This is the first randomized trial to investigate supplemental use of folic acid and B vitamins in the prevention of AMD. The results, based on an average of 7.3 years of treatment and follow-up of women at increased risk of CVD, indicate that those assigned to active treatment had a statistically significant 35–40% decreased risk of AMD. The beneficial effect of treatment began to emerge at approximately 2 years of follow-up and persisted throughout the trial.
Support for the hypothesis that folic acid and B vitamins could lower the risk of AMD has derived largely from observational evidence of a direct association between homocysteine level in the blood and risk of AMD (17
), and the demonstration in intervention studies that treatment with folic acid and B vitamins could lower homocysteine levels (33
). Further support has been provided by laboratory evidence that the damaging sequelae of elevated homocysteine (e.g. endothelial dysfunction [28
], impaired vascular reactivity [29
], promotion of inflammatory processes leading to atherosclerosis [50
]), thought to underlie the increased risk of vascular disease, may also contribute to the pathophysiology of AMD (37
). The trial findings reported here are the strongest evidence to date in support of a possible beneficial effect for folic acid and B vitamins in AMD prevention. Moreover, because these findings apply to the early stages of AMD development (most cases were characterized by a combination of drusen and RPE changes) in persons without a prior diagnosis of AMD, they appear to represent the first identified means, other than avoidance of cigarette smoking, of reducing risks of AMD in persons at usual risk. From a public health perspective, this is particularly important since persons with early AMD are at increased risk of developing advanced AMD, the leading cause of severe irreversible vision loss in older Americans.
Whether the reduced risk of AMD observed in WAFACS is due to homocysteine-lowering by the folic acid, B vitamin combination, or is independent of homocysteine lowering, is an important question to be investigated. We examined the impact of the intervention on homocysteine levels in a sub-study of 300 WAFACS participants (150 in each treatment group) who had blood samples collected at study entry in 1993–1995, and again at study completion in 2005. Details of the sub-study are presented elsewhere (43
). In short, the geometric mean plasma homocysteine level was decreased by 18.5% (95% CI, 12.5–24.1; P<0.001) in the active arm compared to the placebo arm, a difference of 2.27 :mol/L (95% CI, 1.54–2.96). These sub-study findings indicate that the reduced risk of AMD we observed in the treated group may have been due, at least in part, to homocysteine-lowering. However, a treatment benefit independent of homocysteine-lowering is also possible. Plausible mechanisms include a direct antioxidant effect of folic acid and B vitamins, and enhancement of endothelial nitric oxide levels in the choroidal vasculature, with an associated increase in vascular reactivity (53
). Further study is required to distinguish between these and other possibilities.
Our findings for AMD are in sharp contrast to the null findings for CVD observed in WAFACS (43
) and other completed trials of homocysteine-lowering in persons with pre-existing vascular disease, despite substantially lowered homocysteine concentrations by study treatment in those trials (56
). While our findings could be due to chance and need to be confirmed in other populations, it may be worthwhile to consider whether the discordant findings for AMD and CVD reflect important differences between the choroidal and systemic vasculature with respect to responsiveness to homocysteine-lowering. AMD is a disease that likely involves damage to the small vessels of the choroid (67
), and some evidence suggests that homocysteine may be a more potent risk factor for small vessel disease than for large vessel disease (69
). If so, then small vessel diseases such as AMD, and perhaps some subtypes of stroke (e.g. lacunar brain infarcts, cerebral white matter lesions), may be more amenable to benefit from homocysteine-lowering. Of note, a recent meta-analysis of completed trials of homocysteine-lowering indicated that folic acid supplementation had little impact on CVD (pooled RR 0.95; 95% CI, 0.88–1.03) or coronary heart disease (pooled RR 1.04; 95% CI, 0.92–1.17), but was associated with a non-significant 14% reduced risk for total stroke (pooled RR 0.86; 95% CI, 0.71–1.04) (36
). Further detailed analyses of etiologic subtypes of stroke in these trials may suggest a beneficial effect of folic acid supplementation that is observable primarily in diseases of small vessels.
In summary, daily supplementation with folic acid/B6/B12 over seven years reduced the risk of AMD in women at increased risk of vascular disease. Because there are currently no recognized means to prevent the early stages of AMD development other than avoidance of cigarette smoking, theses findings could have important clinical and public health implications and need to be confirmed in other populations of men and women.