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Source: 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 reports no. 8. Arch Ophthalmol 2001;119:1417-1436.
Observational and experimental data suggest that antioxidant and/or zinc supplements may delay progression of age-related macular degeneration (AMD) and vision loss.
To evaluate the effect of high-dose vitamins C and E, beta carotene, and zinc supplements on AMD progression and visual acuity, the Age-Related Eye Disease Study (AREDS), an 11-center, double-blind clinical trial, enrolled participants if they had extensive small drusen, intermediate drusen, large drusen, non-central geographic atrophy, or pigment abnormalities in one or both eyes, or advanced AMD or vision loss due to AMD in one eye. At least one 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. Supplements were taken in divided doses with food.
Outcomes included photographic assessment of progression to or treatment for advanced AMD and at least moderate visual acuity loss from baseline (³ 15 letters). Primary analyses used repeated-measures logistic regression with a significance level of 0.01, unadjusted for covariates. Serum level measurements, medical histories, and mortality rates were used for safety monitoring.
Average follow-up of the 3,640 participants, ages 55-80 years, was 6.3 years; 2.4% were lost to follow-up. Fifty-six percent of the participants were female, 96% were white, and the median age was 69 years. 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 were 0.75 (99% CI, 0.55-1.03) and 0.80 (99% CI, 0.59-1.09), respectively. Participants with extensive small drusen, non-extensive intermediate size drusen, or pigment abnormalities had only a 1.3% five-year probability of progression to advanced AMD. Odds reduction estimates in-creased when these 1,063 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 the antioxidants plus zinc group (OR 0.73, 99% CI, 0.54-0.99). No statistically significant serious adverse effect was associated with any of the formulations.
These data show that persons older than age 55 should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive intermediate size drusen, at least one large druse, non-central geographic atrophy in one or both eyes, or advanced AMD or vision loss due to AMD in one eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc.
Acute macular degeneration is disturbingly common, genetically linked, and mysterious—its pathogenesis re-mains largely unknown. It is the leading cause of blindness in the United States among people age 65 and older.
More than 10 years ago, the National Eye Institute organized this large, multicenter study, and the data from it are invaluable. Due to the cost and focus on inexpensive supplements, it is unlikely to be repeated. With this major effort, the study has sufficient power to answer the question of whether AMD can be delayed and whether visual loss can be prevented or restored.
The study was very well designed and controlled. Patients could be enrolled with minimal or no drusen, or advanced, severe disease. Average follow-up was 6.3 years, and only a small percentage of patients were lost to follow-up.
In contrast to supplementation of beta carotene for stroke and heart disease, these results are very positive. Statistically significant reduction of moderate visual loss occurred in just one group of patients—those who took the antioxidant-zinc combinations. Many other outcomes trended toward significance, but did not reach the P = 0.01 level. Each individual supplement and the combination of supplements all appeared to slow progression of AMD, and all prevented progression to advanced AMD. The combination of all supplements was more effective than any one supplement by itself. One category of patients with AMD did not benefit—those with small drusen. All patients, of course, required ophthalmologic examinations for diagnosis and follow-up.
Whether to use beta carotene in smokers who have AMD, given the demonstrated increase in lung cancers, is a difficult, patient-by-patient decision. Arguably, another carotenoid, such as lutein or zeaxanthin, may be substituted. How long such supplementation should last and when it should be started are questions AREDS doesn’t answer. Nor does it answer questions about long-term (> 10 years) toxicity, though no adverse effects were noted during the trial.
Patients who are at risk for or who already have AMD should take 500 mg vitamin C, 400 IU vitamin E, 80 mg zinc oxide, and 2 mg cupric oxide daily. Consider substituting another carotenoid for beta carotene in smokers.