Original articleEfficacy of folic acid supplementation in cardiovascular disease prevention: An updated meta-analysis of randomized controlled trials
Introduction
In 1969, homocysteine was first hypothesized to promote atherosclerosis based on the observation that children with extreme elevations of plasma homocysteine due to inborn errors of metabolism had premature atherothrombotic disease [1]. Subsequent experimental studies confirmed that homocysteine and its metabolites can cause oxidative stress, enhance inflammation and damage endothelium [2], [3]. Epidemiological studies repeatedly showed that elevated homocysteine is associated with coronary heart disease and stroke [4], [5]. A meta-analysis of prospective observational studies found that a 25% lower homocysteine level was associated with 11% lower coronary heart disease risk and 19% lower stroke risk [6].
Folate and vitamin B12 are important regulators of homocysteine metabolism. Increased folate intake reduces serum homocysteine levels [7]. This information suggested that folic acid might be a useful therapeutic intervention for the prevention of cardiovascular disease. This hypothesis was supported in young adults with extreme metabolic derangements of homocysteine metabolism. Among individuals with homocystinuria, treatment with high dose folic acid, vitamin B6 and vitamin B12 lowered homocysteine levels and dramatically reduced cardiovascular risk and mortality [8].
These observations gave rise to the hope that lowering homocysteine levels in patients with high normal values could also confer therapeutic benefit in a much larger population. In some studies of biomarkers of cardiovascular disease, folic acid supplementation showed beneficial signals of activity, reducing carotid atherosclerosis progression and occurrence of abnormal exercise electrocardiography tests [9], [10].
Several randomized controlled trials of lowering homocysteine with folic acid to reduce clinical cardiovascular endpoints have been initiated since 1990s [11], [12], [13]. A meta-analysis which included trials up to June 2009 failed to demonstrate a benefit of homocysteine-lowering intervention with regard to cardiovascular disease or stroke [14]. However, that meta-analysis excluded end-stage renal disease trials and additional trials have been published in recent 3 years. We therefore undertook an updated meta-analysis.
Section snippets
Search strategy
The study was performed in accordance with the recommendations of the Cochrane Collaboration and Quality of Reporting of Meta-analysis (QUOROM) consensus group [15], [16].
We searched PUBMED, EMBASE, Cochrane Central Register of Controlled Trials, and the clinical trial registry maintained at clinicaltrials.gov (1966 to May 2012) using the search strategy “homocysteine” or “folate” or “folic acid” or “vitamin B12” or “cobalamine” or “vitamin B6” or “pyridoxine” or “multivitamin” and
Results
Of the 29 reports retrieved for detailed assessment, one was excluded because it was derived from the same study as another report [22], two for receiving therapies in addition to folic acid and B vitamin in the active treatment group that control group did not receive (Fig. 1) [23], [24]. Our final analysis included 26 randomized controlled trials [10], [11], [12], [13], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]
Discussion
To date, 26 randomized controlled trials have reported on the effect of folic acid supplementation on risk of cardiovascular events. Our meta-analysis found a strong trend in the reduction of future stroke risk of 7% with folic acid supplementation, but there was no significant benefit or harm of folic acid supplementation on the risk of coronary heart disease all-cause mortality, or composite cardiovascular disease events among persons with a high risk of cardiovascular disease. As far as we
Learning points
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Folic acid supplementation may reduce future stroke risk in people not residing in regions with mandatory grain fortification.
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Folic acid supplementation is not associated with lower risk of future cardiovascular disease, coronary heart disease, or death.
Conflict of interest
We declare that we have no conflict of interest.
Acknowledgments
Meng Lee was supported by a grant from CMRPG 660311, Taiwan and Jeffrey L Saver was supported by NIH SPOTRIAS Center and AHA PRT Health Outcomes Center Awards. We thank Kuo-Hsuan Chang, MD, for search of EMBASE and Yueh Lee, MSc, for retrieval of papers.
References (56)
- et al.
Homocysteine increases as folate decreases in plasma of healthy men during short-term dietary folate and methyl group restriction
J Nutr
(1994) - et al.
Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial
Lancet
(2000) - et al.
Improving the quality of reports of meta-analyses of randomised controlled trials: the QUOROM statement. Quality of reporting of meta-analyses
Lancet
(1999) - et al.
Funnel plots for detecting bias in meta-analysis: guidelines on choice of axis
J Clin Epidemiol
(2001) - et al.
Secondary prevention with folic acid: effects on clinical outcomes
J Am Coll Cardiol
(2003) - et al.
Randomized placebo-controlled trial assessing a treatment strategy consisting of pravastatin, vitamin E, and homocysteine lowering on plasma asymmetric dimethylarginine concentration in mild to moderate CKD
Am J Kidney Dis
(2009) - et al.
Efficacy of folic acid when added to statin therapy in patients with hypercholesterolemia following acute myocardial infarction: a randomised pilot trial
Int J Cardiol
(2004) - et al.
Cardiovascular morbidity and mortality in the Atherosclerosis and Folic Acid Supplementation Trial (ASFAST) in chronic renal failure: a multicenter, randomized, controlled trial
J Am Coll Cardiol
(2006) - et al.
Correlation between total homocysteine, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol in the serum of patients with myocardial infarction
Clin Biochem
(2001) Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis
Am J Pathol
(1969)