Visual Acuity, Vitreous Hemorrhage, and Other Ocular Outcomes After Vitrectomy vs Aflibercept for Vitreous Hemorrhage Due to Diabetic Retinopathy: A Secondary Analysis of a Randomized Clinical Trial

Key Points

Questions  Among eyes with vitreous hemorrhage due to proliferative diabetic retinopathy initially treated with aflibercept or vitrectomy with panretinal photocoagulation, what changes occur in visual acuity and other ocular outcomes?

Findings  In this comparative effectiveness study of 205 eyes undergoing treatment, no difference in mean visual acuity over 24 weeks was noted between treatment groups. Results of post hoc analyses show that the vitrectomy group had better visual acuity over 24 weeks of follow-up in the subgroup of eyes with baseline best-corrected visual acuity worse than 20/800.

Meaning  Aflibercept and vitrectomy are viable treatment options for vitreous hemorrhage due to proliferative diabetic retinopathy, and the results of this study may influence treatment decisions when initiating therapy.

Importance  Although there were no differences in mean visual acuity (VA) over 24 weeks after vitrectomy with panretinal photocoagulation (PRP) vs aflibercept in a randomized clinical trial among eyes with vitreous hemorrhage due to proliferative diabetic retinopathy (PDR), post hoc analyses may influence treatment choices.

Objective  To compare exploratory outcomes between treatment groups that may affect treatment choices for patients with vitreous hemorrhage due to PDR.

Design, Setting, and Participants  This post hoc analysis of a randomized clinical trial conducted at 39 DRCR Retina Network sites included adults with vision loss due to PDR-related vitreous hemorrhage for whom vitrectomy was considered. Data were collected from November 2016 to January 2020.

Interventions  Random assignment to 4 monthly injections of aflibercept vs vitrectomy with PRP. Both groups could receive aflibercept or vitrectomy during follow-up based on protocol-specific criteria.

Main Outcomes and Measures  Visual acuity area under the curve (adjusted for baseline VA) and clearance of vitreous hemorrhage.

Results  A total of 205 eyes were included in the analysis (115 male [56%] and 90 [44%] female participants; mean [SD] age, 57 [11] years). Among 89 eyes with a baseline VA of 20/32 to 20/160 (47 receiving aflibercept, including 4 [9%] that had undergone vitrectomy; 42 undergoing vitrectomy, including 3 [7%] that had received aflibercept), the adjusted mean difference in VA letter score over 24 weeks between the aflibercept and vitrectomy groups was −4.3 (95% CI, −10.6 to 1.9) compared with −16.7 (95% CI, −24.4 to −9.1) among 59 eyes with baseline VA worse than 20/800 (P = .02 for interaction; 26 in the aflibercept group, including 6 [23%] that had undergone vitrectomy; 33 in the vitrectomy group, including 8 [24%] that had received aflibercept). In the full cohort, the median time to clearance of the initial vitreous hemorrhage was 36 (interquartile range [IQR], 24-52) weeks in the aflibercept group vs 4 (IQR, 4-4) weeks in the vitrectomy group (difference, 32 [95% CI, 20-32] weeks; P < .001).

Conclusions and Relevance  Both initial aflibercept and vitrectomy with PRP are viable treatment approaches for PDR-related vitreous hemorrhage. Although this study did not find a significant difference between groups in the primary outcome of mean VA over 24 weeks of follow-up, eyes receiving initial vitrectomy with PRP had faster recovery of vision over 24 weeks when baseline VA was worse than 20/800 and faster vitreous hemorrhage clearance. Approximately one-third of the eyes in each group received the alternative treatment (aflibercept or vitrectomy with PRP). These factors may influence treatment decisions for patients initiating therapy for PDR-related vitreous hemorrhage.

Trial Registration  ClinicalTrials.gov Identifier: NCT02858076

Vitreous hemorrhage is common in patients with proliferative diabetic retinopathy (PDR) and can cause severe vision loss.¹ Despite treatment with panretinal photocoagulation (PRP) or intravitreous ranibizumab for PDR, almost half of the eyes in the DRCR Retina Network Protocol S developed vitreous hemorrhage during 5 years of follow-up.² Although vitreous hemorrhage can clear spontaneously, intervention may hasten visual recovery. Once the clinician and patient decide that intervention for the vitreous hemorrhage is needed, treatment options include injections of anti–vascular endothelial growth factor (anti-VEGF) agents to cause regression of neovascularization while the vitreous hemorrhage is reabsorbed or surgical removal of the vitreous hemorrhage and neovascular membranes with vitrectomy plus PRP.

The DRCR Retina Network Protocol AB compared eyes with vitreous hemorrhage due to PDR randomly assigned to initial intravitreous aflibercept injections or vitrectomy with PRP wherein eyes in both groups could receive aflibercept or vitrectomy during follow-up based on protocol-specific criteria.³ In Protocol AB, the mean visual acuity (VA) letter score over 24 weeks of follow-up (area under the curve) was 59.3 (Snellen equivalent, 20/63) in the aflibercept group vs 63.0 (Snellen equivalent, 20/63) in the vitrectomy group (adjusted difference, −5.0 [95% CI, −10.2 to 0.3]; P = .06). At 4 weeks, the mean VA was significantly better in the vitrectomy group; however, starting at the 12-week visit and over 2 years, VA was not significantly different between the groups. Per protocol, approximately one-third of the eyes assigned to aflibercept received vitrectomy and approximately one-third of eyes assigned to vitrectomy received aflibercept after vitrectomy over 2 years.

The primary results of Protocol AB demonstrated similar long-term VA outcomes and reasonable safety profiles when initiating treatment with either aflibercept or vitrectomy with PRP (eTable 1 in the Supplement).³ This report provides additional details on the DRCR Retina Network treatment regimens for the Protocol AB groups receiving aflibercept and vitrectomy with PRP and post hoc ocular outcomes that might influence treatment decisions for individual patients.

The study procedures have been reported previously.³ The study adhered to the tenets of the Declaration of Helsinki.⁴ Study participants provided written informed consent. The protocol was approved by the ethics board associated with each study site and is available on the DRCR Retina Network website.⁵ Participants were recruited at 39 clinical sites in the US. Study eyes had VA impairment (Snellen equivalent, 20/32 or worse) owing to PDR-related vitreous hemorrhage for which treatment was indicated. Eyes with traction retinal detachment were allowed if the detachment did not involve or threaten the macula. Eyes were randomly assigned to initial intravitreous injections of aflibercept, 2 mg (EYLEA, Regeneron), or vitrectomy with PRP. Data were collected from November 2016 to January 2020.

Eyes assigned to aflibercept received 4 monthly injections starting at baseline. Eyes received 2 additional injections unless neovascularization was absent with a clear view of the fundus at the 16- or 20-week visit, in which case injections were deferred (eFigure 1 in the Supplement). Thereafter, injections continued if the eye was improving or worsening with respect to vitreous hemorrhage and neovascularization. Injections were deferred when the vitreous hemorrhage and neovascularization stabilized (defined as no change since the last visit in the size and density of the hemorrhage and neovascularization on clinical examination after ≥2 consecutive injections). Vitrectomy was not performed within the first 16 weeks after initial aflibercept treatment unless 1 of the following serious adverse events occurred: retinal detachment involving or threating the macula, angle neovascularization, progressive iris neovascularization, or uncontrolled intraocular pressure from neovascular glaucoma or ghost cell glaucoma. Vitrectomy could be performed at the investigator’s discretion if vision-impairing vitreous hemorrhage was present after 16 weeks and 2 consecutive monthly injections. If vitrectomy was performed, the procedure was the same as that for eyes randomly assigned to vitrectomy, including application of intraoperative PRP.

Vitrectomy was performed per the investigator’s usual routine. The only protocol requirements were a 23-gauge or smaller vitrectomy system, no intraoperative aflibercept, and complete PRP during surgery (defined as 500-μm burns on the retina placed ≤1 to 2 burn widths apart beginning approximately  3000 μm from the macular center and extending at least to the equator in all directions). Aflibercept was permitted within 1 to 14 days before surgery but was prohibited during surgery and through 4 weeks after surgery. Cataract extraction and epiretinal or internal limiting membrane peeling were performed at the surgeon’s discretion.

If vitreous hemorrhage recurred 4 weeks after vitrectomy or later, aflibercept was given to clear the hemorrhage without additional surgery. If the hemorrhage persisted after 2 monthly aflibercept injections, repeat vitrectomy or additional aflibercept injections were performed at the investigator’s discretion. Aflibercept also could be given if neovascularization persisted.

The main between-group outcome was the difference in mean VA letter score between treatment groups by baseline VA over 24 weeks (area under the curve; primary outcome in Protocol AB) and at 4, 12, 24, 52, and 104 weeks. Subgroups were chosen post hoc to have similar sample size and were defined as having a VA of 20/32 to 20/160 (letter score, 78-39), 20/200 to 20/800 (letter score, 38-4), and worse than 20/800 (letter score, ≤3). Additional between-group outcomes included the occurrence of any of the following over 2 years: VA of 20/25 or better (letter score, ≥79), clearance of initial vitreous hemorrhage, resolution of retinal neovascularization, or cataract extraction. Presence of vitreous hemorrhage and neovascularization (defined as neovascularization of the disc or elsewhere) were assessed by investigators on clinical examination. Within-group outcomes included presence of traction retinal detachment during initial vitrectomy by timing of preoperative aflibercept injection (vitrectomy group only), presence of vitreous hemorrhage by visit, VA after recurrent vitreous hemorrhage, VA by presence of retinal neovascularization at 4 and 104 weeks, and VA before and after cataract extraction.

Outcomes were evaluated post hoc and should be considered exploratory. Two-sided P < .05 indicated significance. There was no adjustment for multiplicity. Analyses of mean VA were conducted via robust regression using M-estimation and the bisquare weight function with covariate adjustment for baseline VA and lens status. Time-to-event outcomes were compared between treatment groups with the log-rank test, cumulative probabilities were calculated using the product-limit estimator, and 95% CIs for the difference in median time to event were calculated via bootstrapping. Analyses were conducted with SAS software, version 9.4 (SAS Institute Inc).

Among the 205 eyes included (115 male [56%] and 90 female [44%] participants; mean [SD] age, 57 [11] years), the median baseline VA letter score was 37.0 (interquartile range [IQR], 63.0-0.0; Snellen equivalent, 20/200) in the study eye and 78.0 (IQR, 84.0-68.0; Snellen equivalent, 20/32) in the fellow eye. Among fellow eyes, VA was worse than the study eye in 13 (6%) and worse than 20/40 in 54 (26%).

The mean VA over 24 weeks was better for the vitrectomy vs aflibercept groups when baseline VA was worse than 20/800 but not when baseline VA was better (P = .02 for interaction) (Figure 1 and eTable 2 in the Supplement). Among eyes with a baseline VA of 20/32 to 20/160, the mean VA letter score over 24 weeks in the aflibercept group (n = 47) was 72.2 (95% CI, 76.5-68.0; Snellen equivalent, 20/40) vs 76.6 (95% CI, 81.1-72.1; Snellen equivalent, 20/32) in the vitrectomy group (n = 42) (adjusted difference, −4.3 [95% CI, −10.6 to 1.9]). Among eyes with a baseline VA of 20/200 to 20/800, the mean VA letter score over 24 weeks in the aflibercept group (n = 24) was 60.1 (95% CI, 66.1-54.2; Snellen equivalent, 20/63) vs 63.6 (95% CI, 69.7-57.6; Snellen equivalent, 20/63) in the vitrectomy group (n = 23) (adjusted difference, −3.5 [95% CI, −12.0 to 5.0]). Among eyes with a baseline VA worse than 20/800, the mean VA letter score over 24 weeks in the aflibercept group (n = 26) was 48.4 (95% CI, 54.1-42.7; Snellen equivalent, 20/125) vs 65.1 (95% CI, 70.2-60.0; Snellen equivalent, 20/50) in the vitrectomy group (n = 33) (adjusted difference, −16.7 [95% CI, −24.4 to −9.1]).

The effect of baseline vision on VA over 24 weeks was driven by differences at 4 weeks (eTable 2 in the Supplement). The adjusted mean difference in VA letter score between treatment groups at 4 weeks was −6.9 (95% CI, −15.6 to 1.8) among eyes with a baseline VA of 20/32 to 20/160, −8.4 (95% CI, −20.8 to 4.1) among eyes with a baseline VA of 20/200 to 20/800, and −42.9 (95% CI, −54.2 to −31.6) among eyes with a baseline VA worse than 20/800. For interaction between baseline VA and treatment group on VA at 4 weeks, the difference was significant at P < .001, compared with P = .84 at 12 weeks, P = .28 at 24 weeks, P = .74 at 52 weeks, and P = .66 at 104 weeks. The distribution of VA by baseline VA and visit is shown in eFigure 2 in the Supplement.

The probability of achieving VA of 20/25 or better over 4 weeks was 16% (95% CI, 10%-25%) in the aflibercept group and 30% (95% CI, 23%-40%) in the vitrectomy group (difference, −14% [95% CI, −26% to −3%]); over 2 years, the probability was 78% (95% CI, 70%-86%) in the aflibercept group and 70% (95% CI, 61%-79%) in the vitrectomy group (difference, 8% [95% CI, −4% to 20%]; P = .60) (eFigure 3 in the Supplement). The interaction between baseline VA and treatment was not significant with P = .38 (eFigure 4 in the Supplement).

Over 2 years in the aflibercept group, vitrectomy was performed in 11 of 48 eyes (23%) with a baseline VA of 20/32 to 20/160, 6 of 26 eyes (23%) with a baseline VA of 20/200 to 20/800, and 16 of 26 eyes (62%) with a baseline VA of worse than 20/800. Before 24 weeks, the rates were 4 of 47 (9%) for VA of 20/32 to 20/160, 4 of 24 (17%) for VA of 20/200 to 20/800, and 6 of 26 (23%) for VA of worse than 20/800. In the vitrectomy group, aflibercept was given after vitrectomy over 2 years in 14 of 48 eyes (29%) with a baseline VA of 20/32 to 20/160, 7 of 24 eyes (29%) with a baseline VA of 20/200 to 20/800, and 13 of 33 eyes (39%) with a baseline VA worse than 20/800; before 24 weeks, the rates were 3 of 42 (7%) for VA of 20/32 to 20/160, 2 of 23 (9%) for VA of 20/200 to 20/800, and 8 of 33 (24%) for VA worse than 20/800.

Forty-four of 105 eyes (42%) in the vitrectomy group received aflibercept a median of 6 days before the initial vitrectomy. Traction retinal detachments were noted during surgery in 5 of 26 eyes (19%) that received aflibercept 6 or fewer days before initial vitrectomy, 3 of 18 eyes (17%) that received aflibercept 7 or more days before vitrectomy, and 7 of 59 eyes (12%) that did not receive aflibercept before vitrectomy.

Based on clinician assessment, vitreous hemorrhage was present at 24 weeks in 61 of 95 eyes in the aflibercept group (64%) and 10 of 97 eyes in the vitrectomy group (10%) (P < .001) (Figure 2). At 2 years, vitreous hemorrhage was present in 34 of 89 eyes in the aflibercept group (38%) and 3 of 86 eyes in the vitrectomy group (3%) (P < .001). The median time to clearance of initial vitreous hemorrhage was 36 (IQR, 24-52) weeks in the aflibercept group vs 4 (IQR, 4-4) weeks in the vitrectomy with PRP group (difference, 32 [95% CI, 20-32] weeks; P < .001) (Figure 3).

The cumulative probability of recurrent hemorrhage (after initial vitreous hemorrhage clearance) over 2 years was 53% (95% CI, 43%-63%) in the aflibercept group vs 17% (95% CI, 11%-26%) in the vitrectomy group (difference, 36% [95% CI, 23%-48%]; P < .001) (eFigure 5 in the Supplement). The median change in VA letter score from the visit before the first recurrent hemorrhage to the visit with recurrent hemorrhage was −6.0 (IQR, −26.0 to 0.0) in the aflibercept group (n = 51) and −31.0 (IQR, −78.0 to −6.0) in the vitrectomy group (n = 17). At 104 weeks, the median VA letter score among eyes that had recurrent hemorrhage during follow-up was 78.0 (IQR, 85.0-67.0; Snellen equivalent, 20/23) in the aflibercept group (n = 46) and 71.5 (IQR, 80.0-5.0; Snellen equivalent, 20/40) in the vitrectomy group (n = 14); among eyes without recurrent vitreous hemorrhage, the median VA letter score was 76.5 (IQR, 85.0-62.0; Snellen equivalent, 20/32) in the aflibercept group (n = 44) and 80.0 (IQR, 85.0-72.0; Snellen equivalent, 20/25) in the vitrectomy group (n = 73).

The median time to resolution of retinal neovascularization over 2 years was 12 (IQR, 12-24) weeks with aflibercept vs 4 (IQR, 4-12) weeks with vitrectomy (difference, 8 [95% CI, 8-8] weeks; P < .001) (Figure 4). Eyes could not be fully assessed for retinal neovascularization at 151 of 1509 visits (10%; due to vitreous hemorrhage in 127 cases [84%]). The percentage of eyes with retinal neovascularization by visit and group is shown in Figure 5. In the aflibercept group, the median VA letter score at 4 weeks among eyes with retinal neovascularization (n = 31) was 72.0 (IQR, 80.0-54.0; Snellen equivalent, 20/40) vs 71.5 (IQR, 77.0-66.0; Snellen equivalent, 20/40) among eyes without retinal neovascularization (n = 22). Among 42 eyes in which neovascularization could not be assessed, the median VA letter score was 47.5 (IQR, 62.0-0.0; Snellen equivalent, 20/125). At 104 weeks in the aflibercept group, the median VA letter score among eyes with retinal neovascularization (n = 20) was 78.5 (IQR, 84.0-68.0; Snellen equivalent, 20/32) vs 78.0 (IQR, 85.5-65.0; Snellen equivalent, 20/32) among eyes without neovascularization (n = 68).

Among eyes that were phakic at baseline (75 in the aflibercept group and 81 in the vitrectomy group), the cumulative probability of cataract extraction by 2 years was 31% (95% CI, 22%-43%) in the aflibercept group vs 28% (95% CI, 19%-40%) in the vitrectomy with PRP group (difference, 2% [95% CI, −13% to 17%]; P = .81) (eFigure 6 in the Supplement). The median VA letter score gain from the visit preceding cataract extraction to the visit after cataract extraction was 19.0 (IQR, 5.0-31.0) in the aflibercept group (n = 22) and 11.0 (IQR, 1.0-31.0) in the vitrectomy group (n = 21) (eTable 3 in the Supplement). At 104 weeks, the median VA letter score among eyes that underwent cataract extraction during the study was 78.0 (IQR, 83.0-65.0; Snellen equivalent, 20/32) in the aflibercept group (n = 21) and 78.5 (IQR, 86.0-55.0; Snellen equivalent, 20/32) in the vitrectomy group (n = 20).

Although the vitrectomy group experienced faster visual recovery than the aflibercept group, especially among the post hoc subgroup of eyes with a baseline VA of worse than 20/800 (59 of 205 eyes, or 29% of the cohort), visual recovery after 24 weeks and over 2 years was not significantly different between groups regardless of baseline VA. The potential advantages of initial vitrectomy include faster clearance of initial vitreous hemorrhage, lower rate of recurrent vitreous hemorrhage, and avoidance of aflibercept injections in approximately two-thirds of eyes. The potential advantages of initial aflibercept include avoidance of vitrectomy in approximately two-thirds of eyes and similar VA from 12 weeks onward. Rates of cataract extraction were not significantly different between the groups.

The process of choosing a treatment approach for an individual is multifaceted. However, the effect on VA, both in the short and long term, is a critical consideration. Although VA was not significantly different between groups by 12 weeks and over 2 years, there was a difference in VA at 4 weeks favoring initial vitrectomy with PRP. Therefore, patients who want to hasten their visual recovery may choose vitrectomy. This early benefit may be most pronounced in eyes with a baseline VA worse than 20/800, presumably due to dense vitreous hemorrhage. Faster visual recovery may be important for patients who are functionally monocular and rely on vision from the eye with vitreous hemorrhage. In this cohort, 26% of participants had VA in the fellow eye that was worse than 20/40 at baseline, emphasizing the need for prompt VA recovery.

Clinicians and patients may initiate treatment with vitrectomy and PRP for patients seeking to minimize future visits and injections. Compared with initial aflibercept, initial vitrectomy and PRP resulted in fewer visits (median, 19 vs 12) and injections (mean, 9 vs 2) over 2 years.³ Unlike anti-VEGF therapy, vitrectomy directly removes vitreoretinal traction. Release of traction and the performance of endolaser may contribute to the lower likelihood of recurrent vitreous hemorrhage and persistent retinal neovascularization in the vitrectomy group. The presence of neovascularization did not appear to substantially affect VA; however, VA was worse in eyes for which the fundus could not be completely assessed (usually due to vitreous hemorrhage).

Anti-VEGF therapy could be preferable for individuals who prefer in-office procedures to intraocular surgery and its attendant risks, are unable to receive medical clearance for intraocular surgery, have concomitant diabetic macular edema (DME) requiring anti-VEGF treatment, or have limited access to vitreoretinal surgery. Furthermore, PRP damages peripheral visual fields.^2,6 This study provides reassurance that VA outcomes with either approach are, on average, similar from 12 weeks through 2 years.

Based on the Protocol AB results, rates of cataract development and anti-VEGF treatment for DME may not contribute to the risk-benefit comparison between initial aflibercept vs vitrectomy and PRP. Increased rates of cataract have been reported after vitrectomy,⁷ perhaps related to changes in oxygen gradient within the eye.⁸ In Protocol AB, however, rates of cataract extraction were not higher with vitrectomy vs aflibercept. Among eyes that underwent cataract surgery, VA was good in both groups. Furthermore, there was no significant difference in the rate of center-involved DME at 2 years, or the proportion receiving aflibercept for DME over 2 years.³

One-third of eyes in both groups received the alternative treatment per protocol during 2 years of follow-up. Adherence with long-term follow-up should be stressed because eyes with vitreous hemorrhage from PDR may need supplemental treatment after initial aflibercept or vitrectomy with PRP.

This study has several limitations. First, the analyses were post hoc and involved subgroups with limited sample sizes; therefore, the findings should be considered exploratory. Second, although the anti-VEGF treatment algorithm that was used is based on Network Investigator Group consensus and mirrors previous DRCR Retina Network treatment algorithms for DME and PDR, different results might be obtained with different thresholds for treatment or different anti-VEGF agents. Third, although the protocol required the surgical instrumentation to be 23-gauge or smaller, surgeons were allowed to use their standard surgical approaches to improve the generalizability of the results; thus, the vitrectomy procedure varied between surgeons with regard to the use of intraoperative agents, postoperative filtered air or gas, and additional procedures such as epiretinal membrane or internal limiting membrane peeling. Fourth, in the time-to-event analyses, outcomes may have been recorded earlier in the aflibercept group because eyes were examined more frequently (ascertainment bias). Fifth, results beyond 2 years, especially in eyes treated with anti-VEGF without PRP, are unknown.

The results of this comparative effectiveness study suggest that both intravitreous aflibercept and vitrectomy with PRP are viable first-line options for the treatment of vitreous hemorrhage due to PDR. Although a significant difference was not observed between the treatment groups in the primary outcome of mean VA over 24 weeks, eyes that had initial vitrectomy with PRP had faster recovery of vision when baseline VA was worse than 20/800 and faster clearing of initial vitreous hemorrhage. Approximately one-third of the eyes in each group received the alternative treatment (aflibercept or vitrectomy with PRP). These factors may influence treatment decisions for individual patients who are initiating therapy for vitreous hemorrhage from PDR.

Accepted for Publication: March 2, 2021.

Published Online: May 6, 2021. doi:10.1001/jamaophthalmol.2021.1110

Corresponding Author: Adam R. Glassman, MS, Jaeb Center for Health Research, 15310 Amberly Dr, Ste 350, Tampa, FL 33647 (drcrstat2@jaeb.org).

Author Contributions: Mr Glassman had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Glassman, Beaulieu, Antoszyk, Jampol, Sun.

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

Drafting of the manuscript: Glassman, Beaulieu, Antoszyk, Jampol, Sun.

Critical revision of the manuscript for important intellectual content: Beaulieu, Maguire, Antoszyk, Chow, Elman, Jampol, Salehi-Had, Sun.

Statistical analysis: Glassman, Beaulieu, Maguire, Chow.

Obtained funding: Glassman, Jampol, Sun.

Administrative, technical, or material support: Glassman, Salehi-Had.

Supervision: Glassman, Maguire, Antoszyk, Elman, Salehi-Had, Sun.

Conflict of Interest Disclosures: Mr Glassman reported receiving grants from the National Eye Institute (NEI), Regeneron Pharmaceuticals, Inc, and Genentech, Inc. Dr Beaulieu reported receiving grants to his institution from the NEI, Regeneron Pharmaceuticals, Inc, and Genentech, Inc. Dr Maguire reported receiving grants to her institution from the NEI, Regeneron Pharmaceuticals, Inc, and Genentech, Inc, and professional fees paid to her from Genentech, Inc. Dr Antoszyk reported receiving grants from Roche Genentech and personal/consultant fees from Jaeb Center for Health Research, Opthea, Clearside Biomedical, Inc, and Roche Genentech. Dr Elman reported receiving professional fees from Allergan plc, MEDIforce DME, and Genentech, Inc, and clinical/epidemiological research support from Apellis Pharmaceuticals, Inc, Graybug Vision, Inc, National Institutes of Health (NIH), Neurotech FPO, Novartis AG, Optos, and Global Life Science Ltd. Dr Jampol reported receiving grants from the NEI and personal fees from Sanofi SA. Dr Sun reported receiving grants from Roche Genentech, Juvenile Diabetes Research Foundation, and KalVista Pharmaceuticals, Inc; personal fees from Current Diabetes Reports, JAMA Ophthalmology, and Merck & Co, Inc; and nonfinancial support from Optovue (equipment loaned for research), Roche Genentech (food/beverage), and KalVista Pharmaceuticals, Inc (travel support). No other disclosures were reported.

Funding/Support: This study was supported through cooperative agreement EY14231 from the NEI and the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, US Department of Health and Human Services. Regeneron provided aflibercept for the study and funds to the DRCR Retina Network to defray the study’s clinical site costs.

Role of the Funder/Sponsor: As per the DRCR Retina Network Industry Collaboration Guidelines (https://public.jaeb.org/drcrnet/view/Investig_Info), the DRCR Retina Network had complete control over the design of the protocol, ownership of the data, all editorial content of presentation and publication related to the protocol, and the decision to submit the manuscript for publication. The NIH participated in oversight of the conduct of the study and review of the manuscript but not directly in the design or conduct of the study, nor in the collection, management, analysis, or interpretation of the data, or in the preparation of the manuscript.

Group Information: DRCR Retina Network Coordinating Center Staff, Jaeb Center for Health Research, Tampa, Florida (staff as of 2/24/2021): Adam R. Glassman, MS (Interim Executive Director and DRCR Retina Network Principal Investigator), Roy W. Beck, MD, PhD (president), Alyssa Baptista, BS, Wesley T. Beaulieu, PhD, Claire T. Calhoun, MS, Sharon R. Constantine, BS, Isabella Correia, BS, Brian B. Dale, Simone S. Dupre, BS, Sandra Galusic, MSPH, Meagan Huggins, BA, Brenda L. Hunter, BS, Paula A. Johnson, MPH, Kristen Josic, PhD, Brittany Kelly, MS, Danni Liu, MSPH, Maureen G. Maguire, PhD, Michele Melia, ScM, Carin M. Preston, MPH, Cynthia R. Stockdale, MSPH, Katie Stutz, BS, and Alice Zokruah, MS. Duke Reading Center Staff: Katrina Postell Winter, BS (lead reader), Garrett Thompson, MD (reader), Dee Busian, BA (reader), Glenn J. Jaffe, MD (director of grading), Adiel Mora, BA (project manager), Lucia Foster, MA (project manager assistant), and John Keifer McGugan, BS (project manager assistant). DRCR Retina Network Chair: Jennifer K. Sun, MD, MPH, Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology (2018-present); Daniel F. Martin, MD, Cole Eye Institute at Cleveland Clinic (2018-present); Lee M. Jampol, MD, Feinberg School of Medicine, Northwestern University (2013-2017); and Neil M. Bressler, MD, Department of Ophthalmology, Johns Hopkins University School of Medicine (2006-2012). DRCR Retina Network Vice Chairs: Carl W. Baker, MD, Paducah Retinal Center (2011-2013, 2017-2019); Chirag Jhaveri, MD, Retina Consultants of Austin (2016-2018); Mathew MacCumber, MD, PhD, Rush University Medical Center (2018-2020); Andrew N. Antoszyk, MD, Charlotte Eye Ear Nose & Throat Associates, PA (2013-2016, 2020); Susan B. Bressler, MD, Wilmer Eye Institute (2009-2011); Scott Friedman, MD, Florida Retina Consultants (2009-2012); Judy Kim, MD, Medical College of Wisconsin (2015-2017); Ingrid U. Scott, MD, MPH, Penn State College of Medicine (2009-2010); Jennifer K. Sun, MD, MPH, Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology (2012-2014); and John A. Wells III, MD, Palmetto Retina Center (2013-2015). National Eye Institute: Sangeeta Bhargava, PhD (2016-current) and Eleanor Schron, PhD (2009-2015). Executive Committee: Andrew N. Antoszyk, MD, Charlotte Eye Ear Nose & Throat Associates, PA (2009; 2013-present); Darrell Baskin, MD, San Antonio, Texas Retinal Consultants of San Antonio (2021-present); Roy W. Beck, MD, PhD, Jaeb Center for Health Research (2002-present); Sangeeta Bhargava, PhD, NEI/NIH (2016-present); Emily Chew Frederick L. Ferris III, MD, Ophthalmic Research Consultants (2002-present); Adam R. Glassman, MS, Jaeb Center for Health Research (2005-present); Glenn J. Jaffe, MD, Duke Reading Center (2012-present); Lee M. Jampol, MD, Feinberg School of Medicine, Northwestern University (2012-present); Chirag D. Jhaveri, MD, Retina Consultants of Austin (2016-present); Mathew MacCumber, MD, PhD, Rush University Medical Center (2018-present); Daniel F. Martin, MD, Cole Eye Institute at Cleveland Clinic (2017-present); Raj K. Maturi, MD, PC (2009-2011, 2013-present); Sharon D. Solomon, MD, Baltimore, Maryland Wilmer Eye Institute at Johns Hopkins (2021-present); and Jennifer K. Sun, MD, MPH, Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology (2009-present); prior members: Lloyd Paul Aiello, MD, PhD, Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School (2002-2018; chair 2002-2005); Carl W. Baker, MD, Paducah Retinal Center (2009-2019); Abdhish Bhavsar, MD, Retina Center of Minnesota (2007-2008, 2010-2012); Barbra Blodi, MD, University of Wisconsin, Madison (2014-2020); Neil M. Bressler, MD, Department of Ophthalmology, Johns Hopkins University School of Medicine (2006-2019; chair 2006-2008); Susan B. Bressler, MD, Wilmer Eye Institute (2009-2019); Alexander J. Brucker, MD, Scheie Eye Institute (2009-2011); Kakarla V. Chalam, MD, PhD, MBA, Loma Linda University Eye Institute (2009-2011); Ronald P. Danis, MD, University of Wisconsin, Madison (2004-2015); Matthew D. Davis, MD, Medical College of Wisconsin (2002-2017); Michael J. Elman, MD, Elman Retina Group, PA (2006-2018; chair 2009 and 2012); Donald F. Everett, MA, NEI/NIH (2002-2009); Joan Fish, RN, CCRC, Wake Forest University Eye Center (2008-2009); Scott Friedman, MD, Florida Retina Consultants (2007-2013); Joseph Googe Jr, MD, Southeastern Retina Associates, PC (2009-2011); Jeffrey G. Gross, MD, Carolina Retina Center, PA (2012-2017); Diana M. Holcomb, COA, Retina Associates of Kentucky (2011-2012); Judy E. Kim, MD, Medical College of Wisconsin (2020, 2015-2017); Andreas K. Lauer, MD, Casey Eye Center (2007-2008); Brandon Lujan, MD, Casey Eye Center (2017-2020); Dennis M. Marcus, MD, Southeast Retina Center, PC (2011-2012, 2018-present); Ashley A. McClain, BS, CRC, Charlotte Eye Ear Nose & Throat Associates, PA (2013); Brandi J. Perez, Loma Linda University Eye Institute (2013); Eleanor Schron, PhD, NEI/NIH (2009-2015); Ingrid U. Scott, MD, MPH, Penn State College of Medicine (2009-2010); JoAnn Starr, BS, Elman Retina Group, PA (2009-2011); and John A. Wells III, MD, Palmetto Retina Center (2012-2015). Data and Safety Monitoring Committee: Gary Abrams, MD, Kresge Eye Institute; Deborah R. Barnbaum, PhD, Kent State University; Harry Flynn, MD, Bascom Palmer Eye Institute; Kyle D. Rudser, PhD, University of Minnesota; Paul Sternberg Jr, MD, Vanderbilt Eye Institute; Sangeeta Bhargava, PhD, NEI/NIH; Ruth S. Weinstock, MD, PhD, SUNY Upstate Medical University; Stephen Wisniewski, PhD, University of Pittsburgh; John Connett, PhD, University of Minnesota (chair, 2003-2015); and Charles P. Wilkinson, MD, Greater Baltimore Medical Center (2012-2018). DRCR Retina Network clinical sites that participated in this protocol: Atlantis Eye Care, Huntington Beach, California: Hani Salehi-Had, MD (study investigator [I]); Evelyn Ceja (coordinator [C]); Sara Ahmed, BS (C); Stephanie Ramirez (C, photographer [P], visual acuity technician [V]); Mailan Tran, OD (V); Mary Ma, OD (V); Scott F. Lee, OD (V); Nikki Nguyen, BS (P); Lily Castillo (P); and Janet Reyes (P). Retina Research Center, Austin, Texas: Chirag D. Jhaveri, MD (I); Gowtham Jonna, MD (I); Saradha Chexal, MD (I); Daniela Mariel Wilson (C); Ivana Gunderson (V); Tina A. Seidu (C); Cori Renfroe (C); Ryan M. Reid (C, P); Valerie Gatavaski (V); Abla M. Harara (V); Boris Corak, BS (P, V); and Yong Ren (P). Charlotte Eye Ear Nose & Throat Associates, PA, Charlotte, North Carolina: Andrew N. Antoszyk, MD (I); Omar S. Punjabi, MD (I); David Browning, MD, PhD (I); Angela K. Price, MPH (C, V); Christina J. Fleming, BS, CCRP (C, V); Taylor S. Jones (C, V); Sherry L. Fredenberg (C, V); Brittany A. Murphy, BA, COT (C, V); Sarah A. Ennis (V); Kayla A. Bratcher (V); Christina Mutch (V); Angella K. Gentile (V); Erica Breglio (V); Lisa A. Jackson (P); Loraine M. Clark, COA (P); Lynn Watson (P); Donna McClain, COA (P); Carol A. Shore (P); Uma M. Balasubramaniam (P); and Shannon Stobbe (P). Raj K. Maturi, MD, PC, Indianapolis, Indiana: Raj K. Maturi, MD (I); David A. Lightman, MD (I); Stephen J. Saxe (I); Ashley M. Harless (C, P, V); Lorraine White (C, P, V); Myra K. Retrum (V); Carolee K. Novak, CRC (V); and Yesenia Sarmiento (P). Valley Retina Institute, McAllen, Texas: Victor Hugo Gonzalez, MD (I); Nehal R. Patel, MD (I); Elyssa Navarro (C); Nancy L. Salinas (C); Angelina Garza, BS (C); Amber B. Ibarra, BS (C); Ana L. Pina, BA (C); Monica R. Cantu, COT (V); Brenda Velasquez (V); Christina Villegas (V); Enrique Chavez (V); Isaac Cabrera (V); Yvonne Diaz (V); Jennifer Moreno (V); Rebecca R. Flores, COA (V); Janette Arredondo (V); Monique Montemayor, COA (P); Georgia L. Villarreal (P); Stephanie Tamez (P); Samuel Alonso (P); and Santos Garza (P). Palmetto Retina Center, West Columbia, South Carolina: John A. Wells III, MD (I); John F. Payne, MD (I); Tiffany R. Swinford (C, V); Cassandra L. Garrison, BS, COT (C); Kristin R. Stokes (C); Ashley Floyd (V); Tiffany N. Ogbuewu (V); Robbin Spivey (P); and Ashley Studebaker (P). Retinal Diagnostic Center, Campbell, California: Clement Chow, MD (I); Amr Dessouki, MD (I); Lingmin He, MD (I); Joel M. Barra, BSBM, CCRP (C); Whitney Kuang (C, V); Carla Trujillo (C); Danielle Dinh (C, V); Thanh T. Nguyen (C); Lynise Cummins (C, V); Kelly To (V); Hienmy Dang (V); Dao Tran (V); Pete Donovan Fernandez (P); Kenny Trang (P); Tim Kelley (P); and Juan Hernandez (P). Elman Retina Group, PA, Baltimore, Maryland: Michael J. Elman, MD (I); JoAnn Starr (C); Jennifer L. Belz (C); Twyla J. Robinson (C); Pamela V. Singletary, COA (V); Christine Ringrose (V); Alesia K. McCalla (V); Amy Thompson (V); Katherine L. Wentz (V); Peggy R. Orr, MPH, BSN, RN, COMT (V); Teresa Coffey (V); Peter Sotirakos (P); Terri Cain (P); and Ashley M. Metzger (P). Retina Vitreous Center, Edmond, Oklahoma: Sandeep N. Shah, MD (I); Brian S. Phelps, MD (I); Amy L. West, BS (C, P); Romesh Babaria, MS (C, P, V); Jeannette Rodriguez (P); Mayra Viruet-Nieves (P); Kellie Meiwes, COA (P); and Lisa Holley, COA (P). Retinal Consultants of San Antonio, San Antonio, Texas: Calvin E. Mein, MD (I); Richard Gary Lane, MD (I); Darrell E. Baskin, MD (I); Moises A. Chica, MD (I); Lydia Adams (C); Lita Kirschbaum, COA (C); Sara L. Cloudt (C); Stacy Rodriguez (C); Vanessa D. Martinez (C); Jenny M. Bermea (C); Victoria Lopez (V); Samantha Bankston (P); Christopher Sean Wienecke (P); Jorge Castellanos (P); and Brenda Nakoski (P). Paducah Retinal Center, Paducah, Kentucky: Carl W. Baker, MD (I); Ron H. Tilford, MD (I); Tracey M. Caldwell, CCRC (C); Jil D. Baker, MT, ASCP (C); Lynnette F. Lambert, COT (V); Mary J. Sharp, COA (V); Margaret J. Orr, COA (V); Sonya L. Alcaraz (P); Samantha Kettler (P); Alecia B. Camp (P); and Kylie S. Sedberry (P). Loma Linda University Health Care, Department of Ophthalmology, Loma Linda, California: Joseph T. Fan, MD (I); Samuel C. Kim, MD (I); David Isaiah Sierpina, MD (I); Michael E. Rauser, MD (I); Kakarla V. Chalam, MD (I); Raquel Hernandez (C); Anthoni Tampubolon (C, P, V); Tina L. Ramirez (C); Vivian L. Garcia (C); Jayson S. Paw (C); Moises Tellez (P); Adel E. Alset, COA (P); and Marcia Easterly (P). Southwest Retina Specialists, Amarillo, Texas: J. Edward Ysasaga, MD (I); Kasey L. Dalrymple (C); Johnathan R. Hawkins, CRA, COT (V); and Ben Ysasaga, CRA (P). Southeast Retina Center, PC, Augusta, Georgia: Dennis M. Marcus, MD (I); Siobhan O. Ortiz (C); Thomas Bailey (V); Michele Woodward (V); and Ken Ivey, COA (P). Texas Retina Associates, Lubbock: Michel Shami, MD (I); Yolanda Saldivar (C); Ashaki Meeks (V); Glenn R. Gardner, CRA (P); and Ginger K. Rhymes, COA (P). Dean A. McGee Eye Institute, Oklahoma City, Oklahoma: Ronald M. Kingsley, MD (I); Robert E. Leonard, MD (I); Vinay A. Shah, MD (I); Alisha N. Brewer, BA (C); Sonny Icks, COA, CCRC (C, V); Shannon R. Almeida (C); Amy L. Ford, COA (V); Ashley Hughes (V); Markeisha Cheadle (P); Rachel Sohl (P); Russ Burris (P); and JoAnn T. Booth (P). Medical Center Ophthalmology Associates, San Antonio, Texas: Michael A. Singer, MD (I); Darren J. Bell, MD (I); Catherine Ellis, BS (C); Rafael L. Wong (C); Connie Bermea (V); Roxanne Gomez (V); Felicia Huron (P); and Rosa Escobar (P). Marietta Eye Clinic, Marietta, Georgia: Annal Dhanu Meleth, MD, MS (I); Lakshmana Murthy Kooragayala, MD (I); Chigozie Nkemka (C); Chenavia Lewis, MS, CCRP (C,P); Shakirah J. Sewell (C); Minuette S. Jackson, BA, COA (C, V); Adam Goff (P); and Kenneth Thompson (P). Mid-America Retina Consultants, PA, Overland Park, Kansas: William N. Rosenthal, MD (I); Sarah N. Lamaster, RN, BSN (C, V); R. Scott Varner (P); and Mary C. Stewart, RN (P). Kansas Retina Associates, PA, Shawnee Mission: Gregory M. Fox, MD (I); Ravi S. J. Singh, MD (I); Blake A. Cooper, MD (I); Ivan R. Batlle, MD (I); Lexie R. Ainley (C); Karla A. Batlle, BS (C); Amber R. VandeVelde, RN (V); Holly Wyrick (V); Katherine Pippin (P); and Frank T. Yeager (P). The Retina Institute, St Louis, Missouri: Kevin J. Blinder, MD (I); Sabin Dang, MD (I); Rhonda F. Weeks, CCRC (C); Ginny S. Nobel, COT (C); Erika A. Hoehn, BS (C); Kelly E. Pepple (V); Diana Reardon, RNA (V); Maria A. Stuart, COA (V); Brook G. Pulliam, COA (V); Lynda K. Boyd, COT (V); Steve A. Schremp (P); Timothy L. Wright (P); Dana L. Gabel (P); and Jarrod Wehmeier (P). Retina Associates of Sarasota, Sarasota, Florida: Elizabeth R. Richter, MD, PhD (I); John H. Niffenegger, MD (I); Arysol Niffenegger, MD (C); Marianne Cottrill (C, P); Donna Scully (V); and Marisol Lopez (P). Southeastern Retina Associates, Chattanooga, Tennessee: Richard I. Breazeale, MD (I); Rohan J. Shah, MD (I); Francis C. DeCroos, MD (I); Devon Ghodasra, MD (I); Steve W. McBee Jr (C); Elizabeth Lisa McDonald (C, P); Kate Menefee (V); Courtney Duncan (V); David Woods, CRA, COA, CST (P); and Roger P. Melendrez (P). Florida Retina Consultants, Lakeland: Nader Moinfar, MD, MPH (I); Scott M. Friedman, MD (I); Shannon M. Rehling (C, V); Ceara L. Wendel (C); Damanda F. Fagan (C); Karen Seyez, COT (V); Jacqueline Andrews (V); Brenda J. Bobbitt (P); Allen McKinney (P); and Shana E. Williams (P). Retina Vitreous Consultants, Monroeville, Pennsylvania: Karl R. Olsen, MD (I); Jared E. Knickelbein, MD, PhD (I); P. William Conrad, MD, PhD (I); Lori A. Merlotti (C); Lois Stepansky (V); Julie Walter (V); Dawn Diperna (P); and Phyllis P. Ostroska (P). Spokane Eye Clinic, Spokane, Washington: Robert S. Wirthlin, MD (I); Andrew G. Cheek, MD (I); Loren S. Jack, MD (I); Eileen A. Dittman, CCRC, RN (C, V); Jillian N. Erstad (C, P, V); Brian G. Skea (C, P, V); and Dylan C. Waidelich, COA (C, P, V). Retina Associates of Florida, LLC, Tampa: Ivan J. Suner, MD (I); Marc C. Peden, MD (I); Stephanie Munoz, COA (C); Janet R. Traynom, COT (C, P); Rochelle DenBoer, LPN (C); Susan Ramsey (V); Heidi Vargo, COT (V); Anita Kim Malzahn (P); and Lonie Bree Noel, LPN (P). Kellogg Eye Center, University of Michigan, Ann Arbor: Anjali R. Shah, MD (I); Thomas W. Gardner, MD, MS (I); Grant M. Comer, MD, MS (I); Pamela S. Campbell, COT, CCRP (C); Lindsay M. Godsey, MS (C); Laura A. Rozek (P); Laura B. Trebesh (P); and Timothy Sean Costello, BA (P). Massachusetts Valley Eye Physicians and Surgeons, Ayer: Gisela Velez, MD, MPH, MA (I); Oksana Mykhaylyk (C); Elizabeth I. Johnson, MS (C); Maa Ahema Parry, OD, MEd (C); Jhan Carlos Caro (P); and Chandapilla C. Pallipeedikayil (P). Wilmer Eye Institute at Johns Hopkins, Baltimore, Maryland: Sharon D. Solomon, MD (I); Lisa K. Levin (C); Kemi Adeyemo (C); Deborah Donohue (C, V); Mary Frey, BSc, CCRP (V); Brandon S. Gardner (V); Dennis Cain, CRA (P); David Emmert, BA (P); Jacquelyn McDonald (P); Russ Distle (P); and Nick Rhoton, AA (P). Joslin Diabetes Center, Boston, Massachusetts: Jennifer K. Sun, MD, MPH (I); Margaret E. Stockman (C, V); Tor Ekstrom (C); Emily Degan (C, V); Mina Sehizadeh, OD (V); Jerry D. Cavallerano, OD, PhD (V); and Kylie M. Madigan, CRA (P). Northwestern Medical Faculty Foundation, Chicago, Illinois: Alice T. Lyon, MD (I); Rukhsana G. Mirza (I); Carmen Ramirez (C, V); Evan C. Davies (C); Priya M. Thakkar, BS (C); Nicole M. Seddon (C); Julie Pecht (V); Anson Moore (V); Cason Moore (P); Maritza Barragan (P); and Evica Simjanoski, BFA (P). University Hospitals Cleveland Medical Center, Cleveland, Ohio: Shree K. Kurup, MD (I); Georgios Trichonas, MD (I); Yu Hyon Kim, MD (I); Tatiana M Riedel, BA (C); Jasmeen K. Randhawa (C); Sangeetha P. Raghupathy, BS (C); Peggy Allchin (V); Margaret N. Petrosky (V); Claudia Clow (V); Ahmad Al Moshmosh (P); Geraldo R. Miranda (P); Ashley Y. Howard (P); and Irit Baum-Rawraway (P). Southeastern Retina Associates, PC, Knoxville, Tennessee: Joseph M. Googe, MD (I); R. Keith Shuler, MD (I); Nicholas G. Anderson, MD (I); Kristina Oliver (C); Julie Asher (C, V); Steve Morris (C); Jeff Wheeler (V); Justin Walsh (P); Sarah M. Oelrich (P); Raul E. Lince (P); and Hodge A. Griffone (P). Medical College of Wisconsin, Milwaukee: Judy E. Kim, MD (I); Thomas B. Connor, MD (I); Eleanor Dorsey, BS (C); Shay Bourgeois (C, V); Amber N. Roberts (V); Vicki Barwick, BS (V); Brittany Rego (P); and Hannah Sheppard (P). Minnesota Retina Center, PA, Minneapolis: Abdhish R. Bhavsar, MD (I); Andrea Gilchrist (C); Celeste Moreno (C, P); Matt D. Peloquin, AA (V); Jason R. Sweet (V); Alanna C. Evans (P); and Erin C. Kinney (P). The New York Eye and Ear Infirmary/Faculty Eye Practice, New York: Meenakashi Gupta, MD (I); Ronald C. Gentile, MD (I); Melissa Rivas (C, V); and John Bo Soo Choi (C, V). Thomas Eye Group, Sandy Springs, Georgia: Paul L. Kaufman, MD (I); Kathy T. Wynne, BS, COT (C, V); Cynthia Weaver, COT (V); and Sarah Matloff, COA (P). Carle Foundation Hospital, Urbana, Illinois: Michael S. Tsipursky, MD (I); Sarah Berlatsky (C); Elida Iniguez (C); Alexandra Y. Almasov (C, V); Daniel A. Nielsen, OD (V); Tina M. Gore (V); and Zach Dupureur (P).

Additional Information: Network chairs, coordinating center staff, committee members, and the reading center staff are all compensated for their work as members of the DRCR Retina Network.