BACKGROUND: Epidemiological studies suggest that mild to moderate elevation in plasma homocysteine concentration is associated with increased risk of atherothrombotic cardiovascular (CV) disease. Simple, inexpensive and nontoxic therapy with folic acid and vitamins B-6 and B-12 reduces plasma homocysteine levels by approximately 25% to 30% and may reduce CV events. Therefore, a large, randomized clinical trial - the Heart Outcomes Prevention Evaluation (HOPE)-2 study - is being conducted to evaluate this therapy in patients at high risk for CV events.OBJECTIVES: To evaluate whether long-term therapy with folic acid and vitamins B-6 and B-12 reduces the risk of major CV events in a high-risk population. The primary study outcome is the composite of death from CV causes, myocardial infarction and stroke.METHODS: A total of 5522 patients aged 55 years or older with preexisting CV disease or with diabetes and additional risk factor(s) at 145 centres in 13 countries were randomly assigned to daily therapy with combined folic acid 2.5 mg, vitamin B-6 50 mg and vitamin B-12 1 mg, or to placebo. Follow-up will average five years, to be completed by the end of 2005.RESULTS: The patients' baseline characteristics confirmed their high-risk status. Baseline homocysteine levels varied between countries and regions. HOPE-2 is one of the largest trials of folate and vitamins B-6 and B-12 and is expected to significantly contribute to the evaluation of the role of homocysteine lowering in CV prevention.

BACKGROUND:Other than aspirin, there are few oral antithrombotic treatments with proven efficacy in patients with acute coronary syndrome. In this report, we present the rationale, design and baseline characteristics of the Clopidogrel in Unstable angina to prevent Recurrent ischaemic Events (CURE) trial, which includes a meta-analysis of the effects of thienopyridines in patients with vascular disease.METHODS AND RESULTS:Combined data from randomized trials of thienopyrindines in patients with atherosclerotic disease demonstrated a 29% reduction in vascular events when compared with placebo/control (n=2392) (OR 0.71, 95% CI 0.58-0.86, P=0.0006) and a 10% reduction in vascular events when compared with aspirin (n=22 254) (OR 0.91, 95% Cl 0.84-0.99, P=0.039). Similarly, randomized trials of aspirin plus thienopyridines in patients undergoing intracoronary stenting, demonstrated a marked benefit of aspirin plus ticlopidine in reducing death or myocardial infarction compared with aspirin alone (OR 0.23, 95% CI 0.11-0.49, P=0.0001) or aspirin plus warfarin (OR 0.51, 95% CI 0.33-0.78, P=0.002). Whether these benefits extend to the much larger population of patients with acute coronary syndrome is unknown. CURE is an international, randomized, double-blind trial, in which patients with acute coronary syndrome will be randomized to receive either a bolus dose of clopidogrel (300 mg) followed by 75 mg per day for 3-12 months, or matching placebo. Both groups will receive aspirin. The co-primary efficacy end-points of CURE are: (1) the composite of cardiovascular death, myocardial infarction or stroke; and (2) the composite of cardiovascular death, myocardial infarction, stroke or refractory ischaemia. CURE will recruit approximately 12 500 patients with acute coronary syndrome (from 28 countries) and its power to detect moderate treatment benefits will be in the region of 80-90%, while maintaining an overall type I error (alpha) of 0.05. The baseline characteristics of the study population are consistent with at least a moderate risk group of patients with acute coronary syndrome.CONCLUSIONS:Randomized trials of thienopyridines in patients with vascular disease demonstrate that thienopyridines are effective in reducing vascular events when compared with placebo/control or aspirin, as well as when used in combination with aspirin in patients undergoing intracoronary stent implantation. The CURE trial is a large international study to determine if acute and long-term treatment with the combination of clopidogrel and aspirin is superior to aspirin alone in patients with acute coronary syndrome.

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.

Cardiovascular diseases remain the most important cause of morbidity and mortality in Canadians. Over the past 30 years, major advances have been made in the treatment and prevention of cardiovascular disease, many of which have been discovered through the conduct of large randomized clinical trials. Canadian investigators have a long-standing tradition of conducting and participating in clinical trials in the cardiovascular field. At the 1992 Canadian Cardiovascular Society meeting in Ottawa, Ontario a group of individuals from the cardiovascular community met to lay the foundations of the Canadian Cardiovascular Collaboration (CCC). The CCC was formed as a loose collaboration of like minded individuals with the common goal of identifying and addressing questions of major public health importance. In this paper the past and present status of Canadian participation in major cardiovascular clinical trials are reviewed, and the mission statement and fundamental principles of the CCC are outlined.