Evidence Lacking That Folate Supplements Cut CVD Risk

By John R. Bell

Despite the suggestions of epidemiologic studies that supplemental folate can reduce the risk of cardiovascular disease, a new meta-analysis of randomized controlled trials has found no evidence for this benefit.

Dr. Lydia Bazzano and her colleagues at Tulane University, New Orleans, conducted an online search of the literature for studies conducted from January 1966 through July 2006 using various relevant key words, and identified 165 studies.

Inclusion criteria were randomized, controlled-trial design; inclusion of the number of events for cardiovascular disease (CVD), heart disease, stroke, and/or all-cause mortality; folate supplementation as the intervention; and intervention duration of at least 6 months (JAMA 2006; 296:2720-6).

A total of 12 trials comprising about 17,000 patients met all of the inclusion criteria. Two of the investigators abstracted the studies, and relative risk (RR) was used to determine the relationship between folate supplementation and risk of CVD, heart disease, stroke, and all-cause mortality among the patients.

The investigators found that although all trials reported a drop in homocysteine levels, "there was no statistically significant relationship between net change in homocysteine level and RR for any of the clinical outcomes."

A random-effects model pooled relative risks for all four event categories: For participants given folate supplementation, the proportion of CVD events was 18.3%, compared with 19.2% in the control groups. Heart disease occurred in 11.4% of the supplementation groups and 10.6% of the control groups. Of the folate participants, 4.7% experienced stroke, compared with 5.8% of controls, and all-cause mortality had a 12.0% rate among those given folate and 12.3% among controls.

At the same time, Dr. Bazzano and colleagues acknowledged that several observational studies have shown a relationship between serum homocysteine levels--which folate helps regulate--and CVD, with the first suggestions of a possible CVD-prevention benefit for folate posited in the 1960s, when cases of homocystinuria were first associated with thrombosis and vascular disease.

The incongruence of these observational studies with randomized controlled trials of folate supplementation's effect on CVD may be the result of confounding lifestyle factors or a possible protective effect that folic acid may provide in primary--but not secondary--prevention, researchers surmised.