Background

Age-Related Eye Disease Study (AREDS)

Age-related macular degeneration (AMD) and cataract are leading causes of visual impairment and blindness in the United States. Approximately 1.7 million Americans have some form of AMD, and approximately 100,000 are blind from the disease. The NEI estimates that there are 1.5 million surgeries for cataract each year in the U.S. Based on many clinical studies, the frequency of both diseases increases dramatically after age 65, although scientists are not sure why.

Age-Related Macular Degeneration

Risk factors for AMD include:

• Personal characteristics, such as older age, race (Whites are more susceptible), and family history of AMD
• Eye characteristics, such as farsightedness (hyperopia) and light-colored eyes
• Cardiovascular disease, smoking, and hypertension

Presently, treatment for advanced AMD is very limited, and until now there has been no treatment to slow the progression of intermediate AMD. As the average lifespan of our population increases, the number of people who develop AMD will increase dramatically in the years ahead. Unless successful means of prevention or treatment are developed, blindness from advanced AMD -- and its importance as a public health problem -- will increase.

Cataract

Risk factors for cataract include:

• Personal characteristics, such as older age and gender (females are more susceptible)
• Eye characteristics, such as light-colored eyes
• Diabetes, hypertension, steroid medications, smoking, and sunlight exposure

Cataract surgery is very effective and highly successful, and is the most frequently performed surgery in the U.S. Research efforts that focus on preventing or slowing cataract development and determining the causes of cataract formation could lead to treatments that greatly reduce the need for cataract surgery.

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Age-Related Eye Disease Study

Animal studies, observational epidemiologic studies, and a few small clinical trials had previously suggested that antioxidants and the trace elements zinc and selenium may be associated with the risk of AMD and cataract development. Also, a small, randomized clinical trial of zinc supplementation found a statistically significant reduction in vision loss in a group treated with zinc compared with a group treated with a placebo, a harmless substance that has no effect on eye disease. The conclusion of the pilot study was that a more definitive study was necessary.

To help address the increasing public health concern regarding widespread use of high-dose vitamins and minerals for age-related macular degeneration, the National Eye Institute (NEI), one of the Federal government's National Institutes of Health, sponsored a major clinical study called The Age-Related Eye Disease Study (AREDS). The AREDS was designed to:

• Assess the clinical course, prognosis, and risk factors of AMD and cataract.
• Evaluate the effects of high doses of antioxidants and zinc on the progression of AMD and vision loss; and
• Evaluate the effects of high doses of antioxidants on the development and progression of cataract and vision loss.

The AREDS included two clinical trials -- one for AMD and one for cataract -- that generally shared one pool of participants. There were 4,757 participants, ages 55-80 years, enrolled in the study. Because 1,117 participants did not have at least early stages of AMD, the AMD trial included only the 3,640 participants who had at least early AMD. The cataract results are based on 4,629 enrollees; 128 of the 4,757 participants had cataract surgery on both eyes prior to enrollment and therefore were ineligible for the cataract clinical trial.

The participants' stages of disease ranged from no evidence of AMD in either eye, to advanced AMD with vision loss in one eye but good vision (at least 20/30) in the other eye. The participants were enrolled in 11 clinics nationwide. Fifty-six percent were female; the median age was 69 years. Enrollment began in November 1992 and ended in January 1998. About 90 percent of all participants were followed for a minimum of five years; about two percent were lost to followup; about one percent had been in the study less than five years; and about seven percent died before five years.

Category 1	Category 2	Category 3	Category 4
No AMD	Early Stage AMD	Intermediate AMD	Advanced AMD
A few small or no drusen	Several small drusen or a few medium-sized drusen in one or both eyes	Many medium-sized drusen or one or more large drusen in one or both eyes	In one eye only, either a break-down of light-sensitive cells and supporting tissue in the central retinal area (advanced dry form), or abnormal and fragile blood vessels under the retina (wet form)

Depending on their stages of AMD, the AREDS participants were placed in one of four categories. The one constant was that at least one eye of each participant had to be free from any vision-threatening eye disease other than AMD or cataract, and that eye could not have had previous surgery, except for cataract surgery. In Category One, participants had no AMD and a few small or no drusen -- tiny yellow deposits in the retina -- in either eye. In Category Two, participants had early AMD -- either several small drusen or a few medium-sized drusen in one or both eyes. Category Three participants had intermediate AMD -- either many medium-sized drusen or one or more large drusen in one or both eyes; these participants were at high risk for developing advanced AMD, which is generally defined as either a break-down of light-sensitive cells and supporting tissue in the central retinal area (advanced dry form), or abnormal and fragile blood vessels under the retina (wet form). Category Four participants already had advanced AMD in one eye, and in the other eye had good vision with no sign of advanced AMD. Previous studies had shown that the eye without AMD was at high risk for developing advanced AMD.

The participants in each category were randomly selected to receive daily oral tablets for one of four treatments: 1) zinc alone; 2) antioxidants alone; 3) a combination of antioxidants and zinc; or 4) a placebo, a harmless substance that looks like the real treatment but has no effect on eye disease. The antioxidant formulation contained a combination of vitamin C, vitamin E, and beta-carotene. The specific daily amounts of antioxidants and zinc used by the AREDS researchers were 500 milligrams of vitamin C; 400 international units of vitamin E; 15 milligrams of beta-carotene; 80 milligrams of zinc as zinc oxide; and two milligrams of copper as cupric oxide. In the study's planning stages, a panel of nutritionists, ophthalmologists, and biochemists reviewed the basic science and epidemiological data and recommended these vitamins and dosages.

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AREDS scientists found that people at high risk for developing advanced AMD -- those with intermediate AMD, and those with advanced AMD in one eye only -- reduced their risk of developing advanced stages of AMD by about 25 percent when treated with the combination of "antioxidants plus zinc." The combination of "antioxidants plus zinc" also reduced the risk of central vision loss by 19 percent in the same group. Participants at high risk for developing advanced AMD who were treated with "zinc alone" reduced their risk of developing advanced AMD by about 21 percent and their risk of vision loss by about 11 percent. Participants who were treated with "antioxidants alone" reduced their risk of developing advanced stages of AMD by about 17 percent and their risk of vision loss by about 10 percent.

The study was not designed to evaluate the effect of the antioxidants and zinc in study participants who initially had no AMD (Category One). This is because previous studies had indicated that people aged 60 and over with no AMD have a very low risk for developing a clear progression of AMD within a seven-year period (the life of the AREDS clinical trial). The Age-Related Eye Disease Study confirmed this low risk -- participants with no AMD had less than a one percent chance of losing vision from AMD during the study.

For those study participants who initially had early AMD (Category Two), the antioxidants and zinc used by the AREDS researchers did not slow the disease's progression to intermediate AMD. Consequently, there is no apparent need for those diagnosed with early AMD to take the combination studied in the AREDS. However, those with early AMD should get dilated eye examinations every year to determine if the disease is progressing.