A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8

Abstract

Background: Observational and experimental data suggest that antioxidant and/or zinc supplements may delay progression of age-related macular degeneration (AMD) and vision loss.

Objective: To evaluate the effect of high-dose vitamins C and E, beta carotene, and zinc supplements on AMD progression and visual acuity.

Design: The Age-Related Eye Disease Study, an 11-center double-masked clinical trial, enrolled participants in an AMD trial if they had extensive small drusen, intermediate drusen, large drusen, noncentral geographic atrophy, or pigment abnormalities in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye. At least 1 eye had best-corrected visual acuity of 20/32 or better. Participants were randomly assigned to receive daily oral tablets containing: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg); (2) zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide; (3) antioxidants plus zinc; or (4) placebo.

Main outcome measures: (1) Photographic assessment of progression to or treatment for advanced AMD and (2) at least moderate visual acuity loss from baseline (> or =15 letters). Primary analyses used repeated-measures logistic regression with a significance level of.01, unadjusted for covariates. Serum level measurements, medical histories, and mortality rates were used for safety monitoring.

Results: Average follow-up of the 3640 enrolled study participants, aged 55-80 years, was 6.3 years, with 2.4% lost to follow-up. Comparison with placebo demonstrated a statistically significant odds reduction for the development of advanced AMD with antioxidants plus zinc (odds ratio [OR], 0.72; 99% confidence interval [CI], 0.52-0.98). The ORs for zinc alone and antioxidants alone are 0.75 (99% CI, 0.55-1.03) and 0.80 (99% CI, 0.59-1.09), respectively. Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD. Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91; zinc: OR, 0.71; 99% CI, 0.52-0.99; antioxidants: OR, 0.76; 99% CI, 0.55-1.05). Both zinc and antioxidants plus zinc significantly reduced the odds of developing advanced AMD in this higher-risk group. The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99). No statistically significant serious adverse effect was associated with any of the formulations.

Conclusions: Persons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study.

Figure 1

Fundus photographs from participants in the Age-Related Eye Disease Study (AREDS) illustrating eyes in age-related macular degeneration Categories 2 and 3. A, Left eye in Category 2 shows nonextensive intermediate drusen, mostly located superotemporal to the center of the macula. No druse is 125 μm or greater in diameter, although some are 63 μm or greater and their cumulative area is less than AREDS circle O-2 (about 0.2 disc areas). B, One left eye in Category 3 depicts the lower limit of the category, having 1 large druse (≥125 μm in diameter) in the 8-o’clock position from the center of the macula, while another left eye (C) shows many large drusen (totaling at least 1 disc area) scattered throughout the macula.

Figure 2

Age-Related Eye Disease Study (AREDS) randomization schema. AMD indicates age-related macular degeneration.

Figure 3

Participant follow-up and adherence by year in study. A, Number of participants with follow-up visits and percentage of total enrolled (n = 3640). B, Percentage of participants taking at least 75% of their study tablets.

Figure 4

Repeated-measures estimates of the probability of the development of advanced age-related macular degeneration (AMD) in at least 1 eye of participants assigned to placebo by baseline AMD category. Events before year 2 reflect only photocoagulation.

Figure 5

Repeated-measures estimates of the probability of development of advanced age-related macular degeneration (AMD) in at least 1 study eye of participants in Categories 3 and 4 by treatment group. The study eye is an eye without disqualifying lesions or evidence of advanced AMD, and with a visual acuity score of greater than 73 letters (20/32 or better) at baseline. Events before year 2 reflect only photocoagulation.

Figure 6

Repeated-measures estimates of the probability of a loss in the visual acuity score of at least 15 letters in at least 1 study eye of participants in age-related macular degeneration (AMD) Categories 3 and 4 by treatment group. The study eye is an eye without disqualifying lesions or evidence of advanced AMD and with a visual acuity score greater than 73 letters (20/32 or better) at baseline.

Figure 7

Proportion of participants with visual acuity loss of 15 letters or more in at least 1 study eye by treatment group and follow-up time among participants in age-related macular degeneration (AMD) Categories 3 and 4.

Figure 8

Odds ratios (squares) and 99% confidence intervals (colored bars) for each treatment compared with placebo for participants in age-related macular degeneration (AMD) Categories 3 and 4. A, Visual acuity outcomes. B, AMD outcomes. GA indicates geographic atrophy.

Figure 9

Kaplan-Meier estimates of the probability of death among all participants in the age-related macular degeneration trial by treatment group. P= .08, unadjusted comparison across treatments.