Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine

Cardiovascular Disease Clinical Trial

— SEARCH  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00124072
• Other study ID #: CTSUSEARCH1
• Status: Completed
• Phase: Phase 3
• First received: July 22, 2005
• Last updated: January 31, 2012
• Start date: July 1998
• Est. completion date: May 2008

Study information

• Verified date: January 2012
• Source: University of Oxford
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 12064
• Est. completion date: May 2008
• Est. primary completion date: May 2008
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Related Conditions & MeSH terms

• Cardiovascular Disease
• Cardiovascular Diseases

Intervention

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

Drug:
• Simvastatin 80 mg daily
Simvastatin 80 mg tablet once daily
• Placebo
Placebo vitamin B12/folic acid tablet once daily

Locations

Country	Name	City	State
United Kingdom	CTSU, Richard Doll Building, University of Oxford	Oxford	Oxon

Sponsors (2)

Lead Sponsor	Collaborator
University of Oxford	Merck Sharp & Dohme Corp.

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	MVEs Separately in Year 1 and in Later Years		6.7 years median follow-up	No
Secondary	MVEs in Patients Subdivided Into 3 Groups by Baseline Low-density Lipoprotein (LDL)		6.7 years median follow-up	No
Secondary	MVEs in Presence and Absence of the Other Factorial Treatment		6.7 years median follow-up	No
Secondary	Major Coronary Events	Non-fatal MI, coronary death or coronary revascularisation	6.7 years median follow-up	No
Secondary	Total Strokes		6.7 years median follow-up	No