Efficacy of Homocysteine-Lowering Therapy With Folic Acid in Stroke Prevention A Meta-Analysis

UCLA Stroke Center, 710 Westwood Plaza, Los Angeles, CA 90095, USA.
Stroke (Impact Factor: 5.72). 04/2010; 41(6):1205-12. DOI: 10.1161/STROKEAHA.109.573410
Source: PubMed


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.
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.
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).
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.

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    • "In a meta-analysis, Wang et al. [19] indicated that B vitamins significantly reduced the risk of stroke, but subgroup analysis showed that this effect was based on trials that included only participants without a previous stroke history. Lee et al. [55] suggested that folic acid supplementation administered as primary prevention significantly reduced the risk of stroke at>3 years of follow-up and that the homocysteine-lowering effect was>20%. However, this meta-analysis included trials with a male: female ratio of >2. "
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    ABSTRACT: Background Observational studies suggest that B vitamin supplementation reduces cardiovascular risk in adults, but this association remains controversial. This study aimed to summarize the evidence from randomized controlled trials (RCTs) investigating B vitamin supplementation for the primary or secondary prevention of major adverse cardiovascular outcomes and to perform a cumulative meta-analysis to determine the evidence base. Methodology and Principal Findings In April 2013, we searched PubMed, Embase, and the Cochrane Library to identify relevant RCTs. We included RCTs investigating the effect of B vitamin supplementation on cardiovascular outcome. Relative risk (RR) was used to measure the effect using a random-effect model. Statistical heterogeneity scores were assessed using the Q statistic. We included data on 57,952 individuals from 24 RCTs: 12 primary prevention trials and 12 secondary prevention trials. In 23 of these trials, 10,917 major adverse cardiovascular events (MACE) occurred; in 20 trials, 7,203 deaths occurred; in 15 trials, 3,422 cardiac deaths occurred; in 19 trials, 3,623 myocardial infarctions (MI) occurred; and in 18 trials, 2,465 strokes occurred. B vitamin supplementation had little or no effect on the incidence of MACE (RR, 0.98; 95% confidence interval [CI]: 0.93–1.03; P = 0.37), total mortality (RR, 1.01; 95% CI: 0.97–1.05; P = 0.77), cardiac death (RR, 0.96; 95% CI: 0.90–1.02; P = 0.21), MI (RR, 0.99; 95% CI: 0.93–1.06; P = 0.82), or stroke (RR, 0.94; 95% CI: 0.85–1.03; P = 0.18). Conclusion/Significance B vitamin supplementation, when used for primary or secondary prevention, is not associated with a reduction in MACE, total mortality, cardiac death, MI, or stroke.
    PLoS ONE 09/2014; 9(9):e107060. DOI:10.1371/journal.pone.0107060 · 3.23 Impact Factor
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    • "and in studies combining folic acid and vitamin B (RR 0.83; 95% CI, 0.71–0.97) [10]. In another and more recent meta-analysis published by Ji et al and including 14 randomized controlled trials with 54,913 participants, it was concluded that lowering homocysteine with B vitamin supplementation was effective to significantly reduce the overall risk of stroke events (RR 0.93; 95% CI, 0.86–1.00; "
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    ABSTRACT: Recent evidence suggests that migraine is associated with an increased risk of cardiovascular disorders, so that it is increasingly hypothesized that this primary form of headache my be linked to thrombotic diseases by some biological pathways and risk factors. Homocysteine, a sulfur-containing molecule, is now recognized as an independent risk factor for a variety of thrombotic disorders, especially ischemic heart disease and stroke. This article is hence aimed to provide an overview of epidemiological evidence about the association between homocysteine and migraine published in cross-sectional, prospective or interventional studies. Overall, the evidence gathered from cross-sectional studies that measured plasma homocysteine levels suggests that the epidemiological link between the plasma concentration of this biomarker and migraine is very weak, at best. Contradictory evidence emerged from interventional studies, in which treatment of hyperhomocysteinemia with folic acid or vitamin B supplementation was effective to lower plasma homocysteine and decrease frequency and/or severity of migraine. The association remains largely speculative, however, since it could not be clearly demonstrated that these two biological effects were directly linked. The only study that has assessed homocysteine in cerebrospinal fluid reported that the concentration of this biomarker in migraine patients was significantly increased compared to controls. Although this evidence must be obviously confirmed in larger trials, some putative mechanisms may support a causal link between increased generation of homocysteine in the brain environment and migraine.
    Clinica chimica acta; international journal of clinical chemistry 03/2014; 433. DOI:10.1016/j.cca.2014.02.028 · 2.82 Impact Factor
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    • "Further to Hoekstra et al. (2008), it is now well established that in general folic acid decreases plasma homocysteine levels, leading to hypothesis that a high plasma homocysteine level is associated with cardiovascular disease. However, in contrast to earlier expectations , it has been shown that folic acid decreases the risk of stroke only in people without a history of the disease (Wang et al., 2007; Lee et al., 2010) whereas it is ineffective for prevention of all cardiovascular events (including stroke) in patients at risk or with established cardiovascular disease (Marti-Carvajal et al., 2009). In addition, there is some evidence that, folic acid might increase homocysteine in elderly with low vitamin B 12 status, thereby increasing their risk on cognitive impairment (Selhub et al., 2007, 2009; Miller et al., 2009). "
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    ABSTRACT: The respective examples, described in this paper, illustrate how the BRAFO-tiered approach, on benefit-risk assessment, can be tested on a wide range of case studies. Various results were provided, ranging from a quick stop as the result of non-genuine benefit-risk questions to continuation through the tiers into deterministic/probabilistic calculations. The paper illustrates the assessment of benefits and risks associated with dietary interventions. The BRAFO tiered approach is tested with five case studies. In each instance, the benefit-risk approach is tested on the basis of existing evaluations for the individual effects done by others; no new risk or benefit evaluations were made. The following case studies were thoroughly analysed: an example of food fortification, folic acid fortification of flour, macronutrient replacement/food substitution; the isocaloric replacement of saturated fatty acids with carbohydrates; the replacement of saturated fatty acids with monounsaturated fatty acids; the replacement of sugar-sweetened beverages containing mono- and disaccharides with low calorie sweeteners and an example of addition of specific ingredients to food: chlorination of drinking water.
    Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 07/2011; 50 Suppl 4:S710-23. DOI:10.1016/j.fct.2011.06.068 · 2.90 Impact Factor
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