Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine

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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00124072

Acronym

Enrollment

12064

Registered

2005-07-26

Start date

1998-07-31

Completion date

2008-05-31

Last updated

2012-02-01

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Cardiovascular Disease

Keywords

Myocardial infarction, Coronary heart disease, Cholesterol, Stroke

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.

Interventions

DRUGSimvastatin 20 mg daily

Simvastatin 20 mg tablet once daily

DIETARY_SUPPLEMENTFolic acid 2 mg + vitamin B12 1 mg daily

Folic acid 2 mg + vitamin B12 1 mg tablet once daily

DRUGSimvastatin 80 mg daily

Simvastatin 80 mg tablet once daily

DRUGPlacebo

Placebo vitamin B12/folic acid tablet once daily

Study design

Allocation

RANDOMIZED

Intervention model

FACTORIAL

Primary purpose

PREVENTION

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 80 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Major Vascular Events (MVE)	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

Measure	Time frame	Description
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	6.7 years median follow-up	Non-fatal MI, coronary death or coronary revascularisation
Total Strokes	6.7 years median follow-up	—

Countries

United Kingdom

Participant flow

Recruitment details

First Patient In: 28-SEP-1998, Last Patient Last Visit: 22-May-2008 Eighty-eight (88) sites in 3 countries: England 72, Scotland 12 and Wales 4.

Pre-assignment details

Patients entered a run-in period during which they received simvastatin 20 mg daily and placebo-vitamin tablets for 2 months. Eligible patients who completed run-in were then randomized in a 2x2 factorial blinded design between simvastatin 80 mg daily versus simvastatin 20 mg daily and folic acid 2 mg + vitamin B12 1 mg daily versus placebo.

Participants by arm

Arm	Count
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	3,017
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	3,016
Simvastatin 20 mg + Placebo Participants received 20 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily	3,016
Simvastatin 80 mg + Placebo Participants received 80 mg simvastatin once daily, and placebo folic acid with placebo vitamin B12 once daily	3,015
Total	12,064

Withdrawals & dropouts

Period	Reason	FG000	FG001	FG002	FG003
Overall Study	Death	499	484	471	480
Overall Study	Lost to Follow-up for Morbidity	15	25	19	18
Overall Study	Lost to Follow-up for Mortality	0	3	2	2

Baseline characteristics

Characteristic	Simvastatin 20 mg + Folic Acid and B12	Simvastatin 80 mg + Folic Acid and B12	Simvastatin 20 mg + Placebo	Simvastatin 80 mg + Placebo	Total
Age Continuous	64.2 years STANDARD_DEVIATION 8.9	64.2 years STANDARD_DEVIATION 8.9	64.2 years STANDARD_DEVIATION 8.9	64.2 years STANDARD_DEVIATION 8.9	64.2 years STANDARD_DEVIATION 8.9
Region of Enrollment United Kingdom	3017 participants	3016 participants	3016 participants	3015 participants	12064 participants
Sex: Female, Male Female	513 Participants	514 Participants	513 Participants	512 Participants	2052 Participants
Sex: Female, Male Male	2504 Participants	2502 Participants	2503 Participants	2503 Participants	10012 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk	EG003 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —	— / —
other Total, other adverse events	479 / 6,033	493 / 6,031	480 / 6,033	492 / 6,031
serious Total, serious adverse events	5,037 / 6,033	5,024 / 6,031	5,068 / 6,033	4,993 / 6,031

Outcome results

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.