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Hyperhomocysteinemia has been associated with premature atherosclerosis with an increased risk of cardiovascular events.1,–,3 Folate and cyanocobalamin (vitamin B12) are important regulators of the metabolism of homocysteine, and studies have shown an inverse relationship between levels of these factors and levels of homocysteine in the blood.4 5 On the basis of epidemiological studies, clinicians and scientists expected that homocysteine-lowering therapy (HLT) would reduce the incident risk of cardiovascular diseases (including stroke). As a result, HLT has been tested in several randomised clinical trials.6,–,9
In the present study, Lee and colleagues report the results of a meta-analysis including randomised, controlled trials assessing the efficacy of folic acid supplementation in the prevention of stroke. They used a strict inclusion criteria: (1) randomised, controlled study; (2) comparison of folic acid supplementation (with or without vitamins B6 and B12) with inactive or low-dose control; (3) the duration of the intervention was longer than 6 months; and (4) study reporting on the number of stroke events in both active treatment and control groups.
Data sources included MEDLINE (via PubMed), the Cochrane Central Register of Controlled Trials and the clinical trial registry maintained at clinicaltrials.gov using a broad selection of terms from January 1966 to May 2009. Publication bias was estimated visually by funnel plots. Heterogeneity was also assessed.
The authors identified 13 randomised, controlled trials that enrolled 39 005 participants. They found no significant benefit of folic acid supplementation in reducing the risk of stroke (RR 0.93; 95% CI 0.85 to 1.03). They also reported the potential benefit in some groups in a stratified analysis. For example, the combination of folic acid with vitamins B6 and B12 was associated with lower incident risk of stroke (RR 0.83; 95% CI 0.71 to 0.97; p=0.02). As readers can appreciate in figure 2 in the article, with the exception of the HOPE-2 trial, the remaining randomised studies showed no significant benefit in the reduction of stroke. Formal testing did not reveal any substantial resulting heterogeneity or publication bias.
There are several observational and randomised trials of HLT reporting on the risk of myocardial infarction and stroke. Critiques to some of these trials include the use of lower doses of multivitamins, short intervention, lack of complete homocysteine measures and so on.
More recently, the results of the VITAmins TO prevent stroke trial (VITATOPS)8 were presented at the XIX European Stroke Conference in Barcelona. VITATOPS is a double-blind, placebo-controlled trial, including 8164 patients randomised to receive placebo or folic acid and vitamins B12 and B6 in a single tablet. For the primary outcome (nonfatal stroke, nonfatal myocardial infarction and vascular death), there was a non-significant absolute risk reduction of 1.6% (−0.01 to 3.0) with a median of 3.5 years.
Previously and using similar inclusion criteria, Bazzano and colleagues reported the results of a meta-analysis including 12 randomised controlled trials (16 958 participants) of folic acid supplementation in the prevention of cardiovascular events.10 Folic acid supplementation was associated with a non-significant reduction in cardiovascular disease (RR 0.95; 95%CI 0.88 to 1.03), coronary heart disease (RR 1.04; 95%CI 0.92 to 1.17) or stroke (RR 0.86; 95%CI 0.71 to 1.04). Other authors focused on a subset of seven of 12 randomised studies included in the previous meta-analysis, and added a randomised trial from China,11 to assess the efficacy of folic acid supplementation in stroke prevention.12 They found that folic acid supplementation significantly reduced the risk of stroke by 18% (95% CI 68 to 100). The benefit was greater in those trials with longer treatment duration (>36 months) (RR 0.71, 95%CI 0.57 to 0.87), blood level reduction of homocysteine of more than 20% (RR 0.77, 95%CI 0.63 to 0.94), and no history of stroke (RR 0.75, 95%CI 0.62 to 0.90). However, some studies did not use folic acid combined with vitamin B6 or B12.
The overall results of randomised clinical trials (the recently reported SEARCH,13 WENBIT,14 WAFACS15 and the previously reported VISP,6 NORVIT9 and HOPE-216 17) and most recent meta-analyses10 of folic acid supplementation in vascular prevention showed consistent negative results. At present, the general or routine use of folic acid supplementation for cardiovascular prevention is not beneficial (Class III, Level of evidence A according to the American Heart Association18).
In HOPE-2, the authors reported a benefit after adjusting for concomitant antithrombotics, lipid-lowering and antihypertensive treatment at study entry (hazard ratio 0.71; 95% CI 0.56 to 0.91).17 This is hypothesis generating as both hypercholesterolemia and hyperhomocysteinemia can synergistically accelerate atherosclerosis in individuals at risk; therefore, treating both at the same time may be a more effective intervention in stroke prevention.
On the basis of the results of subgroup analysis from meta-analysis, only selected patients (ie, those with no history of stroke living in areas with no grain fortification or those with elevated baseline homocysteine levels capable of responding to HLT) may benefit with the long-term supplementation of appropriate doses of multivitamins (2.5 mg of folic acid, 50 mg of vitamin B6 and 1 mg of vitamin B12) for stroke prevention.
Competing interests GS received research funding from the Heart and Stroke Foundation of Onatario, Canada, the Canadian Institutes for Health Research, Department of Research at St Michael's Hospital and Connaught Foundation (University of Toronto).
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