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WAVE Update December 1, 2002

WAVE Update December 1, 2002. Atherothrombosis. Ruptured Carotid Artery Plaque with Thrombus. 3R. HIGH INTENSITY INR 2.8-4.8 (No Aspirin) n=10,000. 0.78. Mortality. 0.58. MI. 0.43. TEC. 0.57. Combined. Odds Ratio. 0.0. 0.5. 1.0. 1.5. Warfarin Better. Control Better.

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WAVE Update December 1, 2002

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  1. WAVE Update December 1, 2002

  2. Atherothrombosis Ruptured Carotid Artery Plaque with Thrombus 3R

  3. HIGH INTENSITY INR 2.8-4.8 (No Aspirin)n=10,000 0.78 Mortality 0.58 MI 0.43 TEC 0.57 Combined Odds Ratio 0.0 0.5 1.0 1.5 Warfarin Better Control Better Odds Ratio & 95% CI Limits Anand, Yusuf JAMA 1999

  4. LOW INTENSITY : INR 1.5n=10,463 1.03 Mortality 1.06 MI 1.28 Stroke 0.91 Combined 1.29 Major Bleed Odds Ratio 0.0 0.5 1.0 1.5 Favours Warfarin Favours Control Odds Ratio & 95% CI Limits Anand, Yusuf JAMA1999

  5. MODERATE INTENSITY: INR 2-3 WITH ASPIRIN: n=480 0.58 Mortality 0.55 MI 0.13 Stroke 0.43 Combined Odds Ratio 0.0 0.5 1.0 1.5 Warfarin Better Control Better Odds Ratio & 95% CI Limits Anand, Yusuf JAMA1999

  6. Major Bleeding Rates in Patients with Vascular Disease A W&A A W&A A W A W C W N Patients 10,463 480 2,112 1,747 9,527 Intensity • Low • Moderate • High INR=1.5 INR=2 - 3 INR=2.8 - 4.8 with Aspirin vs. Aspirin vs. Control Anand, Yusuf JAMA 1999

  7. Summary Slide • APRICOT - 2

  8. APRICOT - 2 • 308 AMI patients with ST-elevation • All received thrombolytic therapy • Angiography post TT and if artery patent repeat at 3 months • Randomized to ASA or ASA and warfarin • Endpoint: Re-occlusion at 3 months. Circulation 2002;106:659-665

  9. APRICOT-2 study Circulation 2002;106:659-665

  10. ASPECT-2 STUDY • Randomized open label study • 999 patients with acute MI or unstable angina • ST-elevation MI 46% • Aspirin 80 mg • Coumadin – INR 3.0-4.0 (Mean 3.2) • Aspirin 80 mg/Coumadin – INR 2.0-2.5 (Mean 2.4) • Mean follow-up 1 year • Myocardial infarction, stroke or death Van es et al, Lancet 2002; 360:109

  11. ASPIRIN AND COUMADIN AFTER ACUTE CORONARY SYNDROMES (ASPECT-2 STUDY) Aspirin Coumadin Aspirin/Coumadin (n=336) (n=325) (n=332) Composite 28 (8%) 27 (5%) 15 (5%) Death 15 (4%) 4 (1%) 9 (3%) MI 14 (4%) 13 (4%) 10 (3%) Major Haem 3 (1%) 3 (1%) 7 (2%) Minor Haem 16 (5%) 26 (8%) 50 (15%) Van es et al, Lancet 2002; 360:109

  12. ASPECT-2 • Primary endpoint • re-MI • death • stroke Mortality Lancet 2002:360:109-113

  13. WARFARIN, ASPIRIN OR BOTH AFTER MYOCARDIAL INFARCTION (WARIS II) • Randomized multicentre triaql • 3630 patients with acute MI • 60% ST-elevation MI • Warfarin INR 2.8-4.2 • Aspirin 160 mg/day • Aspirin 75 mg/day/Warfarin INR 2.0-2.5 • Mean follow-up four years • Death, non-fatal MI, TE, Stroke Hurlen et al, NEJM 2002; 347:969

  14. WARIS II: Primary endpoint WARIS-II MAIN RESULTS WARIS II W+A vs A=0.71; 0.001 W+A vs W=0.87; P=0.18 Arnesen et al. Presented at the XXIII Congress of the European Society of Cardiology. Sep 2, 2001

  15. Warfarin, aspirin, or both after Myocardial Infarction ( WARIS II) Hurlen et al, N Engl J Med 2002:347 Composite - Death - Non fatal Re-MI - T/E stroke

  16. WARIS II: Major and minor bleeding events WARIS-II BLEEDING WARIS II Arnesen et al. Presented at the XXIII Congress of the European Society of Cardiology. Sep 2, 2001

  17. Compliance with Warfarin

  18. Warfarin Trials to Prevent Limb Complications

  19. Oral Anticoagulants for Local Disease • 831 patients post peripheral bypass surgery • Warfarin INR: 1.4 to 2.8 + 325 mg/day vs Aspirin 325 mg/day • 133 deaths in the WASA group (31.8%) vs 95 deaths in the ASA group (23.0%) • Risk ratio = 1.41; (1.09 to 1.84; P =.0001) • Major bleeding occurred in the WASA group (WASA, n = 35; ASA, n = 15; P =.02). Johnson WB Vascular Sugery 2002

  20. Conclusions • Clear effect of oral anticoagulants (without aspirin) at high intensity in reducing Death, Ischemic Stroke, and MI, with an increase in major bleeds • No apparent effect of oral anticoagulants (with aspirin) at low intensity (INR < 1.5) in reduction of Death, MI and Ischemic Stroke • Promising results of moderate intensity warfarin (with aspirin) – ASPECT-2, APRICOT-2, WARIS-2

  21. 0.0 0.5 1.0 1.5 2.0 ASA better Control better Dose-Response Relationship with Aspirin ASA dose % odds reduction 500–1500 mg daily 160–325 mg daily 75–150 mg daily < 75 mg daily Any ASA dose23% ±2 (p < 0.0001) CURE: ASA GroupBleeds> 200 mg 4.02 %100-200 mg 2.27%< 100 mg 2.03% N ~ 60,000 Antithrombotic Trialists’ Collaboration BMJ 324: 71, 2002

  22. CURE Major/Life Threatening BleedDifferent ASA Doses

  23. Optimal Aspirin Dose • Aspirin 81mg – 325mg daily for all patients unless there is a contraindication • Equal Efficacy and Better safety with the lower dose

  24. WAVE Trial Update: November 2002

  25. WAVE – Patients in run-in Nov. 30/02

  26. WAVE- Fate of Patients N=1754 N=188 1492 Randomized 739 Aspirin 753 Warfarin 7 using warfarin

  27. Reasons for Stopping Run-in

  28. WAVE BASELINE 3 Nov. 30/02

  29. WAVE Medication Use Nov. 30/02

  30. WAVE Risk Factors Nov. 30/02

  31. WAVE Baseline 2 Nov. 30/02

  32. WAVE- Compliance > 80% therapeutic or supra - 16% Subtherapeutic No 30/02

  33. WAVE – Median INR 35 day 6 mo. 12 mo. 18 mo. 24 mo. Nov 30/02

  34. Rationale to Extend Follow-up in WAVE • Extend follow-up in patients who have reached 2.5 years of follow-up • Events are ACCRUED in a linear fashion there is no plateau Events Time

  35. WAVE Future • Canada must Randomize 1000 patients by June 2003 • Extend Follow-up in some patients from 2.5 to 2.5 years • Encourage Patients to stick with study • Minimize Discontinuations from warfarin and maximize compliance

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