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Repeated intravitreal injections of the vascular endothelial growth factor (VEGF) inhibitor bevacizumab (Avastin) may increase the risk of uncontrolled glaucoma, according to a Canadian study in

Compared with a control group, patients who received 7 or more intravitreous injections per year of bevacizumab, an anti-VEGF agent used to treat wet age-related macular degeneration (AMD), had a higher risk of subsequent glaucoma surgery (adjusted RR 2.48; 95% CI 1.25-4.93), according to Mahyar Etminan, PharmD, MSc, of the University of British Columbia in Vancouver, and colleagues.

Patients who received 4 to 6 injections per year had no statistically significant increased risk (adjusted RR 1.65; 95% CI 0.84-3.23) of glaucoma surgery.

"The use of glaucoma surgery as a hard outcome is a novel approach to addressing the potential association between glaucoma and intravitreous bevacizumab injections," the authors wrote. "Previous large studies were limited to associations between repeated intravitreous anti-VEGF injections and sustained increases in intraocular pressure (IOP)."

From British Columbia Ministry of Health records, Etminan and colleagues identified 74 AMD patients who received intravitreal injections of bevacizumab and subsequently underwent glaucoma surgery (case group), matching them with 740 AMD patients who also received bevacizumab injections but did not have glaucoma surgery (control group). They used glaucoma surgical codes for trabeculectomy, complicated trabeculectomy, glaucoma drainage device, and cycloablative procedure to identify cases and excluded laser trabeculoplasty, minimally invasive glaucoma surgery, or combined cataract and glaucoma surgery from their sample.

The groups were matched by age, preexisting glaucoma, calendar time, and follow-up time. Study participants received their first bevacizumab injections for AMD between Jan. 1, 2009 and Dec. 31, 2013. At baseline, 78.4% of each group had glaucoma.

The average age was 81 in both groups; there were more males in the case group (51.4%) than in the control group (36.8%). The frequency of potential confounding variables like diabetes, myocardial infarction, stroke, and verteporfin use was similar in the two groups.

The researchers observed that 44.6% of the case group received 7 or more bevacizumab injections per year, compared to 34.3% of controls. Patients who received 7 or more injections per year experienced more than double the rate (2.48) of glaucoma surgery, compared with patients who had 3 or fewer injections per year. Patients who received 12 or more injections had an adjusted RR for glaucoma surgery of 2.61 (95% CI, 1.14-5.98), compared with those receiving 6 or fewer injections.

"The results of this study are consistent with those of previous studies suggesting that repeated intravitreous injections of anti-VEGF medications can lead to a sustained increase in IOP," they wrote. "Our study expands on those studies by showing that this sustained IOP elevation may lead to a greater need for surgical intervention for glaucoma."

In an , Michael Kass, MD, of Washington University in St. Louis, and colleagues, said it was unclear whether these findings can be extrapolated to other AMD patients since the investigators did not know much about the 78.4% of patients who had glaucoma at baseline -- namely, what form of glaucoma they had or how severe it was. Some pre-existing glaucoma cases might have needed surgery anyway, they speculated, and anti-VEGF injections might not have been a factor.

Moreover, Kass and colleagues noted, the study had no information about changes in patients' IOP or visual field loss.

"While it seems intuitive that elevated IOP would be more common with a greater number of injections, this study does not provide a definite answer to this issue because they did not have access to IOP data," they wrote.

On the (AAO) website, Rajiv Anand, MD, a vitreoretinal specialist at Texas Health in Dallas, also reviewed the Etminan study.

"These findings emphasize that even procedures that appear relatively benign can bear a risk to the patient," Anand wrote. "To minimize risk, physicians should keep in mind that treat-and-extend protocols may be preferable over routine injections at fixed intervals."

The Etminan group limited its research to bevacizumab because it is widely used in Canada and supported by the Provincial Retinal Diseases Treatment Program, but noted that research about other VEGF inhibitors like ranibizumab (Lucentis) is needed.

"Previous studies suggest that the putative effect of intravitreous anti-VEGF medications on sustained increased IOP, and possibly on glaucoma, may not be produced by bevacizumab alone," they wrote. "Larger studies are required to clarify any potential differences in effects of repeated intravitreous injections of different anti-VEGF agents on the need for glaucoma surgery."