1. HOPE: Heart Outcomes Prevention Evaluation study Purpose To evaluate whether the long-acting ACE inhibitor ramipril and/or vitamin E reduce the incidence of cardiovascular morbidity and mortality in a high-risk population References The HOPE Study Investigators. Effects of an angiotensin- converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:145 – 53. The HOPE Study Investigators. Vitamin E supplementation and cardiovascular events in high-risk patients. N Engl J Med 2000;342:154 – 60.

2. HOPE: Heart Outcomes Prevention Evaluation study - TRIAL DESIGN - Treatment Multicenter, multinational, randomized, double-blind, placebo- controlled parallel-group, two-by-two factorial study Patients 55 years or older with history of vascular disease or diabetes mellitus, plus one other cardiovascular risk factor; patients with stroke or MI in previous month, heart failure or evidence of low ejection fraction excluded Follow up and primary endpoint Mean 5.0 years follow up for ramipril (4.5 for vitamin E). Primary endpoint composite of MI, stroke or cardiovascular death

3. HOPE: Heart Outcomes Prevention Evaluation study - TRIAL DESIGN continued - Pre-randomization therapy Ramipril 2.5 mg once daily (7 – 10 days), then placebo (10 – 14 days). Patients with side effects, abnormal serum creatinine/potassium, or noncompliance subsequently excluded Treatment 9297 patients (2480 women, 6817 men) randomly assigned to receive one of four treatments for 5 years: Ramipril 2.5 mg for 1 week, 5 mg for 3 weeks, then 10 mg + vitamin E 400 IU daily Ramipril 2.5 mg for 1 week, 5 mg for 3 weeks, then 10 mg + placebo matching vitamin E treatment Placebo matching ramipril treatment + vitamin E 400 IU daily Placebo matching ramipril treatment + placebo matching vitamin E treatment

4. HOPE: Heart Outcomes Prevention Evaluation study - RESULTS - Ramipril vs. placebo Study halted 6 months early on recommendation of monitoring board because of consistent benefit of ramipril: —Composite primary endpoint of MI, stroke or death from cardiovascular causes significantly lower in ramipril group (14.0 vs. 17.8%, relative risk 0.78, P<0.001) —Individual primary endpoints (MI, stroke, death from cardiovascular causes), all-cause mortality, and secondary outcomes of revascularization and complications related to diabetes, significantly lower in ramipril group New diagnosis of diabetes significantly lower in ramipril group (3.6 vs. 5.4%, relative risk 0.66, P<0.001) Drug well tolerated as defined by permanent discontinuation of treatment (28.9% of ramipril group versus 27.3% placebo)

5. HOPE: Heart Outcomes Prevention Evaluation study - RESULTS continued - Vitamin E vs. placebo No benefit shown for vitamin E vs. placebo: No significant difference in composite primary endpoint of MI, stroke or cardiovascular death in ramipril group (16.0 vs. 15.5%, relative risk 1.05, P=0.33) No significant difference in individual primary endpoints or secondary cardiovascular outcomes or death from any cause No significant adverse effects of vitamin E

6. HOPE: Heart Outcomes Prevention Evaluation study - RESULTS continued - MI, stroke or death from cardiovascular causes Days of follow up P <0.001 0 0.00 50010001500 0.05 0.10 0.15 0.20 The Hope Study Investigators.N Engl J Med 2000;342:145–53. Proportion of patients Placebo Ramipril

7. HOPE: Heart Outcomes Prevention Evaluation study - RESULTS continued - P Primary outcome and deaths from any cause The Hope Study Investigators.N Engl J Med 2000;342:145–53. Relative risk (95% CI) MI, stroke, or death from cardiovascular causes Death from cardiovascular causes MI Stroke Death from noncardiovascular causes Death from any cause Ramipril n=4645 (%) 14.0 6.1 9.9 3.4 4.3 10.4 Placebo n=4652 (%) 17.8 8.1 12.3 4.9 4.1 12.2 0.78 (0.70–0.86) 0.74 (0.64–0.87) 0.80 (0.70–0.90) 0.68 (0.56–0.84) 1.03 (0.85–1.26) 0.84 (0.75–0.95) <0.001 0.74 0.005

8. HOPE: Heart Outcomes Prevention Evaluation study - RESULTS continued - P Secondary outcomes and new diagnosis of diabetes Relative risk Secondary outcomes Revascularization Hospitalization for unstable angina Complications related to diabetes Hospitalization for heart failure New diagnosis of diabetes Placebo n=4652 (%) 18.3 12.1 7.6 3.4 5.4 0.85 (0.77–0.94) 0.98 (0.87–1.10) 0.84 (0.72–0.98) 0.88 (0.70–1.10) 0.66 (0.51–0.85) 0.002 0.68 0.03 0.25 <0.001 The Hope Study Investigators.N Engl J Med 2000;342:145–53. Ramipril (%) 16.0 11.9 6.4 3.0 3.6 n= 4645

9. HOPE: Heart Outcomes Prevention Evaluation study - SUMMARY - In high-risk patients not known to have low ejection fraction or heart failure: Ramipril Reduced rates of death, MI, stroke and revascularization Reduced rates of new diagnosis of diabetes and complications due to diabetes Vitamin E Had no effect on outcomes