Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH)

University of Oxford

Status and phase: Completed; Phase 3

Conditions: Cardiovascular Disease

Treatments: Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily; Drug: Simvastatin 80 mg daily; Drug: Placebo; Drug: Simvastatin 20 mg daily

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT00124072

CTSUSEARCH1

Details and patient eligibility

About

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.

Full 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.

Enrollment: 12,064 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Prior myocardial infarction
• Statin therapy indicated
• No clear indication for folic acid

Exclusion criteria

• No clear contraindication to study treatments
• Screening plasma total cholesterol <3.5 mmol/l in patient already on statin therapy, or <4.5 mmol/l in patient not on statin therapy
• Chronic liver disease
• Severe renal disease or evidence of renal impairment
• Inflammatory muscle disease
• Concurrent treatment with fibrates or high-dose niacin
• Concurrent treatment with cyclosporin (or condition likely to result in organ transplantation and the need for cyclosporin), nefazodone, methotrexate, systemic azole antifungal or systemic macrolide antibiotics
• Child bearing potential
• No other predominant medical problem (other than coronary heart disease [CHD]) which might limit compliance with 5 years of study treatment

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Quadruple Blind

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12,064 participants in 4 patient groups

Simvastatin 20 mg + folic acid and B12

Active Comparator group

Description:

Participants received 20 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily

Treatment:

Drug: Simvastatin 20 mg daily

Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily

Simvastatin 80 mg + folic acid and B12

Active Comparator group

Description:

Participants received 80 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily

Treatment:

Drug: Simvastatin 80 mg daily

Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily

Simvastatin 20 mg + placebo

Active Comparator group

Description:

Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily

Treatment:

Drug: Simvastatin 20 mg daily

Drug: Placebo

Simvastatin 80 mg + placebo

Active Comparator group

Description:

Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily

Treatment:

Drug: Placebo

Drug: Simvastatin 80 mg daily