Clinical Trial Commentary HOPE SYMPHONY Dr Eric Topol Chairman and Professor, Department of Cardiology Director of the Joseph J Jacobs Center for Thrombosis and Vascular Biology at the Cleveland Clinic Dr Robert Califf Professor of Cardiology Associate Vice Chancellor for Clinical Research at Duke University

Heart Outcomes Prevention Evaluation (HOPE) ramipril vs placebo, n = 9541 Age > 55 CAD/CVA/PAD or DM + risk factors no CHF/EF 267 hospitals in 19 countries stopped 3/99 due to sig. death only 3.3 mmHg SBP vit. E no effect at 5 years (11.2 vs 11.1)

Heart Outcomes Prevention Evaluation (HOPE) Placebo Ramipril OR p (%) (%) Mortality 12.2 10.3 0.83 0.0035 CV Death 8.0 6.0 0.75 0.002 Stroke 4.9 3.3 0.68 0.001 MI 12.0 9.8 0.80 0.005 MI, Stroke CV Death 17.5 13.9 0.78 0.000002

Heart Outcomes Prevention Evaluation (HOPE) Placebo Ramipril OR p (%) (%) Revasc. 18.4 16.0 0.85 0.0013 PTCA/CABG 14.8 12.4 0.82 0.0005 CHF 9.4 7.4 0.78 0.005 New DM 5.5 3.8 0.89 < 0.01

Primary endpoint (death/MI/SRI) at 90 days SYMPHONY Primary endpoint (death/MI/SRI) at 90 days 2 4 6 8 10 20 30 40 50 60 70 80 90 Days from Treatment Start days from treatment start ASA/Placebo Sibrafiban LD Sibrafiban HD % of Pts, Death/MI/SRI % of pts, death/MI/SRI 10.14% 10.07% 9.86%

Bleeding complications ASA/Pl. LD Sib HD Sib N = 3074 N = 3080 N = 3015 Major: Investigator 1.2% 1.7% 2.7% Algorithm 3.9% 5.2% 5.7% Transfusion 4.7% 5.9% 6.5% Minor: Investigator 4.5% 9.6% 15.9% Algorithm 12.6% 17.7% 24.6%

Meta-analysis of oral IIb/IIIa trials Death Trial N Odds Ratio & 95% CI Placebo Fiban EXCITE 1.36 7,232 1.0% 1.35% Xemilofiban OPUS 10,302 1.40 1.4% 1.95% Orbofiban SYMPHONY 9,169 1.12 1.8% 2.00% Sibrafiban Pooled 26,703 1.27 p = 0.023 1.4% 1.80% 0.5 1 1.5 2 p = 0.616 Breslow-Day homogeneity Fiban Better Placebo Better