Keeping Thinner: New Oral Anticoagulants Marc J Kahn, MD, MBA,
FACP Peterman-Prosser Professor Sr. Associate Dean Tulane
University School of Medicine New Orleans, LA
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Traditional oral anticoagulants Aspirinirreversibly acetylates
cyclooxygenaase Warfarininhibits vitamin K epoxide reductase
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Problems with older agents Aspirin works in primary hemostatic
system Warfarin requires monitoring, unpredictable kinetics, takes
3-5 days until steady state
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3 new agents Rivaroxaban Apixaban Dabigatran F Xa inhibitors
Thrombin inhibitor
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Rivaroxaban (Xarelto) Direct Xa inhibitor Lasts 8 to 12 hours
Effects can last up to24 hours Once daily dosing
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Rivaroxaban approval DVT prophylaxis for hip and knee
replacement (FDA, Health Canada, European Commission) Stroke
prophylaxis for a-fib (FDA, European Commission) Treatment of DVT
and PE (FDA, European Commission)
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ROCKET trial Rivaroxaban versus Warfarin in Nonvalvular Atrial
Fibrillation Manesh R. Patel, M.D., Kenneth W. Mahaffey, M.D.,
Jyotsna Garg, M.S., Guohua Pan, Ph.D., Daniel E. Singer, M.D.,
Werner Hacke, M.D., Ph.D., Gnter Breithardt, M.D., Jonathan L.
Halperin, M.D., Graeme J. Hankey, M.D., Jonathan P. Piccini, M.D.,
Richard C. Becker, M.D., Christopher C. Nessel, M.D., John F.
Paolini, M.D., Ph.D., Scott D. Berkowitz, M.D., Keith A.A. Fox,
M.B., Ch.B., Robert M. Califf, M.D., and the ROCKET AF Steering
Committee for the ROCKET AF Investigators N Engl J Med 2011;
365:883-891
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Cumulative Rates of the Primary End Point (Stroke or Systemic
Embolism) in the Per- Protocol Population and in the
Intention-to-Treat Population. Patel MR et al. N Engl J Med
2011;365:883-891
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Cumulative Rates of the Primary End Point during Treatment and
after Discontinuation in the Intention-to-Treat Population. Patel
MR et al. N Engl J Med 2011;365:883-891
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Original Article Oral Rivaroxaban for Symptomatic Venous
Thromboembolism The EINSTEIN Investigators N Engl J Med Volume
363(26):2499-2510 December 23, 2010
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KaplanMeier Cumulative Event Rates for the Primary Efficacy
Outcome in the Two Studies. The EINSTEIN Investigators. N Engl J
Med 2010;363:2499-2510
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KaplanMeier Cumulative Event Rates for the Principal Safety
Outcome in the Acute DVT Study. The EINSTEIN Investigators. N Engl
J Med 2010;363:2499-2510
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Apixaban Inhibits Xa Available in Europe Approved for
prevention of clot following hip/knee surgery in Europe Approval
for a-fib in US
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Original Article Apixaban versus Warfarin in Patients with
Atrial Fibrillation Christopher B. Granger, M.D., John H.
Alexander, M.D., M.H.S., John J.V. McMurray, M.D., Renato D. Lopes,
M.D., Ph.D., Elaine M. Hylek, M.D., M.P.H., Michael Hanna, M.D.,
Hussein R. Al-Khalidi, Ph.D., Jack Ansell, M.D., Dan Atar, M.D.,
Alvaro Avezum, M.D., Ph.D., M. Cecilia Bahit, M.D., Rafael Diaz,
M.D., J. Donald Easton, M.D., Justin A. Ezekowitz, M.B., B.Ch.,
Greg Flaker, M.D., David Garcia, M.D., Margarida Geraldes, Ph.D.,
Bernard J. Gersh, M.D., Sergey Golitsyn, M.D., Ph.D., Shinya Goto,
M.D., Antonio G. Hermosillo, M.D., Stefan H. Hohnloser, M.D., John
Horowitz, M.D., Puneet Mohan, M.D., Ph.D., Petr Jansky, M.D., Basil
S. Lewis, M.D., Jose Luis Lopez-Sendon, M.D., Prem Pais, M.D.,
Alexander Parkhomenko, M.D., Freek W.A. Verheugt, M.D., Ph.D., Jun
Zhu, M.D., Lars Wallentin, M.D., Ph.D., for the ARISTOTLE
Committees and Investigators N Engl J Med Volume 365(11):981-992
September 15, 2011
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KaplanMeier Curves for the Primary Efficacy and Safety
Outcomes. Granger CB et al. N Engl J Med 2011;365:981-992
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Dabigatran (Pradaxa) Oral direct thrombin inhibitor Low protein
binding Costs $3,000 per year ($48 for warfarin)
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Dabigatran approval Stroke prevention in non-valvular a-fib
(FDA, Health Canada, European Medicines Agency) Prevention of
thromboembolic disease following hip/knee surgery (Health Canada,
European Medicines Agency)
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RE-LY Trial Dabigatran vs warfarin in over 18,000 patients with
atrial fibrillation 110 mg BID dabigatran NOT inferior to warfarin
in preventing stroke Less bleeding than warfarin NEJM
2009;361:1139
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RE-COVER Trial 2539 patients with VTE Dabigatran 150 BID not
inferior to warfarin for prevention of recurrent VTE Similar major
bleeding, less total bleeding NEJM 2009;361:2342
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Problems with newer agents Bleedingno clear reversal agents
Monitoring Dabigatrannormal aPTT indicates little or no drug in
plasma Elevated aPTT uninterpretable Selected thrombin times and
ecarin clotting times may be helpful but not always available
Rivaroxaban can affect anti-Xa activity but would need to be
calibrated with drug
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Bleeding NO reversal agent (working on one for dagibatran)
Rivaroxaban major bleeding=0.1-0.7% Dabigatran major
bleeding=0.7%
Prothrombin Complex Concentrates Factors II, VII, IX, X,
+/-Protein C&S, +/- Antithrombin, +/-heparin Activated PCC =
Feiba 4 componentonly in Europe 3 componentin US (Bebulin VH and
Profilnine SD)
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PCCs 24 hour half life Dose 25-50 units/kg +FFP as source of
FVIIa Clearly pro-thrombotic
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A, Effect of rivaroxaban followed by prothrombin complex
concentrate (PCC) or placebo on the prothrombin time (PT; meanSD).
Eerenberg E S et al. Circulation 2011;124:1573-1579 Copyright
American Heart Association
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A, Effect of dabigatran followed by prothrombin complex
concentrate (PCC) or placebo on the activated partial
thromboplastin time (aPTT; mean SD). Eerenberg E S et al.
Circulation 2011;124:1573-1579 Copyright American Heart
Association
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Effect of different hemostatic agents on hematoma volume 24
hours after collagenase injection. Zhou W et al. Stroke
2011;42:3594-3599 Copyright American Heart Association
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Bleeding Treatment Summary Rivaroxaban Consider 3-factor PCC
+FFP or high dose rVIIa Cannot be removed by dialysis Dabigatran
Unclear role of 3-factor PCC +FFP, ??activated PCC, ??rVIIA
??emergent dialysis
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New Oral Anticoagulant Summary At least as effective as
warfarin At least as safe as warfarin More expensive than warfarin
When bleeding/monitoring issues resolved potential huge market
