Intraocular Pressure–Related Events After Anti–Vascular Endothelial Growth Factor Therapy for Macular Edema Due to Central Retinal Vein Occlusion or Hemiretinal Vein Occlusion: SCORE2 Report 16 on a Secondary Analysis of a Randomized Clinical Trial

Key Points

Question  What proportion of eyes in SCORE2 participants treated with anti–vascular endothelial growth factor (anti-VEGF) therapy for macular edema associated with central or hemiretinal vein occlusion experienced intraocular pressure (IOP)–related events?

Findings  In this secondary analysis of a randomized clinical trial of 312 participants followed up to 60 months, 25 (8.0%) had IOP elevation more than 10 mm Hg over baseline, 5 (1.6%) had IOP higher than 35 mm Hg, 3 (1.0%) underwent incisional IOP-lowering surgery, and 3 (1.0%) underwent laser IOP-lowering surgery. Although the number of IOP-related events was higher in the bevacizumab group than in the aflibercept group, no definitive differences were noted among participants initially randomly assigned to aflibercept vs bevacizumab.

Meaning  The results of this secondary analysis support monitoring IOP in eyes treated with anti-VEGF therapy for macular edema associated with central or hemiretinal vein occlusion.

Importance  Intravitreal anti–vascular endothelial growth factor (anti-VEGF) injections are used to treat a variety of posterior segment conditions, including some associated with glaucoma, such as macular edema due to central retinal vein occlusion (CRVO). Therefore, information regarding intraocular pressure (IOP)–related events associated with anti-VEGF therapies is important to help balance the risks and benefits over the course of therapy.

Objective  To investigate IOP-related events among participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2).

Design, Setting, and Participants  Secondary analysis of a randomized clinical trial that included 312 participants with macular edema secondary to CRVO or hemiretinal vein occlusion (HRVO) who were not taking IOP-lowering medications at baseline. First randomization occurred on September 14, 2014, and contained data through data freeze on April 1, 2020. Analysis took place from April 2020 through December 2020.

Interventions  Study participants were initially randomized to 6 monthly intravitreal injections of aflibercept or bevacizumab. At month 6, protocol-defined good responders were rerandomized to continued monthly or treat-and-extend dosing of their originally assigned study drug, and protocol-defined poor or marginal responders were switched to alternative treatment. After month 12, participants were treated as per investigator discretion.

Main Outcomes and Measures  Three different outcomes: (1) IOP elevation more than 10 mm Hg from baseline, (2) IOP to a level higher than 35 mm Hg, and (3) IOP-lowering incisional or laser surgery.

Results  Of the 312 participants meeting inclusion criteria (138 [44.2%] were female; mean [SD] age, 67.8 [12.1] years), 25 (8.0%) had IOP elevation more than 10 mm Hg over baseline through month 60, and 5 (1.6%) had IOP higher than 35 mm Hg. The 60-month Kaplan-Meier cumulative incidence of IOP elevation more than 10 mm Hg over baseline was 0.13 (95% CI, 0.08-0.19), and the 60-month Kaplan-Meier cumulative incidence of IOP higher than 35 mm Hg was 0.02 (95% CI, 0.01-0.06), and did not differ among participants initially randomly assigned to receive aflibercept or bevacizumab. Three participants (1.0%) underwent IOP-lowering incisional surgery, and 3 participants (1.0%) underwent IOP-lowering glaucoma laser surgery.

Conclusions and Relevance  Intravitreal anti-VEGF injections are used to treat some conditions associated with glaucoma, such as macular edema due to CRVO, and the rates of IOP-related events in this trial support monitoring IOP in eyes treated with anti-VEGF therapy for macular edema associated with CRVO or HRVO for up to 60 months.

Trial Registration  ClinicalTrials.gov Identifier: NCT01969708

The use of anti–vascular endothelial growth factor (anti-VEGF) injection therapy has increased substantially over the past decade.¹ These agents are highly effective in sustaining and restoring vision in patients with such retinal diseases as age-related macular degeneration, diabetic macular edema, and retinal vein occlusion.² Although the favorable safety profile of these agents permits their frequent use, an associated risk of elevated intraocular pressure (IOP) has been reported.³ This risk is important because elevated IOP may increase the risk for glaucomatous optic neuropathy and associated irreversible vision loss.⁴ Furthermore, an increasing number of patients with baseline glaucoma who require long-term anti-VEGF injection therapy may be expected in the coming years. A recent report from the American Academy of Ophthalmology (AAO) on the association of intravitreal anti-VEGF therapy with IOP and glaucoma cites only 1 study with long-term follow-up that is considered level I evidence.³

In a meta-analysis of data from 5 randomized clinical trials (RCTs) and 17 non-RCTs, Zhou and colleagues⁵ found that long-term anti-VEGF therapy, used to treat a variety of conditions, was associated with a 2-fold increase in sustained elevation of IOP compared with controls treated with sham injection or laser. In both this meta-analysis and the AAO report, few trials were conducted among individuals with retinal vein occlusion (RVO). The AAO report includes a single study of patients with RVO with 6 months of follow-up, and the meta-analysis also includes a single prospective RCT with a similar follow-up duration in a population of patients with RVO. Gado and Macky⁶ reported higher mean (SD) IOP in individuals with macular edema due to central retinal vein occlusion (CRVO) treated with a dexamethasone implant compared with bevacizumab (18 [1.53] mm Hg vs 16 [2.02] mm Hg; P = .02). Holz et al⁷ reported that 2.9% of patients with CRVO in both anti-VEGF and sham treatment groups experienced an increase in IOP of 10 mm Hg or higher from baseline at 6 months of follow-up. Neither of these studies performed further risk analyses for individuals experiencing IOP-related events based on demographic factors and various available anti-VEGF therapies.

The incidence of open-angle glaucoma is higher among patients with RVO, compared with the general population.⁸ It is therefore particularly important to further characterize the risk for an IOP-related event in this patient population because these types of patients may undergo treatment with anti-VEGF injection therapy for longer than 6 months. The Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) was conducted among participants with macular edema associated with CRVO or hemiretinal vein occlusion (HRVO).⁹ The present report aims to evaluate IOP-related events, including IOP-lowering incisional surgery, among SCORE2 participants. The proportions of eyes with these types of events (over time and based on treatment assignment and demographic factors) were analyzed. Findings from this report will aid clinicians in overall risk assessment when initiating and/or continuing anti-VEGF injection therapy. Unlike prior reports, this report collected IOP data in a standardized manner among a large number of patients with RVO and treated with different anti-VEGF therapies.

SCORE2 was a multicenter, randomized, phase 3 clinical trial¹⁰ and adhered to the tenets of the Declaration of Helsinki.¹¹ A full description of the design and methods of SCORE2 is provided elsewhere.⁹ The SCORE2 protocol and informed consent were approved by the respective clinical center institutional review boards or a centralized institutional review board and by a National Eye Institute–appointed data and safety monitoring committee. Study participants provided written informed consent. SCORE2 is registered with ClinicalTrials.gov (NCT01969708). First randomization occurred on September 14, 2014, and contained data through data freeze on April 1, 2020. Analysis took place from April 2020 through December 2020.

Participants were initially randomly assigned to receive 6 monthly intravitreal injections of either bevacizumab (1.25 mg) or aflibercept (2.0 mg). At month 6, participants with a protocol-defined good response were randomly assigned to receive a monthly vs treat-and-extend (TAE) dosing regimen of their originally assigned study drug, and participants with a protocol-defined poor or marginal response at month 6 were assigned to receive alternative therapy: 3 monthly aflibercept injections followed by TAE aflibercept dosing for patients originally randomly assigned to receive bevacizumab and intravitreal dexamethasone implant every 3 months as needed for patients originally randomly assigned to receive aflibercept. Between months 6 and 12, participants underwent a study visit at the time of each scheduled injection based on treatment assignment. After month 12, participants were treated at investigator discretion using any commercially available drug (including a nonstudy drug or no drug), and study visits were conducted at months 24, 36, 48, and 60; at months 18, 30, 42, and 54, there was a medical record review of new ocular conditions and procedures, a change in dose or number of IOP-lowering medications, and other new health conditions occurring since the preceding annual visit.

Intraocular pressure was measured using Goldmann applanation tonometry or hand-held applanation tonometry within 21 days of randomization and at each study visit until last follow-up. After the exclusion of 50 eyes treated with IOP-lowering medication at baseline (since including these treated eyes would confound the temporal relationship of IOP events with initiation of anti-VEGF treatment) and the exclusion of visits from 39 eyes included that occurred after initiation of dexamethasone (or another corticosteroid) therapy, the following main outcomes, overall and by initial anti-VEGF drug assignment, were assessed through month 60: mean change in IOP from baseline, proportion of eyes with IOP elevation more than 10 mm Hg over baseline, proportion of eyes with IOP higher than 35 mm Hg, proportion of patients who started treatment with IOP-lowering medication, and proportion of patients who underwent IOP-lowering incisional or laser surgery (excluding laser procedures for angle-closure glaucoma). Further exploratory analyses were performed to determine whether the proportion of eyes with IOP-related events differed by baseline demographic characteristics, treatment group after rerandomization at month 6, total number of injections received, and mean peak IOP among patients who experienced an IOP-related event.

For many analyses, simple proportions were calculated over the SCORE2 follow-up period, but owing to the varying follow-up period and accounting for censoring of participants, we also calculated Kaplan-Meier estimates of cumulative incidence with 95% CIs for the main IOP outcomes. The cause-specific cumulative incidence functions of IOP-related events were compared using the Gray test.

The outcomes noted in this analysis were included as preplanned secondary analyses in the SCORE2 statistical analysis plan specific to SCORE2 safety outcomes. The main goal of the analyses was to estimate the proportion of study eyes in SCORE2 with an IOP outcome, with no formal hypothesis testing and no formal P value adjustments for multiple testing, with P <  .05 considered statistically significant. Therefore, the findings need to be interpreted in light of the exploratory nature of the analysis. SAS statistical software version 9.4 (SAS Institute Inc) were used to conduct statistical analyses.

A total of 362 participants were enrolled in SCORE2. After excluding 50 participants treated with IOP-lowering medication at baseline, 312 participants (160 participants initially randomly assigned to receive aflibercept and 152 participants initially randomly assigned to receive bevacizumab) met inclusion criteria for the present analysis (138 [44.2%] were female; mean [SD] age, 67.8 [12.1] years). Median follow-up was 38.5 months (IQR, 11.2-49.2 months) in eyes initially randomly assigned to receive aflibercept and 40.5 months (IQR, 11.2-49.8 months) for those initially randomly assigned to receive bevacizumab.

The proportion of eyes with IOP elevation more than 10 mm Hg over baseline was 8.0% (25 of 312), and the proportion of eyes with IOP higher than 35 mm Hg was 1.6% (5 of 312) through 60 months of follow-up. The frequencies of these IOP-related events, based on baseline demographic factors and treatment group, are shown in Table 1. Furthermore, the mean baseline IOP for those with IOP elevation more than 10 mm Hg over baseline was 18.0 (5.8) mm Hg compared with a mean of 15.1 (3.2) mm Hg for those without IOP elevation more than 10 mm Hg over baseline (P < .001). The mean baseline IOP for those with IOP higher than 35 mm Hg was 20.3 (8.2) mm Hg compared with a mean of 15.3 (3.4) mm Hg for those without IOP higher than 35 mm Hg (P < .001).

Overall, the 60-month Kaplan-Meier cumulative incidence of IOP elevation more than 10 mm Hg over baseline was 0.13 (95% CI, 0.08-0.19), and the 60-month Kaplan-Meier cumulative incidence of IOP higher than 35 mm Hg was 0.02 (95% CI, 0.01-0.06). There was no difference in the cumulative incidence of these 2 events through month 60 based on first treatment assignment (P = .22 for IOP elevation >10 mm Hg over baseline, and P = .60 for IOP >35 mm Hg) (Figure). Three participants (1.0% of the cohort) underwent IOP-lowering incisional surgery for open-angle glaucoma, including 2 surgical procedures for participants initially randomly assigned to receive aflibercept (trabeculectomy 705 days after randomization and shunt surgery 1035 days after randomization) and shunt surgery for a participant initially randomly assigned to receive bevacizumab (1328 days after randomization). The participant who received aflibercept and underwent filtering surgery and the participant who received bevacizumab and underwent shunt surgery had IOP elevation more than 10 mm Hg over baseline. Furthermore, 3 participants underwent IOP-lowering laser surgery, including 1 procedure among participants initially randomly assigned to receive aflibercept and 2 procedures among participants initially randomly assigned to receive bevacizumab. None of the participants who underwent laser surgery had an IOP-related event.

The frequencies of initiation of IOP-lowering medication by treatment assignment through month 60 are shown in Table 2. Numerically, there were twice as many IOP-related events in the bevacizumab group (8 of 152) compared with the aflibercept group (4 of 160). The mean peak IOP for those who experienced an increase in IOP more than 10 mm Hg over baseline was 29.7 (7.6) mm Hg among participants randomly assigned to receive aflibercept and 30.7 (11.3) mm Hg among participants randomly assigned to reveive bevacizumab (P = .79). The cumulative number of injections through month 60 among participants who did and among participatns who did not have an IOP elevation more than 10 mm Hg over baseline did not differ in either the aflibercept group (16.3 vs 20.5 injections, respectively; P = .15) or the bevacizumab group (19.6 vs 16.7 injections, respectively; P = .42).

After separating participants based on rerandomization at month 6, we found that, among those with a good response, the proportions of eyes with an IOP elevation more than 10 mm Hg between baseline and month 60 were 6.1% in the group rerandomized to 3 monthly aflibercept injections followed by TAE therapy (n = 33), 12.0% for monthly aflibercept (n = 73), 7.2% for aflibercept TAE (n = 69), 11.0% for monthly bevacizumab (n = 56), and 5.5% for bevacizumab TAE (n = 55). Limiting the analysis to data collected between months 12 and 60, we found that, among 106 eyes that did not receive anti-VEGF therapy after month 12, none had IOP elevation more than 10 mm Hg over baseline, and none had IOP higher than 35 mm Hg compared with 19 of 171 (11.1%) and 5 of 171 (2.9%) who received anti-VEGF after month 12.

In this secondary analysis of data gathered from SCORE2 participants, the cumulative incidence of IOP events over 5 years of follow-up is reported. These findings suggest that the risk for an IOP-related event in eyes treated with intravitreal anti-VEGF injection therapy for macular edema warrants monitoring in the setting of CRVO or HRVO.

In a systematic review and meta-analysis of sustained IOP elevation associated with intravitreal anti-VEGF administration, Zhou et al⁵ reported a pooled prevalence of 4.7% (95% CI, 3.7%-5.8%) using various diagnosis criteria. The authors acknowledge significant heterogeneity among the studies (I² = 67.5%). Likewise, in an Ophthalmic Technology Assessment published by the AAO, Hoguet and colleagues³ noted variability among published studies, with reported incidence rates ranging from 2.6% to 14.8%, depending on the study, the definition of an IOP-related event, and the follow-up period. In that assessment, the authors identified only 1 study deemed to be level I evidence, defined as a “well-designed, well-conducted randomized clinical trial” with long-term follow-up. The authors also identify a need for research to quantify the risk of long-term IOP elevation in these settings.

In an exploratory analysis within the Diabetic Retinopathy Clinical Research Network, Bressler et al¹² reported cumulative probabilities of sustained IOP elevation of 9.5% and 3.4% among participants randomly assigned to receive repeated ranibizumab injections plus prompt or deferred focal/grid laser treatment vs those randomly assigned to receive sham injection plus focal/grid laser treatment, respectively (difference, 6.1% [99% CI, −0.2% to 12.3%]; P = .01) through 36 months of follow-up.

The findings described in the present report are derived from up to 60 months of follow-up data from a multicenter, randomized, phase 3 clinical trial. After exclusion of eyes treated with IOP-lowering medication at baseline and censoring of visits that occurred after initiation of intravitreal dexamethasone therapy, 8.0% of participants (25 of 312) had IOP elevation more than 10 mm Hg over baseline through month 60, and the proportion of eyes with IOP elevation more than 10 mm Hg over baseline did not differ between eyes initially randomly assigned to receive aflibercept (8.8%) vs bevacizumab (7.2%) (P = .61). Our findings indicate that the proportion of eyes with IOP-related events in this patient population is higher than that in a historical control population, which received no treatment, from the Standard of Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) Study.¹³

In a similar population of patients with CRVO, the SCORE Study¹³ followed up with 182 study participants in an observation (untreated) group through month 36 and reported that the proportion of eyes with IOP elevation more than 10 mm Hg over baseline at 36 months was 2% and that the proportion of eyes with IOP higher than 30 mm Hg was 1%. These results serve as a good reference to compare the present results (because both cohorts were followed up within the context of a clinical trial, had standardized IOP measurements, and had similar baseline characteristics). The proportion of eyes with IOP-related events in the untreated SCORE group was numerically lower than those observed in the present report for participants treated with anti-VEGF therapy. However, the events being relatively uncommon in both studies limits the ability to draw definitive conclusions.

Although the exact pathogenesis of sustained increases in IOP associated with long-term anti-VEGF therapy remains unclear, evidence suggests decreased aqueous outflow facility. Wen et al¹⁴ conducted a study involving the measurement of IOP and tonographic outflow facility in patients who had received unilateral intravitreal anti-VEGF injections. They reported that the outflow facility of injected eyes was, on average, 46% lower than uninjected fellow eyes (P = .01).¹⁴ Proposed theories for why a decrease in aqueous outflow facility may occur include direct pharmacological toxic effects,¹⁵ chronic trabeculitis,¹⁶ and leaching of syringe silicone microdroplets causing trabecular protein aggregation in compounded drug formulations.¹⁷ Our finding that individuals with higher baseline IOP were more likely to have IOP elevation more than 10 mm Hg over baseline may indicate that increased aqueous outflow resistance at baseline could increase the risk for an IOP-related event with intravitreal anti-VEGF therapy.

The present study did not find a significant association between the cumulative number of anti-VEGF injections and the proportion of eyes with an IOP-related event, but we did find a greater number of IOP-related events in individuals who received intravitreal anti-VEGF therapy beyond 12 months. Wingard and colleagues¹⁸ predicted an elevated risk for glaucoma or ocular hypertension with higher injection frequency using statistical modeling. Patients in the present study underwent a less intensive pattern of injection therapy compared with the patients reported by Wingard et al.¹⁸ The latter study also showed a higher frequency of events in phakic individuals, and the present report shows a similar trend (P = .07; Table 1). Wingard and colleagues¹⁸ hypothesize that repeated intravitreal anti-VEGF injections lead to a pressure imbalance between the anterior and posterior segments in individuals with a phakic lens and that this strains the eye’s outflow system, leading to compromised outflow facility. This issue deserves further study because individuals with a phakic lens may require closer monitoring in the setting of intravitreal injection therapy.

In a retrospective study of 53 patients switched from bevacizumab to aflibercept, Rusu and colleagues¹⁹ report a decrease in IOP of 1.1 mm Hg after the change in therapy. Our study did not find a difference in mean IOP, mean peak IOP, or proportion of eyes with an IOP-related event in eyes initially randomly assigned to receive either aflibercept or bevacizumab and then followed up for over 60 months. However, it should be noted that, at month 6, poor responders in the group originally randomly assigned to receive bevacizumab were assigned to receive aflibercept between months 6 and 12, and after month 12, all study participants were treated per investigator discretion. When comparing the eyes randomly assigned to receive aflibercept with the eyes randomly assigned to receive bevacizumab over the first 6 months of follow-up, the cumulative incidence of an IOP-related event (Figure) was similar between the 2 groups.

A limitation of this study includes a reduction in sample size after month 12, when study participants were treated per investigator discretion instead of according to a protocol-defined anti-VEGF treatment regimen. We excluded eyes that were treated with IOP-lowering medication at baseline to assess new initiation of IOP-lowering treatment, so our findings are not generalizable to eyes of patients who received anti-VEGF treatment while already receiving IOP-lowering medications. Furthermore, gonioscopy was not performed at baseline, and we did not look at the effect of an IOP-related event on the risk of the development of glaucomatous optic neuropathy. Finally, the decision to initiate IOP-lowering therapy during the study was not based on standardized criteria.

In summary, the proportion of eyes with IOP-related events in SCORE2 participants supports monitoring IOP in eyes treated with intravitreal anti-VEGF injection therapy for macular edema associated with CRVO or HRVO.

Accepted for Publication: September 9, 2021.

Published Online: October 28, 2021. doi:10.1001/jamaophthalmol.2021.4395

Corresponding Author: Paul C. VanVeldhuisen, PhD, The Emmes Company, LLC, 401 N Washington St, Ste 700, Rockville, MD 20850 (pvanveldhuisen@emmes.com).

Author Contributions: Dr VanVeldhuisen and Ms King had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Aref, Scott, VanVeldhuisen, Ip.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Aref, VanVeldhuisen, Ip.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: VanVeldhuisen, King, Oden.

Obtained funding: VanVeldhuisen.

Administrative, technical, or material support: Aref, Scott.

Supervision: Aref, Ip, Blodi.

Conflict of Interest Disclosures: Dr Aref reported receiving an unrestricted institutional grant from Research to Prevent Blindness during the conduct of the study, personal fees from Aerie Pharmaceuticals, and speaker honoraria and other consulting work from Allergan for clinical trial research support outside the submitted work. Dr Scott reported receiving grants from the National Eye Institute, nonfinancial support from Allergan (donation of study drug), nonfinancial support from Regeneron (donation of study drug) during the conduct of the study, personal fees from Novartis, and personal fees from Regeneron outside the submitted work. Dr VanVeldhuisen reported receiving grants from the National Eye Institute of the National Institutes of Health during the conduct of the study. Dr Ip reported receiving personal fees from Novartis, Genentech, Allergan, Regeneron, RegenexBio, Apellis, Aerie, Alimera, Amgen, Cell Lineage Therapeutics, Clearside Biomedical, and OccuRX outside the submitted work. No other disclosures were reported.

Funding/Support: SCORE2 was funded by the National Eye Institute (National Institutes of Health, Department of Health and Human Services) under grants U10EY023529, U10EY023533, and U10EY023521. Regeneron and Allergan also supported SCORE2 through the donation of the study drug. Support was also provided for this work from Research to Prevent Blindness through an unrestricted grant to the Department of Ophthalmology and Visual Sciences of the University of Illinois at Chicago, the Jules Stein Eye Institute, the Doheny Eye Institute, the Department of Ophthalmology at the University of California, Los Angeles, and the Department of Ophthalmology and Visual Sciences at the University of Wisconsin–Madison.

Role of the Funder/Sponsor: The National Institutes of Health participated in the oversight of the conduct of the study and review of the manuscript but not directly in the design or conduct of the study, nor in the collection, management, analysis, or interpretation of the data, or in the preparation of the manuscript. Research to Prevent Blindness did not participate in the oversight, design, or conduct of the study nor in the analysis, interpretation, or review of the manuscript.

Group Information: The members of the SCORE2 Investigator Group are listed in the Supplement.