Thirteen RCTs (n=39,005 participants, range 88 to 12,064) were included. Eight trials reported adequate generation of allocation sequence and allocation concealment. Ten trials reported adequate blinding of participants and outcome assessors.
No significant effect of folic acid on stroke was found. Folic acid was associated with a significant reduction in risk of stroke in non-secondary prevention trials (RR 0.89, 95% CI 0.79 to 0.99; n=25,325).
Subgroup analysis: Combination of folic acid plus vitamin B6 and B12 was associated with significant reductions in risk of stroke (RR 0.83, 95% CI 0.71 to 0.97; n=19,768). Similarly, folic acid was associated with significant reductions in the risk of stroke in trials that enrolled a disproportionate number of males (RR 0.84, 95% CI 0.74 to 0.94; n=27,418), trials with substantial achieved homocysteine reduction of at least 20% (RR 0.87, 95% CI 0.77 to 0.98) and in trials with treatment duration of at least three years (RR 0.87, 95% CI 0.78 to 0.98).
No significant effect of folic acid on risk of effect was found in trials of folic acid alone, or folic acid plus vitamin B12.
No evidence of publication bias was found.