FAQ
Cardiovascular Disease and Homocysteine
Background
Heart disease is the leading cause of death and disability in the United States. It accounts for more than 36% of all deaths or approximately 850,000 deaths each year. In light of these statistics, the focus of many clinical trials has been to examine primary and secondary preventative measures for people with heart disease. One example of a risk factor for cardiovascular disease that has been identified as a possible target for preventative measures is elevation in homocysteine levels. Homocysteine is an amino acid derivative that has been identified as a marker for increased risk for premature atherosclerosis and venous thromboembolism. The actions of homocysteine in patients with severe elevations (plasma levels >100mmol/L) are unclear, but they are thought to include endothelial dysfunction, accelerated oxidation of low-density lipoprotein cholesterol, impaired thrombolysis, increased production of hydrogen peroxide, platelet activation, and increased oxidative stress. Patients can develop high homocysteine levels because of rare inherited genetic defects, but in the general population mild to moderately elevated levels (plasma levels >15mmol/L) are more common due to low dietary intake of folic acid. Folic acid is the most important dietary determinate of homocysteine. It is present in the diet of most Americans because of the mandatory fortification of cereal grains with folic acid that began in 1998. Daily supplementation of folic acid lowers plasma homocysteine levels by as much as 25% in some patients. This level can further be reduced by the addition of vitamins B12 and B6, which also play an important role in the reduction of homocysteine levels.
Literature Review
Observational studies have suggested that reducing plasma homocysteine levels would decrease patient risk for cardiovascular disease, but large randomized controlled trials have failed to demonstrate statistically significant effects. However, because supplementation with folic acid and vitamins B12 and B6 are inexpensive ways to possibly reduce the risk for cardiovascular disease, many recent clinical trials have attempted to further investigate this hypothesis. Many of the previous trials have had limitations including lack of follow-up, short duration, the initiation of grain fortification during the study, and under-representation of women and patients with preexisting vascular disease. These limitations can make it difficult to interpret and also to extrapolate the results to patients in the general population; recent trials have been designed to try and correct some of these limitations. One example is a trial conducted by Albert and colleagues, published in the Journal of the American Medical Association (JAMA) May 7, 2008 issue. The main objective of this study was to determine if supplementation with a combination of folic acid, vitamin B12, and vitamin B6 would lower the risk of cardiovascular disease among high-risk women with and without cardiovascular disease.
The Women’s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) was a randomized, double-blind, placebo-controlled trial that tested whether a combination of folic acid, vitamin B12, and vitamin B6 would reduce the number of total cardiovascular events both among women with cardiovascular disease and those at high risk for the development of cardiovascular disease. This trial was developed as a part of the larger Women’s Antioxidant Cardiovascular Study (WACS), which was designed to determine effect of antioxidant vitamins (vitamins C, E, and beta carotene) on women’s cardiovascular health. The women recruited for the study were female healthcare professionals and were eligible to participate in the WAFACS if they were 40 years or older, were post-menopausal or had no intention of becoming pregnant, and had either a reported diagnosis of cardiovascular disease or at least 3 risk factors. Cardiovascular disease was defined as history of myocardial infarction (MI), stroke, coronary or peripheral revascularization, angina pectoris, or transient ischemic attack. Risk factors for cardiovascular disease included diagnosed hypertension, high cholesterol, diabetes mellitus, family history of MI, obesity (body mass index >30 kg/m2), and current cigarette use.
Of those women eligible, 5442 were randomized to receive either a combination drug containing folic acid (2.5 mg/day), vitamin B12 (1 mg/day), and vitamin B6 (50 mg/day) or an identical matching placebo. The planned duration of follow-up was 7.3 years. The women in both treatment groups were mailed monthly calendar packs of study medications and were followed annually with questionnaires on adherence, use of non-study medications, occurrence of major illness, or adverse events. The primary outcome of this trial was a combined endpoint of cardiovascular morbidity and mortality, which included incidence of MI, stroke, coronary revascularization procedures, and cardiovascular death. The secondary endpoints were the individual components of the composite endpoint analyzed separately. Medical records were examined for cardiovascular endpoints to determine primary and secondary follow-up in patients.
After completing the 7.3 year follow-up analysis, no statistical difference was seen between treatment groups on the primary outcome of cardiovascular morbidity and mortality. The analysis was performed using an intent-to-treat approach, and during the 7.3 years of follow-up, 796 participants (14.6%) experienced a confirmed cardiovascular event. A total of 406 (14.9%) women in the active group and 390 (14.3%) women in the placebo group experienced an event corresponding to a relative risk (RR) of 1.03 (95% confidence interval [CI], 0.90-1.19; P=0.65). When the components of the composite endpoint were analyzed as secondary endpoints individually, no significant difference was demonstrated in the active versus placebo treatment groups across any event. In addition, no significant differences were found in response to adverse events in the active versus placebo groups. A sub-group analysis was performed with 300 women who had provided blood samples in 1996, prior to the mandatory folic acid fortification of grains. One hundred fifty participants were in the placebo group and 150 in the active treatment group. Prior to folic acid grain fortification and randomization in the study, folate and homocysteine levels were similar between the 2 groups. Although grain fortification with folic acid significantly increased the folate levels in the placebo group, no reductions in homocysteine levels were seen at the end of study period. However, among the 150 participants in the sub-group given supplementation during the trial, folate levels increased more than in the placebo group and significant reductions were seen in homocysteine levels.
Overall, the study results showed that, although folic acid and vitamins B12 and B6 supplementation resulted in decreases in homocysteine levels, the study failed to demonstrate that homocysteine reduction has an effect on cardiovascular morbidity and mortality as suggested.
The WAFACS results are consistent with other studies. Along with this conclusion, it is important to consider this study’s limitations. This study was evaluating only women, therefore, it can not be generalized other populations. While the study did improve on previous studies that did not include a large population of women, it still failed to show any significant improvements. Also the participants were healthcare professionals, who may have a better dietary consistency with respect to vitamins and minerals, including those supplements studied. These participants’ results may not be the same as patients in the population who do not have adequate intake of dietary sources. And finally, even though this trial did include patients without prior cardiovascular disease, which has not been seen in many previous studies, the study was not sufficiently powered to detect a primary prevention effect among these individuals.
Conclusion
In conclusion, the Women’s Antioxidant and Folic Acid Cardiovascular Study was unable to demonstrate a benefit of combined supplementation with folic acids and vitamins B12 and B6 in the prevention of cardiovascular disease in women. While the trial did not demonstrate additional adverse events and the supplements were safe to use and well-tolerated, the results do not support the use of these supplements in the primary or secondary prevention of women at high risk for cardiovascular disease.
References
- American Heart Association. Cardiovascular Disease Statistics. Available at: http://www.americanheart.org/presenter.jhtml?identifier=4478. Accessed May 16, 2008.
- Bazzano LA, Reynolds K, Holder KN, et al. Effect of folic acid supplementation on risk of cardiovascular diseases: a meta-analysis of randomized controlled trials. JAMA. 2006; 296(22):2720-26.
- Libby Peter, Bonow, Robert O., Mann Douglas L., Zipes Douglas P. eds. Braunwald’s Heart Disease: A Textbook of Cardiovascular Medicine-7th Edition. Pennsylvania: Elsevier Saunders.2005.
- Toole JF, Malinow MR, Chambless LE, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction, and death: the Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA. 2004; 291:565-75.
- Bonaa KH, Njolstad I, Ueland PM, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med. 2006; 354: 1578-88
- Lonn E, Yusuf S, Arnold MJ, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006; 354: 1567-77
- Cook NR, Albert CM, Gaziano JM, et al. Effect of folic acid and B vitamins on the risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized controlled trial. JAMA.2008; 299(17):2027-36
- Cook NR, Albert CM, Gaziano JM, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular disease events in women: results from the Women’s Antioxidant Cardiovascular Study. Arch Intern med. 2007; 167(15): 1610-1618.