1. 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

2. Traditional oral anticoagulants Aspirin—irreversibly acetylates cyclooxygenaase Warfarin—inhibits vitamin K epoxide reductase

3. Problems with older agents Aspirin works in primary hemostatic system Warfarin requires monitoring, unpredictable kinetics, takes 3-5 days until steady state

5. 3 new agents Rivaroxaban Apixaban Dabigatran F Xa inhibitors Thrombin inhibitor

6. Rivaroxaban (Xarelto®) Direct Xa inhibitor Lasts 8 to 12 hours Effects can last up to24 hours Once daily dosing

7. 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)

8. 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., Günter 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

9. 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

10. 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

11. Original Article Oral Rivaroxaban for Symptomatic Venous Thromboembolism The EINSTEIN Investigators N Engl J Med Volume 363(26):2499-2510 December 23, 2010

12. Kaplan–Meier Cumulative Event Rates for the Primary Efficacy Outcome in the Two Studies. The EINSTEIN Investigators. N Engl J Med 2010;363:2499-2510

13. Kaplan–Meier Cumulative Event Rates for the Principal Safety Outcome in the Acute DVT Study. The EINSTEIN Investigators. N Engl J Med 2010;363:2499-2510

14. Apixaban Inhibits Xa Available in Europe Approved for prevention of clot following hip/knee surgery in Europe Approval for a-fib in US

15. 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

16. Kaplan–Meier Curves for the Primary Efficacy and Safety Outcomes. Granger CB et al. N Engl J Med 2011;365:981-992

17. Dabigatran (Pradaxa®) Oral direct thrombin inhibitor Low protein binding Costs $3,000 per year ($48 for warfarin)

18. 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)

19. 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

20. 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

21. Problems with newer agents Bleeding—no clear reversal agents Monitoring Dabigatran—normal 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

22. Bleeding NO reversal agent (working on one for dagibatran) Rivaroxaban major bleeding=0.1-0.7% Dabigatran major bleeding=0.7%

23. Potential antidotes FFP Prothrombin Complex Concentrates FVIIa Dialysis Activated charcoal—acute ingestion only

24. Prothrombin Complex Concentrates Factors II, VII, IX, X, +/-Protein C&S, +/- Antithrombin, +/-heparin Activated PCC = Feiba® 4 component—only in Europe 3 component—in US (Bebulin VH® and Profilnine SD®)

25. PCCs 24 hour half life Dose 25-50 units/kg +FFP as source of FVIIa Clearly pro-thrombotic

26. A, Effect of rivaroxaban followed by prothrombin complex concentrate (PCC) or placebo on the prothrombin time (PT; mean±SD). Eerenberg E S et al. Circulation 2011;124:1573-1579 Copyright © American Heart Association

27. 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

28. 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

29. 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

30. 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

31. Questions?