Mortality and cardiovascular events in patients treated with homocysteine-lowering B vitamins after coronary angiography -: A Randomized controlled trial

Context Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B-12 can lower plasma total homocysteine levels. Objective To assess the effect of treatment with folic acid and vitamin B-12 and the effect of treatment with vitamin B-6 as secondary prevention in patients with coronary artery disease or aortic valve stenosis. Design, Setting, and Participants Randomized, double-blind controlled trial conducted in the 2 university hospitals in western Norway in 1999-2006. A total of 3096 adult participants undergoing coronary angiography (20.5% female; mean age, 61.7 years) were randomized. At baseline, 59.3 % had double- or triple-vessel disease, 83.7% had stable angina pectoris, and 14.9% had acute coronary syndromes. Interventions Using a 2 x 2 factorial design, participants were randomly assigned to 1 of 4 groups receiving daily oral treatment with folic acid, 0.8 mg, plus vitamin B-12, 0.4 mg, plus vitamin B-6, 40 mg (n = 772); folic acid plus vitamin B-12 (n = 772); vitamin B-6 alone (n = 772); or placebo (n = 780). Main Outcome Measures The primary end point was a composite of all-cause death, nonfatal acute myocardial infarction, acute hospitalization for unstable angina pectoris, and nonfatal thromboembolic stroke. Results Mean plasma total homocysteine concentration was reduced by 30% after 1 year of treatment in the groups receiving folic acid and vitamin B-12. The trial was terminated early because of concern among participants due to preliminary results from a contemporaneous Norwegian trial suggesting adverse effects from the intervention. During a median 38 months of follow-up, the primary end point was experienced by a total of 422 participants (13.7%): 219 participants (14.2%) receiving folic acid/vitamin B-12 vs 203 (13.1 %) not receiving such treatment (hazard ratio, 1.09; 95% confidence interval, 0.90-1.32; P=.36) and 200 participants (13.0%) receiving vitamin B-6 vs 222 (14.3%) not receiving vitamin B-6 (hazard ratio, 0.90; 95% confidence interval, 0.74-1.09; P=.28). Conclusions This trial did not find an effect of treatment with folic acid/vitamin B-12 or vitamin B-6 on total mortality or cardiovascular events. Our findings do not support the use of B vitamins as secondary prevention in patients with coronary artery disease. Trial Registration clinicaltrials.gov Identifier: NCT00354081.