Clinical trial NCT00124072
Conditions: Cardiovascular Disease
Keywords: Myocardial infarction Coronary heart disease Cholesterol Stroke
Sponsor: University of Oxford
Start date: 1998-07-01; Completion date: 2008-05-01
Enrollment: 12064 participants; Allocation: RANDOMIZED; Intervention model: FACTORIAL

Brief summary:
SEARCH is a randomised, double-blind, multi-centre United Kingdom (UK) trial of 12,064 patients with myocardial infarction (MI) prior to study entry which aims to demonstrate whether a more intensive cholesterol lowering regimen using 80 mg simvastatin daily produces a larger and worthwhile reduction in cardiovascular events compared with a standard 20 mg daily regimen and whether reducing blood homocysteine levels with a daily dose of folic acid 2 mg + vitamin B12 1 mg compared with matching placebo produces a worthwhile reduction in vascular disease.

Detailed description:
In observational studies, lower blood cholesterol concentrations are associated with lower coronary risk, without any clear threshold below which lower levels are not associated with lower risk. Cholesterol reduction with statins reduces such risk but there is uncertainty about whether greater reductions with more intensive statin therapy will produce greater benefits. Elevated blood homocysteine levels appear to be an independent marker of cardiovascular risk, but it is unknown whether taking vitamins to reduce homocysteine concentrations will translate into cardiovascular benefit.

12,064 survivors of myocardial infarction have been randomised in a 2x2 factorial design to more intensive versus standard cholesterol-lowering treatment, using 80 mg or 20 mg daily simvastatin, and separately to homocysteine-lowering with folic acid plus vitamin B12 or matching placebo. Follow-up will continue until there are at least 2800 confirmed major vascular events (MVE), defined as non-fatal myocardial infarction, coronary death, stroke or arterial revascularisation. The primary outcome is the incidence of first MVE during the scheduled treatment period.

SEARCH should provide reliable evidence of the effectiveness and safety of more intensive cholesterol-lowering for the reduction of major vascular events in a high-risk population, and of the effects of homocysteine-lowering with folic acid plus vitamin B12.

Arms: arm 1: Participants received 20 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily arm 2: Participants received 80 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily arm 3: Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily arm 4: Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily
Interventions: intervention 1: Simvastatin 20 mg daily intervention 2: Folic acid 2 mg + vitamin B12 1 mg daily intervention 3: Simvastatin 80 mg daily intervention 4: Placebo
Intervention descriptions: intervention 1: Simvastatin 20 mg tablet once daily intervention 2: Folic acid 2 mg + vitamin B12 1 mg tablet once daily intervention 3: Simvastatin 80 mg tablet once daily intervention 4: Placebo vitamin B12/folic acid tablet once daily

Protocol documents: