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A Randomized Controlled Trial

Marta Ebbing, MD; Øyvind Bleie, MD, PhD; Per Magne Ueland, MD, PhD; Jan Erik Nordrehaug, MD, PhD; Dennis W. Nilsen, MD, PhD; Stein Emil Vollset, MD, DrPH; Helga Refsum, MD, PhD; Eva Kristine Ringdal Pedersen, MD; Ottar Nygård, MD, PhD

JAMA. 2008;300(7):795-804.

Context  Observational studies have reported associations between circulating total homocysteine concentration and risk of cardiovascular disease. Oral administration of folic acid and vitamin B₁₂ can lower plasma total homocysteine levels.

Objective  To assess the effect of treatment with folic acid and vitamin B₁₂ and the effect of treatment with vitamin B₆ 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 B₁₂, 0.4 mg, plus vitamin B₆, 40 mg (n = 772); folic acid plus vitamin B₁₂ (n = 772); vitamin B₆ 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 B₁₂. 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 B₁₂ 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 B₆ vs 222 (14.3%) not receiving vitamin B₆ (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 B₁₂ or vitamin B₆ 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

Author Affiliations: Department of Heart Disease, Haukeland University Hospital (Drs Ebbing, Bleie, Nordrehaug, and Nygård), Sections for Pharmacology (Dr Ueland) and Cardiology (Drs Nordrehaug, Nilsen, Ringdal Pedersen, and Nygård), Institute of Medicine, University of Bergen and Haukeland University Hospital, and Department of Public Health and Primary Health Care, University of Bergen (Dr Vollset), Bergen, Norway; Department of Cardiology, Stavanger University Hospital, Stavanger, Norway (Dr Nilsen); Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (Dr Refsum); and Department of Physiology, Anatomy, and Genetics, University of Oxford, Oxford, England (Dr Refsum).

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