Large AMD Study Associates Frequent Bevacizumab Injections with Risk of Glaucoma Surgery

Several studies have indicated that intravitreous injections of anti-vascular endothelial growth factor (VEGF) agents may increase the risk of sustained elevation in intraocular pressure (IOP). However, whether such injections increase the risk of the development of glaucoma requiring surgery has remained unclear. One small case series suggested that some patients treated with anti-VEGF agents who did not have glaucoma at baseline may eventually need trabeculectomy.

To determine whether this finding holds true in a large population, a Canadian team recently completed an observational, nested case-control study by using data from the British Columbia Ministry of Health linked databases. The study was done by Brennan Eadie, MD, PhD, (pictured) and colleagues in the Department of Ophthalmology and Visual Sciences, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.

The study cohort consisted of patients who received a first intravitreous injection of bevacizumab (Avastin/Roche) for exudative AMD from 2009 through 2013. The team used glaucoma surgical codes to identify 74 cases in this cohort. They defined cases as those who had trabeculectomy, placement of a glaucoma drainage device, or a cycloablative procedure for glaucoma. The team then identified 10 controls for each case. They defined controls as those who did not have a surgical procedure.

The team matched cases and controls for age, pre-existing glaucoma, calendar time, and follow-up time. They also determined the number of intravitreous injections of bevacizumab received annually by both cases and controls.

The study’s main outcome measure was risk of glaucoma surgery compared with number of intravitreous injections of bevacizumab received annually in cases and controls. The study team adjusted rate ratios for this risk for covariates that included comorbidities (ie, diabetes mellitus, myocardial infarction, and stroke) and use of verteporfin (Visudyne/Tocris Bioscience).

After this adjustment, the team determined that the rate ratio for glaucoma surgery among those who had ≥ 7 intravitreal injections annually compared with those who had ≤ 3 annually was 2.48 (95% confidence interval (CI), 1.25—4.93). They also determined that the glaucoma surgery rate ratio for those who had 4–6 injections annually compared with those who had ≤ 3 annually was 1.65 (CI, 0.84–3.23).

“These data show that receipt of 7 or more, but not 4 to 6, intravitreous bevacizumab injections per year is associated with an increased risk of subsequent glaucoma surgery,” the study team concluded in their study report.

An accompanying editorial emphasized that most patients in the study (78%) had glaucoma at baseline, which makes it difficult to extrapolate the study’s conclusions to AMD patients in general. Moreover, the editorialists noted that for those in the study group who did not have glaucoma at baseline, the study team did not separately report the number of injections given or the duration of follow-up.

The editorial team added that the use of a control group with glaucoma at baseline who did not get anti-VEGF injections could have enabled the investigators to determine the incidence of glaucoma surgery in uninjected AMD patients with glaucoma at baseline during the same period.

According to the editorial, the study team’s hypothesis could have been tested more efficiently by studying all patients who received intravitreous bevacizumab injection during a given calendar year and then had glaucoma surgery. This approach would have allowed the investigators to estimate the effect of age, pre-existing glaucoma, exposure time, and number of injections on the risk of glaucoma surgery. The editorialists also faulted the investigators’ definition of glaucoma surgery as not being sufficiently comprehensive.

Furthermore, the editorial team noted that no standard protocol for glaucoma surgery was used and no data were available to help the study investigators determine why patients had glaucoma surgery. Thus, some patients with pre-existing glaucoma may have needed glaucoma surgery whether or not they received intravitreal bevacizumab injections.

In conclusion, the editorial writers emphasized that ocular hypertension or glaucoma do not develop in most patients who receive intravitreal injections of anti-VEGF agents. “Nonetheless, it is prudent to observe all patients receiving intravitreous anti-VEGF injections for evidence of elevated IOP and glaucoma,” the editorial team stated. They added that particularly careful observation is crucial in patients with pre-existing ocular hypertension or glaucoma.

A report on the study, “Association of repeated intravitreous bevacizumab injections with risk for glaucoma surgery,” and an accompanying editorial, “Anti-VEGF injections and glaucoma surgery,” were published in the March 16, 2017, issue of JAMA Ophthalmology.

Related Coverage:

Uveitic Glaucoma: Intensive Treatment Necessary Following Trabeculectomy

Study Disputes Anti-VEGF Injection Link to Long-Term Intraocular Pressure Increase

Comparing Quality of Life in Patients with Age-Related Macular Degeneration and Glaucoma