Anticoagulation Update for Internists

1. Anticoagulation Update for Internists ACP Meeting September 17, 2011

2. Disclosure: H.-Joachim Reimers • Dr. Reimers has no relevant financial interests to disclose • Dr. Reimers will discuss use of drugs for unapproved indications

3. Background Coagulation pathway involved in the formation of venous and arterial thrombi Inhibition of coagulation pathway (“anticoagulation”) major strategy for venous thromboembolism (VTE) prophylaxis and treatment

4. “Classical Anticoagulants” Parenteral agents that potentiate indirectly antithrombin activity - Unfractionated heparin - LMWH - Fondaparinux Oral Vitamin K antagonists - warfarin

5. Disadvantages of Warfarin • >10-fold interindividual variation in therapeutic dose due to genetic polymorphisms (e.g. CYP 2C9 and VKORC1) • Pharmacokinetics influenced by - dietary Vitamin K - other medications - alcohol - patient age - body weight - various disease states • Necessitates monitoring

6. New Oral Anticoagulants Selective for one specific coagulation factor (either thrombin or factor Xa) Clinical development advanced Some available for prevention and treatment of thrombosis

7. New Oral Anticoagulants • Developed to replace warfarin • Streamline long-term prevention and treatment of thrombosis

8. Comparison of the Features of New Oral Anticoagulants Features Rivaroxab. ApixabanDabigatran • Target • Molecular weight (D) • Prodrug • Bioavailability (%) • Time to peak (h) • Half – Life (h) • Renal excretion (%)

9. Comparisons of Features of New Anticoagulants with Warfarin Features Warfarin New agents

10. New Oral Anticoagulants

11. VTE Prophylaxis in Orthopedic Surgery • Summary of published studies • Dabigatran • Rivaroxaban • Apixaban

12. Major VTE and Related Mortality PopulationDabigatran doseRisk difference*, % ± 95% CI 150 mg RE-NOVATE THR 220 mg 150 mg RE-MODEL TKR 220 mg RE-MOBILIZE TKR 150 mg 220 mg All Studies‡ 150 mg 220 mg -4 -2 -5 -3 -1 0 1 2 3 4 5 Dabigatran better Enoxaparin better Caprini HR et al. Presented at ISTH. 2007;O-W-050.

13. RECORD programme Major orthopaedic surgery Rivaroxaban 10 mg once-daily investigated Same study design and efficacy and safety outcomes Same independent, blinded adjudication committees > 12,500 patients HIP replacement Rivaroxaban 10 mg ODfor 5 weeks vs. enoxaparin 40 mg ODfor 10 – 14 days then oral placebo KNEE replacement Rivaroxaban 10 mg OD for 10 – 14 daysvs.enoxaparin 30 mg BID for 10 – 14 days KNEE replacement Rivaroxaban 10 mg OD for 10 – 14 daysvs. enoxaparin 40 mg ODfor 10 – 14 days HIP replacement Rivaroxaban 10 mg OD for 5 weeksvs. enoxaparin 40 mg OD for 5 weeks N = 4,541 N = 2,509 N = 2,531 N = 3,148

14. Results: pooled 1° efficacy outcome Symptomatic VTE + all-cause mortality at 2 weeks 2.5 2.0 RRR = 58% OR = 0.44 P = 0.005* 1.5 Incidence (%) 1.0 0.8% 0.5 0.4% 0 Enoxaparin40 mg39/4,692 Rivaroxaban 10 mg17/4,657 *Calculated from odds ratio, two-sided 95% confidence interval 0.23, 0.79;safety population, n = 9,349

15. Apixaban for prevention of VTE after elective TKR: total VTE ADVANCE–1DVT, PE, and all-cause mortality (%)P = 0.64 for non-inferiority 10 Apixaban 2.5 mg BID Enoxaparin 30 mg BID 8 6 Incidence (%) 9.0% 8.9% 4 2 0

16. Magellan Trial • Rivaroxaban compared with enoxaparin for the prevention of venous thromboembolism in acutelly ill medical patients: Magellan study methodology

17. Magellan Trial • Background: • LMWH and pentasaccharide provide effective prophylaxis in acutely ill medical patients • Oral rivaroxaban effective in orthopedic surgery prophylaxis

18. Magellan Trial • Study design: • Multinational • Multicenter • Randomized • Double-blind • Double-dummy • Active comparator

19. Magellan Trial • Study design: • Mandatory bilateral lower limb venous US days 10 and 35; follow up until day 90.

20. Magellan Trial • Inclusion criteria: • Age > 40 years • Immobilization • Heart failure • Active cancer • Acute ischemic stroke • Acute infection • Acute inflammatory or rheumatic disorder • Acute respiratory insufficiency

21. Magellan Trial • Exclusion criteria: • Increased risk of bleeding • Prohibited drugs or procedures • (e.g. anticoagulant treatment) • Concomitant conditions such as severe renal or liver disease

22. Magellan Trial • Primary efficacy outcome: • Composite of asymptomatic proximal DVT, symptomatic proximal and distal DVT, symptomatic PE and fatal PE

23. Magellan Trial • Primary safety outcome: • Composite of major bleeding events and clinically relevant non-major bleeding events

24. Magellan Triaal • Enrollment (December 2007 – July 2010): 8,101subjects • 34 % Heart failure • 32 % Acute infectious disease • 24 % Acute respiratory insufficiency • 17 % Acute ischemic stroke • 8 % Active cancer • 5 % Acute inflammatory or rheumatic disease

25. Prophylaxis of VTE in Acutely Ill Medical Patients

26. New Oral Anticoagulants

27. Treatment of VTE • Summary of published studies: • Dabigatran

28. Cumulative Risk of Recurrent Venous Thromboembolism or Related Death during 6 Months of Treatment among Patients Randomly Assigned to Dabigatran or Warfarin Schulman S et al. N Engl J Med 2009;361:2342-2352

29. Cumulative Risks of a First Event of Major Bleeding and of Any Bleeding among Patients Randomly Assigned to Dabigatran or Warfarin Schulman S et al. N Engl J Med 2009;361:2342-2352

30. On behalf of the Einstein investigators Oral rivaroxaban for the acute and continued treatment of symptomatic venous thromboemboli 37

31. Rivaroxaban – EINSTEIN program • consists of three randomized trials of rivaroxaban: • one for the treatment of acute DVT • one for the treatment of acute PE • one for continued treatment in patients who have received treatment for acute deep-vein thrombosis or pulmonary embolism (the Continued Treatment Study). • Report of the results of the first and third trials; the second trial is ongoing.

32. EINSTEIN: study designs Open-label, non-inferiority 3, 6, or 12 months March 2007-Sept 2009 Rivaroxaban Rivaroxaban N=3,449 15 mg bid 20 mg od Double-blind, superiority R Day 21 Enoxaparin bid for at least 5 days, plus VKA target INR 2.5 (INR range 2–3) 6 or 12 months Rivaroxaban 20 mg od Feb 2007-March 2009 N=1,197 Open-label, non-inferiority R Placebo 3, 6, or 12 months Rivaroxaban Rivaroxaban N~4,500 15 mg bid 20 mg od Day 21 R Enoxaparin bid for at least 5 days, plus VKA target INR 2.5 (INR range 2–3) Outside of the EINSTEIN programme: Patients with confirmed symptomatic DVT or PE completing 6 or 12 months of VKA 39

33. Eligibility • Acute DVT Study • Acute, symptomatic • Confirmed proximal DVT • No PE • No previous LMWH, fondaparinux, UFH>48h, >1 dose of VKA • No thrombectomy, IVC filter, fibrinolytic • No contraindications to warfarin, enoxaparin • Extension Study • Confirmed DVT or PE • Treated for 6-12 months with warfarin or rivaroxaban • Equipoise with respect to need for continued anticoagulation

34. EINSTEIN DVT and EXT: major outcomes Efficacy* • Symptomatic recurrent venous thromboembolism Safety* • Major bleeding + clinically relevant non-major bleeding • Major bleeding Other* • Net clinical benefit (composite primary efficacy outcome or major bleed) • Total mortality • Cardiovascular events • Liver parameters 41 *Outcomes adjudicated by the central independent and blinded adjudication committee

35. EINSTEIN DVT: primary efficacy outcome 4.0 Enoxaparin/VKA (N=1,718) 3.0 Rivaroxaban (N=1,731) Cumulative event rate (%) 2.0 1.0 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) 1.04 0.44 0.68 0 1.00 2.00 Hazard ratio Rivaroxaban superior Rivaroxaban non-inferior Rivaroxaban inferior p=0.076 for superiority (two-sided) p<0.0001 for non-inferiority (one-sided) 44

36. Extension study 47

37. EINSTEIN EXT: primary efficacy outcome analysis (time to first event) 13 12 11 Number needed to treat to prevent 1 primary efficacy outcome: 15 10 9 8 HR=0.184; p<0.0001 RRR=82% 7 Cumulative event rate (%) 6 5 4 3 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Time to event (days) Rivaroxaban (N=602) Placebo (N=594) 48 ITT population; *Some patients had more than one event

38. EINSTEIN EXT: safety outcome (major bleeding) Number needed to harm: approximately 139 *p=0.11 50 50 Safety population

39. Oral rivaroxaban given initially in the acute phase in a dose of 15 mg twice daily for 3 weeks, followed by 20 mg once daily, offers clinicians and patients a simple, single-drug approach for the acute and continued treatment of VTE that potentially improves the benefit–risk profile of anticoagulation Conclusions 54

40. Atrial fibrillation and stroke • Summary of studies: • Dabigatran/warfarin (RE-LY) • Apixaban/ASA (AVERROES) • Apixaban/warfarin (Aristotle) • Rivaroxaban/warfarin (Rocket-AF)

41. Cumulative Hazard Rates for the Primary Outcome of Stroke or Systemic Embolism, According to Treatment Group Connolly SJ et al. N Engl J Med 2009;361:1139-1151

46. Cumulative Hazard Rates for the Primary Efficacy and Safety Outcomes, According to Treatment Group. Connolly SJ et al. N Engl J Med 2011;364:806-817

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

48. Trial ResultsKenneth W. Mahaffey, MD on Behalf of the ROCKET AF Investigators

49. Study Design • Risk Factors • CHF • Hypertension • Age  75 • Diabetes • OR • Stroke, TIA or Systemic embolus At least 2 or 3 required* Atrial Fibrillation Rivaroxaban Warfarin Randomize Double Blind / Double Dummy (n ~ 14,000) 20 mg daily 15 mg for Cr Cl 30-49 ml/min INR target - 2.5 (2.0-3.0 inclusive) Monthly Monitoring Adherence to standard of care guidelines Primary Endpoint: Stroke or non-CNS Systemic Embolism * Enrollment of patients without prior Stroke, TIA or systemic embolism and only 2 factors capped at 10%

50. Study Conduct