Further information: Atherosclerosis: Pathogenesis, Morphology, and Risk Factors (see p1593) and Hematologic Disease and Heart Disease (see p2409) from Cardiovascular Medicine, 3rd Edn*

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial was conducted to evaluate whether lowering blood levels of homocysteine with folic acid plus vitamin B12 had a protective effect in preventing cardiovascular disease and stroke [1]. Although earlier observational studies [2,3] have indicated that significantly lowering blood levels of homocysteine resulted in lower risk of coronary heart disease (CAD) and stroke, data that showed definite protective effects had not resulted from any of the large-scale randomized trials.

SEARCH was a double-blind randomized trial that enrolled 12,064 survivors of myocardial infarction (MI). The trial was conducted at 88 hospitals in the United Kingdom, and men and women between 18 to 80 years of age with a history of MI were enrolled between 1998 and 2008. Patients were randomized to receive either 2 mg of folic acid plus 1 mg of vitamin B12 or placebo. The primary outcome was a major vascular event, such as coronary death, MI, or coronary revascularization, stroke, or noncoronary revascularization.

During the follow-up period for patients randomized to folic acid plus vitamin B12, major vascular events occurred in 1537 of the 6033 participants (25.5%) vs. 1493 of 6031 (24.8%) of patients on placebo (risk ratio [RR], 1.04; 95% confidence interval [CI], 0.97–1.12; P=0.28). No apparent effects were shown for major coronary events (folic acid/vitamins, 1229 [20.4%], vs. placebo, 1185 [19.6%]; RR, 1.05; 95% CI, 0.97–1.13), stroke (folic acid/vitamins, 269 [4.5%], vs. placebo, 265 [4.4%; RR, 1.02; 95% CI, 0.86–1.21, or noncoronary revascularization (folic acid/vitamins, 178 [3.0%], vs placebo, 152 [2.5%]; RR, 1.18, 95%, CI, 0.95–1.46). No significant differences in numbers of deaths were due to vascular causes (folic acid/vitamins, 578 [9.6%], vs. placebo, 559 [9.3%]) or nonvascular causes (folic acid/vitamins, 405 [6.7%], vs. placebo, 392 [6.5%]).

SEARCH investigators concluded that folic acid/vitamin supplementation did not produce a benefit for major vascular events overall or in any of the subgroups, nor was benefit shown for incidence of stroke prevention.

[1] Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) Collaborative Group. Effect of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors. JAMA 2010;303:2486-94

[2] Clarke R, Daly L, Robinson K, et al. Hyperhomocysteinemia: an independent risk factor for vascular disease. N Eng J Med 1991;324:1149-55

[3] Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease: probable benefits of increasing folic acid intakes. JAMA 1995;274:1049-57

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