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Figure 1.
Flowchart of Participant Progress in the SCORE2 Trial
Flowchart of Participant Progress in the SCORE2 Trial

aPatients may be ineligible at screening for multiple reasons; thus, the number of reasons for ineligibility may not sum to the number of ineligible patients.

bEligibility criteria included central retinal thickness on spectral-domain optical coherence tomography (SD-OCT), which was defined as central subfield thickness of 300 µm or greater if measured with a Carl Zeiss Meditec Cirrus OCT machine or 320 µm or greater if measured with a Heidelberg Spectralis OCT machine.

cFor example, chronic alcoholism or drug abuse, personality disorder, or use of major tranquilizers, indicating difficulty in long-term follow-up and likelihood of survival of less than 12 months.

Figure 2.
Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score at Baseline and Monthly Through Month 6
Electronic Early Treatment Diabetic Retinopathy Study Visual Acuity Letter Score at Baseline and Monthly Through Month 6

The center horizontal line of each box indicates the median; circle, mean; and top and bottom borders of each box, 75th and 25th percentiles, respectively. The whiskers extend to the minimum observation above the lower fence and maximum observation below the upper fence, which are defined as 1.5 times the interquartile range below the 25th percentile and above the 75th percentile, respectively. The outliers (squares) mark any observation below the lower fence or above the upper fence.

Figure 3.
Spectral-Domain Optical Coherence Tomography Central Subfield Thickness at Baseline and Monthly Through Month 6
Spectral-Domain Optical Coherence Tomography Central Subfield Thickness at Baseline and Monthly Through Month 6

The center horizontal line of each box indicates the median; circle, mean; and top and bottom borders of each box, 75th and 25th percentiles, respectively. The whiskers extend to the minimum observation above the lower fence and maximum observation below the upper fence, which are defined as 1.5 times the interquartile range below the 25th percentile and above the 75th percentile, respectively. The outliers (squares) mark any observation below the lower fence or above the upper fence.

Figure 4.
Color Fundus Photograph and Optical Coherence Tomogram of the Left Eye at Baseline and Month 6 in a Representative SCORE2 Participant With a Central Retinal Vein Occlusion
Color Fundus Photograph and Optical Coherence Tomogram of the Left Eye at Baseline and Month 6 in a Representative SCORE2 Participant With a Central Retinal Vein Occlusion

At baseline, the color fundus photograph of the central 30° of the retina showed extensive retinal hemorrhages and dilated retinal veins. The optic nerve was not visible because of retinal edema and blood. Retinal edema was present throughout the retina and is best seen on optical coherence tomography (OCT), which provides a cross-sectional image of the retina. The OCT scan shown here was taken through the center of the retina. The participant’s visual acuity was 20/400 at baseline. At month 6, the color fundus photograph of the retina in the same participant showed nearly complete resolution of intraretinal blood after receiving monthly injections of aflibercept for 6 months. The optic nerve was visible and appeared normal. The OCT scan showed that retinal edema resolved and the fovea returned to its normal contour. At month 6, the participant’s visual acuity improved to 20/40.

Table 1.  
Baseline Characteristics of SCORE2 Participants
Baseline Characteristics of SCORE2 Participants
Table 2.  
Electronic ETDRS VALS Secondary Outcomes, Overall and Within Subgroup Through Month 6
Electronic ETDRS VALS Secondary Outcomes, Overall and Within Subgroup Through Month 6
Table 3.  
Spectral-Domain Optical Coherence Tomography Central Subfield Thickness Secondary Outcomes, Overall and Within Subgroup Through Month 6
Spectral-Domain Optical Coherence Tomography Central Subfield Thickness Secondary Outcomes, Overall and Within Subgroup Through Month 6
Table 4.  
Ocular and Systemic Events Within 6 Months Among Study Eyes
Ocular and Systemic Events Within 6 Months Among Study Eyes
1.
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Martin  DF, Maguire  MG, Ying  GS, Grunwald  JE, Fine  SL, Jaffe  GJ; CATT Research Group.  Ranibizumab and bevacizumab for neovascular age-related macular degeneration.  N Engl J Med. 2011;364(20):1897-1908.PubMedGoogle ScholarCrossref
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Gross  JG, Glassman  AR, Jampol  LM,  et al; Writing Committee for the Diabetic Retinopathy Clinical Research Network.  Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: a randomized clinical trial.  JAMA. 2015;314(20):2137-2146.PubMedGoogle ScholarCrossref
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Heier  JS, Clark  WL, Boyer  DS,  et al.  Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study.  Ophthalmology. 2014;121(7):1414-1420, e1.PubMedGoogle ScholarCrossref
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Original Investigation
May 23/30, 2017

Effect of Bevacizumab vs Aflibercept on Visual Acuity Among Patients With Macular Edema Due to Central Retinal Vein Occlusion: The SCORE2 Randomized Clinical Trial

Author Affiliations
  • 1Department of Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania
  • 2Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania
  • 3The Emmes Corporation, Rockville, Maryland
  • 4Doheny Eye Institute, University of California, Los Angeles
  • 5University of Wisconsin Fundus Photograph Reading Center, Madison
  • 6Tennessee Retina, PC, Nashville
  • 7Retinal Consultants of Arizona, Phoenix
  • 8Southeast Retina Center, PC, Augusta, Georgia
  • 9Cumberland Valley Retina Consultants, Hagerstown, Maryland
JAMA. 2017;317(20):2072-2087. doi:10.1001/jama.2017.4568
Key Points

Question  Is bevacizumab, a commonly used off-label treatment, noninferior to aflibercept, a US Food and Drug Administration–approved treatment, for visual acuity in eyes with macular edema due to central retinal or hemiretinal vein occlusion?

Findings  In this randomized clinical trial that included 362 patients, the mean visual acuity letter score increase from baseline was 18.6 in the bevacizumab group and 18.9 in the aflibercept group (model-based estimate of mean difference, −0.14, meeting criteria for noninferiority).

Meaning  Among patients with macular edema secondary to central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept for visual acuity after 6 months of treatment.

Abstract

Importance  Studies have established the efficacy and safety of aflibercept for the treatment of macular edema due to central retinal vein occlusion. Bevacizumab is used off-label to treat this condition despite the absence of supporting data.

Objective  To investigate whether bevacizumab is noninferior to aflibercept for the treatment of macular edema secondary to central retinal or hemiretinal vein occlusion.

Design, Setting, and Participants  The SCORE2 randomized noninferiority clinical trial was conducted at 66 private practice or academic centers in the United States, and included 362 patients with macular edema due to central retinal or hemiretinal vein occlusion who were randomized 1:1 to receive aflibercept or bevacizumab. The first participant was randomized on September 17, 2014, and the last month 6 visit occurred on May 6, 2016. Analyses included data available as of December 30, 2016.

Interventions  Eyes were randomized to receive intravitreal injection of bevacizumab (1.25 mg; n = 182) or aflibercept (2.0 mg; n = 180) every 4 weeks through month 6.

Main Outcomes and Measures  The primary outcome was mean change in visual acuity (VA) letter score (VALS) from the randomization visit to the 6-month follow-up visit, based on the best-corrected electronic Early Treatment Diabetic Retinopathy Study VALS (scores range from 0-100; higher scores indicate better VA). The noninferiority margin was 5 letters, and statistical testing for noninferiority was based on a 1-sided 97.5% confidence interval.

Results  Among 362 randomized participants (mean [SD] age, 69 [12] years; 157 [43.4%] women; mean [SD] VALS at baseline, 50.3 [15.2] [approximate Snellen VA 20/100]), 348 (96.1%) completed the month 6 follow-up visit. At month 6, the mean VALS was 69.3 (a mean increase from baseline of 18.6) in the bevacizumab group and 69.3 (a mean increase from baseline of 18.9) in the aflibercept group (model-based estimate of between-group difference, −0.14; 97.5% CI, −3.07 to ∞; P = .001 for noninferiority), meeting criteria for noninferiority. Ocular adverse events in the aflibercept group included 4 participants with intraocular pressure (IOP) more than 10 mm Hg greater than baseline; ocular adverse events in the bevacizumab group included 1 participant with endophthalmitis (culture negative), 9 with IOP more than 10 mm Hg greater than baseline, 2 with IOP higher than 35 mm Hg, and 1 with angle-closure glaucoma not attributed to the study drug or procedure.

Conclusions and Relevance  Among patients with macular edema due to central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept with respect to visual acuity after 6 months of treatment.

Introduction

Retinal vein occlusion is the most common retinal vascular disease after diabetic retinopathy, with population-based prevalence estimates in individuals aged 40 years or older of 0.4% in a German cohort,1 0.6% in Beaver Dam, Wisconsin,2 and 1.6% in an Australian cohort.3 Analysis across 15 population-based studies from the United States, Europe, Asia, and Australia estimated the worldwide prevalence of retinal vein occlusion at 16 million adults.4Quiz Ref ID There are 3 general types of retinal vein occlusion based on obstruction site: branch retinal vein occlusion, central retinal vein occlusion, and hemiretinal vein occlusion. Macular edema (central retinal swelling) is the most frequent cause of vision loss in retinal vein occlusion.5

Quiz Ref IDAflibercept is approved by the US Food and Drug Administration for macular edema due to central retinal vein occlusion.6,7 Off-label use of bevacizumab8,9 for this indication is widespread because its efficacy and safety have been demonstrated for other retinal diseases (age-related macular degeneration [AMD]10 and diabetic macular edema [DME]11) and its cost (approximately $60/dose)12 is much less than the cost of aflibercept ($1850/dose).13 This investigation, the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) trial, investigated whether bevacizumab was noninferior to aflibercept for treatment of macular edema due to central retinal or hemiretinal vein occlusion.

Methods
Study Conduct and Oversight

The SCORE2 trial was a multicenter, randomized clinical trial and adhered to the tenets of the Declaration of Helsinki.14 The protocol and informed consent were approved by either a site-specific institutional review board or centralized institutional review board and by a National Eye Institute–appointed data and safety monitoring committee (DSMC). Study participants provided written informed consent.

Study Population

The full trial protocol is shown in the Supplement. Participants had a best-corrected electronic Early Treatment Diabetic Retinopathy Study (E-ETDRS) visual acuity (VA) letter score (VALS) between 19 and 73 (possible range is 0-100 letters; higher scores indicate better VA), center-involved macular edema due to central retinal or hemiretinal vein occlusion on clinical examination, and central retinal thickness on spectral-domain optical coherence tomography (SD-OCT), defined as central subfield thickness of 300 µm or greater if measured with a Carl Zeiss Meditec Cirrus OCT machine or 320 µm or greater if measured with a Heidelberg Spectralis OCT machine (Figure 1). Patients with hemiretinal vein occlusion have been reported to be similar to patients with branch and central retinal vein occlusion with respect to demographic characteristics, with fundus findings of hemiretinal vein occlusion intermediate between those of branch and central retinal vein occlusion.15 For the results of this trial to be as generalizable as possible, eligibility criteria permitted inclusion of patients with hemiretinal vein occlusion to a maximum of 25% of the total study sample.

A history of intravitreal corticosteroid use was allowed if it was more than 4 months before randomization, and prior intravitreal anti–vascular endothelial growth factor (VEGF) use was allowed if it was more than 2 months before randomization. Each participant’s eligibility was determined by the site’s principal investigator or coinvestigator. Race and ethnicity were collected per requirements of the National Institutes of Health, they were determined by the participant, and data collection instruments had fixed categories; for race, there was an option to specify free text if the fixed categories were not relevant.

Interventions

Study eyes were randomized 1:1 to intravitreal bevacizumab (1.25 mg) every 4 weeks for 6 months vs intravitreal aflibercept (2.0 mg) every 4 weeks for 6 months. Bevacizumab was purchased with trial funding and repackaged into single-use vials by the University of Pennsylvania Investigational Drug Service. Aflibercept was provided by Regeneron in single-use vials.

Another US Food and Drug Administration–approved drug for macular edema due to central retinal vein occlusion,16 ranibizumab, was not investigated in this trial. Although similar efficacy and safety of ranibizumab compared with bevacizumab have been demonstrated in AMD and DME,11 the cost of ranibizumab ($1950/dose) is much higher than the cost of bevacizumab,13 and its target specificity is similar to that of bevacizumab (both drugs inhibit VEGF-A). In contrast, aflibercept has a broader mechanism of action (inhibits VEGF-A, VEGF-B, and placental growth factor) and a higher in vitro binding affinity than bevacizumab and ranibizumab17 and was associated with visual outcomes superior to those associated with bevacizumab and ranibizumab at 12 months in a clinical trial for DME.11

Randomization to intravitreal bevacizumab or intravitreal aflibercept was performed centrally through a web-based data entry system maintained at the data coordinating center (The Emmes Corporation) using a permuted block design with random block sizes of 4 and 8, stratified into 1 of 3 baseline screening VA groups in the same manner as in the SCORE Study18: good (VALS of 73-59 [approximate Snellen VA 20/40 to 20/63]), moderate (VALS of 58-49 [approximate Snellen VA 20/80 to 20/100]), and poor (VALS of 48-19 [approximate Snellen VA 20/125 to 20/400]).

Study visits were scheduled every 4 weeks for 6 months. Following primary outcome assessment at month 6, participants were followed through month 12 according to a protocol-defined treatment strategy based on response at month 6. Eyes with a protocol-defined good response at month 6 were randomized to continue treatment with the originally assigned drug on either a monthly or treat-and-extend schedule. Eyes with a protocol-defined poor response at month 6 were switched to an alternative treatment; eyes in the bevacizumab group with a poor response at month 6 were to receive aflibercept treatment, and eyes in the aflibercept group with a poor response at month 6 were to receive intravitreal dexamethasone implant treatment. This article focuses on the first 6 months of follow-up. At each study follow-up visit, both eyes had VA assessed by the E-ETDRS method,19 intraocular pressure (IOP) measurement, and slitlamp and dilated ophthalmoscopic examinations. Images from SD-OCT were obtained monthly. Fundus photographs and (at selected sites) ultra–wide-field fluorescein angiograms were obtained at baseline and month 6. Study participants were masked to treatment assignment through month 6. At month 6, VA examiners and SD-OCT technicians were masked to treatment assignments.

Outcomes

Quiz Ref IDThe prespecified primary outcome was change in best-corrected E-ETDRS VALS from baseline to month 6, with the noninferiority margin set at 5 letters. The noninferiority margin was selected in part because it was the same margin used in prior trials evaluating anti-VEGF agents for retinal disease.10,20 Further, it has been reported that a true difference exceeding 5 letters represents a clinically important difference.21 Secondary outcomes include mean change from baseline in VALS at other time points, percentage of participants with a VALS decrease from baseline of at least 15, percentage of participants with a VALS gain from baseline of at least 15, and mean change from baseline in central subfield thickness. Post hoc outcomes include the proportion of eyes with a VALS of 70 or better and the proportion of eyes with resolution of macular edema (defined as central subfield thickness <300 µm, no subretinal or intraretinal fluid, and no cystoid spaces within the ETDRS grid based on reading center evaluation). The secondary VA outcomes were selected because a VALS gain or decrease of at least 15 and meeting a VALS of 70 represent clinically meaningful outcomes to the patient. The SD-OCT secondary outcomes of mean change before and after treatment as well as the proportion of eyes with resolution of macular edema were included because they are important measures used by ophthalmologists in assessing treatment response and need for additional treatment in patients with macular edema.

The statistical analysis plan (Supplement) describes other secondary efficacy outcomes not included in this article. These other secondary outcomes include VA categorized into improved, stable, and worse, overall and within baseline VA strata; SD-OCT outcomes of center point thickness, macular volume, measurement of photoreceptor length, outer segment length, integrity of the photoreceptor inner segment–outer segment junction, and percentage change from baseline in calculated retinal thickness at the center of the macula; fundus photography outcome of area of retinal hemorrhage; ultra–wide-field fluorescein angiography outcome of area of peripheral retinal nonperfusion and leakage; and vision-related quality of life as measured by the National Eye Institute 25-Item Visual Function Questionnaire. These outcomes, including data from the analyses at 12 months, will be included in subsequent reports.

Medical Dictionary for Regulatory Activities coding of adverse events was used to select events specified by the Antiplatelet Trialists’ Collaboration.22

Statistical Analysis

The target sample size of 360 study eyes, calculated to attain at least 80% power, was based on testing noninferiority of bevacizumab to aflibercept using a VALS margin of 5 and a 1-tailed type I error of .025, assuming an SD of 16 letters for change from baseline in VALS (based on a prior study16) and 10% attrition by month 6. Interim efficacy testing was carried out using the Lan-DeMets23 interim monitoring boundary with a 1-tailed level .025 O’Brien-Fleming–type spending function, adapted for noninferiority testing. The DSMC reviewed outcome data by treatment group, but no formal statistical tests were examined by the DSMC until the sample size reestimation was performed. The DSMC recommended no modification to this trial’s sample size or early stopping due to efficacy based on these analyses.

The noninferiority analysis for the primary outcome was performed based on the treatment group to which study participants were randomized, consistent with intention-to-treat principles. The noninferiority test modeled baseline and 6-month VALS as a 2-step time series in which each 6-month outcome is correlated with its corresponding baseline measure. Sensitivity analysis used multiple imputation modified to explore missing-at-random and missing-not-at-random hypotheses to assess the effect of missing data on the primary outcome finding. The multiple imputation technique was used based on a model that imputed missing month 6 VALS, based on treatment assignment and nonmissing VALS from baseline through month 5, and central subfield thickness values from baseline through month 6. To assess the potential influence of conflict of interest on the primary outcome findings, a secondary analysis of the primary outcome was performed that included a covariate to identify patients from sites with investigators who reported a financial conflict of interest.

Confidence intervals were based on t distributions for means and mean changes and Wald approximation for percentages. P values for analysis of baseline VA stratum (good, moderate, poor), anti-VEGF treatment for macular edema prior to baseline (yes, no), and disease status (central retinal or hemiretinal vein occlusion) subgroups were based on normal-based and logistic regression mixed models in which month 6 data were regressed on treatment assignment, subgroup indicator, and treatment-by-subgroup interaction. Prior anti-VEGF treatment and disease status variables were not listed in the statistical analysis plan, and analyses of these variables need to be interpreted as post hoc. In the monthly analyses, participant-level temporal autocorrelation is modeled as an autoregressive time series, which included a time-by-treatment interaction. P values tested the unweighted average across 6 months of the estimated treatment effect in each month. Controlling for multiple testing of secondary findings was accomplished by adjusting P values using the Hochberg sequentially rejective method.24 Adjusted 2-tailed P < .05 was considered statistically significant in secondary analyses. Confidence intervals are uncorrected for multiple testing and intended only to describe the uncertainty in the estimates.

SAS statistical software versions 9.3 and 9.4 (SAS Institute Inc) were used to conduct statistical analyses. Analyses included data available as of December 30, 2016.

Results
Demographic Characteristics and Follow-up

Three hundred sixty-two participants were enrolled at 66 private practice or academic centers within the United States between September 17, 2014, and November 18, 2015, and randomly assigned to receive aflibercept (n = 180) or bevacizumab (n = 182). Participants’ mean (SD) age was 69 (12) years, 157 (43.4%) were women, 276 (76.2%) were white, and 54 (14.9%) were black. The mean (SD) VALS at baseline was 50.3 (15.2) (approximate Snellen VA 20/100), and participants had macular edema for a mean of 7 months (range, 0-104 months; median, 1 month [interquartile range, 0-6 months]) before randomization. The mean (SD) central subfield thickness was 665.5 (224.4) µm. Among the 362 participants, 121 (33.4%) had received prior anti-VEGF treatment, 28 (7.7%) had prior intravitreal steroid treatment, and 57 (15.7%) were diagnosed with hemiretinal vein occlusion (Table 1). The month 6 visit was completed by 348 participants (96.1%), including 175 of the 180 participants (97.2%) in the aflibercept group and 173 of the 182 participants (95.1%) in the bevacizumab group (Figure 1).

Anti-VEGF Treatments

The mean (SD) number of anti-VEGF injections between randomization and month 5, the last visit with an injection prior to measurement of the primary outcome, was 5.83 (0.64) in the aflibercept group and 5.78 (0.74) in the bevacizumab group (P = .47), with 164 participants (91.1%) in the aflibercept group and 160 participants (87.9%) in the bevacizumab group receiving all 6 expected monthly injections between randomization and month 5 (P = .32).

VA Outcomes

The mean VALS improved from 50.3 at baseline to 64.1 at month 1 and to 69.3 at month 6 in the aflibercept group, and improved from 50.4 at baseline to 62.3 at month 1 and to 69.3 at month 6 in the bevacizumab group (Figure 2). At month 6, bevacizumab was noninferior to aflibercept based on a VALS margin of 5 (bevacizumab minus aflibercept mean difference, −0.14; 1-tailed 97.5% CI, −3.07 to ∞; P for noninferiority = .001; within the noninferiority margin of −5). Missing month 6 outcomes (5 of 180 participants [2.8%] in the aflibercept group; 9 of 182 participants [4.9%] in the bevacizumab group) were ignored in the primary analysis, consistent under a maximum likelihood analysis with the missing-at-random assumption. In the missing-at-random analysis, the bevacizumab minus aflibercept mean difference was −0.49 (1-tailed 97.5% CI, −3.39 to ∞; P for noninferiority = .001). A sensitivity analysis used multiple imputation modified to explore not-missing-at-random hypotheses and showed that the primary analysis was robust to moderate departures from missing at random. In a secondary analysis, after adjusting for all factors in Table 1, the noninferiority result remained (bevacizumab minus aflibercept mean difference, −0.72; 1-tailed 97.5% CI, −3.87 to ∞; P for noninferiority = .01). In another secondary analysis in which sites were grouped according to whether an investigator affirmed a financial conflict of interest or not and in which the primary outcome analysis was repeated including in the model an indicator variable for conflict of interest and the conflict-by-treatment interaction, there was neither a significant effect of conflict (P = .73) nor a conflict × treatment interaction (P = .99).

In the aflibercept group, 114 eyes (65.1%) had a VALS gain of at least 15 at month 6 compared with 106 eyes (61.3%) in the bevacizumab group. The odds of a VALS gain of at least 15 averaged over months 1 to 6 was not significantly different for aflibercept relative to bevacizumab (odds ratio [OR] = 0.85; 95% CI, 0.62-1.17; P = .89). Less than 2% in each group had a VALS decrease of at least 15 at month 6 (3 of 175 eyes [1.7%] in the aflibercept group; 3 of 173 eyes [1.7%] in the bevacizumab group). In post hoc analysis, the number of eyes achieving a VALS of at least 70 (approximate Snellen VA 20/40) at month 6 was 101 (57.7%) in the aflibercept group and 99 (57.2%) in the bevacizumab group, with the odds of a VALS of at least 70 over months 1 to 6 for the aflibercept group not significantly different from those of the bevacizumab group (OR = 0.82; 95% CI, 0.59-1.13; P = .89). The treatment effect comparing bevacizumab with aflibercept was homogeneous in the identified subgroups (Table 2).

SD-OCT Outcomes

Both groups showed statistically significant SD-OCT central subfield thickness decreases from baseline through month 6 (Table 3 and Figure 3). With a mean (SD) baseline central subfield thickness of 652 (215) µm in the aflibercept group, there was a mean decrease of 394 µm (95% CI, −429 to −360 µm) at month 1 and 425 µm (95% CI, −461 to −389 µm) at month 6. For the bevacizumab group, with a mean (SD) baseline central subfield thickness of 678 (233) µm, there was a mean decrease of 333 µm (95% CI, −366 to −299 µm) at month 1 and 387 µm (95% CI, −426 to −348 µm) at month 6. The bevacizumab minus aflibercept estimate of the change from baseline treatment effect averaged over the 6 months was 49.3 µm (95% CI, 1.93 to 96.74 µm) in favor of aflibercept, a difference that is not statistically significant (P = .83).

Post hoc analyses showed that at month 6, 92 of 169 eyes (54.4%) in the aflibercept group had resolution of macular edema compared with 49 of 172 eyes (28.5%) in the bevacizumab group. The odds of complete resolution of fluid averaged over months 1 to 6 was significantly lower in the bevacizumab group compared with the aflibercept group (OR = 0.28; 95% CI, 0.20 to 0.39; P < .001). The treatment effect comparing bevacizumab with aflibercept was homogeneous in the identified subgroups (Table 3). An example of both baseline and month 6 color fundus photographs and SD-OCT scans in a participant in this trial is shown in Figure 4.

Adverse Events

Most ocular adverse events of interest were rare (Table 4). One case of endophthalmitis (culture negative) occurred in the bevacizumab group. Two participants receiving bevacizumab had IOP higher than 35 mm Hg at a monthly visit through month 6, and 4 participants (2.2%) receiving aflibercept and 9 (4.9%) receiving bevacizumab had IOP more than 10 mm Hg greater than baseline, with 1 participant receiving bevacizumab experiencing angle-closure glaucoma not attributed to the anti-VEGF agent or procedure. Antiplatelet Trialists’ Collaboration events occurred in 2 participants (1.1%) receiving aflibercept (including a fatal myocardial infarction) and 2 participants (1.1%) receiving bevacizumab. Two deaths (myocardial infarction and metastatic bladder cancer) occurred, 1 in each group, through 6 months.

Discussion

Quiz Ref IDIn this study of patients with macular edema due to central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to intravitreal aflibercept for VA after 6 months of treatment, based on a VALS noninferiority margin of 5. In secondary analyses, there were no significant differences between bevacizumab and aflibercept in terms of VA throughout 6 months of follow-up. The magnitude of improvement in mean VALS from baseline to month 6 in the aflibercept and bevacizumab groups (18.9 and 18.6 letters, respectively) was comparable with that reported with monthly ranibizumab injections in the CRUISE Study16 (14.9 letters) and with monthly aflibercept injections in the COPERNICUS6 (17.3 letters) and GALILEO7 (18.0 letters) trials. The proportion of eyes with a VALS gain of at least 15 from baseline to month 6 in the aflibercept and bevacizumab groups (65.1% and 61.3%, respectively) is 13% to 17% higher than that reported in CRUISE (47.7%), and more similar to those with gains reported in both the COPERNICUS (56.1%) and GALILEO (60.2%) trials. These trials support the favorable effect of anti-VEGF therapy on vision loss due to macular edema from central retinal vein occlusion. While the COPERNICUS and GALILEO trials included only treatment-naive patients with central retinal vein occlusion,6,7 this trial included both treatment-naive patients as well as patients who had received prior anti-VEGF treatment. In this trial, there was no significant difference in treatment effect between treatment-naive and previously treated participants.

In Protocol T11 conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net) to evaluate the relative efficacy and safety of aflibercept, bevacizumab, and ranibizumab for the treatment of DME, there was a greater treatment effect on VALS at 1 year associated with aflibercept compared with bevacizumab in the poor VA stratum (20/50 to 20/320) and no difference in treatment effect in the good VA stratum (20/32 to 20/40) (P < .0001); the treatment advantage of aflibercept over bevacizumab among eyes with worse baseline VA persisted at 2 years.25 The current trial found no such interaction of treatment effect with baseline VA. This difference in findings between this trial and Protocol T may be due to variation in the a priori definition of baseline VA strata (there were only 38 eyes in this trial with VA of 20/40 or better). Additionally, response to treatment may vary based on the retinal disease studied.

Both aflibercept and bevacizumab were associated with significant central subfield thickness reduction, consistent with previous clinical trials of anti-VEGF therapy for macular edema due to central retinal vein occlusion.6,7,16 In this trial, DRCR.net Protocol T,11 and the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT)10 (which evaluated the relative efficacy and safety of ranibizumab and bevacizumab for treatment of neovascular AMD), bevacizumab was associated with a significantly lower proportion of eyes that achieved resolution of macular edema than the comparative on-label anti-VEGF agents (ranibizumab in CATT; aflibercept and ranibizumab in Protocol T). In this trial and CATT, the lower proportion of eyes with resolution of fluid among eyes treated with bevacizumab did not translate into poorer VA outcomes at the primary outcome visits of these 2 clinical trials.10,11 This was also true at 12 months (primary outcome) in the participants with better baseline VA in Protocol T.11 Continued follow-up of participants in this trial will allow evaluation of the cumulative effect of the presence of fluid on VA in all treatment groups and on the number of injections administered in participants assigned to the treatment groups not defined by a fixed-dosing schedule.

Baseline characteristics were balanced between the 2 treatment groups except for the shorter time between diagnosis of macular edema and randomization in the bevacizumab group. The extent to which baseline characteristics like duration between diagnosis of macular edema and randomization may confound the primary results was examined through a secondary noninferiority analysis that adjusted for all factors in Table 1. The adjusted secondary analysis supported the noninferiority conclusion reached in the primary analysis.

Rates of adverse events in the current study were similar for both drugs and are consistent with those reported in other phase 3 trials evaluating anti-VEGF therapy for retinal vein occlusion,6,7,16,26-29 neovascular AMD,10,26 and DME.11,25,27 Although this trial was not powered to identify differences between treatment groups in rare adverse events, new safety concerns associated with anti-VEGF therapy were not identified. The bevacizumab used in this trial was commercially acquired and repackaged into single-use vials by the University of Pennsylvania Investigational Drug Service, which performed a similar service in CATT10 and DRCR.net Protocol T.11 The adverse event profile and efficacy associated with commercially available single-use syringes of repackaged bevacizumab may differ from the adverse event profile and efficacy associated with the repackaged bevacizumab study drug evaluated in this trial. However, in a retrospective cohort study using medical claims data from ambulatory care centers across the United States from 2005 through 2012, the rate of postinjection endophthalmitis was not significantly different among the 296 565 injections of compounded bevacizumab packaged into single-use syringes compared with the 87 245 injections of ranibizumab packaged in single-use glass vials.30

Quiz Ref IDCost is one of many factors that may contribute to drug selection when treating patients. The cost of a single dose of aflibercept is substantially greater than a single dose of off-label repackaged bevacizumab, and because most patients treated with anti-VEGF therapy for macular edema associated with central retinal or hemiretinal vein occlusion are treated with multiple doses of anti-VEGF drug, the cost differential between the 2 drugs has important economic implications.

Limitations

Limitations of the current trial include lack of a ranibizumab treatment group, lack of as-needed treatment groups that were evaluated from baseline, and relatively short follow-up. Caution should be exercised when extrapolating results from clinical trials to clinical practice. For instance, findings of the current trial must be interpreted in light of the high rate of treatment adherence, with approximately 90% of study participants receiving all 6 of the monthly anti-VEGF injections. Cross-trial comparisons include such caveats as differences among trials in the timing of outcome assessments; for instance, the primary outcome of the current trial is 6 months, compared with 1 year in CATT10 and DRCR.net Protocol T.11

Conclusions

Among patients with macular edema secondary to central retinal or hemiretinal vein occlusion, intravitreal bevacizumab was noninferior to aflibercept with respect to VA after 6 months of treatment.

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Article Information

Corresponding Author: Paul C. VanVeldhuisen, PhD, The Emmes Corporation, 401 N Washington St, Ste 700, Rockville, MD 20850 (score2@emmes.com).

Accepted for Publication: April 17, 2017.

Published Online: May 9, 2017. doi:10.1001/jama.2017.4568

Author Contributions: Drs Scott and Ip had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Scott, VanVeldhuisen, Ip, Blodi, Oden, Wroblewski.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Scott, VanVeldhuisen, Oden.

Critical revision of the manuscript for important intellectual content: VanVeldhuisen, Ip, Blodi, Oden, Awh, Kunimoto, Marcus, Wroblewski, King.

Statistical analysis: VanVeldhuisen, Oden, King.

Obtained funding: Scott, VanVeldhuisen, Blodi.

Administrative, technical, or material support: Scott, VanVeldhuisen, Ip, Blodi, Kunimoto, Marcus.

Supervision: Scott, VanVeldhuisen, Ip, Blodi.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Scott reported serving as a data and safety monitoring committee member for Thrombogenics. Dr Ip reported serving as a consultant for Thrombogenics, Omeros, Genentech, Quark, and Boehringer Ingelheim. Dr Awh reported receiving research funding from Regeneron and Genentech. Dr Kunimoto reported serving as a consultant for Allergan and Genentech. Dr Marcus reported receiving grants from Penn State University and Regeneron. No other disclosures were reported.

Funding/Support: This study was supported by grants U10EY023529, U10EY023533, and U10EY023521 from the National Eye Institute, National Institutes of Health, Department of Health and Human Services. Support was also provided in part by Regeneron Inc and Allergan Inc through donation of investigational drug. This work was supported in part by an unrestricted grant from Research to Prevent Blindness Inc to the Department of Ophthalmology and Visual Sciences, University of Wisconsin, Madison.

Role of the Funder/Sponsor: The National Institutes of Health participated in oversight of the conduct of the study and review of the manuscript but not directly in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or in the preparation of the manuscript. Regeneron and Allergan reviewed the protocol and Regeneron provided comments on the manuscript.

Group Information: The SCORE2 Investigator Group members include the following: SCORE2 Executive Committee: Ingrid U. Scott (study chair), Penn State College of Medicine; Michael S. Ip (study co-chair), Doheny Eye Center, University of California, Los Angeles; Barbara A. Blodi (principal investigator), Fundus Photograph Reading Center; Sangeeta Bhargava (program director, Collaborative Clinical Research Program), National Eye Institute, National Institutes of Health; Paul C. VanVeldhuisen (data coordinating center [DCC] principal investigator), The Emmes Corporation; Neal L. Oden (DCC statistician), The Emmes Corporation; and Maria J. Figueroa (DCC project director), The Emmes Corporation. SCORE2 Data and Safety Monitoring Committee: David C. Musch (chair), University of Michigan; Sangeeta Bhargava, National Eye Institute, National Institutes of Health; Dennis P. Han, Medical College of Wisconsin; Srinivas R. Sadda, Doheny Eye Institute; George A. Williams, Beaumont Eye Institute; and Stephen Wisniewski, University of Pittsburgh. Penn State University Study Chair’s Office: Ingrid U. Scott (study chair) and Janelle Gaston (research project manager). SCORE2 DCC: Paul VanVeldhuisen (principal investigator), Maria Figueroa (project director), Lena Bradley, Jodi De Stefano, Eileen Guan, Anne Hoehn, Alexa Irazabal, Sue Isman, Jacquie King, Radhika Kondapaka, Hamsa Kumar, Matt Lahut, Robert Lindblad, Neal Oden, Michael Patschak, Jan Peterson, Ro Shauna Rothwell, Rosemary Smith, Janet Van Dyke, Valerie Watson, and Lauren Yesko. SCORE2 Fundus Photograph Reading Center: Barbara A. Blodi (principal investigator), Amitha Domalpally (research director), Susan Reed (research program manager), and Pam Vargo (lead imaging specialist). Institute for Personalized Medicine: Cynthia Reed (patient enrollment specialist). SCORE2 clinical sites that participated in this study: Sites are listed in alphabetical order. Personnel are listed by their primary role as principal investigator (PI), subinvestigator (SI), clinic coordinator (CC), visual acuity technician (V), photographer (P), pharmacist (PH), and other (O). Black Hills Regional Eye Institute: Prema Abraham (PI), Beth Bement-Stump (V), Leah Callahan (CC), Mindi Dockter (V), Kristi Livermont (CC), Robert Nixon (SI), Dan Parks (P), Nathan Steinle (SI), Alison Thompson (CC), and Stephen Khachikian (SI); Casey Eye Institute, Oregon Health & Science University: Steven Bailey (SI), Jordan Barth (P), J. Peter Campbell (SI), Christina Flaxel (SI), Christopher Howell (P), Jocelyn Hui (P), Thomas Hwang (SI), Shirley Ira (V), Andreas Lauer (PI), Phoebe Lin (SI), Ann Lundquist (CC), Susan Nolte (V), Scott Pickell (P), Dawn Ryan (P), Mitchell Schain (CC), Peter Steinkamp (P), Chiedozie Ukachukwu (P), Sara Blefgen (PH), Brad Fujisaki (PH), Jeanne Liming (PH), Frank Mistretta (PH), and Jennifer Petrolati (PH); Center for Retina and Macular Disease: Adam Berger (SI), Erika Darby (P), Vera Dilts (V), Richard Hamilton (SI), Tammy McCarty (CC), Esmeralda Medina (CC), David Misch (SI), Suk Jin Moon (SI), Kari Owen (P), John Randolph (SI), Jason Strickland (P), Michael Tolentino (PI), Laura Holm (V), and Dawn Sutherland (CC); Charlotte Eye Ear Nose & Throat: Andrew Antoszyk (PI), David Browning (SI), Loraine Clark (P), Sarah Ennis (V), Christina Fleming (CC), Sherry Fredenberg (V), Lisa Jackson (P), Angie Karow (CC), Donna McClain (P), Michael McOwen (P), Angela Price (CC), Omar Punjabi (SI), Lynn Watson (P), Uma Balasubramaniam (P), Swann Bojaj (P), Autumn Finch (P), and Beverly Rowland (P); Cumberland Valley Retina Consultants: Allen Hu (SI), Donna King (V), Christa McChancy (P), Wendy McCullough (V), George Sanborn (SI), Becca Varner (P), Leslee Wallech (V), Shayla Ward (CC), David Warrow (SI), Cherie Wenger (P), Alison Wentz (CC), John Wroblewski (PI), Nicole Hollimon (P), Ejiatu Sesay (P), Veronica Shetler (V), and Kimberly Wood (P); Dean McGee Eye Institute: Shannon Almeida (CC), Joann Booth (P), Reagan Bradford (SI), Russ Burris (P), Mandi Butt (P), Stephen Fransen (SI), Sonny Icks (V), Ronald Kingsley (PI), Robert Leonard (SI), Alisha Parrett (CC), Vinay Shah (SI), and Vicki Wolzen (P); Delaware Valley Retina Associates: Krista Bayer (P), Morgan Harper (V), Darmakusuma Ie (PI), Lauren Knezek (P), Jeffrey Lipkowitz (SI), Beverly Sannazzaro (CC), Kekul Shah (SI), Lorraine Eggert (V), and Susan Geraghty (P); East Bay Retina Consultants Inc: Renjini Balakrishnan (CC), Fazilla Bano (V), Daniel Brinton (SI), Elyssa Casugay (CC), Roby Casupanan (V), Patty Chung (V), Caroline Frambach (V), Afsoon Jamali (P), Scott Lee (SI), Eugene Lit (PI), Scotty Renslow (CC), Soraya Rofagha (SI), Heidi Winje (CC), Heather Enyart (P), and Khaliah Jackson (V); Elman Retina Group PA: Jennifer Belz (CC), Theresa Cain (P), Teresa Coffey (V), Michael Elman (PI), Henry Leder (SI), Ashley Metzger (P), Dallas Sandler (V), Jennifer Simmons (V), Perel Simpson (V), Pamela Singletary (V), Peter Sotirakos (P), JoAnn Starr (CC), Amy Thompson (V), Ashley Davis (V), and Peggy Orr (V); Emory University Eye Center: Judy Brower (V), Linda Curtis (CC), Jannah Dobbs (P), Deborah Gibbs (CC), Andrew Hendrick (PI), G. Baker Hubbard (SI), Jiong Yan (SI), Debbie Jordan (P), Darien Middleton (O), and Susan Rogers (PH); Florida Retina Consultants: Steve Carlton (P), Damanda Fagan (CC), Scott Friedman (PI), Allen McKinney (V), Nader Moinfar (SI), Paige Walters (V), Katrina Dawson (CC), and Kimberly Williamson (CC); Georgia Retina: Jini Jones (P), Leslie Jones (V), Scott Lampert (SI), Leslie Marcus (CC), Krishna Mukkamala (SI), Maria Rogers (V), Atul Sharma (SI), Robert Stoltz (PI), Morgan West (P), Lindsey Neal (P), and Lauren Nunn (CC); Henry Ford Health System: Nitin Kumar (SI), Megan Allis (P), Paul Edwards (PI), John Grybas (P), Julianne Hall (CC), Nicole Massu (P), Mary Monk (CC), Jessica Nelson (P), Brian Rusinek (P), Jenny Shaheen (P), Bradley Stern (P), Tracey Troszak (P), David Burley (P), Uday Desai (SI), Hua Gao (SI), Thomas Hessburg (SI), Melina Mazurek (V), Janet Murphy (V), and Katie Ventimiglia (V); Illinois Eye and Ear Infirmary, University of Illinois at Chicago: Catherine Carroll (P), Felix Chau (SI), Mark Janowicz (P), Tametha Johnson (V), Jennifer Lim (PI), Yesenia Ovando (V), Natasa Stankovic (V), Jie (Jessica) Sun (CC), Lauren Talasnik (CC), Yannek Leiderman (SI), Marcia Niec (CC), and Lawrence Ulanski (SI); Loma Linda University: Raquel Hernandez (CC), Armand Assissini (P), Marvyn Cerdenio (CC), Joseph Fan (SI), Lynn Huang (SI), William Kiernan (V), Jesse Knabb (P), Michael Rauser (PI), Gisela Santiago (CC), Mukesh Suthar (SI), and Brandon Williams (P); Long Island Vitreoretinal Consultants: Michael Chitjian (P), Kristen D’Amore (CC), Vincent Deramo (SI), David Fastenberg (SI), Philip Ferrone (PI), Barry Golub (SI), Kenneth Graham (SI), Sandra Jaya (V), Jonathan Jonisch (SI), David Rhee (SI), Juan Romero (SI), Brett Rosenblatt (SI), Marianne Schlameuss (CC), Jeffrey Shakin (SI), Eric Shakin (SI), Vasanti Sookhai (V), and Jamie Szczepanski (V); Mayo Clinic: Sophie Bakri (PI), Andrew Barkmeier (SI), Jean Burrington (V), Shannon Goddard (P), Denise Lewison (P), Jessica Morgan (V), Joan Overend (V), Heidi Rubin (CC), Wendy Smith (SI), Jamie Tesmer (P), Stephanie Thatcher (P), Betsy Baker (CC), Gillian Currie (CC), Melissa Franzen (CC), Rebecca Nielsen (CC), and Diane Vogen (CC); Medical Center Ophthalmology Associates: Darren Bell (SI), Carrisa Bolado (CC), Jason Burns (SI), Melissa Dominguez (V), Rosa Escobar (P), Richard Evans (SI), Shelli Goel (P), Roxanne Gomez (V), Felicia Huron (V), Judy Rittimann (CC), Vincent Segovia (P), Michael Singer (PI), Catherine Ellis (CC), Guillermo Montoya (CC), and Cynthia Myrick (CC); Medical College of Wisconsin: Vicki Barwick (V), Joe Beringer (P), Joseph Carroll (SI), Thomas Connor (SI), Eleanor Dorsey (CC), Kristy Keller (P), Judy Kim (PI), Katie McKenney (CC), Stephanie Moebius (P), Krissa Packard (CC), David Weinberg (SI), Vesper Williams (CC), Pat Winter (V), William Wirostko (SI), Mara Goldberg (P), and Kimberly Stepien (SI); Mid Atlantic Retina: Hannah Benfield (CC), Christina Centinaro (V), Allen Chiang (SI), Lauren Devine (V), Mitchell Fineman (SI), Michele Formoso (CC), Sunir Garg (SI), Cedric George (O), Elaine Gonzales (P), Lisa Grande (V), Omesh Gupta (SI), Allen Ho (SI), Samuel Houston (SI), Jason Hsu (SI), Maryann Jay (P), Richard Kaiser (SI), Brianna Kenney (CC), Lisa Lavetsky (P), Theresa Listner (CC), Joseph Maguire (SI), Sonia Mehta (SI), Jill Noble (O), Carl Park (SI), Ehsan Rahimy (SI), David Reed (SI), Carl Regillo (PI), Noga Senderowitsch (CC), Arunan Sivalingam (SI), Marc Spirn (SI), and Jamilla Sudler (V); Midwest Eye Institute: Neil Finnen (PI), Charlotte Harris (P), Ingrid Kerr (CC), Raj Maturi (SI), Bethany Sink (CC), Thomas Ciulla (SI), Tammy Dale (V), Cindi Hood (P), Kristin Phillips (V), Ashley Radtke (V), Shyla Robson (P), and Tom Steele (P); National Ophthalmic Research Institute: A. Thomas Ghuman (PI), Cheryl Kiesel (CC), Ray Kiesel (P), Eileen Knips (P), Anita Leslie (V), Kristi Maro (CC), Crystal Peters (CC), Paul Raskauskas (SI), Cheryl Ryan (CC), Ashish Sharma (SI), Danielle Turnbo (V), Joseph Walker (SI), Laura Greenhoe (CC), Jessica Lynn Saez (CC), Natalie Torres (Crawford) (CC), and Glenn Wing (SI); New Jersey Medical School: Tamara Berezina (P), Neelakshi Bhagat (PI), Kathryn Boschert (CC), Eileen Buroff (V), Janie Ellenberger (CC), Catherine Fay (CC), Marian Konop (P), Michael Lazar (P), Tatiana Mikheyeva (P), Monique Roy (SI), and Marco Zarbin (SI); New York Eye and Ear Infirmary: Wanda Carrasquillo-Boyd (P), Yuen Ping Chui (SI), Ronald Gentile (SI), Melissa Rivas (CC), Richard Rosen (PI), Katy Tai (CC), Meliza Unson (V), Paul Whitten (P), Priya Mehta (V), and Alex Yang (V); NJ Retina: Howard Fine (SI), Laura Fox Gadless (CC), Eric Friedman (SI), Stuart Green (SI), Bruce Keyser (SI), Amy Leviton (V), Celeste Nelson (CC), Jennifer Pilato (CC), Jonathan Prenner (SI), Daniel Roth (SI), Alex Schlosser (P), Sumit Shah (PI), H. Matthew Wheatley (SI), David Yarian (SI), and Robyn Green (CC); Northern California Retina Vitreous Associates: Alok Bansal (SI), Edwin Boldrey (SI), Jesus Borrillo (SI), Louis Chang (SI), Sharon Depaz (CC), Andrea Gadda (V), Rahul Khurana (PI), Diana Lam (CC), James Palmer (SI), Olga Sessions (P), Mark Wieland (SI), Amy Dennis (V), Amy Goldstein (P), and Celeste Obando (P); Orange County Retina Medical Group: Trisha Ambrocio (CC), Marinel Casiano (CC), Eugene Chang (SI), Sanford Chen (PI), Millie Liu (V), Jessica Lowery (P), John Maggiano (SI), Rajiv Rathod (SI), and Timothy You (SI); Paducah Retinal Center: Carl Baker (PI), Tracey Caldwell (CC), Alecia Camp (P), Samantha Kettler (P), Margaret Orr (V), Mary Jill Palmer (V), Ron Tilford (SI), Lynnette Lambert (CC), Tracey Martin (V), and Tana Williams (P); Palmetto Retina Center: Lloyd Clark (PI), Rene Griggs (O), David Johnson (SI), Stephanie Karuza (CC), Peggy Miller (CC), Tiffany Ogbuewu (V), John Payne (SI), Robin Spivey (P), Ashley Studebaker (P), Deborah Watts (O), John Wells (SI), Ruth Bearden (O), Pamela Darlington (O), Tiffany Swinford (V), Mallie Taylor (CC), and Amanda Wilson (O); Palmetto Retina Center, LLC Florence: W. Lloyd Clark (SI), Ashley Floyd (V), Cassandra Garrison (CC), David Johnson (SI), Crystal Parker (V), John Payne (PI), Erin Poston (P), Kristin Welch (CC), John Wells (SI), Tyler Huggins (P), and Ashley Williams (P); Retina & Vitreous of Texas: Diana Abdelgani (CC), Colin Blank (P), Emmanuel Chang (SI), Deborah Fredrickson (V), Joseph Khawly (PI), Desiree Lopez (P), Donald Lowd (P), Jason Muniz (P), Erica Pineda (V), Hassan Rahman (SI), Lorena Martinez (V), Pam Miller (CC), and Arthur Willis (SI); Retina Associates: Ivan Batlle (PI), Karla Batlle (CC), Kiersten Bruce (V), Lexie Manning (CC), Samantha Perkins (P), Katherine Pippin (P), Frank Yeager (P), Ryan Christensen (SI), Blake Cooper (SI), David Dyer (SI), Gregory Fox (SI), Ravi Singh (SI), and Beatty Suiter (SI); Retina Associates of Cleveland Inc: Brett Amonett (CC), Cindy Boehm (P), Joseph Coney (SI), Jim Coyne (P), Tia Drugan (V), John DuBois (P), Gregg Greanoff (P), Mary Ilc (V), Aimee Kenska (P), Elizabeth McNamara (P), David Miller (SI), Michael Novak (SI), Llewelyn Rao (SI), Susan Rath (CC), Cecelia Rykena (V), Jerome Schartman (SI), Lawrence Singerman (PI), Vivian Tanner (CC), and Veronica Smith (CC); Retina Associates of Kentucky: Michelle Buck (P), Vernie Daniels (CC), Diana Holcomb (CC), Ricky Isernhagen (SI), John Kitchens (SI), Thomas Stone (SI), Jeanne Van Arsdall (V), Brenda VanHoose (V), William Wood (PI), Andrew Moshfeghi (PI), and Ed Slade (P); Retina Associates of Western New York: Mindy Burgess (V), Brian Connolly (SI), Mary Jo Doran (CC), Ernest Guillet (SI), Edward Hall (PI), Anne Reynard (V), Steven Rose (SI), Joseph Territo (P), Margaret Whelehan (P), and Meg Yagoda (CC); Retina Centers: Dyonne Bachmann (V), Sally Brandon (CC), Crystal Duncan (P), Stacey Halper (P), Amy Kan (CC), Shree Kurup (SI), George Novalis (SI), Ryan Wong (SI), Martin Worrall (PI), Kassandra Burdick (V), Jennifer Carreon (CC), Susana Flores (V), Henry Hudson (SI), Claudia Mendoza (P), Brianna Morris (V), and Patricia Wilkins (CC); Retina Consultants of Houston PA: Belinda Almanza (V), Matthew Benz (SI), David Brown (PI), JoLene Carranza (CC), Eric Chen (SI), Richard Fish (SI), Amy Hernandez (CC), Eric Kegley (P), Rosa Kim (SI), Nubia Landaverde (CC), James Major (SI), Beau Richter (P), Amy Schefler (SI), Robert Smith (O), Veronica Sneed (V), Tien Wong (SI), Charles Wykoff (SI), Meredith Berry (CC), Brenda Dives (V), Lauren Epp (CC), Nikki Franks (CC), Debbie Gillaspia (CC), Elizabeth Quellar (V), Tressa Royse (V), Cary Stoever (P), and Sushma Vance (SI); Retina Consultants of Nevada: Kelly Anderson (CC), Jennie Fabro (V), Joe Galura (P), Nikki Garcia (V), Leide Gomes (V), Rodney Hollifield (SI), Roy Loo (SI), Janet Marchese (CC), Ifeyinwa Okeke (V), Matthew Pezda (SI), Treseelyn Spencer (P), Allen Thach (PI), Jason Wickens (SI), Meher Yepremyan (SI), Thomas Arambula (P), Marcy Henry (P), Javier Rendorio (P), and Irene Voo (SI); Retina Group of Florida: Scott Anagnoste (SI), Lawrence Halperin (SI), Monica Hamlin (CC), Ann Marie Lamb (V), Angelia Mannarelli (P), Jamie Mariano (V), Krista Rosenberg (SI), Barry Taney (SI), W. Scott Thompson (SI), Eduardo Uchiyama (SI), Rita Veksler (P), Mario del Cid (PI), Jaclyn Brady-Pyka (CC), Mandeep Dhalla (SI), and Linda O’Koren (V); Retina Group of New England: Heather Casey (V), Nauman Chaudhry (PI), Justin Cocilo (P), Alison Fontecchio (V), and Emma German (CC); Retina Northwest: Peggy Charpentier (V), Michele Connaughton (P), Richard Dreyer (SI), Stephanie Ho (V), Christine Hoerner (P), Marcia Kopfer (CC), Michael Lee (SI), Joseph Logan (P), Colin Ma (SI), Apurva Patel (SI), Mark Peters (PI), Paul Tlucek (SI), Stephen Hobbs (CC), and Amanda Milliron (V); Retina Research Institute of Texas: Leah Adams (V), Cecilia Escamilla (O), Geneva Espinoza (P), Kristen Garcia (CC), Grant Janzen (SI), Seong Lee (SI), Priscilla Moreno (V), Sunil Patel (PI), Cindy Petty (CC), Gary Rickert (P), Deisy Villarreal (CC), and Eric Zavaleta (SI); Retina Vitreous Consultants: Robert Bergren (PI), Paul Conrad (SI), Dawn DiPerna (P), Amanda Fec (P), Keith McBroom (P), Lori Merlotti (CC), Karl Olsen (SI), David Steinberg (P), Lois Stepansky (V), Avni Vyas (SI), Julie Walter (V), Jennifer Chamberlin (CC), Bernard Doft (SI), James Eadie (SI), Moryssa Grossman (P), Pamela Rath (SI), and Christina Schultz (V); Retina Vitreous Surgeons of Central New York PC: Jamin Brown (SI), Stefanie DeSantis (P), Teresa Deforge (P), Christine Dorr (CC), G. Robert Hampton (PI), Lynn Kwasniewski (V), Michelle Manley (V), Nicole Robarge (P), Kevin Rosenberg (SI), Rajeev Seth (SI), Laurie Sienkiewycz (CC), Brandi Bellows (V), Viki Gabris (CC), Cindy Grinnell (CC), Christy Hall (CC), and Peter Hay (P); Retinal and Ophthalmic Consultants PC: Kim Clark (P), Brett Foxman (SI), Scott Foxman (SI), Natalie Mahan (CC), Thomas Margolis (PI), Chastity Mendez (V), Felisha Morales (P), Suzie Post (P), Julie Rosenthal (SI), and Qahdirah Torres (V); Retinal Consultants Medical Group: Margaret Chang (SI), Robert Equi (SI), Danny Lopez (P), Erin Nickerman (CC), Arun Patel (SI), Joel Pearlman (PI), Nanette Podesta (CC), J. Brian Reed (SI), David Telander (SI), Tony Tsai (SI), Brooke Waller (V), Robert Wendel (SI), and Kimberlee Wong (V); Retinal Consultants of Arizona: Mark Barakat (SI), Dayna Bartoli (P), Pravin Dugel (SI), David Goldenberg (SI), L. Milad Haak (SI), Valerie Hoback (CC), Sujit Itty (SI), Karim Jamal (SI), Norma Jimenez (P), Derek Kunimoto (PI), Ashleigh Levison (SI), Georgina Lopez-Wood (CC), John Martin (P), Sachin Mehta (SI), Neal Palejwala (SI), Edward Quinlan (SI), Nohemi Ramirez (V), Ignacio Torres (P), Diania Joy Wilson (CC), Sandra Arenas (V), and Elena Marcos (V); Retinal Consultants of San Antonio: Jaynee Baker (CC), Moises Chica (SI), Sarah Holy (SI), Lita Kirschbaum (CC), Richard Gary Lane (SI), Calvin Mein (PI), Brenda Nakoski (P), C. Sean Wienecke (P), Elaine Castillo (V), and Tori Moore (V); Sabates Eye Centers: Michael Cassell (PI), Yin Chen (CC), Gary Gallimore (P), Abraham Poulose (SI), Nelson Sabates (SI), Kelli Burge (V), Heather Elliott (P), Kristen Kietzman (CC), Nancy Kunjukunju (SI), Jeanne Niblock (V), Felix Sabates (PI), and April Snider (V); Sarasota Retina Institute: Melvin Chen (PI), Evelyn Inlow (CC), Peggy Jelemensky (CC), Marc Levy (SI), Rosa Miller (V), Tara Raphael (V), and Mark Sneath (P); Scheie Eye Institute: Jim Berger (P), Alexander Brucker (PI), Dominique Caggiano (CC), Judy Chen (CC), Sheri Drossner (V), Joan DuPont (CC), Benjamin Kim (SI), Sara Morales (P), Jessica Morgan (SI), Beth Serpentine (P), Brian VanderBeek (SI), and Armin Farazdaghi (V); Southeast Retina Center: Thomas Bailey (V), Ken Ivey (P), Dennis Marcus (PI), Siobhan Ortiz (CC), Harinderjit Singh (SI), Kim Tuey (CC), Michele Woodward (CC), Amina Farooq (CC), and Allison Foster (CC); Southeastern Retina Associates PC: Joseph Googe (SI), Raul Lince (P), Lisa Lovelady (CC), Tod McMillan (SI), Steve Morris (CC), Sarah Oelrich (P), Kristina Oliver (CC), Julie Rauen (V), R. Keith Shuler (PI), Justin Walsh (V), Patricia Coppola (V), and Jerry Whetstone (P); Southern California Desert Retina: Clement Chan (PI), Tiana Gonzales (CC), Kenneth Huff (P), Maziar Lalezary (SI), Steven Lin (SI), Lenise Myers (V), and Kim Walther (CC); Tennessee Retina: Everton Arrindell (SI), Carl Awh (PI), Amanda Briley (V), Brandon Busbee (SI), Talisha Campbell (V), Narey Cooper (CC), Tara Farmer (P), Sarah Hines (CC), Kenneth Moffat (SI), Stephanie Morrow (P), Franco Recchia (SI), David Reichstein (SI), Eric Schneider (SI), Natalie Schwebel (V), Shari Scott (V), Peter Sonkin (SI), Caleb Walker (P), R. Trent Wallace (SI), Julia Wray (P), Michelle Bowers (P), Amanda Ferrell (CC), Casi Fleischman (P), Paul (Dustin) Freeman (P), Kris Rose (V), Gina Smith (CC), Cora Sonnier (CC), Kyra Stepney (V), Katlyne Thompson (V), and Susan Wiser (CC); Texas Retina Associates–Arlington: Melissa Alva (CC), Michelle Curry (CC), Bob Boleman (P), David Callanan (SI), Jodi Creighton (V), Chris Dock (P), Sandy Lash (V), Wayne Solley (SI), and Patrick Williams (PI); Texas Retina Associates–Dallas: Rajiv Anand (SI), Sally Arceneaux (V), Daniel Carpintero (P), Deborah Chong (SI), Lori Coors (SI), Karl Csaky (SI), Karen Duignan (CC), Gary Fish (PI), Dwain Fuller (SI), Nick Hesse (P), Diana Jaramillo (CC), Michael Mackens (P), Samantha Marin (P), Brenda Sanchez (V), Tina Stanley (P), and Robert Wang (SI); The Ohio State University: William Bloom (CC), PJ Fish (P), Alan Letson (PI), Barbara Mihalik (V), Matthew Ohr (SI), Jerilyn Perry (V), and Jill Salerno (CC); The Retina Group of Washington: Daniel Berinstein (PI), Justin Davis (P), Irene Fanous (CC), Richard Garfinkel (SI), Jessica Iglesias (O), Thomas Johnson (SI), Molly Kalisch (V), Michael Lai (SI), Myradis Marin-Quinones (O), Alexander Melamud (SI), Bryan Murphy (P), Steve Rauch (P), Gayatri Reilly (SI), Maya Talatory (CC), Danielle Walker (V), Tanya Alexander-Snowden (CC), Sekou Alou (P), Thomas Blondo (V), Jennifer Camia (V), Ashley Chancey (CC), Clete Clark (O), William Deegan (SI), Vanessa Denny (V), Bryan Gallerson (V), Smitha Gopakumar (CC), Sarah Hanselman (V), Yury Iraheta (V), Andrew King (V), Robert Murphy (SI), Stacie Orencia (P), Michael Osman (SI), Jennifer Phosaksee (V), Pamela Renteria (V), Michael Rivers (SI), Reginald Sanders (SI), Nicole Schorer (V), Mona Shah (V), Manali Shah (CC), Tiffany Tam (V), and Manfred von Fricken (SI); The Retina Institute: Kevin Blinder (PI), Lynda Boyd (V), Erika Hoehn (CC), Ginny Nobel (CC), Kelly Pepple (V), Brooke Pulliam (V), Diana Reardon (V), Gaurav Shah (SI), Bradley Smith (SI), Maria Stuart (V), Rhonda Weeks (CC), Jarrod Wehmeier (P), Tim Wright (P), and Stephanie Guevara (V); The Retina Research Center: Brian Berger (PI), Saradha Chexal (SI), Boris Corak (V), Ivana Gunderson (V), Kimberly Hosein (CC), Chirag Jhaveri (SI), Ginger Manhart (CC), Yong Ren (P), Tina Seidu (CC), Chandler Stovall (P), Chelsey Bravenec (V), Brandon Nguyen (V), and Ryan Reid (V); TLC Eyecare & Laser Centers: Kristi Ballard (P), Ashley Blaisdell (P), Carmelina Gordon (PI), Heather Hill (V), Susan Partridge (V), Jennifer Wireman (CC), April Clay (CC), Shellie Fuentes (CC), Stephanie Gillispie (CC), Hailey Litzer (P), Elaine Lok (P), Bonnie Minier (CC), Tiffany Westgate (P), and Celia Wohlscheid (CC); University of California, Davis: Ashley Bryant (PH), Dominique Cargill (PH), Karishma Chandra (P), Sashi Deo (P), Lawrence Morse (SI), Ala Moshiri (SI), Susanna Park (PI), Ellen Redenbo (P), Marisa Salvador (V), Nadir Sarwary (PH), Igor Slabosnitskiy (P), Peter Trovitch (PH), Jessica Turner (PH), Cindy Wallace (CC), Marie Andrada (PH), and Katrina Imson (CC); University of California, San Francisco: Jacque Duncan (PI), Don Eubank (CC), Scott Fields (PH), Betty Hom (P), Mary Lew (V), Andrew Light (P), Arshia Mian (CC), and Jay Stewart (SI); University of Florida: Kakarla Chalam (PI), Ashley Cowart (V), Sandeep Grover (SI), Shailesh Gupta (SI), Shamim Haji (V), Ghulam Hamdani (CC), Sherri Hart (P), and Kumar Sambhav (CC); University of Kentucky: Miroslava Aprelkov (V), Claire Fraser (SI), Mike Hanson (P), Eric Higgins (SI), Mark Kleinman (SI), Deborah McDonald (P), P. Andrew Pearson (PI), Susan Phillips (O), Michele Reg (CC), Stephen Sitzlar (PH), Lakisha Smith (V), Peter Blackburn (SI), and Lyudmila Pigulko (V); University of Rochester Flaum Eye Institute: Mina Chung (PI), Gary Gagarinas (V), Rachel Hollar (P), Lisa Latchney (CC), Brittany Richardson (P), Andrea Czubinski (V), David DiLoreto (SI), Tanya Forbes (CC), and Taylor Pannell (P); University of Wisconsin: Angie Adler (CC), Michael Altaweel (PI), Barbara Blodi (SI), Kristine Dietzman (V), Justin Gottlieb (SI), Michael Ip (SI), Denise Krolnik (P), Jennie Perry-Raymond (CC), Sandie Reed (P), Christopher Smith (V), and John Peterson (P); UNMC Truhlsen Eye Institute: Lola Berg (P), Kristi Miller (CC), Maria Blaiotta (V), Diana Do (SI), Lisa Greer (CC), Fayez Jawed (V), Donna Neely (P), and Quan Nguyen (SI); UW Medicine Eye Institute: Brad Clifton (P), Patricia Ernst (V), Ron Jones (P), James Kinyoun (PI), Soojin Kyle (P), Jim Leslie (P), Juli Pettingill (V), Jeffrey Purcell (PH), Sue Rath (CC), Kasra Rezaei (SI), Gurunadh Vemulakonda (SI), and Bao-Chau Vo (O); Valley Retina Institute: Rohit Adyanthaya (SI), Monica Cantu (V), Santos Garza (P), Victor Gonzalez (PI), Jessica Muniz (P), Nehal Patel (SI), Yesenia Salinas (CC), Nancy Salinas (CC), Juan Santiago (SI), Lazaro Aguero (P), Deyla Anaya (CC), Roberto Diaz-Rohena (SI), Hector Jasso (P), Karina Miranda (V), Rachel Rodriguez (V), Jessica Rodriguez (CC), Kethsaly Salinas (CC), and Lissete Villanueva (CC); Vanderbilt Eye Institute: Tony Adkins (P), Milam Brantley (PI), Rocky Munn (P), Scott Ruark (CC), Richard Skellie (P), Anita Agarwal (SI), Joshua Carlson (SI), Edward Cherney (SI), Anthony Daniels (SI), Gowtham Jonna (SI), Stephen Kim (SI), Janice Law (SI), Sandy Owings (CC), Shriji Patel (SI), Paul Sternberg (SI), and Maryann Taylor-Ward (V); Virginia Eye Institute: Lea Anderlini (V), Mark Bartlett (P), James Combs (SI), Eleanore Ebert (SI), George Sanborn (SI), Michael Hughes (P), Byron Ladd (PI), Lynn Roderick (P), Karen Sullivan (CC), Melissa Vaughan (CC), and Kristin McKeever (V); Vitreoretinal Associates of Washington: A. Samuel Barloon (SI), Charles Birnbach (SI), Andrea Blustein (V), Robert Francis (SI), Renee Gagnon (CC), Pamela Goldman (P), Ray Hunt (V), Frances Kipp (V), Todd Klesert (SI), DeShawn Minnis (P), Robert Nash (SI), Tetyana Nazarchuk (CC), David Saperstein (PI), and Craig Wells (SI); and Vitreoretinal Surgery: Steven Bennett (SI), Tamra Bogolin (V), Holly Cheshier (P), John Davies (SI), Sundeep Dev (PI), Timothy Gromov (V), Jill Johnson (SI), Tori Jones (P), Robert Mittra (SI), Neal Oestreich (CC), D. Wilkin Parke (SI), Polly Quiram (SI), Robert Ramsay (SI), Joy Royle (V), Trenise Steele (P), Jessica Tonsfeldt (P), David Williams (SI), Carmen Chan-Tram (CC), Julianne Enloe (CC), Peggy Gilbert (V), and Carol Rogers (V).

Meeting Presentation: This article was presented at the Association for Research in Vision and Ophthalmology Annual Meeting; May 9, 2017; Baltimore, Maryland.

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