Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial.

Randomized, placebo-controlled trial in female health professionals in the United States who were age 40 years or older, postmenopausal or not intending pregnancy, and had prior cardiovascular disease or at least 3 cardiac risk factors. For the active intervention arm, 2721 participants were randomized; baseline mean age was 62.8 years.

Women in the active intervention arm received a daily combination pill containing folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 1 mg for about 7 years, compared with placebo. The regimen was intended as cardiovascular prevention.

The folic acid and B vitamin combination did not reduce major cardiovascular events or total mortality in this high-risk women’s trial. In the active arm versus placebo, combined major cardiovascular disease occurred in 406 (14.9%) versus 390 (14.3%) participants (RR 1.03, 95% CI 0.90-1.19; P = .65), and total mortality was 250 (9.2%) versus 256 (9.4%) (RR 0.97, 95% CI 0.81-1.15; P = .73). Myocardial infarction, stroke, coronary revascularization, cardiovascular death, and the composite of myocardial infarction, stroke, and cardiovascular death were also not significantly different. Homocysteine was lowered in the blood substudy, but this did not translate into cardiovascular benefit.

The trial was conducted in women at high cardiovascular risk, so findings may not generalize beyond this population. The intervention lowered homocysteine, but no clinical cardiovascular benefit was seen, limiting support for this mechanistic rationale. Outcome differences were small and not statistically significant across multiple endpoints.