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Meta-analysis of folic acid efficacy trials in stroke prevention: Insight into effect modifiers
Min Zhao1, Guangliang Wu1, Youbao Li1
1From the National Clinical Research Study Center for Kidney Disease (M.Z., Y.L., F.F.H., X.X., X.Q.), State Key Laboratory for Organ Failure Research, Renal Division, Nanfang Hospital, Southern Medical University; Second Clinical Medical College of Guangzhou University of Chinese Medicine (G.W.), Guangdong, China; Department of Population, Family, and Reproductive Health (X.W.), Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; and Department of Neurology (M.Z., Y.C.), Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.
Objective:
To examine the efficacy and effect modifiers of folic acid supplementation in the prevention of stroke in regions without folic acid fortification based on relevant, up-to-date published randomized trials.
Methods:
Relative risk (RR) was used to measure the effect of folic acid supplementation on risk of stroke using a fixed effects model.
Findings:
Overall, folic acid supplementation significantly reduced the stroke risk by 11% (22 trials, n = 82,723; RR 0.89, 95% confidence interval [CI] 0.84-0.96). The effect was greater in low folate regions (2 trials, n = 24,020; Asia, 0.78, 0.67-0.90) compared to high folate regions (7 trials, n = 14,655; America, 1.05, 0.90-1.23), and among patients without folic acid fortification (11 trials, n = 49,957; 0.85; 0.77-0.94) compared with those with folic acid fortification (7 trials, n = 14,655; 1.05, 0.90-1.23). In further stratified analyses among trials without folic acid fortification, a larger beneficial effect was found in those trials that used a low dosage of folic acid (≤0.8 mg: 0.78, 0.69-0.88) or low baseline vitamin B12 levels (<384 pg/mL: 0.78, 0.68-0.89). In the corresponding comparison groups, the effect sizes were attenuated and insignificant (p for interaction <0.05 for both). Although the interaction tests were not significant, there might be a higher benefit in trials with a low dosage of vitamin B12, a low prevalence of statin use, but a high prevalence of hypertension.
Conclusions:
Folic acid supplementation could reduce the stroke risk in regions without folic acid fortification, particularly in trials using a relatively low dosage of folic acid and with low vitamin B12 levels.