To evaluate long-term effects of multiple intravitreal antivascular endothelial growth factor (VEGF) injections on intraocular pressure (IOP) in eyes with neovascular age-related macular degeneration (AMD) or retinal vein occlusion (RVO).
Retrospective cohort study.
This study enrolled patients who underwent multiple (more than 3) intravitreal anti-VEGF injections and who were followed for more than 12 months after their last injection. IOP elevation was defined as an increase of 5 mm Hg over the baseline measurement on 2 consecutive visits. The frequency of IOP elevation was determined. A hazard ratio of each putative risk factor for IOP elevation was calculated using the Cox proportional hazard model for all participants, incorporating underlying disease as a covariate, as well as for each cohort.
Included in the analysis were 629 eyes with neovascular AMD and 95 eyes with RVO. Twenty eyes with neovascular AMD (3.0%) and 7 eyes with RVO (7.4%) experienced IOP elevation after multiple anti-VEGF injections, with an overall incidence of 3.7%. In the Cox proportional hazard analysis of total participants, a diagnosis of RVO (3.424, P = 0.005), a history of glaucoma (8.441, P = 0.001), and low baseline IOP (0.865, P = 0.040) were all significant risk factors for IOP elevation after multiple anti-VEGF injections.
A history of multiple intravitreal anti-VEGF injections was not a significant risk factor for IOP elevation in our study. IOP elevation was more common in eyes with RVO than with AMD after anti-VEGF injection.
Intravitreal ranibizumab (Lucentis; Genentech, San Francisco, California) and bevacizumab (Avastin; Genentech) are antivascular endothelial growth factor (VEGF) agents widely used to treat neovascular age-related macular degeneration (AMD) and other retinal vascular disorders. Ocular adverse events with anti-VEGF injection therapy are rarely reported, and reported risks are usually correlated with the intravitreal injection procedure itself, including intraocular inflammation, retinal tears, vitreous hemorrhage, endophthalmitis, lens changes, and transient intraocular pressure (IOP) elevation. Transient IOP elevation after anti-VEGF injection is considered to be related to a volume effect caused by the addition of fluid into the vitreous cavity.
The duration of action of anti-VEGF agents is limited, and pathologic lesions are typically not completely extinguished by a single anti-VEGF treatment. In most cases therefore, repeated injections are required to maintain anti-VEGF effects, and this makes the identification of adverse effects crucially important for continuous treatment. Recently, there have been several reports relating to multiple intravitreal injections of anti-VEGF agents to sustain an elevated IOP. However, no consensus has emerged in terms of a direct causal relationship between the use of an anti-VEGF agent and a sustained elevated IOP. Further, risk factors for IOP elevation following repeated intravitreal injections of anti-VEGF agents have yet to be determined. It is interesting that this complication was not noted in randomized clinical trials of novel therapeutics, including anti-VEGF antibody in the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR) trial, the Minimally Classic/Occult Trial of the anti-VEGF antibody Ranibizumab in the Treatment of Neovascular Age-Related Macular Degeneration (MARINA) trial, or the VEGF Inhibition Study in the Ocular Neovascularization (VISION) trial. In addition, some retrospective studies have reported no significant risk of IOP elevation with repeated anti-VEGF therapy. Furthermore, for retinal disorders other than AMD, there has been no report on the long-term effects of anti-VEGF injections on persistent IOP elevation.
This study was designed to evaluate the long-term effects on IOP after multiple anti-VEGF injections to treat various retinal disorders in a relatively large number of subjects. We assessed the frequency and possible predictive factors related to IOP elevation over baseline IOP in patients with neovascular AMD or retinal vein occlusion (RVO) who underwent multiple intravitreal ranibizumab and/or bevacizumab injections.
This retrospective cohort study followed the principles of the Declaration of Helsinki and was approved by the Institutional Review Board of the Asan Medical Center at the University of Ulsan, Seoul, South Korea. Patients who were treated with multiple intravitreal injections of anti-VEGF agents for neovascular AMD or RVO at a university-based retina clinic (Asan Medical Center, Seoul, South Korea) between February 2005 and January 2012 and who met the inclusion criteria were selected by medical record reviews in a consecutive manner. At the initial diagnosis, all patients received comprehensive ophthalmologic examinations, including reviews of their medical histories, measurements of best-corrected visual acuity (BCVA) and IOP, slit-lamp biomicroscopy, autorefractometry, gonioscopy, and dilated fundoscopic examinations of both eyes. Among patients diagnosed with neovascular AMD or RVO, those who underwent multiple anti-VEGF treatments (more than 3) unilaterally and who were followed for more than 12 months after their last injections were included in this study.
The presence of glaucoma or suspected glaucoma was verified by reviewing existing medical records dated prior to when the patient received their first injections of anti-VEGF agents. Patients with baseline diagnoses of glaucoma were included when their IOP was well controlled, with a preinjection baseline IOP < 21 mm Hg while on IOP-lowering medication. Any patient with any other ophthalmic condition that could have an effect on IOP (eg, closed angle on gonioscopy, factors associated with secondary glaucoma, history of silicone oil tamponade, or thyroid-associated ophthalmopathy) or the accuracy of IOP measurements (eg, history of corneal refractive surgery and corneal pathology) were excluded. Patients with bilateral anti-VEGF agent treatment were not included in this analysis. If other ocular treatments (eg, surgical, laser or intravitreal or periocular steroid injection) were performed during the follow-up period, only the data that were obtained during the period before such treatment were analyzed.
Intravitreal injections of anti-VEGF agents and IOP measurements
Intravitreal injections of either ranibizumab (0.5 mg/0.05 mL) or bevacizumab (1.25 mg/0.05 mL) were administered in the office using an aseptic technique after the administration of topical anesthesia (alkaline proparacaine chloride 5 mg/mL; Alcon, Fort Worth, Texas). Bevacizumab was compounded by the hospital pharmacy on site and stored in a refrigerator for no more than 2 weeks before usage. Ranibizumab was drawn up using a filtered needle immediately before use. After injection, patients were instructed to use antibiotic eye drops 4 times daily for 1 week. No prophylactic therapies for IOP elevation (eg, the use of IOP-lowering eye drops, ocular compression, or anterior chamber paracentesis) were performed before or after intravitreal injection. The dosing regimen for ranibizumab or bevacizumab was a once-monthly injection for 3 months following diagnosis and followed the treat-and-extend method, which extends the interval between reinjection without macular fluid and the next follow-up visit. In some patients who showed recurrence of intraretinal or subretinal fluid at the follow-up optical coherence tomography, the interval was adjusted appropriately.
IOP was measured in all patients for both eyes by Goldmann applanation tonometry (Haag-Streit, Cincinnati, Ohio, and Reliance Medical Products, Mason, Ohio) before dilation. Central retinal artery perfusion was evaluated immediately after injection by funduscopic examination. Baseline IOP values were calculated as the mean of up to 3 of the most recent IOP measurements before the patients’ first anti-VEGF injections. Follow-up IOP measurements after each injection were performed at the next visit before any additional injections. IOP elevation was defined as an increase of 5 mm Hg above baseline on 2 consecutive visits. For patients who showed an increased IOP, however, the IOP was measured again 5 minutes later to confirm elevation. Patients experiencing increased IOP were sent to a glaucoma specialist (KRS) for evaluation and management.
The following variables were recorded for each patient: diagnosis, age, sex, baseline best-corrected visual acuity, baseline IOP, lens status, spherical equivalent, total follow-up period, total number of anti-VEGF agent injections, mean interval between injections, and glaucoma history. The prevalence of IOP elevation was noted for the entire population as well as for each subgroup of neovascular AMD and RVO. Commencement of a new IOP-lowering medication treatment or glaucoma filtration surgery during the follow-up period was also reviewed.
The Wilk-Shapiro test was used to explore the distribution of numerical data. Normally, distributed data are presented as means with standard deviations (SDs), whereas non-normally distributed data are shown as medians with interquartile ranges. Descriptive statistics were initially evaluated to determine the demographic and ocular baseline characteristics of subjects with IOP elevation compared to those without. Normally distributed data were compared between the 2 groups by using the unpaired t test. Non-normally distributed data were compared using the Mann-Whitney U test. To compare categorical data, the chi-square test of the Fisher exact test was used as appropriate on the basis of the data distribution. Hazard ratios (HRs) for associations between potential risk factors were obtained using the Cox proportional hazards model. Univariate analyses were performed separately for each variable. Variables with a probability value of 0.2 on univariate analysis were included in a multivariate Cox proportional hazards model. A backward elimination process was used to develop the final multivariate model, and adjusted HRs with 95% confidence intervals (CIs) were calculated. Schoenfeld residuals and the log [−log (survival rate)] test were used to verify that proportional hazards assumptions were not violated. Model fit was assessed using residual analyses. In each subject in the neovascular AMD and RVO group, uni- and multivariate Cox proportional hazards analyses were performed to evaluate risk factors. Cox proportional hazard analysis was performed for all participants, with underlying disease incorporated as another variable. All statistical analyses were performed using SAS v 9.1 software (SAS Institute, Cary, North Carolina) and SPSS v 18.0 software (SPSS, Chicago, Illinois).
Baseline characteristics of study patients
A total of 724 eyes (629 eyes with neovascular AMD and 95 eyes with RVO) of 724 Korean subjects were included in our study. The mean patient age at the initiation of treatment was 67 years ( Table 1 ). The pretreatment IOPs of the treated eyes were 14.1 ± 3.1 mm Hg. The mean number of injections per patient in this study was 9.4 ± 5.6 (range, 3–37), and the mean follow-up period was 35 ± 15.5 months (range, 17–75 months).
|Parameter||Total Eyes (n = 724)||Treated Eyes without IOP Elevation (n = 697)||Treated Eyes with IOP Elevation (n = 27)||P value|
|Sex (male), n (%)||455 (62.8)||437 (61.8)||18 (66.7)||0.610|
|Age at first anti-VEGF injection, years||67.2 ± 9.9||67.2 ± 10.0||66.8 ± 8.5||0.316|
|Diagnosis, n (AMD vs. RVO)||629 vs 95||609 vs 88||20 vs 7||<0.001|
|Baseline logMAR BCVA||0.67 ± 0.50||0.67 ± 0.48||0.69 ± 0.52||0.820|
|Lens status (phakic vs pseudophakic), n||603 vs 121||579 vs 118||24 vs 3||0.601|
|MRSE of treated eye (only phakic eyes), diopter||0 ± 2.06||−0.01 ± 2.05||0.01 ± 1.97||0.795|
|History of glaucoma, n (%)||47 (6.5)||39 (5.6)||8 (29.6)||<0.001|
|Total number of anti-VEGF injection, n||9.5 ± 5.6||9.4 ± 5.6||9.7 ± 5.9||0.360|
|Mean interval among anti-VEGF injections, weeks||7.3 ± 2.3||7.3 ± 2.2||7.7 ± 3.0||0.441|
|Bevacizumab only, n||401||387||14||0.235|
|Ranibizumab only, n||92||88||4||0.198|
|Bevacizumab and ranibizumab, n||231||222||9||0.220|
|Pre-injection baseline IOP of treated eye, mm Hg||14.1 ± 3.1||14.1 ± 3.2||12.9 ± 3.3||0.065|
|Postinjection peak IOP of treated eye, mm Hg||17.0 ± 3.5||17.0 ± 3.5||19.6 ± 2.5||<0.001|
|Postinjection last IOP of treated eye, mm Hg||14.2 ± 3.4||14.1 ± 3.6||15.3 ± 3.9||0.045|
The incidence and characteristics of intraocular pressure elevation after antivascular endothelial growth factor treatment
Of the treated eyes, 27 (3.7%) experienced IOP elevation of ≥5 mm Hg on ≥2 consecutive visits during the follow-up period. In subgroup analysis, 7 (7.4%) patients with RVO and 20 (3.0%) patients with AMD showed IOP elevation. When patients were stratified by the number of total injections into 3–5, 6–8, 9–14, or 15–37, the frequency of IOP elevation was not significantly different in terms of number of injections (4.3%, 2.9%, 4.7%, and 2.6%, respectively, P = 0.783). Among the treated eyes that showed IOP elevation, the median time to development of peak IOP after the last injection was 9 weeks (range, 4–30), and the median number of injections before reaching the peak IOP was 5 (range, 3–13). Among 27 treated eyes that experienced IOP elevation, 8 eyes had glaucoma at baseline. To control the IOP during anti-VEGF treatment, 2 eyes required the use of an additional topical IOP-lowering agent, and 1 eye required initiation of glaucoma therapy. These 3 eyes were all eyes of patients with glaucoma. In the remaining cases, IOP was normalized (≤21 mm Hg) within 2 weeks without additional IOP-lowering treatment.
In our analysis of the IOP in untreated fellow eyes, 23 (3.1%) eyes experienced IOP elevation during the study period, and 12 patients experienced IOP elevation in both the treated and the untreated fellow eyes simultaneously. In other words, in 27 patients who experienced IOP elevation in their treated eyes, 12 patients (44.4%) showed IOP elevation also in their untreated fellow eyes. The incidence of IOP elevation did not differ between treated eyes and fellow eyes ( P = 0.565).
When comparing eyes with and without IOP elevation, the group with IOP elevation included a greater proportion of patients who had been diagnosed with RVO ( P < 0.001) and had a history of glaucoma ( P < 0.001). Most of our patients with glaucoma had been using IOP-lowering agents during the study period. In addition, whereas 6 patients (22.2%) were using IOP-lowering medication among the 27 patients in the IOP elevation group, 33 patients (4.7%) were using medication among the 697 patients of the non-IOP elevation group ( P < 0.001). The postinjection IOP levels of the treated eyes were higher in the IOP-elevation group at the last follow-up. However, there were no differences in terms of sex, baseline age, pretreatment IOP, types of drugs, number of total anti-VEGF injections, treatment interval, lens status, or spherical equivalent of the treated eyes between the 2 groups ( Table 1 ).
Risk factors associated with intraocular pressure elevation after anti-VEGF treatment
Table 2 lists the univariate and multivariate HRs for each putative risk factor, including underlying disease as another variable, in all study participants according to the Cox proportional hazard model. Because a diagnosis of RVO, a history of glaucoma, and the baseline IOP of treated eyes were found to be predictive of IOP elevation in treated eyes according to univariate analysis (variables with a probability of <0.2), they were included in multivariate analysis. On multivariate analysis using a backward elimination method, a diagnosis of RVO (HR, 3.424; P = 0.005), history of glaucoma (HR, 8.44; P = 0.001), and baseline IOP of the treated eyes (HR, 0.865; P = 0.040) were found to be significant risk factors for IOP elevation after multiple anti-VEGF injections. None of the ranibizumab vs bevacizumab, refractive error, or phakic status variables was a significant risk factor for persistent IOP elevation.