Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH)
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Purpose
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.
| Condition | Intervention | Phase |
|---|---|---|
|
Cardiovascular Disease |
Drug: Simvastatin 20 mg daily Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily Drug: Simvastatin 80 mg daily Drug: Placebo |
Phase 3 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Factorial Assignment Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor) Primary Purpose: Prevention |
| Official Title: | SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine |
- Major Vascular Events (MVE) [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]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.
- MVEs Separately in Year 1 and in Later Years [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
- MVEs in Patients Subdivided Into 3 Groups by Baseline Low-density Lipoprotein (LDL) [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
- MVEs in Presence and Absence of the Other Factorial Treatment [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
- Major Coronary Events [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]Non-fatal MI, coronary death or coronary revascularisation
- Total Strokes [ Time Frame: 6.7 years median follow-up ] [ Designated as safety issue: No ]
| Enrollment: | 12064 |
| Study Start Date: | July 1998 |
| Study Completion Date: | May 2008 |
| Primary Completion Date: | May 2008 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: Simvastatin 20 mg + folic acid and B12
Participants received 20 mg simvastatin once daily, and 2 mg folic acid with 1 mg vitamin B12 once daily
|
Drug: Simvastatin 20 mg daily
Simvastatin 20 mg tablet once daily
Dietary Supplement: Folic acid 2 mg + vitamin B12 1 mg daily
Folic acid 2 mg + vitamin B12 1 mg tablet once daily
|
|
Active Comparator: Simvastatin 80 mg + folic acid and B12
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
Folic acid 2 mg + vitamin B12 1 mg tablet once daily
Drug: Simvastatin 80 mg daily
Simvastatin 80 mg tablet once daily
|
|
Active Comparator: Simvastatin 20 mg + placebo
Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily
|
Drug: Simvastatin 20 mg daily
Simvastatin 20 mg tablet once daily
Drug: Placebo
Placebo vitamin B12/folic acid tablet once daily
|
|
Active Comparator: Simvastatin 80 mg + placebo
Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily
|
Drug: Simvastatin 80 mg daily
Simvastatin 80 mg tablet once daily
Drug: Placebo
Placebo vitamin B12/folic acid tablet once daily
|
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.
Eligibility| Ages Eligible for Study: | 18 Years to 80 Years |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
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
Contacts and Locations| United Kingdom | |
| CTSU, Richard Doll Building, University of Oxford | |
| Oxford, Oxon, United Kingdom, OX3 7LF | |
| Study Director: | Rory Collins, MB BS FRCP | University of Oxford |
More Information
Additional Information:
No publications provided
| Responsible Party: | Professor Rory Collins, University of Oxford |
| ClinicalTrials.gov Identifier: | NCT00124072 History of Changes |
| Other Study ID Numbers: | CTSUSEARCH1 |
| Study First Received: | July 22, 2005 |
| Results First Received: | March 29, 2010 |
| Last Updated: | January 31, 2012 |
| Health Authority: | United Kingdom: Medicines and Healthcare Products Regulatory Agency |
Keywords provided by University of Oxford:
|
Myocardial infarction Coronary heart disease Cholesterol Stroke |
Additional relevant MeSH terms:
|
Cardiovascular Diseases Folic Acid Vitamin B Complex Vitamin B 12 Hydroxocobalamin Hematinics Vitamins Simvastatin Micronutrients Growth Substances Physiological Effects of Drugs |
Pharmacologic Actions Hematologic Agents Therapeutic Uses Hypolipidemic Agents Antimetabolites Molecular Mechanisms of Pharmacological Action Lipid Regulating Agents Hydroxymethylglutaryl-CoA Reductase Inhibitors Anticholesteremic Agents Enzyme Inhibitors |
ClinicalTrials.gov processed this record on May 16, 2013