Update and clinical pearls from the European Glaucoma Prevention Study

April 15, 2008

The European Glaucoma Prevention Study (EGPS) has produced reports on baseline factors that predict development of primary open-angle glaucoma as well as intercurrent factors also associated with development of the disease. The study also confirmed the importance of IOP reduction and identified systemic diuretics as a risk factor.

Key Points

New Orleans-The European Glaucoma Prevention Study (EGPS) has contributed important findings to glaucoma management, including data on baseline risk and predictive factors and intercurrent, post-baseline risk and predictive factors.

Recently, results from the EGPS, combined with data from another large study of patients with ocular hypertension, were used to develop a predictive model for glaucoma. In addition, the EGPS was believed to be the first study to suggest that the use of diuretics is a risk factor. This finding is consistent with several other studies and increases the bulk of evidence on the interaction between blood pressure and IOP in the development of glaucoma, according to Stefano Miglior, MD, project coordinator and one of the principal investigators for EGPS, who addressed colleagues during a Glaucoma Subspecialty Day presentation at the annual meeting of the American Academy of Ophthalmology.

The EGPS was unique because it was the only large study designed to compare the effectiveness of a single drug versus placebo in preventing or delaying primary open-angle glaucoma (POAG) in individuals with ocular hypertension, said Dr. Miglior, who is professor of ophthalmology, Policlinico di Monza, University of Milan, Bicocca, Monza, Italy. The study found that although dorzolamide (Trusopt, Merck) reduced IOP by 15% to 22% over a 5-year follow-up period, the difference between medication and placebo in reducing the incidence of POAG was not statistically significant.

EGPS was conducted at 18 sites-including a data management and biostatistical center-in Belgium, Germany, Italy, and Portugal. In this study, 1,077 patients were randomly assigned to receive dorzolamide or placebo from January 1, 1997 to May 31, 1999.

Dr. Miglior discussed results of several published papers that delved into the data produced in the EGPS. One of those papers described the baseline risk factors that were predictive of the development of glaucoma among the EGPS patients, excluding factors related to the optic disk and visual field. Those factors included patient age, IOP, and central corneal thickness (CCT).

The results were similar to those of another large glaucoma trial, the Ocular Hypertension Treatment Study (OHTS), except that EGPS did not confirm the OHTS finding that diabetes also was a risk factor, Dr. Miglior said. The EGPS also found that there was no correlation between IOP and CCT.

The EGPS investigators found a number of predictive factors for POAG. The multivariate hazard ratios were age, 1.32 (1.04 to 1.69); CCT, 1.32 (1.05 to 1.67); vertical cup-to-disk ratio, 1.34 (1.14 to 1.58); pattern standard deviation (PSD), 1.66 (1.15 to 2.38); and vertical cup-to-disk asymmetry, 1.46 (1.11 to 1.93).

Because the results of the EGPS and OHTS were similar and the studies shared similarities in study design and measurement protocols, pooled datasets from both were used to develop a glaucoma risk calculator that was published in 2007. Factors included in that calculator were age, IOP, CCT, vertical cup-to-disk ratio, and PSD.

Analyzing intercurrent factors

Dr. Miglior also discussed the analysis of intercurrent factors from EGPS. Those are factors that were noted after baseline up to the time of development of POAG, for patients who developed disease, or up to the end of the study, for individuals who did not have progression to glaucoma. First, investigators took a closer look at three IOP-related factors: mean IOP decrease from baseline, mean IOP during follow-up, and area under the curve of IOP during follow-up. All were adjusted for baseline factors and treatment in a multivariate model.

"It turned out that IOP was a relevant factor for the development of glaucoma, and in fact we could show that for each single millimeter of mercury of reduction from baseline IOP, there was a 9% to 12% decrease in the risk of glaucoma in our study population, confirming the results of the other studies that have addressed this issue," Dr. Miglior said.

Optic disk hemorrhages, another important risk factor, also were included in the analysis and were found to be significantly associated with the development of POAG; the hazard ratio (HR) was 3.7 (2.1 to 6.6).

A strong association also was found between the use of systemic diuretics for hypertension (HR 2.41 to 2.94) and development of glaucoma, according to Dr. Miglior. He and his colleagues looked as well at associations with other treatments for hypertension, such as one anti-hypertensive (except diuretics), two or more anti-hypertensives (except diuretics), diuretics only, and diuretics plus any other anti-hypertensive.

Although there were no statistically significant correlations, there were trends suggesting that different treatment combinations could affect development of glaucoma, Dr. Miglior said. Those findings are consistent with results from the Rotterdam Eye Study, which found an association between calcium-channel antagonists and development of glaucoma.

"We tried to interpret these data, and while we cannot rule out the possibility that diuretics can be harmful to the patient, this finding probably could be related to something that interferes with perfusion pressure in the eye," Dr. Miglior continued. "If this holds true, our results may be consistent with all the results from published studies on populations from Baltimore, the Caribbean, Italy, and Arizona. These studies found a high risk for glaucoma if the diastolic pressure is <50 mm Hg or if the systolic pressure is <125 mm Hg."

Related findings emerged from the Thessaloniki Eye Study, which showed that in patients without glaucoma who had normal blood pressure resulting from antihypertensive treatment, the cup area and cup-to-disk ratio as measured with the Heidelberg Retina Tomograph were larger than in subjects with high diastolic blood pressure, regardless of treatment, or in untreated subjects with normal blood pressure.

Findings from those studies suggest the need for future investigations to clarify the role of systemic diuretics in the development of glaucoma, Dr. Miglior concluded.