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Homocysteine, vitamins, and vascular disease prevention: more negative results

Epidemiology Cardiology Research Center (EPICARE)
Department of Epidemiology and Prevention
Division of Public Health Sciences
Wake Forest University School of Medicine
Medical Center Boulevard
Winston-Salem, NC 27157-1063
E-mail: esoliman{at}wfubmc.edu

Omaima A Shalash

Section of Nutrition Epidemiology
Department of Epidemiology and Prevention
Division of Public Health Sciences Wake Forest University School of Medicine
Medical Center Boulevard
Winston-Salem, NC 27157-1063
E-mail: oshalish{at}wfubmc.edu

Dear Sir:

With much interest we read the article by McCully (1), which implies a potential role of homocysteine reduction in the primary prevention of cardiovascular disease (CVD). Although the author did note the negative results of the homocysteine reduction clinical trials, he further raised doubts about their conclusion because of the lack of statistical power, the length of the trials required, and the fortification of the North American food supply with folic acid. We believe that the evidence supporting any benefit of homocysteine reduction, whether in primary or secondary CVD prevention, is getting weaker and weaker.

In addition to the negative results of the 3 major studies mentioned in McCully's article (VISP, NORVIT, and HOPE2), negative results from the HOST trial have also been published (2). The HOST trial (2) was designed to assess the effects of a reduction in homocysteine concentrations on mortality and vascular outcomes in 2056 patients with renal disease. Participants with advanced chronic kidney disease (estimated creatinine clearance of 30 mL/min, or 0.50 mL/s) or end-stage renal disease and with homocysteine concentrations of 15 µmol/L were randomly assigned to receive 40 mg folic acid, 2 mg cyanocobalamin (vitamin B-12), and 100 mg vitamin pyridoxine hydrochloride (vitamin B-6) daily or a placebo. Despite a 26% reduction in homocysteine concentrations (achieved with a dose of folic acid substantially in excess of that required to achieve a maximal reduction in homocysteine), the HOST study reported no significant reduction in the primary endpoint of all-cause mortality and no significant reductions in any of the secondary outcomes, which included myocardial infarction, stroke, and amputations. Considering the high baseline homocysteine concentration of participants in the HOST study, the argument that the negative results in the published clinical trials were due to the already lower serum homocysteine concentrations in the general population, because of fortification of the North American food supply with folic acid, is invalid.

More negative results have been also published from a recent meta-analysis of randomized controlled trials, which included 165 relevant reports and 12 randomized controlled trials that compared folic acid supplementation with either placebo or usual care for a minimum duration of 6 mo and with clinical cardiovascular disease events reported as the endpoint. In this meta-analysis, the relative risk (RR) of coronary heart disease (CHD) was 1.04 (95% CI: 0.92, 1.17) and of stroke was 0.86 (95% CI: 0.71, 1.04) (3). When these results were updated with the results of the HOST trial, the overall inverse-variance weighted odds ratio per each 3-µmol/L reduction in homocysteine concentration, for a mean duration of treatment of 3.1 y, was 1.00 (95% CI: 0.92, 1.09) for CHD events (n = 12 trials) and 0.88 (95% CI: 0.78, 1.00) for stroke (n = 9 trials) (4). Given the large sample size of the abovementioned meta-analysis, the issue of low power should be irrelevant. It is worth mentioning that, although the HOPE-2 study did report a significant reduction in stroke, as mentioned in McCully's article, this was a secondary outcome.

All of these negative results make doubtful the evidence in support of a possible reduction in CVD risk through a reduction in homocysteine concentrations. The argument that a reduction in homocysteine concentrations via vitamin B supplementation is helpful in the primary prevention of CVD needs to be revised. It is well known that a reduction in established CVD risk factors, such as hypercholesterolemia, smoking, obesity, hypertension, and diabetes, results in a more significant reduction in CVD as a secondary prevention approach than as a primary prevention approach. Why then should we expect the opposite from homocysteine if it is really a causal risk factor for CVD and not just a disease marker?!

ACKNOWLEDGMENTS

Neither author reported a conflict of interest.

REFERENCES

1. McCully KS. Homocysteine, vitamins, and vascular disease prevention. Am J Clin Nutr 2007;86(suppl):1563S–8S.[Abstract/Free Full Text]
2. Jamison RL, Hartigan P, Kaufman JS, et al. Effect of homocysteine lowering on mortality and vascular disease in advanced chronic kidney disease and end-stage renal disease: a randomized controlled trial. JAMA 2007;298(10):1163–70.[Abstract/Free Full Text]
3. Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA 2006;296(22):2720–6.[Abstract/Free Full Text]
4. Baigent C, Clarke R. B Vitamins for the prevention of vascular disease: insufficient evidence to justify treatment. JAMA. 2007;298:1212–4.[Free Full Text]

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