1. 1 HOT LINE PRESENTATION World Congress of Cardiology 2006 Barcelona, Spain September 5, 2006 Warfarin Antiplatelet Vascular Evaluation - 2161 PAD Patients Dr. Sonia Anand Associate Professor of Medicine McMaster University

2. 2 Rationale Atherosclerosis is a systemic disease PAD patients suffer the highest rates of CV death, MI, and ischemic stroke Antiplatelet therapy reduces CV events in broad spectrum of patients with vascular disease (CAD, CBVD, PAD) Role of Oral anticoagulants (OAC) together with antiplatelets in CAD appears promising

3. 3 Primary Objectives To determine if moderate intensity OAC (INR 2-3), in combination with antiplatelet therapy, is superior to antiplatelet therapy alone in preventing –cardiovascular death, MI, or stroke, and –cardiovascular death, MI, stroke, or severe ischemia of the coronary or peripheral arterial circulation

4. 4 Study Design Follow-up - q 3 mo. x 30-42 mo. AP only (1,081 patients) AP + OAC (1,080 patients) 6 mo.9 mo. 42 mo. or Final Visit 3 mo. Day 35 PAD Patients 2-4 weeks AP + OAC (INR 1.8-3.5) Rand AP only Run-In AP + OAC Central Randomization, Open trial, Blinded adjudication, 80 Centres, 7 Countries

5. 5 Key Inclusion/Exclusion Criteria Men and women, 35-85 years plus >1 of –Intermittent claudication with objective evidence of PAD (e.g. ABI <0.9) –Previous vascular reconstruction (including amputation) or angioplasty of a peripheral artery –Significant carotid artery disease –Prior Vascular disease and ABI < 0.9 Inclusion: Exclusion: - Active bleeding or high-risk for bleeding - Clear indication for long-term OAC use - Clear indication for long-term (> 3 months) daily NSAIDs - Recent Stroke < 6 months

6. 6 Key Outcomes Co-Primary 1: CV death, MI, or stroke Co-Primary 2: CV death, MI, stroke, or severe ischemia of the coronary or peripheral arterial circulation Life-threatening bleeding: Fatal or intra-cranial, or requiring surgical intervention, or transfusion of at least 4 units of blood products Moderate bleeding: < 3 units of blood products Efficacy Safety

7. 7 Flow of Patients 2,417 eligible patients enter active run-in 256 stopped Run-in 115 patient decision 66 minor bleeding or unstable INR values 50 poor adherence 25 other reasons 2,161 patients randomized 1,080 allocated to oral anticoagulation therapy plus antiplatelet therapy 1,081 allocated to antiplatelet therapy alone Mean INR = 2.2 2 lost to follow-up 319 permanently discontinued oral anticoagulants 126 bleeding 129 patient / physician decision 64 other reasons 1,080 analyzed 21 permanently discontinued antiplatelet therapy 1 bleeding 20 other reasons 45 began oral anticoagulants 12 atrial fibrillation 10 venous thromboembolism 12 patient / physician decision 2 prosthetic heart valves 9 other reasons 1,081 analyzed 0 lost to follow-up Mean INR = 2.2

8. 8 Baseline Characteristics OAC/APAP N Randomized10801081 Age –years63.9 (9.4)63.8 (9.5) Sex-women (%)284 (26.3)286 (26.5) Current Smokers318 (29.4)315 (29.1) History Coronary artery disease n (%)483 (44.7)539 (49.9) History of Stroke n (%)166 (15.4)177 (16.4) Qualifying Condition PAD Limbs Other PAD 880 (81.5) 200 (18.5) 887 (82.1) 194 (17.9) Mean Blood Pressure (Sys/Dias) Ankle Brachial Index [median (IQR)]0.83 (0.7-1.0)0.84 (0.7 – 1.0) Antiplatelet therapy98.599.0

9. As of July 6, 2006 9 Primary Outcomes OAC/AP N=1080 (%) AP N=1081 (%) RR95%CIP- value P1:Cvd/MI/Stk132 (12.2)144 (13.3)0.920.73-1.160.49 P2: P1+SI172 (15.9)188 (17.4)0.910.74-1.120.38 CV Death66 (6.1)65 (6.0)1.040.74-1.460.84 MI54 (5.0)66 (6.1)0.820.57-1.180.28 Stroke38 (3.5) 1.010.65-1.590.96 Severe ischemia 62 (5.7)59 (5.5)1.060.74-1.510.76 Note: P1 =composite of CV death, MI, stroke; P2= CV death, MI, stroke, SI of limb or coronaries

10. 10 Figure 2a Co-Primary 1: CV Death, MI, Stroke OAC+AP AP

11. 11 Figure 2b Co-Primary 2: CV Death, MI, Stroke, Severe Ischemia OAC+AP AP

12. As of July 6, 2006 12 Safety Outcomes OAC/AP N=1080 (%) AP N=1081 (%) RR95%CIP-value Life-threat bleed 43 (4.0)13 (1.2)3.411.84-6.35 <0.001 Hem stroke14 (1.3)0 (0)15.22.0-115.6<0.001 Fatal Bleed10 (0.9)3 (0.3)3.340.92-12.10.0513 Moderate Bleeding 31 (2.9)11 (1.0)2.821.43-5.580.0018 LT or Mod Bleed 74 (6.9)24 (2.2)3.212.02-5.080.0001 Cvd/MI/stk (-bleeds) 117 (10.8)143 (13.2)0.820.64-1.050.11

13. 13 Life-Threatening Bleeding OAC+AP AP

14. 14 Life-Threatening or Moderate Bleeding OAC+AP AP

15. 15 Summary 1) Oral anticoagulants (targeting an INR range of 2 to 3) added to Antiplatelet therapy do not lower the rate of cardiovascular events, and increase life-threatening bleeding compared to Antiplatelet therapy alone in patients peripheral arterial disease. 2) Other antithrombins with a better safety profile or dual antiplatelet agents should be evaluated in this population

16. 16 Australia: Eikelboom, 1 centre, 16 patients; Canada: Anand, 26 centres, 880 patients; China: Liu, 18 centres, 347 patients; Hungary: Keltai, 8 centres, 85 patients; Netherlands: van Urk, 1 centre, 18 patients; Poland: Budaj, 15 centres, 566 patients; Ukraine: Parkhomenko, 11 centres, 249 patients. DSMB chair: Dagenais; Adjudication chair: Sussex. Project office: Anand, Yusuf, Chin, Joldersma, Xie, Antaya, Sloane, Nowacki, Parkinson Study Organization