Folic Acid and Cardiovascular Disease: No Support for Risk Reduction

NEW ORLEANS, Dec. 14 -- For secondary prevention of vascular disease, skip the folic acid supplements, according to a meta-analysis.

The study of 12 randomized controlled trials including 16,958 patients with preexisting vascular disease found no significant improvement in any mortality or cardiovascular outcomes for patients with preexisting vascular disease, reported Lydia A. Bazzano, M.D., Ph.D., of Tulane University here, and colleagues, in the Dec. 13 issue of the Journal of the American Medical Association.

The overall relative risk of death from any cause was 0.96 (95% confidence interval 0.88 to 1.04) for patients treated with folic acid supplements compared with controls.

Likewise, the risk of cardiovascular disease outcomes was unchanged at 0.95 (95% CI 0.88 to 1.03) as were coronary heart disease (1.04, 95% CI 0.92 to 1.17) and stroke (0.86, 0.71 to 1.04).

Folic acid has been of interest because it, along with the other B vitamins, reduces levels of the amino acid homocysteine, which has been associated with increased cardiovascular risk in some observational studies. Findings from previous clinical trials have been generally underpowered and inconsistent, though, as reported last month, a large, well-designed study among women found no benefit. (http://www.medpagetoday.com/MeetingCoverage/AHAMeeting/tb/4513)

Although folic acid supplementation is ineffective for secondary prevention, it is apparently harmless, the researchers said. Nevertheless, they suggested that physicians turn to other strategies that are known to be effective.

"It is important to focus on strategies of proven benefit in the secondary prevention of cardiovascular disease," they wrote, "including smoking cessation, lipid reduction, treatment of hypertension and diabetes, maintenance of a healthy weight, and physical activity."

The investigators searched MEDLINE for randomized controlled trials comparing folic acid supplementation (with or without other vitamin B supplementation) with placebo or usual care for a minimum of six months and including an end point of clinical cardiovascular disease events.

All trials were conducted among patients with preexisting cardiovascular or renal disease. Most were conducted in Europe (eight) with another two in the United States, one in Australia and New Zealand, and one in Canada. The dose of folic acid administered to participants ranged from 0.5 mg/d to 15 mg/d, and duration of treatment and follow-up ranged from six months to five years.

The total proportion of events by outcome was:

• For cardiovascular disease, 18.3% among the 7,755 participants treated with folic acid and 19.2% among the 6,685 participants in control groups.
• For coronary heart disease, 11.4% among 8,962 patients treated with folic acid and 10.6% among 7,915 in control groups.
• For stroke, 4.7% among 7,432 folic-acid treated patients and 5.8% among 6,374 controls.
• For all-cause mortality, 12.0% among 8,020 and 12.3% among 6,975, respectively.

The findings were consistent whether participants had preexisting cardiovascular or end-stage renal disease. The relative risks were, respectively:

• For cardiovascular disease outcomes, 0.96 (95% CI 0.88 to 1.05) and 0.89 (95% CI 0.74 to 1.08).
• For coronary heart disease outcomes, 1.04 (95% CI 0.90 to 1.19) and 1.06 (95% CI 0.75 to 1.51).
• For stroke, 0.89 (95% CI 0.74 to 1.07) and 0.68 (95% CI 0.37 to 1.25).
• For all-cause mortality, 0.97 (95% CI 0.88 to 1.06) and 0.93 (95% CI 0.78 to 1.11).

In sensitivity analyses, the researchers found no significant heterogeneity for trials reporting cardiovascular disease, coronary heart disease, or all-cause mortality outcomes, and excluding any one trial did not change the overall findings. For stroke, however, excluding the Vitamin Intervention for Stroke Prevention trial yielded a significant protective effect for folic acid supplementation (RR 0.76, 95% CI 0.63 to 0.93).

While all the trials showed a reduction in homocysteine levels (ranging from -1.5 to -26.0 ?mol/L), none of the outcome risks was significantly linked to the net change in homocysteine.

The researchers noted that clinical trials as well as their meta-analysis have limited statistical power due in part to mandatory folic acid fortification of cereal grains in the United States and Canada and voluntary fortification in Australia and New Zealand, where some of the trials were conducted. The meta-analysis had 84.2% statistical power to detect a 10% reduction in cardiovascular disease risk and 64.1% power to detect a 10% reduction in mortality.

They said that several large trials of folic acid supplementation are currently being conducted, and a meta-analysis of the these trials is expected to have sufficient power to detect a 10% lowering of coronary heart disease risk with about 25% lower homocysteine levels.

"While we are waiting for more data from ongoing large trials," the researchers wrote, "our findings that folic acid supplementation does not lower risk of [cardiovascular disease] and all-cause mortality among persons with a history of vascular disease should be interpreted in the context of evolving evidence in this area."

The researchers cautioned that the findings do not reflect on any possible effect of folic acid supplements for primary prevention, which has not been studied in trials.