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

• ClinicalTrials.gov Identifier: NCT00124072
• Recruitment Status: Completed
• First Posted: July 26, 2005
• Results First Posted: June 9, 2010
• Last Update Posted: February 1, 2012
• Sponsor: University of Oxford
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by: University of Oxford

Study Description

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.

Condition or disease	Intervention/treatment	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

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 12064 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine
• Study Start Date: July 1998
• Actual Primary Completion Date: May 2008
• Actual Study Completion Date: May 2008

Arms and Interventions

Arm	Intervention/treatment
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

Outcome Measures

Primary Outcome Measures :

1. Major Vascular Events (MVE) [ Time Frame: 6.7 years median follow-up ]
   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.

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Locations

United Kingdom

CTSU, Richard Doll Building, University of Oxford

Oxford, Oxon, United Kingdom, OX3 7LF

Sponsors and Collaborators

University of Oxford

Merck Sharp & Dohme Corp.

Investigators

• Study Director: Rory Collins, MB BS FRCP; University of Oxford

More Information

Additional Information:

SEARCH study website (primarily for dissemination of the results) 

• Responsible Party: Professor Rory Collins, University of Oxford
• ClinicalTrials.gov Identifier: NCT00124072
• Other Study ID Numbers: CTSUSEARCH1
• First Posted: July 26, 2005
• Results First Posted: June 9, 2010
• Last Update Posted: February 1, 2012
• Last Verified: January 2012

Keywords provided by University of Oxford:

Myocardial infarction; Coronary heart disease; Cholesterol; Stroke

Additional relevant MeSH terms:

Cardiovascular Diseases; Folic Acid; Vitamin B 12; Hydroxocobalamin; Simvastatin; Vitamins; Micronutrients; Physiological Effects of Drugs; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors; Hematinics; Vitamin B Complex