New Orleans, LA - A new meta-analysis of 12 randomized controlled trials of folic acid has found that it does not reduce the risk of cardiovascular diseases or all-cause mortality in those with a prior history of vascular disease [1]. Dr Lydia A Bazzano (Tulane University School of Public Health and Tropical Medicine, New Orleans, LA) and colleagues report their findings in the December 13, 2006 issue of the Journal of the American Medical Association.

The findings are in line with results from a number of randomized controlled clinical trials, which have led experts to conclude that any intervention with folic acid is of little benefit in cardiovascular terms. However, a recent BMJ commentary begged to differ, stating that there was enough combined evidence from cohort, genetic, and clinical trials to support a modest protective effect of folic acid on cardiovascular events [2].

We had a good chance of finding a relationship if it was truly there, but we didn't.

But Bazzano told heartwire that her team's analysis had had excellent statistical power: "We had a good chance of finding a relationship if it was truly there, but we didn't." Nevertheless, she says that "we have a few more years to get all the data," referring to the B-Vitamin Treatment Trialists' Collaboration, a new meta-analysis planned by the Clinical Trial Service Unit at Oxford University, UK, which will look at all studies examining the effects of B vitamins and including 1000 or more participants and expects to report in a few years [3].

In the meantime, "it is important to focus on strategies of proven benefit in the prevention of CVD, including smoking cessation, lipid reduction, treatment of hypertension and diabetes, maintenance of a healthy weight, and physical activity," the authors stress.

Using a random-effects model, Bazzano and colleagues pooled the results of 12 trials—involving 16 958 participants—comparing folic acid with either placebo or usual care for a minimum duration of six months and with clinical cardiovascular disease reported as an end point.

The meta-analysis included studies published until July of this year, but not the WAFACS trial, reported at the American Heart Association Scientific Sessions last month, which had seven-year follow-up in a mixed secondary/primary-prevention population and also found no benefit of folic acid.

"In our current meta-analysis, we found no significant benefit or harm of folic-acid supplementation on the risk of CVD, CHD, stroke, or all-cause mortality among persons with a history of cardiovascular or end-stage renal disease," they state.

In their discussion they say that observational studies that suggested a benefit of folic acid via its effects on homocysteine "may have overestimated the effect size." Also, this type of study is open to confounding, they note.

But despite the lack of benefit seen in this new analysis, they suggest that folic acid "may have a protective effect in primary rather than secondary prevention," as to date all the trials included have looked at secondary prevention.

Also, it's possible that people with specific genetic backgrounds or populations with folate deficiency may benefit from folic acid, they note: "Future clinical trials of folic-acid supplementation are needed in special subgroups."

And it could be that the duration of follow-up may also contribute to differences seen in the results of observational studies and clinical trials, they add, noting that the longest follow-up in this meta-analysis was five years.