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Women's Antioxidant & Folic Acid Study

Results from the vision component of the Women's Antioxidant and Folic Acid Cardiovascular Study, also known as WACS, were presented at the ARVO 2007 Annual Meeting. Researchers from the Brigham and Women's Hospital and the National Eye Institute concluded that the data from this randomized trial indicate that supplementation with folic acid, vitamins B6 and B12 reduced the risk of AMD in women with cardiovascular disease (CVD) (1).

These three B-vitamins, particularly folic acid, have been shown to reduce high levels of the naturally occurring compound, homocysteine. Research has implicated elevated plasma levels of homocysteine in the development of vascular diseases including choroidal neovascularization in exudative AMD.

Study Design and Methods

A total of 8,171 female health professionals, 40 years or older with pre-existing CVD or having at least three risk factors for the disease were enrolled in the trial. The women were randomized to receive vitamin C (500 mg daily), vitamin E (600 IU every other day), beta-carotene (50 mg every other day) or placebo in the WACS secondary prevention trial.

Of this group, 5,422 women were subsequently randomized to also receive a placebo or folic acid (2.5 mg), vitamin B6 (50 mg) and vitamin B12 (1 mg) daily. Of these women, 5,205 did not have a diagnosis of AMD, and were included in this analysis. There were two primary outcome measures: a) confirmed AMD (self reported and supported by medical record evidence of an AMD diagnosis after randomization) and b) confirmed AMD with vision loss - defined as vision to 20/30 or worse which was attributable to this condition.

Results

A total of 137 cases of AMD were documented, including 69 cases of AMD with vision loss, during an average of 7.3 years of treatment and follow-up. Fifty-five cases occurred in the treatment group, while the placebo group had 82 documented cases. Relative risk was 0.66 (95% confidence interval, p = 0.02). For AMD with vision loss, there were 26 cases in the B-vitamin group compared to 43 among placebo takers. Relative risk was 0.60 (95% confidence interval, p = 0.04). In summary, women taking supplemental B vitamins were 34% less likely to develop AMD and 40% less likely to have AMD-related vision loss than women in the control group.

Commentary

While very high doses of the 3 B vitamins were tested in this group of women with CVD, lower doses may well have been effective. For example, a placebo-controlled, randomized dose response study in people with a history of CVD found that the decrease in homocysteine was proportionate to the folate dose up to - and not beyond - 800 mcg daily (2). This dose achieved an average 23% drop in plasma homocysteine compared to placebo - a drop of about the same magnitude found in trials using up to 5,000 mcg folate daily (3). Additionally, excessive amounts of folic acid have recently been implicated in colorectal tumor growth (4,5).

Antioxidant - CVD Outcomes in WACS

The WACS authors report that vitamins C, E or beta-carotene had no overall effects on CVD events in these high-risk women (6), pointing out that antioxidants are no magic bullets for the secondary prevention of this disease. However, the study did confirm the safety of high potency antioxidants, and women who received both vitamins C and E experienced fewer strokes. The same research group is following up to determine whether the combination of vitamins C and E affect the biomarkers in blood that strongly predict stroke. That work will use blood samples from 300 participants taken at the beginning and end of the WACS study.

References

1. Christen WG, et al. Folic acid plus B-vitamins and age-related macular degeneration in a randomized trial in women. Invest Ophthalmol Vis Sci 48:E-abstract 1152, ARVO, 2007.
2. Wald DS, et al. Randomized trial of folic acid supplementation and serum homocysteine levels. Arch of Internal Med 161:695-700, 2001.
3. Homocysteine Lowering Trialists' Collaborative. Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomized trials. BMJ 316:894-8, 1998.
4. Mason JB, et al. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: A hypothesis. Cancer Epidemiol Biomarkers Prev 16:1325-9, 2007.
5. Cole BF, et al. Folic acid for the prevention of colorectal adenomas. JAMA 297:2351-9, 2007.
6. Cook NR, et al. A randomized factorial trial of vitamins C and E and beta carotene in the secondary prevention of cardiovascular events in women: Results from the WAC Study. Arch of Int Med 167:1610-18, 2007.