Abstract
Importance
For the management of retinal disease, use of intravitreous injections of anti-vascular endothelial growth factor has increased. Recent reports have suggested that this therapy may cause persistent intraocular pressure (IOP) elevation and potentially increase the risk of glaucoma in patients with retinal disease.
Objective
To assess the risk of sustained IOP elevation or the need for IOP-lowering treatments in eyes with diabetic macular edema following repeated intravitreous injections of ranibizumab.
Main Outcome Measure(s)
The cumulative probability of sustained IOP elevation, defined as an IOP of at least 22 mmHg and an increase of at least 6 mmHg from baseline at 2 consecutive visits, or initiation or augmentation of ocular hypotensive therapy, through 3 years of follow up.
Design, Setting, and Participants
An exploratory analysis was conducted within a Diabetic Retinopathy Clinical Research Network randomized clinical trial. Of 486 participants (582 eyes) with center-involved diabetic macular edema and no pre-existing open-angle glaucoma, 260 eyes were randomly assigned to receive sham injection plus focal/grid laser; 322 to ranibizumab plus deferred or prompt focal/grid laser.
Results
The mean baseline IOP in both treatment groups was 16±3 mmHg (range 5–24 mm Hg). The cumulative probability of sustained IOP elevation or initiation or augmentation of ocular hypotensive therapy by 3 years, after repeated ranibizumab injections, was 9.5% in the ranibizumab plus prompt or deferred laser group versus 3.4% in the sham plus laser group (difference = 6.1%, 99% CI: −0.2% to 12.3%; hazard ratio = 2.9, 99% CI: 1.0 to 7.9, P = 0.01). The distribution of IOP and the change in IOP from baseline at each visit through 3 years was similar in each group.
Conclusions
In 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 consider this information when following patients who have received intravitreous injections of anti-vascular endothelial growth factor for the treatment of diabetic macular edema.
Introduction
Intravitreous injections of any agent may transiently increase intraocular volume which may also increase intraocular pressure (IOP). 1–4 Sustained elevation of IOP following repeated intravitreous anti-vascular endothelial growth factor (anti-VEGF) injections in eyes with diabetic macular edema (DME) has not been previously reported, however, recent reports have suggested a potential association between repeated intravitreous anti-VEGF injections and sustained IOP elevation in eyes with age-related macular degeneration.5–9 Considering sustained IOP elevation may increase the risk of developing glaucoma, further evaluation of a possible association between repeated intravitreous anti-VEGF injections and sustained IOP elevation is indicated.5, 6, 10–13 An exploratory ad hoc analysis that assesses whether repeated intravitreous injections of ranibizumab increase the risk of sustained elevation in IOP or initiation or augmentation of IOP-lowering treatment in eyes with DME compared with eyes receiving focal/grid laser through 3 years is reported herein.
Methods
Study Design
The Diabetic Retinopathy Clinical Research Network study “Intravitreal Ranibizumab or Triamcinolone Acetonide in Combination with Laser Photocoagulation for Diabetic Macular Edema Trial” (NCT00444600) was a multi-center randomized clinical trial that compared focal/grid laser to 0.5 mg intravitreous ranibizumab with prompt or deferred (≥24 weeks) laser and 4 mg intravitreous triamcinolone plus prompt laser, for the treatment of center-involved DME causing vision impairment. Only eyes randomly assigned to the sham plus prompt laser, ranibizumab plus prompt laser, and the ranibizumab plus deferred laser treatment groups are included in this report. Data from the ranibizumab groups were similar (data not shown) and are therefore combined in this report. The complete protocol is available online (http://www.drcr.net) and the trial methods, treatment algorithm, and efficacy and safety results have been published elsewhere.14–16
Relevant to this report, eyes with a history of open-angle glaucoma or steroid-induced IOP elevation that required IOP-lowering treatment, had neovascular glaucoma, or an IOP of ≥25 mmHg at baseline, were ineligible for the study. However, history of angle-closure glaucoma was not an exclusion criterion. Eyes were permitted to have ocular hypertension if IOP was <25 mmHg with use of up to one topical glaucoma medication. Gonioscopy was not performed at baseline. Both eyes from the same participant could be enrolled if both were eligible, with one eye randomly assigned to the sham group, and the other assigned to one of the 3 remaining treatments.
Although not required, it was recommended that the IOP measurements occur before pupillary dilation. Sixty-three (10%) eyes (8.5% sham, 11% ranibizumab) in the original study cohort with a baseline IOP measurement obtained post-dilation were excluded from the analysis cohort. Follow-up IOP measurements obtained post-dilation also were excluded from analyses. The method used to obtain the IOP measurement was at the discretion of the investigator. Measurements obtained with Goldmann applanation tonometry were combined with those obtained from tonopen.
Study Outcome
The primary outcome was defined as sustained IOP elevation (IOP of at least 22 mmHg, with an increase of at least 6 mmHg from baseline occurring at two consecutive visits at least 1 month apart) or initiation or augmentation of IOP-lowering treatments, including ocular hypotensive medications, laser trabeculoplasty or surgery. These thresholds were selected since the majority of the general population has IOP measurements below 22 mmHg and less than 6 mmHg of variability of IOP between visits. IOP of 30 mmHg or higher and IOP increase of 10 mmHg or more also were reported as these were pre-specified safety outcomes for this protocol.14
Protocol visits occurred every 4 weeks during the first year of follow-up. After one year, the frequency between visits differed according to treatment group; therefore only data collected at visits that occurred at 16-week intervals, which were common to all treatment groups, were included in the sustained IOP definition after 52 weeks.
Statistical Analysis
The hazard ratio for the composite study outcome over the 3 years of follow up and corresponding 99% confidence interval (CI) were estimated with the Cox proportional hazards model, with adjustment for correlation between two study eyes from the same participant. The cumulative probabilities of outcome and standard errors from this model were used to estimate the cumulative outcome rate at 3 years by treatment group and construct a 99% CI on the difference using a Z-score method. The association between the number of injections and the primary outcome was evaluated by including the number of injections as a time-dependent covariate in a proportional hazards model. Table 1 reports reasons for data censoring in the primary outcome analysis. Results for the treatment groups were similar from a sensitivity analysis censoring data at time of cataract surgery during study participation for 126 (22%) eyes (data not shown). All analyses were conducted using SAS 9.3 (SAS Institute, Inc).
Table 1.
: Participant disposition and data censoring during 3-year follow-up
| Sham n = 260 | Ranibizumab n = 322 | Total n = 582 | |
|---|---|---|---|
| Met primary outcome†, n | 6 | 22 | 28 |
|
| |||
| Did not meet primary outcome, n | 254 | 300 | 554 |
|
| |||
| Censored prior to 3 years^, n (%) | 201 (79%) | 184 (61%) | 385 (69%) |
| Reason for censoring: | |||
| Lost to follow up | 7 (3%) | 9 (3%) | 16 (3%) |
| Withdrew from study | 13 (5%) | 18 (6%) | 31 (6%) |
| Death | 15 (6%) | 16 (5%) | 31 (6%) |
| Exposure to corticosteroids* | 65 (26%) | 92 (31%) | 157 (28%) |
| Sham eyes receiving anti-VEGF | 64 (25%) | 0 (0%) | 64 (12%) |
| Too many consecutively missed visits or only post-dilation IOP** | 27 (11%) | 38 (13%) | 65 (12%) |
| Vitrectomy | 9 (4%) | 7 (2%) | 16 (3%) |
| Neovascular or ghost-cell glaucoma or endophthalmitis | 1 (<1%) | 4 (1%) | 5 (<1%) |
| Completed 3 year visit, n (%) | 53 (21%) | 116 (39%) | 169 (31%) |
Anti-VEGF = anti-vascular endothelial growth factor; IOP = intraocular pressure
Persistent IOP elevation (IOP≥22 mmHg at two consecutive visits at least 4 weeks apart with at least 6mmHg increase in IOP from baseline) or initiation or augmentation of IOP-lowering medicine or surgery.
Data censored on date of exposure
Oral, nasal, intra-articular, intramuscular, inhaler, topical cutaneous, intravenous, subcutaneous, topical ocular, intradermal, transdermal
Data from eyes with ≥4 missing IOP measurements during year one, and data from eyes missing any 16-week interval IOP measurement after year one were censored, as were data from eyes with IOP exclusively measured post-dilation.
Results
Four hundred eighty-six participants contributed 582 study eyes among which 260 were randomly assigned to the sham plus laser group; 322 to the combined ranibizumab plus prompt or deferred laser group. The baseline characteristics were similar in each group (Table 2). Three percent of study eyes in each group had a history of glaucoma or were using IOP-lowering medications at baseline. Primary and secondary forms of open-angle glaucoma were exclusion criteria, therefore eyes with a reported history of glaucoma at baseline (sham [5];ranibizumab groups [3]) were presumed to have had previous angle closure glaucoma or were misreported. The majority (82%) of baseline measurements were obtained with Goldmann tonometry. Through the 3-year visit, 59% and 63% of all IOP measurements in sham and ranibizumab groups, respectively, were obtained with Goldmann tonometry, and 72% and 79% of eyes in sham and ranibizumab groups, respectively, had IOP measurements consistently obtained with the same method (Goldmann applanation or tonopen).
Table 2.
Baseline Characteristics of Analysis Cohort
| Sham n = 260 eyes | Ranibizumab n = 322 eyes | |
|---|---|---|
| Age at randomization (years), mean±SD | 63±10 | 63±10 |
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| Gender, women, n (%) | 113 (43%) | 138 (43%) |
|
| ||
| Race/Ethnicity, n (%) | ||
| White | 188 (72%) | 237 (74%) |
| Black/African American | 48 (18%) | 53 (16%) |
| Hispanic or Latino | 19 (7%) | 24 (7%) |
| Other | 5 (2%) | 8 (2%) |
|
| ||
| Bilateral study eyes, n (%) | 96 (37%) | 96 (30%) |
|
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| Baseline IOP (mmHg), mean±SD (range) | 16±3 (8–24) | 16±3 (5–24) |
|
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| IOP 22 to 24mmHg, n (%) | 10 (4%) | 16 (5%) |
|
| ||
| Device used for IOP measurement, n (%) | ||
| Goldmann | 213 (82%) | 263 (82%) |
| Tonopen | 47 (18%) | 59 (18%) |
|
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| History of glaucoma* , n (%) | 5 (2%) | 3 (<1%) |
| With lOP-lowering treatment at baseline, n | 2 | 1 |
|
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| On IOP lowering treatment at baseline without a history of glaucoma, n (%) | 3 (1 %) | 7 (2%) |
SD=standard deviation; IOP=intraocular pressure
No study eyes had a history of primary or secondary open-angle glaucoma as these were study exclusion criteria. However, these eyes had a history of glaucoma presumed to be angle-closure glaucoma or were miss-reported.
The cumulative probability of the primary outcome, sustained IOP elevation, or need for IOP-lowering therapy through the first year was 2.0% and 5.7% in the sham and ranibizumab groups, respectively. Throughout the first year of the study, eyes in both the sham and ranibizumab groups had an average of 13 visits. Among eyes that were still at risk of meeting the outcome at 1 year (i.e., those without the outcome and not censored before the 1 year visit), the average number of injections received (±SD) were 10±4 in the sham group and 8±3 in the ranibizumab groups.
During the 3-year study period, a total of 6 eyes in the sham group, and 22 eyes in the ranibizumab groups met the composite outcome for a 3-year cumulative probability of 3.4% and 9.5% in the sham and ranibizumab groups, respectively, for a difference of 6.1% (99% CI: −0.2% to 12.3%; hazard ratio [HR] for ranibizumab/sham: 2.9, 99%CI: 1.03 to 7.9, P = 0.01; Figure 1). One eye in the sham group and 2 eyes in the ranibizumab groups, that met the study outcome, had a history of (presumed angle-closure) glaucoma or were on IOP-lowering treatment prior to study entry.
Figure 1.
Cumulative Probability of the Composite Study Outcome through 3 years. Sustained intraocular pressure (IOP) (≥22 mm Hg+≥6 mm Hg change from baseline at two consecutive visits) or initiation/augmentation of IOP-lowering medication, laser or surgery for glaucoma. Eyes with ocular hypertension at study entry are not included in the composite study outcome unless they fulfilled the criteria for the study outcome during the study follow-up.
During the 3 year follow-up period, among the 6 eyes in the sham group and 22 eyes in the ranibizumab groups that met the primary outcome, the mean IOP at the time of the event was 23 and 28 mmHg; the mean change in IOP from baseline was +7 and +9 mmHg from baseline, respectively. Intraocular pressure measurements were not available at the time of the primary outcome in 3 and 2 eyes from the sham and ranibizumab groups, respectively, because initiation of IOP medication did not coincide with a study visit.
At any single visit, an increase in IOP of ≥10 mmHg from baseline occurred in 5% vs. 4% through year 1, and 9% vs. 6% through the 3-year visit, in the sham and ranibizumab groups, respectively. Intraocular pressure of ≥30 mmHg at any single visit was reported in 1% vs. 2% through year 1, and 3% vs. 2% through year 3 in the sham and ranibizumab groups respectively. There were no eyes at risk for the study outcome that required an IOP lowering procedure (laser or intraocular surgery) throughout the 3 year period (Table 3).
Table 3.
Cumulative Percent with Sustained IOP Elevation or Ocular Hypotensive Treatment*
| Through Year 1† | Through Year 3†† |
|||||
|---|---|---|---|---|---|---|
| All Eyes | Only Bilateral Study Eyes | |||||
|
| ||||||
| Sham | Ranibizumab | Sham | Ranibizumab | Sham | Ranibizumab | |
| Composite Outcome § | ||||||
|
| ||||||
| N | 260 | 322 | 260 | 322 | 96 | 96 |
|
| ||||||
| No. of Eyes meeting outcome | 5 | 15 | 6 | 22 | 5 | 10 |
|
| ||||||
| Cumulative Probability (%) | 2.0 | 5.7 | 3.4 | 9.5 | 8.3 | 15.0 |
|
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| Sustained IOP Elevation Component of Study Outcome, Only | ||||||
|
| ||||||
| No. of Eyes meeting outcome | 2 | 6 | 2 | 9 | 2 | 4 |
|
| ||||||
| Cumulative Probability (%) | 0.7 | 2.4 | 1.1 | 3.8 | 2.6 | 5.1 |
|
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| IOP Medication Component of Study Outcome, Only | ||||||
|
| ||||||
| Number of Eyes meeting outcome | 2 | 4 | 3 | 7 | 2 | 2 |
|
| ||||||
| Cumulative Probability (%) | 0.9 | 1.5 | 1.9 | 3.2 | 4.7 | 3.7 |
| Both Sustained IOP Elevation and Medication component of Study Outcome Met | ||||||
|
| ||||||
| No. of Eyes meeting outcome | 1 | 5 | 1 | 6 | 1 | 4 |
|
| ||||||
| Cumulative Probability (%) | 0.4 | 1.9 | 0.5 | 2.4 | 1.6 | 5.8 |
|
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| Any Glaucoma Procedure | ||||||
|
| ||||||
| Eyes meeting outcome, n | 0 | 0 | 0 | 0 | 0 | 0 |
|
| ||||||
| Cumulative Probability (%) | ||||||
CI= confidence interval; IOP=intraocular pressure
Eyes with ocular hypertension at study entry are not included in the composite study outcome unless they fulfilled the criteria for the study outcome during the study follow-up.
Study visits every 4 weeks
Study visits every 4 weeks through 1 year then every 16 weeks thereafter.
IOP (≥22 mm Hg+≥6 mm Hg change from baseline at two consecutive visits) or initiation/augmentation of IOP-lowering mefor glaucoma.
Among the 22 eyes in the ranibizumab group that met the primary outcome during the 3-years of follow-up, the mean (±SD) cumulative number of ranibizumab injections at the time of meeting the outcome was 7±4. The average cumulative number of ranibizumab injections received through 3 years in eyes that completed the 3-year visit (n = 116), without meeting the composite outcome, was 15±8. The number of injections received was not associated with the primary outcome when it was included in the proportional hazard model as a time-dependent covariate (HR 0.95, 95% CI: 0.83 to 1.10, P = 0.50). The distribution of IOP and IOP change from baseline through 3 years at each visit was similar across treatment groups (Figure 2).
Figure 2.
The distribution of IOP (A) and IOP change (B) from baseline at each visit through 3 years. Error bars represent 95% confidence interval.
Ninety six participants had two study eyes in the trial, with one eye randomly assigned to the sham group and the other to ranibizumab plus prompt or deferred laser. Within this restricted cohort, the cumulative probability of meeting the study outcome was 8.3% and 15.0% in the sham and ranibizumab groups, respectively, for a differences of 6.6% (99% CI: −8% to 21%; HR ranibizumab/sham = 1.9, 99% CI = 0.7 to 5.1, P = 0.11).
Discussion
In this ad hoc analysis of phase III clinical trial data evaluating repeated ranibizumab injections in eyes with DME, the cumulative rate of sustained IOP elevation or initiation or augmentation of therapy for elevated IOP through 3 years visit was higher in eyes that were randomly assigned to receive ranibizumab injections (with prompt or deferred laser) than in eyes receiving prompt laser alone.
Intravitreous injections of therapeutic agents may transiently elevate IOP or lead to a sustained elevation of IOP.2, 4, 9 Elevated IOP is an important risk factor for glaucoma, which raises concerns about the long-term safety of administering intravitreous injections. Theories potentially explaining the relationship between repeated intravitreous injections and elevated IOP include increased inflammation, and mechanical or functional alteration of the trabecular meshwork. Several studies of patients with neovascular AMD receiving repeated injections of anti-VEGF agents have reported rates of sustained IOP elevations varying from 3% to 13%.5–9 Definitions of “sustained” IOP differed across these studies, which may account for the variability.5–9 Some of these studies were retrospective, did not all have standardized procedures for measuring IOP, and sometimes lacked a control arm for comparison. In large randomized trials for neovascular AMD, the frequency of IOP-related serious ocular adverse events and mean IOP measurements over time were similar between eyes managed with repeated intravitreous injections (at least 24) and control eyes.2, 9, 17, 18 More recently, in a post hoc analysis from ANCHOR and MARINA, investigators reported 11% of ranibizumab eyes had an IOP of at least 25 mmHg while 5% of control eyes behaved similarly. 9 Also a combined endpoint of 6 mmHg or more in IOP rise from baseline with an IOP of at least 21 was more common with ranibizumab.9
This analysis explored a potential association between repeated intravitreous injections of ranibizumab and an increased risk of sustained IOP or ocular hypotensive therapy among eyes with DME. The cumulative probability of meeting the composite study outcome was approximately three times higher for eyes managed with repeated intravitreous injections as compared with eyes receiving sham injections, with an absolute risk increase of 6% at 3 years. However, since the total number of events was small, the confidence intervals around the estimates are wide,indicating that ranibizumab eyes may have anywhere from 6 times the risk of this event to no increased risk. It is unknown whether eyes with the outcome had visual field or optic nerve alterations as these glaucoma assessments were not collected. Other risk factors for glaucoma, such as central corneal thickness and family history of glaucoma were not evaluated in our study. In most cases these eyes were managed solely with observation or a single medication.
The majority of eyes that met the study outcome did so within the first year of treatment when the requirement for monthly study visits facilitated detection of sustained IOP elevation relative to later follow up, when visits were less frequent. This is the interval in which we have the greatest confidence in our data, given an identical visit schedule for all treatment arms that limits potential ascertainment bias.
Review of the average number of injections at the time of an event through 3 years, and the IOP distribution among eyes across a spectrum of total number of injections did not suggest that the number of intravitreous injections was linked to the outcomes of interest. Furthermore, including the number of injections as a time-dependent covariate in the proportional hazard model did not reveal an association with the study primary outcome. Past studies evaluating eyes with neovascular AMD have reported an inconsistent relationship between total number of injections and IOP increases.9, 19, 20 While we explored the effect of repeated intravitreous anti-VEGF injections on IOP, we did not explore the potential mechanism(s) by which these injections might influence the IOP.
The study composite outcome was selected to capture eyes believed to be at increased risk of glaucoma for which intervention may be indicated to preserve vision function. Thresholds for IOP level and change from baseline were defined to exclude those that were likely within the normal range. The criteria used are similar to previous studies exploring this issue.5, 7, 21 Our data have limitations in that we chose a conservative outcome that combined sustained elevated IOP and variability of IOP. Given that IOP and variability of IOP are two separate risk factors for glaucoma the proportion of participants in our study at risk may be higher than our results suggest. In addition, IOP may have been subject to diurnal fluctuations or variation between the two measurement techniques used for IOP determination, and there was no stratification at enrollment for glaucoma risk factors. Eyes placed on new IOP lowering medicines were part of the outcome irrespective of whether they manifested sustained IOP elevation. To what extent the eyes that met our study outcome were truly at risk of glaucoma and its consequences on visual fields is unknown. The level of IOP at the time point at which sustained elevation in IOP was met in the ranibizumab groups averaged 28±6 mmHg (range 22 to 43 mmHg), while initiation of IOP-lowering therapy was deferred in 9 (60%) of 15 of these eyes. The mean IOP was 30 mmHg (range 23 to 42 mmHg) among the ranibizumab eyes that only met the criteria of IOP-lowering medications and for which an IOP measurement was collected at the same visit; however, these data were captured incompletely. Throughout the study, there was no difference identified between eyes in the sham group vs the ranibizumab plus prompt or deferred laser treatment group for any serious IOP complications, including an IOP increase to at least 30 mmHg, an increase of at least 10 mmHg from baseline, or the need for IOP-lowering surgical or laser procedures. Although there was a difference in our primary outcome between treatment groups, we do not know the clinical relevance of this finding. This analysis was not designed to determine incidence of glaucoma but rather to determine the incidence of sustained IOP or requirement for ocular hypotensive therapy, which are risk factors for glaucoma.
Additional limitations in this study include the fact that treating physicians were unmasked to treatment assignment, generally examined ranibizumab-treated participants more often than laser-alone-treated participants during years 2 and 3 (which increased the probability of capturing an event), and the protocol did not specify initiation of IOP lowering therapy at a specific threshold. Study ophthalmologists may have been biased to withhold therapy to sham eyes when IOP fluctuations occurred or to initiate treatment in intravitreous injection eyes when minimal changes in IOP occurred.
A particular strength of this review is the subgroup analysis of participants with two study eyes, one assigned to sham and the other to ranibizumab. Endogenous factors that would predispose these study eyes to glaucoma should be similar between the sham and ranibizumab groups, affording the opportunity to isolate the effects of the intravitreous injection. In this bilateral subgroup, intravitreous injection eyes appeared to behave similarly to the full cohort. Although more data was censored from sham eyes because of the per-protocol switch to anti-VEGF injections, it is unlikely that censoring this data resulted in bias since there is no rationale for why sham eyes that switched to anti-VEGF would have increased susceptibility to IOP elevation relative to sham eyes not initiating anti-VEGF. Additional strengths of the full analysis include the large number of eyes evaluated, the prospective data collection, standardized intervals between IOP assessment during the first year of follow-up, and the censoring of data for intervening factors that could affect IOP, such as corticosteroids, vitreous hemorrhage, and vitrectomy.
Repeated intravitreous injections of ranibizumab were associated with an increased risk of sustained elevation in IOP or initiation of medications to lower IOP. This exploratory analysis suggests about a 3-fold increased risk of sustained IOP elevation or initiation of IOP-lowering treatment among individuals treated with an average of 15 intravitreous ranibizumab injections over 3 years for DME in the absence of a history of open-angle glaucoma. Although the risk of meeting the outcome appeared higher in the ranibizumab group than it did in the sham group, it is unknown whether this difference is related to intravitreous injections of 0.05 ml of fluid, the ranibizumab itself, and/or to certain intrinsic factors in eyes that made them more susceptible. Because they were ineligible, this study provides no information of risk of sustained IOP elevation in individuals receiving repeated intravitreous ranibizumab who have open-angle glaucoma, or ocular hypertension with an IOP of 25 mmHg or higher, that require management with more than one medication, or who have had a steroid associated IOP rise in the past. The absolute increase in the percentage of people that may be affected appears to be limited and the magnitude of risk for actual loss of vision function remains unknown. These data suggest that IOP should be monitored periodically in eyes receiving repeated injections of anti-VEGF therapy with consideration of ancillary testing and referral or treatment as needed.
ACKNOWLEDGEMENT
Bressler, S- Consultancy (GlaxoSmithKline); Clinical or lab research grants (Bausch and Lomb, Bayer, Emmes, Boehringer-Ingelheim, Notal Vision, Novartis, Regeneron, Thrombogenics, Sanofi-Aventis).
Bressler, N- Clinical lab or research grants (Bayer, Genentech, Regeneron); Expert testimony (Novartis); Other (Emmes)
Jampol, L- Consultancy (Quintiles/Stem Cell Organization)
Almukhtat T, Bhorade A, Huang S, Kim J, Melia M- None
Funding/Support: Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services EY14231, EY14229, EY18817.
Role of the Sponsor: The funding organization (National Institutes of Health) participated in 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.
Footnotes
Author Contributions: Mr. Almukhtar, Dr. S. Bressler, and Ms. Melia had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: N. Bressler, S. Bressler, Glassman, Melia.
Acquisition of data: Almukhtar, N. Bressler, S. Bressler, Glassman, Huang, Jampol, Kim, Melia.
Analysis and interpretation of data: Almukhtar, Bhorade, N. Bressler, S. Bressler, Glassman, Huang, Jampol, Kim, Melia.
Drafting of the manuscript: Almukhtar, Bhorade, N. Bressler, S. Bressler, Glassman, Melia.
Critical revision of the manuscript for important intellectual content: Almukhtar, Bhorade, N. Bressler, S. Bressler, Glassman, Huang, Jampol, Kim, Melia.
Obtained funding: N. Bressler, Glassman, Jampol.
Administrative, technical, and material support: Almukhtar, N. Bressler, Glassman, Jampol, Melia.
Conflict of Interest Disclosures: A complete list of all DRCR.net investigator financial disclosures can be found at www.drcr.net.
Previous Presentations: Portions of these data were presented at the ASRS 31st Annual Meeting; August 24–28, 2013; Toronto, Ontario, Canada; the World Ophthalmology Congress Annual Meeting, April 2–6, 2014 Tokyo, Japan; Macula Society Annual Meeting, February 19–22, 2014, Key Largo, Florida; Retina Society Annual Meeting, September –14, 2014, Philadelphia, Pennsylvania
Additional Contributions: Genentech provided the ranibizumab for this study. As per the DRCR.net Industry Collaboration Guidelines (available at www.drcr.net), the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol. Genentech has provided funds restricted to DRCR.net clinical sites.
Publisher's Disclaimer: Dr. Neil Bressler is the JAMA Ophthalmology Editor-in-Chief but was not involved in the review process or the acceptance of the manuscript.
A published list of the Diabetic Retinopathy Clinical Research Network investigators and staff participating in this protocol can be found in Ophthalmology 2010;117:1064-1077.e35 with a current list available at www.drcr.net.
References
- 1.Nguyen QD, Brown DM, Marcus DM, et al. Ranibizumab for Diabetic Macular Edema: Results from 2 Phase III Randomized Trials: RISE and RIDE. Ophthalmology. 2012;119:789–801. doi: 10.1016/j.ophtha.2011.12.039. [DOI] [PubMed] [Google Scholar]
- 2.Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006;355:1432–44. doi: 10.1056/NEJMoa062655. [DOI] [PubMed] [Google Scholar]
- 3.Kaiser PK, Brown DM, Zhang K, et al. Ranibizumab for predominantly classic neovascular age-related macular degeneration: subgroup analysis of first-year ANCHOR results. Am J Ophthalmol. 2007;144:850–7. doi: 10.1016/j.ajo.2007.08.012. [DOI] [PubMed] [Google Scholar]
- 4.Bakri SJ, Pulido JS, McCannel CA, Hodge DO, Diehl N, Hillemeier J. Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab. Eye (Lond) 2009;23:181–5. doi: 10.1038/sj.eye.6702938. [DOI] [PubMed] [Google Scholar]
- 5.Good TJ, Kimura AE, Mandava N, Kahook MY. Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents. Br J Ophthalmol. 2011;95:1111–4. doi: 10.1136/bjo.2010.180729. [DOI] [PubMed] [Google Scholar]
- 6.Adelman RA, Zheng Q, Mayer HR. Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections. J Ocul Pharmacol Ther. 2010;26:105–10. doi: 10.1089/jop.2009.0076. [DOI] [PubMed] [Google Scholar]
- 7.Mathalone N, Arodi-Golan A, Sar S, et al. Sustained elevation of intraocular pressure after intravitreal injections of bevacizumab in eyes with neovascular age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2012;250:1435–40. doi: 10.1007/s00417-012-1981-0. [DOI] [PubMed] [Google Scholar]
- 8.Choi DY, Ortube MC, McCannel CA, et al. Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib. Retina. 2011;31:1028–35. doi: 10.1097/IAE.0b013e318217ffde. [DOI] [PubMed] [Google Scholar]
- 9.Bakri SJ, Moshfeghi DM, Francom S, et al. Intraocular Pressure in Eyes Receiving Monthly Ranibizumab in 2 Pivotal Age-Related Macular Degeneration Clinical Trials. Ophthalmology. 2014 doi: 10.1016/j.ophtha.2013.11.029. [DOI] [PubMed] [Google Scholar]
- 10.Bakri SJ, McCannel CA, Edwards AO, Moshfeghi DM. Persisent ocular hypertension following intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol. 2008;246:955–8. doi: 10.1007/s00417-008-0819-2. [DOI] [PubMed] [Google Scholar]
- 11.Kahook MY, Kimura AE, Wong LJ, Ammar DA, Maycotte MA, Mandava N. Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections. Ophthalmic Surg Lasers Imaging. 2009;40:293–5. doi: 10.3928/15428877-20090430-12. [DOI] [PubMed] [Google Scholar]
- 12.Tseng JJ, Vance SK, Della Torre KE, et al. Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular age-related macular degeneration. J Glaucoma. 2012;21:241–7. doi: 10.1097/IJG.0b013e31820d7d19. [DOI] [PubMed] [Google Scholar]
- 13.Pershing S, Bakri SJ, Moshfeghi DM. Ocular hypertension and intraocular pressure asymmetry after intravitreal injection of anti-vascular endothelial growth factor agents. Ophthalmic Surg Lasers Imaging Retina. 2013;44:460–4. doi: 10.3928/23258160-20130909-07. [DOI] [PubMed] [Google Scholar]
- 14.Diabetic Retinopathy Clinical Research Network Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2010;117:1064–77. e35. doi: 10.1016/j.ophtha.2010.02.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Elman MJ, Bressler NM, Qin H, et al. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology. 2011;118:609–14. doi: 10.1016/j.ophtha.2010.12.033. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Elman MJ, Qin H, Aiello LP, et al. Intravitreal ranibizumab for diabetic macular edema with prompt versus deferred laser treatment: three-year randomized trial results. Ophthalmology. 2012;119:2312–8. doi: 10.1016/j.ophtha.2012.08.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Rosenfeld PJ, Heier JS, Hantsbarger G, Shams N. Tolerability and efficacy of multiple escalating doses of ranibizumab (Lucentis) for neovascular age-related macular degeneration. Ophthalmology. 2006;113:623, e1. doi: 10.1016/j.ophtha.2006.01.027. [DOI] [PubMed] [Google Scholar]
- 18.Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009;116:57–65. e5. doi: 10.1016/j.ophtha.2008.10.018. [DOI] [PubMed] [Google Scholar]
- 19.Kim D, Nam WH, Kim HK, Yi K. Does Intravitreal Injections of Bevacizumab for Age-related Macular Degeneration Affect Long-term Intraocular Pressure? J Glaucoma. 2013 doi: 10.1097/IJG.0b013e3182946505. [DOI] [PubMed] [Google Scholar]
- 20.Hoang QV, Tsuang AJ, Gelman R, et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal anti-vascular endothelial growth factor therapy. Retina. 2013;33:179–87. doi: 10.1097/IAE.0b013e318261a6f7. [DOI] [PubMed] [Google Scholar]
- 21.Wehrli SJ, Tawse K, Levin MH, Zaidi A, Pistilli M, Brucker AJ. A lack of delayed intraocular pressure elevation in patients treated with intravitreal injection of bevacizumab and ranibizumab. Retina. 2012;32:1295–301. doi: 10.1097/IAE.0b013e31823f0c95. [DOI] [PubMed] [Google Scholar]