Vitamin supplementation with B₁₂, B₆, and folic acid does not reduce cardiovascular events, according to the results of 2 large randomized studies reported in the March 12 Early Release issue of The New England Journal of Medicine. One study suggests a trend toward harm from this combination. The editorialist suggests that other means to reduce homocysteine may still be beneficial, but that we should no longer recommend vitamin therapy.

"In observational studies, lower homocysteine levels are associated with lower rates of coronary heart disease and stroke," write Eva Lonn, MD, from McMaster University in Hamilton, Ontario, and colleagues from The Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. "Folic acid and vitamins B₆ and B₁₂ lower homocysteine levels."

In this study, 5522 patients aged 55 years or older with vascular disease or diabetes were randomized to daily treatment either with the combination of 2.5 mg of folic acid, 50 mg of vitamin B₆, and 1 mg of vitamin B₁₂ or with placebo for an average of 5 years. The main endpoint was a composite of death from cardiovascular causes, myocardial infarction, and stroke.

Mean plasma homocysteine levels decreased by 2.4 μmol/L (0.3 mg/L) in the active-treatment group and increased by 0.8 μmol/L (0.1 mg/L) in the placebo group. Cardiovascular death, myocardial infarction, or stroke occurred in 519 patients (18.8%) in the active therapy group and in 547 (19.8%) in the placebo group (relative risk [RR], 0.95; 95% confidence interval [CI], 0.84 - 1.07; P = .41). Compared with placebo, active treatment was not associated with significant reductions in the risk for death from cardiovascular causes (RR, 0.96; 95% CI, 0.81 - 1.13), myocardial infarction (RR, 0.98; 95% CI, 0.85 - 1.14), or in any of the secondary endpoints.

Compared with the placebo group, fewer patients in the active treatment group had a stroke (RR, 0.75; 95% CI, 0.59 - 0.97), but more patients in the active treatment group were hospitalized for unstable angina (RR, 1.24; 95% CI, 1.04 - 1.49).

"Supplements combining folic acid and vitamins B₆ and B₁₂ did not reduce the risk of major cardiovascular events in patients with vascular disease," the authors write. "Our results do not support the use of folic acid and B vitamin supplements as a preventive treatment."

Study limitations include inability to definitively rule out the possibility that B vitamin supplements have a small beneficial effect on coronary heart disease; number of strokes much lower than the number of coronary events, with wide CIs around the estimated risk reduction for stroke; lack of adjustment for multiplicity of outcomes; and exposure to folate-fortified food in more than 70% of study patients.

The authors have disclosed no relevant financial relationships. The Canadian Institutes of Health Research and Jamieson Laboratories supported this study.

The Norwegian Vitamin (NORVIT) Trial, led by Kaare Harald Bønaa, MD, PhD, from the University of Tromsø in Norway, evaluated the efficacy of homocysteine-lowering treatment with B vitamins for secondary prevention in 3749 men and women who had experienced an acute myocardial infarction within 7 days before randomization. In a 2-by-2 factorial design, patients were randomized to receive 0.8 mg of folic acid, 0.4 mg of vitamin B₁₂, and 40 mg of vitamin B₆; 0.8 mg of folic acid and 0.4 mg of vitamin B₁₂; 40 mg of vitamin B₆; or placebo daily. The main outcome was a composite of recurrent myocardial infarction, stroke, and sudden death attributed to coronary artery disease. Median follow-up was 40 months.

In patients given folic acid plus vitamin B₁₂, the mean total homocysteine level decreased by 27%, but no significant effect occurred on the primary endpoint (RR, 1.08; 95% CI, 0.93 - 1.25; P = .31). Treatment with vitamin B₆ was not associated with any significant benefit regarding the primary endpoint (RR, 1.14; 95% CI, 0.98 - 1.32; P = .09). The group given folic acid, vitamin B₁₂, and vitamin B₆ showed a trend toward increased risk (RR, 1.22; 95% CI, 1.00 - 1.50; P = .05).

"Treatment with B vitamins did not lower the risk of recurrent cardiovascular disease after acute myocardial infarction," the authors write. "A harmful effect from combined B vitamin treatment was suggested. Such treatment should therefore not be recommended."

Study limitations include power slightly less than planned.

The Norwegian Research Council, the Council on Health and Rehabilitation, the University of Tromsø, the Norwegian Council on Cardiovascular Disease, the Northern Norway Regional Health Authority, the Norwegian Red Cross, the Foundation to Promote Research into Functional Vitamin B₁₂ Deficiency, and an unrestricted private donation supported this study. One of the authors has disclosed various relevant financial relationships with Nycomed, the nonprofit Foundation to Promote Research into Functional Vitamin B₁₂ Deficiency; and Bevital, a company owned by the foundation. Alpharma provided the study medication free of charge.

In an accompanying editorial, Joseph Loscalzo, MD, PhD, from the Brigham and Women's Hospital and Harvard Medical School in Boston, Mass, compares these findings with those of other trials.

"The consistency among the results leads to the unequivocal conclusion that there is no clinical benefit of the use of folic acid and vitamin B₁₂ (with or without the addition of vitamin B₆) in patients with established vascular disease," Dr Loscalzo writes. "The straightforward but incorrect view that folic acid can decrease homocysteine levels and, thus, reduce the risk of atherosclerosis effectively may be an unintended consequence of oversimplifying a complicated metabolic network.... We should consider alternative approaches to reducing homocysteine concentrations, perhaps with new methods of enhancing the conversion of homocysteine to cysteine in the liver or enhancing the urinary excretion of the amino acid."