Vascular Changes in Eyes Treated with Dexamethasone Intravitreal Implant for Macular Edema after Retinal Vein Occlusion SriniVas Sadda, MD,1 Ronald P. Danis, MD,2 Rajeev R. Pappuru, MD,3 Pearse A. Keane, MD,4 Jenny Jiao, PhD,5 Xiao-Yan Li, MD,6 Scott M. Whitcup, MD7 Objective: To evaluate the angiographic findings in eyes from 2 clinical trials of the dexamethasone intravitreal implant (DEX implant) 0.7 mg in the treatment of macular edema (ME) after branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO). Design: Post hoc analysis of pooled data from 2 identical phase 3 clinical trials. Participants: Patients with vision loss as a result of ME (ⱖ6 weeks’ duration) after BRVO or CRVO for whom angiographic data were available (n ⫽ 329 eyes). Methods: Fluorescein angiography (FA) results assessed by masked, certified graders using standardized grading protocols. Main Outcome Measures: The primary outcome measure in the parent studies was change from baseline in best-corrected visual acuity. Prospectively defined secondary outcomes included FA measurements (to assess macular capillary leakage, neovascularization, and nonperfusion) and optical coherence tomography results (to assess central retinal thickness [CRT]). Results: At baseline, 42% of eyes in the DEX implant group and 38% of eyes in the sham group had unreadable assessments because of hemorrhage. At day 180, significantly fewer DEX implant–treated eyes (2%) than sham-treated eyes (9%) had unreadable assessments because of hemorrhage (P ⫽ 0.029). Among eyes with gradable assessments, the incidence of nonperfusion remained fairly steady from baseline to day 180. The proportion of eyes with active neovascularization increased from baseline to day 180 in the sham group, but stayed relatively constant in the DEX implant group (P ⫽ 0.026 for DEX vs. sham). The mean area of overall nonperfusion and the mean area of macular capillary nonperfusion increased from baseline to day 180 in both treatment groups (no statistically significant between-group difference). There was a statistically significant positive correlation between changes in macular leakage and changes in CRT in both the DEX implant group (r ⫽ 0.22; 95% confidence interval, 0.03– 0.40; P ⫽ 0.023) and the sham group (r ⫽ 0.29; 95% confidence interval, 0.10 – 0.46; P ⫽ 0.003). Conclusions: This study demonstrated that the clinical improvements observed with the DEX implant were accompanied by significant improvements in vascular parameters and suggests that treatment with the DEX implant may be associated with some clinically significant improvements in angiographic findings, specifically active neovascularization. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references. Ophthalmology 2013;xx:xxx © 2013 by the American Academy of Ophthalmology. Macular edema (ME) is a leading cause of vision loss in a variety of ocular disorders, including diabetic retinopathy1 and retinal vein occlusion (RVO).2,3 The mechanism by which ME affects vision is multifactorial and has been incompletely characterized but likely results from the interaction of vascular abnormalities and inflammatory processes.4 – 6 Vascular abnormalities may include, but likely are not limited to, increased vascular permeability and a breakdown of the blood–retina barrier.4,5 Very little is known about how treatment may impact these abnormalities and © 2013 by the American Academy of Ophthalmology Published by Elsevier Inc. other vascular changes in RVO or how vascular changes may correlate with anatomic changes in eyes being treated for RVO. Dexamethasone intravitreal implant 0.7 mg (DEX implant 0.7 mg; Ozurdex; Allergan, Inc., Irvine, CA) has been shown in 2 multicenter, randomized, sham-controlled clinical trials to reduce ME and to improve visual acuity in patients with either branch RVO (BRVO) or central RVO (CRVO).7,8 The purpose of this study was to evaluate the angiographic findings before and after treatment with the ISSN 0161-6420/13/$–see front matter http://dx.doi.org/10.1016/j.ophtha.2012.12.021 1 Ophthalmology Volume xx, Number x, Month 2013 DEX implant 0.7 mg or sham in the subset of eyes with available angiographic data in the Global Evaluation of implaNtable dExamethasone in retinal Vein occlusion with macular edemA (GENEVA) trials. Patients and Methods The data for these analyses were drawn from a subset of patients from 2 identical, prospective, multicenter, phase 3 clinical studies of the safety and efficacy of the DEX implant 0.7 mg in the treatment of ME associated with BRVO or CRVO: the GENEVA trials (registered at ClinicalTrials.gov as NCT00168324 and NCT00168298).7,8 Only patients with fluorescein angiography (FA) data were included in the present analyses. Each GENEVA trial consisted of a 6-month randomized, shamcontrolled, parallel-group, double-masked phase followed by a 6-month open-label extension in which all eligible eyes could be treated with the DEX implant. In this report, only data collected during the initial 6-month double-blind phase of the GENEVA trials were evaluated. Both trials were conducted in compliance with regulatory obligations, the tenets of the Declaration of Helsinki, and the institutional review board and informed consent regulations at each investigational site. The protocol for these studies has been described previously in detail7 and is summarized briefly in the following text. These studies enrolled adult patients who had decreased visual acuity as a result of clinically detectable ME associated with BRVO or CRVO. Disease duration was required to be between 6 weeks and 12 months in patients with BRVO and between 6 weeks and 9 months in patients with CRVO. Best-corrected visual acuity was required to be between 34 letters (20/200) and 68 letters (20/50) in the study eye and better than 34 letters in the nonstudy eye. Central retinal thickness (CRT), as measured by time-domain optical coherence tomography (OCT; StratusOCT 3; Carl Zeiss, Dublin, CA), was required to be 300 ␮m or more in the study eye. Key exclusion criteria for the GENEVA trials included the presence of the following: epiretinal membrane, active retinal or optic disc neovascularization, active or history of choroidal neovascularization, diabetic retinopathy in either eye, any active ocular infection at baseline, or any ocular condition in the study eye that, in the opinion of the investigator, would prevent a 15-letter improvement in visual acuity. Although FA was performed at baseline, no inclusion or exclusion criteria were based on these findings. At baseline, study eyes (1 per patient) were randomized either to a sham procedure or to treatment with the DEX implant 0.7 mg or 0.35 mg. In this report, only data from the sham and DEX implant 0.7 mg groups are evaluated; the DEX implant 0.35 mg is not commercially available, and thus the results are not relevant clinically. The primary outcome measure in the GENEVA trials was the change from baseline in best-corrected visual acuity. Prospectively defined secondary outcomes included the measurement of morphologic changes using OCT, color photography, and FA. The FA was performed at baseline and day 180 after each treatment, but no specific analyses of the FA data were defined prospectively in the protocol, and FA data were not submitted prospectively to a centralized reading center. The analyses presented in this article were conducted in a post hoc manner. Grading protocols for the FA data set were adapted from the Central Vein Occlusion Study Group, the Branch Vein Occlusion Study Group, and the Early Treatment of Diabetic Retinopathy clinical trials and were designed to provide qualitative and semiquantitative (i.e., nonplanimetric) assessments of angiographic end points. All reading center (Doheny Image Reading Center, Los Angeles, CA) assessments were conducted by certified graders 2 who were masked to study treatment and visit sequence (baseline vs. follow-up) and focused on several key areas: presence and extent of macular capillary leakage (in Macular Photocoagulation Study [MPS] disc areas within the Early Treatment Diabetic Retinopathy Study grid), presence of neovascularization, presence of active neovascularization (active being defined by the predominance of small preretinal vessels relative to fibrous tissue), presence and extent of global (peripheral and macular) nonperfusion (measured in approximated MPS disc areas using standardized reference circles), and the presence and severity of macular capillary nonperfusion. For this analysis, more than 10 MPS disc areas of global nonperfusion was defined to be evidence of an ischemic occlusion. Ten disc areas generally is accepted as the threshold for an increased risk of neovascular events in eyes with CRVO.9 Macular capillary nonperfusion was assessed in 3 subfields based on the Early Treatment Diabetic Retinopathy Study grid: the foveal central subfield, the middle ring, and the outer ring, each corresponding to a circle with a 500-, 1500-, and 3000-␮m radius in the fundus of an average eye, respectively (Fig 1, available at: http://aaojournal.org). The severity of macular capillary nonperfusion was graded using standardized photographs and the scale shown in Table 1 (available at: http://aaojournal.org). Eyes with extensive areas of dense hemorrhage obscuring vascular details were deemed to be ungradable for certain parameters. Statistical Analysis All eyes that received the DEX implant 0.7 mg or a sham procedure at baseline and had evaluable FA data were included in the analysis. These data were summarized with descriptive statistics. The Spearman correlation coefficient was used to assess the relationship between changes in CRT and both macular leakage and global nonperfusion. The confidence interval (CI) for the Spearman correlation coefficient was calculated using a Fisher transformation. Global nonperfusion rates were compared using the chisquare or Fisher exact test. The area of nonperfusion (in MPS disc areas) was compared using a t test. Effect of RVO type (BRVO vs. CRVO) on global nonperfusion and active neovascularization at day 180 was evaluated using logistic regression analysis, which included treatment group, age, and baseline nonperfusion status (for the nonperfusion variable only) as covariates. Odds ratios and the corresponding 95% CIs were calculated based on the logistic regression models. Statistical analyses were performed using Statistical Analysis Software version 9.2 (SAS, Inc., Cary, NC). Results Study Population At baseline, a total of 853 eyes were randomized to treatment with either the DEX implant 0.7 mg (n ⫽ 427) or a sham procedure (n ⫽ 426). Of these, 403 eyes from the DEX implant 0.7 mg group and 398 from the sham group completed day 180 of the study. Of 167 clinical sites participating in the GENEVA trials, 55 responded to the retrospective request to submit FA images and sent FA data to the reading center for assessment. The number of eyes for which any FA data were available included 166 treated with the DEX implant 0.7 mg and 163 eyes treated with the sham procedure. Approximately one half of the FA data set for reading center analysis was obtained on film. Demographic, systemic, and ocular differences between patients with FA data were compared with patients without FA data to identify any systematic differences between the reading center subset and the total study population (Table 2, available at: http://aaojournal.org). The demo- Sadda et al 䡠 Vascular Changes with Intravitreal DEX for RVO Table 3. Global (Peripheral and Macular) Nonperfusion* All Eyes Baseline Eyes with FA evaluation for global nonperfusion, no. Eyes with nongradable/nonevaluable data for global nonperfusion Eyes with gradable or evaluable data for global nonperfusion Eyes with no nonperfusion evident Eyes with nonperfusion evident Mean area of nonperfusion, MPS disc areas (SD) Day 180 Eyes with FA evaluation for global nonperfusion, no. Eyes with nongradable or nonevaluable data for global nonperfusion Eyes with gradable/evaluable data for global nonperfusion at day 180 Eyes with no nonperfusion evident Eyes with nonperfusion evident Mean area of nonperfusion, MPS disc areas (SD) Dexamethasone Intravitreal Implant 0.7 mg Sham 157 71 (45) 86 (55) 12 (14) 74 (86) 3.62 (5.62) 160 69 (43) 91 (57) 12 (13) 79 (87) 3.32 (6.16) 149 13 (9) 136 (91) 14 (10) 122 (90) 5.93 (7.36) 146 27 (18) 119 (82) 16 (13) 103 (87) 5.08 (8.53) P Value† ⬎0.999 0.754 0.444 0.424 FA ⫽ fluorescein angiography; MPS ⫽ Macular Photocoagulation Study; SD ⫽ standard deviation. *Percentages may not sum to 100% because of rounding. † P values are based on the Fisher exact test for proportion of patients with nonperfusion and t test for disc area. Values are shown as n (%) unless otherwise indicated. graphics and disease characteristics for these 2 populations were very similar: mean age was approximately 64 years, approximately two thirds of patients had BRVO, and mean visual acuity was approximately 54 letters. Global Vascular Changes At baseline, 54 of 129 eyes (42%) in the DEX implant 0.7 mg group and 48 of 126 eyes (38%) in the sham group had unreadable assessments because of hemorrhage (based on those eyes with FA data for both baseline and day 180). The number of unreadable images decreased during the course of the study in both groups, which is consistent with the resolution of intraretinal hemorrhages. At day 180, significantly fewer DEX implant–treated eyes (3/129; 2%) than sham-treated eyes (11/126; 9%) had unreadable assessments because of hemorrhage (P ⫽ 0.029). An example of the typical appearance and resolution of retinal hemorrhage in a representative patient at baseline and day 180 is shown in Figure 2 (available at: http://aaojournal.org). At baseline, the proportion of eyes with gradable assessments (obtained by subtracting those eyes that were ungradable for any reason, including hemorrhage) was 55% (86/157) in the DEX implant group and 57% (91/160) in the sham group. This increased to 91% (136/157) in the DEX implant group and 82% (119/160) in the sham group at day 180 (Table 3). The proportion of eyes with gradable assessments at baseline was higher among eyes with CRVO (70%; 83/119) than among those with BRVO (47%; 94/ 198; Table 4). Among eyes with gradable assessments, the incidence of nonperfusion remained fairly steady between baseline and day 180 (increasing from 86% to 90% in the DEX implant 0.7 mg group and remaining at 87% in the sham group; Table 3). At day 180, the proportion of evaluable eyes with nonperfusion was similar in the DEX implant–treated eyes (90%) and the sham-treated eyes (87%; P ⫽ 0.444). Similar results were found when eyes with BRVO or CRVO were evaluated separately (Table 4). The likelihood of global (i.e., peripheral and macular) nonperfusion at day 180 was not affected by the presence of intraretinal hemorrhage at baseline. The mean area of nonperfusion increased from baseline to day 180 in both the sham and DEX implant groups. At day 180, the mean ⫾ standard deviation area of nonperfusion was slightly larger in the DEX implant group (5.93⫾7.36 MPS disc areas) than in the sham group (5.08⫾8.53 MPS disc areas), but this difference was not statistically significant (P ⫽ 0.424). At baseline, the mean area of nonperfusion was lower in eyes with CRVO (1.42–1.65 MPS disc areas) than BRVO (4.82–5.37 MPS disc areas; Table 4). Across all groups, only 5.1% of eyes (16 of 317 eyes with global nonperfusion data at baseline) had more than 10 MPS disc areas of nonperfusion at baseline (data not shown). Changes in nonperfusion also were evaluated for the subset of eyes that had gradable assessments at both baseline and day 180 (Table 5). The results of this analysis confirmed that there was very little change from baseline to day 180 in either the incidence of nonperfusion or the mean area of nonperfusion and that there was no significant difference in these findings between the 2 treatment groups. This subgroup was not divided into CRVO and BRVO populations for further analysis because of the small sample size. As expected, a small percentage of eyes with RVO became ischemic (defined as ⬎10 MPS disc areas of nonperfusion) during the course of the study (Table 6). However, the precise rate of ischemic conversion with time cannot be determined because more scans were readable at day 180 than at baseline because of the resolution of intraretinal hemorrhages. The proportion of eyes with active neovascularization (Fig 3) increased from baseline to day 180 among eyes treated with sham (from 10.2% to 16.2%), whereas it stayed relatively constant among eyes treated with the DEX implant 0.7 mg (from 7.3% to 7.5%). At day 180, the percentage of eyes with active neovascularization was significantly greater in the sham group than in the DEX implant 0.7 mg group (P ⫽ 0.026). Eyes with BRVO were significantly less likely to have active neovascularization at day 180 than were eyes with CRVO (odds ratio, 0.35; 95% CI, 0.17– 0.75; P ⫽ 0.007). Macular Vascular Changes Macular capillary nonperfusion was observed more frequently in the foveal central subfield than in the middle or outer rings (Fig 4). The area of macular capillary nonperfusion increased from base- 3 Ophthalmology Volume xx, Number x, Month 2013 Table 4. Global (Peripheral and Macular) Nonperfusion* by Diagnosis (Branch or Central Retinal Vein Occlusion) BRVO Baseline Eyes with FA evaluation for global nonperfusion, no. Eyes with nongradable or nonevaluable data Eyes with gradable or evaluable data Eyes with no nonperfusion evident Eyes with nonperfusion evident Mean area of nonperfusion, MPS disc areas (SD) Day 180 Eyes with FA evaluation for global nonperfusion, no. Eyes with nongradable or nonevaluable data Eyes with gradable or evaluable data Eyes with no nonperfusion evident Eyes with nonperfusion evident Mean area of nonperfusion, MPS disc areas (SD) CRVO Baseline Eyes with FA evaluation for global nonperfusion, no. Eyes with nongradable/nonevaluable Eyes with gradable/evaluable data Eyes with no nonperfusion evident Eyes with nonperfusion evident Mean area of nonperfusion, MPS disc areas (SD) Day 180 Eyes with FA evaluation for global nonperfusion, no. Eyes with nongradable/nonevaluable data Eyes with gradable/evaluable data Eyes with no nonperfusion evident Eyes with nonperfusion evident Mean area of nonperfusion, MPS disc areas (SD) Dexamethasone Intravitreal Implant 0.7 mg Sham 107 56 (52) 51 (48) 5 (10) 46 (90) 4.82 (6.68) 91 48 (53) 43 (47) 5 (12) 38 (88) 5.37 (7.98) 106 10 (9) 96 (91) 4 (4) 92 (96) 7.06 (7.90) 84 13 (15) 71 (85) 9 (13) 62 (87) 7.01 (9.73) 0.971 50 15 (30) 35 (70) 7 (20) 28 (80) 1.65 (2.17) 69 21 (30) 48 (70) 7 (15) 41 (85) 1.42 (2.72) 0.563 0.222 43 3 (7) 40 (93) 10 (25) 30 (75) 2.45 (3.71) 62 14 (23) 48 (77) 7 (15) 41 (85) 2.12 (5.07) 0.281 0.083 P Value† ⬎0.999 0.731 0.076 BRVO ⫽ branch retinal vein occlusion; CRVO ⫽ central retinal vein occlusion; FA ⫽ fluorescein angiography; MPS ⫽ Macular Photocoagulation Study; SD ⫽ standard deviation. *Percentages may not sum to 100% because of rounding. † P values are based on Fisher exact test for proportion of patients with nonperfusion and t test for disc area. Values are shown as n (%) unless otherwise indicated. line to day 180 in both treatment groups, with no statistically significant between-group differences. It is worth noting that the number of cases that were ungradable because of hemorrhage also decreased by day 180. Eyes with BRVO were more likely to have macular capillary nonperfusion—and more severe nonperfusion— than were patients with CRVO. Table 5. Global (Peripheral and Macular) Nonperfusion for the Subset of Patients with Gradable or Evaluable Data for Global Nonperfusion at Both Baseline and Day 180 No. of patients Baseline Eyes with no nonperfusion evident Eyes with nonperfusion evident Mean area of nonperfusion, MPS disc areas (SD) Day 180 Eyes with no nonperfusion evident Eyes with nonperfusion evident Mean area of nonperfusion, MPS disc areas (SD) Mean change from baseline in the area of nonperfusion, MPS disc areas (SD) Dexamethasone Intravitreal Implant 0.7 mg Sham 75 74 10 (13) 65 (87) 4.03 (5.89) 9 (12) 65 (88) 3.59 (6.67) 8 (11) 67 (89) 4.54 (6.55) n ⫽ 65 0.64 (2.88) 11 (15) 64 (85) 4.11 (7.11) n ⫽ 62 0.51 (2.70) P Value* ⬎0.999 0.697 0.624 0.720 0.798 MPS ⫽ Macular Photocoagulation Study; SD ⫽ standard deviation. *P values are based on Fisher’s Exact test for proportion of patients with nonperfusion and t-test for disc area. Values are shown as n (%) unless otherwise indicated. 4 Sadda et al 䡠 Vascular Changes with Intravitreal DEX for RVO Table 6. Percentage of Patients with Ischemic or Nonischemic Retinal Vein Occlusion Dexamethasone Intravitreal Implant 0.7 mg Sham P Value* ischemic RVO† nonischemic RVO‡ 7/74 (9) 67/74 (91) 9/79 (11) 70/79 (89) 0.692 ischemic RVO† nonischemic RVO‡ 26/122 (21) 96/122 (79) 19/104 (18) 85/104 (82) 0.568 Eyes with Global Nonperfusion Baseline Eyes with Eyes with Day 180 Eyes with Eyes with MPS ⫽ Macular Photocoagulation Study; RVO ⫽ retinal vein occlusion. *Chi-square test. † Includes patients with ⱖ10 MPS disc areas of nonperfusion. ‡ Includes patients with ⬍10 MPS disc areas of nonperfusion. Values are shown as n/N (%) unless otherwise indicated. The area of macular leakage declined over the course of the study in all groups (Table 7). Macular leakage was similar across all groups at baseline. By day 180, there was no statistically significant difference in the reduction of macular angiographic leakage between eyes treated with the DEX implant 0.7 mg and eyes treated with sham. Correlation Analyses There was a statistically significant direct correlation between the changes in macular leakage and changes in CRT in both the DEX implant 0.7 mg group (r ⫽ 0.22; 95% CI, 0.03– 0.40; P ⫽ 0.023) and in the sham group (r ⫽ 0.29; 95% CI, 0.10 – 0.46; P ⫽ 0.003). This means that if macular leakage decreased, CRT also decreased. There was also a statistically significant direct correlation between the mean change in global nonperfusion and changes in CRT in the DEX implant 0.7 mg group (r ⫽ 0.39; 95% CI, 0.16 – 0.58; P ⫽ 0.001), but not in the sham group (P ⫽ 0.127). Although there was a large percentage of patients in the DEX implant 0.7 mg group with no change in nonperfusion area, the correlation was driven by patients who had an increase in nonperfusion from baseline. There was no significant correlation between the changes in bestcorrected visual acuity and changes in either global nonperfusion or macular leakage. Discussion This study presents the results of a post hoc evaluation of the angiographic changes that occurred during a large, multicenter, 6-month, randomized controlled trial of the DEX implant 0.7 mg in the treatment of ME associated with RVO. The most important findings were that there seemed to be greater improvements in intraretinal hemorrhage and better stabilization of active neovascularization in eyes treated with the DEX implant 0.7 mg than in eyes treated with sham. This study also found that the percentage of eyes with at least some evidence of nonperfusion remained fairly steady with time, whereas the area of nonperfusion increased in both the DEX implant and the sham groups. There was also a decrease in macular leakage with time in both treatment groups. Another notable finding was that there was a correlation between vascular and anatomic changes; specifically, changes in macular leakage were cor- related significantly with changes in CRT (as measured by OCT) in both treatment groups. Intraretinal hemorrhage is common in eyes with RVO and often resolves without treatment.2,3 The presence of an intraretinal hemorrhage, however, can interfere with the ability to assess other vascular changes accurately in the eye and is a contraindication for laser photocoagulation therapy. Hemorrhages often take several months to resolve sufficiently, so any treatment that can help to promote the resolution of intraretinal hemorrhage in RVO may improve the ability to evaluate and treat this condition in a timely manner. In this study, the proportion of eyes with unreadable assessments resulting from hemorrhage decreased from 42% at baseline to 2% at day 180 in the DEX implant group, whereas it decreased from 38% to 9% in the sham group (P ⫽ 0.029 for DEX vs. sham at day 180). The betweengroup difference in the resolution of intraretinal hemorrhage, although statistically significant, is small and will need to be confirmed in a larger clinical trial. A similar beneficial effect of treatment on intraretinal hemorrhages was seen in eyes with RVO treated with intravitreal ranibizumab.10,11 In 2 randomized, controlled studies, eyes with either BRVO or CRVO treated with monthly intravitreal ranibizumab injections (0.3 mg or 0.5 mg) exhibited greater and more rapid improvements in intraretinal hemorrhage than did eyes treated with sham.10,11 Less than 5% of eyes in both of these ranibizumab studies had no retinal hemorrhages at baseline. After 6 months of follow-up, however, the percentage of eyes with no retinal hemorrhages had increased to more than 30% (33% for BRVO and 39% for CRVO) among eyes treated with ranibizumab 0.5 mg, while remaining less than 10% among eyes treated with sham.10,11 It is not known if intravitreal triamcinolone (IVTA) injections have any effect on intraretinal hemorrhage in eyes with RVO. There is no mention of an effect of IVTA treatment on the rate of clearance of hemorrhage in the Standard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) studies.12–14 Retinal neovascularization represents the formation of new, abnormal blood vessels in the retina. They tend to form above the retina or on the retinal surface without the 5 Ophthalmology Volume xx, Number x, Month 2013 baseline to 16% at day 180 in the sham group, but remained near 7% throughout the study in the DEX implant group. Interestingly, neovascularization was much more common among eyes with CRVO than BRVO, although the area of nonperfusion was, on average, greater in the BRVO eyes. Figure 3. Bar graphs showing the proportion of eyes with active neovascularization: A, all eyes; B, eyes with branch retinal vein occlusion; and C, eyes with central retinal vein occlusion. The number of eyes used in the calculation of the proportion with active neovascularization excluded those eyes that were not evaluated or not evaluable. DEX implant ⫽ dexamethasone intravitreal implant. branching patterns characteristic of normal retinal vessels.6,15,16 They also tend to be fragile and to leak profusely and can lead to sight-threatening complications such as vitreous hemorrhage, retinal detachment, or the exacerbation of macular edema.6,15,16 In this study, the proportion of eyes with active neovascularization increased from 10% at 6 Figure 4. Bar graphs showing the severity of macular capillary nonperfusion: A, in all eyes; B, in eyes with branch retinal vein occlusion; and C, in eyes with central retinal vein occlusion. DEX ⫽ dexamethasone intravitreal implant. Sadda et al 䡠 Vascular Changes with Intravitreal DEX for RVO Table 7. Macular Leakage All eyes Baseline Eyes with FA evaluation, no. Eyes with no macular leakage evident Eyes with macular leakage evident Could not grade/not evaluated Area of macular leakage, mean MPS disc Day 180 Eyes with FA evaluation, no. Eyes with no macular leakage evident Eyes with macular leakage evident Could not grade/not evaluated Area of macular leakage, mean MPS disc BRVO Baseline Eyes with FA evaluation, no. Eyes with no macular leakage evident Eyes with macular leakage evident Could not grade/not evaluated Area of macular leakage, mean MPS disc Day 180 Eyes with FA evaluation Eyes with no macular leakage evident Eyes with macular leakage evident Could not grade/not evaluated Area of macular leakage, mean MPS disc CRVO Baseline Eyes with FA evaluation, no. Eyes with no macular leakage evident Eyes with macular leakage evident Could not grade/not evaluated Area of macular leakage, mean MPS disc Day 180 Eyes with FA evaluation, no. Eyes with no macular leakage evident Eyes with macular leakage evident Could not grade/not evaluated Area of macular leakage, mean MPS disc Dexamethasone Intravitreal Implant 0.7 mg Sham areas (SD) 157 0 124 (79) 33 (21) 6.53 (4.18) 160 0 123 (77) 37 (23) 6.34 (4.08) areas (SD) 148 0 141 (95) 7 (5) 5.15 (3.80) 144 1 (1) 134 (93) 9 (6) 5.15 (3.80) areas (SD) 107 0 76 (71) 31 (29) 5.06 (2.40) 91 0 67 (74) 24 (26) 5.16 (3.26) areas (SD) 106 0 100 (94) 6 (6) 3.95 (2.49) 83 1 (1) 78 (94) 4 (5) 4.44 (3.05) areas (SD) 50 0 48 (96) 2 (4) 8.86 (5.23) 69 0 56 (81) 13 (19) 7.76 (4.53) areas (SD) 42 0 41 (98) 1 (2) 8.02 (4.76) 61 0 56 (92) 5 (8) 6.14 (4.49) BRVO ⫽ branch retinal vein occlusion; CRVO ⫽ central retinal vein occlusion; FA ⫽ fluorescein angiography; MPS ⫽ Macular Photocoagulation Study; SD ⫽ standard deviation. Values are shown as n (%) unless otherwise indicated. The incidence of active neovascularization was 3.3% at baseline and 9.6% at day 180 in sham-treated eyes with BRVO (Fig 3B) and 19% at baseline and 25% at day 180 among sham-treated eyes with CRVO (Fig 3C). To our knowledge, a well-documented beneficial effect of medical treatment on neovascularization in RVO has not been reported previously. There was some anecdotal evidence suggesting a beneficial effect of IVTA in the adverse event findings for neovascular events in the primary publications of the SCORE studies,12,13 but this was not confirmed when the neovascular events in the SCORE studies were analyzed in detail.14 A slightly higher rate of retinal neovascularization reported as an adverse event was found in the observation group (4/88; 5%) as compared with the IVTA treatment groups (4/183; 2%) in the SCORE CRVO study12 and in the standard-of-care (laser photocoagulation) group (5/137; 4%) as compared with the IVTA treatment groups (4/274; 1%) in the SCORE BRVO study.13 This was not confirmed, however, in a separate assessment of the data that combined disc or retinal neovascularization with preretinal or vitreous hemorrhage in the analysis.14 This analysis found no statistically significant difference in the cumulative rate of disc or retinal neovascularization plus preretinal or vitreous hemorrhage between the IVTA and standard-of-care treatment groups in either BRVO or CRVO eyes.14 This suggests that IVTA may not have as potent of an effect on neovascularization as does the DEX implant, but this will need to be confirmed in future studies. Surprisingly, there has been no documented effect of ranibizumab on neovascularization in eyes with RVO.10,11 Ranibizumab is a vascular endothelial growth factor antagonist and therefore would be expected to have an effect on 7 Ophthalmology Volume xx, Number x, Month 2013 neovascularization in eyes with RVO. Other anti–vascular endothelial growth factor agents have been reported to cause regression of neovascularization in eyes with proliferative diabetic retinopathy,16 so further investigation into the possible effects of ranibizumab on neovascularization in RVO is warranted. This analysis found that global (combined macular and peripheral) nonperfusion was relatively common in the GENEVA trials at baseline (occurring in approximately 87% of eyes with gradable assessments; Table 3). The proportion of eyes with nonperfusion remained relatively steady between 86% and 90% throughout the study, and there was no statistically significant difference between the DEX implant and the sham groups at day 180. The area of global nonperfusion increased with time and was similar in both treatment groups. However, the area of nonperfusion was affected by the type of RVO; eyes with BRVO were notably more likely to have nonperfusion than were eyes with CRVO. The percentage of eyes with ischemic RVO (ⱖ10 MPS disc areas of nonperfusion) also increased somewhat between baseline and day 180 in both groups. Similar changes in nonperfusion were reported in the SCORE studies. The percentage of eyes with 10 MPS disc areas or more of nonperfusion increased somewhat from baseline to month 12, but was similar between eyes treated with IVTA and those in the control groups (observation for eyes with CRVO and standard-of-care for eyes with BRVO).12–14 There was, however, a significant correlation between the extent of nonperfusion at baseline and the risk of a neovascularization event during the next 3 years in eyes with BRVO, but not in eyes with CRVO.14 In this study, the changes in macular nonperfusion were similar to the changes in global nonperfusion. As was seen for global nonperfusion, the proportion of eyes with macular nonperfusion increased with time in both treatment groups and was more common, as well as more severe, in eyes with BRVO than CRVO (data not shown). Although some of the increase in area was the result of ischemic conversion or progression, a portion also was likely the result of clearance of hemorrhage and unmasking of small areas of hidden nonperfusion (if large areas were obscured by hemorrhage, the case would have been deemed to be ungradable). It is unclear how the higher rates of nonperfusion in eyes with BRVO relate to the lower rate of retinal neovascularization in this subgroup. The higher levels of nonperfusion in the BRVO cohort compared with that in the CRVO cohort may be explained partly by the visual acuity inclusion criteria of the study. Because patients were required to have visual acuities better than 20/200, many CRVO patients with severe levels of ischemia may have been excluded. In contrast, BRVO patients with extensive nonperfusion still might have had relatively good vision and might have qualified for the study. In this study, the area of macular leakage declined over the course of the study to a similar extent in both the DEX implant and sham treatment groups. A decrease in the area of macular leakage also was seen in both the IVTA and observation groups in the SCORE CRVO study,12 but not in either of the IVTA or standard-of-care groups in the SCORE BRVO study.13 8 As expected, decreases in macular leakage in this study mirrored the decreases in CRT.7 A correlation analysis found that there was a direct correlation between changes in macular leakage and changes in CRT. This observation is consistent with the idea that macular swelling results from excess fluid leakage from nearby capillaries. It is important to note that the OCT measurements used to determine CRT and the FA measurements used to determine angiographic changes were evaluated completely independently in a masked fashion by 2 different reading centers. A similar analysis of the relationship between changes in CRT and FA outcomes has not been reported for the SCORE study, but an analysis of baseline predictors of CRT outcomes found that the presence of dense macular hemorrhage at baseline was predictive of more favorable changes in CRT in eyes with BRVO, but not CRVO.17 The chief limitation of this study was the large number of FA evaluations that were ungradable for some parameters at baseline because of hemorrhage. Moreover, the dramatic decrease in this number during the course of the study made it difficult to assess changes in vascular parameters accurately between baseline and day 180. However, this factor has much less of an effect on between-group comparisons at day 180. Other limitations of this study included the small proportion of eyes with available FA data and the fact that a detailed analysis of the FA data was not defined prospectively in the GENEVA trials. In conclusion, this study demonstrated that the clinical improvements demonstrated in the GENEVA trials were accompanied by significant changes in vascular parameters. This study also suggested that treatment with the DEX implant 0.7 mg may be associated with some clinically significant improvements in angiographic findings, specifically active neovascularization. Several statistically significant differences in angiographic findings also were noted between the BRVO and CRVO subgroups. Overall, this study showed that vascular changes in eyes with RVO are common, and these changes, as well as their response to treatment, should be evaluated more carefully in future clinical trials. Acknowledgments. Amy Lindsay, PhD, provided professional writing assistance, funded by Allergan, Inc., involving preparation of the manuscript, but did not meet authorship criteria. Dr. Lindsay assisted the authors with the drafting of a detailed outline for the manuscript, produced a first draft after all authors had approved the outline, and revised the manuscript repeatedly based on input from all authors. References 1. Ferris FL III, Patz A. Macular edema. A complication of diabetic retinopathy. Surv Ophthalmol 1984;28(suppl):452– 61. 2. McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1113–23. 3. Rogers SL, McIntosh RL, Lim L, et al. Natural history of branch retinal vein occlusion: an evidence-based systematic review. Ophthalmology 2010;117:1094 –101. 4. Antonetti DA, Barber AJ, Khin S, et al, Penn State Retina Research Group. Vascular permeability in experimental diabetes is associated with reduced endothelial occludin content: Sadda et al 䡠 Vascular Changes with Intravitreal DEX for RVO 5. 6. 7. 8. 9. 10. 11. vascular endothelial growth factor decreases occludin in retinal endothelial cells. Diabetes 1998;47:1953–9. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther 2008;16:791–9. Scholl S, Kirchhof J, Augustin AJ. Pathophysiology of macular edema. Ophthalmologica 2010;224(suppl):8 –15. Haller JA, Bandello F, Belfort R Jr, et al, OZURDEX GENEVA Study Group. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to retinal vein occlusion. Ophthalmology 2010; 117:1134 – 46. Haller JA, Bandello F, Belfort R Jr, et al, Ozurdex GENEVA Study Group. Dexamethasone intravitreal implant in patients with macular edema related to branch or central retinal vein occlusion: twelve-month study results. Ophthalmology 2011; 118:2453– 60. Central Vein Occlusion Study Group. Natural history and clinical management of central retinal vein occlusion. Arch Ophthalmol 1997;115:486 –91. Brown DM, Campochiaro PA, Bhisitkul RB, et al. Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study. Ophthalmology 2011;118:1594 – 602. Campochiaro PA, Brown DM, Awh CC, et al. Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study. Ophthalmology 2011;118:2041–9. 12. SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with observation to treat vision loss associated with macular edema secondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 5. Arch Ophthalmol 2009;127:1101–14. 13. SCORE Study Research Group. A randomized trial comparing the efficacy and safety of intravitreal triamcinolone with standard care to treat vision loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study report 6. Arch Ophthalmol 2009;127:1115–28. 14. Chan CK, Ip MS, VanVeldhuisen PC, et al, SCORE Study Investigator Group. SCORE Study report #11: incidences of neovascular events in eyes with retinal vein occlusion. Ophthalmology 2011;118:1364 –72. 15. Buehl W, Sacu S, Schmidt-Erfurth U. Retinal vein occlusions. Dev Ophthalmol 2010;46:54 –72. 16. Al-Latayfeh M, Silva PS, Sun JK, Aiello LP. Antiangiogenic therapy for ischemic retinopathies. Cold Spring Harb Perspect Med [serial online] 2012;2:a006411. Available at: http:// perspectivesinmedicine.cshlp.org/content/2/6/a006411.long. Accessed November 13, 2012. 17. Scott IU, VanVeldhuisen PC, Oden NL, et al, Standard Care versus COrticosteroid for REtinal Vein Occlusion Study Investigator Group. Baseline predictors of visual acuity and retinal thickness outcomes in patients with retinal vein occlusion: Standard Care Versus COrticosteroid for REtinal Vein Occlusion Study report 10. Ophthalmology 2011;118:345–52. Footnotes and Financial Disclosures Originally received: August 2, 2012. Final revision: December 4, 2012. Accepted: December 10, 2012. Available online: ●●● Manuscript no. 2012-1173. 1 Doheny Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California. 2 Department of Ophthalmology & Visual Sciences, University of WisconsinMadison, Madison, Wisconsin. 3 Smt. Kanuri Santhamma Centre for Vitreo Retinal Diseases, L. V. Prasad Eye Institute, Hyderabad, India. 4 NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust, London, United Kingdom. 5 Biostatistics, Allergan, Inc., Irvine, California. 6 Clinical Development - Ophthalmology, Allergan, Inc., Irvine, California. 7 Research and Development, Allergan, Inc., Irvine, California. Presented in part at: 2010 Joint Meeting of the American Academy of Ophthalmology and the Middle East Africa Council of Ophthalmology, October 2010, Chicago, Illinois. Financial Disclosure(s): The author(s) have made the following disclosure(s): SriniVas Sadda Consultant - Allergan, Inc.; Financial support - Allergan, Inc. Ronald P. Danis - Financial support - Allergan, Inc. Jenny Jiao - Employee - Allergan, Inc. Xiao-Yan Li - Employee - Allergan, Inc. Scott M. Whitcup - Employee Allergan, Inc. The remaining authors have no conflicts of interest to disclose. Supported by Allergan, Inc., Irvine, California, which participated in the design of the study and data analysis and interpretation. Allergan, Inc., also supervised the preparation of the manuscript and approved the final version. Dr. Keane has received a proportion of his funding from the United Kingdom Department of Health’s NIHR Biomedical Research Centre for Ophthalmology at Moorfields Eye Hospital and UCL Institute of Ophthalmology. The views expressed in the publication are those of the authors and not necessarily those of the Department of Health. Correspondence: SriniVas Sadda, MD, Doheny Eye Institute, 1450 San Pablo Street, Suite 3623, Los Angeles, CA 90033. E-mail: SSadda@doheny.org. 9