Dosage exploration of combined B-vitamin supplementation in stroke prevention: a meta-analysis and systematic review

Background: The optimal dosage range for B -vitamin supplementation for stroke prevention has not received sufficient attention. Objective: Our aim was to determine the optimal dosage range of a combination of folic acid, vitamin B12, and vitamin B6 supplementation in stroke prevention. Methods: We searched PubMed, the Cochrane Central Register of Controlled Trials, and Embase database for randomized controlled trials published between January 1966 and April 2023, whose participants received B -vitamin supplementation and that reported the number of stroke cases. Relative risk (RR) was used to measure the effect of combined supplementation on risk of stroke using a fixed -effects model. Risk of bias was assessed with the Cochrane risk -of -bias algorithm. Results: The search identified 14 randomized controlled trials of folic acid combined with vitamin B12 and vitamin B6 supplementation for stroke prevention that included 76,664 participants with 2720 stroke cases. In areas without and with partial folic acid fortification, combined B -vitamin supplementation significantly reduced the risk of stroke by 34% [RR: 0.66; 95% confidence interval (CI): 0.50, 0.86] and 11% (RR: 0.89; 95% CI: 0.79, 1.00), respectively. Further analysis showed that a dosage of folic acid <= 0.8 mg/d and vitamin B12 <= 0.4 mg/d was best for stroke prevention (RR: 0.65; 95% CI: 0.48, 0.86) in these areas. In contrast, no benefit of combined supplementation was found in fortified areas (RR: 1.04; 95% CI: 0.94, 1.16). Conclusions: Our meta -analysis found that the folic acid combined with vitamin B12 and vitamin B6 supplementation strategy significantly reduced the risk of stroke in areas without and with partial folic acid fortification. Combined dosages not exceeding 0.8 mg/d for folic acid and 0.4 mg/d for vitamin B12 supplementation may be more effective for populations within these areas. This trial was registered at PROSPERO asCRD42022355077.