1. Trials of Antithrombotic Therapy in AF – Where Do We Stand Now? Daniel E. Singer, M.D. Massachusetts General Hospital Harvard Medical School

2. Speaker Disclosure Information DISCLOSURE INFORMATION: The following relationships exist related to this presentation: Daniel E. Singer, M.D. has served as a consultant to AstraZeneca, Bayer, GSK, Boehringer Ingelheim, ev3, Medtronic, Johnson and Johnson.

3. Trials of Antithrombotic Therapy in AF Chronology: 1950s:LA thrombus in MS plus AF 1970s+:NRAF raises risk of embolic stroke 1980s-1990s:Superiority trials of VKA and ASA Late 1990s  :Non-inferiority trials of novel agents vs VKA

4. Stroke Prevention in AF Core Efficacy/Superiority Trials

5. Stroke Prevention in AF: Core Trials AFASAKBAATAF CAFAPrimary Prevention SPAF I/II SPINAF EAFTSecondary Prevention SPAF IIIVery Low INR + ASA vs. INR 2-3 in high-risk pts

6. RCTs of VKA v. Control to Prevent Stroke in AF* *Go et al. Progr Cardiovasc Dis 2005 *P<0.05

7. Efficacy of Anticoagulation for AF Trial Target Ranges: INR ~1.8-4.2 RelativeAbsolute Risk ReductionRisk Reduction Pooled 1° RCTs 68% (50-79%)3.1% per year EAFT 66% (43-80%)8.4% per year

8. Warfarin for AF: Secondary Outcomes Primary prevention pooled analysis: 1.Severe/fatal strokeRRR=68% (39-83%) 2.Death, all causeRRR=33% (9-51%)

9. Safety of Anticoagulation for AF Pooled 1° RCTs 0.3% per yr 0.1% per yr Intracranial Hemorrhage: Anticoagulation Control Absolute Rates of

10. Efficacy of Aspirin for AF Pooled 3 trials versus placebo*: AFASAK75 mg daily SPAF I325 mg daily EAFT300 mg daily Relative Risk Reduction: 21% (0-38%) No signif impact on severe/fatal stroke *Arch Intern Med 1997; 157:1237-1240

11. Warfarin vs. Aspirin Pooled Analysis*: All stroke RRR: 45% All stroke RRR: 45% All CVD RRR: 29% All CVD RRR: 29% MIRRR: 37% MIRRR: 37% * JAMA 2002;288:2441-2448 (AFASAK I &II, EAFT, PATAF, SPAF I-III)

12. The Optimal INR

13. SPAF III: INR 1.2-1.5 plus ASA versus INR 2.0-3.0 TE rate: 7.9% vs 1.9% per yr RRR favoring warfarin: 74% (50-87%) RRR favoring warfarin: 74% (50-87%) No reduction in risk of ICH No reduction in risk of ICH

14. Hylek, et al. N Engl J Med 1996;335:540-546. INROdds Ratio 2.01.0 1.72.0 1.53.3 1.36.0 1.01.53.04.07.0 1 3 5 10 15 2.0 Odds Ratio INR Lowest Effective Anticoagulation Intensity for Warfarin Therapy

15. Relative Odds of ICH by INR Intervals Fang et al. Ann Intern Med 2004;141:745-52

16. Stroke Prevention in AF More Recent Efficacy/Superiority Trials

17. Spanish NASPEAF Trial Triflusal vs triflusal + lower INR vs INR 2-3 Triflusal vs triflusal + lower INR vs INR 2-3 Overall n=1209 Overall n=1209 Complex design; includes mitral stenosis pts Complex design; includes mitral stenosis pts 1 o outcome: vascular death + nonfatal stroke or systemic embolism 1 o outcome: vascular death + nonfatal stroke or systemic embolism Results at 2.76 yrs: Results at 2.76 yrs: e.g., hi risk: median INR 2.08 vs INR 2-3 Trifl + Warf:2.44%/yrRRR=49% (!!) INR 2-3:4.76%/yr Provocative, though many non-stroke outcome events Provocative, though many non-stroke outcome events

18. Recent Superiority Trials for Stroke Prevention in AF 1. Chinese RCT: INR 2-3 v ASA 2. Japanese JAST RCT: ASA v PLBO 3. Swedish RCT: warf 1.25 mg plus 75 mg ASA v Control

19. Antithrombotic Trials in AF: Core Findings Anticoag. at INR 2.0-3.0 very effective - Generally safe - Moderately burdensome Aspirin is much less effective

20. Stroke Prevention in AF Novel Agents/Non-Inferiority Trials

21. Ximelagatran Oral Direct Thrombin Inhibitor Prompt onset and offset of anticoagulationPrompt onset and offset of anticoagulation Predictable pharmacokinetics: bid dosePredictable pharmacokinetics: bid dose Low potential for food and drug interactionsLow potential for food and drug interactions ~No dose adjustment~No dose adjustment No coagulation monitoringNo coagulation monitoring Sarich TC, et al. J Am Coll Cardiol 2003;41:557. Eriksson H, et al. Drug Metab Disp 2003;31:294.

22. SPORTIF III and V: Trial Design Ximelagatran, 36 mg bid vs. Warfarin, INR 2-3Ximelagatran, 36 mg bid vs. Warfarin, INR 2-3 Outcome: all stroke and systemic embolismOutcome: all stroke and systemic embolism Non-inferiority (Risk Difference <2.0%)Non-inferiority (Risk Difference <2.0%) Patients with AF and  1 additional stroke risk factorPatients with AF and  1 additional stroke risk factor Minimum exposureMinimum exposure – 12 months/patient – 4000 patient-yrs  80 events

23. SPORTIF III & V: Quality of Warfarin Rx SPORTIF IIISPORTIF V INR 2.0-3.0 66% 68% INR 1.8-3.2 81% 83%

24. Pooled SPORTIF III and V: Stroke and Systemic Embolism Cerebrovasc Dis 2006;21:279-293

25. SPORTIF V: Bleeding XimelagatranWarfarin Major extracerebral Bleeding, ns Fatal, ns 63 cases 84 cases (2.4% per year) (3.1% per year) 2 cases 1 case

26. SPORTIF V: Liver Toxicity ALT > 3 x ULN ALT > 3 x ULN + Bili > 2 x ULN Bili > 2 x ULN (“Hy’s Law”) Liver Fatality All Cause Mortality 117 (6.0%)15 (0.8%) 9 (0.46%)1 (0.05%) 1 case (?3)0 cases 116 (6.0%)123 (6.3%)XimelagatranWarfarin

27. FDA CardioRenal, 9 Sept, 2005 Ximelagatran Not Approved AZeneca, Jan 2006, withdraws Ximelagatran

28. ACTIVE-W Trial Non-inferiority; open; clopidogrel 75mg + 150-200mg ASA vs. adjusted dose OAC; n=6706 Non-inferiority; open; clopidogrel 75mg + 150-200mg ASA vs. adjusted dose OAC; n=6706 Patients with AF and at least a moderate risk for stroke Patients with AF and at least a moderate risk for stroke Primary outcome: combined stroke, peripheral embolism, myocardial infarction, vascular death Primary outcome: combined stroke, peripheral embolism, myocardial infarction, vascular death

29. ACTIVE-W Results Annual Event Rate, % ASA+Clopido.OACRRRp Primary Outcome 5.63.930%<0.01 Isch. Stroke 2.151.0(!)53%<0.01 MI0.860.5536%0.09 Major bleed 2.42.28.6%0.5 Stopped early because OAC clearly superior Stopped early because OAC clearly superior OAC less dominant among pts newly starting OAC

30. RCTs of Other Novel Antithrombotics AMADEUS: idraparinux vs warfarin (INR 2-3) in “hi-risk” AF: stopped early in favor of warfarin Multiple other agents near or in phase 3 trials

31. PROGRESS Trial: Anti-hypertensives as Antithrombotics Perindopril+/-indapamide vs placebo in all patients with a prior stroke, all types, with/without hx of HTN? Perindopril+/-indapamide vs placebo in all patients with a prior stroke, all types, with/without hx of HTN? Outcome: all stroke Outcome: all stroke N=6105; #AF=476, 51% on anticoag; f/u=3.9 yrs N=6105; #AF=476, 51% on anticoag; f/u=3.9 yrs RRR=38% (-13 to 61%) RRR=38% (-13 to 61%)

32. Stroke Prevention in AF: The Future 1.More new antithrombotics: oral direct thrombin and Xa inhibitors, othersoral direct thrombin and Xa inhibitors, others Irbesartan (ACTIVE-I)Irbesartan (ACTIVE-I) 2. “Rx” of LAA: surgery, catheter approach 3. True cure of AF: initiator: ablation/isolation of PVinitiator: ablation/isolation of PV substrate:“maze” proceduresubstrate:“maze” procedure 4. Preventing AF

33. Trials of Antithrombotic Therapy in AF Lessons learned: Warfarin, INR 2-3, is extremely effective and can be safe Warfarin, INR 2-3, is extremely effective and can be safe ASA has little efficacy in AF ASA has little efficacy in AF Warfarin is tough to beat or even tie in RCTs Warfarin is tough to beat or even tie in RCTs

34. Trials of Antithrombotic Therapy in AF Concerns: Warfarin’s performance in the real world Warfarin’s performance in the real world 1. Patient selection in RCTs 2. INR control in RCTs 3. Initiation phase Secular decrease in absolute stroke risk for AF patients Secular decrease in absolute stroke risk for AF patients Bleeds: adding ASA, or ASA + clopidogrel to warfarin Bleeds: adding ASA, or ASA + clopidogrel to warfarin

35. Trials of Antithrombotic Therapy in AF – Where Do We Stand Now? Warfarin, INR 2-3, remains the treatment of choice for patients with AF and risk factors for stroke, but the field is “alive” with novel research, and we can anticipate additional management and treatment options soon.

36. END