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New Antithrombotic Agents

New Antithrombotic Agents. Jason Taylor, MD PhD Oregon Health and Sciences University. Tom somewhere in Wyoming. DISCLOSURE. Relevant Financial Relationship(s) Speaker Bureau - None Consultant – Biogen Idec. What I am Talking About. New Antithrombotic Agents Dabigatran Rivaroxaban

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New Antithrombotic Agents

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  1. New Antithrombotic Agents Jason Taylor, MD PhD Oregon Health and Sciences University Tom somewhere in Wyoming

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

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

  4. New Anticoagulants A long time coming…

  5. New Anticoagulants • Warfarin and Heparin around since 1940’s • Now new drugs on market and late trials

  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 • Variable 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. The Big Five

  17. 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

  18. 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.

  19. 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)

  20. 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)

  21. Effectiveness vs CHADS2

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

  23. Recurrent DVT or Death

  24. 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)

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

  26. 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

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

  28. 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

  29. Dabigatran- Surgery

  30. 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

  31. 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

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

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

  34. Rivaroxaban in “Real World” • Beyer- Westendorf#210 • Retropective study of 5346 patients undergoing orthopedic surgery in 3 “eras” • LMWH • Fondaparnux • Rivoaroxaban

  35. 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%

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

  37. 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

  38. 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)

  39. Atrial Fibrillation

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

  41. Results

  42. Acute DVTs

  43. Safety

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

  45. Results

  46. DVT Recurrence DVT Recurrence

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

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