Folic acid supplementation does not reduce CVD risk nor mortality

Clinical Question

Does folic acid supplementation decrease morbidity or mortality from cardiovascular diseases?

Bottom Line

The available evidence does not support the use of folic acid supplementation as secondary prevention of cardiovascular disease events, stroke, or all-cause mortality among patients with preexisting vascular diseases. (LOE = 1a)


Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases. A meta-analysis of randomized controlled trials. JAMA 2006;296:2720-2726.  [PMID:17164458]

Study Design

Meta-analysis (randomized controlled trials)




Various (meta-analysis)


These investigators searched MEDLINE, reference lists from relevant studies, and contacted experts in the field to identify trials investigating the effect of folic acid supplementation on cardiovascular disease risk. No language restrictions were applied. Inclusion criteria included randomized controlled trials of folic acid supplementation with a duration of at least 6 months. Two investigators independently performed the search and identified reports meeting inclusion criteria. Discrepancies were resolved by consensus discussion with a third investigator. From an initial pool of 165 potentially relevant studies, the authors included a total of 12 trials representing data from 16,958 patients with preexisting cardiovascular or renal disease. The dosage of folic acid in the intervention groups ranged from 0.5 mg per day to 15 mg per day. All trials reported a reduction in homocysteine levels. However, compared with control patients, there was no significant reduction in the risk of total cardiovascular disease events, stroke, or all-cause mortality among patients using folic acid supplementation. A formal analysis found no evidence for publication bias or significant heterogeneity among the various trials (no significant differences in reported outcomes among the various individual trials). The longest follow-up period for any of the individual trials was 5 years, so it is possible that a benefit could occur with more prolonged use. Multiple large trials are currently underway addressing this issue.