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Review
. 2016 Aug 15;5(8):e003768.
doi: 10.1161/JAHA.116.003768.

Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials

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Free PMC article
Review

Folic Acid Supplementation and the Risk of Cardiovascular Diseases: A Meta-Analysis of Randomized Controlled Trials

Yanping Li et al. J Am Heart Assoc. .
Free PMC article

Abstract

Background: Results from observational and genetic epidemiological studies suggest that lower serum homocysteine levels are associated with lower incidence of cardiovascular disease (CVD). Numerous randomized controlled trials have investigated the efficacy of lowering homocysteine with folic acid supplementation for CVD risk, but conflicting results have been reported.

Methods and results: Three bibliographic databases (Medline, Embase, and the Cochrane Database of Systematic Reviews) were searched from database inception until December 1, 2015. Of the 1933 references reviewed for eligibility, 30 randomized controlled trials involving 82 334 participants were included in the final analysis. The pooled relative risks of folic acid supplementation compared with controls were 0.90 (95% CI 0.84-0.96; P=0.002) for stroke, 1.04 (95% CI 0.99-1.09; P=0.16) for coronary heart disease, and 0.96 (95% CI 0.92-0.99; P=0.02) for overall CVD. The intervention effects for both stroke and combined CVD were more pronounced among participants with lower plasma folate levels at baseline (both P<0.02 for interaction). In stratified analyses, a greater beneficial effect for overall CVD was seen in trials among participants without preexisting CVD (P=0.006 for interaction) or in trials with larger reduction in homocysteine levels (P=0.009 for interaction).

Conclusions: Our meta-analysis indicated a 10% lower risk of stroke and a 4% lower risk of overall CVD with folic acid supplementation. A greater benefit for CVD was observed among participants with lower plasma folate levels and without preexisting CVD and in studies with larger decreases in homocysteine levels. Folic acid supplementation had no significant effect on risk of coronary heart disease.

Keywords: cardiovascular disease prevention; folate; stroke prevention.

Figures

Figure 1
Figure 1
Flow diagram of study selection process. CHD indicates coronary heart disease; CVD, cardiovascular disease; RCT, randomized controlled trial.
Figure 2
Figure 2
Relative risk estimates for stroke (folic acid supplementation vs control) by individual trials and pooled results. RCT indicates randomized controlled trial.
Figure 3
Figure 3
Relative risk estimates for coronary heart disease (folic acid supplementation vs control) by individual trials and pooled results. RCT indicates randomized controlled trial.
Figure 4
Figure 4
Relative risk estimates for cardiovascular diseases (folic acid supplementation vs control) by individual trials and pooled results. RCT indicates randomized controlled trial.
Figure 5
Figure 5
Funnel plot of data from the meta‐analysis of the effects of folic acid supplementation for preventing stroke (A), CHD (B) and CVD. CHD indicates coronary heart disease; CVD, cardiovascular disease; OR, odds ratio.
Figure 6
Figure 6
Relative risk of CVD in relation to percentage decreases in homocysteine concentration based on 16 trials with full records of homocysteine changes after the intervention. CVD indicates cardiovascular disease.

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