Efficacy of homocysteine-lowering therapy with folic Acid in stroke prevention: a meta-analysis

Abstract

Background and purpose: Although a lower serum homocysteine concentration is associated with a reduced risk of stroke in epidemiologic studies, randomized, controlled trials have yielded mixed findings regarding the effect of therapeutic homocysteine lowering on stroke prevention. We performed a meta-analysis of randomized, controlled trials to assess the efficacy of folic acid supplementation in the prevention of stroke.

Methods: Salient trials were identified by formal literature search. Relative risk (RR) with 95% CI was used as a measure of the association between folic acid supplementation and risk of stroke, after pooling data across trials in a fixed-effects model.

Results: The search identified 13 randomized, controlled trials that had enrolled 39 005 participants for folic acid therapy to reduce homocysteine in which stroke was reported as an outcome measure. Across all trials, folic acid supplementation was associated with a trend toward mild benefit that did not reach statistical significance in reducing the risk of stroke (RR=0.93; 95% CI, 0.85-1.03; P=0.16). The RR for nonsecondary prevention trials was 0.89 (95% CI, 0.79-0.99; P=0.03). In stratified analyses, a greater beneficial effect was seen in the trials testing combination therapy of folic acid plus vitamins B6 and B12 (RR=0.83; 95% CI, 0.71-0.97; P=0.02) and in the trials that disproportionately enrolled male patients (men:women >2; RR=0.84; 95% CI, 0.74-0.94; P=0.003).

Conclusions: Folic acid supplementation did not demonstrate a major effect in averting stroke. However, potential mild benefits in primary stroke prevention, especially when folate is combined with B vitamins and in male patients, merit further investigation.

Figure 1

Flow of study selection process

Figure 2

Relative risk (risk ratio) with 95% confidence interval (CI) estimates stroke (active treatment vs. control), by trial and pooled

Figure 3

Effect of folic acid supplements on the risk of stroke in pre-specified subgroups. Hcy: homocysteine; FA: folic acid; ESRD: end-stage renal disease; ACKD: advanced chronic kidney disease

Figure 4

Relative risk (RR) of stroke (A) RR of stroke in relation to percentage change in homocysteine concentrations (Mark 1996 and Liem 2004 were excluded due to no homocysteine concentrations recorded) (B) RR of stroke in relation to active treatment duration (an outlier, Liem 2004, was excluded)