Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine

Study Overview
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Brief Summary
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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
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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.

Official Title
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SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine

Conditions
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Cardiovascular Disease

Intervention / Treatment
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* Drug: Simvastatin 20 mg daily
* Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily
* Drug: Simvastatin 80 mg daily
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Simvastatin 20 mg + folic acid and B12<br>Participants received 20 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily | Drug: Simvastatin 20 mg daily<br>* Simvastatin 20 mg tablet once daily<br>Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily<br>* Folic acid 2 mg + vitamin B12 1 mg tablet once daily<br>|
| Active Comparator: Simvastatin 80 mg + folic acid and B12<br>Participants received 80 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily | Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily<br>* Folic acid 2 mg + vitamin B12 1 mg tablet once daily<br>Drug: Simvastatin 80 mg daily<br>* Simvastatin 80 mg tablet once daily<br>|
| Active Comparator: Simvastatin 20 mg + placebo<br>Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily | Drug: Simvastatin 20 mg daily<br>* Simvastatin 20 mg tablet once daily<br>Drug: Placebo<br>* Placebo vitamin B12/folic acid tablet once daily<br>|
| Active Comparator: Simvastatin 80 mg + placebo<br>Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily | Drug: Simvastatin 80 mg daily<br>* Simvastatin 80 mg tablet once daily<br>Drug: Placebo<br>* Placebo vitamin B12/folic acid tablet once daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Major Vascular Events (MVE) | Major vascular events (MVE) defined as major coronary events (MCE [non-fatal MI, coronary death or coronary revascularisation]), non-fatal or fatal stroke, or peripheral revascularization (peripheral artery angioplasty or arterial surgery, including amputations), during the scheduled study treatment period. | 6.7 years median follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| MVEs Separately in Year 1 and in Later Years |  | 6.7 years median follow-up | 
| MVEs in Patients Subdivided Into 3 Groups by Baseline Low-density Lipoprotein (LDL) |  | 6.7 years median follow-up | 
| MVEs in Presence and Absence of the Other Factorial Treatment |  | 6.7 years median follow-up | 
| Major Coronary Events | Non-fatal MI, coronary death or coronary revascularisation | 6.7 years median follow-up | 
| Total Strokes |  | 6.7 years median follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Myocardial infarction, Coronary heart disease, Cholesterol, Stroke