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Presenter Disclosure Information. Stuart J. Connolly The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE). DISCLOSURE INFORMATION: The following relationships exist related to this presentation:

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  1. Presenter Disclosure Information Stuart J. Connolly The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE) DISCLOSURE INFORMATION: The following relationships exist related to this presentation: ACTIVE was sponsored by Sanofi-Aventis and by Bristol-Myers Squibb

  2. Background • AF is a risk factor for stroke and other vascular events (VE) • Oral anticoagulation (OAC) reduces the risk of stroke and VE, but is difficult to use and is poorly tolerated by some patients.

  3. Clopidogrel Plus ASA • ASA reduces the risk of stroke in AF by 20% • Addition of clopidogrel to ASA in ACS and acute MI further reduces risk of vascular events • Addition of clopidogrel to ASA in AF could provide an easy to use alternate to OAC

  4. ACTIVE Program: Three Trials Documented AF + 1 risk factor: Age 75, Hypertension, Prior stroke/TIA, LVEF<45, PAD, Age 55-74 + CAD or diabetes Contra-indications to OAC or Unwilling ACTIVE W Clopidogrel+ASA vs. OAC ACTIVE A Clopidogrel+ASA vs. ASA 6500 patients 7500 patients No Exclusion criteria for ACTIVE I Partial Factorial Design ACTIVE I Irbesartan vs placebo ~9000 patients

  5. ACTIVE W: Treatments • OAC • Standard Care (INR 2.0 – 3.0) • INR at least monthly • Clopidogrel plus ASA • Clopidogrel 75 mg once daily • ASA 75-100 mg once daily

  6. Outcome Events • Primary Outcome • Stroke, Non-CNS Systemic Embolism, MI, Vascular Death • Safety Outcome • Major Bleeding

  7. Non-Inferiority Trial • Preserves  50% of a conservative estimate of the proven effect of oral anticoagulation in AF • Non-inferiority margin = 1.186 • With an expected event rate of 6 %/year, 6500 patients needed for 84% power

  8. 6706 pts from 522 centers in 31 countries

  9. Early Termination of ACTIVE W • DSMB recommended early termination of ACTIVE W due to evidence of superiority of oral anticoagulation • Recommends continuation of the • ACTIVE A & ACTIVE I studies

  10. Risk Factor Profile

  11. Pre-Randomization Anti-thrombotic Medications

  12. ACTIVE W - INR Control

  13. Stroke, Non-CNS Systemic Embolism, MI & Vascular Death 5.64 %/year RR = 1.45 P = 0.0002 3.93 %/year Cumulative Hazard Rates # at Risk C+A 3335 3149 2387 916 OAC 3371 3220 2453 911 Years

  14. Major Bleeding 2.4 %/year RR = 1.06 P = 0.67 2.2 %/year Cumulative Hazard Rates # at Risk C+A 3335 3172 2403 914 OAC 3371 3212 2423 901 Years

  15. Primary Outcome Components & Death

  16. Subgroup Analyses

  17. Permanent Study Drug Discontinuation Entry OAC No Entry OAC 13.4% 13.2% 12.4% Cumulative Hazard Rates 6.1% Years

  18. INR Control

  19. Stroke, Non-CNS Systemic Embolism, MI, Vascular Death Entry OAC No Entry OAC Interaction P = 0.55 RR = 1.50 P = 0.0006 RR = 1.32 P = 0.17 Cumulative Hazard Rates Years

  20. Major Bleeding Entry OAC No Entry OAC Interaction P = 0.032 RR = 1.27 P = 0.14 RR = 0.58 P = 0.09 Cumulative Hazard Rates Years

  21. Primary Outcome +Major Bleeding Entry OAC No Entry OAC Interaction P = 0.17 RR = 1.51 P < 0.0001 RR = 1.14 P = 0.45 Cumulative Hazard Rates Years

  22. Primary Outcome by Center INR Control  65% INR in Range <65% INR in Range Interaction P = 0.013 RR = 1.83 P < 0.0001 RR = 1.11 P = 0.47 Cumulative Hazard Rates Years

  23. Major Bleeding by Center INR Control  65% INR in Range <65% INR in Range Interaction P = 0.0006 RR = 1.55 P = 0.027 RR = 0.68 P = 0.08 Cumulative Hazard Rates Years

  24. Primary+Major Bleed by Centre INR Control  65% INR in Range <65% INR in Range Interaction P = 0.002 RR = 1.80 P < 0.0001 RR = 1.06 P = 0.66 Cumulative Hazard Rates Years

  25. Conclusions • Oral anticoagulation is superior to clopidogrel plus ASA for prevention of vascular events • Rates of major hemorrhage are similar

  26. Conclusions: Sub-groups • Benefit and safety of oral anticoagulation versus clopidogrel plus aspirin is uncertain for patients not on oral anticoagulation at entry • For patients at centers not achieving good INR control, oral anticoagulation may offer little benefit over clopidogrel plus ASA

  27. Clinical Implication • Oral anticoagulation is the most effective currently available antithrombotic therapy for use in AF. • To achieve its benefits it must be used optimally

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