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.
BACKGROUND
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.


METHODS
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.


METHODS
Daily intake of a combination pill of 2.5 mg of folic acid, 50 mg of vitamin B6, and 1 mg of vitamin B12.


METHODS
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).


CONCLUSIONS
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.


BACKGROUND
clinicaltrials.gov Identifier: NCT00000541.
Albert
Christine M
CM
Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Ave E, Boston, Massachusetts 02215-1204, USA. calbert@partners.org
Cook
Nancy R
NR
Gaziano
J Michael
JM
Zaharris
Elaine
E
MacFadyen
Jean
J
Danielson
Eleanor
E
Buring
Julie E
JE
Manson
JoAnn E
JE
D000328:Adult; D000368:Aged; D002318:Cardiovascular Diseases / Q000401:mortality / Q000517:prevention & control*; D019587:Dietary Supplements; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D005492:Folic Acid / Q000097:blood / Q000627:therapeutic use*; D006710:Homocysteine / Q000097:blood; D006801:Humans; D008875:Middle Aged; D012306:Risk; D014805:Vitamin B 12 / Q000627:therapeutic use*; D025101:Vitamin B 6 / Q000627:therapeutic use*; D014803:Vitamin B Complex / Q000627:therapeutic use*
D004338:Drug Combinations; D006710:Homocysteine; D014803:Vitamin B Complex; D025101:Vitamin B 6; D005492:Folic Acid; D014805:Vitamin B 12