1. JOURNAL REVIEW Newer Antithrombotics in AF 1 Dr Ranjith MP Senior Resident Department of Cardiology Government Medical college Kozhikode

2. Introduction  Atrial fibrillation is associated with a five-fold risk of stroke 1  The increase in risk of stroke is similar for paroxysmal, persistent and permanent AF 2  Strokes associated with AF are usually more severe than those from other causes, conferring an increased risk of morbidity, mortality and poor functional outcome 1 2 1. Savelieva et al. Ann Med 2007;39:371–391 2. Hart R et al. JACC 2000; 35:183-187

3. Introduction  Warfarin -most effective treatment to prevent stroke in patients with AF & it reduces the risk by about two thirds compared with placebo 3 Hart R, et al. Ann Intern Med 1999;131:492 Warfarin Better Control Better AFASAK SPAF BAATAF CAFA SPINAF EAFT 100% 50% 0 -50% -100% Aggregate

4. Limitations of vitamin K antagonists Limitations of vitamin K antagonists  Slow onset and offset of action  Considerable variability in dose response among individuals  Multiple food and drug interactions  Narrow therapeutic window & considerable risk of hemorrhage  Even with careful laboratory monitoring, major bleeding occurs in 1% to 3% per year 4

5. Introduction  Therefore, there is a need for novel approaches to stroke prevention in AF with new antithrombotic agents  The Newer Antithrombotics for stroke prevention in AF fall into two classes:  Oral direct thrombin inhibitors (e.g. dabigatran)  Oral direct factor Xa inhibitors (e.g. rivaroxaban, apixaban) 5

6. Pharmacology of newer Antithrombotics 6

7. Advantages of direct thrombin inhibitors over indirect inhibitors 7 Advantage Mechanism Better suppression of thrombusInhibit free and bound growth thrombin Retain activity in presenceDo not bind PF4 or Vwf of platelet-rich thrombi Predictable anticoagulantDo not bind plasma proteins response No risk of HITDo not bind PF4

8. Trials with new agents vs warfarin in AF (aim INR 2.0-3.0) 8

9. Ximelagatran  First oral direct thrombin inhibitor  As effective as warfarin for prevention of stroke and systemic embolic events in patients with atrial fibrillation 1  Prolonged administration (35 days) of ximelagratan was associated with a risk of liver toxicity, which led to withdrawal of the drug from the market 2 1Testa L et al. Expert Opin Drug Saf. 2007;6(4):397-406 2Agnelli G et al. Thromb Res. 2008

10. 10 N Engl J Med 2009;361:1139-51.

11. The RE-LY Study: The RE-LY Study: Randomized Evaluation of Long-term anticoagulant therapy  Dabigatran Compared to Warfarin in 18,113 Patients with AF at Risk of Stroke Atrial fibrillation ≥ 1 risk factor Absence of contraindications 951 centers/44 countries R Warfarin adjusted (INR 2.0-3.0) n = 6022 Dabigatran Etexilate 110 mg BID n = 6015 Dabigatran Etexilate 150 mg BID n = 6076 Blinded Event Adjudication Open Blinded Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

12. RE-LY: Baseline Characteristics 12 Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

13. RE-LY: Primary Outcome 13 Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

14. RE-LY: Summary of Results 14 Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

15. RE-LY: Stroke or Systemic Embolism 15.. Cumulative Hazard Rates 0.0 0.01 0.02 0.03 0.04 0.05 00.51.01.52.02.5 Years of follow-up Dabigatran 110 mg Dabigatran 150 mg Warfarin Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151.

16. RE-LY: Drug Discontinuation 16 Connolly, SJ. et al. N Engl J Med 2009;361:1139-1151. a. Rates of discontinuation at 1 and 2 years were higher with dabigatran than with warfarin (P <.001). Rates are based on Kaplan-Meier estimates

17. RE−LY Summary Dabigatran 150 mg superior to warfarin for stroke/systemic embolism; dabigatran 110 mg was non-inferior Stroke ↓ in dabigatran 150 mg arm (p < 0.001) Major bleeding was higher in warfarin arm compared with dabigatran 110 mg, but was similar to dabigatran 150 mg Trial design: Patients with AF were randomized to either dabigatran 110 mg, 150 mg, or open-label warfarin. Patients were followed for a mean of 2 years. Results Conclusions Connolly SJ, et al. N Engl J Med 2009;Aug 30:[Epub] Stroke/systemic embolism Dabigatran 150 mg superior to warfarin in reducing stroke or systemic embolism, with a similar bleeding profile. The 110 mg dose was non- inferior for efficacy, associated with lower bleeding compared with warfarin 0 5 %/year 1.53 1.11 2.71 3.11 5 10 Major bleeding 10 1.69 Dabigatran 110 mg Dabigatran 150 mg Warfarin 0 %/year 3.36 (p <0.001*, p = 0.34 † )(p = 0.31*, p = 0.03 † ) *Dabigatran 150 mg vs. warfarin; †Dabigatran 110 mg vs. warfarin

18. 18 N Engl J Med 2011;365:883-91.

19. ROCKET AF: Study Design Rivaroxaban 20 mg daily (15 mg for Cr Cl 30-49 ml/min) Warfarin INR target: 2.5 (2.0-3.0 inclusive) Primary Endpoint: Stroke or non-CNS Systemic Embolism Atrial Fibrillation Randomize Double Blind / Double Dummy (N= 14,264) Monthly Monitoring Adherence to standard of care guidelines Risk Factors, at least 2 of: CHF Hypertension Age  75 Diabetes OR Stroke, TIA or systemic embolus MR Patel et al.N Engl J Med 2011;365:883-91.

20. ROCKET AF: Baseline Demographics 20 Rivaroxaban (n = 7081) Warfarin (n = 7090) CHADS 2 Score (mean)3.483.46 2 (%)13 3 (%)4344 4 (%)2928 5 (%)1312 6 (%)22 Prior VKA Use (%)6263 Heart Failure (%)6362 Hypertension (%)9091 Diabetes Mellitus (%)4039 Prior Stroke/TIA/Embolism (%)55 Prior Myocardial Infarction (%)1718 MR Patel et al.N Engl J Med 2011;365:883-91.

21. ROCKET AF: Primary Efficacy Outcome Stroke and non-CNS Embolism 21 MR Patel et al.N Engl J Med 2011;365:883-91.

22. ROCKET AF: Primary Safety Outcomes ROCKET AF: Primary Safety Outcomes Bleeding: RivaroxabanWarfarin HR 95% CIP-value Event Rate Major and non-major Clinically Relevant 14.9114.52 1.03 0.96, 1.11.442 Major3.603.45 1.04 0.90, 1.20.576 Non-major Clinically Relevant 11.8011.37 1.04 0.96, 1.13.345 MR Patel et al.N Engl J Med 2011;365:883-91.

23. RivaroxabanWarfarin HR (95% CI)P-value Event Rate or N (Rate) Major3.603.451.04 (0.90, 1.20).576 ≥ 2 g/dL Hgb drop2.772.261.22 (1.03, 1.44).019 Transfusion (> 2 units)1.651.321.25 (1.01, 1.55).044 Critical organ bleeding0.821.180.69 (0.53, 0.91).007 Bleeding causing death0.240.480.50 (0.31, 0.79).003 Intracranial Hemorrhage55 (0.49)84 (0.74)0.67 (0.47, 0.94).019 Intraparenchymal37 (0.33)56 (0.49)0.67 (0.44, 1.02).060 Intraventricular2 (0.02)4 (0.04) Subdural14 (0.13)27 (0.27)0.53 (0.28, 1.00).051 Subarachnoid4 (0.04)1 (0.01) ROCKET AF: Primary Safety Outcomes ROCKET AF: Primary Safety Outcomes MR Patel et al.N Engl J Med 2011;365:883-91.

24. ROCKET AF- Summary Stroke or non-CNS systemic embolism (per 100 patient-years): 1.7 with rivaroxaban vs. 2.2 with warfarin (p for noninferiority < 0.001, p for superiority = 0.12 by intention to treat analysis, p for superiority = 0.015 by on-treatment analysis) Major and nonmajor clinically relevant bleeding (per 100 patient-years): 14.9 vs. 14.5 (p = 0.44) Intracranial hemorrhage (per 100 patient-years): 0.5 vs. 0.7 (p = 0.019) Trial design: Patients with atrial fibrillation at increased risk for stroke were randomized to the direct factor Xa inhibitor rivaroxaban 20 mg oral daily (n = 7,131) vs. warfarin with target INR 2-3 (n = 7,133). Results Conclusions Among AF patients with high stroke risk, rivaroxaban was noninferior to warfarin Rivaroxaban was associated with a reduced incidence of the primary outcome without an excess of major bleeding or intracranial hemorrhage (p for non- inferiority < 0.001) Rivaroxaban, 20 mg daily Per 100 patient-years 1.7 2.2 Stroke or non-CNS systemic embolism Warfarin, INR 2-3 MR Patel et al.N Engl J Med 2011;365:883-91.

25. N Engl J Med 2011;365:981-92.

26. ARISTOTLE: Study Design Apixaban 5 mg bd (2.5-mg for- age≥80, Wt≤60kg 60 kg, or serum creatinine level of 1.5mg%) Warfarin INR target: 2.0-3.0 Primary Endpoint: ischemic or hemorrhagic stroke or systemic embolism Atrial Fibrillation Randomized Double Blind (N= 18,201) Monthly Monitoring Adherence to standard of care guidelines Risk Factors, at least 1 of: CHF Hypertension Age  75 Diabetes OR Stroke, TIA or systemic embolus Christopher B. G et al.N Engl J Med 2011;365:981-92.

27. ARISTOTLE : Baseline Characteristics ARISTOTLE : Baseline Characteristics Christopher B. G et al.N Engl J Med 2011;365:981-92. Characteristic Apixaban (n=9120) Warfarin (n=9081) Age, years, median (25 th, 75 th %ile) 70 (63, 76) Women, %35 Region, % North America25 Latin America19 Europe40 Asia/Pacific16 Warfarin naïve, %43 CHADS score, mean (+/- SD)2.1 (+/- 1.1) 1, %34 2, %36 ≥ 3, %30

28. ARISTOTLE :Baseline Characteristics Christopher B. G et al.N Engl J Med 2011;365:981-92. Characteristic Apixaban (n=9120) Warfarin (n=9081) Qualifying risk factors, % Age ≥75 yrs31 Prior stroke, TIA, or SE1920 Heart failure or reduced LV EF3536 Diabetes25 Hypertension8788 Renal function (Cl Cr ml/min), % Normal (>80)41 Mild impairment (>50 – 80)42 Moderate impairment (>30 – 50)15 Severe impairment (≤ 30)1.5

29. ARISTOTLE :Primary Outcome Stroke or systemic embolism Christopher B. G et al.N Engl J Med 2011;365:981-92.

30. ARISTOTLE :Primary Outcome Stroke or systemic embolism Christopher B. G et al.N Engl J Med 2011;365:981-92. Outcome Apixaban (N=9120) Warfarin (N=9081) HR (95% CI)P Value Event Rate (%/yr) Event Rate (%/yr) Stroke or systemic embolism*1.271.600.79 (0.66, 0.95)0.011 Stroke1.191.510.79 (0.65, 0.95)0.012 Ischemic or uncertain0.971.050.92 (0.74, 1.13)0.42 Hemorrhagic0.240.470.51 (0.35, 0.75)<0.001 Systemic embolism (SE)0.090.100.87 (0.44, 1.75)0.70 All-cause death*3.523.940.89 (0.80, 0.998)0.047 Stroke, SE, or all-cause death4.495.040.89 (0.81, 0.98)0.019 Myocardial infarction0.530.610.88 (0.66, 1.17)0.37

31. ARISTOTLE :Major Bleeding Christopher B. G et al.N Engl J Med 2011;365:981-92.

32. ARISTOTLE :Bleeding Outcomes Outcome Apixaban (N=9088) Warfarin (N=9052) HR (95% CI)P Value Event Rate (%/yr) Event Rate (%/yr) Primary safety outcome: ISTH major bleeding* 2.133.090.69 (0.60, 0.80)<0.001 Intracranial0.330.800.42 (0.30, 0.58)<0.001 Gastrointestinal0.760.860.89 (0.70, 1.15)0.37 Major or clinically relevant non-major bleeding 4.076.010.68 (0.61, 0.75)<0.001 GUSTO severe bleeding0.521.130.46 (0.35, 0.60)<0.001 TIMI major bleeding0.961.690.57 (0.46, 0.70)<0.001 Any bleeding18.125.80.71 (0.68, 0.75)<0.001 Christopher B. G et al.N Engl J Med 2011;365:981-92.

33. ARISTOTLE : Conclusion  Compared with warfarin, apixaban (over 1.8 years) prevented  6 Strokes  15 Major bleeds  8 Deaths  Treatment with apixaban as compared to warfarin in patients with AF & at least one additional risk factor for stroke:  Reduces stroke and systemic embolism by 21% (p=0.01)  Reduces major bleeding by 31% (p<0.001)  Reduces mortality by 11% (p=0.047) Christopher B. G et al.N Engl J Med 2011;365:981-92.

34. ARISTOTLE : Summary Primary efficacy outcome (stroke/systemic embolism) for apixaban vs. warfarin: 1.27%/year vs. 1.6%/year; p noninferiority < 0.001, p superiority = 0.01 All strokes:1.19%/year vs. 1.51%/year, p = 0.01; all- cause mortality: 3.52%/year vs. 3.94%/year, p = 0.047 Primary safety outcome (ISTH major bleeding): 2.13%/year vs. 3.09%/year, p < 0.001 Trial design: Patients with atrial fibrillation (AF) and at least one additional risk factor for stroke were randomized to either apixaban 5 mg twice daily or dose-adjusted warfarin (titrated to a target INR of 2.0-3.0). Patients were followed for a median of 1.8 years. Results Conclusions (p < 0.001)* Apixaban (n = 9,120) Primary efficacy outcome Landmark trial, demonstrates superiority of apixaban over warfarin in patients with AF for efficacy, with a significant reduction in bleeding Apixaban is an oral anti-Xa agent that does not require routine blood monitoring 0 5 10 1.27 1.6 (p < 0.001) 2.13 3.09 5 Primary safety outcome Warfarin (n = 9,081) 0 10 % % * For noninferiority Christopher B. G et al.N Engl J Med 2011;365:981- 92.

35. N Engl J Med 2011;364:806-17.

36. AVERROES (Apixaban versus Acetylsalicylic Acid to Prevent Strokes): Study Design AVERROES (Apixaban versus Acetylsalicylic Acid to Prevent Strokes): Study Design Stuart JC et al.N Engl J Med 2011;364:806-17. Apixaban 2.5 mg bid or 5 mg bid Aspirin 81-324 mg qd Primary outcome measures: Time to composite outcome of stroke or systemic embolism Time to major bleeding Patient characteristics Aged  50 years Atrial fibrillation  1 additional risk factor for stroke Not suitable for vitamin K antagonist ≈ 1.6 years Randomization N=5600

37. AVERROES: Results (efficacy)  Apixaban significantly reduced risk of stroke or systemic embolic events by 54%  The trial was stopped early as interim analysis showed significant benefit with apixaban Stuart JC et al.N Engl J Med 2011;364:806-17. Primary and secondary end points OutcomesApixaban (n=2809), % Aspirin (n=2791), % Relative risk (95% CI) Primary end point1.63.60.46 (0.33–0.64) Stroke, embolic event, MI, or vascular death 4.16.20.66 (0.53–0.83) -MI0.70.80.85 (0.48–1.50) -Vascular death2.52.90.86 (0.64–1.16) CV hospitalization11.814.90.79 (0.68–0.91) Total death3.44.40.79 (0.62–1.02)

38. AVERROES: Results (safety) AVERROES: Results (safety)  The risk of major bleeding increased by a statistically nonsignificant 14%  There was no increased risk of fatal or intracranial hemorrhage, two particular concerns with AF patients who receive anticoagulation therapy Stuart JC et al.N Engl J Med 2011;364:806-17. Bleeding events OutcomesApixaban (n=2809), % Aspirin (n=2791), % Relative risk (95% CI) Major bleeding1.41.21.14 (0.74–1.75) Clinical relevant nonmajor bleeding 3.02.61.18 (0.88–1.58) Minor bleeding5.24.11.27 (1.01–1.61) Fatal bleeding0.1 0.84 (0.26–2.75) Intracranial0.40.31.09 (0.50–2.39)

39. Am Heart J 2010:160:635-641.e2.

40. ENGAGE-AF-TIMI 48; Study Design Low Exposure Strategy DU-176b 30 mg QD (n=5500) Active Control Warfarin (n=5500) High Exposure Strategy DU-176b 60 mg QD (n=5500) 1º EP = Stroke or SEE (Noninferiority Boundary HR 1.38) 2º EP = Stroke or SEE or All-Cause Mortality Safety EP’s = Major Bleeding, Hepatic Function AF on ECG < 12 mos Intended oral A/C CHADS 2 Score > 2 R Randomization Strata: 1. CHADS 2 2-3 vs 4-6 2. Drug clearance Median Duration of Followup 24 months n~16,500 Chritian TR et al.Am Heart J 2010:160:635-641.e2.

41. European Heart Journal doi:10.1093/eht039

42. Characteristics of Betrixaban  Orally-active and selective fXa inhibitor  Oral bioavailability 34%,  Peak to trough concentration profile 2.5 : 1  ~20 hour effective half-life  No dose adjustment expected for renal impairment  Excreted mostly unchanged through bile with minimal renal excretion (<5%)  Antidote in development  No major drug interactions expected  Not substrate for CYP450 system  Substrate for efflux proteins including P-glycoprotein Stuart JC et al. European Heart Journal. doi:10.1093

43. EXPLORE-Xa : Study Objectives  Primary Objective  Safety and tolerability of oral betrixaban at doses of 40, 60 and 80 mg once a day compared with dose-adjusted warfarin in patients with non-valvular atrial fibrillation or atrial flutter  Primary Endpoint Time to major and clinically relevant non-major bleeding  Secondary Endpoints Time to any bleeding, death, stroke, MI or systemic embolism  Secondary Objective  Pharmacokinetics (PK) and pharmacodynamics (PD) of betrixaban Stuart JC et al. European Heart Journal. doi:10.1093

44. EXPLORE-Xa: Main Inclusion Criteria EXPLORE-Xa: Main Inclusion Criteria  Male or female, age ≥ 18 years  AF at the time of enrollment or documented within the last year  At least one risk factor for stroke  Need for renal dialysis within one year  AF due to reversible causes, mechanical prosthetic valve  SBP > 160 mmHg on repeated measurements  Active infective endocarditis Stuart JC et al. European Heart Journal. doi:10.1093 EXPLORE-Xa: Main Exclusion Criteria EXPLORE-Xa: Main Exclusion Criteria

45. EXPLORE-Xa: Patient Disposition & Follow-Up EXPLORE-Xa: Patient Disposition & Follow-Up Stuart JC et al. European Heart Journal. doi:10.1093 N=561 Patients Screened N=508 Patients Randomized N=53 Patients Not Randomized N=127 Betrixaban 40 mg N=127 Betrixaban 60 mg N=127 Betrixaban 80 mg N=127 Open-Label Warfarin N=116 Completed N=115 Completed N=116 Completed N=119 Completed Minimum follow-up 3 months; Maximum 12 months; Median 4.9 months

46. EXPLORE-Xa: Baseline Characteristics EXPLORE-Xa: Baseline Characteristics Stuart JC et al. European Heart Journal. doi:10.1093

47. EXPLORE-Xa: Major Bleeding or Clinically Relevant Non-Major Bleeding EXPLORE-Xa: Major Bleeding or Clinically Relevant Non-Major Bleeding Stuart JC et al. European Heart Journal. doi:10.1093

48. EXPLORE-Xa: Bleeds, strokes & deaths EXPLORE-Xa: Bleeds, strokes & deaths Stuart JC et al. European Heart Journal. doi:10.1093

49. EXPLORE-Xa: ALT Elevations (in % of Patients) EXPLORE-Xa: ALT Elevations (in % of Patients) Stuart JC et al. European Heart Journal. doi:10.1093 BetrixabanWarfarin >2x ULN2.4 >3x ULN1.80.8 >5x ULN0.50.8 >10x ULN0.30.0 Consecutive elevations ≥ 3xULN 0.50.8

50. EXPLORE-Xa: Type of GI Adverse Events by Treatment EXPLORE-Xa: Type of GI Adverse Events by Treatment Stuart JC et al. European Heart Journal. doi:10.1093

51. EXPLORE-Xa: Conclusion  Bleeding was significantly less for betrixaban 40 mg vs.warfarin  Bleeding at 60 and 80 mg was comparable to warfarin  The number of strokes were within the range expected for warfarin (0-1 /gp)  All 3 doses were well tolerated  D-dimer shows activity across dose spectrum with a trend toward a dose response  Compared to well-treated experienced warfarin patients there was a dose dependent effect on the primary endpoint of major and clinically relevant non-major bleeding

52. Summary of recommendations for antithrombotic agent Summary of recommendations for antithrombotic agent

53.  Dabigatran-The FDA has approved the 150 mg b.i.d. dose, and the 75 mg b.i.d. dose in severe renal impairment, while the EMA has approvedboth the 110 mg b.i.d. and 150 mg b.i.d. doses  Rivaroxaban has been approved for stroke prevention in nonvalvular AF by both the FDA and the EMA  Apixaban has not yet gained regulatory approval from the EMA or FDA

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