Repeated Intravitreous Ranibizumab Injections for Diabetic Macular Edema and the Risk of Sustained Elevation of Intraocular Pressure or the Need for Ocular Hypotensive Treatment

Abstract

IMPORTANCE For the management of retinal disease, the use of intravitreous injections of anti-vascular endothelial growth factor has increased. Recent reports have suggested that this therapy may cause sustained elevation of intraocular pressure (IOP) and may potentially increase the risk of glaucoma for patients with retinal disease.OBJECTIVE To assess the risk of sustained IOP elevation or the need for IOP-lowering treatments for eyes with diabetic macular edema following repeated intravitreous injections of ranibizumab. DESIGN, SETTING, AND PARTICIPANTS An exploratory analysis was conducted within a Diabetic Retinopathy Clinical Research Network randomized clinical trial. Study enrollment dates were from March 20, 2007, to December 17, 2008. Of 582 eyes (of 486 participants) with center-involved diabetic macular edema and no preexisting open-angle glaucoma, 260 were randomly assigned to receive a sham injection plus focal/grid laser treatment, and 322 were randomly assigned to receive ranibizumab plus deferred or prompt focal/grid laser treatment. MAIN OUTCOMES AND MEASURESThe cumulative probability of sustained IOP elevation, defined as IOP of at least 22 mm Hg and an increase of at least 6 mm Hg from baseline at 2 consecutive visits, or the initiation or augmentation of ocular hypotensive therapy, through 3 years of follow-up. RESULTSThe mean (SD) baseline IOP in both treatment groups was 16 (3) mm Hg (range, 5-24 mm Hg). The cumulative probability of sustained IOP elevation or of initiation or augmentation of ocular hypotensive therapy by 3 years, after repeated ranibizumab injections, was 9.5% for the participants who received ranibizumab plus prompt or deferred focal/grid laser treatment vs 3.4% for the participants who received a sham injection plus focal/grid laser treatment (difference, 6.1% [99% CI, −0.2% to 12.3%]; hazard ratio, 2.9 [99% CI, 1.0-7.9]; P = .01). The distribution of IOP and the change in IOP from baseline at each visit through 3 years were similar in each group. CONCLUSIONS AND RELEVANCEIn eyes with center-involved diabetic macular edema and no prior open-angle glaucoma, repeated intravitreous injections of ranibizumab may increase the risk of sustained IOP elevation or the need for ocular hypotensive treatment. Clinicians should be aware of this risk and should consider this information when following up with patients who have received intravitreous injections of anti-vascular endothelial growth factor for the treatment of diabetic macular edema.

Sustained Elevation of Intraocular Pressure Associated with Intravitreal Administration of Anti-vascular Endothelial Growth Factor: A Systematic Review and Meta-Analysis

“…There were five RCTs1920212223 and 17 non-RCT studies1415161724252627282930313233343536. The latter group included 11 retrospective case series1417242526272829303132, two prospective studies3334, and four post hoc analyses15163536. Follow-up in the included articles ranged from 2.2627 to 6031 months.…”

2018 Update on Intravitreal Injections: Euretina Expert Consensus Recommendations

“…Anti-vascular endothelial growth factor (VEGF) agents have also been associated with elevated IOP, in as many as 12% of cases. Several mechanisms have been suggested for this adverse effect, including toxic changes, transient inflammation with production of cytokines that promote IOP elevation, and mechanical blockage of the trabecular meshwork [44-48]. …”

Practical Lessons from Protocol I for the Management of Diabetic Macular Edema

“…A mean of 7 ± 4 injections were given to the 22 eyes that met the primary outcome measure, compared to 15 ± 8 in the remaining eyes. Therefore, the number of injections was not associated with an increased risk of sustained IOP elevation [12] . No patients required laser or incisional surgery to achieve IOP control.…”

“…These patients revealed an 8.3 versus 15.0% cumulative probability of the primary outcome measure at 3 years in the ranibizumab and sham cohorts, respectively, thereby resulting in a 6.6% difference (99% CI -8 to 21%; HR ranibizumab/sham = 1.9; 99% CI 0.7-5.1, p = 0.11) [12] . In summary, Protocol I data demonstrate no definitive link between ranibizumab and increased risk of glaucoma, but a trend of increased IOP was noted, and therefore the investigators suggested IOP monitoring during follow-up visits.…”

“…IOP elevation at 1 and 3 years in patients receiving ranibizumab in Protocol I Percentage of eyes that met primary outcome at 1 year (n) Mean change in IOP from BL, mm Hg +7 +9 Number of eyes that had a history of glaucoma (angle closure) or IOP meds Adapted from Bressler et al[12]. BL, baseline.Bandello F, Zarbin MA, Lattanzio R, Zucchiatti I (eds): Management of Diabetic Retinopathy.…”