Assessment of the DRCR Retina Network Approach to Management With Initial Observation for Eyes With Center-Involved Diabetic Macular Edema and Good Visual Acuity: A Secondary Analysis of a Randomized Clinical Trial | Diabetic Retinopathy | JAMA Ophthalmology | JAMA Network
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Figure 1.  DRCR Retina Network Initial Observation Treatment Algorithm
DRCR Retina Network Initial Observation Treatment Algorithm

anti-VEGF indicates anti–vascular endothelial growth factor.

aVisual acuity was considered worse if it was 5 to 9 letters (1 line) worse from baseline at 2 consecutive visits every 4 weeks (±2 weeks) apart or at least 10 letters (2 lines or more) worse at any visit. Of note, increasing central subfield thickness or change in any other parameter did not initiate injections if the visual acuity was not worse.

bOnce injections were initiated, the DRCR Retina Network anti-VEGF for diabetic macular edema regimen was followed.8

cIf central subfield thickness worsened by at least 10% from the last visit or became greater than 400 μm (Zeiss-Stratus equivalent) without vision loss, the follow-up interval was halved with a minimum interval of 4 weeks. If central subfield thickness subsequently stabilized at 2 consecutive visits without vision loss, follow-up could be extended to 8 weeks and then to 16 weeks.

Figure 2.  Eyes Completing the 104-Week Visit in the Initial Observation Group
Eyes Completing the 104-Week Visit in the Initial Observation Group

Injections for “other” category were given for 1 case of proliferative diabetic retinopathy and 1 case of vision loss of 7 letters accompanied by a 150-μm increase in central subfield thickness. Group included 208 of 236 randomized; excluding 4 participants who died during follow-up, 90% of participants completed the 4-year visit.

Table 1.  Receipt of Aflibercept During 2 Years of Follow-up by Baseline Characteristics
Receipt of Aflibercept During 2 Years of Follow-up by Baseline Characteristics
Table 2.  Two-Year Outcomes by Receipt of Aflibercept During Follow-up in the Initial Observation Group
Two-Year Outcomes by Receipt of Aflibercept During Follow-up in the Initial Observation Group
1.
Baker  CW, Glassman  AR, Beaulieu  WT,  et al; DRCR Retina Network.  Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial.   JAMA. 2019;321(19):1880-1894. doi:10.1001/jama.2019.5790 PubMedGoogle ScholarCrossref
2.
Bhavsar  AR, Glassman  AR, Stockdale  CR, Jampol  LM; Diabetic Retinopathy Clinical Research Network.  Elimination of topical antibiotics for intravitreous injections and the importance of using povidone-iodine: update from the Diabetic Retinopathy Clinical Research Network.   JAMA Ophthalmol. 2016;134(10):1181-1183. doi:10.1001/jamaophthalmol.2016.2741 PubMedGoogle ScholarCrossref
3.
Schatz  H, Madeira  D, McDonald  HR, Johnson  RN.  Progressive enlargement of laser scars following grid laser photocoagulation for diffuse diabetic macular edema.   Arch Ophthalmol. 1991;109(11):1549-1551. doi:10.1001/archopht.1991.01080110085041 PubMedGoogle ScholarCrossref
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World Medical Association.  World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects.   JAMA. 2013;310(20):2191-2194. doi:10.1001/jama.2013.281053 PubMedGoogle ScholarCrossref
5.
Beck  RW, Moke  PS, Turpin  AH,  et al.  A computerized method of visual acuity testing: adaptation of the early treatment of diabetic retinopathy study testing protocol.   Am J Ophthalmol. 2003;135(2):194-205. doi:10.1016/S0002-9394(02)01825-1 PubMedGoogle ScholarCrossref
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Chalam  KV, Bressler  SB, Edwards  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Retinal thickness in people with diabetes and minimal or no diabetic retinopathy: Heidelberg Spectralis optical coherence tomography.   Invest Ophthalmol Vis Sci. 2012;53(13):8154-8161. doi:10.1167/iovs.12-10290 PubMedGoogle ScholarCrossref
7.
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. doi:10.1001/jama.2015.15217 PubMedGoogle ScholarCrossref
8.
Wells  JA, Glassman  AR, Ayala  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema.   N Engl J Med. 2015;372(13):1193-1203. doi:10.1056/NEJMoa1414264PubMedGoogle ScholarCrossref
9.
Bressler  SB, Edwards  AR, Chalam  KV,  et al; Diabetic Retinopathy Clinical Research Network Writing Committee.  Reproducibility of spectral-domain optical coherence tomography retinal thickness measurements and conversion to equivalent time-domain metrics in diabetic macular edema.   JAMA Ophthalmol. 2014;132(9):1113-1122. doi:10.1001/jamaophthalmol.2014.1698 PubMedGoogle ScholarCrossref
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Cox  DR.  Regression models and life-tables.   J R Stat Soc B. 1972;34(2):187-220.Google Scholar
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Lin  DY, Wei  LJ, Ying  Z.  Checking the Cox model with cumulative sums of martingale-based residuals.   Biometrika. 1993;80(3):557-572. doi:10.1093/biomet/80.3.557 Google ScholarCrossref
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Kaplan  EL, Meier  P.  Nonparametric estimation from incomplete observations.   J Am Stat Assoc. 1958;53(282):457-481. doi:10.1080/01621459.1958.10501452 Google ScholarCrossref
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Spiegelman  D, Hertzmark  E.  Easy SAS calculations for risk or prevalence ratios and differences.   Am J Epidemiol. 2005;162(3):199-200. doi:10.1093/aje/kwi188 PubMedGoogle ScholarCrossref
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Early Treatment Diabetic Retinopathy Study Research Group.  Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12.   Ophthalmology. 1991;98(5)(suppl):823-833. doi:10.1016/S0161-6420(13)38014-2 PubMedGoogle ScholarCrossref
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Kaiser  PK. Prospective evaluation of visual acuity assessment: a comparison of snellen versus ETDRS charts in clinical practice (an AOS thesis). Trans Am Ophthalmol Soc. 2009;107:311-324.
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    Original Investigation
    February 20, 2020

    Assessment of the DRCR Retina Network Approach to Management With Initial Observation for Eyes With Center-Involved Diabetic Macular Edema and Good Visual Acuity: A Secondary Analysis of a Randomized Clinical Trial

    Author Affiliations
    • 1Jaeb Center for Health Research, Tampa, Florida
    • 2Paducah Retinal Center, Paducah, Kentucky
    • 3Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • 4Editor, JAMA Ophthalmology
    • 5Charlotte Eye, Ear, Nose, and Throat Associates PA, Charlotte, North Carolina
    • 6Retina Consultants of Houston, Blanton Eye Institute, Houston, Texas
    • 7Feinberg School of Medicine, Northwestern University, Chicago, Illinois
    • 8Joslin Diabetes Center, Beetham Eye Institute, Harvard Department of Ophthalmology, Boston, Massachusetts
    • 9CME Editor, JAMA Ophthalmology
    JAMA Ophthalmol. 2020;138(4):341-349. doi:10.1001/jamaophthalmol.2019.6035
    Key Points

    Question  For eyes with center-involved diabetic macular edema and good vision, what was the DRCR Retina Network Protocol V protocol–defined approach for initial observation plus aflibercept only if visual acuity worsened, and which characteristics were associated with receiving aflibercept injections?

    Findings  In this secondary analysis of a randomized clinical trial, during 2 years, 80 of 236 eyes (34%) assigned to initial observation received aflibercept. Participants who had thicker retinas, more severe diabetic retinopathy, or a nonstudy eye receiving diabetic macular edema treatment within 4 months of baseline were more likely to receive aflibercept.

    Meaning  The findings suggest that understanding this approach to initial observation is important for clinicians who manage eyes with center-involved diabetic macular edema and good visual acuity.

    Abstract

    Importance  Among eyes with center-involved diabetic macular edema (CI-DME) and good visual acuity (VA), randomized clinical trial results showed no difference in VA loss between initial observation plus aflibercept only if VA decreased, initial focal/grid laser plus aflibercept only if VA decreased, or prompt aflibercept. Understanding the initial observation approach is relevant to patient management.

    Objective  To assess the DRCR Retina Network protocol-defined approach and outcomes of initial observation with aflibercept only if VA worsened.

    Design, Setting, and Participants  This was a post hoc secondary analyses of a randomized clinical trial of the DRCR Retina Network Protocol V that included 91 US and Canadian sites from November 2013 to September 2018. Participants were adults (n = 236) with type 1 or 2 diabetes, 1 study eye with CI-DME, and VA letter score at least 79 (Snellen equivalent, 20/25 or better) assigned to initial observation. Data were analyzed from March 2019 to November 2019.

    Interventions  Initial observation and follow-up with aflibercept only for VA loss of at least 10 letters from baseline at 1 visit or 5 to 9 letters at 2 consecutive visits. Follow-up occurred at 8 weeks and then every 16 weeks unless VA or optical coherence tomography central subfield thickness worsened.

    Main Outcomes and Measures  Whether individuals received aflibercept.

    Results  Among 236 eyes in 236 individuals (149 [63%] male; median age, 60 years [interquartile range, 53-67 years]) randomly assigned to initial observation, 80 (34%) were treated with aflibercept during 2 years of follow-up. At 2 years, the median VA letter score was 86.0 (interquartile range, 89.0-81.0; median Snellen equivalent, 20/20 [20/16-20/25]). Receipt of aflibercept was more likely in eyes with baseline central subfield thickness at least 300 μm (Zeiss-Stratus equivalent) vs less than 300 μm (45% vs 26%; hazard ratio [HR], 1.98 [95% CI, 1.26-3.13], continuous P = .005), moderately severe nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study retinopathy severity level 47) and above vs moderate nonproliferative diabetic retinopathy (retinopathy severity level 43) and below (51% vs 27%; HR, 2.22 [95% CI, 1.42-3.47], ordinal P < .001), and among participants whose nonstudy eye received DME treatment within 4 months of randomization vs not (52% vs 25%; HR, 2.55 [95% CI, 1.64-3.99], P < .001).

    Conclusions and Relevance  Most eyes managed with initial observation plus aflibercept only if VA worsened maintained good vision at 2 years and did not require aflibercept for VA loss. However, the eyes in the trial were approximately twice as likely to receive aflibercept for VA loss if they had greater baseline central subfield thickness, worse diabetic retinopathy severity level, or a nonstudy eye receiving treatment for DME.

    Trial Registration  ClinicalTrials.gov Identifier: NCT01909791

    Introduction

    The DRCR Retina Network Protocol V1 compared strategies of initial treatment using intravitreous aflibercept, focal/grid laser photocoagulation, and observation for eyes with center-involved diabetic macular edema (CI-DME) and visual acuity (VA) 20/25 or better. The groups initially managed with laser photocoagulation or observation received aflibercept treatment only if VA worsened during follow-up. Aflibercept treatment was not initiated if optical coherence tomography (OCT) central subfield thickness (CST) worsened in the absence of VA decline. There were no significant differences in rates of at least 5-letter VA loss after 2 years between the 3 treatment strategies, and each led to 20/20 mean VA at 2 years.1

    These results suggest that eyes with CI-DME and good vision managed with initial observation vs immediate anti–vascular endothelial growth factor (anti-VEGF) therapy can achieve similarly good visual outcomes with reduced costs and lower risk of injection-associated adverse events, such as endophthalmitis (previous research estimates the risk to be <0.1% per injection).2 Of note, fewer eyes in the laser photocoagulation group (26%) received anti-VEGF injections compared with eyes in the observation group (36%) (P = .01) but obtained similar visual outcomes at the end of 2 years.1 However, laser can cause macular scarring and visual scotomas.3

    Although each treatment strategy was effective, ophthalmologists may choose a strategy of initial observation for eyes with CI-DME and good vision given the aforementioned reasons. This report provides additional details and post hoc analyses of the observation strategy and outcomes beyond the scope of the primary report,1 including an analysis of baseline characteristics associated with receipt of aflibercept during follow-up.

    Methods

    This was a post hoc secondary analysis of a randomized clinical trial of the DRCR Retina Network Protocol V. Protocol V1 was conducted at 91 clinical sites in the United States and Canada from November 2013 to September 2018. The protocol and statistical analysis plan are published elsewhere1 and are available with the primary outcome report. This study adhered to the tenets of the Declaration of Helsinki.4 The ethics board associated with each site provided approval and participants provided written informed consent (available in the primary report).1

    Baseline VA of 20/25 or better using Electronic-Early Treatment Diabetic Retinopathy Study (E-ETDRS) testing5 after protocol refraction was confirmed at both screening and randomization visits no more than 4 weeks apart. At the screening visit, OCT CST was at least 290 μm in women and at least 305 μm in men on Zeiss Cirrus (Zeiss International) or at least 305 μm in women and at least 320 μm in men on Heidelberg Spectralis (Heidelberg Engineering).6,7 At the randomization visit, OCT CST was at least 275 μm in women and at least 290 μm in men on Zeiss Cirrus or at least 290 μm in women and at least 305 μm in men on Heidelberg Spectralis. Investigators confirmed definite retinal thickening due to DME involving the center of the macula on clinical examination.

    Initial Observation Strategy in Protocol V

    At each visit, protocol-defined best-corrected E-ETDRS VA was measured after protocol refraction, and OCT CST was measured. Eyes assigned to initial observation had follow-up visits at least every 16 weeks (±4 weeks) through 2 years with an additional visit 8 weeks (±2 weeks) from randomization to check for early VA deterioration (Figure 1). Follow-up remained at 16-week intervals unless VA or CST worsened. Even when CST did not worsen, treatment with aflibercept was initiated only if either of the following VA worsening criteria were met: (1) best-corrected VA decreased at least 10 letters (2 lines) from baseline because of DME at any visit or (2) best-corrected VA decreased 5 to 9 letters (1 line) from baseline because of DME at any visit and was confirmed at a second visit 4 weeks (±2 weeks) later. Baseline VA was defined as the mean of the screening and randomization VAs. Once initiated, aflibercept was given according to the DRCR Retina Network anti-VEGF for DME regimen8 described below. If an eye with 5- to 9-letter VA decrease did not have a decrease from baseline by 5 or more letters at the subsequent 4-week visit, follow-up was extended to 8 weeks and then every 16 weeks.

    In the absence of VA worsening, follow-up remained at 16-week intervals unless CST increased by at least 10% from the previous visit or became greater than 400 μm (time-domain [Zeiss Stratus] equivalent),9 at which point the follow-up interval was halved to every 8 weeks. If CST further increased at least 10% compared with the previous visit without meeting criteria for initiating aflibercept, the follow-up interval was reduced to every 4 weeks. If CST stabilized (ie, did not worsen at 2 consecutive visits) without meeting VA worsening criteria, the follow-up interval was doubled to a maximum of 16-week intervals. If the follow-up interval determined by VA and CST criteria differed, the shorter interval was used. Injections were initiated only by worsening of VA regardless of CST.

    DRCR Retina Network Anti-VEGF for DME Regimen

    The anti-VEGF retreatment regimen was identical in the aflibercept, laser photocoagulation, and observation groups (after loss of VA in the laser photocoagulation and observation groups). Aflibercept was given every 4 weeks (±1 week) for 24 weeks (6 injections) with 1 exception: injections were deferred if neither VA nor CST improved or worsened after at least 2 consecutive injections and the CST was less than the spectral-domain OCT threshold for CI-DME (defined by OCT machine and sex: Heidelberg Spectralis CST of at least 305 μm in women and at least 320 μm in men and Zeiss Cirrus CST of at least 290 μm in women and at least 305 μm in men) and the VA letter score was at least 84 (Snellen equivalent, 20/20 or better) (Figure 1). Improvement and worsening for retreatment determination were defined as at least a 5-letter VA or 10% CST change.

    If the eye achieved sustained stability (ie, had not improved or worsened with respect to VA or CST for at least 2 consecutive injections) 24 weeks after initiation of aflibercept or later, injections were deferred. If neither VA nor CST improved from the previous 2 consecutive injections and the CST thickness was greater than the spectral-domain CST threshold, focal/grid laser photocoagulation to treat residual DME was optional based on investigator discretion. If the VA or CST worsened from the previous 2 consecutive injections, laser photocoagulation was administered unless complete laser photocoagulation had previously been administered or all treatable microaneurysms were within 500 μm of the fovea.

    If injections were deferred at 3 consecutive visits 24 weeks after aflibercept initiation, follow-up intervals were extended to 8 and then 16 weeks if deferral criteria were still met. If VA or CST worsened from the most recent visit or the visit at which the last injection occurred, injections were resumed. The study protocol did not specify any treatment for systemic conditions, and treatment for diabetes was usual care.

    Statistical Analysis

    All analyses were post hoc, followed the intention-to-treat principle, and included observed data from all eyes randomly assigned to initial observation. To limit the influence of potential outliers, changes in VA and CST were truncated at 3 SDs from the mean. Cox proportional hazards regression was used to test for associations between baseline characteristics and time to first aflibercept injection.10 Visual inspection of Kaplan-Meier plots and martingale residuals were used to verify the proportional hazards assumption.11 Cumulative probabilities accounting for loss to follow-up were estimated using the Kaplan-Meier method.12 Poisson regression with robust variance estimation was used to model the relationship between baseline characteristics and at least 5-letter loss of vision at 2 years.13 All P values and 95% CIs are 2-sided. Characteristics with P < .05 in univariable analysis were entered into a multivariable model (priority was given to the P value for the continuous or ordinal version of the characteristic if available), and stepwise selection with backward elimination of variables with P > .05 was used to select a final model. SAS/STAT software, version 15.1 (SAS Institute Inc) was used for all analyses. There was no adjustment for multiplicity. Data were analyzed from March 2019 to November 2019.

    Results

    A total of 236 eyes in 236 individuals (149 [63%] male; median age, 60 years [interquartile range [IQR], 53-67 years]) were randomly assigned to initial observation. As reported previously, the cumulative probability (Kaplan-Meier estimate, adjusting for loss to follow-up) of receiving aflibercept in the observation group within 2 years was 36% (95% CI, 30%-43%).1 Median VA letter score at 2 years for the entire observation cohort was 86.0 (IQR, 89.0-81.0; median Snellen equivalent, 20/20 [20/16-20/25]); the percentage of eyes with no CI-DME and at least 10% CST decrease from baseline at 2 years was 36% (74 of 208).1

    Table 1 presents the cumulative probability of receiving an aflibercept injection during 2 years of follow-up by baseline characteristics. Among eyes with baseline VA of 20/25, the probability of receiving aflibercept by 2 years was 42% vs 32% among eyes with VA of 20/20 or better (hazard ratio [HR], 1.42 [95% CI, 0.91-2.21], categorical P = .12, continuous P = .34). Among eyes with Zeiss-Stratus equivalent CST of at least 300 μm at baseline, the probability of receiving aflibercept was 45% vs 26% among eyes with CST less than 300 μm (HR, 1.98 [95% CI, 1.26-3.13], categorical P = .003, continuous P = .005). Among eyes with moderately severe nonproliferative or more severe diabetic retinopathy (ETDRS retinopathy severity level ≥47),14 the probability of receiving an aflibercept injection was 51% vs 27% among eyes with moderate nonproliferative or less severe diabetic retinopathy (ETDRS retinopathy severity level ≤43) (HR, 2.22 [95% CI, 1.42-3.47], categorical P < .001, ordinal P < .001). Among eyes in which DME treatment was planned or performed for the nonstudy eye within 4 months of randomization (at investigator discretion), the probability of receiving an aflibercept injection was 52% vs 25% among eyes for which the nonstudy eye did not have recent or planned DME treatment within 4 months of randomization (HR, 2.55 [95% CI, 1.64-3.99], P < .001).

    After multivariable model selection, results were similar in a final model that included diabetic retinopathy severity, CST, and recent or planned DME treatment in the nonstudy eye (eTable 1 in the Supplement). The percentage of eyes that received injections during follow-up and the percentage that lost at least 5 letters of VA at 2 years (the primary outcome of Protocol V) by diabetic retinopathy severity level, CST, recent or planned DME treatment in the nonstudy eye, and the total number of risk factors are shown in eTable 2 in the Supplement. The likelihood of eyes receiving aflibercept increased as the number of risk factors present increased (ordinal P < .001); however, the risk of vision loss at 2 years did not appear to increase as the number of risk factors present increased (ordinal P = .52). Furthermore, none of the baseline characteristics associated with risk of aflibercept injection were associated with at least 5-letter vision loss at 2 years (eTable 3 in the Supplement); however, participants with higher glycated hemoglobin (HbA1c) levels more likely to lose vision (relative risk for 1% increase in baseline HbA1c level, 1.26 [95% CI, 1.09-1.46], P = .001).

    Figure 2 shows the cumulative probability of initiating aflibercept during 2 years of follow-up, by indication. Among 236 eyes, 44 (19%) initiated aflibercept injections because of at least 10-letter vision loss at a single visit, 34 eyes (14%) initiated aflibercept injections because of 5- to 9-letter vision loss at 2 consecutive visits, and 2 eyes (<1%) initiated injections counter to the protocol (1 for proliferative diabetic retinopathy and 1 for 7-letter VA loss with 150-μm CST increase).

    While being observed, 92 of 236 eyes (39%) experienced a 5- to 9-letter loss at least once before their final visit. In this subgroup, 29 of 92 eyes (32%) had sustained VA loss because of DME at the next follow-up visit and began aflibercept treatment; 20 eyes (22%) received aflibercept for vision loss from DME later; and 42 eyes (46%) never received aflibercept. One eye received aflibercept for proliferative diabetic retinopathy after an initial loss of 5 letters.

    Among 80 eyes in the observation group that began aflibercept therapy (63 eyes [79%] in year 1 and 17 [21%] in year 2), injections were deferred for success within the first 24 weeks after aflibercept initiation in 16 eyes (20%). Laser was administered per protocol in 5 of 236 eyes (2%) (all previously received aflibercept).1

    Among eyes in the observation group that received at least 1 aflibercept injection (34% [80 of 236]), the percentage of eyes with a VA decrease of 5 or more letters at 2 years (Table 2) was 30% (23 of 76). Median letter change in VA from baseline at 2 years was –2.0 (IQR, –6.0 to 1.0), and median VA was 83.5 (87.0 to 78.5; median Snellen equivalent, 20/25 [20/20-20/32]). Median change in CST from baseline at 2 years was –53 μm (IQR, –117 to –14), and median CST (Zeiss-Stratus equivalent) was 250 μm (IQR, 218-315 μm); the percentage of eyes with no CI-DME and at least 10% CST decrease from baseline was 44% (33 of 75). Among 61 eyes without proliferative diabetic retinopathy at baseline (excluding eyes without gradable photos), 1 eye (2%) had proliferative diabetic retinopathy at 2 years.

    Among eyes in the observation group that did not receive aflibercept injections (66% [156 of 236]), the percentage with a VA decrease of at least 5 letters at 2 years was 12% (16 of 132) (Table 2). Median change in VA from baseline at 2 years was 1.5 (IQR, –1.0 to 5.0), and median VA was 87.0 (IQR, 90.0 to 83.5; median Snellen equivalent, 20/20 [20/16-20/25]). Median change in CST from baseline at 2 years was –33 μm (IQR, –68 to –1 μm), and median CST (Zeiss-Stratus equivalent) was 264 μm (IQR, 229-306 μm); the percentage of eyes with no CI-DME and at least 10% CST decrease from baseline was 31% (41 of 132). Among 112 eyes without proliferative diabetic retinopathy at baseline (excluding eyes without gradable photos), 8 (7%) had proliferative diabetic retinopathy at 2 years.

    Examples of clinical scenarios with OCT scans and color fundus photographs are in the Supplement. eFigure 1 in the Supplement shows an eye that never experienced worsening of VA because of DME (defined as loss of ≥10 letters at any visit or loss of 5-9 letters at 2 consecutive visits) and therefore never received aflibercept; in addition, the CST never worsened (defined as ≥10% increase) before the final visit (42% [88 of 208] of eyes completing 104 weeks). eFigure 2 in the Supplement shows an eye that experienced worsening of VA and CST and therefore received aflibercept (25% [53 of 208] of eyes completing 104 weeks). eFigure 3 in the Supplement shows an eye that experienced worsening of CST but not VA and did not receive aflibercept (21% [44 of 208] of eyes completing 104 weeks). eFigure 4 in the Supplement shows an eye that experienced worsened VA even though CST never worsened and therefore received aflibercept (11% [23 of 208] of eyes completing 104 weeks).

    Discussion

    Based on the results of Protocol V, many clinicians and patients might choose initial observation for eyes with CI-DME and good VA while withholding anti-VEGF treatment unless vision worsens. These analyses explored whether select baseline characteristics within the initial observation group were associated with receiving aflibercept injections during 2 years of follow-up. Greater baseline CST in the study eye, more severe diabetic retinopathy in the study eye, and recent or planned treatment for DME in the nonstudy eye were associated with greater likelihood of initiating anti-VEGF treatment. Each of these characteristics approximately doubled the likelihood of receiving an injection; however, even among study eyes having greater CST or more severe retinopathy or a nonstudy eye receiving DME treatment, only approximately half received an injection during 2 years of follow-up. Furthermore, none of these characteristics were associated with loss of VA at 2 years; among the additional variables evaluated, only higher HbA1c level was associated with greater risk of 2-year VA loss.

    The results of these post hoc analyses highlight the variability of VA sometimes seen from visit to visit among patients with DME. Among eyes in the observation group that lost 1 line of VA at any visit, 46% tested better at the next visit and did not require aflibercept at any subsequent time during the trial. Thus, when vision loss is less than 2 lines (10 letters), the approach of confirming sustained vision loss before initiating anti-VEGF therapy in eyes with good vision appears to be reasonable.

    Eyes with good VA despite CI-DME often experience spontaneous resolution of retinal thickening, further supporting initial observation as a management approach. Approximately two-thirds of eyes in the observation group never received aflibercept. Among eyes not receiving aflibercept treatment, 46% of eyes had a 10% or greater reduction in CST and 31% had spontaneous resolution of CI-DME by 2 years. Although some eyes assigned to initial observation in Protocol V lost at least 1 line of VA at 2 years (19%; 95% CI, 14%-25%), mean VA at 2 years was 20/20 overall (inclusive of participants receiving aflibercept). For comparison, among eyes assigned to aflibercept, 16% lost at least 1 line of VA at 2 years (95% CI, 12%-22%).1

    Among eyes that received aflibercept for vision worsening, mean 2-year VA was approximately 1-line worse than eyes not requiring aflibercept. Although whether starting aflibercept earlier in these eyes would have resulted in better VA outcomes is unknown, overall rates of at least 5-letter VA worsening were not different in eyes immediately treated with aflibercept vs those managed with initial observation (–3%; 95% CI, –11% to 4%; P = .77).1 Whether more frequent follow-up of such eyes would lead to earlier anti-VEGF therapy and alter the VA outcomes obtained in this study also is unknown. Without biomarkers that predict vision in individual eyes with DME, clinicians may guide their treatment decisions based on the overall group results from this study coupled with individual patient preferences.

    Limitations

    This study has several limitations. First, the analyses were conducted post hoc, and with multiple characteristics being evaluated, some associations could have been identified by chance. Second, a formal statistical comparison between eyes receiving vs not receiving aflibercept could not be undertaken without substantial bias because initiating injections was based on VA loss after randomization. Thus, visual outcomes in the subgroups of observation-group eyes that did vs did not receive aflibercept should not be compared. Third, treatment decisions were guided by VA obtained using E-ETDRS testing after protocol refraction, which may differ from VA obtained in clinical settings15; therefore, a strict application of this approach assumes careful clinical VA evaluation. Fourth, treatment in nonstudy eyes was at investigator discretion; however, randomization was stratified by recent or planned DME treatment in the nonstudy eyes because these participants were expected to be seen more frequently, increasing the likelihood of detecting a decrease in VA and initiating aflibercept. Fifth, follow-up time from initiation of aflibercept was variable (ie, eyes initiated aflibercept at various times, but follow-up ended at 2 years for all study participants). Furthermore, we cannot say whether results at 5 or 10 years after standard clinical care would differ substantially from what was seen at 2 years in this study cohort. Also, this analysis did not consider the initial laser photocoagulation group, which required fewer aflibercept injections during 2 years of follow-up than the initial observation group.

    Conclusions

    Most eyes with CI-DME and good VA initially managed with observation did not require subsequent aflibercept for VA loss. On average, eyes in the initial observation group that required aflibercept treatment because of VA worsening still achieved good visual outcomes at 2 years. These results were achieved using regular follow-up intervals and a strict treatment algorithm. Clinicians should be aware that participants with greater CST or more severe retinopathy in the study eye and those receiving DME treatment in the nonstudy eye were more likely to experience VA worsening that required treatment.

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    Article Information

    Accepted for Publication: December 4, 2019.

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

    Published Online: February 20, 2020. doi:10.1001/jamaophthalmol.2019.6035

    Author Contributions: Mr Glassman had full access to all of 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, Baker, Bressler, Punjabi, Stockdale, Jampol, Sun.

    Acquisition, analysis, or interpretation of data: Glassman, Baker, Beaulieu, Bressler, Punjabi, Wykoff, Jampol, Sun.

    Drafting of the manuscript: Glassman, Baker, Beaulieu, Punjabi, Jampol, Sun.

    Critical revision of the manuscript for important intellectual content: Baker, Beaulieu, Bressler, Punjabi, Stockdale, Wykoff, Jampol, Sun.

    Statistical analysis: Beaulieu.

    Obtained funding: Glassman, Wykoff, Jampol, Sun.

    Administrative, technical, or material support: Glassman, Bressler, Punjabi, Stockdale, Wykoff, Jampol, Sun.

    Supervision: Glassman, Baker, Punjabi, Sun.

    Conflict of Interest Disclosures: Mr Glassman reported receiving grants from the National Institutes of Health (NIH) and grants and nonfinancial support from Regeneron Pharmaceuticals Inc during the conduct of the study and receiving grants from JDRF and grants and nonfinancial support from F. Hoffman-LaRoche Ltd outside the submitted work. Dr Baker reported receiving grants for clinical research from Allergan, F. Hoffman-LaRoche Ltd, Novartis AG, and Regeneron Pharmaceuticals Inc outside the submitted work. Dr Beaulieu reported receiving grants from the NIH and grants and nonfinancial support from Regeneron Pharmaceuticals Inc during the conduct of the study and receiving grants from JDRF and grants and nonfinancial support from F. Hoffman-LaRoche Ltd outside the submitted work. Dr Bressler reported receiving grants from Jaeb Center for Health Research during the conduct of the study and receiving grants from Bayer AG, F. Hoffman-LaRoche Ltd, Novartis AG, and Samsung Bioepis outside the submitted work. Dr Punjabi reported receiving clinical and epidemiological research support from F. Hoffman-LaRoche Ltd. Ms Stockdale reported receiving grants from the NIH and grants and nonfinancial support from Regeneron Pharmaceuticals Inc during the conduct of the study and receiving grants from JDRF and grants and nonfinancial support from F. Hoffman-LaRoche Ltd outside the submitted work. Dr Wykoff reported receiving grants and personal fees from Adverum Biotechnologies, Aerpio Pharmaceuticals Inc, Allergan, Apellis Pharmaceuticals, Chengdu Kanghong, Clearside Biomedical, F. Hoffman-LaRoche Ltd, Iveric Bio (formerly Ophthotech), Kodiak, Novartis AG, Recens Medical, Regeneron Pharmaceuticals Inc, Regenxbio Inc, and Santen Pharmaceutical Co Inc; receiving grants from Neurotech, Opthea, Outlook Therapeutics, and Samsung; and receiving personal fees from Alimera Sciences, Allegro, Bayer, DORC, EyePoint, Fosun, ONL Therapeutics, PolyPhotonix, and Takeda outside the submitted work. Dr Jampol reported receiving grants from the NIH, National Eye Institute during the conduct of the study and receiving personal fees from Sanofi and Appelis Pharmaceuticals outside of the submitted work. Dr Sun reported receiving grants from the Jaeb Center during the conduct of the study; receiving nonfinancial support from Adaptive Sensory Technologies, Boston Micromachines, Novo Nordisk, and Optovue; receiving grants and nonfinancial support from Boehringer Ingelheim International, F. Hoffman-LaRoche Ltd, and Kalvista; receiving grants from JDRF; receiving personal fees from Current Diabetes Reports and JAMA Ophthalmology; and receiving personal fees and nonfinancial support from Merck and Novartis AG outside the submitted work. No other disclosures were reported.

    Funding/Support: Research reported in this publication was supported by grants UG1EY014231 (Mr Glassman) and U10 EY023207 (Dr Jampol) from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health.

    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, nor in the collection, management, analysis, or interpretation of the data, or in the decision to submit for publication or the preparation of the manuscript. Regeneron Pharmaceuticals Inc provided aflibercept for the study and funds to the DRCR Retina Network to defray the study’s clinical site costs. As per the DRCR Retina Network Industry Collaboration Guidelines (www.drcr.net), the DRCR Retina Network had complete control over the design of the protocol, ownership of the data, all editorial content of presentations and publications related to the protocol, and the decision to submit for publication.

    DRCR Retina Network members: Personnel are labeled I for study investigator, C for coordinator, V for visual acuity technician, and P for photographer. Charlotte Eye, Ear, Nose and Throat Associates PA, Charlotte, North Carolina: Justin C. Brown (I); Andrew N. Antoszyk (I); David Browning (I); Angela K. Price (C, V); Sherry L. Fredenberg (C, V); Jenna T. Herby (C, V); Merri F. Walker (C, V); Christina J. Fleming (C, V); Ashley A. McClain (C, V); Angella S. Karow (V); Autumn C. Grupp (V); Kelly R. Gallagher (V); Sarah A. Ennis (V); Donna McClain (P); Joan P. Mondello (P); Autumn K. Finch (P); Kathryn Kimrey (P); Loraine M. Clark (P); Lisa A. Jackson (P); Lynn Watson (P); Jeff A. Kuopus (P); Robin Kerr (P); Swann J. Bojaj (P); Susannah J. Held (P); Uma M. Balasubramaniam (P); Michael D. McOwen (P); Matt Dunlap (P). Elman Retina Group PA, Baltimore, Maryland: Michael J. Elman (I); Henry A. Leder (I); JoAnn Starr (C); Jennifer L. Belz (C); Charlene K. Putzulo (C); Dena Y. Salfer-Firestone (V); Perel M. Simpson (V); Pamela V. Singletary (V); Jennifer L. Simmons (V); Teresa Coffey (V); Dallas R. Sandler (V); Ashley Davis (V); Ashley M. Metzger (P); Peter Sotirakos (P); Terri Cain (P); Daniel J. Ketner (P). Florida Retina Consultants, Lakeland, Florida: Scott M. Friedman (I); Nader Moinfar (I); Kimberly A. Williamson (C, V); Karen Sjoblom (C, V); Katrina L. Dawson (C); Damanda F. Fagan (C, V); Paige N. Walters (V); Steve Carlton (P); Allen McKinney (P). Paducah Retinal Center, Paducah, Kentucky: Carl W. Baker (I); Ron H. Tilford (I); Tracey M. Caldwell (C); Lynnette F. Lambert (C, V); Margaret J. Orr (V); Mary J. Palmer (V); Tracey R. Martin (V); Alecia B. Camp (P); Samantha Kettler (P); Tana R. Williams (P). Southeast Retina Center PC, Augusta, Georgia: Dennis M. Marcus (I); Harinderjit Singh (I); Siobhan O. Ortiz (C); Teresa J. Acklie (C); Michele Woodward (C); Courtney N. Roberts (C); Geri L. Floyd (C); Judith Hendrickson (V); Lindsay Allison Foster (V); Christy Coursey (V); Virginia Mims (V); Jared C. Gardner (P); Kimbi Y. Overton (P); Ken Ivey (P). Retina Research Center, Austin, Texas: Brian B. Berger (I); Chirag D. Jhaveri (I); Tori Moore (C); Ivana Gunderson (C, V); Rachel A. Walsh (C); Ginger J. Manhart (C); Jenny J. Tracy (C); Dietrich Riepen (V); Boris Corak (V); Chelsey A. Bravenec (V); Brandon Nguyen (V); Ryan M. Reid (V); Yong Ren (P); Christopher C. Stovall (P); Ben Ostrander (P). California Retina Consultants, Santa Barbara, California: Dante J. Pieramici (I); Alessandro A. Castellarin (I); Sarah Fishbein (C, V); Michelle S. Hanna (C, V); Erica D. Morasse (C, V); Gina Hong (C, V); Jack Giust (C); Lisha Wan (C, V); Melvin D. Rabena (C); Sara Esau (C, V); Jerry Smith (V); Kelly Avery (V); Layne J. Bone (V); Aimee Walker (P); Matthew Giust (P); Nitce L. Ruvalcaba (P); Aimee H. Shook (P). Carolina Retina Center, Columbia, South Carolina: Jeffrey G. Gross (I); Michael A. Magee (I); Barron C. Fishburne (I); Amy M. Flowers (C, V); Christen Ochieng (C, V); Riley Stroman (C, V); Angelique S.A. McDowell (V); Randall L. Price (P); Hunter Matthews (P). Texas Retina Associates, Lubbock, Texas: Michel Shami (I); Sushma K. Vance (I); Yolanda Saldivar (C); Keri S. Neuling (C); Brenda K. Arrington (C, P, V); Ashaki Meeks (V); Natalie R. Garcia (V); Kayla Blair (P); Janet Medrano (P); Ginger K. Rhymes (P). Fort Lauderdale Eye Institute, Plantation, Florida: Stuart K. Burgess (I); Tirso M. Lara (I); Noel H. Pereda (C, V); Cindy V. Fernandez (C, V); Evelyn Quinchia (V); Deborah Davis (V); Karen Workman (P). New England Retina Associates PC, Trumbull, Connecticut: Nauman A. Chaudhry (I); Sumit P. Shah (I); Gregory M. Haffner (I); Emiliya German (C); Laura A. Fox (C, V); JoAnna L. Pelletier (C); Jennifer M. Matteson (C); Shannan Moreau (C); Kristin E. Brown (V); Michelle Esler (V); Alison Fontecchio (V); Emily Morse (P); Marie Grace Laglivia (P); Justin A. Cocilo (P); Greg McNamara (P); Stefanie R DeSantis (P); Marissa L. Scherf (P); Angela LaPre (P). Valley Retina Institute, McAllen, Texas: Victor Hugo Gonzalez (I); Nehal R. Patel (I); Rohit Adyanthaya (I); Roberto Diaz-Rohena (I); Deyla Anaya (C); Crystal A. Alvarez (C); Ruth Iracheta (C); Edna E. Cruz (C); Jessica Rodriguez (C); Gabriela Zavala (C); Kethsaly J. Salinas (C); Tabitha Trevino (V); Krystle R. Lozano (V); Karina Miranda (V); Monica R. Cantu (V); Maricela Garza (V); Hector Jasso (V); Rebecca R. Flores (V); Rachel Rodriguez (V); Samuel Alonso (P); Amanda L. Sandoval (P); Santos Garza (P); John Trevino (P); Lazaro Aguero (P); Monique Montemayor (P). Retina Northwest PC, Portland, Oregon: Mark A. Peters (I); Paul S. Tlucek (I); Michael S. Lee (I); Colin Ma (I); Stephen Hobbs (C, V); Stephanie L. Ho (C, V); Amanda C. Milliron (V); Marcia Kopfer (V); Joe Logan (P); Christine Hoerner (P). Retinal Consultants of San Antonio, San Antonio, Texas: Calvin E. Mein (I); R. Gary Lane (I); Moises A. Chica (I); Sarah Elizabeth Holy (I); Lita Kirschbaum (C, V); Vanessa D. Martinez (C); Jaynee Baker (C); Adriana A. Lopez (C); Christa G. Kincaid (V); Sara L. Schlichting (P); Brenda Nakoski (P); Christopher Sean Wienecke (P); Elaine Castillo (P); Clarissa M. Marquez (P). Vitreo-Retinal Associates PC, Worcester, Massachusetts: Frank J. McCabe (I); Brad J. Baker (I); Melvyn H. Defrin (I); Marie V. Lampson (C); Heather Pratte (V); Selena A. Baron (V); Aundrea S. Borelli (V). National Ophthalmic Research Institute, Fort Myers, Florida: A. Thomas Ghuman (I); Paul A. Raskauskas (I); Glenn Wing (I); Ashish G. Sharma (I); Joseph P. Walker (I); Eileen Knips (C, P); Natalie N. Torres (C); Crystal Y. Peters (C); Cheryl Ryan (C); Laura Greenhoe (C); Cheryl Kiesel (C); Rebecca J. Youngblood (C); Anita H. Leslie (V); Danielle Turnbo (V); Etienne C. Schoeman (P); Raymond K. Kiesel (P). Retina Consultants of Houston PA, Houston, Texas: Charles C. Wykoff (I); Eric Chen (I); David M. Brown (I); Matthew S. Benz (I); Tien P. Wong (I); Amy C. Schefler (I); Richard H. Fish (I); James C. Major (I); Rosa Y. Kim (I); Meredith Lipman (C); Ashley E. Chancey (C); Amy Hutson (C); Cassie Cone (C); Stacy M. Supapo (C); Nubia Landaverde (C); Belinda A. Almanza (V); Brenda Dives (V); Veronica A. Sneed (V); Eric N. Kegley (P); Cary A. Stoever (P); Beau A. Richter (P). Loma Linda University Health Care, Department of Ophthalmology, Loma Linda, California: Joseph T. Fan (I); Mukesh Bhogilal Suthar (I); Michael E. Rauser (I); Gisela Santiago (C, V); Brandi J. Perez (C, V); Liel Marvyn Cerdenio (C, V); Kara E. Halsey (C, V); William H. Kiernan (V); Raquel Hernandez (V); Diana Povero (P); Jesse Knabb (P). Casey Eye Institute, Portland, Oregon: Andreas K. Lauer (I); Christina J. Flaxel (I); Ann D. Lundquist (C, V); Mitchell Schain (C, V); Shelley A. Hanel (C); Susan K. Nolte (V); Shirley D. Ira (V); Scott R. Pickell (P); Peter N. Steinkamp (P); Jocelyn T. Hui (P); Jordan Barth (P); Dawn M. Ryan (P); Chris S. Howell (P); Michelle Brix (P). Retina Associates of Cleveland, Inc., Beachwood, Ohio: Michael A. Novak (I); David G. Miller (I); Llewelyn J. Rao (I); Jerome P. Schartman (I); Joseph M. Coney (I); Lawrence J. Singerman (I); Susan C. Rath (C, V); Veronica A. Smith (C); Larraine Stone (C); Elizabeth McNamara (C, V); Kimberly A. DuBois (V); Vivian Tanner (V); Mary A. Ilc (V); Kim Drury (V); Cecelia Rykena (V); Trina M. Nitzsche (P); Gregg A. Greanoff (P); John C. DuBois (P). Family Eye Group, Lancaster, Pennsylvania: Michael R. Pavlica (I); Noelle S. Matta (C, V); Alyson B. Keene (P); Cristina M. Brubaker (P); Christine M. Keefer (P). Ocala Eye Retina Consultants, Ocala, Florida: Chander N. Samy (I); Robert J. Kraut (I); Kathy Shirley (C); Linsey Corso (C); Karen Ely (V); Elizabeth Scala (P); Vanessa Alava (P); Stewart Gross (P). Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan: Thomas W. Gardner (I); Grant M. Comer (I); Pamela S. Campbell (C, V); Lindsay M. Godsey (C, V); Linda Fournier (V); Moe Hesselgrave (V); Timothy Steffens (P); Robert Prusak (P); Hillary Bernard (P); Linda Goings (P); Alexis L. Smith (P). Retina Vitreous Center, Grand Blanc, Michigan: Robin D. Ross (I); Susan M. Sanford (C); Nicole Martini Markiewicz (C); Tracy M. Utley (C, V); Shannon Henderson (V); Mary D. Walker (V); Joanie H. Lippincott (P); Patricia Streasick (P). Joslin Diabetes Center/Harvard Vanquard Medical Associates, Boston, Massachusetts: Jennifer K. Sun (I); Paolo S. Silva (I); Lloyd Paul Aiello (I); Paul Arrigg (I); Margaret E. Stockman (C, V); Hanna Kwak (C); Ann Kopple (C); Jerry D. Cavallerano (V); Rita K. Kirby (P); Leila Bestourous (P); Elizabeth S. Weimann (P); Robert W. Cavicchi (P). Denver Health Medical Center, Denver, Colorado: Hugo Quiroz-Mercado (I); Leif S. Ryman (C); Teresa E. Rudesyle (C); Daniela Santos Canto (C); Guillermo Salcedo-Villanueva (C); Chelsea Lynn Mastin (V); Rosemary C. Rhodes (V); Carolyn J. Jackson (P); Regina Victoria (P). Raj K. Maturi, MD, PC, Indianapolis, Indiana: Raj K. Maturi (I); Ashley M. Harless (C, V); Carolee K. Novak (C, V); Laura A. Bleau (C, V); Nicole Ellingwood (P); Thomas Steele (P); Missy Livengood (P); Alisha Bildner (P); Abby Maple (P); Charlotte Harris (P). University of Florida College of Medicine, Department of Ophthalmology, Jacksonville Health Science Center, Jacksonville, Florida: Kakarla V. Chalam (I); Ghulam Shabbir Hamdani (C); Shamim A. Haji (C); Wenhua Li (C, V); Kumar Sambhav (C, V); Ashley Cowart (C, V); Nicholas Freeman (P); Jose J. Carrion (P). Southeastern Retina Associates PC, Knoxville, Tennessee: Joseph M. Googe (I); Stephen L. Perkins (I); Nicholas G. Anderson (I); Kristina Oliver (C); Lisa Lovelady (C); Christy Berry (V); Cecile Hunt (V); Jennifer Beerbower (V); Ann Arnold (V); Nicole Grindall (V); Patricia Coppola (V); Kathy L. Schulz (V); Jerry K. Whetstone (P); Sarah M. Oelrich (P); Raul E. Lince (P); Justin Walsh (P). Medical College of Wisconsin, Milwaukee, Wisconsin: Judy E. Kim (I); Dennis P. Han (I); David V. Weinberg (I); William J. Wirostko (I); Thomas B. Connor (I); Vesper V. Williams (C); Krissa L. Packard (C); Tracy L. Kaczanowski (C); Judy Flanders (V); Vicki Barwick (V); Pat A. Winter (V); Dennis B. Backes (P); Mara Goldberg (P); Joseph R. Beringer (P); Kathy J. Selchert (P). Medical Center Ophthalmology Associates, San Antonio, Texas: Michael A. Singer (I); Darren J. Bell (I); Catherine Ellis (C); Tamara M. Urias (C); Beatrice A. Guajardo (C); Roxanne Gomez (V); Ann-Marie Mora (V); Celia Maria Pena (P); Vincent Segovia (P); Rosa Escobar (P). Retina-Vitreous Surgeons of Central New York PC, Syracuse, New York: G. Robert Hampton (I); Jamin S. Brown (I); Laurie J. Sienkiewycz (C); Cindy J. Grinnell (C); Lynn M. Kwasniewski (V); Michelle L. Manley (V); Nicole E. Robarge (P); Peter B. Hay (P); Teresa M. DeForge (P). Wolfe Eye Clinic, West Des Moines, Iowa: Jared S. Nielsen (I); Kyle J. Alliman (I); Marianne Parker (C); Bethany George (C); Jennifer L. Coleman (V); Jamie Spillman (V); Marilyn A. Johnson (V); Holly Keenan (V); Bailey R. Bennett (P); Jay Rostvold (P); Jodi Weier (P). Austin Retina Associates, Austin, Texas: Robert W. Wong (I); Shelley Day (I); Peter A. Nixon (I); Chris A. Montesclaros (C); Carrie E. Leung (C); Phill Le (V); Margaret A. Rodriguez (P); Mary Laremont (P); Cory Mangham (P); Codey L. Harborth (P). Retinal and Ophthalmic Consultants PC, Northfield, New Jersey: Brett T. Foxman (I); Scott G. Foxman (I); Natalie S. Mahan (C); Chastity Mendez (V). University of Rochester, Rochester, New York: David Allen DiLoreto (I); George W. O'Gara (C); Andrea M. Czubinski (C, V); Kari M. Steinmetz (C); Melissa S. Keim (V); Yvonne F. Yu (V); Salina M. Tongue (V); Dan A. Castillo (V); Laura Guzman (P); Lynn Singer (P); Rachel Hollar (P); Taylor A. Pannell (P); Brittany S. Richardson (P); Brandi N. Deats (P); Steven DeRidder (P); TKe Long (P). University of Washington Medical Center, Seattle, Washington:James L. Kinyoun (I); Gurunadh Atmaram Vemulakonda (I); Susan A. Rath (C, V); Patricia K. Ernst (C, V); Juli A. Pettingill (V); Brad C. Clifton (P); James D. Leslie (P); Ronald C. Jones (P). Spokane Eye Clinic, Spokane, Washington: Robert S. Wirthlin (I); Eric S. Guglielmo (I); Eileen A. Dittman (C, V); Dylan C. Waidelich (C, V); Christina Owens (V); Vicki M. Stanton (P); Adeline M. Stone (P); Ashley Nicole Oakes (P); Cristofer J. Garza (P). Bay Area Retina Associates, Walnut Creek, California: Stewart A. Daniels (I); Tushar M. Ranchod (I); Stacey Touson (C, V); Shannon R. Earl (C); Jessica Garcia (V); Melissa C. Bartlett (V); Christine Fernando (V); Jose Carlos Suazo (P); Grace M. Marudo (P); Matthew D. Hughes (P); Fred Hanamoto (P); Cathy Walker (P); Betty Hom (P); Leah M. McNeil (P); Yesenia Cerna (P). Retina Specialists of Michigan, Grand Rapids, Michigan: Thomas M. Aaberg (I); Scott J. Westhouse (I); Holly L. Vincent (C, V); Rebecca Malone (V); Kristine L. VanDerKooi (P); Casey Le Roy (P); Kathy L. Karsten (P). Retina and Vitreous of Texas, Houston, Texas: Joseph A. Khawly (I); H. Michael Lambert (I); Pam S. Miller (C, V); Valerie N. Lazarte (V); Debbie Fredrickson (V); Colin Blank (P); Donald K. Lowd (P); Desiree Lopez (P); Jason E. Muniz (P); Lorena R. Martinez (P). Baylor Eye Physicians and Surgeons, Houston, Texas: Petros Euthymiou Carvounis (I); Robert E. Coffee (I); Pejman Hemati (C, V); Cindy J. Dorenbach (C, V); Annika S. Joshi (C, V); April Leger (V); Dana B. Barnett (P); Joseph F. Morales (P). Retina Vitreous Consultants, Monroeville, Pennsylvania: Karl R. Olsen (I); P. William Conrad (I); Pamela P. Rath (I); Judy C. Liu (I); Bernard H. Doft (I); Robert L. Bergren (I); Lori A. Merlotti (C); Mary E. Kelly (C); Holly M. Mechling (C); Jennifer L. Chamberlin (C); Missy A. Forish (V); Veronica L. Bennett (V); Christina M. Schultz (V); Grace A. Rigoni (V); Lois Stepansky (V); Kimberly A. Yeckel (V); Kellianne Marfisi (V); Christina R. Fulwylie (V); Julie Walter (V); Courtney L. Foreman (P); David Steinberg (P); Brandi L. Sherbine (P); Amanda Fec (P); Keith D. McBroom (P). University of Pennsylvania Scheie Eye Institute, Philadelphia, Pennsylvania: Alexander J. Brucker (I); Benjamin J. Kim (I); Sheri Drossner (C, V); Joan C. DuPont (C, V); Armin Farazdaghi (V); Laurel Weeney (P); Michael Bodine (P); Beth Serpentine (P); Cheryl Devine (P); Jim M. Berger (P); William Nyberg (P). Retina Associates of Florida PA, Tampa, Florida: Ivan J. Suner (I); Marc C. Peden (I); Mark E. Hammer (I); Janet R. Traynom (C); Rochelle DenBoer (C); Susan Ramsey (V); Heidi Vargo (V); Debra Jeffres (P); Anita Kim Malzahn (P). Wilmer Eye Institute at Johns Hopkins, Baltimore, Maryland: Sharon D. Solomon (I); Susan Bressler (I); Lisa K. Levin (C); Mary Frey (C, V); Deborah Donohue (C, V); Rita L. Denbow (V); Keisha Murray (V); David Emmert (P); Joe Belz (P); Janis Graul (P); Jacquelyn McDonald (P); Nick Rhoton (P). Montefiore Medical Center, Bronx, New York: Umar Khalil Mian (I); Rebecca L. Riemer (C); Louise V. Wolf (C); Evelyn Koestenblatt (C); Erica Otoo (V); Irina Katkovskaya (V); Christine Kim (V); Kevin A. Ellerbe (P); Caroline Costa (P); Kenneth Boyd (P). Retinal Diagnostic Center, Campbell, California: Amr Dessouki (I); Joel M. Barra (C); Jessenia Perez (C); Rose Monahan (C); Kelly To (V); Hienmy Dang (V); Tim Kelley (P). Rush University Medical Center, Chicago, Illinois: Mathew W. MacCumber (I); Eileen E. Tonner (C, V); Danielle R. Carns (C); Denise L. Voskuil-Marre (C, V); Evan R. Rosenberg (V); Kisung Woo (P). Texas Retina Associates, Dallas, Texas: Gary E. Fish (I); Sally Arceneaux (C, V); Karen Duignan (V); Nicholas Hesse (P); Michael Mackens (P). North Shore University Health System, Glenview, Illinois: Manvi P. Maker (I); Mira Shiloach (C, V); Courtney Kastler (P); Lynn Wasilewski (P). Retina Associates of Kentucky, Lexington, Kentucky: Thomas W. Stone (I); John W. Kitchens (I); Diana M. Holcomb (C, V); Jeanne Van Arsdall (V); Edward A Slade (P); Michelle Buck (P). Southern California Desert Retina Consultants MC, Palm Desert, California: Clement K. Chan (I); Maziar Lalezary (I); Kimberly S. Walther (C); Tiana Gonzales (C); Lenise E. Myers (V); Kenneth M. Huff (P). Retinal Consultants of Arizona, Phoenix, Arizona: Karim N. Jamal (I); David T. Goldenber (I); Sachin Mehta (I); Scheleen R. Dickens (C); Jessica L. Miner (C); Heather Dunlap (V); Lydia Saiz (V); Dayna Bartoli (P); John J. Bucci (P); Rohana Yager (P). Sarasota Retina Institute, Sarasota, Florida: Melvin Chen (I); Peggy A. Jelemensky (C); Tara L. Raphael (V); Mark Sneath (P); Evelyn Inlow (P). The Retina Institute, St. Louis, Missouri: Kevin J. Blinder (I); Ginny S. Nobel (C); Rhonda F. Weeks (C, V); Maria A. Stuart (V); Brook G. Pulliam (V); Kelly E. Pepple (V); Lynda K. Boyd (V); Timothy L. Wright (P); Dana L. Gabel (P); Jarrod Wehmeier (P).

    Disclaimer: Dr Bressler is the Editor and Dr Sun is the CME Editor of JAMA Ophthalmology, but they were not involved in any of the decisions regarding review of the manuscript or its acceptance.

    Meeting Presentation: This study was presented in part at the 43rd Annual Macula Society Meeting; February 20, 2020; San Diego, California.

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