Folic acid plus B vitamins do not lower cardiovascular disease risk

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Supplementation with folic acid and vitamins B-12 and B-6 does not reduce the risk of major cardiovascular events in patients with cardiovascular disease (CVD), and may even be deleterious, according to two reports in the New England Journal of Medicine for April 13.

Because a high level of homocysteine is a risk factor for CVD, the researchers theorized that lowering homocysteine levels by treatment with folate and B vitamins would reduce the risk.

The Heart Outcomes Prevention Evaluation (HOPE)-2 investigators, led by Dr. Eva Lonn at McMaster University in Hamilton, Ontario, enrolled patients age 55 and older who had a history of vascular disease or diabetes and other risk factors for atherosclerosis. The 5522 patients were recruited at 145 centers in 13 countries and followed prospectively.

Subjects were randomly assigned a daily tablet containing 2.5 mg folic acid, 50 mg vitamin B-6 and 1 mg vitamin B-12 or matching placebo.

Baseline homocysteine levels were similar in the two groups (12.2 µmol/L). After a mean of 5 years of follow-up, levels had declined to 9.7 µmol/L in the active treatment group, but had increased to 12.9 µmol/L in the placebo group.

Despite the changes in homocysteine levels, the authors observed no significant differences in the primary endpoint of the composite of death from cardiovascular causes, MI, and stroke (18.8% in the supplement group and 19.8% in the placebo group). There were also no significant differences in hospitalization for heart failure or revascularization, total ischemic events, or venous thromboembolism.

Even among subjects with the highest baseline levels of homocysteine, outcomes were similar between the two groups.

The only significant differences were a slightly decreased risk of stroke in the active treatment group (4.0% versus 5.3%, p = 0.03) and an increased hazard of hospitalization for unstable angina (9.7% versus 7.9%, p = 0.02). The investigators note that the confidence intervals were wide and the results were not adjusted for confounders.

"Homocysteine could be a marker, but not a cause of vascular disease," the investigators suggest, "and the epidemiologic data could be the result of residual confounding that cannot be fully adjusted for, of reverse causality, or of both."

Dr. Lonn and her associates conclude that "our results do not support the use of folic acid and B vitamin supplements as a preventive treatment."

In the second report, Dr. Kaare Harald Bonaa, from the University of Tromso, and members of the Norwegian Vitamin (NORVIT) trial group conducted a similar prospective study that included 3749 patients ages 30 to 85 years who had had an acute MI.

Participants were randomly assigned to one of four groups. They were given 0.8 mg folic acid plus 0.4 mg vitamin B-12 and 40 mg vitamin B6 (combination therapy), 0.8 mg folic acid and 0.4 mg vitamin B-12, 40 mg of vitamin B6 or placebo.

Supplements were taken once daily, and outcomes were assessed after a mean of 36 months. In the two groups treated with folate and vitamin B-12, total homocysteine levels declined by 27%, while B-6 alone and placebo had no effect.

In the combination therapy group, the odds of stroke, MI, or cardiovascular death was increased 22% compared with placebo. Vitamin B-6 was associated with a 17% increase in the risk of MI, and combination therapy increased the risk of nonfatal MI by 30% (p = 0.05 for all three).

Although Dr. Bonaa's group recognizes that lack of adjustment for confounders may mean that the increased risks observed were due to chance alone, they still maintain that "such therapy may even be harmful after acute MI or coronary stenting and should therefore not be recommended."

In a related editorial, Dr. Joseph Loscalzo, from Harvard Medical School in Boston, reviews the mechanism underlying the homocysteine and the methylation cycle, and suggests that "the use of folic acid and vitamin B-12 in the setting of mild hyperhomocysteinemia may alter the methylation potential in vascular cells, resulting in a change in the cell phenotype that promotes the development of plaque."

N Engl J Med 2006;1567-1588,1629-1631.