Advanced AMD places patient at increased risk of mortality

July 15, 2005

Madison, WI—An association between mortality and age-related macular degeneration (AMD) was found in the Age-Related Eye Disease Study (AREDS). All-cause mortality increased with increasing severity of disease, with category 4 AMD having a significantly increased association with death compared with category 1 AMD. A protective effect was seen for zinc in participants randomly assigned to therapy with the mineral.

Madison, WI-An association between mortality and age-related macular degeneration (AMD) was found in the Age-Related Eye Disease Study (AREDS). All-cause mortality increased with increasing severity of disease, with category 4 AMD having a significantly increased association with death compared with category 1 AMD. A protective effect was seen for zinc in participants randomly assigned to therapy with the mineral.

"Previous studies have shown that various ocular disorders are predictors of decreased lifespan," said Justin Gottlieb, MD, associate professor, University of Wisconsin-Madison. "This increased association between eye disease and mortality may include the direct effect of vision loss in increasing the risk of falls or depression or that ocular disease may be a marker of a systemic aging process."

While previous studies were too small to show a direct correlation between mortality and AMD, the AREDS is a long-term, randomized, controlled trial in which almost 5,000 patients participated and antioxidants and zinc were evaluated.

The antioxidants that were evaluated included 500 mg of vitamin C, 400 international units vitamin E, 15 mg of beta caro-tene, in addition to 80 mg of zinc oxide with 2 mg of cupric oxide.

AMD was divided into four categories: 1, no or small drusen; 2, extensive small drusen or non-extensive intermediate drusen; 3, extensive intermediate drusen, at least one or more large drusen, or non-central geographic atrophy; and 4, advanced AMD in the fellow eye (the presence of neovascular AMD or central geographic atrophy), Dr. Gottlieb explained.

The participants with category 2 to category 4 AMD were randomly assigned to receive antioxidants alone, zinc alone, antioxidants and zinc, or placebo. The patients with category 1 disease were randomly assigned to either placebo or antioxidants because of the low risk of vision loss from AMD.

Death certificates obtained The primary outcome of this analysis was all-cause mortality. Death certificates and hospital-discharge records were obtained for all patients who died during the study to determine the cause of death. The specific cause of death was analyzed as a secondary outcome of the study, and the specific international classification of disease (ICD-9) codes were analyzed, according to Dr. Gottlieb.

A total of 4,753 patients participated; 534 patients (11%) died during the study. The patients were followed for a mean of 6.5 years, he said.

"Mortality was found to increase with increasing severity of macular disease. Participants with advanced AMD in one eye had a significantly increased risk of mortality," Dr. Gottlieb said. "This association remained statistically significant after adjustment for lifestyle and comorbid conditions.

"All-cause mortality decreased significantly for participants who had been randomly assigned to receive zinc compared with those who were not randomly assigned to receive zinc," Dr. Gottlieb added. "No association was found between mortality and random assignment to high-dose antioxidants."

The ICD-9 codes were available for 93% of the patients who died. Most deaths were attributed to diseases of the circulatory system (37%) and neoplasms (31%), he explained. The other deaths were classified as other (25%) or unknown (7%).

Cardiovascular deaths Importantly, AMD category 4 was found to be significantly associated with cardiovascular deaths. No significant association was found between deaths from neoplasms or with less advanced forms of AMD.

The strong points of the study are the large number of patients, the long follow-up, and the availability of mortality data for most patients.

"We found that all-cause mortality was significantly increased among participants with category 4 AMD and remained a significant predictor of mortality after adjustment for other risk factors and interventional effect," Dr. Gottlieb said. "Unilateral AMD was significantly associated with cardiovascular deaths, which perhaps can be explained by an underlying vascular basis for AMD.

"Several epidemiologic studies have suggested such a link," he added.

Even after adjustment for some risk factors associated with cardiovascular disease, such as age, smoking, and hypertension, this relationship persisted, he said.