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Arch Ophthalmol. 2001 October; 119(10): 1417–1436. PMCID: PMC1462955 NIHMSID: NIHMS9674 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 Age-Related Eye Disease Study Research Group AREDS Coordinating Center, The EMMES Corporation, 401 N Washington St, Suite 700, Rockville, MD 20850-1707 (e-mail: aredspub@emmes.com ).

Background: Observational and experimental data suggest that antioxidant use of zinc 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 (≥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.