The effect of folate supplementation on cardiovascular disease has been studied in many observational studies and randomized trials and has been a topic of debate for a number of years. In this issue of JAMA, Huo and colleagues1 provide results from their important clinical trial of folic acid therapy for primary prevention of stroke. In a carefully designed and executed randomized trial, 20 702 adults with hypertension were randomized to receive enalapril alone (n = 10 354) or enalapril combined with 0.8 mg folic acid (n = 10 348). As recommended by the data and safety monitoring board, the trial was terminated early, after 4.5 years, with emergence of a significant reduction in the incidence of first stroke, the primary end point, of 2.7% (282 events) in the enalapril–folic acid group vs 3.4% (355 events) in the enalapril alone group (hazard ratio, 0.79; 95% CI, 0.68-0.93). In further support of the finding, the benefit was more pronounced in the prespecified subgroup of study participants with the lowest baseline levels of plasma folate (ie, <5.6 ng/mL) with rates of first stroke of 2.8% (73 events among 2600 participants) in the enalapril–folic acid group vs 4.6% (116 events among 2548 participants) in the enalapril alone group (hazard ratio, 0.61; 95% CI, 0.45-0.82). There was a smaller effect among those in higher baseline folate categories.
Stampfer M, Willett W. Folate Supplements for Stroke PreventionTargeted Trial Trumps the Rest. JAMA. 2015;313(13):1321-1322. doi:10.1001/jama.2015.1961