New Antithrombotic Agents

1. New Antithrombotic Agents Tom DeLoughery, MD FACP FAWM Oregon Health and Sciences University

2. DISCLOSURE Relevant Financial Relationship(s) Speaker Bureau - None Consultant – Amgen

3. What I am Talking About • New Antithrombotic Agents • Dabigatran • Rivaroxaban • Apixaban • Compare and contrast trials • Practical issues in use

5. New Anticoagulants • Warfarin and Heparin around since 1940’s • Will there ever be anything else?

6. Disadvantages of Heparin • Not oral • Variable dosing (UFH) • Short half-life • Heparin thrombocytopenia • Injection site reactions

7. Disadvantages of Warfarin • Drug interactions • Food interactions • Variable2 metabolism • Frequent monitoring

8. Advantages of Old Anticoagulants • Familiarity • No unexpected side effects • Demonstrated use in multiple clinical areas

9. New Anticoagulants • Two Classes • Thrombin inhibitors • Anti-Xa inhibitors

10. Direct Thrombin Inhibitors • Thrombin is key step in thrombosis • Turns fibrinogen into clot • Activates platelets • Activates clotting factors

11. Coagulation TF + VII IX + VIII X + V II CLOT

12. DTI • Parental • Argatroban • Lepirudin • Bivalirudin • Oral • Ximelagatran • Dabigatran

13. Factor Xa Inhibitors • Xa creates thrombin • Blocking prevents amplification of coagulation

14. Coagulation TF + VII IX + VIII X + V II CLOT

15. Factor Xa Inhibitors • Rivaroxaban • Apixaban • Endobaxiban • Betrixaban

16. Dabigatran • Oral Thrombin Inhibitor • Bioavailability: 6.5% • Onset of action: 2-3 hours • Half-life : 12-14 hours • Renal excretion: 80% • Drug interactions: p-glycoprotein • Rifampin

17. Dabigatran: TKR Remodel: J Thromb Haemost. 2007 Nov;5(11):2178-85 Remobilize: J Arthroplasty. 2009 Jan;24(1):1-9. * P < 0.01

18. Dabigatran: THR Lancet. 2007 370:949-56

19. Atrial Fibrillation • RCT of 18,113 • Warfarin INR 2-3 • Dabigatran 110mg or 150 mg BID • Mean F/u 2 years • N Engl J Med. 2009 Sep 17;361(12):1139-51.

20. Atrial Fibrillation – 150mg • RCT • Warfarin INR 2-3 • Dabigatran 150 mg BID • More effective than warfarin • RR 0.66 (0.53-0.80) • No increase in bleeding • RR 0.93 (0.81-1.07) • Intracranial hemorrhage 0.40 (0.14-0.49)

21. Atrial Fibrillation – 110mg • RCT • Warfarin INR 2-3 • Dabigatran 110 mg BID • Same as warfarin • RR 0.91 (0.74-1.11) • Decrease in bleeding • RR 0.80 (0.69-0.93) • Intracranial hemorrhage 0.32 (0.20-0.47)

23. Effectiveness vs CHADS2

24. DVT Therapy • NEJM Volume 361:2342-2352, 2009 • All patients got heparin • Randomized between warfarin and dabigatran 150 mg BID • N = 1274

25. Recurrent DVT or Death

26. Bleeding Dabigatran Major bleeding 0.82 (0.45 to 1.48; P=0.38) Dabigatran Any bleeding 0.71 (0.59 to 0.85; P<0.001)

27. Side Effects • No difference in liver function tests • Increase in dyspepsia • 3.0 vs 0.7%

28. Dabigatran • Effective in DVT prevention • 220mg dose in EU/Canada • Effective in DVT therapy • Effective in stroke prevention in atrial fibrillation • Same or lesser bleeding risk

29. Dabigatran • Completed studies • DVT prophylaxis • DVT Therapy • Afib stroke prophylaxis • Ongoing • Long term DVT treatment • Cardiac Valves

30. Dabigatran • 150 and 75 mg dose approved by FDA • Dosing • CrCl > 30 mL/ml– 150mg BID • CrCl 15-30mL/ml 75 mg BID • CrCl < 15 not indicated • No major drug-drug interactions • Rifampin

31. Dabigatran- Surgery

32. Monitoring • aPTT • 150 mg twice daily the median peak aPTT is approximately 2x control. • Twelve hours after the last dose the median aPTT is 1.5x control • Unsure if can be use to adjust dose • Assess compliance and drug effect • Reference labs can do specific level •  INR insensitive

34. Rivaroxaban • Oral Xa Inhibitor • Bioavailability: 80-100% • Onset of action: 2.5-4 hours • Half-life : 5-9 hours • Renal excretion: ~66% • Drug interactions: CYP 3A4

35. Total Hip Replacement R1: N Engl J Med. 2008 358:2765-75. R2: Lancet. 2008 372:31-9. * P < 0.01

36. Total Knee Replacement * P < 0.01 R3: N Engl J Med. 2008 358:2776-86 R4: Lancet. 2009 373(9676):1673-80.

37. Rivaroxaban in “Real World” • Beyer- Westendorf#210 • Retropective stduy of 5346 patients undergoing orthopedicu srugeyr in 3 “eras” • LMWH • Fondaparnux • Rivoaroxaban

38. Rivaroxaban in “Real World” • Rivaroxaban with • Less total VTE than LMWH or fondaparinux (distal) • Less bleeding • Major: L:14.9% F: 11.1% R:7.4% • Txn: L:14% F:11% R:7%

39. Rivaroxaban in “Real World” • Restrospective • Suggests benefits of rivaroxaban may be better with clincal use

40. Atrial Fibrillation • RCT of 14,264 • Warfarin INR 2-3 • Rivaroxaban 20mg • 15mg CrCl 49-30 • Mean F/u 1.6 years • N Engl J Med 2011; 365:883-891

41. Atrial Fibrillation • RCT • Warfarin INR 2-3 • Rivaroxaban 20mg • As effective than warfarin • RR 0.79 (0.66-0.96) • No increase in bleeding • RR 1.04 (0.90-1.20) • Intracranial hemorrhage 0.67 (0.47-0.94)

42. Atrial Fibrillation

43. Rivaroxaban: Acute DVT Therapy • N = 3,449 with DVT • RCT • Rivaroxaban 15mg BID then 20mg after 3 weeks • Enoxaparin -> Warfarin

44. Results

46. Safety

47. Extension Study • N = 1,197 • Finished 6-12 months of therapy • RCT: 20mg of rivaroxaban vs placebo • No increase in major bleeding

48. Results

50. Rivaroxaban • Effective in: • Prophylaxis • Atrial Fibrillation • DVT therapy • Acute Coronary syndromes • Ongoing • PE therapy