What We Should and Should Not be Recommending for Our Patients
EMILY Y. CHEW, MD
Age-related macular degeneration is the leading cause of visual impairment in the United States.1 Oxidative stress may play an important role in the pathogenesis of age-related macular degeneration (AMD). The Age-Related Eye Disease Study (AREDS) is a randomized, multicenter, placebo-controlled clinical trial designed to test the effect of pharmacologic doses of antioxidants and zinc on the incidence and progression of AMD. The results of AREDS demonstrated that in persons with a moderate risk of AMD or advanced AMD in 1 eye, high doses of antioxidant vitamins and minerals reduced the risk of developing advanced AMD by 25% in 5 years.2 The risk of moderate vision loss (15 or more letter decrease compared to baseline visual acuity [VA] measured on the logMAR chart) was also reduced by 19% at 5 years in those patients assigned to the combination of antioxidant vitamins and minerals compared to participants assigned to placebo.
The AREDS investigators recommend the participants who have moderate AMD (AREDS category 3) or those who have advanced AMD in 1 eye (AREDS category 4) consider taking the AREDS supplementation. Participants who have moderate risk of AMD have extensive intermediate drusen (>63 µm<125 µm) or large drusen (>=125 µm). A simple rule to determine the distance of 125 µm is to evaluate the central retinal vein as it merges out of the nerve, and as its branches cross the rim of the optic nerve, the diameter of the vein is approximately 125 µm. Advanced AMD is defined as neovascular if the eye has received laser photocoagulation, or has one of the following characteristics: nondrusenoid retinal pigment epithelial (RPE) detachment, serous or hemorrhagic retinal detachment, hemorrhage under the retina or the RPE, or subretinal fibrosis. Advanced AMD of geographic atrophy consists of eyes that have geographic atrophy involving the center of the fovea.
In the AREDS study, participants with early AMD were also enrolled and assigned to different treatment strategies. The rate of development of advanced AMD in this group was exceedingly low, 1.3% in 5 years. These numbers were insufficient for investigating the effects of treatment on advanced AMD. One of the goals of AREDS was to develop a scale of AMD severity, similar to that of diabetic retinopathy. The publication of this scale is currently under review. A separate, photographic grading scale was used to analyze the size and the area of drusen. It was also used to assess whether the antioxidant vitamins and minerals would reduce the progression of eyes with early AMD to more severe levels of AMD.3 No beneficial effects of the combination treatment in preventing these early AMD eyes to the more severe stages of AMD were seen. For this reason, the AREDS supplements are recommended for persons with AREDS categories 3 or 4 ocular diseases and not milder diseases.
FAMILY HISTORY OF AMD
What about persons who have no early AMD, but have a family history of AMD? This particular clinical scenario has not been addressed in a clinical study. However, since we were not able to detect appreciable beneficial effects of vitamins and minerals for these individuals, we would recommend that they have regular eye exams that include dilated evaluation of the macula to determine their AMD risk. Once they have reached the level of category 3, with extensive intermediate drusen or large drusen, the AREDS combination treatment would then be recommended.
For those eyes with more severe disease than categories 3 and 4, would the AREDS formulation also be advisable? This question was addressed partially in the first report of the mainline results of the AREDS study in which eyes with advanced AMD (neovascular) at enrollment with VA of 20/100 or better at baseline had a reduced risk of moderate vision loss in the treated groups compared to the placebo group.2 Further studies evaluating the risk of vision loss for those who develop advanced AMD in the fellow eye of participants who already have advanced AMD (AREDS category 4) are underway. Treatment with the combination of antioxidants and minerals may be considered for patients with advanced AMD, especially those with VA of 20/100 or better at presentation.
COMPONENTS OF THE AREDS FORMULATION
The AREDS combination formulation consisted of vitamin C (500 mg), E (400 IU), beta-carotene (15 mg or 25000 IU), zinc (80 mg of zinc oxide), and copper (2 mg of cupric oxide). This formulation was designed following a number of workshops conducted by the study investigators with leading nutritional experts prior to the start of the randomized trial. The antioxidant vitamins C, E, and beta-carotene were considered important to include because of their antioxidative potential. The doses chosen reflected the dosages that were accepted to be safe and important to test in the early 1990s. The study design only evaluated the antioxidant vitamins as a group and not each component separately.
Beta-carotene, although not found in the eye, was considered important because of its antioxidative potential. Also, lutein/zeaxanthin and other carotenoids, which are important components of the macular pigment, were not commercially available at the time the study began. Since epidemiologic data suggested persons with higher serum levels of beta-carotene had a lower associated risk of lung cancer, beta-carotene of similar dose to that used in AREDS was tested in large chemoprevention trials for lung cancer. The results of these studies showed that supplementation of beta-carotene increased the risk of lung cancer and its associated mortality.4 An amendment was made to the AREDS protocol during the course of the study as these findings became evident. We offered all smokers participating in the AREDS the chance to stop the study medication, and offered them the opportunity to consider randomization to placebo or zinc only. Approximately 8% of the AREDS population smoked at the time of the study. The AREDS formulation is not recommended to persons who smoke.
Zinc was tested at the high dose of 80 mg because of the beneficial results of treatment reported by a single- center, randomized, controlled clinical trial of small sample size with short duration of follow-up.5 The outcome measurement of a few letters gained in the zinc-treated group was considered to be of questionable clinical significance. If the AREDS investigators did not test this particular dose, any negative results would have caused the supporters of zinc therapy to cite the insufficient dose as the reason for failure. Thus, this dose has become a standard of treatment for AMD. This is the largest dose of zinc and the longest duration of zinc supplements ever given. Nutritional experts continue to raise concerns about this dosage.
Copper deficient anemia is one of the adverse effects, which can be eliminated by concurrent copper supplementation. Although AREDS participants reported increased anemia, the measured hematocrits did not show a difference by treatment group. Hospitalization for genitourinary conditions was the main adverse effect reported among participants in the zinc arm of AREDS. Zinc treatment was also shown to be associated with decreased mortality in the AREDS (RR=0.73; 95% CI 0.600.89).6 The significance of this finding is not known because this is a selected population of volunteers in a randomized trial of vitamins and minerals. A relationship of zinc with Alzheimer's disease has been reported in vitro; and the AREDS study evaluated all participants with cognitive function testing.7 We were not able to find a decrease in cognitive function in participants who were assigned to zinc compared to those assigned to placebo. We remain concerned about the dose of zinc because a large dose was used compared to other studies.
Vitamin E is typically given in doses of 400 IU or higher. A recent meta-analysis of vitamin E concluded that doses of vitamin E of 400 IU or higher were associated with an increased risk of mortality.8 There were limitations associated with this analysis because it did not weigh studies on the basis of sample size or follow-up duration. In addition, the analysis used prevalence data rather then incidence data from 19 studies. The distribution-based cut point for exposure was arbitrarily set to 400 IU or higher. An analysis of studies using 400 IU440 IU of vitamin E in more than 15000 subjects did not yield the same results; there was no strong basis for inferring increased mortality among participants exposed to these levels of vitamin E. The pooled risk ratio for these 3 studies was 0.998 with a risk difference of -1.8 per 10000 persons in the direction of benefit. Based on these data, it would appear to be safe to take this dose of vitamin E in the AREDS formulation.9
The AREDS will be closing by the end of 2005. A number of scientific questions remain unanswered. The National Eye Institute will be conducting another study, AREDS II, in the prevention of AMD with nutritional supplements in patients at risk for AMD. The primary objective of AREDS-II is to determine whether oral supplementation with macular xanthophylls (lutein at 10 mg/d + zeaxanthin at 2 mg/d) and/or omega-3 long-chain polyunsaturated fatty acids (LCPUFAs, docosahexaenoic acid (DHA) + eicosapentaenoic acid (EPA) at a total of 1 g/d) will decrease the risk of progression to advanced AMD, as compared to placebo. These 2 nutrients are of particular interest because of the mounting epidemiologic data to suggest that nutrients are associated with a decreased risk of AMD. The design of this trial will be a 2 x 2, factorial, placebo-controlled study, which will maximize the ability to evaluate the effects of the nutrients. One quarter of the patients will be assigned to a placebo group, one quarter will be assigned to a lutein/zeaxanthin group, one quarter will be assigned to an omega-3 LCPUFAs group, and finally one quarter will be assigned to a combination of the two.
There is considerable interest in the role of dietary lipids in the pathogenesis of AMD. A number of aging cohorts have been examined to test the relationship of dietary lipid intake with AMD. Some studies have shown inverse relationships of omega-3 LCPUFA and omega-3 LCPUFA-rich food intake with various forms of AMD. These relationships did not always persist after multivariable adjustments.10-13
Lutein and zeaxathin, members of the carotenoid family, are compounds that compose macular pigment.14,15 They are found in photoreceptor axons, as well as the inner plexiform layer of the macula where they may operate as protective factors for AMD by absorbing the light that may be associated with photochemical damage and by quenching reactive oxygen species (antioxidative potential). Epidemiologic data suggest that increased dietary intake and elevated serum levels of lutein/zeaxanthin are associated with a decreased risk of advanced AMD.16-18 Despite the lack of data from a randomized, controlled clinical trial, the press has given lutein center stage resulting in an increased proportion of the persons at risk of AMD taking lutein.
Currently, AREDS II will include participants with a moderate risk of AMD or AMD in 1 eye. Age-related macular degeneration outcomes will be ascertained on the basis of annual fundus photographs graded with a standardized protocol. Sample size calculations may need further assessment, but approximately 4000 subjects will be required. This will be a multicentered study with clinical centers from both academic centers and private practices, and will be conducted according to the NIH Roadmap Plan, possibly adding diversity and providing more generalized results.
REFINEMENT OF AREDS FORMULATION
In addition to testing the above 2 important nutrients, AREDS II will provide an opportunity to refine the current AREDS formulation. The study population in AREDS II consists of those persons in whom the AREDS formulation should be recommended. Since the AREDS formulation is now the standard of care for prevention of AMD, it will be offered to the AREDS II study population. It is anticipated that the proportion of the subject taking the AREDS supplements may range from 65%75%.
What changes may be incorporated in the AREDS formulation? We may incorporate a secondary randomization that occurs following the first randomization in those subjects who choose to take the AREDS formulation. The two most likely changes will be lowering the zinc level and elimination or decrease in beta-carotene level.
This design will maximize our opportunity to answer important questions in the treatment of AMD. We hope this study will generate enthusiasm from our clinical colleagues to participate in this collaborative clinical research effort.
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National Eye Institute/National Institutes of Health, Bethesda, MD. The author has no financial interest in the content of this article.