Efficacy of folic acid supplementation in cardiovascular disease prevention: An updated meta-analysis of randomized controlled trials

Background: In observational studies, lower serum homocysteine levels are associated with a lower incidence of cardiovascular disease (CVD). However, individual randomized controlled trials (RCTs) have yielded mixed findings regarding the efficacy of therapeutic homocysteine in lowering cardiovascular risk. Our aim was to perform an updated meta-analysis of relevant RCTs to assess the efficacy of folic acid supplementation in the prevention of CVD, coronary heart disease (CHD), and stroke. Methods: We performed systematic search to identify RCTs reported at least one of the CVD, CHD, or stroke as outcomes. Relative risk (RR) with 95% confidence interval was used as a measure of the association between folic acid supplementation and risk of CVD, CHD, stroke, and all-cause mortality. The analysis was further stratified by factors that could affect the treatment effects. Results: The systematic search identified 26 RCTs enrolling 58,804 participants. Pooling the RRs showed that folic acid supplementation was not associated with any significant change in the risk of CVD (RR 0.98, 0.95 to 1.02; p = 0.36), CHD (RR 1.03, 0.98 to 1.08; p = 0.23), and all-cause mortality (RR 1.00, 0.96 to 1.04; p = 0.92), but was linked to a decreasing trend in stroke risk (RR 0.93, 0.86 to 1.00; p = 0.05). In stratified analyses, the only heterogeneity was found for stroke risk reduction among groups with (RR 1.07, 0.92 to 1.25) vs. without (RR 0.88, 0.81 to 0.96) mandatory grain fortification (P for heterogeneity = 0.03). Conclusions: This meta-analysis suggests that there might be a potentially modest benefit of folic acid supplementation in stroke prevention.