Folic acid is safe - but it lacks any cardiovascular benefits - according to researchers presenting at the American Heart Association's Scientific Sessions 2008. The results from the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), a 12,064-person, randomized study, were presented as a late-breaking clinical trial.

Study participants were assigned to folic acid (2mg) plus vitamin B12 (1mg) daily versus matching placebo. The folic acid group yielded reductions in homocysteine levels of 3.9μmol/L at 1 year and of 3.6μmol/L over the whole trial period (mean 6.7 years).

Researchers reported that the folic acid group failed to show any reduction in the primary outcome of major vascular events (MVEs, defined as non-fatal heart attack, coronary death, stroke or arterial revascularization) compared to placebo. MVEs were found among 1537 (25.5%) patients in the folic acid group versus 1492 (24.7%) on placebo corresponding to a risk ratio of 1.04 (95%CI 0.97-1.12). The vitamins also did not increase non-vascular death rates or cancer rates during an average follow-up of 6.7 years among patients who had previously had a heart attack, said Professor Jane M. Armitage, co-principal investigator of the study and professor of clinical trials and epidemiology at the University of Oxford, England.

"There was no difference between the treatment groups in terms of vascular events, but importantly, we also didn't see any kind of safety concerns with folic acid," she said. "SEARCH throws cold water on a once-promising hypothesis, based on a well-known association between higher blood levels of the amino acid homocystine and higher cardiovascular disease (CVD) risk, that using B vitamins to reduce blood levels of homocystine would prevent CVD."

The study's finding of no excess risk of cancer or other adverse events from higher than average doses of folic acid provides reassurance for the United States, Canada and several other countries that require folic acid fortification of flour, bread and many cereals to protect newborns from neural tube defects, Armitage said.

At the same late breaking clinical trials session, Armitage's co-principal investigator, Professor Rory Collins, professor of medicine and epidemiology at the University of Oxford, presented a second randomized comparison from the SEARCH trial of 80mg versus 20mg per day of simvastatin - the largest direct comparison of more versus less intensive lowering of low-density lipoprotein cholesterol (LDL-C).

Previous studies have found that statin therapy reduces the relative risk of MVE by about 20 percent per 40 milligram per deciliter (mg/dL) reduction in LDL-C. Compared with the patients assigned 20mg per day of simvastatin in SEARCH, LDL-C was reduced by an average of 14mg/dL more among the patients assigned 80mg per day of simvastatin.

Collins presented the results of SEARCH in the context of an update of a meta-analysis of individual patient data from previous studies of statin therapy published in The Lancet in 2005 (Lancet 2005 Oct 8: 366:1267-78.) Based on that meta-analysis, a 14 mg/dL greater reduction in LDL-C would be expected to produce a 6 percent to7 percent relative reduction in MVE, which is what researchers observed in the SEARCH trial.

Daily doses of 80mg simvastatin were associated with more myopathy cases than 20mg simvastatin, although the SEARCH trial had identified a genetic variant that accounted for much of the excess myopathy risk with the higher-dose simvastatin regimen.

Co-authors are the SEARCH Collaborative Group.

The University of Oxford's Clinical Trial Service Unit designed, conducted, analyzed and interpreted the SEARCH study, which was funded by a research grant from Merck & Co.