INTRAOCULAR PRESSURE TRENDS AFTER INTRAVITREAL INJECTIONS OF ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR AGENTS FOR DIABETIC MACULAR EDEMA ABDULELAH A. AL-ABDULLAH, MD,* SAWSAN R. NOWILATY, MD,* NASIRA ASGHAR,† ABDULLAH S. A. AL-KHARASHI, MD,‡ NICOLA G. GHAZI, MD*§ Purpose: To study intraocular pressure (IOP) trends and risk factors of IOP elevation after intravitreal anti-vascular endothelial growth factor injections in diabetic macular edema. Methods: A retrospective review of 760 eyes treated with intravitreal anti-vascular endothelial growth factor injections for diabetic macular edema was performed. The rate and risk factors of IOP elevation were assessed. Intraocular pressure elevation was defined as an increase above baseline IOP by $6 mmHg, increase above baseline by .20%, or IOP elevation to .24 mmHg on 2 or more consecutive visits after treatment. When more than one pretreatment IOP reading was available, baseline IOP was calculated as the mean of the available pretreatment IOP readings (up to a maximum of three last IOP readings). Intraocular pressure elevation was considered transient unless it was maintained throughout the follow-up or required treatment (persistent elevation). Results: Over a mean follow-up of 18 months, persistent and transient IOP elevation occurred in 44 (5.8%) and 53 (7%) eyes, respectively. The majority of eyes with persistent IOP elevation (70.4%) showed IOP elevation of .20% from baseline. Only 13 eyes (1.71%) met the more strict criteria (.6 mmHg from baseline or an IOP elevation .24 mmHg). Final IOP was higher in the persistent IOP elevation group than the rest of the eyes (P , 0.001). Only the number of injections was associated with IOP elevation (P , 0.001). Conclusion: Persistent IOP elevation after intravitreal anti-vascular endothelial growth factor injections for diabetic macular edema is uncommon but may be associated with a higher number of injections. RETINA 35:440–448, 2015
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particularly that a very small dose is administered intravitreally (1/400th of the intravenous dose).7 The ocular side effects include intraocular inflammation, intraocular hemorrhage, infectious endophthalmitis, and retinal detachment.8,9 Persistent/sustained ocular hypertension has been recently reported as a potential ocular side effect of intravitreal anti-VEGF injections in patients with NVAMD.10–14 The incidence has been reported to vary from approximately 3% to 10% (6% on average).12,13,15–17 However, the mechanism of the sustained elevation in intraocular pressure (IOP) remains speculative. It is believed that the cause of IOP elevation is injection related rather than disease related. Some attempt to explain this phenomenon based on inflammatory response,14 direct toxic effect of anti-VEGF agents
iabetic macular edema (DME) is the most common cause of visual loss in patients with diabetic retinopathy. For a long time, the only treatment available was macular laser treatment.1 More recently, several clinical trials have proven the superiority of antivascular endothelial growth factor (anti-VEGF) agents to laser therapy in the case of center-involved DME.2–4 Anti-VEGF injections are also the mainstay of treatment for neovascular age-related macular degeneration (NVAMD).5,6 Although intravitreal anti-VEGF injections have potential ocular and systemic side effects and all studies using intravitreal anti-VEGF agents so far have not been powered enough to assess the systemic safety of their use, it seems from the world-wide experience that the systemic side effects are rare,
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IOP TRENDS AFTER ANTI-VEGF IN DME AL-ABDULLAH ET AL
to the trabecular meshwork (TM),18 subvisible silicone oil leashed from the syringes,19 and/or the volume associated with repeated injections, which may induce damage to the drainage outflow.12 As all the cases of IOP elevation reported, to date, have been in the setting of NVAMD, a condition that typically affects the aged population (older than 65 years) that is inherently susceptible to IOP elevation and glaucoma,10–14 documenting the occurrence of sustained IOP elevation after intravitreal anti-VEGF injections in conditions other than NVAMD, particularly if the population studied is considerably younger than that of NVAMD, lends more support to the hypothesis that the injections themselves are causative and minimizes the confounding effects of NVAMD and age. Furthermore, although the occurrence of sustained IOP elevation after intravitreal anti-VEGF agents is believed to be real, further retrospective comparative studies or prospective studies are needed to provide higher level evidence for such an association. In this study, we aim to investigate whether intravitreal anti-VEGF injections are associated with persistent elevation of IOP in a population of patients with DME that is relatively younger than the NVAMD patient populations that have been previously reported.10–14 The risk factors for IOP elevation after intravitreal anti-VEGF therapy will also be investigated. The findings of this study may shed light on the pathogenesis of IOP elevation after intravitreal injections of these agents. Methods The study was performed at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, after approval by the institutional review board. We retrospectively reviewed the medical records of patients with DME treated with a single or multiple intravitreal antiVEGF injections during the period from 2007 to 2011. To be included in the study, patients had to have received at least a single intravitreal injection of bevacizumab (Avastin; Genentech, Inc, South San From the *Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; †Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; ‡Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia; and §Department of Ophthalmology, University of Virginia, Charlottesville, Virginia. Scientific poster presentation at the annual meeting of The American Academy of Ophthalmology (AAO), New Orleans, LA, November 16–19, 2013. None of the authors have any conflicting interests to disclose. A. A. Al-Abdullah and S. R. Nowilaty equally contributed to this article. Reprint requests: Nicola G. Ghazi, MD, Vitreoretinal Division, King Khaled Eye Specialist Hospital, Al-Oruba Street, P.O., Box 7191, Riyadh 11462, Saudi Arabia; e-mail: [email protected]
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Francisco, CA) or ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA) with at least 1 month follow-up after the first injection. Patients were excluded from this study if they had incomplete records, intravitreal steroid in the same eye within 6 months from initiation of the anti-VEGF therapy, a history of glaucoma, past or current neovascularization of the angle or iris, or a paracentesis before or after the anti-VEGF agent injection. Patients with glaucoma were excluded from the study to avoid the confounding effect of preexisting glaucoma on the trajectory of IOP after intravitreal injection. The bevacizumab syringes were prepared in the hospital’s pharmacy. Bevacizumab was withdrawn from its original vial into insulin syringes under sterile conditions according to techniques described elsewhere.20 Thioglycollate broth was used to randomly culture two syringes, and cultures had to be negative before allowing the prepared batch of syringes to be dispensed. Each batch was used before its shelf life (2 weeks) was due. The intravitreal injection technique was similar for all eyes. Eyes received 0.05 mL injection containing either 1.25 mg of bevacizumab or 0.5 mg of ranibizumab. Before the injection, povidone–iodine 5% was applied over the eyelids and instilled into the conjunctival sac. Using a sterile ophthalmic lid speculum and topical anesthesia, the intravitreal injection was given using a 30-gauge needle, generally at a superotemporal site 3.5 mm to 4 mm posterior to the limbus. No IOPlowering agents were administered before or after injection. Anterior chamber paracentesis was not performed in any of the eyes included in this study. The interval between injections was no less than 4 weeks. The data collected from each patient included age, gender, ethnicity, medical and ocular history, family history of glaucoma, presenting visual acuity, lens status, stage of diabetic retinopathy, baseline and posttreatment IOP levels, type of intravitreal medication used, the number of injections, the interval between injections, the length of follow-up, and associated complications. The IOP was measured using applanation tonometry in all our patients, and the baseline (before treatment) IOP was defined as the IOP recorded before the first anti-VEGF injection. When more than one pretreatment IOP reading was available, baseline IOP was calculated as the mean of the available pretreatment IOP readings (up to a maximum of three last IOP readings). During follow-up visits, eyes were considered to have IOP elevation if they met any of the following criteria: 1) an IOP rise to .24 mmHg, 2) an increase of 6 mmHg or more from baseline IOP, and/ or 3) a 20% rise from baseline IOP. Postinjection IOP elevation was also classified into persistent or
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transient. Persistent IOP elevation was defined as a rise meeting any of the above criteria that persisted throughout follow-up. Transient IOP elevation was defined as an elevation of IOP from baseline that met any of the above-mentioned criteria for at least two consecutive visits but that returned to baseline afterward without treatment. Immediate same-day IOP measurement was not included in this study, as this is not routinely performed in our clinics, and also as assessing immediate transient IOP elevation, which is expected to occur in all injected eyes immediately after injection, is not the aim of this study. Statistical Analysis All data were entered into an Excel spreadsheet. Patients with IOP elevation were identified. The mean and median IOP levels and the proportion of patients with IOP elevation (as defined above) after intravitreal injections were analyzed. The main outcome measure was the proportion of eyes with IOP elevation after intravitreal anti-VEGF injections. The Chi-square test was used to study associations between elevated IOP, whether persistent or transient, categorical variables (diabetic retinopathy grade and lens status), and dichotomous variables (interval between injections more or less than 2 months, gender, and nonproliferative or proliferative stage of diabetic retinopathy). The t-test or the Mann–Whitney test, when appropriate, was used to analyze the mean differences in continuous variables (age, number of bevacizumab injections, number of ranibizumab injections, total number of injections, IOP at baseline, and intervals between injections). In addition, the eyes were divided into 4 groups: 1) those with persistent IOP elevation (persistent IOP elevation group), 2) those with transient IOP elevation (transient IOP elevation group), 3) all eyes that exhibited either transient or persistent IOP elevation (any IOP elevation group), and 4) eyes that did not demonstrate any rise in IOP throughout follow-up (no IOP elevation group). The four groups were compared in terms of baseline characteristics, baseline IOP, final IOP, number of injections per eye, and interval between injections. All P-values were 2-sided, and statistical significance was defined as P , 0.05. Results A total of 486 patients were included in this study (Table 1). Their mean age was 60.73 years (range, 22– 94; SD, 10.54; median, 61). Three hundred and twenty-six patients (67.1%) were men. The mean duration of diabetes mellitus was 14.03 years (SD, 8.05),
Table 1. Patients’ Baseline and Injection-Related Characteristics Number of patients (%) 486 (100) Number of eyes (%) 760 (100) Age, median (IQR) 61 (54–68) Gender, male (%) 326 (67.1) Duration of DM, mean (SD), years 14.03 (8.05) Patients on insulin (%) 243 (50) Patients with arterial hypertension (%) 178 (36.6) Eyes with NPDR (%) 604 (79.5) Eyes with prior macular laser (%) 340 (44.7) Eyes with prior PRP (%) 276 (36.3) Eyes with pseudophakia (%) 224 (29.5) Baseline IOP, mean (SD), mmHg 17.2 (3.2) Baseline IOP, median (IQR), mmHg 17 (15–19) Last IOP, mean (SD), mmHg 17.47 (3.5) Total injections per eye, mean (SD) 3.38 (2.33) Interval between injections, mean (SD), 4.8 (4.93) months Eyes with injection interval #60 days (%) 173 (22.8) Eyes that received ,3 injections (%) 314 (41.3) Follow-up, mean (SD), months 17.89 (11.58) Eyes with follow-up .4 months (%) 652 (87.8) IQR, interquartile range; NPDR, nonproliferative diabetic retinopathy; PRP, panretinal photocoagulation.
and 50% of the patients were on insulin therapy. The number of eyes that met the inclusion criteria of the study was 760, among which 224 eyes (29.5%) were pseudophakic and 604 eyes (79.5%) had nonproliferative diabetic retinopathy. The mean and median baseline IOP for the entire group of eyes before initiation of intravitreal injections was 17.2 mmHg and 17 mmHg, respectively (Table 1). The total number of injections performed was 2,566, including 2,338 bevacizumab injections and 228 ranibizumab injections. Of the 760 eyes, 672 (88.42%) received bevacizumab alone, 4 eyes (0.53%) received ranibizumab alone, and 84 eyes (11.05%) received both bevacizumab and ranibizumab (Table 2). The mean number of injections per eye was 3.38 injections (range, 1–24; SD, 2.33), and 314 of the 760 eyes (41.3%) received ,3 injections. The interval between injections was #2 months in 173 eyes (22.8%). The mean followup was 17.9 months (range, 1–68; SD, 11.58), with 652 eyes (87.8%) completing at least 4 months of follow-up (Table 1). Table 2. Distribution of Anti-VEFG Injections and the Rate of Persistent IOP Elevation Anti-VEGF Agent Bevacizumab Ranibizumab Both Total
Number of Eyes (%) 672 4 84 760
(88.42) (0.53) (11.05) (100)
Eyes With Persistent IOP Elevation (%) 32/672 (4.76) 0/4 (0) 12/84 (14.29) 44/760 (5.79)
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IOP TRENDS AFTER ANTI-VEGF IN DME AL-ABDULLAH ET AL
of injections was higher in eyes that developed transient IOP elevation and in those that exhibited persistent IOP elevation compared with the group of eyes with no IOP elevation (P , 0.001 for both) (Table 4). There was no statistical difference, however, when the number of injections in the persistent IOP elevation group was compared with that in the transient IOP elevation group (P = 0.66) (Table 4). The mean interval between injections was 3.26 months (range, 1–7.8; SD, 1.7) in the persistent IOP elevation group, 3.8 months (range, 1.2–12.9; SD, 2.7) in the transient IOP elevation group, 3.6 months (range, 1–12.9; SD, 2.4) in the any IOP elevation group, and 5.03 (range, 1–31.3; SD, 5.27) in the no IOP elevation group. Although a shorter interval between injections was noted in the group with persistent IOP elevation (3.26 months) compared with the group with no IOP elevation (5.03 months), this difference did not reach statistical significance (P = 0.54) (Table 4). Of note is that the three groups (persistent IOP elevation, transient IOP elevation, and no IOP elevation) were balanced with respect to baseline characteristics with the exception of two factors: the duration of diabetes mellitus, which was statistically significantly different between the transient and persistent IOP elevation groups (P = 0.038, Table 4), and the baseline IOP. A significant difference in the baseline IOP was in fact found among the 3 groups with a higher mean baseline IOP in the no IOP elevation group (mean, 17.54 mmHg; SD, 3.23) compared with both the persistent IOP elevation group (mean, 16.33 mmHg; SD, 2.09; P = 0.003) and the transient IOP elevation group (mean, 16.21 mmHg; SD, 2.7; P = 0.003) (Table 4). Despite this, the final IOP was significantly higher in the persistent IOP elevation group (mean, 21.03 mmHg; SD, 3.31) compared with both the no IOP elevation group (P , 0.001) and the transient IOP elevation group (P , 0.001). None of the patients required surgery, laser therapy, or systemic medications to control the IOP elevation. Only 3 patients were initiated on topical IOP-lowering agents for IOP levels of 41, 29 and 26 mmHg, respectively.
Based on the study criteria, a total of 97 eyes of 79 patients developed IOP elevation (12.76%) during follow-up. Transient IOP elevation was recorded in 53 of these 97 eyes (6.97% of the total cohort), whereas 44 eyes (5.79% of the total cohort) developed persistent IOP elevation (Tables 2 and 3). Persistent IOP elevation developed in 32 of the 672 eyes (4.76%), which received intravitreal bevacizumab alone, in none of the 4 eyes (0%), which received intravitreal ranibizumab alone, and in 12 of the 84 eyes (14.29%), which received intravitreal bevacizumab and ranibizumab during the course of treatment. Of the 274 patients who received bilateral injections, 29 (10.6%) patients developed persistent IOP elevation in at least 1 eye as follows: 8 (2.9%) developed persistent IOP elevation in both eyes, 6 (2.2%) developed persistent IOP elevation in 1 eye and transient elevation in the fellow eye, and 15 (5.5%) developed persistent elevation in 1 eye and no IOP elevation in their fellow eye. The remaining 245 patients (89.4%) did not develop persistent IOP elevation after bilateral injections. The mean interval between the first anti-VEGF injection and IOP elevation was 8.93 months (range, 1–26; SD, 6.73; median, 7) in the persistent IOP elevation group and 6.53 months in the transient IOP elevation group (range, 1–28; SD, 5.61; median, 4; P = 0.07). Furthermore, IOP elevation was first noted after a mean number of 3.61 injections (range, 1–12; SD, 2.63) in the persistent IOP elevation group and after a mean of 2.57 injections (range, 1–13; SD, 2.05) in the transient IOP elevation group (P = 0.032). Elevated IOPs ranged from 20 mmHg to 41 mmHg, with a mean IOP of 23.93 (SD, 4.77). The mean number of injections per eye was 5.45 (range, 2–14; SD, 3.06) in the persistent IOP elevation group, 5.08 injections (range, 2–24; SD, 3.27) in the transient IOP elevation group, 5.2 injections (range, 2– 24; SD, 3.2) in the any IOP elevation group, and 3.83 (range, 2–12; SD, 1.91) in the no IOP elevation group (Table 4). The total number of injections was found to be higher in the persistent IOP elevation group compared with the group that did not develop any IOP elevation (P , 0.001) (Table 4). Similarly, the number
Table 3. Rate of IOP Elevation According to the Study Criteria Specific Criteria IOP elevation to .24 mmHg $6 mmHg elevation from baseline IOP 20% elevation from baseline IOP $6 mmHg elevation or .24 mmHg only Total number with IOP elevation
Persistent IOP Elevation (%) 7 6 31 13 44
eyes eyes eyes eyes eyes
(0.92) (0.79) (4.08) (1.71) (5.79)
Transient IOP Elevation (%) 5 4 44 9 53
eyes eyes eyes eyes eyes
(0.66) (0.53) (5.79) (1.18) (6.97)
0.089 0.002 0.001 0.24 17 (11.75) 21.5 (10.2) 18.5 (10.64)
20.1 (10.5)
0.089 0.73 0.959 0.55 5.0 (5.27) 3.8 (2.7) 3.3 (1.7)
3.6 (2.4)
,0.001 0.66 ,0.001 ,0.001 0.174 ,0.001 17.8 (2.9) 5.08 (3.27) 21 (3.3) 5.45 (3.06)
19.3 (3.5) 5.20 (3.2)
17.4 (3.5) 3.83 (1.91)
,0.001 ,0.001
0.82 ,0.001 0.01 16.2 (3.7) 16.3 (2)
16.3 (2.7)
17.5 (3.2)
0.003
— — 0.45 0.038 — — 0.245 0.293 — — 0.676 0.096 — — 0.71 0.94 407 663 61 (10.8) 13.9 (6) 79 97 60.4 (10.3) 15.8 (6.7) 49 53 60 (7.7) 17.7 (7) 36 44 60.8 (12.7) 13.8 (8.2)
Number of patients Number of eyes Mean age (SD), years Mean duration of diabetes (SD), years Mean baseline IOP (SD), mmHg Mean last IOP (SD), mmHg Mean total number of injections per eye (SD) Mean interval between injections (SD), months Mean follow-up (SD), months
Persistent IOP Elevation (P)
Transient IOP Elevation (T)
Persistent and Transient IOP Elevation (PT)
No IOP P Value (P P Value (T P Value (PT P Value (P Elevation (N) vs. N) vs. N) vs. N) vs. T)
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 3
Factor
Table 4. Comparison Between Eyes With Persistent IOP Elevation (P), Transient IOP Elevation (T), Combined Persistent and Transient IOP Elevation (PT), and No IOP Elevation (N)
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Discussion To the best of our knowledge, this retrospective study is the only study that exclusively addresses IOP trends after intravitreal bevacizumab and/or ranibizumab injections in eyes with DME. Many retrospective studies and case series have reported the occurrence and prevalence of IOP elevation in NVAMD after such treatment.10–17,21 Diabetic macular edema is the most common indication for intravitreal anti-VEGF therapy in our institution; therefore, it was intriguing to assess whether IOP elevation after such therapy is an issue in DME patients as has been reported for NVAMD. One main difference between patients with NVAMD and DME is age at presentation, which was clearly lower in this study compared with that in previous NVAMD reports. For example, the mean age in this study was 60.7 years (SD, 10.54) compared with the study by Choi et al16 who reported a mean age of 81 years (SD, 10) in their patients with NVAMD. As age is a significant risk factor for IOP elevation and open-angle glaucoma,22 a careful analysis of the confounding effect of age on the incidence of IOP elevation after anti-VEGF therapy should be undertaken particularly in an elderly population like patients with NVAMD. Few published studies23–26 reported limited data regarding IOP elevation after intravitreal bevacizumab therapy for DME as part of a comparison between intravitreal bevacizumab and intravitreal triamcinolone with or without intravitreal bevacizumab. Three of these studies23–25 had a very short follow-up of 12 weeks to 24 weeks, and 2 looked at the effect of either a single24 or only 226 injections of intravitreal bevacizumab. In addition, some of these studies had only few patients in the intravitreal bevacizumab treatment group.23,25,26 The limitations inherent to the design of these studies, including a short-term follow-up, a limited number of intravitreal bevacizumab injections, and a small number of patients included in some, do not allow for meaningful conclusions regarding the long-term effect of multiple intravitreal bevacizumab injections on the IOP in eyes with DME. Careful analysis of our data disclosed that most of the eyes developed transient rather than persistent IOP elevation after intravitreal injections. Moreover, most of the eyes that developed persistent IOP elevation (31 of 44 or 70.4%) met the inclusion criteria of a 20% elevation from baseline IOP. This is a very inclusive criterion that may include eyes that had, for example, a rise from 10 mmHg at baseline to 12 mmHg. If one were to consider eyes with more restrictive criteria of IOP elevation such as an IOP rise to more than
IOP TRENDS AFTER ANTI-VEGF IN DME AL-ABDULLAH ET AL
24 mmHg or an increase of 6 mmHg or more from baseline, then only 13 of 760 eyes (1.71%) would have been included in the IOP elevation group (Table 3). In addition, only three patients were started on a topical IOP-lowering agent to control the IOP. None of the eyes required any intervention by laser or surgery to control the IOP elevation. Therefore, our findings suggest that the majority of eyes with DME and IOP elevation after intravitreal anti-VEGF injections experience a transient form of IOP elevation that requires no treatment. In addition, even when the elevation is persistent, the majority of the eyes experience only mild forms of IOP elevation, whereas significant IOP elevations are experienced in ,2% of the eyes. In fact, such low level of IOP elevation was shown in a recent case–control study in NVAMD by Wehrli et al27 who compared the incidence of IOP elevation in eyes with NVAMD that received bevacizumab and/or ranibizumab with control eyes that did not receive either. They found that the incidence by eye-year was 0.51% (3 of 270) and 1% (4 of 195) in anti-VEGF treated eyes versus control eyes, respectively. This was much lower than the previously reported rates of IOP elevation in the other 5 retrospective studies in patients with NVAMD that ranged from 3.45% to 11.6%12,13,15–17 (Table 5). The findings of this study and that of Wehrli et al27 support the possibility that age may be a confounding factor in the association between IOP elevation and intravitreal injections in patients with NVAMD. The disparity between the rate of IOP elevation in patients with DME and NVAMD after anti-VEGF therapy can also be explained by the differences in the number of injections received. The mean number of injections in this study was 3.38 (SD, 2.3 injections) compared with a much higher number in patients with NVAMD, such as in the retrospective study by Good et al13 who reported a median of 9 injections per eye (range, 1–30 injections). In this study, we showed an association between the number of anti-VEGF injections and IOP elevation. Similarly, Tseng et al21 and Hoang et al15 showed an association between the total number of injections and IOP elevation. In the latter study,15 the odds ratio of experiencing the IOP elevation was higher in patients receiving 29 or more injections compared with those receiving 12 or less injections (5.75; 95% CI, 1.19– 27.8; P = 0.03). However, such an association remains controversial. For example, Choi et al16 in a retrospective review of 155 eyes showed no association between the number of injections and IOP elevation .25 mmHg. In another most recent study,28 addressing IOP elevation after intravitreal ranibizumab in two clinical trials of patients with AMD, more ranibizumab-treated eyes had IOP
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increase from baseline compared with sham or photodynamic therapy–treated eyes. Interestingly, the IOP increase did not seem to be related to the number of injections. Perhaps, the number of patients included and the proportion that sustains IOP elevation among a cohort influences the statistical power to detect an association between IOP elevation and the number of injections administered. If the total number of injections per eye were truly a risk factor for IOP elevation, then the low rate of persistent IOP elevation noted in this study may be at least partly explained by the low number of injections received per eye (mean, 3.38 injections). This may be a reflection of the “real-world scenario” where it is difficult to follow-up and treat patients with diabetes every month knowing the busy clinical schedule such patients have due to their multiple comorbidities. Therefore, the risk of significant IOP elevation in this population seems to be relatively low and reassuring. Mathalone et al17 identified an association between IOP elevation and an interval between anti-VEGF injections of less than 8 weeks. In this study, the interval between injections was not associated with IOP elevation. Likewise, Good et al13 and Hoang et al15 reported no correlation between IOP elevation and the interval between anti-VEGF injections. Similarly, Choi et al16 demonstrated no relationship between the frequency of injections that an eye received and any progressive changes in its IOP measurements. The specific intravitreal medication used may also play a role in IOP elevation after therapy. For example, one study reported that the rate of IOP rise was 3 times higher after bevacizumab injections compared with ranibizumab alone with a rate of 9.9% and 3.1%, respectively.13 A possible mechanism of IOP elevation is a direct toxicity of anti-VEGF agents on the TM. A study by Kahook and Ammar18 on cultured human TM showed that only bevacizumab is toxic to the TM when used at four times the concentration of the clinical dose. Ranibizumab, however, did not cause any toxicity to the TM even at very high doses. In this study, only 4 eyes received ranibizumab alone and none of these eyes developed elevated IOP. The small number of ranibizumab injections in our cohort prohibits any meaningful conclusions in this regard. However, in this study, the rate of persistent IOP elevation was noted to be higher in the group that received both agents, ranibizumab and bevacizumab (12/84 [14.29%]), compared with the group that received bevacizumab alone (32/672 [4.76%]). In addition, the packaging technique of the medication used may play a role in IOP elevation. Good et al13 found that 9 of 10 eyes with elevated IOP received their bevacizumab in one center. The center with higher rate
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Author
Adelman et al12
Mean age (SD), years Total number of cases
83 in the IOP rise group 116 patients
Rate of IOP elevation
3.45%
Sustained versus transient IOP elevation Agents IOP (mmHg)*
NA
B and/or R Range, 28–36
Number of 3–19 injections, range* Interval between Mean, 4–6 injections* weeks Study criteria for IOP .21 IOP elevation mmHg on 2 separate visits
Good et al13
Choi et al16
Hoang et al15
Mathalone et al17
77 (8.5)
81 (10)
79
215 eyes
127 patients (155 eyes)
207 treated eyes, 174 patients (201 eyes) 207 fellow eyes (controls) Treated: 11.6%, 11% untreated: 5.3%
Overall: 6%; B: 9.9%; Overall: 9.4%; R: 3.1% sustained: 5.5% Sustained: 6%, transient: 8.4% B and/or R Range, 23–36; mean, 29.2 IQR, 6–13.7 Mean, 81.3 days
B, R, or P Range, 11–39; mean, 20 3.4–9.7 per year
Mean, 52 days (calculated) IOP $22 mmHg IOP .25 mmHg lasting $30 days on on 2 visits $2 separate visits requiring and a change of .6 glaucoma medication or mmHg from surgery baseline IOP
79 (8.3)
NA
NA
B and/or R NM
B Range, 22–36; mean 25.9 3–18
9–39 Mean, 7.5 weeks (calculated) IOP elevation .5 mmHg from baseline on $2 consecutive visits
*Data shown for the group of eyes that exhibited sustained IOP elevation. B, bevacizumab; IQR, interquartile range; NA, information not available; P, pagabtanib; R, ranibizumab.
Wehrli et al27 75.2
60.7 (10.5)
302 treated eyes, 226 control eyes
486 patients (760 eyes)
Overall 12.8% Treated: 0.51% per eye-year, untreated: 1% per eye-year NA Sustained: 5.8% (with stricter criteria, 1.71%), transient: 7% B and/or R B and/or R Range, 25–60 Range, 20–41; mean, 23.9 NA 2–14 (mean, 5.45)
Median, 7 weeks Mean, 54 days IOP $22 mmHg and a change of $6 mmHg from baseline IOP on $2 consecutive visits and lasting $30 days
Current Study
IOP $22 mmHg on 2 consecutive visits with .6 mmHg increase from baseline IOP or IOP .26 mmHg on 1 visit requiring IOPlowering therapy
Mean, 90 days IOP .24 mmHg or $6 mmHg increase from baseline IOP or .20% increase from baseline IOP
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Table 5. Comparison of Retrospective Series Addressing IOP Increase After Intravitreal Injections of VEGF Antagonists
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of IOP elevation obtained prepackaged bevacizumab from an outside pharmacy that stores and transports bevacizumab in plastic syringes. In contrast, the other center used bevacizumab obtained from an original vial available on site before injection. Based on these findings, Good et al and others proposed that transportation and storage of bevacizumab in plastic syringes coated with silicone may result in leashing of silicone particles into the drug solution that could, in turn, obstruct the TM after injection into the eye.19 Another speculative mechanism for the IOP rise after anti-VEGF agents is that proteins like bevacizumab and ranibizumab may produce secondary inflammation and trabeculitis with subsequent compromise in the TM function. In this study, no inflammation was noted after anti-VEGF injections. Similarly, apart from one case report of a single patient who developed white deposits over the TM,14 none of the previous reports implicated this factor as a mechanism for IOP elevation after such treatment. Tseng et al21 suggested that sustained IOP elevation could be related to the repeated transient IOP spikes related to the volume of the drug injected, which eventually alters the aqueous outflow pathways. Adelman et al12 reported that a disrupted posterior capsule in pseudophakic eyes might be associated with IOP elevation after intravitreal anti-VEGF therapy. In this study, 2 of 10 eyes with capsulotomy developed persistent IOP elevation after treatment. To date, the exact mechanism of sustained IOP elevation after intravitreal anti-VEGF injections remains speculative. In summary, despite the limitations of this study, including its retrospective nature, lack of a control group, variations in baseline characteristics between groups such as duration of diabetes (the value of which remains unknown) (Table 4), and absence of gonioscopic documentation of the angle in most of our patients, the results suggest that the rate of significant and persistent IOP elevation in patients with DME after intravitreal anti-VEGF injections is less than that published for the NVAMD population. Although the reasons for that may be multiple, age and the number of injections received per eye may be important variables behind this disparity. Although further studies are needed to confirm whether such an association even exists at all, especially knowing the apparent low rate seen in this study, clinicians should be aware of the potential for IOP elevation after intravitreal antiVEGF therapy in eyes with DME, particularly when the patients require a higher number of injections. Further prospective comparative studies are needed to address several questions that remain unanswered in this topic.
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Key words: diabetic macular edema, intravitreal injections, anti-vascular endothelial growth factor agents, ranibizumab, bevacizumab, intraocular pressure, ocular hypertension. References 1. Group ETDRSR. Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol 1985;103:1796–1806. 2. Nguyen QD, Shah SM, Khwaja AA, et al. Two-year outcomes of the ranibizumab for edema of the mAcula in diabetes (READ-2) study. Ophthalmology 2010;117:2146–2151. 3. Massin P, Bandello F, Garweg J, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE study). Diabetes Care 2010;33:2399–2405. 4. The 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;117:1064–1077. 5. Rosenfeld P, Brown D, Heier J, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419–1431. 6. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med 2006;355:1432–1444. 7. Nicholson BP, Schachat AP. A review of clinical trials of antiVEGF agents for diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 2010;248:915–930. 8. Ladas ID, Karagiannis DA, Rouvas AA, et al. Safety of repeat intravitreal injections of bevacizumab versus ranibizumab: our experience after 2,000 injections. Retina 2009;29:313–318. 9. Tolentino M. Systemic and ocular safety of intravitreal antiVEGF therapies for ocular neovascular disease. Surv Ophthalmol 2011;56:95–113. 10. Bakri SJ, McCannel CA, Edwards AO, et al. Persisent ocular hypertension following intravitreal ranibizumab. Graefes Arch Clin Exp Ophthalmol 2008;246:955–958. 11. Kahook MY, Kimura AE, Wong LJ, et al. Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections. Ophthalmic Surg Lasers Imaging 2009;40:293–295. 12. Adelman RA, Zheng Q, Mayer HR. Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections. J Ocul Pharmacol Ther 2010;26:105–110. 13. Good TJ, Kimura AE, Mandava N, et al. Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents. Br J Ophthalmol 2011;95:1111–1114. 14. Sniegowski M, Mandava N, Kahook MY. Sustained intraocular pressure elevation after intravitreal injection of bevacizumab and ranibizumab associated with trabeculitis. Open Ophthalmol J 2010;4:28–29. 15. Hoang QV, Mendonca LS, Della Torre T, et al. Effect on intraocular pressure in patients receiving unilateral intravitreal anti-vascular endothelial growth factor injections. Ophthalmology 2012;119:321–326. 16. Choi DY, Ortube MC, McCannel CA, et al. Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib. Retina 2011;31:1028–1035. 17. 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;250:1435–1440.
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18. Kahook MY, Ammar DA. In vitro effects of antivascular endothelial growth factors on cultured human trabecular meshwork cells. J Glaucoma 2010;19:437–441. 19. Liu L, Ammar DA, Ross LA, et al. Silicone oil microdroplets and protein aggregates in repackaged bevacizumab and ranibizumab: effects of long-term storage and product mishandling. Invest Ophthalmol Vis Sci 2011;52:1023–1034. 20. Gonzalez S, Rosenfeld PJ, Stewart MW, et al. Avastin doesn’t blind people, people blind people. Am J Ophthalmol 2012;153: 196–203.e1. 21. 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;21:241–247. 22. Quigley HA, Broman AT. The number of people with glaucoma worldwide in 2010 and 2020. Br J Ophthalmol 2006;90: 262–267. 23. Synek S, Veselý P. Intravitreal Bevacizumab with or without triamcinolone for refractory diabetic macular oedema. Coll Antropol 2011;35:841–845.
24. Zhang Y, Ma J, Meng N, et al. Comparison of intravitreal triamcinolone acetonide with intravitreal bevacizumab for treatment of diabetic macular edema: a meta-analysis. Curr Eye Res 2013;38:578–587. 25. Ahmadieh H, Ramezani A, Shoeibi N, et al. Intravitreal bevacizumab with or without triamcinolone for refractory diabetic macular edema; a placebo-controlled, randomized clinical trial. Graefes Arch Clin Exp Ophthalmol 2008;246:483–489. 26. Lim JW, Lee HK, Shin MC. Comparison of intravitreal bevacizumab alone or combined with triamcinolone versus triamcinolone in diabetic macular edema: a randomized clinical trial. Ophthalmologica 2012;227:100–106. 27. Wehrli S, Tawse K, Levin M, et al. A lack of delayed intraocular pressure elevation in patients treated with intravitreal injection of bevacizumab and ranibizumab. Retina 2012;32: 1295–1301. 28. Bakri SJ, Moshfeghi DM, Francom S, et al. Intraocular pressure in eyes receiving monthly ranibizumab in 2 pivotal agerelated macular degeneration clinical trials. Ophthalmology 2014;121:1102–1108.
D
particularly that a very small dose is administered intravitreally (1/400th of the intravenous dose).7 The ocular side effects include intraocular inflammation, intraocular hemorrhage, infectious endophthalmitis, and retinal detachment.8,9 Persistent/sustained ocular hypertension has been recently reported as a potential ocular side effect of intravitreal anti-VEGF injections in patients with NVAMD.10–14 The incidence has been reported to vary from approximately 3% to 10% (6% on average).12,13,15–17 However, the mechanism of the sustained elevation in intraocular pressure (IOP) remains speculative. It is believed that the cause of IOP elevation is injection related rather than disease related. Some attempt to explain this phenomenon based on inflammatory response,14 direct toxic effect of anti-VEGF agents
iabetic macular edema (DME) is the most common cause of visual loss in patients with diabetic retinopathy. For a long time, the only treatment available was macular laser treatment.1 More recently, several clinical trials have proven the superiority of antivascular endothelial growth factor (anti-VEGF) agents to laser therapy in the case of center-involved DME.2–4 Anti-VEGF injections are also the mainstay of treatment for neovascular age-related macular degeneration (NVAMD).5,6 Although intravitreal anti-VEGF injections have potential ocular and systemic side effects and all studies using intravitreal anti-VEGF agents so far have not been powered enough to assess the systemic safety of their use, it seems from the world-wide experience that the systemic side effects are rare,
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to the trabecular meshwork (TM),18 subvisible silicone oil leashed from the syringes,19 and/or the volume associated with repeated injections, which may induce damage to the drainage outflow.12 As all the cases of IOP elevation reported, to date, have been in the setting of NVAMD, a condition that typically affects the aged population (older than 65 years) that is inherently susceptible to IOP elevation and glaucoma,10–14 documenting the occurrence of sustained IOP elevation after intravitreal anti-VEGF injections in conditions other than NVAMD, particularly if the population studied is considerably younger than that of NVAMD, lends more support to the hypothesis that the injections themselves are causative and minimizes the confounding effects of NVAMD and age. Furthermore, although the occurrence of sustained IOP elevation after intravitreal anti-VEGF agents is believed to be real, further retrospective comparative studies or prospective studies are needed to provide higher level evidence for such an association. In this study, we aim to investigate whether intravitreal anti-VEGF injections are associated with persistent elevation of IOP in a population of patients with DME that is relatively younger than the NVAMD patient populations that have been previously reported.10–14 The risk factors for IOP elevation after intravitreal anti-VEGF therapy will also be investigated. The findings of this study may shed light on the pathogenesis of IOP elevation after intravitreal injections of these agents. Methods The study was performed at King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia, after approval by the institutional review board. We retrospectively reviewed the medical records of patients with DME treated with a single or multiple intravitreal antiVEGF injections during the period from 2007 to 2011. To be included in the study, patients had to have received at least a single intravitreal injection of bevacizumab (Avastin; Genentech, Inc, South San From the *Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; †Research Department, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia; ‡Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia; and §Department of Ophthalmology, University of Virginia, Charlottesville, Virginia. Scientific poster presentation at the annual meeting of The American Academy of Ophthalmology (AAO), New Orleans, LA, November 16–19, 2013. None of the authors have any conflicting interests to disclose. A. A. Al-Abdullah and S. R. Nowilaty equally contributed to this article. Reprint requests: Nicola G. Ghazi, MD, Vitreoretinal Division, King Khaled Eye Specialist Hospital, Al-Oruba Street, P.O., Box 7191, Riyadh 11462, Saudi Arabia; e-mail: [email protected]
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Francisco, CA) or ranibizumab (Lucentis; Genentech, Inc, South San Francisco, CA) with at least 1 month follow-up after the first injection. Patients were excluded from this study if they had incomplete records, intravitreal steroid in the same eye within 6 months from initiation of the anti-VEGF therapy, a history of glaucoma, past or current neovascularization of the angle or iris, or a paracentesis before or after the anti-VEGF agent injection. Patients with glaucoma were excluded from the study to avoid the confounding effect of preexisting glaucoma on the trajectory of IOP after intravitreal injection. The bevacizumab syringes were prepared in the hospital’s pharmacy. Bevacizumab was withdrawn from its original vial into insulin syringes under sterile conditions according to techniques described elsewhere.20 Thioglycollate broth was used to randomly culture two syringes, and cultures had to be negative before allowing the prepared batch of syringes to be dispensed. Each batch was used before its shelf life (2 weeks) was due. The intravitreal injection technique was similar for all eyes. Eyes received 0.05 mL injection containing either 1.25 mg of bevacizumab or 0.5 mg of ranibizumab. Before the injection, povidone–iodine 5% was applied over the eyelids and instilled into the conjunctival sac. Using a sterile ophthalmic lid speculum and topical anesthesia, the intravitreal injection was given using a 30-gauge needle, generally at a superotemporal site 3.5 mm to 4 mm posterior to the limbus. No IOPlowering agents were administered before or after injection. Anterior chamber paracentesis was not performed in any of the eyes included in this study. The interval between injections was no less than 4 weeks. The data collected from each patient included age, gender, ethnicity, medical and ocular history, family history of glaucoma, presenting visual acuity, lens status, stage of diabetic retinopathy, baseline and posttreatment IOP levels, type of intravitreal medication used, the number of injections, the interval between injections, the length of follow-up, and associated complications. The IOP was measured using applanation tonometry in all our patients, and the baseline (before treatment) IOP was defined as the IOP recorded before the first anti-VEGF injection. When more than one pretreatment IOP reading was available, baseline IOP was calculated as the mean of the available pretreatment IOP readings (up to a maximum of three last IOP readings). During follow-up visits, eyes were considered to have IOP elevation if they met any of the following criteria: 1) an IOP rise to .24 mmHg, 2) an increase of 6 mmHg or more from baseline IOP, and/ or 3) a 20% rise from baseline IOP. Postinjection IOP elevation was also classified into persistent or
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transient. Persistent IOP elevation was defined as a rise meeting any of the above criteria that persisted throughout follow-up. Transient IOP elevation was defined as an elevation of IOP from baseline that met any of the above-mentioned criteria for at least two consecutive visits but that returned to baseline afterward without treatment. Immediate same-day IOP measurement was not included in this study, as this is not routinely performed in our clinics, and also as assessing immediate transient IOP elevation, which is expected to occur in all injected eyes immediately after injection, is not the aim of this study. Statistical Analysis All data were entered into an Excel spreadsheet. Patients with IOP elevation were identified. The mean and median IOP levels and the proportion of patients with IOP elevation (as defined above) after intravitreal injections were analyzed. The main outcome measure was the proportion of eyes with IOP elevation after intravitreal anti-VEGF injections. The Chi-square test was used to study associations between elevated IOP, whether persistent or transient, categorical variables (diabetic retinopathy grade and lens status), and dichotomous variables (interval between injections more or less than 2 months, gender, and nonproliferative or proliferative stage of diabetic retinopathy). The t-test or the Mann–Whitney test, when appropriate, was used to analyze the mean differences in continuous variables (age, number of bevacizumab injections, number of ranibizumab injections, total number of injections, IOP at baseline, and intervals between injections). In addition, the eyes were divided into 4 groups: 1) those with persistent IOP elevation (persistent IOP elevation group), 2) those with transient IOP elevation (transient IOP elevation group), 3) all eyes that exhibited either transient or persistent IOP elevation (any IOP elevation group), and 4) eyes that did not demonstrate any rise in IOP throughout follow-up (no IOP elevation group). The four groups were compared in terms of baseline characteristics, baseline IOP, final IOP, number of injections per eye, and interval between injections. All P-values were 2-sided, and statistical significance was defined as P , 0.05. Results A total of 486 patients were included in this study (Table 1). Their mean age was 60.73 years (range, 22– 94; SD, 10.54; median, 61). Three hundred and twenty-six patients (67.1%) were men. The mean duration of diabetes mellitus was 14.03 years (SD, 8.05),
Table 1. Patients’ Baseline and Injection-Related Characteristics Number of patients (%) 486 (100) Number of eyes (%) 760 (100) Age, median (IQR) 61 (54–68) Gender, male (%) 326 (67.1) Duration of DM, mean (SD), years 14.03 (8.05) Patients on insulin (%) 243 (50) Patients with arterial hypertension (%) 178 (36.6) Eyes with NPDR (%) 604 (79.5) Eyes with prior macular laser (%) 340 (44.7) Eyes with prior PRP (%) 276 (36.3) Eyes with pseudophakia (%) 224 (29.5) Baseline IOP, mean (SD), mmHg 17.2 (3.2) Baseline IOP, median (IQR), mmHg 17 (15–19) Last IOP, mean (SD), mmHg 17.47 (3.5) Total injections per eye, mean (SD) 3.38 (2.33) Interval between injections, mean (SD), 4.8 (4.93) months Eyes with injection interval #60 days (%) 173 (22.8) Eyes that received ,3 injections (%) 314 (41.3) Follow-up, mean (SD), months 17.89 (11.58) Eyes with follow-up .4 months (%) 652 (87.8) IQR, interquartile range; NPDR, nonproliferative diabetic retinopathy; PRP, panretinal photocoagulation.
and 50% of the patients were on insulin therapy. The number of eyes that met the inclusion criteria of the study was 760, among which 224 eyes (29.5%) were pseudophakic and 604 eyes (79.5%) had nonproliferative diabetic retinopathy. The mean and median baseline IOP for the entire group of eyes before initiation of intravitreal injections was 17.2 mmHg and 17 mmHg, respectively (Table 1). The total number of injections performed was 2,566, including 2,338 bevacizumab injections and 228 ranibizumab injections. Of the 760 eyes, 672 (88.42%) received bevacizumab alone, 4 eyes (0.53%) received ranibizumab alone, and 84 eyes (11.05%) received both bevacizumab and ranibizumab (Table 2). The mean number of injections per eye was 3.38 injections (range, 1–24; SD, 2.33), and 314 of the 760 eyes (41.3%) received ,3 injections. The interval between injections was #2 months in 173 eyes (22.8%). The mean followup was 17.9 months (range, 1–68; SD, 11.58), with 652 eyes (87.8%) completing at least 4 months of follow-up (Table 1). Table 2. Distribution of Anti-VEFG Injections and the Rate of Persistent IOP Elevation Anti-VEGF Agent Bevacizumab Ranibizumab Both Total
Number of Eyes (%) 672 4 84 760
(88.42) (0.53) (11.05) (100)
Eyes With Persistent IOP Elevation (%) 32/672 (4.76) 0/4 (0) 12/84 (14.29) 44/760 (5.79)
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of injections was higher in eyes that developed transient IOP elevation and in those that exhibited persistent IOP elevation compared with the group of eyes with no IOP elevation (P , 0.001 for both) (Table 4). There was no statistical difference, however, when the number of injections in the persistent IOP elevation group was compared with that in the transient IOP elevation group (P = 0.66) (Table 4). The mean interval between injections was 3.26 months (range, 1–7.8; SD, 1.7) in the persistent IOP elevation group, 3.8 months (range, 1.2–12.9; SD, 2.7) in the transient IOP elevation group, 3.6 months (range, 1–12.9; SD, 2.4) in the any IOP elevation group, and 5.03 (range, 1–31.3; SD, 5.27) in the no IOP elevation group. Although a shorter interval between injections was noted in the group with persistent IOP elevation (3.26 months) compared with the group with no IOP elevation (5.03 months), this difference did not reach statistical significance (P = 0.54) (Table 4). Of note is that the three groups (persistent IOP elevation, transient IOP elevation, and no IOP elevation) were balanced with respect to baseline characteristics with the exception of two factors: the duration of diabetes mellitus, which was statistically significantly different between the transient and persistent IOP elevation groups (P = 0.038, Table 4), and the baseline IOP. A significant difference in the baseline IOP was in fact found among the 3 groups with a higher mean baseline IOP in the no IOP elevation group (mean, 17.54 mmHg; SD, 3.23) compared with both the persistent IOP elevation group (mean, 16.33 mmHg; SD, 2.09; P = 0.003) and the transient IOP elevation group (mean, 16.21 mmHg; SD, 2.7; P = 0.003) (Table 4). Despite this, the final IOP was significantly higher in the persistent IOP elevation group (mean, 21.03 mmHg; SD, 3.31) compared with both the no IOP elevation group (P , 0.001) and the transient IOP elevation group (P , 0.001). None of the patients required surgery, laser therapy, or systemic medications to control the IOP elevation. Only 3 patients were initiated on topical IOP-lowering agents for IOP levels of 41, 29 and 26 mmHg, respectively.
Based on the study criteria, a total of 97 eyes of 79 patients developed IOP elevation (12.76%) during follow-up. Transient IOP elevation was recorded in 53 of these 97 eyes (6.97% of the total cohort), whereas 44 eyes (5.79% of the total cohort) developed persistent IOP elevation (Tables 2 and 3). Persistent IOP elevation developed in 32 of the 672 eyes (4.76%), which received intravitreal bevacizumab alone, in none of the 4 eyes (0%), which received intravitreal ranibizumab alone, and in 12 of the 84 eyes (14.29%), which received intravitreal bevacizumab and ranibizumab during the course of treatment. Of the 274 patients who received bilateral injections, 29 (10.6%) patients developed persistent IOP elevation in at least 1 eye as follows: 8 (2.9%) developed persistent IOP elevation in both eyes, 6 (2.2%) developed persistent IOP elevation in 1 eye and transient elevation in the fellow eye, and 15 (5.5%) developed persistent elevation in 1 eye and no IOP elevation in their fellow eye. The remaining 245 patients (89.4%) did not develop persistent IOP elevation after bilateral injections. The mean interval between the first anti-VEGF injection and IOP elevation was 8.93 months (range, 1–26; SD, 6.73; median, 7) in the persistent IOP elevation group and 6.53 months in the transient IOP elevation group (range, 1–28; SD, 5.61; median, 4; P = 0.07). Furthermore, IOP elevation was first noted after a mean number of 3.61 injections (range, 1–12; SD, 2.63) in the persistent IOP elevation group and after a mean of 2.57 injections (range, 1–13; SD, 2.05) in the transient IOP elevation group (P = 0.032). Elevated IOPs ranged from 20 mmHg to 41 mmHg, with a mean IOP of 23.93 (SD, 4.77). The mean number of injections per eye was 5.45 (range, 2–14; SD, 3.06) in the persistent IOP elevation group, 5.08 injections (range, 2–24; SD, 3.27) in the transient IOP elevation group, 5.2 injections (range, 2– 24; SD, 3.2) in the any IOP elevation group, and 3.83 (range, 2–12; SD, 1.91) in the no IOP elevation group (Table 4). The total number of injections was found to be higher in the persistent IOP elevation group compared with the group that did not develop any IOP elevation (P , 0.001) (Table 4). Similarly, the number
Table 3. Rate of IOP Elevation According to the Study Criteria Specific Criteria IOP elevation to .24 mmHg $6 mmHg elevation from baseline IOP 20% elevation from baseline IOP $6 mmHg elevation or .24 mmHg only Total number with IOP elevation
Persistent IOP Elevation (%) 7 6 31 13 44
eyes eyes eyes eyes eyes
(0.92) (0.79) (4.08) (1.71) (5.79)
Transient IOP Elevation (%) 5 4 44 9 53
eyes eyes eyes eyes eyes
(0.66) (0.53) (5.79) (1.18) (6.97)
0.089 0.002 0.001 0.24 17 (11.75) 21.5 (10.2) 18.5 (10.64)
20.1 (10.5)
0.089 0.73 0.959 0.55 5.0 (5.27) 3.8 (2.7) 3.3 (1.7)
3.6 (2.4)
,0.001 0.66 ,0.001 ,0.001 0.174 ,0.001 17.8 (2.9) 5.08 (3.27) 21 (3.3) 5.45 (3.06)
19.3 (3.5) 5.20 (3.2)
17.4 (3.5) 3.83 (1.91)
,0.001 ,0.001
0.82 ,0.001 0.01 16.2 (3.7) 16.3 (2)
16.3 (2.7)
17.5 (3.2)
0.003
— — 0.45 0.038 — — 0.245 0.293 — — 0.676 0.096 — — 0.71 0.94 407 663 61 (10.8) 13.9 (6) 79 97 60.4 (10.3) 15.8 (6.7) 49 53 60 (7.7) 17.7 (7) 36 44 60.8 (12.7) 13.8 (8.2)
Number of patients Number of eyes Mean age (SD), years Mean duration of diabetes (SD), years Mean baseline IOP (SD), mmHg Mean last IOP (SD), mmHg Mean total number of injections per eye (SD) Mean interval between injections (SD), months Mean follow-up (SD), months
Persistent IOP Elevation (P)
Transient IOP Elevation (T)
Persistent and Transient IOP Elevation (PT)
No IOP P Value (P P Value (T P Value (PT P Value (P Elevation (N) vs. N) vs. N) vs. N) vs. T)
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 3
Factor
Table 4. Comparison Between Eyes With Persistent IOP Elevation (P), Transient IOP Elevation (T), Combined Persistent and Transient IOP Elevation (PT), and No IOP Elevation (N)
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Discussion To the best of our knowledge, this retrospective study is the only study that exclusively addresses IOP trends after intravitreal bevacizumab and/or ranibizumab injections in eyes with DME. Many retrospective studies and case series have reported the occurrence and prevalence of IOP elevation in NVAMD after such treatment.10–17,21 Diabetic macular edema is the most common indication for intravitreal anti-VEGF therapy in our institution; therefore, it was intriguing to assess whether IOP elevation after such therapy is an issue in DME patients as has been reported for NVAMD. One main difference between patients with NVAMD and DME is age at presentation, which was clearly lower in this study compared with that in previous NVAMD reports. For example, the mean age in this study was 60.7 years (SD, 10.54) compared with the study by Choi et al16 who reported a mean age of 81 years (SD, 10) in their patients with NVAMD. As age is a significant risk factor for IOP elevation and open-angle glaucoma,22 a careful analysis of the confounding effect of age on the incidence of IOP elevation after anti-VEGF therapy should be undertaken particularly in an elderly population like patients with NVAMD. Few published studies23–26 reported limited data regarding IOP elevation after intravitreal bevacizumab therapy for DME as part of a comparison between intravitreal bevacizumab and intravitreal triamcinolone with or without intravitreal bevacizumab. Three of these studies23–25 had a very short follow-up of 12 weeks to 24 weeks, and 2 looked at the effect of either a single24 or only 226 injections of intravitreal bevacizumab. In addition, some of these studies had only few patients in the intravitreal bevacizumab treatment group.23,25,26 The limitations inherent to the design of these studies, including a short-term follow-up, a limited number of intravitreal bevacizumab injections, and a small number of patients included in some, do not allow for meaningful conclusions regarding the long-term effect of multiple intravitreal bevacizumab injections on the IOP in eyes with DME. Careful analysis of our data disclosed that most of the eyes developed transient rather than persistent IOP elevation after intravitreal injections. Moreover, most of the eyes that developed persistent IOP elevation (31 of 44 or 70.4%) met the inclusion criteria of a 20% elevation from baseline IOP. This is a very inclusive criterion that may include eyes that had, for example, a rise from 10 mmHg at baseline to 12 mmHg. If one were to consider eyes with more restrictive criteria of IOP elevation such as an IOP rise to more than
IOP TRENDS AFTER ANTI-VEGF IN DME AL-ABDULLAH ET AL
24 mmHg or an increase of 6 mmHg or more from baseline, then only 13 of 760 eyes (1.71%) would have been included in the IOP elevation group (Table 3). In addition, only three patients were started on a topical IOP-lowering agent to control the IOP. None of the eyes required any intervention by laser or surgery to control the IOP elevation. Therefore, our findings suggest that the majority of eyes with DME and IOP elevation after intravitreal anti-VEGF injections experience a transient form of IOP elevation that requires no treatment. In addition, even when the elevation is persistent, the majority of the eyes experience only mild forms of IOP elevation, whereas significant IOP elevations are experienced in ,2% of the eyes. In fact, such low level of IOP elevation was shown in a recent case–control study in NVAMD by Wehrli et al27 who compared the incidence of IOP elevation in eyes with NVAMD that received bevacizumab and/or ranibizumab with control eyes that did not receive either. They found that the incidence by eye-year was 0.51% (3 of 270) and 1% (4 of 195) in anti-VEGF treated eyes versus control eyes, respectively. This was much lower than the previously reported rates of IOP elevation in the other 5 retrospective studies in patients with NVAMD that ranged from 3.45% to 11.6%12,13,15–17 (Table 5). The findings of this study and that of Wehrli et al27 support the possibility that age may be a confounding factor in the association between IOP elevation and intravitreal injections in patients with NVAMD. The disparity between the rate of IOP elevation in patients with DME and NVAMD after anti-VEGF therapy can also be explained by the differences in the number of injections received. The mean number of injections in this study was 3.38 (SD, 2.3 injections) compared with a much higher number in patients with NVAMD, such as in the retrospective study by Good et al13 who reported a median of 9 injections per eye (range, 1–30 injections). In this study, we showed an association between the number of anti-VEGF injections and IOP elevation. Similarly, Tseng et al21 and Hoang et al15 showed an association between the total number of injections and IOP elevation. In the latter study,15 the odds ratio of experiencing the IOP elevation was higher in patients receiving 29 or more injections compared with those receiving 12 or less injections (5.75; 95% CI, 1.19– 27.8; P = 0.03). However, such an association remains controversial. For example, Choi et al16 in a retrospective review of 155 eyes showed no association between the number of injections and IOP elevation .25 mmHg. In another most recent study,28 addressing IOP elevation after intravitreal ranibizumab in two clinical trials of patients with AMD, more ranibizumab-treated eyes had IOP
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increase from baseline compared with sham or photodynamic therapy–treated eyes. Interestingly, the IOP increase did not seem to be related to the number of injections. Perhaps, the number of patients included and the proportion that sustains IOP elevation among a cohort influences the statistical power to detect an association between IOP elevation and the number of injections administered. If the total number of injections per eye were truly a risk factor for IOP elevation, then the low rate of persistent IOP elevation noted in this study may be at least partly explained by the low number of injections received per eye (mean, 3.38 injections). This may be a reflection of the “real-world scenario” where it is difficult to follow-up and treat patients with diabetes every month knowing the busy clinical schedule such patients have due to their multiple comorbidities. Therefore, the risk of significant IOP elevation in this population seems to be relatively low and reassuring. Mathalone et al17 identified an association between IOP elevation and an interval between anti-VEGF injections of less than 8 weeks. In this study, the interval between injections was not associated with IOP elevation. Likewise, Good et al13 and Hoang et al15 reported no correlation between IOP elevation and the interval between anti-VEGF injections. Similarly, Choi et al16 demonstrated no relationship between the frequency of injections that an eye received and any progressive changes in its IOP measurements. The specific intravitreal medication used may also play a role in IOP elevation after therapy. For example, one study reported that the rate of IOP rise was 3 times higher after bevacizumab injections compared with ranibizumab alone with a rate of 9.9% and 3.1%, respectively.13 A possible mechanism of IOP elevation is a direct toxicity of anti-VEGF agents on the TM. A study by Kahook and Ammar18 on cultured human TM showed that only bevacizumab is toxic to the TM when used at four times the concentration of the clinical dose. Ranibizumab, however, did not cause any toxicity to the TM even at very high doses. In this study, only 4 eyes received ranibizumab alone and none of these eyes developed elevated IOP. The small number of ranibizumab injections in our cohort prohibits any meaningful conclusions in this regard. However, in this study, the rate of persistent IOP elevation was noted to be higher in the group that received both agents, ranibizumab and bevacizumab (12/84 [14.29%]), compared with the group that received bevacizumab alone (32/672 [4.76%]). In addition, the packaging technique of the medication used may play a role in IOP elevation. Good et al13 found that 9 of 10 eyes with elevated IOP received their bevacizumab in one center. The center with higher rate
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Author
Adelman et al12
Mean age (SD), years Total number of cases
83 in the IOP rise group 116 patients
Rate of IOP elevation
3.45%
Sustained versus transient IOP elevation Agents IOP (mmHg)*
NA
B and/or R Range, 28–36
Number of 3–19 injections, range* Interval between Mean, 4–6 injections* weeks Study criteria for IOP .21 IOP elevation mmHg on 2 separate visits
Good et al13
Choi et al16
Hoang et al15
Mathalone et al17
77 (8.5)
81 (10)
79
215 eyes
127 patients (155 eyes)
207 treated eyes, 174 patients (201 eyes) 207 fellow eyes (controls) Treated: 11.6%, 11% untreated: 5.3%
Overall: 6%; B: 9.9%; Overall: 9.4%; R: 3.1% sustained: 5.5% Sustained: 6%, transient: 8.4% B and/or R Range, 23–36; mean, 29.2 IQR, 6–13.7 Mean, 81.3 days
B, R, or P Range, 11–39; mean, 20 3.4–9.7 per year
Mean, 52 days (calculated) IOP $22 mmHg IOP .25 mmHg lasting $30 days on on 2 visits $2 separate visits requiring and a change of .6 glaucoma medication or mmHg from surgery baseline IOP
79 (8.3)
NA
NA
B and/or R NM
B Range, 22–36; mean 25.9 3–18
9–39 Mean, 7.5 weeks (calculated) IOP elevation .5 mmHg from baseline on $2 consecutive visits
*Data shown for the group of eyes that exhibited sustained IOP elevation. B, bevacizumab; IQR, interquartile range; NA, information not available; P, pagabtanib; R, ranibizumab.
Wehrli et al27 75.2
60.7 (10.5)
302 treated eyes, 226 control eyes
486 patients (760 eyes)
Overall 12.8% Treated: 0.51% per eye-year, untreated: 1% per eye-year NA Sustained: 5.8% (with stricter criteria, 1.71%), transient: 7% B and/or R B and/or R Range, 25–60 Range, 20–41; mean, 23.9 NA 2–14 (mean, 5.45)
Median, 7 weeks Mean, 54 days IOP $22 mmHg and a change of $6 mmHg from baseline IOP on $2 consecutive visits and lasting $30 days
Current Study
IOP $22 mmHg on 2 consecutive visits with .6 mmHg increase from baseline IOP or IOP .26 mmHg on 1 visit requiring IOPlowering therapy
Mean, 90 days IOP .24 mmHg or $6 mmHg increase from baseline IOP or .20% increase from baseline IOP
RETINA, THE JOURNAL OF RETINAL AND VITREOUS DISEASES 2015 VOLUME 35 NUMBER 3
Table 5. Comparison of Retrospective Series Addressing IOP Increase After Intravitreal Injections of VEGF Antagonists
IOP TRENDS AFTER ANTI-VEGF IN DME AL-ABDULLAH ET AL
of IOP elevation obtained prepackaged bevacizumab from an outside pharmacy that stores and transports bevacizumab in plastic syringes. In contrast, the other center used bevacizumab obtained from an original vial available on site before injection. Based on these findings, Good et al and others proposed that transportation and storage of bevacizumab in plastic syringes coated with silicone may result in leashing of silicone particles into the drug solution that could, in turn, obstruct the TM after injection into the eye.19 Another speculative mechanism for the IOP rise after anti-VEGF agents is that proteins like bevacizumab and ranibizumab may produce secondary inflammation and trabeculitis with subsequent compromise in the TM function. In this study, no inflammation was noted after anti-VEGF injections. Similarly, apart from one case report of a single patient who developed white deposits over the TM,14 none of the previous reports implicated this factor as a mechanism for IOP elevation after such treatment. Tseng et al21 suggested that sustained IOP elevation could be related to the repeated transient IOP spikes related to the volume of the drug injected, which eventually alters the aqueous outflow pathways. Adelman et al12 reported that a disrupted posterior capsule in pseudophakic eyes might be associated with IOP elevation after intravitreal anti-VEGF therapy. In this study, 2 of 10 eyes with capsulotomy developed persistent IOP elevation after treatment. To date, the exact mechanism of sustained IOP elevation after intravitreal anti-VEGF injections remains speculative. In summary, despite the limitations of this study, including its retrospective nature, lack of a control group, variations in baseline characteristics between groups such as duration of diabetes (the value of which remains unknown) (Table 4), and absence of gonioscopic documentation of the angle in most of our patients, the results suggest that the rate of significant and persistent IOP elevation in patients with DME after intravitreal anti-VEGF injections is less than that published for the NVAMD population. Although the reasons for that may be multiple, age and the number of injections received per eye may be important variables behind this disparity. Although further studies are needed to confirm whether such an association even exists at all, especially knowing the apparent low rate seen in this study, clinicians should be aware of the potential for IOP elevation after intravitreal antiVEGF therapy in eyes with DME, particularly when the patients require a higher number of injections. Further prospective comparative studies are needed to address several questions that remain unanswered in this topic.
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