Eight RCTs (n=16,841) were included in the review.
Folic acid supplementation was associated with a statistically significant risk reduction of stroke (RR 0.82, 95% CI: 0.68, 1.00, p=0.045); there was no evidence of statistical heterogeneity for this outcome (8 RCTs). Folic acid supplementation for more than 36 months seemed to produce a greater benefit (RR 0.71, 95% CI: 0.57, 0.87, p=0.001) than a shorter term prophylaxis (RR 1.00, 95% CI: 0.83, 1.21, p=0.95).
The subgroup analysis suggested that folic acid supplementation was more effective in the primary prevention of stroke (RR 0.75, 95% CI: 0.62, 0.94, p=0.002; 7 RCTs) than for secondary prophylaxis (RR 1.04, 95% CI: 0.84, 1.29, p=0.71; 1 RCT).
Patients without additional grain fortification appeared to have a statistically significant stroke risk reduction (RR 0.75, 95% CI: 0.62, 0.91, p=0.003), while no statistically significant benefit was observed among those receiving such supplementation (RR 0.89, 95% CI: 0.55, 1.42, p=0.62).
The relative reduction in homocysteine concentration varied largely among the trials, ranging from 10.9 to 39.4%. Stratification by degree of homocysteine reduction suggested that folic acid supplementation was able to reduce the risk of stroke when homocysteine concentrations were lowered by at least 20% (RR 0.77, 95% CI: 0.63, 0.94, p=0.012).