In this large randomized trial, women assigned to alternate-day treatment with 600 IU of natural-source vitamin E and followed for an average of 10 years had a non-significant 7% reduced risk of the primary study endpoint of visually-significant AMD. The 95% CIs excluded with reasonable certainty reductions of 28% or greater, and harmful effects of 20% or greater. Vitamin E treatment had no significant effect on the secondary endpoints of advanced AMD and total AMD with or without vision loss.
The WHS is the longest randomized trial of vitamin E supplementation in AMD to date. Three other trials have examined vitamin E in AMD, but only two were able to evaluate the separate effects of vitamin E supplementation. The Alpha-Tocopherol Beta-Carotene (ATBC) Study was a 2 × 2 factorial trial of vitamin E (50 mg daily) and beta carotene (20 mg daily) conducted among more than 29,000 Finnish male smokers aged 50 to 69 years. Median treatment duration was 6.1 years (24
). End-of-trial eye examinations for a small sub-sample of 941 participants aged 65 years and older identified 269 (29%) participants who showed signs of AMD based on evaluation of fundus photographs. The majority of cases (239/269 [89%]) were classified as dry maculopathy with hard drusen and/or pigmentary changes. There was no beneficial effect of vitamin E (RR, 1.13; 95% CI, 0.81–1.59) on the prevalence of AMD in that trial. In the Vitamin E, Cataract and Age-Related Maculopathy Trial (VECAT), comprised of 1193 participants aged 55 to 80 years, there was no overall benefit of 4 years of treatment with daily vitamin E (500 IU) on incidence of early (RR, 1.05; 95% CI, 0.69–1.61; n=69 cases) or late AMD (RR, 1.36; 95% CI, 0.67–2.77; n=7 cases), although the number of cases was small (25
). Our findings in WHS are broadly consistent with the findings for early AMD in ATBC and VECAT. Furthermore, with a treatment duration of 10 years, our findings extend these earlier findings by showing that very long-term supplementation with vitamin E alone is unlikely to have an important effect on AMD occurrence.
Comparison of our findings with the findings in AREDS is limited by differences in the study populations and primary endpoints, and by the absence of specific information on the effect of vitamin E in the AREDS formulation. AREDS tested a higher-risk population and the primary study endpoint was progression to advanced AMD (choroidal neovascularization or central geographic atrophy). Our primary endpoint was visually-significant AMD which represents, on average, a less severe stage of disease development than cases meeting the criteria for advanced AMD in AREDS. When we examined the more advanced cases of AMD in our population (defined as the occurrence of exudative neovascular disease or geographic atrophy), we found no evidence that vitamin E supplementation reduced the risk of advanced AMD. However, the number of advanced cases was small and the 95% confidence interval was compatible with the risk reduction observed in AREDS for combined treatment with antioxidants and zinc. Of course, it is possible that the benefit observed for the antioxidant combination in AREDS reflects the actions of other antioxidants tested (i.e. vitamin C, beta carotene) and that vitamin E has little effect on AMD at any stage.
There are several possible limitations of our study that warrant consideration, particularly in view of the absence of any statistically significant effects. The dose of vitamin E tested in this trial (600 IU taken every other day) was slightly lower than the dose tested in AREDS (400 IU daily), but was considerably greater than doses associated with a possible benefit in AMD in observational studies (38
). Thus, an inadequate dose of vitamin E seems unlikely to explain the observed lack of benefit. Compliance with study medication in WHS decreased over time (78.9% reported taking at least two thirds of the study capsules at 5 years), but was similar to that reported in AREDS (71% reported taking at least three fourths of the study capsules at 5 years). Inadequate duration of treatment also seems an unlikely explanation. The WHS was several years longer than AREDS which observed a benefit during an average of 6.3 years of treatment and follow-up. Several aspects of our methodology also deserve consideration. Identification of AMD cases was based on participant reports, and thus some degree of underascertainment of AMD is plausible. Such underascertainment would likely reduce study power (and limit the comparison of incidence rates between this and other populations), but is not associated with bias in randomized comparisons. Random misclassification of reported AMD, which would tend to shift the relative risk estimate toward the null, was reduced by the use of medical records to confirm the participant reports. Non-random or differential misclassification was unlikely since medical records were reviewed by an investigator (WGC) masked to treatment assignment, and study participants and treating ophthalmologists and optometrists were similarly unaware of treatment assignment. Finally, the equal distribution of baseline characteristics between the vitamin E and placebo groups in this large randomized trial indicates that confounding by measured factors is unlikely, and provides reassurance that other potential confounders, which were either unmeasured or unknown, were also likely to be evenly distributed between the two treatment groups.
In summary, these randomized trial data from a large population of healthy women indicate that 10 years of alternate-day treatment with 600 IU of natural source vitamin E alone has no material beneficial or harmful effect on AMD occurrence. Whether vitamin E as a component of an antioxidant combination can help to reduce risks of AMD, as suggested by the findings in AREDS, warrants continued investigation.