Complex Effects of B-Vitamin Combinations on Cardiovascular Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials over Three Decades.

B-vitamin combinations were associated with a nonsignificant reduction in stroke and 3-point MACE in the overall pooled analysis.

• Stroke: RR 0.91, 95% CI 0.81–1.04
• 3-point MACE: RR 0.93, 95% CI 0.86–1.01
• Neither result reached statistical significance
• Analysis based on 13 RCTs enrolling 68,363 participants
• Random-effects models were used to calculate pooled risk ratios

No significant effects of B-vitamin combinations were observed for all-cause mortality, cardiovascular mortality, or myocardial infarction in the overall analysis.

• All-cause mortality: RR 1.01, 95% CI 0.96–1.06
• Cardiovascular mortality: RR 0.97, 95% CI 0.88–1.07
• Myocardial infarction: RR 0.97, 95% CI 0.91–1.03
• None of these outcomes showed statistically significant benefit or harm

In primary prevention populations, B-vitamin combinations were associated with significant reductions in both stroke and MACE.

• Stroke in primary prevention: RR 0.79, 95% CI 0.68–0.93
• MACE in primary prevention: RR 0.80, 95% CI 0.69–0.92
• Both results were statistically significant
• Between-study heterogeneity was minimal to low for ischemic outcomes in this subgroup, supporting robustness of estimates

A modest but statistically significant reduction in MACE was observed in secondary prevention populations.

• MACE in secondary prevention: RR 0.91, 95% CI 0.83–0.99
• The effect size was smaller than that seen in primary prevention populations (RR 0.91 vs. RR 0.80)
• Substantial heterogeneity was observed for mortality outcomes in secondary prevention populations

The systematic review included 13 randomized controlled trials spanning nearly three decades with a large pooled sample.

• 13 RCTs were included in the meta-analysis
• Total enrollment was 68,363 participants
• Trials covered both primary and secondary prevention populations
• Studies were published between January 1996 and November 2025 with a minimum trial duration of 24 months
• PubMed, Embase, Web of Science, and the Cochrane Library were searched; risk of bias was assessed using the Cochrane Risk of Bias 2.0 tool

Between-study heterogeneity varied substantially by outcome type, being minimal to low for ischemic outcomes but substantial for mortality outcomes in secondary prevention populations.

• Minimal to low heterogeneity was observed for ischemic outcomes, described as supporting the robustness of stroke and MACE estimates
• Substantial heterogeneity was observed for mortality outcomes in secondary prevention populations
• This inconsistency for mortality outcomes limits the interpretability of those pooled estimates

The authors concluded that baseline cardiovascular risk and regional folic acid fortification are likely treatment effect modifiers that should guide future trial design and clinical use.

• Evidence was described as limited by heterogeneity in trial populations, vitamin formulations and doses, and outcome definitions
• Substantial between-study inconsistency was noted for mortality outcomes
• Imprecision in subgroup estimates was attributed to a small number of contributing trials
• Folic acid fortification status of the study region was identified as a potentially important modifier of treatment effects