Value of Homocysteine-lowering Folic-Acid/ vitamin B Therapy in Cardiovascular Prevention—Have We Been Wrong Again?

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Source: Albert CM , et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease. JAMA. 2008; 299:2027-2036.

Synopsis: After 7.3 years of treatment and follow-up, a combination pill of folic acid, vitamin B6 and vitamin B12 did not reduce a combined endpoint of total cardiovascular events among high-risk women despite significant homocysteine lowering.

Almost 40 years ago it was first suggested that homocysteine, an amino acid produced during catabolism of methionine, could cause arterial and venous atherothrombotic disease1 by promoting oxidative stress, endothelial cell damage, endothelial dysfunction, inflammation, thrombosis, and cell proliferation.2 Although epidemiological studies in general have demonstrated associations between elevated homocysteine levels and increased risk of coronary heart disease (CVD) and stroke,6 new results from multiple recent clinical trials have not provided clear evidence of any beneficial effects of vitamin B and/or folic acid supplementation in CVD risk reduction.3,4,5,7

Women had been under-represented in observational studies and in randomized trials of homocysteine lowering despite the fact that observational studies have suggested that women may benefit from homocysteine lowering to a greater extent than men.6 Albert and his colleagues conducted the Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS) which tested whether a combination of 2.5 mg of Folic acid, 50 mg of vitamin B6 and 1.0 mg of Vitamin B12 would reduce total cardiovascular events among women at high risk for the development of CVD over 7.3 years of follow-up.8 A total of 8171 female health professionals were randomized in a carefully controlled 2 x 2 x 2 factorial designed trial. After 7.3 years of treatment and follow-up, the combination pill of folic acid, vitamin B6 and vitamin B12 did not reduce the combined endpoint of total cardiovascular events among high-risk women despite significant homocysteine lowering.


The WAFACS trial8 had several unique strengths in that it was focused on women (who were under-represented in the other homocysteine-lowering trials), follow-up was substantially longer (ie, 7.3 years) than was the case in previous trials and as many as 33% of the women studied had no prior vascular events thereby providing some limited data regarding high risk primary prevention. However, it should also be noted that there were some limitations in the trial, the most important being that the trial was conducted after the introduction of federal policies that mandated the addition of folic acid to white flour, cereal grains and related products in the United States which resulted in lower homocysteine concentrations in the US population. Therefore administration of folic acid and vitamin B6 lowered the homocysteine concentrations in the trial subjects to a lesser extent than had been anticipated at the time of its design and may have therefore affected its ability to adequately test the study hypotheses. Also, homocysteine levels were measured in only 5% of study participants and therefore detailed analysis of potential benefits in subsets of patients with high retreatment homocysteine levels could not be performed and finally, it should be recognized that the trial evaluated a highly selective population of female health care professionals with relatively low CVD event rates. Despite these limitations the results obtained in the WAFACS trial were consistent with the results obtained in prior randomized trials performed primarily among men with established vascular disease7 and do not support the use of folic acid and/or vitamin supplements as preventative interventions for CVD even in high-risk populations.

In conclusion, Folic acid and B vitamin supplements cannot currently be recommended for prevention of CVD events with the possible exception of individuals afflicted with rare genetic disorders. Therefore, there is no role for routine screening for elevated homocysteine levels at this time. However, ongoing clinical research may yield new evidence of the overall importance of homocysteine as a CVD risk factor at which time the issue of Folic acid/vitamin B therapy will almost certainly have to be re-addressed. So.....don't throw these apparently valueless pills away just yet!


1. McCully KS, et al. Am J Pathol. 1969;56(1):111-128.

2. Welch GN, et al. N Engl J Med. 1998;338(15):1042-1050.

3. Toole JF, et al. JAMA. 2004;291(5): 565-575.

4. Lonn E, et al. N Engl J Med. 2006;354(15):1567-1577.

5. Bonaa KH, et al. N Engl J Med. 2006;354 (15):1578-1588.

6. Homocysteine Studies Collaboration. JAMA. 2002;288(16):2015-2022.

7. Bazzano LA, et al. JAMA. 2006; 296(22):2720-2726.

9. Albert CM, et al. JAMA. 2008;299:2027-2036.