AREDS study evaluated whether vitamins were helpful in patients with macular degeneration. The study enrolled 3640 subjects, who had an average follow up of 6.3 years, few of whom (2.4%) were lost to follow-up. Subjects in the intervention group were assigned to vitamin doses that were 5 to 15 times the recommended dietary allowances (RDA) [C (500mg) and E (400IU), beta-carotene (15mg), zinc oxide (80mg with 2mg of copper)]. [Table 1] The initial high dose of zinc at 80mg was chosen in AREDS because of a reported beneficial effect at this dose in a previous study.
The participants were divided into four groups. One group received the antioxidants alone, one received the antioxidants plus zinc, the other zinc alone, and one group received placebo, serving as the control. Participants could be enrolled with few to no drusen and one eye had to have a visual acuity of 20/32 or better. Patients were categorized into four groups. Category 1 was intended to evaluate the effect of supplementation on cataract progression. Category 2 had multiple small drusen, few intermediate drusen, or pigmentary changes. Category 3 had extensive intermediate drusen or any amount of large drusen. And Category 4 had advanced AMD in only one eye which was defined as geographic atrophy involving the fovea, choroidal neovascularization, or exudative detachments. The study reported that either zinc alone, antioxidants alone, or the combination of the two modestly prevented the progression to advanced AMD from Categories 3 and 4. Furthermore, they found that the combination of antioxidants and zinc was more effective than either group alone. Specifically, the vitamin formulation decreased the risk of advanced AMD by 25% for participants with intermediate AMD. Participants who began the study with early AMD were so unlikely to develop advanced AMD (1.3%) during the course of their study that the beneficial effect on this group could not be evaluated. Combination formulations also decreased the risk of moderate visual loss of three lines or more at five years compared to baseline by about 19%. Those receiving either antioxidants alone or zinc alone failed to achieve statistical significance.
The AREDS group also examined the effects of treatment with AREDS formulation on the progression of further vision loss in eyes with advanced AMD and the effects on mortality.They found that persons assigned to the antioxidants alone had a reduced risk of progression to visual acuity loss of three lines. Those in the zinc group alone or the combination group also enjoyed a protective effect. They reported that after a median follow up of 6.5 years, 11% of the 4753 AREDS participants had died. Mortality increased with worsening macular pathology. Though a relationship between zinc and Alzheimer’s disease has been reported, AREDS found a decreased mortality (relative risk = 0.73) associated with a dose of 80 mg and there were no cognitive deficiencies found in participants. Furthermore, vitamin E was not found to increase the risk of mortality. They concluded that the AREDS formulation is safe for patients with intermediate AMD and those with advanced disease in one eye.
Dr. Jampol illustrated potential weakness in this study that should be considered when interpreting the data. First, the exclusion of Category 2 patients from many of the analyses is troubling because it occurred after reviewing the data. Second, the trial was only marginally powerful in demonstrating a beneficial effect of the vitamins, though it had a long follow-up. Third, many of the results were reported as trends since they did not meet statistical significance set a priori. Fourth, we cannot determine which or if all of the antioxidants provided the protective effect.