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Canadian Glaucoma Study yields expected and surprising findings


Halifax, Nova Scotia-Initial analyses of data collected in the Canadian Glaucoma Study (CGS) have identified four variables as powerful independent risk factors for glaucoma progression.

Halifax, Nova Scotia-Initial analyses of data collected in the Canadian Glaucoma Study (CGS) have identified four variables as powerful independent risk factors for glaucoma progression.

Using Cox proportional hazards regression models and based on up to 11 years of prospective follow-up, the presence of anticardiolipin antibodies at study entry was found to be the most potent predictor of progression, said Balwantray Chauhan, PhD, chairman of vision research, Department of Ophthalmology and Visual Sciences, Dalhousie University, Halifax, Nova Scotia, and lead investigator for the CGS.

Other factors associated with a statistically significant increased risk of progression were female gender, age, and mean follow-up IOP, he said.

“We still have a mountain of data from this study to cull through and many other analyses to complete, including evaluations of rates of progression,” Dr. Chauhan said. “The findings of those initial analyses have provided us with some brand new information that now presents us with a need for further research to explain the mechanism(s) underlying their association with progression risk.”

Design of the CGS began in 1992, and the clinical trial was launched in 1994. A total of 258 patients with early to moderate, newly or previously diagnosed glaucoma were enrolled at five universities across Canada: McGill University and the University of Montreal, Montreal; Dalhousie University; the University of British Columbia, Vancouver; and the University of Toronto. Follow-up continued through 2005.

Primary objective

The primary objective of the CGS was to determine systemic and ocular risk factors for glaucoma progression. At baseline, patients underwent a comprehensive battery of tests that included standard ophthalmologic examinations along with laboratory evaluations of blood rheology, biochemistry, coagulability, and anticardiolipin antibodies. In addition, finger blood flow was measured to evaluate susceptibility to peripheral vasospasm.

“Vasospasm compromising blood supply to the optic nerve has been implicated in the pathophysiology of glaucoma,” Dr. Chauhan said. “We could not measure that feature directly but used finger blood flow for a systemic assessment of vasospasm.”

IOP was tightly controlled to achieve and maintain a target IOP using a standardized treatment protocol. Follow-up visits were conducted quarterly. Patients in whom visual field progression was demonstrated according to the protocol-specified criteria-which were based on glaucoma change probability analyses for standard automated perimetry-had their treatment modified to achieve further IOP lowering.

“Even in the early 1990s when we were designing the study, IOP was the most potent known risk factor for glaucoma progression. Subsequent to launch of the CGS, its role across the spectrum of disease was reaffirmed in major randomized clinical trials, including the Ocular Hypertension Treatment Study, the Collaborative Normal-Tension Glaucoma Study, and the Early Manifest Glaucoma Trial,” Dr. Chauhan said. “However, our primary aim was to determine what factors in addition to IOP influence progression, so the study was designed to minimize treated IOP variation within the population.”

The analyses showed that patients who tested positive for anticardiolipin antibodies had a fourfold increased risk for glaucoma progression relative to their counterparts who had negative results for that finding. Notably, only a small proportion (<10%) of those tested had abnormal levels of anticardiolipin antibodies found in their baseline blood specimens. All but two of those patients experienced glaucoma progression during follow-up.

“We consider identification of anticardiolipin antibodies as a risk factor a fascinating finding, but now we need to figure out why it is such a powerful predictor of progression,” Dr. Chauhan said. “So far, we have considered some obvious explanations, but nothing tangible has emerged. Interestingly, this antibody is also elevated in patients with ischemic stroke, heart disease, and lupus, as well as in women who have had miscarriages. Across these various medical specialties, no one yet fully understands its role, and now we have the same task in some patients with glaucoma.”

Risk factors

The CGS population comprised 130 men and 128 women. The analysis of gender influence showed that women were twice as likely to experience disease progression compared with men. An association between female gender and glaucoma progression has been alluded to in some other studies but has not been a consistent finding in risk factor studies, he noted.

“The role of gender was quite powerful in the CGS. Presumably, there are some systemic factors at play in postmenopausal women that are promoting glaucoma progression, but we will need to determine what they are,” he said.

The study participants were aged an average of 65 years at baseline, with a range of 43 to 78 years. The outcomes analyses showed that each 1 year of age added a 4% risk of progression.

“The effect of age was not too surprising, because previous research has demonstrated that the risk of glaucoma and glaucoma progression increases with increasing age,” Dr. Chauhan said.

The role of IOP as a risk factor was surprising because the study was carefully designed to minimize its role. The results, however, showed that for every 1 mm Hg increase in IOP, the risk of progression increased by a staggering 20%.

“In spite of all of our attempts to minimize IOP variation among the study patients, IOP raised its ugly head,” Dr. Chauhan said. “The fact that IOP emerged as a major risk factor in this cohort whose IOP was so tightly controlled within a narrow window reemphasizes the important role of IOP in glaucoma and the importance of reducing it to provide a more favorable outcome.”

The study also found that diabetes, hypertension, and a history of cardiovascular disease were not significant predictors of glaucoma progression.OT

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