Cardiovascular disease remains the commonest cause of mortality in people with diabetes. Previous attempts to reduce the burden of heart disease in people with diabetes have tended to concentrate on the reduction of conventional cardiovascular risk factors, and less attention has been paid to wider aspects of cardiovascular disease in this group of people. The Heart Outcomes Prevention Evaluation (HOPE) study was a large, randomized trial with wide entry criteria which examined the hypothesis that ACE inhibition using ramipril would reduce cardiovascular events in patients at high risk who would not previously be treated with ACE inhibitors. Diabetes was a pre-defined subgroup, and over three thousand patients with diabetes were recruited who had evidence of vascular disease, or had diabetes and one other cardiovascular risk factor (cholesterol > 5.2, hypertension, microalbuminuria, smoking). The study was discontinued prematurely because of a significant reduction in the composite primary end-point of myocardial infarction, stroke, and death from cardiovascular disease. In the diabetic patients the primary event rate of the combination of myocardial infarction, stroke and cardiovascular death was reduced by a quarter in patients on ramipril, and this reduction was seen both in patients with and without previous cardiovascular disease. The benefit was greater than could be accounted for by the minor decrease in blood pressure, suggesting wider effects on the cardiovascular system. Ramipril also reduced the development of overt nephropathy in diabetic subjects with microalbuminuria. Ramipril should be considered for diabetic patients with existing cardiovascular disease, or who have a high risk of disease because of the presence of cardiovascular risk factors. Copyright 2001 Harcourt Publishers Ltd Copyright 2001 Harcourt Publishers Ltd doi: 10.1054/chec.2001.0111, available online at http://www.idealibrary.com on

Background Diabetes mellitus is a strong risk factor for cardiovascular and renal disease. We investigated whether the angiotensin-converting-enzyme (ACE) inhibitor ramipril can lower these risks in patients with diabetes.Methods 3577 people with diabetes included in the Heart Outcomes Prevention Evaluation study, aged 55 years or older, who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure, or low ejection fraction, and who were not taking ACE inhibitors, were randomly assigned ramipril (10 mg/day) or placebo, and Vitamin E or placebo, according to a two-by-two factorial design. The combined primary outcome was myocardial infarction, stroke, or cardiovascular death. Overt nephropathy was a main outcome in a substudy.Findings The study was stopped 6 months early (after 4.5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25% (95% CI 12-36, p=0.0004), myocardial infarction by 22% (6-36), stroke by 33% (10-50), cardiovascular death by 37% (21-51), total mortality by 24% (8-37), revascularisation by 17% (2-30), and overt nephropathy by 24% (3-40, p=0.027). After adjustment for the changes in systolic (2.4 mm Hg) and diastolic (1.0 mm Hg) brood pressures, ramipril stilt lowered the risk of the combined primary outcome by 25% (12-36, p=0.0004).Interpretation Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. The cardiovascular benefit was greater than that attributable to the decrease in blood pressure. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.

OBJECTIVE: To describe the design of the HOPE (Heart Outcomes Prevention Evaluation) Study.DESIGN: Description of the key design features of HOPE, a large, simple randomized trial of two widely applicable treatments - ramipril, an angiotensin-converting enzyme inhibitor; and vitamin E, a naturally occurring antioxidant vitamin - in the prevention of myocardial infarction, stroke or cardiovascular death.SETTING: Two-hundred and sixty-seven hospitals, physician offices and clinics in Canada, the United States, Mexico, Europe and South America.PATIENTS: Over 9000 women and men aged 55 years and above at high risk for cardiovascular events such as myocardial infarction and stroke were recruited over 18 months.INTERVENTIONS: A 2x2 factorial design with ramipril and vitamin E with follow-up for up to four years.CONCLUSIONS: HOPE will be one of the largest trials of two new interventions to prevent myocardial infarction, stroke or cardiovascular death in high risk patients. The results of HOPE will have direct public health impact and are likely to be readily incorporated into clinical practice. Key design features of HOPE are inclusion of individuals at high risk of cardiovascular disease, inclusion of a substantial proportion of patients with diabetes (36%) and women (27%), and detailed substudies to provide data on mechanisms of benefit.