A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E and beta carotene for age-related cataract and vision loss: AREDS report no. 9.

Adults enrolled in the Age-Related Eye Disease Study were randomized across a multicenter factorial design at 11 U.S. retinal clinics. Participants had varying severity of age-related macular degeneration and at least one natural lens, and were followed with annual lens photography and 6-month visual acuity assessments.

In this multicenter randomized, placebo-controlled AREDS trial, participants received oral high-dose antioxidant tablets containing vitamin C 500 mg, vitamin E 400 IU, and beta carotene 15 mg daily, with some arms also receiving zinc 80 mg as zinc oxide plus copper 2 mg as cupric oxide. Tablets were taken as 2 each morning and 2 each evening with food for an average follow-up of 6.3 years.

High-dose antioxidant supplementation did not reduce age-related lens opacity progression, cataract surgery, or visual acuity loss. For any lens event, the adjusted OR was 1.00; for cataract surgery, the adjusted RR was 0.97; and in the AMD category 1 subgroup, visual acuity loss showed an adjusted OR of 1.07. Zinc analyses were also reported as showing no difference in lens event risk, although numeric results were not shown. Some adverse events were more common with antioxidants, including yellow skin, skin and subcutaneous tissue adverse experiences, and chest pain, but there were no significant mortality concerns.

Zinc-specific and combination-arm effect estimates were not reported numerically, limiting interpretation of those components. The trial involved subgroup analyses and multiple outcomes over long follow-up, which increases the chance of selective emphasis despite the overall randomized design. Generalizability is mainly to AREDS participants with age-related macular degeneration and at least one natural lens.