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A Randomized Trial

Christine M. Albert, MD, MPH; Nancy R. Cook, ScD; J. Michael Gaziano, MD, MPH; Elaine Zaharris, BA; Jean MacFadyen, BA; Eleanor Danielson, MIA; Julie E. Buring, ScD; JoAnn E. Manson, MD, DrPH

JAMA. 2008;299(17):2027-2036.

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 µmol/L (95% CI, 1.54-2.96 µmol/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

Author Affiliations: Divisions of Preventive Medicine (Drs Albert, Cook, Gaziano, Buring, and Manson and Mss Zaharris, MacFadyen, and Danielson), Cardiovascular Medicine (Drs Albert and Gaziano), and Aging (Drs Gaziano and Buring), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Veterans Affairs Boston Healthcare System, Boston, Massachusetts (Dr Gaziano); Department of Ambulatory Care and Prevention, Harvard Medical School (Dr Buring); and Department of Epidemiology, Harvard School of Public Health, Boston (Drs Cook, Buring, and Manson).

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