mechanism of action
Direct factor Xa inhibitor
Direct factor IIa (thrombin)
inhibitor
Direct factor Xa inhibitor
Renal clearance 33% 85% 27%
1. Xarelto® PM, June 2013; 2. Pradaxa ® PM November, 2012; 3. Eliquis® PM November, 2012; 4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review
New OACs: Total Drug Exposure (AUC) with Declining Renal Function
Apixaban (27% cleared renally†)3
Dabigatran (85% cleared renally)2
Rivaroxaban (33% cleared renally*)1
AU
C r
atio
vs.
No
rmal
Ren
al F
un
ctio
n
* active drug † Factoring in the absolute bioavailability of apixaban, ~ 50 % of the systemically available dose is eliminated in urine4
1. Xarelto® PM, July 18, 2012 ; 2. Pradaxa ® PM November 12, 2012; 3. Eliquis® PM November 27, 2012; 4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review
Perioperative and Bleeding Management
Practical Considerations: Perioperative Management of Anticoagulant Therapy
• Alteration of oral anticoagulant regimen may not be necessary for most patients undergoing low risk procedures: – Dental procedures (including extractions of up to 4 teeth), joint
and soft tissue injections, arthrocentesis, cataract surgery, upper endoscopy or colonoscopy with/without biopsy
• For other invasive and surgical procedures, oral
anticoagulation needs to be withheld: – Decision on whether to pursue an aggressive strategy of perioperative
administration of IV heparin or SQ low molecular-weight heparin should be individualized based on an estimation of the patient’s risks of thromboembolism and bleeding and the patient’s preference
Douketis J, et al. Chest 2008;133:299S-339S; Dunn AS and Turpie AGG. Arch Intern Med 2003;163:901-908
• Determine renal function (CrCl or eGFR)
• Determine drug half-life
• Evaluate stroke and bleeding risks
– Decide timing of temporary discontinuation
– Consider any need for bridging therapy
– Plan timing of resumption of therapy
• Re-evaluate after surgical or diagnostic procedure
Crowther MA & Warkentin TE. J Thromb Haemostat 2009;7 (Suppl 1):107-110 van Ryn J, et al. Thromb Haemostat 2010;103:1116-1127 Cairns et al. Can J Card 2011 27:74-90
Practical Considerations: Perioperative Management of Anticoagulant Therapy
Practical Considerations: Perioperative management – Summary of CCS Guidelines
Cairns et al. Can J Card 2011 27:74-90
Patient with AF Undergoing Surgical or Diagnostic Procedure With Major Bleeding Risk
Very Low to Moderate Stroke Risk*
High Stroke Risk**
Low Bleeding Risk
High Bleeding Risk
Low Bleeding Risk
High Bleeding Risk
Continue Antithrombotic
(INR <3 if warfarin)
Stop Antithrombotic Preprocedure
Reinstitute when risk of bleeding reduced
Continue OAC or stop OAC and bridge with
UFH or LMWH perioperatively
Stop OAC and bridge with
UFH or LMWH perioperatively¶
* CHADS2 ≤ 2 ** Mechanical valve, recent stroke or TIA, rheumatic valve disease, CHADS2 ≥ 3 ¶ Stop 12 to 24 hours preprocedure , restart when hemostasis secure and bridge to therapeutic OAC
• For dabigatran: – If CrCl ≥ 30 ml/min and patient is at low risk of bleeding, withhold
dabigatran for ≥ 24 hours; restart the evening after the procedure
– If CrCl < 30 ml/min and if the procedure is complicated, withhold
dabigatran for 2-5 days; consider switching the patient to warfarin after the procedure
• For apixaban and rivaroxaban: – If CrCl ≥ 30 ml/min and patient is at low risk of bleeding, withhold for
≥ 24 hours; restart the evening after the procedure
– If CrCl < 30 ml/min and if the procedure is complicated, withhold for ≥ 36 hours; consider switching the patient to warfarin after the procedure
1. Pradax Product Monograph 2010, Boehringer Ingelheim Canada Ltd 2. Xarelto Product Monograph 2012, Bayer Inc (Canada)
Practical Considerations: If a Novel Anticoagulant Must be Stopped Before a Procedure
New OACs: Total Drug Exposure (AUC) with Declining Renal Function
Apixaban (27% cleared renally†)3
Dabigatran (85% cleared renally)2
Rivaroxaban (33% cleared renally*)1
AU
C r
atio
vs.
No
rmal
Ren
al F
un
ctio
n
* active drug † Factoring in the absolute bioavailability of apixaban, ~ 50 % of the systemically available dose is eliminated in urine4
1. Xarelto® PM, July 18, 2012 ; 2. Pradaxa ® PM November 12, 2012; 3. Eliquis® PM November 27, 2012; 4. FDA Eliquis Drug Approval Package, Clinical Pharmacology/Biopharmaceutics Review
Renal Function: Timing of Dabigatran Discontinuation Prior to Procedure
Renal function
(CrCl ml/min)
Half-life, hours
(range)
Timing of discontinuation of
dabigatran before surgery
Moderate
bleeding risk
High
bleeding risk
> 50 to ≤ 80 15 (12–34) 1–2 days 2–3 days
31–50 18 (13–23) 3–4 days 4–5 days
≤ 30* 27 (22–35) 4–5 days > 5 days
*Dabigatran is contraindicated for use in patients with severe renal impairment (CrCl < 30ml/min)
Adapted from:
1. van Ryn J, et al. Thromb Haemostat 2010;103:1116-1127
2. Pradax Monograph 2010, Boehringer Ingelheim Canada Ltd
Measures to Take for Bleeding on NOAC
Direct thrombin inhibitors (dabigatran) – Ask about last intake + dosing regimen – Estimate normalization of hemostasis
• Normal renal function: 12-24 hours • CrCl 50-80 ml/min: 24-36 hours • CrCl 30-50 ml/min: 36-48 hours • CrCl <30 ml/min: ≥48 hours
FXa inhibitors (apixaban, rivaroxaban) – Ask about last intake + dosing regimen – Normalization of hemostasis: 12-24 hours
Heidbuchel H, et al. Europace 2013; 15: 625-51
Assess whether a NOAC is in circulation: • Check PTT for dabigatran • Check PT for rivaroxaban • No clear method for apixaban
Dabigatran and MI Risk
Efficacy and Safety Endpoints Across Trials
Connolly N Engl J Med 2010;363:1876; Patel N Engl J Med 2011;365:883; Granger N Engl J Med 2011;365:981; CADTH Report 2012
(Odds Ratio, 95% CI)
0.10 1.00 10.00
Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od Apixaban 5 mg bid Dabigatran 110 mg bid Dabigatran 150 mg bid Rivaroxaban 20 mg od
All-cause Stroke/SE
Major Bleeding
All-cause Mortality
Intracranial Hemorrhage
Myocardial Infarction
Myocardial Infarction in RELY
Connolly NEJM 2009;361:1139 *Connolly NEJM 2010;363:1876
D 110mg
Annual rate
D 150mg
Annual rate
W
Annual rate
Myocardial Infarction
0.72%
P=0.07
0.74%
P=0.048
0.53%
D 110mg
Annual rate
D 150mg
Annual rate
W
Annual rate
D 110 mg vs. W RR
95% CI P
D 150 mg vs. W
RR
95% CI P
Myocardial Infarction
0.82% (0.72%)
0.81% (0.74%)
0.64% (0.53%)
1.29 0.96-1.75
0.09 (0.07)
1.27 0.94-1.71
0.12 (0.048)
Mak K-H. BMJ Open 2012;2:e001592. doi:10.1136/bmjopen-2012-001592
Dabigatran
Rivaroxaban
Apixaban
P=0.021
P<0.001
P=0.333
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