Intraocular Pressure in Patients with Neovascular Age-Related Macular Degeneration Receiving Intravitreal Aflibercept or Ranibizumab K. Bailey Freund, MD,1,2,3,4 Quan V. Hoang, MD, PhD,1,2,3,4 Namrata Saroj, OD,5 Desmond Thompson, PhD5 Purpose: To assess change in intraocular pressure (IOP) in patients with neovascular age-related macular degeneration (NVAMD) receiving intravitreal aflibercept injection (IAI) or ranibizumab in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2 studies. Design: Analyses from 2 randomized, active-controlled, phase III trials. Participants: A total of 2457 patients with NVAMD. Methods: Patients received IAI 2 mg every (q) 4 weeks (2q4), 0.5 mg q4 weeks (0.5q4), 2 mg q8 weeks (after 3 monthly doses; 2q8), or ranibizumab 0.5 mg q4 weeks (Rq4) for 52 weeks. At week 52, patients were switched to a variable regimen requiring at least quarterly dosing and allowing interim injections based on anatomic and visual assessment. Main Outcome Measures: Pre-injection IOP was analyzed in study and uninjected fellow eyes from baseline to week 96. Prespecified end points included mean change in IOP from baseline and prevalence of a >21 mmHg and >10 mmHg increase in IOP from baseline. Cumulative incidence of sustained (at 2 consecutive visits) IOP >21 mmHg, a single event of IOP >25 mmHg, and sustained IOP increase from baseline (5 mmHg) was also evaluated. Results: Mean IOP change from baseline over 96 weeks in all IAI groups was consistently lower than in the Rq4 group, and this finding was replicated in both trials. In an analysis integrating both studies, the proportion of study eyes with IOP >21 mmHg at week 96 was 20.2%, 14.2%, 12.1%, and 12.5% in Rq4, 2q4, 2q8, and 0.5q4, respectively. Reduction in risk, relative to Rq4, of having sustained IOP >21 mmHg over 96 weeks was 62% (95% confidence interval [CI], 36%e78%), 50% (95% CI, 19%e70%), and 69% (95% CI, 45%e84%) for 2q4, 2q8, and 0.5q4, respectively. Risk reduction in the IAI groups for a sustained IOP increase 5 mmHg was 31% (95% CI, 8%e48%), 38% (95% CI, 17%e54%), and 47% (95% CI, 27%e61%), respectively. In uninjected fellow eyes, only sustained IOP >21 mmHg events were higher in the Rq4 group compared with all IAI groups. Conclusions: Incidence of elevated IOP in eyes with NVAMD was lower in all IAI groups than in the ranibizumab group. Ophthalmology 2015;122:1802-1810 ª 2015 by the American Academy of Ophthalmology See Editorial on page 1735.
Intravitreal antievascular endothelial growth factor (VEGF) agents, including ranibizumab (Lucentis; Genentech, San Francisco, CA), bevacizumab (Avastin; Genentech), and aflibercept (Eylea, also referred to as “VEGF Trap-Eye”; Regeneron Pharmaceuticals, Inc., Tarrytown, NY), are frequently used to treat choroidal neovascularization and retinal vascular disorders.1e4 With the addition of fluid into the vitreous cavity, it is not surprising that intraocular pressure (IOP) increases occur transiently after intravitreal injections.5e8 Recent reports suggest sustained ocular hypertension can occur after intravitreal ranibizumab or bevacizumab.9e18 A post hoc analysis of the 24-month data from the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) and Minimally Classic/Occult Trial of the AntiVEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trials by Bakri et al18 showed
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2015 by the American Academy of Ophthalmology Published by Elsevier Inc.
more eyes treated with intravitreal ranibizumab had 1 or more pre-injection IOP increases from baseline of 6 or 8 mmHg, with concurrent highest IOPs of 21 and 25 mmHg, versus eyes receiving sham injections. Also, a recent report demonstrated that in 207 patients with neovascular age-related macular degeneration (NVAMD) who received unilateral ranibizumab and/or bevacizumab intravitreal injections, 11.6% of injected versus 5.3% of contralateral, uninjected control eyes experienced an IOP elevation of 6 mmHg on 2 consecutive visits.17 In a larger study of 449 eyes of 328 patients with NVAMD, a greater number of intravitreal injections of ranibizumab and bevacizumab was shown to be associated with an increased risk for sustained IOP elevation in eyes when controlling for the confounder (prior intravitreal steroid injection).16 The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2 studies have
http://dx.doi.org/10.1016/j.ophtha.2015.04.018 ISSN 0161-6420/15
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IOP after Intravitreal Aflibercept versus Ranibizumab
demonstrated that intravitreal aflibercept injection (IAI), also referred to as “VEGF Trap-Eye,” given monthly or every 2 months after 3 initial doses is noninferior and clinically equivalent to monthly ranibizumab for maintaining vision of patients with NVAMD at week 52.4 All IAI groups and ranibizumab were also equally effective in improving visual acuity and preventing visual acuity loss at week 96.19 We evaluate changes in IOP in patients with NVAMD receiving IAI or ranibizumab for 96 weeks in the VIEW 1 and 2 studies. Analyses were conducted to determine whether elevated IOPs before injection, relative to baseline, were related to treatment group assignment or other baseline characteristics in the study eye. In addition, IOP events in uninjected fellow eyes were evaluated to investigate whether they were related to similar events in the study eyes.
Methods Analyses were conducted in patients enrolled in 2 large, multicenter, controlled trials (VIEW 1 and 2) comparing IAI with intravitreal ranibizumab. Each study center’s review board or ethics committee approved the study protocols. Both trials were registered with ClinicalTrials.gov (identifier no. NCT00509795 and NCT00637377), and all patients signed a written consent form before initiation of the study-specific procedures. The VIEW 1 and 2 studies were conducted in compliance with regulations of the Health Insurance Portability and Accountability Act and the Declaration of Helsinki.
VIEW 1 and 2 Study Designs The VIEW 1 and 2 studies were 2 similarly designed, randomized, double-masked, active-controlled, multicenter, 96-week, phase III trials comparing the efficacy and safety of IAI and ranibizumab in patients with NVAMD. The design of the VIEW studies has been described by Heier et al.4 Patients were randomized in a 1:1:1:1 ratio to 1 of the following 4 regimens for the first 52 weeks: (a) 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), (b) 2 mg IAI every 4 weeks (2q4), (c) 0.5 mg IAI every 4 weeks (0.5q4), and (d) 2 mg IAI every 8 weeks (2q8) after 3 initial monthly injections. From week 52 to 96, patients were treated with the same dose as the first 52 weeks at least every 12 weeks, with monthly evaluations for interim injections based on assessment of anatomic and visual outcomes. Patients could receive intravitreal ranibizumab in the fellow eye if there was evidence of NVAMD that required treatment. For these analyses, only fellow eyes that were not injected were used for IOP assessments.
Intraocular Pressure Measurements Intraocular pressure was measured using applanation tonometry (Goldmann [Haag-Streit Diagnostics, Koeniz, Switzerland] or Tono-Pen [Reichert Technologies, Depew, NY]). The same method of IOP measurement had to be used in each patient throughout the study. Unmasked study personnel measured IOP at every visit in both eyes before injection and in the study eye 30 to 60 minutes after the intravitreal injection. Only 1 IOP measurement for both eyes was recorded before injection at every visit as required by the study protocol.
Statistical Analysis Of the 2457 patients randomized into the VIEW studies, 2419 were included in the safety data set. Simple proportions were
used to describe the various binary events through weeks 52 and 96. Least-squares means were used to compare continuous variables (e.g., observed IOP at each visit) between treatment groups. Time-to-event methodology was used to assess the key outcomes: reaching IOPs >21 or 25 mmHg and changes from baseline of 5 mmHg. Cumulative incidence, which is the proportion of an event that occurs before a given time, was computed for each of the preceding events. For all time-to-event analyses (except the threshold of 25 mmHg), the outcome of interest had to be sustained for at least 2 consecutive visits. Event rates are presented as the number of events per 100 patient-years based on the ratio of the observed number of events to the total number of patient-years of exposure to Rq4 or to the different dosing regimens of IAI. The KaplaneMeier method was used to estimate the cumulative incidence. This provides a means to estimate the cumulative incidence and accounts for eyes not having complete follow-up. The log-rank test was used to test the difference between the cumulative incidence curves of the treatment groups. The relative risks comparing the various IAI treatment groups with the Rq4 group were estimated by the proportional-hazards analysis. The relative risk analyses were stratified by study (VIEW 1 vs. VIEW 2). Only within-stratum analyses contributed to the overall relative risks. This was done iteratively. PROC Means, PROC LIFETEST, and PROC GENMOD were used in the analyses.
Outcome Measures Intraocular pressure was assessed before injection at each visit in both study and fellow eyes. Prespecified IOP measurements that were evaluated included (a) mean change in IOP from baseline through week 96, (b) prevalence of IOP >21 mmHg through week 96, and (c) prevalence of IOP change from baseline of 10 mmHg through week 96. Cumulative incidence of sustained IOP >21 mmHg, cumulative incidence of IOP 25 mmHg, and cumulative incidence of sustained IOP changes from baseline of 5 mmHg were evaluated in both the study and uninjected fellow eyes. A sustained event was defined as changes from baseline or IOP exceeding a specific threshold for at least 2 consecutive visits. This definition of a sustained event was chosen because of its reproducibility and because it represented a measure of clinically important elevation of IOP. Single events for IOP 25 mmHg were evaluated because too few patients had sustained IOP 25 mmHg for reliable conclusions to be drawn from a time-to-event analysis.
Results Baseline Characteristics There were no meaningful differences in pre-injection IOPs among the 4 dosing regimens at baseline (Table 1). Slightly fewer patients in the 2q4 group had a history of preexisting glaucoma or used glaucoma medication compared with the Rq4, 2q8, and 0.5q4 groups.
Outcomes Overall, a small decrease in mean change in IOP in the study eye of patients in all IAI groups from baseline over the 96 weeks of follow-up, was observed. The mean change in IOP was consistently higher in the Rq4 group than in all IAI groups, and this higher mean change in IOP in the Rq4 group was observed in both VIEW studies (Fig 1A, B). Because of the similar results with regard to mean IOP in both VIEW studies, an integrated perspective combining the VIEW 1 and 2 studies is used for
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Ophthalmology Volume 122, Number 9, September 2015 Table 1. Baseline Characteristics Intravitreal Aflibercept Injection
Patients, no (safety analysis set) Age, mean yrs (SD) Female, n (%) Race, n (%) White Other Study eye Baseline IOP, mean mmHg (SD) BCVA, mean (SD) Preexisting glaucoma, n (%) Patients who used IOP medication, n (%) Phakic, n (%) Fellow eye Baseline IOP, mean mmHg (SD) BCVA, mean (SD) Preexisting glaucoma, n (%) Patients who used IOP medication, n (%) Phakic, n (%)
Rq4
2q4
2q8
0.5q4
595 75.6 (8.7) 341 (57.3)
613 75.9 (8.4) 370 (60.4)
610 75.8 (8.8) 355 (58.2)
601 76.5 (8.5) 317 (52.7)
509 (85.5) 86 (14.5)
521 (85.0) 92 (15.0)
507 (83.1) 103 (16.9)
513 (85.4) 88 (14.6)
15.0 53.9 60 45 267
(3.0) (13.4) (10.1) (7.6) (44.9)
14.8 54.0 45 36 277
(3.1) (13.6) (7.3) (5.9) (45.2)
15.0 53.6 56 41 266
(3.0) (13.5) (9.2) (6.7) (43.6)
15.0 53.5 54 40 254
(3.0) (13.8) (9.0) (6.7) (42.3)
15.2 66.6 56 45 286
(3.3) (24.9) (9.4) (7.6) (48.1)
14.8 63.9 43 35 289
(3.0) (26.3) (7.0) (5.7) (47.1)
15.1 64.5 53 37 285
(3.0) (25.9) (8.7) (6.1) (46.7)
15.0 65.7 49 39 258
(3.1) (25.9) (8.2) (6.5) (42.9)
0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; BCVA ¼ best-corrected visual acuity; IOP ¼ intraocular pressure; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks; SD ¼ standard deviation.
most of the following analyses (Fig 1C). In the integrated analysis, there was no apparent difference in mean change in IOP in the fellow eye (Fig 1D). The prespecified categoric outcomes assessing changes in IOP were the single-event incidence of change >10 mmHg in IOP from baseline at any visit through weeks 52 and 96, as well as the single-event incidence of IOP >21 mmHg at any visit through weeks 52 and 96. For both of the prespecified outcomes, at both time points, the proportion of patients in the Rq4 group with elevated IOP was higher than in all the IAI groups (Table 2). These data suggest that elevated IOP in the study eye may be associated with treatment group. There was a smaller but similar direction in terms of these categoric outcomes in the fellow eye (Table 2).
Study Eye Incidence Using Selected Thresholds (Intraocular Pressure >21 and ‡25 mmHg). The cumulative incidence of sustained IOP >21 mmHg (noted at 2 consecutive visits) was similar between all treatment groups during the initial follow-up. At approximately weeks 8 to 12, the incidence curves began to separate (Fig 2A). Starting at week 16, the cumulative incidence of sustained IOP >21 mmHg was 50% to 60% less likely in the IAI groups compared with the Rq4 group. At week 52, the end of the fixedschedule dosing period, there were 34, 16, 17, and 9 study eyes that had sustained IOPs >21 mmHg in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. At the end of 96 weeks of follow-up, 47, 19, 24, and 15 study eyes in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively, had sustained IOP >21 mmHg. At week 96, the cumulative incidences were 8.4%, 3.2%, 4.2%, and 2.7% in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. Over the 96-week follow-up period, compared with Rq4, IAI reduced the risk of elevated IOP by 62%, 50%, and 69% in the 2q4, 2q8, and 0.5q4 groups, respectively (Table 3). Because there were too few patients with sustained IOP 25 mmHg over 96 weeks, single events of IOP 25 mmHg were evaluated. For the single event (first visit with IOP 25 mmHg),
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the cumulative incidence was similar among all treatment groups up to week 40 (Fig 2B). Thereafter, the cumulative incidence for Rq4 began to separate from the 3 IAI groups. At week 52, there were 21, 14, 12, and 7 study eyes with IOPs 25 mmHg in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. The corresponding numbers at week 96 were 35, 19, 16, and 17, respectively. At week 96, the corresponding cumulative incidences were 6.3%, 3.2%, 2.8%, and 3.1% for Rq4, 2q4, 2q8, and 0.5q4, respectively. Over the 96-week follow-up period, compared with Rq4, risk of IOP 25 mmHg was reduced in the IAI groups by 48%, 52%, and 55%, respectively (Table 3). Incidence Using Changes from Baseline (‡5 mmHg). The cumulative incidence of sustained 5 mmHg change in IOP from baseline was similar for a short period only and started to differ beginning at week 8 (Fig 2C). During the first 52 weeks of followup, there were 77, 68, 52, and 43 study eyes with sustained changes of 5 mmHg from baseline in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. The corresponding numbers of patients with events by week 96 were 111, 82, 72, and 62, respectively. At week 96, the cumulative incidences were 19.7%, 14.1%, 12.6%, and 11.1% in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. Over the 96 weeks of follow-up, compared with Rq4, IAI groups reduced the risk of sustained changes of 5 mmHg by 31%, 38%, and 47% in the 2q4, 2q8, and 0.5q4 groups, respectively (Table 3). The test for trend for Rq4 > 2q4 > 2q8 > 0.5q4 yielded a P value of 21 mmHg appeared higher in the fellow eyes with Rq4 treatment, as it had in the study eyes (Fig 3A). There were minor trends associated with higher IOP in fellow eyes of patients treated with Rq4 in the study eye, although it was not as prominent as noted earlier for study eyes (Fig 3B and C, Table 4).
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IOP after Intravitreal Aflibercept versus Ranibizumab
Figure 1. Mean intraocular pressure (IOP) change from baseline over 96 weeks in (A) study eyes in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1, (B) study eyes in VIEW 2, (C) study eyes in both VIEW 1 and 2, and (D) fellow eyes in both VIEW 1 and 2. 0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks.
Results for sustained incidence of IOP >21 mmHg were also consistent with those seen in Figure 4.
Subgroup Analyses Intraocular pressure changes in the study eyes and for the uninjected fellow eyes were also evaluated for subgroups of selected baseline characteristics: history of glaucoma, use of IOP-lowering medication, and lens status. To examine the consistency or lack thereof, the outcome used was the sustained incidence of IOP change of 5 mmHg from baseline. There was consistency of relative risk, as seen by the overlap of the 95% confidence intervals within each subgroup (Fig 4). The trends Rq4 > 2q4 > 2q8 > 0.5q4 were consistent with observations in the entire cohort.
Intraocular PressureeLowering Medication Use during the Study The proportions of patients starting IOP-related medications after baseline were 6.9%, 7.5%, 6.9%, and 6.0% in the Rq4, 2q4, 2q8, and 0.5q4 treatment groups, respectively. There were no significant differences among the groups.
Table 2. Total Number of Prespecified Intraocular Pressure Events through Weeks 52 and 96 Through Week 52
Through Week 96
Intravitreal Aflibercept Injection Rq4 No. of patients (safety analysis set) Study eye Change 10 mmHg (%) IOP >21 mmHg (%) Fellow eye Change 10 mmHg (%) IOP >21 mmHg (%)
595
2q4 613
2q8 610
Intravitreal Aflibercept Injection
0.5q4 601
Rq4 595
2q4 613
2q8 610
0.5q4 601
3.2 13.6
1.1 10.1
2.3 8.0
2.3 8.2
6.4 20.2
2.9 14.2
3.1 12.1
3.8 12.5
3.7 15.4
2.1 10.4
3.1 12.7
1.2 10.5
5.1 20.3
3.1 12.9
3.3 16.6
1.5 13.6
0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; IOP ¼ intraocular pressure; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks.
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Figure 2. Cumulative incidence of (A) sustained intraocular pressure (IOP) >21 mmHg, (B) a single event of IOP 25 mmHg, and (C) sustained IOP increase of 5 mmHg in study eyes. 0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks.
Discussion Post hoc analysis of the ANCHOR and MARINA data and other recent reports suggest sustained IOP elevation may occur in 3.5% to 8.5% of NVAMD eyes receiving
intravitreal ranibizumab or bevacizumab, depending on the criteria used to define sustained elevation.9e18 The 52week data from the VIEW 1 and 2 studies demonstrated that IAI monthly or every 2 months was noninferior and clinically equivalent to ranibizumab monthly for
Table 3. Cumulative Incidence and Event Rates of Intraocular Pressure, and Relative Risks (Study Eye) Baseline to Week 52 Outcome IOP >21 mmHg
Cumulative Group N* Events (n) Incidence (%)
Rq4 2q4 2q8 0.5q4 Rq4 IOP 25 mmHgy 2q4 2q8 0.5q4 Change 5 mmHg Rq4 2q4 2q8 0.5q4 Change 10 mmHg Rq4 2q4 2q8
595 612 607 597 595 612 607 597 595 612 607 597 595 612 607
30 15 14 9 21 14 12 7 75 63 49 41 2 1 3
5.2 2.5 2.4 1.5 3.7 2.3 2.0 1.2 13.0 10.6 8.4 7.1
Rate 5.40 2.58 2.48 1.61 3.49 2.27 1.98 1.17 14.09 11.20 8.89 7.47 e e e
Baseline to Week 96
RR (95% CI) 0.48 0.46 0.30 0.65 0.57 0.33 0.79 0.63 0.53
1.00 (0.25e0.87) (0.24e0.85) (0.13e0.60) 1.00 (0.32e1.27) (0.27e1.14) (0.13e0.75) 1.00 (0.57e1.11) (0.44e0.90) (0.36e0.77) e e e
Cumulative Events (n) Incidence (%) 47 19 24 15 35 19 16 17 111 82 72 62 8 1 4
8.4 3.2 4.2 2.7 6.3 3.2 2.8 3.1 19.7 14.1 12.6 11.1
Rate 3.94 1.50 1.98 1.23 2.93 1.53 1.33 1.42 11.39 7.91 7.06 6.08 e e e
RR (95% CI) 0.38 0.50 0.31 0.52 0.45 0.48 0.69 0.62 0.53
P Value
1.00 e (0.22e0.64) 21 mmHg, and sustained changes in IOP from baseline (5 mmHg). These differences were observed early and maintained through week 96. The increases in IOP seen in the current study with ranibizumab are similar to those in previous reports.9e17 Comparison of key IOP measures between the sham/photodynamic therapy control groups in the ANCHOR and MARINA trials and the IAI groups in the VIEW trials suggests that there is no difference between these groups.18 This could imply that the rates for IAI in the VIEW trials are background changes occurring in an aged population over time. The decreased incidence associated with IAI use compared with ranibizumab occurred across multiple IOP end points in the 2 VIEW studies (Fig 5). Consistent with these findings, a retrospective chart review of 53 patients with NVAMD indicated that IOP was significantly decreased after switching from ranibizumab or bevacizumab to IAI.20 A variety of mechanisms have been proposed to explain a notable and occasionally clinically significant IOP elevation after ranibizumab and bevacizumab treatments. Such mechanisms include mechanical trauma to the trabecular meshwork from repeated injection-related IOP spikes and a
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decrease in aqueous outflow due to VEGF blockade, as potentially mediated by inhibition of nitric oxide synthesis, or obstruction by high molecular-weight protein aggregates or silicone microdroplets.18,21,22 A higher incidence of IOP elevation with ranibizumab compared with IAI cannot be easily explained by a mechanical trauma or decrease in aqueous outflow due to VEGF blockade or obstruction by silicone microdroplets because both anti-VEGF agents act through a similar mechanism of action and were given in similar volume and frequency with a similar needle gauge in this study. It remains to be elucidated whether the difference in the incidence of IOP elevation reported in this study is caused by a decrease in aqueous outflow due to relatively larger or more protein aggregates formed by 1 anti-VEGF agent compared with the other agent. It is conceivable that the glycosylation of aflibercept may improve solubility in the vitreous compared with ranibizumab and avoid potential protein accumulation.23,24 It is also possible that an endotoxin-induced inflammatory response may lead to trabeculitis and IOP elevation in some patients over time and with repeated treatment with ranibizumab manufactured using Escherichia coli compared with aflibercept manufactured using Chinese hamster ovary cells.23,24 Consistent with the findings of Hoang et al,16 a personal history of glaucoma at baseline did not influence the outcomes. These results differ from those reported in a small study of 21 patients by Good et al,9 who found higher rates of IOP elevation in patients with preexisting glaucoma. As previously reported, lens status also did not play a role.16 Furthermore, results within each subgroup were consistent with what was observed in the overall cohort, further supporting the overall outcomes. The findings for the uninjected fellow eyes also indicated a possible association of ranibizumab with higher IOP, although it was not as robust as the study eye results. This could be associated with the triggering of a broader-acting immune or inflammatory response, which would have a lesser effect on the fellow eye. A higher incidence of
Figure 5. Relative risk of intraocular pressure (IOP) increase in study eyes in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 (v1), VIEW 2 (v2), and both VIEW 1 and VIEW 2 (C) at week 96. 0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; IAI ¼ intravitreal aflibercept injection.
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sustained IOP increase was observed in uninjected fellow eyes in this study compared with that previously reported in a smaller study of 207 patients with NVAMD unilaterally injected with ranibizumab or bevacizumab17 on a treat-andextend regimen.25 The difference in frequency of visits and injections might account for these observations. There are strengths and limitations to our study. This is the first set of analyses including integrated data from 2 large, similarly designed, prospective, double-masked, randomized clinical trials evaluating differences of the effect and frequency of dosing between 2 different anti-VEGF agents on elevated IOP. Instructions for IOP measurement were limited to use of the same type of instrument throughout the study, with no requirement for use of the same instrument and calibration checks. Complete data on the type of tonometer used for each patient were not available, and thus results could not be stratified on the basis of this variable. This could be a confounder if different treatment groups had IOP assessed more often with 1 type of tonometer. The time of day of the IOP measurement was not controlled in these studies, and the variability could be considered a limitation. Fluctuations in IOP during a day have been reported.26 However, these variations, if present, would be among all treatment groups. On the other hand, we expect that using sustained incidence instead of a single incidence minimized the effect of such limitations. We were also limited to the data reported on ocular history and ocular medications. In summary, our results suggest that patients with NVAMD who receive IAI injections (every 4 or 8 weeks after 3 monthly treatments) seem less likely to experience sustained IOP elevation compared with patients receiving ranibizumab every 4 weeks. Given reports showing the clinical equivalence of IAI to ranibizumab in terms of visual outcomes, IAI may be preferred in patients with NVAMD in whom there are concerns about IOP elevation.
8.
9. 10. 11. 12. 13.
14. 15. 16.
17.
18. 19.
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ranibizumab (Lucentis) for the treatment of wet age-related macular degeneration. Br J Ophthalmol 2008;92:584. Bakri SJ, Pulido JS, McCannel CA, et al. Immediate intraocular pressure changes following intravitreal injections of triamcinolone, pegaptanib, and bevacizumab. Eye (Lond) 2009;23:181–5. 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. Bakri SJ, McCannel CA, Edwards AO, Moshfeghi DM. Persistent ocular hypertension following intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol 2008;246:955–8. Kahook MY, Kimura AE, Wong LJ, et al. Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections. Ophthalmic Surg Lasers Imaging 2009;40:293–5. Adelman RA, Zheng Q, Mayer HR. Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections. J Ocul Pharmacol Ther 2010;26:105–10. Tseng JJ, Vance SK, Della Torre KE, et al. Sustained increased intraocular pressure related to intravitreal antivascular endothelial growth factor therapy for neovascular agerelated macular degeneration. J Glaucoma 2012;21:241–7. Loukianou E, Brouzas D, Apostolopoulos M. Sustained ocular hypertension following intravitreal injections of 0.5 mg/ 0.05 ml ranibizumab. Int Ophthalmol 2011;31:211–3. 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. Hoang QV, Tsuang AJ, Gelman R, et al. Clinical predictors of sustained intraocular pressure elevation due to intravitreal antivascular endothelial growth factor therapy. Retina 2013;33: 179–87. Hoang QV, Mendonca LS, Della Torre KE, et al. Effect on intraocular pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor injections. Ophthalmology 2012;119:321–6. 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;121:1102–8. Schmidt-Erfurth U, Kaiser PK, Korobelnik JF, et al. Intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the VIEW studies. Ophthalmology 2014;121:193–201. Rusu IM, Deobhakta A, Yoon D, et al. Intraocular pressure in patients with neovascular age-related macular degeneration switched to aflibercept injection after previous antivascular endothelial growth factor treatments. Retina 2014;34:2161–6. Bakri SJ, Ekdawi NS. Intravitreal silicone oil droplets after intravitreal drug injections. Retina 2008;28:996–1001. Ricca AM, Morshedi RG, Wirostko BM. High intraocular pressure following anti-vascular endothelial growth factor therapy: proposed pathophysiology due to altered nitric oxide metabolism. J Ocul Pharmacol Ther 2015;31:2–10. Eylea [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; 2014. Lucentis [package insert]. South San Francisco, CA: Genentech, Inc.; 2013. Engelbert M, Zweifel SA, Freund KB. “Treat and extend” dosing of intravitreal antivascular endothelial growth factor therapy for type 3 neovascularization/retinal angiomatous proliferation. Retina 2009;29:1424–31. Chakraborty R, Read SA, Collins MJ. Diurnal variations in axial length, choroidal thickness, intraocular pressure, and ocular biometrics. Invest Ophthalmol Vis Sci 2011;52:5121–9.
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Footnotes and Financial Disclosures Originally received: November 13, 2014. Final revision: April 15, 2015. Accepted: April 15, 2015. Available online: May 27, 2015. 1
Author Contributions: Conception and design: Freund, Hoang, Saroj, Thompson Manuscript no. 2015-1825.
Vitreous Retina Macula Consultants of New York, New York, New York.
2
LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, New York, New York.
3
Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, New York.
4
Department of Ophthalmology, New York University Medical Center, New York, New York.
5
Regeneron Pharmaceuticals, Inc., Tarrytown, New York. Presented as a poster at: the American Academy of Ophthalmology Annual Meeting, November 10e13, 2012, Chicago, Illinois. Financial Disclosure(s): The author(s) have made the following disclosure(s): K.B.F.: Consultant e Bayer HealthCare, Genentech, Heidelberg Engineering, Regeneron Pharmaceuticals, Inc. N.S. and D.T.: Employees e Regeneron Pharmaceuticals, Inc. Funded by the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, New York, New York; The Macula Foundation Inc., New York, New York; and Regeneron Pharmaceuticals, Inc., Tarrytown, New York. The sponsors participated in the design and conduct of the study, analysis of the data, and preparation of the manuscript.
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Data collection: Freund, Hoang, Saroj, Thompson Analysis and interpretation: Freund, Hoang, Saroj, Thompson Obtained funding: Not applicable Overall responsibility: Freund, Hoang, Saroj, Thompson Abbreviations and Acronyms: 0.5q4 ¼ 0.5 mg intravitreal aflibercept injection every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept injection every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept injection every 8 weeks after 3 initial monthly injections; ANCHOR ¼ Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD; CI ¼ confidence interval; IAI ¼ intravitreal aflibercept injection; IOP ¼ intraocular pressure; MARINA ¼ Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks; NVAMD ¼ neovascular agerelated macular degeneration; VEGF ¼ vascular endothelial growth factor; VIEW ¼ VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD. Correspondence: K. Bailey Freund, MD, Vitreous Retina Macula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022. E-mail: [email protected].
Intravitreal antievascular endothelial growth factor (VEGF) agents, including ranibizumab (Lucentis; Genentech, San Francisco, CA), bevacizumab (Avastin; Genentech), and aflibercept (Eylea, also referred to as “VEGF Trap-Eye”; Regeneron Pharmaceuticals, Inc., Tarrytown, NY), are frequently used to treat choroidal neovascularization and retinal vascular disorders.1e4 With the addition of fluid into the vitreous cavity, it is not surprising that intraocular pressure (IOP) increases occur transiently after intravitreal injections.5e8 Recent reports suggest sustained ocular hypertension can occur after intravitreal ranibizumab or bevacizumab.9e18 A post hoc analysis of the 24-month data from the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD (ANCHOR) and Minimally Classic/Occult Trial of the AntiVEGF Antibody Ranibizumab in the Treatment of Neovascular AMD (MARINA) trials by Bakri et al18 showed
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2015 by the American Academy of Ophthalmology Published by Elsevier Inc.
more eyes treated with intravitreal ranibizumab had 1 or more pre-injection IOP increases from baseline of 6 or 8 mmHg, with concurrent highest IOPs of 21 and 25 mmHg, versus eyes receiving sham injections. Also, a recent report demonstrated that in 207 patients with neovascular age-related macular degeneration (NVAMD) who received unilateral ranibizumab and/or bevacizumab intravitreal injections, 11.6% of injected versus 5.3% of contralateral, uninjected control eyes experienced an IOP elevation of 6 mmHg on 2 consecutive visits.17 In a larger study of 449 eyes of 328 patients with NVAMD, a greater number of intravitreal injections of ranibizumab and bevacizumab was shown to be associated with an increased risk for sustained IOP elevation in eyes when controlling for the confounder (prior intravitreal steroid injection).16 The VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 and 2 studies have
http://dx.doi.org/10.1016/j.ophtha.2015.04.018 ISSN 0161-6420/15
Freund et al
IOP after Intravitreal Aflibercept versus Ranibizumab
demonstrated that intravitreal aflibercept injection (IAI), also referred to as “VEGF Trap-Eye,” given monthly or every 2 months after 3 initial doses is noninferior and clinically equivalent to monthly ranibizumab for maintaining vision of patients with NVAMD at week 52.4 All IAI groups and ranibizumab were also equally effective in improving visual acuity and preventing visual acuity loss at week 96.19 We evaluate changes in IOP in patients with NVAMD receiving IAI or ranibizumab for 96 weeks in the VIEW 1 and 2 studies. Analyses were conducted to determine whether elevated IOPs before injection, relative to baseline, were related to treatment group assignment or other baseline characteristics in the study eye. In addition, IOP events in uninjected fellow eyes were evaluated to investigate whether they were related to similar events in the study eyes.
Methods Analyses were conducted in patients enrolled in 2 large, multicenter, controlled trials (VIEW 1 and 2) comparing IAI with intravitreal ranibizumab. Each study center’s review board or ethics committee approved the study protocols. Both trials were registered with ClinicalTrials.gov (identifier no. NCT00509795 and NCT00637377), and all patients signed a written consent form before initiation of the study-specific procedures. The VIEW 1 and 2 studies were conducted in compliance with regulations of the Health Insurance Portability and Accountability Act and the Declaration of Helsinki.
VIEW 1 and 2 Study Designs The VIEW 1 and 2 studies were 2 similarly designed, randomized, double-masked, active-controlled, multicenter, 96-week, phase III trials comparing the efficacy and safety of IAI and ranibizumab in patients with NVAMD. The design of the VIEW studies has been described by Heier et al.4 Patients were randomized in a 1:1:1:1 ratio to 1 of the following 4 regimens for the first 52 weeks: (a) 0.5 mg intravitreal ranibizumab every 4 weeks (Rq4), (b) 2 mg IAI every 4 weeks (2q4), (c) 0.5 mg IAI every 4 weeks (0.5q4), and (d) 2 mg IAI every 8 weeks (2q8) after 3 initial monthly injections. From week 52 to 96, patients were treated with the same dose as the first 52 weeks at least every 12 weeks, with monthly evaluations for interim injections based on assessment of anatomic and visual outcomes. Patients could receive intravitreal ranibizumab in the fellow eye if there was evidence of NVAMD that required treatment. For these analyses, only fellow eyes that were not injected were used for IOP assessments.
Intraocular Pressure Measurements Intraocular pressure was measured using applanation tonometry (Goldmann [Haag-Streit Diagnostics, Koeniz, Switzerland] or Tono-Pen [Reichert Technologies, Depew, NY]). The same method of IOP measurement had to be used in each patient throughout the study. Unmasked study personnel measured IOP at every visit in both eyes before injection and in the study eye 30 to 60 minutes after the intravitreal injection. Only 1 IOP measurement for both eyes was recorded before injection at every visit as required by the study protocol.
Statistical Analysis Of the 2457 patients randomized into the VIEW studies, 2419 were included in the safety data set. Simple proportions were
used to describe the various binary events through weeks 52 and 96. Least-squares means were used to compare continuous variables (e.g., observed IOP at each visit) between treatment groups. Time-to-event methodology was used to assess the key outcomes: reaching IOPs >21 or 25 mmHg and changes from baseline of 5 mmHg. Cumulative incidence, which is the proportion of an event that occurs before a given time, was computed for each of the preceding events. For all time-to-event analyses (except the threshold of 25 mmHg), the outcome of interest had to be sustained for at least 2 consecutive visits. Event rates are presented as the number of events per 100 patient-years based on the ratio of the observed number of events to the total number of patient-years of exposure to Rq4 or to the different dosing regimens of IAI. The KaplaneMeier method was used to estimate the cumulative incidence. This provides a means to estimate the cumulative incidence and accounts for eyes not having complete follow-up. The log-rank test was used to test the difference between the cumulative incidence curves of the treatment groups. The relative risks comparing the various IAI treatment groups with the Rq4 group were estimated by the proportional-hazards analysis. The relative risk analyses were stratified by study (VIEW 1 vs. VIEW 2). Only within-stratum analyses contributed to the overall relative risks. This was done iteratively. PROC Means, PROC LIFETEST, and PROC GENMOD were used in the analyses.
Outcome Measures Intraocular pressure was assessed before injection at each visit in both study and fellow eyes. Prespecified IOP measurements that were evaluated included (a) mean change in IOP from baseline through week 96, (b) prevalence of IOP >21 mmHg through week 96, and (c) prevalence of IOP change from baseline of 10 mmHg through week 96. Cumulative incidence of sustained IOP >21 mmHg, cumulative incidence of IOP 25 mmHg, and cumulative incidence of sustained IOP changes from baseline of 5 mmHg were evaluated in both the study and uninjected fellow eyes. A sustained event was defined as changes from baseline or IOP exceeding a specific threshold for at least 2 consecutive visits. This definition of a sustained event was chosen because of its reproducibility and because it represented a measure of clinically important elevation of IOP. Single events for IOP 25 mmHg were evaluated because too few patients had sustained IOP 25 mmHg for reliable conclusions to be drawn from a time-to-event analysis.
Results Baseline Characteristics There were no meaningful differences in pre-injection IOPs among the 4 dosing regimens at baseline (Table 1). Slightly fewer patients in the 2q4 group had a history of preexisting glaucoma or used glaucoma medication compared with the Rq4, 2q8, and 0.5q4 groups.
Outcomes Overall, a small decrease in mean change in IOP in the study eye of patients in all IAI groups from baseline over the 96 weeks of follow-up, was observed. The mean change in IOP was consistently higher in the Rq4 group than in all IAI groups, and this higher mean change in IOP in the Rq4 group was observed in both VIEW studies (Fig 1A, B). Because of the similar results with regard to mean IOP in both VIEW studies, an integrated perspective combining the VIEW 1 and 2 studies is used for
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Ophthalmology Volume 122, Number 9, September 2015 Table 1. Baseline Characteristics Intravitreal Aflibercept Injection
Patients, no (safety analysis set) Age, mean yrs (SD) Female, n (%) Race, n (%) White Other Study eye Baseline IOP, mean mmHg (SD) BCVA, mean (SD) Preexisting glaucoma, n (%) Patients who used IOP medication, n (%) Phakic, n (%) Fellow eye Baseline IOP, mean mmHg (SD) BCVA, mean (SD) Preexisting glaucoma, n (%) Patients who used IOP medication, n (%) Phakic, n (%)
Rq4
2q4
2q8
0.5q4
595 75.6 (8.7) 341 (57.3)
613 75.9 (8.4) 370 (60.4)
610 75.8 (8.8) 355 (58.2)
601 76.5 (8.5) 317 (52.7)
509 (85.5) 86 (14.5)
521 (85.0) 92 (15.0)
507 (83.1) 103 (16.9)
513 (85.4) 88 (14.6)
15.0 53.9 60 45 267
(3.0) (13.4) (10.1) (7.6) (44.9)
14.8 54.0 45 36 277
(3.1) (13.6) (7.3) (5.9) (45.2)
15.0 53.6 56 41 266
(3.0) (13.5) (9.2) (6.7) (43.6)
15.0 53.5 54 40 254
(3.0) (13.8) (9.0) (6.7) (42.3)
15.2 66.6 56 45 286
(3.3) (24.9) (9.4) (7.6) (48.1)
14.8 63.9 43 35 289
(3.0) (26.3) (7.0) (5.7) (47.1)
15.1 64.5 53 37 285
(3.0) (25.9) (8.7) (6.1) (46.7)
15.0 65.7 49 39 258
(3.1) (25.9) (8.2) (6.5) (42.9)
0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; BCVA ¼ best-corrected visual acuity; IOP ¼ intraocular pressure; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks; SD ¼ standard deviation.
most of the following analyses (Fig 1C). In the integrated analysis, there was no apparent difference in mean change in IOP in the fellow eye (Fig 1D). The prespecified categoric outcomes assessing changes in IOP were the single-event incidence of change >10 mmHg in IOP from baseline at any visit through weeks 52 and 96, as well as the single-event incidence of IOP >21 mmHg at any visit through weeks 52 and 96. For both of the prespecified outcomes, at both time points, the proportion of patients in the Rq4 group with elevated IOP was higher than in all the IAI groups (Table 2). These data suggest that elevated IOP in the study eye may be associated with treatment group. There was a smaller but similar direction in terms of these categoric outcomes in the fellow eye (Table 2).
Study Eye Incidence Using Selected Thresholds (Intraocular Pressure >21 and ‡25 mmHg). The cumulative incidence of sustained IOP >21 mmHg (noted at 2 consecutive visits) was similar between all treatment groups during the initial follow-up. At approximately weeks 8 to 12, the incidence curves began to separate (Fig 2A). Starting at week 16, the cumulative incidence of sustained IOP >21 mmHg was 50% to 60% less likely in the IAI groups compared with the Rq4 group. At week 52, the end of the fixedschedule dosing period, there were 34, 16, 17, and 9 study eyes that had sustained IOPs >21 mmHg in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. At the end of 96 weeks of follow-up, 47, 19, 24, and 15 study eyes in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively, had sustained IOP >21 mmHg. At week 96, the cumulative incidences were 8.4%, 3.2%, 4.2%, and 2.7% in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. Over the 96-week follow-up period, compared with Rq4, IAI reduced the risk of elevated IOP by 62%, 50%, and 69% in the 2q4, 2q8, and 0.5q4 groups, respectively (Table 3). Because there were too few patients with sustained IOP 25 mmHg over 96 weeks, single events of IOP 25 mmHg were evaluated. For the single event (first visit with IOP 25 mmHg),
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the cumulative incidence was similar among all treatment groups up to week 40 (Fig 2B). Thereafter, the cumulative incidence for Rq4 began to separate from the 3 IAI groups. At week 52, there were 21, 14, 12, and 7 study eyes with IOPs 25 mmHg in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. The corresponding numbers at week 96 were 35, 19, 16, and 17, respectively. At week 96, the corresponding cumulative incidences were 6.3%, 3.2%, 2.8%, and 3.1% for Rq4, 2q4, 2q8, and 0.5q4, respectively. Over the 96-week follow-up period, compared with Rq4, risk of IOP 25 mmHg was reduced in the IAI groups by 48%, 52%, and 55%, respectively (Table 3). Incidence Using Changes from Baseline (‡5 mmHg). The cumulative incidence of sustained 5 mmHg change in IOP from baseline was similar for a short period only and started to differ beginning at week 8 (Fig 2C). During the first 52 weeks of followup, there were 77, 68, 52, and 43 study eyes with sustained changes of 5 mmHg from baseline in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. The corresponding numbers of patients with events by week 96 were 111, 82, 72, and 62, respectively. At week 96, the cumulative incidences were 19.7%, 14.1%, 12.6%, and 11.1% in the Rq4, 2q4, 2q8, and 0.5q4 groups, respectively. Over the 96 weeks of follow-up, compared with Rq4, IAI groups reduced the risk of sustained changes of 5 mmHg by 31%, 38%, and 47% in the 2q4, 2q8, and 0.5q4 groups, respectively (Table 3). The test for trend for Rq4 > 2q4 > 2q8 > 0.5q4 yielded a P value of 21 mmHg appeared higher in the fellow eyes with Rq4 treatment, as it had in the study eyes (Fig 3A). There were minor trends associated with higher IOP in fellow eyes of patients treated with Rq4 in the study eye, although it was not as prominent as noted earlier for study eyes (Fig 3B and C, Table 4).
Freund et al
IOP after Intravitreal Aflibercept versus Ranibizumab
Figure 1. Mean intraocular pressure (IOP) change from baseline over 96 weeks in (A) study eyes in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1, (B) study eyes in VIEW 2, (C) study eyes in both VIEW 1 and 2, and (D) fellow eyes in both VIEW 1 and 2. 0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks.
Results for sustained incidence of IOP >21 mmHg were also consistent with those seen in Figure 4.
Subgroup Analyses Intraocular pressure changes in the study eyes and for the uninjected fellow eyes were also evaluated for subgroups of selected baseline characteristics: history of glaucoma, use of IOP-lowering medication, and lens status. To examine the consistency or lack thereof, the outcome used was the sustained incidence of IOP change of 5 mmHg from baseline. There was consistency of relative risk, as seen by the overlap of the 95% confidence intervals within each subgroup (Fig 4). The trends Rq4 > 2q4 > 2q8 > 0.5q4 were consistent with observations in the entire cohort.
Intraocular PressureeLowering Medication Use during the Study The proportions of patients starting IOP-related medications after baseline were 6.9%, 7.5%, 6.9%, and 6.0% in the Rq4, 2q4, 2q8, and 0.5q4 treatment groups, respectively. There were no significant differences among the groups.
Table 2. Total Number of Prespecified Intraocular Pressure Events through Weeks 52 and 96 Through Week 52
Through Week 96
Intravitreal Aflibercept Injection Rq4 No. of patients (safety analysis set) Study eye Change 10 mmHg (%) IOP >21 mmHg (%) Fellow eye Change 10 mmHg (%) IOP >21 mmHg (%)
595
2q4 613
2q8 610
Intravitreal Aflibercept Injection
0.5q4 601
Rq4 595
2q4 613
2q8 610
0.5q4 601
3.2 13.6
1.1 10.1
2.3 8.0
2.3 8.2
6.4 20.2
2.9 14.2
3.1 12.1
3.8 12.5
3.7 15.4
2.1 10.4
3.1 12.7
1.2 10.5
5.1 20.3
3.1 12.9
3.3 16.6
1.5 13.6
0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; IOP ¼ intraocular pressure; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks.
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Figure 2. Cumulative incidence of (A) sustained intraocular pressure (IOP) >21 mmHg, (B) a single event of IOP 25 mmHg, and (C) sustained IOP increase of 5 mmHg in study eyes. 0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks.
Discussion Post hoc analysis of the ANCHOR and MARINA data and other recent reports suggest sustained IOP elevation may occur in 3.5% to 8.5% of NVAMD eyes receiving
intravitreal ranibizumab or bevacizumab, depending on the criteria used to define sustained elevation.9e18 The 52week data from the VIEW 1 and 2 studies demonstrated that IAI monthly or every 2 months was noninferior and clinically equivalent to ranibizumab monthly for
Table 3. Cumulative Incidence and Event Rates of Intraocular Pressure, and Relative Risks (Study Eye) Baseline to Week 52 Outcome IOP >21 mmHg
Cumulative Group N* Events (n) Incidence (%)
Rq4 2q4 2q8 0.5q4 Rq4 IOP 25 mmHgy 2q4 2q8 0.5q4 Change 5 mmHg Rq4 2q4 2q8 0.5q4 Change 10 mmHg Rq4 2q4 2q8
595 612 607 597 595 612 607 597 595 612 607 597 595 612 607
30 15 14 9 21 14 12 7 75 63 49 41 2 1 3
5.2 2.5 2.4 1.5 3.7 2.3 2.0 1.2 13.0 10.6 8.4 7.1
Rate 5.40 2.58 2.48 1.61 3.49 2.27 1.98 1.17 14.09 11.20 8.89 7.47 e e e
Baseline to Week 96
RR (95% CI) 0.48 0.46 0.30 0.65 0.57 0.33 0.79 0.63 0.53
1.00 (0.25e0.87) (0.24e0.85) (0.13e0.60) 1.00 (0.32e1.27) (0.27e1.14) (0.13e0.75) 1.00 (0.57e1.11) (0.44e0.90) (0.36e0.77) e e e
Cumulative Events (n) Incidence (%) 47 19 24 15 35 19 16 17 111 82 72 62 8 1 4
8.4 3.2 4.2 2.7 6.3 3.2 2.8 3.1 19.7 14.1 12.6 11.1
Rate 3.94 1.50 1.98 1.23 2.93 1.53 1.33 1.42 11.39 7.91 7.06 6.08 e e e
RR (95% CI) 0.38 0.50 0.31 0.52 0.45 0.48 0.69 0.62 0.53
P Value
1.00 e (0.22e0.64) 21 mmHg, and sustained changes in IOP from baseline (5 mmHg). These differences were observed early and maintained through week 96. The increases in IOP seen in the current study with ranibizumab are similar to those in previous reports.9e17 Comparison of key IOP measures between the sham/photodynamic therapy control groups in the ANCHOR and MARINA trials and the IAI groups in the VIEW trials suggests that there is no difference between these groups.18 This could imply that the rates for IAI in the VIEW trials are background changes occurring in an aged population over time. The decreased incidence associated with IAI use compared with ranibizumab occurred across multiple IOP end points in the 2 VIEW studies (Fig 5). Consistent with these findings, a retrospective chart review of 53 patients with NVAMD indicated that IOP was significantly decreased after switching from ranibizumab or bevacizumab to IAI.20 A variety of mechanisms have been proposed to explain a notable and occasionally clinically significant IOP elevation after ranibizumab and bevacizumab treatments. Such mechanisms include mechanical trauma to the trabecular meshwork from repeated injection-related IOP spikes and a
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decrease in aqueous outflow due to VEGF blockade, as potentially mediated by inhibition of nitric oxide synthesis, or obstruction by high molecular-weight protein aggregates or silicone microdroplets.18,21,22 A higher incidence of IOP elevation with ranibizumab compared with IAI cannot be easily explained by a mechanical trauma or decrease in aqueous outflow due to VEGF blockade or obstruction by silicone microdroplets because both anti-VEGF agents act through a similar mechanism of action and were given in similar volume and frequency with a similar needle gauge in this study. It remains to be elucidated whether the difference in the incidence of IOP elevation reported in this study is caused by a decrease in aqueous outflow due to relatively larger or more protein aggregates formed by 1 anti-VEGF agent compared with the other agent. It is conceivable that the glycosylation of aflibercept may improve solubility in the vitreous compared with ranibizumab and avoid potential protein accumulation.23,24 It is also possible that an endotoxin-induced inflammatory response may lead to trabeculitis and IOP elevation in some patients over time and with repeated treatment with ranibizumab manufactured using Escherichia coli compared with aflibercept manufactured using Chinese hamster ovary cells.23,24 Consistent with the findings of Hoang et al,16 a personal history of glaucoma at baseline did not influence the outcomes. These results differ from those reported in a small study of 21 patients by Good et al,9 who found higher rates of IOP elevation in patients with preexisting glaucoma. As previously reported, lens status also did not play a role.16 Furthermore, results within each subgroup were consistent with what was observed in the overall cohort, further supporting the overall outcomes. The findings for the uninjected fellow eyes also indicated a possible association of ranibizumab with higher IOP, although it was not as robust as the study eye results. This could be associated with the triggering of a broader-acting immune or inflammatory response, which would have a lesser effect on the fellow eye. A higher incidence of
Figure 5. Relative risk of intraocular pressure (IOP) increase in study eyes in VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD (VIEW) 1 (v1), VIEW 2 (v2), and both VIEW 1 and VIEW 2 (C) at week 96. 0.5q4 ¼ 0.5 mg intravitreal aflibercept every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept every 8 weeks after 3 initial monthly injections; IAI ¼ intravitreal aflibercept injection.
Freund et al
IOP after Intravitreal Aflibercept versus Ranibizumab
sustained IOP increase was observed in uninjected fellow eyes in this study compared with that previously reported in a smaller study of 207 patients with NVAMD unilaterally injected with ranibizumab or bevacizumab17 on a treat-andextend regimen.25 The difference in frequency of visits and injections might account for these observations. There are strengths and limitations to our study. This is the first set of analyses including integrated data from 2 large, similarly designed, prospective, double-masked, randomized clinical trials evaluating differences of the effect and frequency of dosing between 2 different anti-VEGF agents on elevated IOP. Instructions for IOP measurement were limited to use of the same type of instrument throughout the study, with no requirement for use of the same instrument and calibration checks. Complete data on the type of tonometer used for each patient were not available, and thus results could not be stratified on the basis of this variable. This could be a confounder if different treatment groups had IOP assessed more often with 1 type of tonometer. The time of day of the IOP measurement was not controlled in these studies, and the variability could be considered a limitation. Fluctuations in IOP during a day have been reported.26 However, these variations, if present, would be among all treatment groups. On the other hand, we expect that using sustained incidence instead of a single incidence minimized the effect of such limitations. We were also limited to the data reported on ocular history and ocular medications. In summary, our results suggest that patients with NVAMD who receive IAI injections (every 4 or 8 weeks after 3 monthly treatments) seem less likely to experience sustained IOP elevation compared with patients receiving ranibizumab every 4 weeks. Given reports showing the clinical equivalence of IAI to ranibizumab in terms of visual outcomes, IAI may be preferred in patients with NVAMD in whom there are concerns about IOP elevation.
8.
9. 10. 11. 12. 13.
14. 15. 16.
17.
18. 19.
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Ophthalmology Volume 122, Number 9, September 2015
Footnotes and Financial Disclosures Originally received: November 13, 2014. Final revision: April 15, 2015. Accepted: April 15, 2015. Available online: May 27, 2015. 1
Author Contributions: Conception and design: Freund, Hoang, Saroj, Thompson Manuscript no. 2015-1825.
Vitreous Retina Macula Consultants of New York, New York, New York.
2
LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, New York, New York.
3
Edward S. Harkness Eye Institute, Columbia University College of Physicians and Surgeons, New York, New York.
4
Department of Ophthalmology, New York University Medical Center, New York, New York.
5
Regeneron Pharmaceuticals, Inc., Tarrytown, New York. Presented as a poster at: the American Academy of Ophthalmology Annual Meeting, November 10e13, 2012, Chicago, Illinois. Financial Disclosure(s): The author(s) have made the following disclosure(s): K.B.F.: Consultant e Bayer HealthCare, Genentech, Heidelberg Engineering, Regeneron Pharmaceuticals, Inc. N.S. and D.T.: Employees e Regeneron Pharmaceuticals, Inc. Funded by the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Institute, New York, New York; The Macula Foundation Inc., New York, New York; and Regeneron Pharmaceuticals, Inc., Tarrytown, New York. The sponsors participated in the design and conduct of the study, analysis of the data, and preparation of the manuscript.
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Data collection: Freund, Hoang, Saroj, Thompson Analysis and interpretation: Freund, Hoang, Saroj, Thompson Obtained funding: Not applicable Overall responsibility: Freund, Hoang, Saroj, Thompson Abbreviations and Acronyms: 0.5q4 ¼ 0.5 mg intravitreal aflibercept injection every 4 weeks; 2q4 ¼ 2 mg intravitreal aflibercept injection every 4 weeks; 2q8 ¼ 2 mg intravitreal aflibercept injection every 8 weeks after 3 initial monthly injections; ANCHOR ¼ Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD; CI ¼ confidence interval; IAI ¼ intravitreal aflibercept injection; IOP ¼ intraocular pressure; MARINA ¼ Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab in the Treatment of Neovascular AMD; Rq4 ¼ 0.5 mg intravitreal ranibizumab every 4 weeks; NVAMD ¼ neovascular agerelated macular degeneration; VEGF ¼ vascular endothelial growth factor; VIEW ¼ VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD. Correspondence: K. Bailey Freund, MD, Vitreous Retina Macula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022. E-mail: [email protected].
