Clinical trial NCT00124072: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine
Official title: SEARCH: Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Cardiovascular Disease
Keywords: Myocardial infarction
Coronary heart disease
Cholesterol
Stroke
Lead sponsor: University of Oxford
Sponsor class: OTHER
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2005-07-26
Enrollment: 12064
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

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.

Eligibility 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

Primary outcomes:
measure: Major Vascular Events (MVE)
timeFrame: 6.7 years median follow-up
Secondary outcomes:
measure: MVEs Separately in Year 1 and in Later Years
timeFrame: 6.7 years median follow-up
measure: MVEs in Patients Subdivided Into 3 Groups by Baseline Low-density Lipoprotein (LDL)
timeFrame: 6.7 years median follow-up
measure: MVEs in Presence and Absence of the Other Factorial Treatment
timeFrame: 6.7 years median follow-up
measure: Major Coronary Events
timeFrame: 6.7 years median follow-up
measure: Total Strokes
timeFrame: 6.7 years median follow-up
Other outcomes:
Locations:
city: Oxford
country: United Kingdom
facility: CTSU, Richard Doll Building, University of Oxford
state: Oxon
Study officials:
affiliation: University of Oxford
name: Rory Collins, MB BS FRCP
role: STUDY_DIRECTOR
References: