how to handle the bleeding risk related to oral anticoagulants · ammar majeed, hun-gyu hwang,...
TRANSCRIPT
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Ammar Majeed
Hematology Center, Karolinska University Hospital and Karolinska Institute,
Stocklholm, Sweden;
How to Handle the Bleeding Risk Related
to Oral Anticoagulants
-
Comparing bleeding on NOACs and warfarin
Bleeding on NOACs vs bleeding on warfarin
The “possibility to reverse warfarin with PCC, no antidote for NOACs”
If you get a head bleeding on warfarin we can treat it
with PCC (Octaplex)
If you bleed on the new agents, there is no antidote
Puts off both patients and doctors from using NOACs
-
Comparing bleeding on NOACs and warfarin
Bleeding on NOACs vs bleeding on warfarin
The “possibility to reverse warfarin with PCC, no antidote for NOACs”
If you get a head bleeding on warfarin we can treat it
with PCC (Octaplex)
If you bleed on the new agents, there is no antidote
Puts off both patients and doctors from using NOACs
Dose the fact that having / not
having a reversal agent/antidote
equals good/bad prognosis and
outcome?
-
Questions
Introduction
Can the major bleeding evens on the new anticoagulants be
managed only by volume substitution and transfusion of blood
products?
Is there a role for non-specific hemostatic agents?
Antidotes under development
Prevention of bleeding on NOACs
-
Questions
Introduction
Can the major bleeding evens on the new anticoagulants be
managed only by volume substitution and transfusion of blood
products?
Is there a role for non-specific hemostatic agents?
Antidotes under development
Prevention of bleeding on NOACs
-
Development of NOACs focus on two targets in the
coagulation cascade
Fibrin Clot
Intrinsic ExtrinsicXII
VII
IX
XI
Fibrinogen
II
V
Tissue Factor
XDirect Xa Inhibitors
“-xaban”
Direct Thrombin Inhibitors
“-gatran”
warfarin
VIII
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New and Emerging Anticoagulants
Anti – Xa : direct
Rivaroxaban (oral) Xarelto®
Apixaban (oral) Eliquis®
Edoxaban (oral) Lixiana®
Betrixiban (oral)
Otamixaban (parenteral)
LY – 517717 (oral)
DU – 176B (oral)
DX – 9065a (parenteral)
PRT054021 (oral)
Anti – IIa
Dabigatran (oral) Pradaxa®
Odiparcil (oral)
Flovagatran (parenteral)
Pegmusirudin (parenteral)
Peg Hirudin
Desiruidin
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Status of NOACs
8
Dabigatran
Pradaxa®
Rivaroxaban
Xarelto®
Apixaban
Eliquis®
Edoxaban
Savaysa®
Atrial
FibrillationApproved Approved Approved
Applied for
approval
8/1/2014
VTE
TreatmentApproved Approved
Applied for
approval
19/12/2013
Applied for
approval
8/1/2014
VTE
Prevention
Orth Surgery
Approved Approved Approved No activity
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Incidence of Major Bleeding in Phase III studies*
Annual rate of major bleeding≈1-3%
1. N Engl J Med. 2009 Sep 17;361(12):1139-51. 2. N Engl J Med. 2011 Sep 8;365(10):883-91 3. N Engl J Med. 2009 Dec 10;361(24):2342-52. 4. N Engl J Med. 2010 Dec
23;363(26):2499-510 5. N Engl J Med. 2012 Apr 5;366(14):1287-97 6. Thromb Res. 2010 Sep;126(3):175-82 7. Thromb Haemost. 2011 Mar;105(3):444-53. Epub 2010 Dec 6. 8. N
Engl J Med. 2011 Sep 15;365(11):981-92. Epub 2011 Aug 27. 9. N Engl J Med, 2013. 369(9): p. 799-808 . 10. Giuglianpo NEJM 2013. 11. Buller NEJM 2013 12 Kawaji ort res 2012
*Figures in table are unadjusted for treatment duration
Figures in red indicate rates significantly lower than warfarin
Indication AF studies VTE studiesThromboprophylaxis
studies
Dabigatran 5.4-6.2%1 0.9-1.6%3 1.1-1.4%6
Rivaroxaban 5.6%2 0.8-1.1%4,5 0.3%7
Apixaban 3.6%8 0.69 0.6-0.8%
Edoxaban 3.6-6.010 1.411 3.412
Treatment Duration 1.5-2 years 3-12 months 2-5 weeks
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Rate of Intracranial Bleeding in AF studies
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Rate of Gastrointestinal Bleeding in AF studies
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General recommendation for the management of NOAC
bleeding
*Recommendation based only on limited non-clinical data; there is almost no experience in volunteers or patients.
CFC: coagulation factor concentrate; PCC: prothrombin complex concentrate; rFVIIa: recombinant activated factor VIIa. Eerenberg ES et al. Circulation 2011;124:1573–1579; van Ryn J et al. Thromb Haemost 2010;103(6):1116–1127
Patient with bleeding on NOACs
Mild bleeding Moderate to severe bleeding Life-threatening bleeding
Delay next dose or discontinue treatment as
appropriate
• Symptomatic treatment
• Mechanical compression
• Surgical intervention
• Fluid replacement and hemodynamic support
• Blood product transfusion
• Oral charcoal application* (if drug ingested
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Questions
Introduction
Can the major bleeding evens on the new anticoagulants be
managed only by volume substitution and transfusion of blood
products?
Rationale: Short half life of NOACs – effect diminishes quickly when
discontinued
Is there a role for non-specific hemostatic agents?
Antidotes under development
Prevention of bleeding on NOACs
-
SchulmanEzekowitz, Lars Wallentin, Martina Brueckmann, Mandy Fraessdorf, Salim Yusuf and Sam
Ammar Majeed, Hun-Gyu Hwang, Stuart J. Connolly, John W. Eikelboom, Michael D.Warfarin
Management and Outcomes of Major Bleeding During Treatment With Dabigatran or
Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2013 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/CIRCULATIONAHA.113.002332
2013;128:2325-2332; originally published online September 30, 2013;Circulation.
http://circ.ahajournals.org/content/128/21/2325World Wide Web at:
The online version of this article, along with updated information and services, is located on the
http://circ.ahajournals.org/content/suppl/2013/09/30/CIRCULATIONAHA.113.002332.DC1.htmlData Supplement (unedited) at:
http://circ.ahajournals.org//subscriptions/
is online at: Circulation Information about subscribing to Subscriptions:
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document. Permissions and Rights Question and Answer this process is available in the
click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,
can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialCirculationin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:
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Patient Population: Phase III Dabigatran Trials
Phase III trial Patients TreatmentsDuration of
treatment
RE-LY118,113 atrial fibrillation
patients
(stroke prevention)
• Dabigatran 110 mg
• Dabigatran 150 mg bid
• Warfarin
Median, 2 years
RE-COVER22539 VTE patients
(treatment)
• Dabigatran 150 mg bid
• Warfarin6 months
RE-COVER II32568 VTE patients
(treatment)
• Dabigatran 150 mg bid
• Warfarin 6 months
RE-MEDY42856 VTE patients
(secondary prevention)
• Dabigatran 150 mg bid
• Warfarin Mean, 15.5 months
RE-SONATE51343 VTE patients
(secondary prevention)
• Dabigatran 150 mg bid
• Placebo 6 months
Number of patients randomized and treated in these 5 trials: 27,419
Dabigatran: 16,755 Warfarin: 10,002
VTE: venous thromboembolism. 1. Connolly SJ et al. N Engl J Med 2009; 361:1139-1151; 2. Schulman S et al. N Engl J Med
2009;361:2342–2352; 3. Schulman S et al. Proceedings of ASH Conference 2011:Abstr 205; 4. Schulman S et al. J Thromb
Haemost 2011;9:22 (Abstr. O-Thu-033); 5. Schulman S et al. J Thromb Haemost 2011;9;22 (Abstr. O-Mo-037)
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Strategies Used for Management of Major Bleeding
Dabigatran* Warfarin P-Value
Blood transfusion, n (%) 439 (59.2) 210 (49.9) 0.002
Fresh frozen plasma, n (%) 147 (19.8) 127 (30.2)
-
Dabigatran* Warfarin P-Value
Patients with hospitalization*, n (%) 456 (61.5) 254 (60.3) 0.68
Length of stay, days, mean (SD) 8.4 (9.1) 8.9 (9.8) 0.48
Nights in ICU/CCU, mean (SD) 1.6 (4.3) 2.7 (6.6) 0.01
Nights in step-down unit, mean (SD) 1.0 (2.5) 1.0 (2.7) 0.84
Patients with major bleed requiring
surgery, n (%)90 (12.1) 63 (15.0) 0.17
Short-term Consequences of Major Bleeding
Length of stay in ICU is shorter with
dabigatran treatment than with comparator
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Mortality After a Major Bleed – 5 Phase III Trials
* Data combined from dabigatran 150 and dabigatran 110 mg bid treatment groups. Only first
major bleed included. Analysis not adjusted for covariates.
The Kaplan-Meier analysis indicated a reduced risk for death with dabigatran*
vs. warfarin during 30 days from the bleeding (P=0.057).
-
Adjusted Analysis of Mortality following a Major Bleed
OR for 30-day mortality adjusted for sex, age, weight, renal function and
additional antithrombotic therapy
CI: confidence interval; OR: odds ratio
Favours dabigatran Favours warfarin10.1 10
0.66 (0.44, 1.00)
0.60 (0.35,1.03)
0.68 (0.42, 1.08)
0.56 (0.36,0.86)
0.53 (0.31,0.88)
0.009
0.015
0.064
0.099
0.051
P-ValueOR (95% CI)Treatment and Database Used
Dabigatran 150 mg + 110 mg, all studies
Dabigatran 150 mg, all studies
Dabigatran 110 mg, RE-LY
Dabigatran 150 mg + 110 mg, RE-LY
Dabigatran 150 mg, RE-LY
Adjusted analysis demonstrates mortality benefit for dabigatran in RE-LY
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Prognosis of Intracranial Hemorrhage – RE-LY trial
No significant difference between treatments in modified Rankin
scale score for intracranial hemorrhage since admission
Treatment comparisonP-Value for comparison of change in
modified Rankin score
Dabigatran* vs warfarin 0.97
Dabigatran 150 mg bid vs warfarin 0.81
Dabigatran 110 mg bid vs warfarin 0.80
Dabigatran 150 bid mg vs 110 mg bid 0.78
* Data combined from dabigatran 150 and dabigatran 110 mg bid treatment groups
Data on the initial and final Rankin score evaluations were available
for 78 (55%) patients with intracranial hemorrhage.
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Rivaroxaban Major Bleeding
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Strategies Used for Management of Rivaroxaban Major
Bleeding
Rivaroxaban* Warfarin P-Value
n= 431 409
Blood transfusion, n (%) 176(40.8) 143(34.9)
Plasma transfusion, n (%) 45(10.4) 81(19.8)
Vitamin K, n (%) 72 (16.7) 132(32.3)
Prothrombin complex
concentrate, n (%) 8(1.9) 18(4.4)
Recombinant factor VIIa, n (%) 8 (1.9) 2(0.5)
• Major bleeds in the rivaroxaban group were more frequently treated with blood
transfusions than those on warfarin but less frequently with plasma.
• Most of the bleeds were managed by transfusion of blood products
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Hospitalization and Mortality after Rivaroxaban MBE
Rivaroxaban* Warfarin P-Value
Hospitalization, n 101 91
Hospitalization, duration 5 (4-10) days 6 (4-11) days
Death 86 (20.4%) 105 (25.6%) 0.11
Time to death (days) 60 (8–246) 7 (2–88)
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Apixaban Major Bleeding
-
Apixaban Major Bleeding
Apixaban Warfarin P-Value
N= 327 462 0.0052
Led to transfusion 137 188 0.0025
Required surgical or medical intervention 100 136 0.012
Led to hospitalization 162 212
Death within 30 days 36 71
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Questions
Can the major bleeding evens on the new anticoagulants be
managed only by volume substitution and transfusion of blood
products?
Yes!
Without worse outcome
Low-therapeutic drug concentration
Non-ICH
ICH
This dose not answer the question of how to deal with NOACs
pre-operatively
-
Questions
Introduction
Can the major bleeding evens on the new anticoagulants be
managed only by volume substitution and transfusion of blood
products?
Is there a role for non-specific hemostatic agents?
Thrombin Inhibitors
Xa Inhibitors
Antidotes under development
Prevention of bleeding on NOACs
-
Thrombin inhibitors
28
-
Prothrombin Complex Concentrates Octaplex
Animal models showed good effectICeH mouse model
Rabbit kidney injury
Human studies more difficult to evaluateEerenburg study
Case series of 4(2) patients with poor outcome
-
Short case-series-PCC for dabigatran bleeding
Age Gende
r
Weigh
t
eGFR Bleedin
g
Hours
from
last
dose
PCC RBC Hours
to
bleed
stop
Death
83 Male 57 37 Rectal 1.5 1000 No
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PCC in Surgery on dabigatran
86 year old man
Atrial fibrillation: dabigatran 110mg x 2
Acute abdomen: Peritonitis
Need surgery urgently
Dabigatran intake 8 hours ago
eGFR 45 ml/min
APTT 50 sec
-
PCC in Surgery on dabigatran
Tranexamic acid + plasma pre-operatively
Surgeon: Bleeds easily
PCC 1500 IU (70 kg)
Better hemostasis
-
No reversal of the in vitro anticoagulant effect of
dabigatran by prothrombin complex concentrate
Eerenberg et al, Circulation 2011
-
PCC for dabigatran bleeding
Age Gender eGFR Bleeding Hours
last
dose
PCC RBC Hours to
bleeding stop
Death
72 Female 14 Intraabdominal 48 40 IU/kg Yes(22) -- Yes
74 Male 14 Gastrointestinal 38 36 IU/kg Yes(12) 10 hrs after
hemodialysis
Yes
Lillo-Le Louet Thromb Haemos 2012
All patients received rVIIa in addition to PCC
-
Warkentin T E et al. Blood 2012;119:2172-2174
rFVIIa in dabigatran-associated hemorrhage
-
Experimental evidence: haemodialysis
ESRD = end-stage renal disease
Stangier J et al. Clin Pharmacokinet 2010;49:259–68 Mar 2013
Experimental evidence: haemodialysis
! Dialysis removed 62–68% of dabigatran in patients with ESRD
ESRD = end-stage renal disease
Stangier J et al. Clin Pharmacokinet 2010;49:259–68 Disclaimer: Dabigatran etexilate is now approved for clinical use in stroke prevention in atrial fibrillation in certain countries. Please check local prescribing information for further details
43
Patient 1
Patient 2
Patient 3
Patient 4
Patient 5
Patient 6
25
0
20
10
0.5 hrs
Dabig
atr
an c
once
ntr
ation (
ng/m
L)
15
5
Outlet Inlet Outlet Inlet Outlet Inlet
2 hrs 4 hrs
Total dabigatran plasma concentration in dialyser inlet and outlet lines after oral administration of 50 mg dabigatran
Updated slide
36
-
Dialysis
37
-
Activated PCC (FEIBA)
67 y.o. male with AF, last dose dabi 7 h preop.
Ablation Rx, UFH 5000 u, transseptal perforation, hypotension
Pericardiocentesis: 4.5 L blood drained
Time
Protamine
100 mg
FEIBA
3159 IU
Bleeding slows
and stops
-
Xa inhibitors
39
-
Eerenberg E S et al. Circulation 2011;124:1573-1579
PCC for the reversal of Xa inhibitors
-
PCC in rivaroxaban Bleeding
76 year old male
Atrial fibrillation
Last intake 8 hours
Confusion: ICH
INR 1.3
PCC 1500
Good effect
-
rVIIa (Novoseven) and rivaroxaban
Rat model on edoxaban + 3mg/kg rVIIa: PT, TAT, BT normalized
Baboons on rivaroxaban +210 mkg/kg rVIIa: PT shortened
Rats on rivaroxaban or apixaban: rVIIa shortened PT but did not
affect blood loss
Rabbits treated with rivaroxaban or apixaban, rFVIIa reduced the
bleeding time and the aPTT but did not have any effect on the
amount of blood loss.
-
APCC (FEIBA)
100 IU/kg:
Shortened PT in baboons on rivaroxaban
Corrected PT in rats on edoxaban
No report on blood loss
-
Questions
Is there a role for non-specific hemostatic agents?
No RCT or large cohort studies
PCC:
Xa inhibitors (laboratory evidence)
Dabigatran: probably in patients with low – therapeutic concentration
Availability
Low thrombogenicity compared to APCC and rVIIa
APCC (FEIBA)
Especially for dabigatran
rVIIa
Inconclusive evidence
-
Questions
Introduction
Can the major bleeding evens on the new anticoagulants be
managed only by volume substitution and transfusion of blood
products?
Is there a role for non-specific hemostatic agents?
Antidotes under development
Prevention of bleeding on NOACs
-
Anti-dabigatran antibody
46
-
Anti-dabigatran antibody: rapid neutralization
-
PRT064445: recombinant FXa
PRT064445 is a recombinant fX a var iant with modifications in
the Gla-domain and active site
PRT064445 (r-Antidote)
S S
EGF1,2
S419A
FXa
S S
S419
EGF1,2 Gla
Light Chain Heavy Chain
Catalytic Domain
Two modifications introduced to human fXa • Removal of the Gla-domain
• Mutation at the active site (S419A)
PRT064445 (r-Antidote) • No pro- or anti-coagulant activity
• Retains binding ability for fXa inhibitors
4
Two modifications introduced to human fXa
•Removal of the Gla-domain
•Mutation at the active site (S419A)
PRT064445 (r-Antidote)
•No pro- or anti-coagulant activity
•Retains binding ability for fXa inhibitors
-
PRT064445 PRT064445 reversed anti-fX a activity in ASA+r ivaroxaban
treated mice
Vehi ASA Riva ASA+Riva ASA+Riva+PRT0644450
25
50
75
100
125
150P=0.011P=0.431
P=0.001
Anti-f
Xa
(%)
11
Treatment (n=5-8) Riva ASA+Riva ASA+Riva+PRT064445
Total Riva. plasma conc. (µM) 0.20±0.10 0.14±0.06 1.14±0.25
PRT064445 plasma conc. (µM) N/A N/A 2.20±0.47
-
Small Molecule Reversal
PER977
Heparin
Enoxaparin
Edoxaban
Dabigatran
Effect within 30 min
-
PER977
-
Questions
Introduction
Can the major bleeding evens on the new anticoagulants be
managed only by volume substitution and transfusion of blood
products?
Is there a role for non-specific hemostatic agents?
Antidotes under development
Prevention of bleeding on NOACs
-
N Engl J Med 2012; 366: 864
-
Choose Wisely
54
Recommendations set by the European Medicine Agency
(EMA) for dabigatran were met in 50%, 90.3 of patients
treated with dabigatran 110mg, 150 mg.
-
Efficacy of warfarin reversal
If you get a head bleeding on warfarin we can
reverse it with PCC (Octaplex)
If you bleed on the new agents, we cant do anything
about it
Comparing bleeding on NOACs and warfarin
-
PCC (Octaplex) for warfarin reversal
-
PCC (Octaplex) for warfarin reversal
Billie L. Durn and Joshua N. GoldsteinRavi Sarode, Truman J. Milling, Jr, Majed A. Refaai, Antoinette Mangione, Astrid Schneider,
Plasma-Controlled, Phase I I Ib StudyVitamin K Antagonists Presenting With Major Bleeding: A Randomized,
Efficacy and Safety of a 4-Factor Prothrombin Complex Concentrate in Patients on
Print ISSN: 0009-7322. Online ISSN: 1524-4539 Copyright © 2013 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation doi: 10.1161/CIRCULATIONAHA.113.002283
2013;128:1234-1243; originally published online August 9, 2013;Circulation.
http://circ.ahajournals.org/content/128/11/1234World Wide Web at:
The online version of this article, along with updated information and services, is located on the
http://circ.ahajournals.org/content/suppl/2013/08/09/CIRCULATIONAHA.113.002283.DC1.htmlData Supplement (unedited) at:
http://circ.ahajournals.org//subscriptions/
is online at: Circulation Information about subscribing to Subscriptions:
http://www.lww.com/reprints Information about reprints can be found online at: Reprints:
document. Permissions and Rights Question and Answer this process is available in the
click Request Permissions in the middle column of the Web page under Services. Further information aboutOffice. Once the online version of the published article for which permission is being requested is located,
can be obtained via RightsLink, a service of the Copyright Clearance Center, not the EditorialCirculationin Requests for permissions to reproduce figures, tables, or portions of articles originally publishedPermissions:
at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from at MCMASTER UNIV on December 23, 2013http://circ.ahajournals.org/Downloaded from
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PCC (Octaplex) for warfarin reversal
Underused
33% of warfarin bleeds get any reversal
Given too late
Inadequate doses
Poor clinical efficacy
-
Efficacy of warfarin reversal
If you get a head bleeding on warfarin we can
reverse it with PCC (Octaplex)
If you bleed on the new agents, we cant do anything
about it
-
Efficacy of warfarin reversal
If you get a head bleeding on warfarin we can
reverse it with PCC (Octaplex)
If you bleed on the new agents, we cant do anything
about it
-
Conclusions
Incidence of major bleeding on NOACs is comparable to or lower
than warfarin
Most cases can be managed conservatively by transfusion of
blood products without resulting in worse outcome
No good evidence supporting the use of hemostatic agents (yet)
For Xa inhibitorsPCC(Octaplex) (?)
For dabigatran bleeding PCC/FEIBA (?)
Specific antidotes are evaluated in clinical trials
Warfarin bleeding is poorly managed in many centers resulting in
poor outcome
-
Thank you
62