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.

JAMA

May 2008

DOI: 10.1001/jama.299.17.2027

Citations:509

Influential Citations:14

Interventional (Human) Studies

Enhanced Details

Methods

Randomized, double-blind, placebo-controlled trial (WAFACS) in high-risk women with either prior cardiovascular disease or at least three risk factors; mean age 62.8 years; 64.2% had history of CVD; female health professionals in the United States; 2721 participants per arm.

Intervention

Combination pill containing folic acid 2.5 mg daily, vitamin B6 50 mg daily, and vitamin B12 1 mg daily; taken daily for 7.3 years.

Results

No reduction in major cardiovascular events with folic acid/B6/B12 over 7.3 years. Primary endpoint occurred in 406 of 2721 active participants (14.9%) vs 390 of 2721 placebo (14.3%); relative risk 1.03 (95% CI 0.90–1.19; P=0.65). No significant differences for MI, stroke, CVD mortality, or all-cause mortality. Conclusion: The regimen does not improve cardiovascular outcomes in high-risk fortified populations and is not recommended for CVD prevention in such settings; no evident harm observed.

Limitations

Not powered to detect moderate effects in primary prevention; population largely folate-replete due to fortification; homocysteine data available for only ~5% of participants; potential unexamined interactions; follow-up completeness may affect generalizability.

Abstract

CONTEXT Recent randomized trials among patients with preexisting cardiovascular disease (CVD) have failed to support benefits of B-vitamin supplementation on cardiovascular risk. Observational data suggest benefits may be greater among women, yet women have been underrepresented in published randomized trials. OBJECTIVE To test whether a combination of folic acid, vitamin B6, and vitamin B12 lowers risk of CVD among high-risk women with and without CVD. DESIGN, SETTING, AND PARTICIPANTS Within an ongoing randomized trial of antioxidant vitamins, 5442 women who were US health professionals aged 42 years or older, with either a history of CVD or 3 or more coronary risk factors, were enrolled in a randomized, double-blind, placebo-controlled trial to receive a combination pill containing folic acid, vitamin B6, and vitamin B12 or a matching placebo, and were treated for 7.3 years from April 1998 through July 2005. INTERVENTION Daily intake of a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12. MAIN OUTCOME MEASURES A composite outcome of myocardial infarction, stroke, coronary revascularization, or CVD mortality. RESULTS Compared with placebo, a total of 796 women experienced a confirmed CVD event (406 in the active group and 390 in the placebo group). Patients receiving active vitamin treatment had similar risk for the composite CVD primary end point (226.9/10,000 person-years vs 219.2/10,000 person-years for the active vs placebo group; relative risk [RR], 1.03; 95% confidence interval [CI], 0.90-1.19; P = .65), as well as for the secondary outcomes including myocardial infarction (34.5/10,000 person-years vs 39.5/10,000 person-years; RR, 0.87; 95% CI, 0.63-1.22; P = .42), stroke (41.9/10,000 person-years vs 36.8/10,000 person-years; RR, 1.14; 95% CI, 0.82-1.57; P = .44), and CVD mortality (50.3/10,000 person-years vs 49.6/10,000 person-years; RR, 1.01; 95% CI, 0.76-1.35; P = .93). In a blood substudy, geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5%-24.1%; P < .001) in the active group (n = 150) over that observed in the placebo group (n = 150), for a difference of 2.27 micromol/L (95% CI, 1.54-2.96 micromol/L). CONCLUSION After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6, and vitamin B12 did not reduce a combined end point of total cardiovascular events among high-risk women, despite significant homocysteine lowering. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000541. show less