Elsevier

The Lancet

Volume 369, Issue 9576, 2–8 June 2007, Pages 1876-1882
The Lancet

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Efficacy of folic acid supplementation in stroke prevention: a meta-analysis

https://doi.org/10.1016/S0140-6736(07)60854-XGet rights and content

Summary

Background

The efficacy of treatments that lower homocysteine concentrations in reducing the risk of cardiovascular disease remains controversial. Our aim was to do a meta-analysis of relevant randomised trials to assess the efficacy of folic acid supplementation in the prevention of stroke.

Methods

We collected data from eight randomised trials of folic acid that had stroke reported as one of the endpoints. Relative risk (RR) was used as a measure of the effect of folic acid supplementation on the risk of stroke with a random effect model. The analysis was further stratified by factors that could affect the treatment effects.

Findings

Folic acid supplementation significantly reduced the risk of stroke by 18% (RR 0·82, 95% CI 0·68–1·00; p=0·045). In the stratified analyses, a greater beneficial effect was seen in those trials with a treatment duration of more than 36 months (0·71, 0·57–0·87; p=0·001), a decrease in the concentration of homocysteine of more than 20% (0·77, 0·63–0·94; p=0·012), no fortification or partly fortified grain (0·75, 0·62–0·91; p=0·003), and no history of stroke (0·75, 0·62–0·90; p=0·002). In the corresponding comparison groups, the estimated RRs were attenuated and insignificant.

Interpretation

Our findings indicate that folic acid supplementation can effectively reduce the risk of stroke in primary prevention.

Introduction

Cardiovascular disease is the leading cause of death in the developed world,1 and has emerged as one of the leading causes of death in developing countries such as China.2 As early as 1969, homocysteine, the sulphur-containing aminoacid, was postulated to affect atherosclerotic processes.3 Since that time, substantial evidence has accumulated linking homocysteine in blood to the risk of cardiovascular disease.4, 5, 6, 7 Raised concentrations of homocysteine in blood have been suggested to be a modifiable, independent risk factor for coronary artery disease, stroke, and deep vein thrombosis.8, 9, 10 The initial epidemiological evidence in support of this hypothesis came from case-control studies.11, 12, 13 Furthermore, a meta-analysis of genetic studies and prospective studies lent further support that the association between homocysteine and cardiovascular disease is causal.8 However, inconsistent results have been reported,14 and the efficacy of treatments that lower homocysteine concentrations in reducing the risk of cardiovascular disease has not been confirmed by randomised trials.15, 16, 17 There are several possible reasons for the inconsistent findings between the recent clinical trials and earlier observational studies.18 Most trials were done among patients with pre-existing cardiovascular disease as a secondary prevention strategy; it is possible that folic acid supplementation could have a greater protective effect in primary rather than secondary prevention. Additionally, cardiovascular disease is a heterogeneous clinical entity; different cardiovascular endpoints could respond differently to folic acid supplementation.

Although results were negative for other cardiovascular endpoints, the HOPE-2 study did show that folic acid supplementation reduced the risk of stroke by 24%.17 In the USA and Canada, folic acid fortification of grain products was fully implemented by 1998. If high homocysteine concentrations are an independent risk factor for stroke, one might expect a reduction in stroke mortality following folic acid fortification. Indeed, a recent population-based study showed that decline in stroke mortality accelerated in 1998–2002 in nearly all population strata in the USA and Canada;19 by contrast, the rate of decline in stroke mortality in England and Wales (where fortification is not mandatory) did not change significantly between 1990 and 2002. These data raised the possibility that stroke is a disease endpoint that could particularly benefit from folic acid supplementation. Our aim was thus to do a meta-analysis focusing on stroke as the disease endpoint in relation to folic acid supplementation.

Section snippets

Search strategy and selection criteria

We attempted to conform to Quality of Reporting of Meta-analyses (QUOROM) guidelines in the report of this meta-analysis.20

To select studies, we used methods similar to those in a recent meta-analysis that assessed the effect of folic acid supplementation on the risk of cardiovascular disease.21 We (XQ, GM, JL, XX, XW) first reviewed all relevant trials included in that meta-analysis,21 in which a comprehensive literature search of the Medline database was done from January, 1966, to July,

Results

Of the 15 trials retrieved for detailed assessment, five were excluded for lack of data on stroke,26, 27, 28, 29, 30 one31 because it was derived from the same study population as another report,34 and one for small number incident cases of stroke32 (figure 1). Our final analysis included eight randomised controlled trials, consisting of 16 841 individuals.15, 16, 17, 33, 34, 35, 36, 37 These trials compared folic acid supplementation (with or without combination with other B vitamins,

Discussion

Our meta-analysis provides coherent evidence that folic acid supplementation can significantly reduce the risk of stroke in primary prevention. Although Bazzano and colleagues' meta-analysis21 reported that the overall effect of folic acid supplementation on stroke was not significant, the association became significant after removal of the VISP trial,15 which was done in individuals with a history of stroke.

The inverse relation between the duration of folic acid supplementation and the risk of

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