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Figure 1.
Persistent Diabetic Macular Edema (DME) Through 24 Weeks
Persistent Diabetic Macular Edema (DME) Through 24 Weeks

At 24 weeks, P < .001 for aflibercept vs bevacizumab, P = .05 for aflibercept vs ranibizumab, and P < .001 for ranibizumab vs bevacizumab.

Figure 2.
Probability of Chronic Persistent Diabetic Macular Edema (DME) Through 2 Years by Treatment Group
Probability of Chronic Persistent Diabetic Macular Edema (DME) Through 2 Years by Treatment Group

Eyes in which chronic persistent diabetic macular edema (DME) did not resolve by 104 weeks were censored at their last visit (n = 145), on the date of the first nonprotocol DME treatment (n = 3), or on the date of the 52-week visit if there were fewer than 4 visits in year 2 (n = 10). Two-year life-table survival estimates are shown for each group. Dark blue indicates aflibercept, bright blue indicates bevacizumab, and orange indicates ranibizumab. An event was defined as central subfield thickness less than 250 μm (Stratus equivalent) and at least 10% reduction relative to the 24-week study visit at 2 consecutive visits subsequent to the 24-week visit.

Table 1.  
Visual Acuity and OCT Outcomes Through 24 Weeks by Presence of Persistent Diabetic Macular Edema
Visual Acuity and OCT Outcomes Through 24 Weeks by Presence of Persistent Diabetic Macular Edema
Table 2.  
Visual Acuity and OCT Outcomes by Presence of Chronic Persistent Diabetic Macular Edema
Visual Acuity and OCT Outcomes by Presence of Chronic Persistent Diabetic Macular Edema
Supplement.

eFigure 1. Flowchart of Study Eyes Included in Analyses

eFigure 2. Probability of Chronic Persistent Diabetic Macular Edema Through 2 Years by Treatment Group Among Eyes With Baseline Visual Acuity Letter Score of 78 to 69 (Approximate Snellen Equivalent 20/32 to 20/40)

eFigure 3. Probability of Chronic Persistent Diabetic Macular Edema Through 2 Years by Treatment Group Among Eyes With Baseline Visual Acuity Letter Score of 68 to 24 (Approximate Snellen Equivalent 20/50 to 20/320)

eTable 1. Persistent Diabetic Macular Edema Through 24 Weeks Stratified by Baseline Visual Acuity

eTable 2. Baseline Participant and Ocular Characteristics by Presence of Persistent Diabetic Macular Edema Through 24 Weeks

eTable 3. Visual Acuity and Optical Coherence Tomography Outcomes at 24 Weeks by Presence of Persistent Diabetic Macular Edema Among Eyes With Baseline Visual Acuity Letter Score of 78 to 69 (Approximate Snellen Equivalent 20/32 to 20/40)

eTable 4. Visual Acuity and Optical Coherence Tomography Outcomes at 24 Weeks by Presence of Persistent Diabetic Macular Edema Among Eyes With Baseline Visual Acuity Letter Score of 68 to 24 (Approximate Snellen Equivalent 20/50 to 20/320)

eTable 5. Injections and Laser Treatment by Presence of Chronic Persistent Diabetic Macular Edema

eTable 6. Injections and Laser Treatment by Presence of Chronic Persistent Diabetic Macular Edema Among Eyes With Baseline Visual Acuity Letter Score 78 to 69 (Approximate Snellen Equivalent 20/32 to 20/40)

eTable 7. Injections and Laser Treatment by Presence of Chronic Persistent Diabetic Macular Edema Among Eyes With Baseline Visual Acuity Letter Score 68 to 24 (Approximate Snellen Equivalent 20/50 to 20/320)

eTable 8. Visual Acuity and Optical Coherence Tomography Outcomes by Presence of Chronic Persistent Diabetic Macular Edema Among Eyes With Baseline Visual Acuity Letter Score 78 to 69 (Approximate Snellen Equivalent 20/32 to 20/40)

eTable 9. Visual Acuity and OCT Outcomes by Presence of Chronic Persistent Diabetic Macular Edema Among Eyes With Baseline Visual Acuity Letter Score 68 to 24 (Approximate Snellen Equivalent 20/50 to 20/320)

1.
Solomon  SD, Chew  E, Duh  EJ,  et al.  Diabetic retinopathy: a position statement by the American Diabetes Association.  Diabetes Care. 2017;40(3):412-418.PubMedGoogle ScholarCrossref
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Bressler  SB, Ayala  AR, Bressler  NM,  et al; Diabetic Retinopathy Clinical Research Network.  Persistent macular thickening after ranibizumab treatment for diabetic macular edema with vision impairment.  JAMA Ophthalmol. 2016;134(3):278-285.PubMedGoogle ScholarCrossref
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Elman  MJ, Aiello  LP, Beck  RW,  et al; Diabetic Retinopathy Clinical Research Network.  Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema.  Ophthalmology. 2010;117(6):1064-1077.e35.PubMedGoogle ScholarCrossref
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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.PubMedGoogle ScholarCrossref
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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.PubMedGoogle ScholarCrossref
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Hochberg  Y.  A sharper Bonferroni procedure for multiple tests of significance.  Biometrika. 1988;75(4):800-802. doi:10.1093/biomet/75.4.800Google ScholarCrossref
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Gonzalez  VH, Campbell  J, Holekamp  NM,  et al.  Early and long-term responses to anti-vascular endothelial growth factor therapy in diabetic macular edema: analysis of Protocol I data.  Am J Ophthalmol. 2016;172:72-79.PubMedGoogle ScholarCrossref
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Ferris  FL  III, Maguire  MG, Glassman  AR, Ying  G-s, Martin  DF.  Evaluating effects of switching anti–vascular endothelial growth factor drugs for age-related macular degeneration and diabetic macular edema.  JAMA Ophthalmol. 2017;135(2):145-149.PubMedGoogle ScholarCrossref
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Maturi  RK, Glassman  AR, Liu  D.  Diabetic Retinopathy Clinical Research Network. Effect of adding dexamethasone to continued ranibizumab treatment in patients with persistent diabetic macular edema: a DRCR Network phase 2 randomized clinical trial [published online November 11, 2017.  JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2017.4914Google Scholar
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Wells  JA, Glassman  AR, Ayala  AR,  et al; Diabetic Retinopathy Clinical Research Network.  Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial.  Ophthalmology. 2016;123(6):1351-1359.PubMedGoogle ScholarCrossref
Original Investigation
March 2018

Persistent Macular Thickening Following Intravitreous Aflibercept, Bevacizumab, or Ranibizumab for Central-Involved Diabetic Macular Edema With Vision Impairment: A Secondary Analysis of a Randomized Clinical Trial

Author Affiliations
  • 1Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 2Jaeb Center for Health Research, Tampa, Florida
  • 3The Retina Institute, St Louis, Missouri
  • 4Feinberg School of Medicine, Northwestern University Medical School, Chicago, Illinois
  • 5Palmetto Retina Center, Columbia, South Carolina
JAMA Ophthalmol. 2018;136(3):257-269. doi:10.1001/jamaophthalmol.2017.6565
Key Points

Question  What is the prevalence of persistent central-involved diabetic macular edema through 24 weeks and subsequent outcomes using different anti–vascular endothelial growth factor drugs?

Findings  In this post hoc analysis of a clinical trial, persistent diabetic macular edema through 24 weeks was less likely with 2.0-mg aflibercept or 0.3-mg ranibizumab than 1.25-mg bevacizumab, and among eyes with persistent DME through 24 weeks, chronic persistent diabetic macular edema through 2 years was more likely with bevacizumab than aflibercept. Regardless of diabetic macular edema persistence or anti–vascular endothelial growth factor agent, few eyes lost substantial vision.

Meaning  Using this protocol, at least 2-line visual acuity loss was uncommon through 2 years with any of these anti–vascular endothelial growth factor agents, even when diabetic macular edema chronically persisted.

Abstract

Importance  Prevalence of persistent central-involved diabetic macular edema (DME) through 24 weeks of anti–vascular endothelial growth factor therapy and its longer-term outcomes may be relevant to treatment.

Objective  To assess outcomes of DME persisting at least 24 weeks after randomization to treatment with 2.0-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab.

Design, Setting, and Participants  Post hoc analyses of a clinical trial, the DRCR.net Protocol T among 546 of 660 participants (82.7%) meeting inclusion criteria for this investigation.

Interventions  Six monthly intravitreous anti–vascular endothelial growth factor injections (unless success after 3 to 5 injections); subsequent injections or focal/grid laser as needed per protocol to achieve stability.

Main Outcomes and Measures  Persistent DME through 24 weeks, probability of chronic persistent DME through 2 years, and at least 10-letter (≥ 2-line) gain or loss of visual acuity.

Results  The mean age of participants was 60 years, 363 (66.5%) were white, and 251 (46.0%) were women. Persistent DME through 24 weeks was more frequent with bevacizumab (118 of 180 [65.6%]) than aflibercept (60 of 190 [31.6%]) or ranibizumab (73 of 176 [41.5%]) (aflibercept vs bevacizumab, P < .001; ranibizumab vs bevacizumab, P < .001; and aflibercept vs ranibizumab, P = .05). Among eyes with persistent DME through 24 weeks (n = 251), rates of chronic persistent DME through 2 years were 44.2% with aflibercept, 68.2% with bevacizumab (aflibercept vs bevacizumab, P = .03), and 54.5% with ranibizumab (aflibercept vs ranibizumab, P = .41; bevacizumab vs ranibizumab, P = .16). Among eyes with persistent DME through 24 weeks, proportions with vs without chronic persistent DME through 2 years gaining at least 10 letters from baseline were 62% of 29 eyes vs 63% of 30 eyes (P = .88) with aflibercept, 51% of 70 vs 55% of 31 (P = .96) with bevacizumab, and 45% of 38 vs 66% of 29 (P = .10) with ranibizumab. Only 3 eyes with chronic persistent DME lost at least 10 letters.

Conclusions and Relevance  Persistent DME was more likely with bevacizumab than with aflibercept or ranibizumab. Among eyes with persistent DME, eyes assigned to bevacizumab were more likely to have chronic persistent DME than eyes assigned to aflibercept. These results suggest meaningful gains in vision with little risk of vision loss, regardless of anti–vascular endothelial growth factor agent given or persistence of DME through 2 years. Caution is warranted when considering switching therapies for persistent DME following 3 or more injections; improvements could be owing to continued treatment rather than switching therapies.

Trial Registration  clinicaltrials.gov Identifier: NCT01627249

Introduction

Anti–vascular endothelial growth factor (anti-VEGF) injections are typically standard care for eyes with central-involved diabetic macular edema (DME) and vision impairment.1 Despite the positive effects of anti-VEGF injections on both visual acuity and retinal thickening, DME can persist in some eyes. An exploratory analysis of data from Diabetic Retinopathy Clinical Research Network (DRCR.net) Protocol I investigated the frequency of persistent DME through 24 weeks and whether chronic persistent DME had deleterious effects on visual acuity outcomes through 3 years.2,3 Approximately 40% of eyes receiving monthly ranibizumab had persistent DME through 24 weeks. As these eyes continued treatment, applying a protocol based on changes in visual acuity and optical coherence tomography, the percentage of patients with chronic persistent DME (ie, never resolving at 2 consecutive visits) was 55.8% and 40.1% at the 2-year and 3-year visits, respectively. Visual acuity outcomes appeared slightly less favorable among the eyes in which DME persisted through 3 years; however, visual acuity typically improved from baseline, and substantial (≥ 2-line) loss was uncommon. The DRCR.net retreatment algorithm treats DME to stability (2 consecutive visits without improvement or worsening of vision and central subfield thickness [CST]), not resolution.

To further our understanding of the prevalence of persistent DME and its effect on visual acuity across different anti-VEGF agents, the DRCR.net conducted a similar post hoc analysis of eyes treated for DME with aflibercept, bevacizumab, or ranibizumab in a randomized comparative effectiveness trial (Protocol T). In Protocol T, all 3 agents, on average, improved vision, but the relative effect depended on baseline visual acuity.4 Specifically, when the initial visual acuity was 20/32 to 20/40 (approximate Snellen equivalent), on average, there were no apparent differences in mean change in visual acuity from baseline to 1 or 2 years. However, when visual acuity was 20/50 to 20/320, aflibercept was more effective at improving vision.

Methods

The methods for the DRCR.net Protocol T clinical trial have been published in detail elsewhere, with the complete protocol available online.4 The study adhered to the tenets of the Declaration of Helsinki. Study participants provided written informed consent. The protocol and Health Insurance Portability and Accountability Act–compliant informed consent forms were approved by institutional review boards at all participating sites. Principal eligibility criteria included eyes with central-involved DME on clinical examination and a best-corrected electronic visual acuity letter score of 78 through 24 (approximate Snellen equivalent 20/32 to 20/320) following a protocol refraction.5

Quiz Ref IDVisits were every 4 weeks through the 52-week visit and every 4, 8, or 16 weeks thereafter, depending on the clinical course. The protocol required injections at baseline and every 4 weeks for the initial 20 weeks unless CST was less than 250 μm (time-domain [Zeiss Stratus] equivalent) and the visual acuity letter score was 84 or better (approximate Snellen equivalent 20/20 or better) after 2 consecutive 4-week injections (Box). Thereafter, injections were repeated every 4 weeks if there was successive improvement or worsening in visual acuity (≥5 letters) or CST (change by ≥10%) and vision remained worse than 20/20, with CST of at least 250 μm. Otherwise, reinjection was withheld starting with the 24-week visit if there was no improvement or worsening of visual acuity or CST after 2 consecutive injections (sustained stability). Injections resumed if there was subsequent worsening of visual acuity or CST until sustained stability of visual acuity and CST were attained. Focal/grid laser was given as needed per protocol at or following the 24-week visit if DME persisted, the eye had not improved in visual acuity or CST from the last 2 consecutive injections, and there were lesions amenable to photocoagulation. Alternative treatments, such as intravitreous corticosteroids, were not permitted unless failure criteria were met.

Box Section Ref ID
Box.

Diabetic Retinopathy Clinical Research Network Principles of Anti-VEGF Treatment Regimen for Diabetic Macular Edema

  • Six monthly injections unless vision is 20/20 or better and optical coherence tomography (OCT) central subfield thickness (CST) is normal after at least 3 consecutive injections.

    • For Heidelberg Spectralis machines, normal was defined as central subfield thickness <305 μm for women and <320 μm for men. For Zeiss Cirrus machines, normal was defined as central subfield thickness <290 μm for women and <305 μm for men. For Zeiss Stratus machines, normal was defined as central subfield thickness <250 μm for both sexes.

  • After the 6-month visit, withhold anti-VEGF if visual acuity or OCT CST has neither improved nor worsened compared with the last 2 injection visits, ie, no injection if either of the following scenarios:

    • Diabetic macular edema (DME) has resolved (“normal” OCT results)

    • Persistent but stable DME in the absence of visual acuity improvement or worsening

      • Improvement or worsening was defined as OCT central subfield thickness ≥10% change or best-corrected E-ETDRS visual acuity ≥5 letters change (approximately ≥1 line on an ETDRS eye chart)

  • Resume anti-VEGF if either of the following scenarios:

    • Visual acuity worsens in the setting of persistent but stable DME

    • Optical coherence tomography CST worsens

  • If there is persistent but stable DME and an injection has been deferred, then add focal/grid laser if indicated. Focal/grid laser is indicated if all of the following criteria are met:

    • At least 4 months since prior focal/grid laser treatment

    • Treatable lesions within thickened areas of the macula between 500 and 3000 microns from the center of the macula, including either of the following: previously untreated microaneurysms or areas of thickening without untreated microaneurysms and without prior grid laser treatment at least 1 to 2 burn widths apart.

  • Abbreviation: VEGF, vascular endothelial growth factor.

Among the 660 eyes initially randomized to aflibercept (n = 224), bevacizumab (n = 218), or ranibizumab (n = 218), 114 eyes were excluded from this analysis. This included 14 eyes with baseline CST less than 250 μm, 23 that received less than 4 injections prior to 24 weeks, 47 that missed more than 2 visits between the 28-week and 52-week visits, 6 that received alternative treatment for DME prior to 52 weeks, and 24 that missed the 24-week visit (eFigure 1 in the Supplement). These exclusion criteria are based on those used in the previous analysis of Protocol I data and were determined prior to looking at data from Protocol T. The persistent DME cohort included all eyes that did not meet the exclusion criteria and had CST of at least 250 μm at each completed study visit through 24 weeks. Thereafter, these eyes were labeled as having chronic persistent DME until they achieved a CST less than 250 μm and achieved a reduction of at least 10% in CST relative to the 24-week visit on at least 2 consecutive study visits. To increase the likelihood that eyes were correctly classified with respect to chronic persistent DME between the 52-week and 104-week visits, 14 eyes with fewer than 4 visits completed in the second year (including the 104-week visit) and 4 eyes that received alternative treatment for DME during the second year were excluded from analysis at 2 years.

Treatment-group comparisons of binary outcomes (eg, percentage of eyes gaining 10 or more letters or with persistent DME) were conducted with a generalized linear model adjusting for baseline vision or CST. Within-group comparisons of visual acuity by presence of persistent or chronic persistent DME were conducted with anaylsis of covariance, adjusting for baseline visual acuity. The cumulative probability of chronic persistent DME for each treatment group with corresponding 95% confidence interval was calculated using the life table method, and treatment-group comparisons were conducted with proportional hazards regression adjusting for baseline CST. For between-group comparisons, P values and confidence intervals were adjusted for multiplicity using the Hochberg method.6 Owing to the large number of tests performed, P less than .05 was considered to be suggestive, rather than definitive, evidence of a difference. All P values were 2-sided. Statistical analyses were conducted using SAS, version 9.4 (SAS Institute Inc).

Results
Persistent DME Through 24 Weeks

Quiz Ref IDThe percentage of eyes with persistent DME at each visit through 24 weeks is shown in Figure 1. At week 12 (after 3 consecutive monthly injections), DME persisted in 50.8% (95 of 187), 72.9% (129 of 177), and 53.2% (91 of 171) of eyes in the aflibercept, bevacizumab, and ranibizumab groups, respectively. This percentage continued to decrease through 24 weeks (after 3 to 6 consecutive monthly injections), with persistent DME noted in 31.6% (60 of 190), 65.6% (118 of 180), and 41.5% (n = 73 of 176) of eyes. Diabetic macular edema was more likely to persist through 24 weeks with bevacizumab than aflibercept or ranibizumab; adjusted differences were 34.4% (adjusted 95% CI, 23.0% to 45.8%; P < .001) for bevacizumab-aflibercept, 9.5% (adjusted 95% CI, −0.1% to 19.1%; P = .05) for ranibizumab-aflibercept, and 24.9% (adjusted 95% CI, 13.8% to 36.1%; P < .001) for bevacizumab-ranibizumab. Results were similar within the subgroups of eyes with better (20/32 to 20/40) and worse (20/50 to 20/320) baseline visual acuity (eTable 1 in the Supplement).

Baseline participant and ocular characteristics are shown in eTable 2 in the Supplement by treatment group and the presence of persistent DME through 24 weeks. Baseline CST was greater among eyes with persistent DME (median values for aflibercept, bevacizumab, and ranibizumab were 412 μm, 413 μm, and 427 μm with persistent DME vs 365 μm, 327 μm, and 355 μm, respectively, without persistent DME). Regarding injections, eyes with persistent DME through 24 weeks received 4 to 6 injections (median, 6 in all groups) prior to 24 weeks, while eyes without persistent DME received 3 to 6 injections (median, 6 in all groups) because injections could be deferred if success criteria were met after 3 injections.

Quiz Ref IDChanges in visual acuity and CST from baseline to 24 weeks among eyes with and without persistent DME are shown in Table 1. At 24 weeks, mean improvement in visual acuity from baseline was greater among eyes without persistent DME vs those with persistent DME in the aflibercept (adjusted difference, 3.1; 95% CI, 0.7 to 5.5; P = .01) and ranibizumab (adjusted difference, 3.7; 95% CI, 1.4 to 6.0; P = .002) groups, but not in the bevacizumab group (adjusted difference, 0.7; 95% CI, −1.8 to 3.1; P = .59). Mean change in visual acuity from baseline to 104 weeks among eyes with persistent DME through 24 weeks (irrespective of their subsequent anatomic course) was within 1 to 2 letters of eyes without persistent DME through 24 weeks for each treatment group. Among eyes with persistent DME, mean (SD) change in visual acuity from 24 to 104 weeks was 2.5 (9.5), 1.1 (9.3), and 3.4 (9.2) letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively, indicating that most of the improvement in vision in these eyes occurred in the first 24 weeks. Among eyes without persistent DME, mean change in visual acuity from 24 weeks to 104 weeks was less than 1.5 letters in each group. These outcomes stratified by baseline visual acuity are presented in eTable 3 in the Supplement (20/32 to 20/40) and eTable 4 in the Supplement (20/50 to 20/320).

Chronic Persistent DME at 1 and 2 Years

For eyes with persistent DME through 24 weeks, Figure 2 shows the probability of chronic persistent DME within each of the 3 anti-VEGF groups during the remainder of the 2-year follow-up period. At 2 years, the cumulative probability that these eyes manifested chronic persistent DME with aflibercept, bevacizumab, or ranibizumab was 44.2% (95% CI, 29.5%-57.9%), 68.2% (95% CI, 57.6%-76.6%), and 54.5% (95% CI, 40.8%-66.3%), respectively. The hazard ratios for resolution of chronic persistent DME were 1.93 (adjusted 95% CI, 1.05-3.53; P = .03) for aflibercept/bevacizumab, 1.24 (adjusted 95% CI, 0.74-2.05; P = .41) for aflibercept/ranibizumab, and 1.56 (adjusted 95% CI, 0.89-2.74; P = .16) for ranibizumab/bevacizumab. Similar trends were noted among the subgroups of eyes with better visual acuity (20/32 to 20/40, eFigure 2 in the Supplement) and worse visual acuity (20/50 to 20/320, eFigure 3 in the Supplement) at baseline.

The number of injections and laser treatment sessions administered in eyes with persistent DME (through 24 weeks), stratified by the presence of chronic persistent DME at the 52-week and 104-week visits, are shown in eTable 5 in the Supplement. There were no significant differences in the median number of injections given over 2 years by presence of chronic persistent DME at 2 years. There also were no significant differences in the percentage of eyes receiving focal/grid laser by presence of chronic persistent DME at 2 years. The same outcomes stratified by baseline visual acuity are presented in eTable 6 in the Supplement (20/32 to 20/40) and eTable 7 in the Supplement (20/50 to 20/320).

Quiz Ref IDChanges in visual acuity from baseline to 1 and 2 years in eyes with and without chronic persistent DME (among those with persistent DME through 24 weeks) by treatment group are shown in Table 2. At 2 years, the adjusted difference in mean change in visual acuity between eyes without and with persistent DME was −4.3 (95% CI, −8.8 to 0.2; P = .06) for aflibercept, −0.3 (95% CI, −3.9 to 3.3; P =  .87) for bevacizumab, and 4.7 (95% CI, 0.1 to 9.3; P = .05) for ranibizumab. The percentage of eyes gaining 10 or more letters from baseline at 2 years was not significantly different in eyes with vs without chronic persistent DME at 2 years (aflibercept, 62.1% [18 of 29] vs 63.3% [19 of 30]; P = .88; bevacizumab, 51.4% [36 of 70] vs 54.8% [17 of 31]; P = .96; and ranibizumab, 44.7% [17 of 38] vs 65.5% [19 of 29]; P = .10). Overall, only 3 eyes with chronic persistent DME and 2 eyes without chronic persistent DME lost at least 10 letters (≤3.3% in each treatment by persistent DME subgroup) with no definitive differences identified within each treatment group (P > .99 for all groups). Similar results were found when stratifying by baseline visual acuity (eTable 8 in the Supplement [20/32 to 20/40] and eTable 9 in the Supplement, [20/50 to 20/320]).

Discussion

These data from Protocol T suggest that, in a group of eyes treated with anti-VEGF for DME, there is continued resolution of DME on optical coherence tomography in an increasing number of eyes from week 12 through week 24 with continued monthly injections, particularly with aflibercept and ranibizumab. Therefore, caution should be exercised when considering switching therapies for DME if there is a limited response following 3 or more initial anti-VEGF injections.7 These data show that by remaining on the DRCR.net retreatment algorithm for DME, many eyes will have resolution of DME with additional injections at weeks 12, 16, and 20. Furthermore, these data suggest meaningful gains in visual acuity from baseline and a low risk of vision loss across all 3 anti-VEGF agents, even if DME chronically persists through 2 years. The DRCR.net retreatment algorithm allows for deferral of injections, even in the presence of persistent DME, after the first 24 weeks of injections, provided there has not been improvement or worsening of visual acuity (≥5 letters) or CST (≥10%) at 2 consecutive visits. The only adjuvant or alternative therapy permitted in the absence of substantial visual acuity loss was focal/grid laser, which was added to thickened areas in the macula, warranting treatment per protocol at or after 24 weeks if CST was at least 250 μm (Stratus equivalent) and if vision and CST were stable despite injections for 2 consecutive visits.

A question that remains is whether switching eyes with persistent DME to alternative therapies other than focal/grid laser after 3 or at least 6 injections would improve on the outcomes reported here in eyes that were not given alternative therapies. To determine the true effect of adding or switching therapies compared with the current DRCR.net treatment regimen for DME, it is essential to have a control arm in which the treatment does not change,8 as in the results presented in this post hoc analysis. As an example where an alternative therapy was not shown to be beneficial, in the DRCR.net Protocol U, ranibizumab with or without addition of sustained release dexamethasone implant (Ozurdex) was compared among eyes that had persistent DME despite at least 3 prior anti-VEGF injections before enrollment and 3 additional ranibizumab injections during a 12-week run-in phase. There was no significant difference between the groups for the primary outcome of change in visual acuity from baseline to 24 weeks.9

Importantly, almost no eyes with chronic persistent DME lost substantial visual acuity (≥2 lines [≥10 letters]) from baseline at 2 years (≤3.3% in each treatment by chronic persistent DME subgroup), while a gain of at least 2 lines from baseline at 2 years was achieved in 62.1%, 51.4%, and 44.7% of aflibercept-treated, bevacizumab-treated, and ranibizumab-treated eyes with chronic persistent DME, respectively. These outcomes were in the setting of no definitive differences identified between eyes with and without chronic persistent DME in the number of injections given or the percentage of eyes receiving focal/grid laser through 2 years. It is unknown what effect continuing intravitrous anti-VEGF injections after eyes were stable for 2 consecutive visits beyond the 6-month visit may have had on outcomes presented here.

For eyes with persistent DME through 24 weeks, there were no definitive differences identified in visual acuity change from baseline at 2 years between eyes with and without chronic persistent DME in the aflibercept or bevacizumab groups. However, for the ranibizumab group, vision outcomes were slightly worse among eyes with chronic persistent DME, as was seen in Protocol I at 3 years.2 There also were several additional findings in this study that were similar to findings from Protocol I, which is not surprising given the similar cohorts and retreatment algorithms.2 First, the percentage of ranibizumab-treated eyes with persistent DME through 24 weeks was 39.5% in Protocol I vs 41.5% in Protocol T. Second, persistent DME through 24 weeks appeared to be associated with greater baseline CST (median 415 μm with persistent DME vs 353 μm, combining groups in Protocol T), as was found in Protocol I. Finally, the 54.5% rate of chronic persistent DME at 2 years among those with persistent DME through 24 weeks seen in the ranibizumab group in Protocol T is comparable with the rate of 55.8% in Protocol I.2

Limitations

One limitation of this study is that the primary comparisons are based on groups determined by response to treatment, which is not a randomized comparison. Another limitation is the reduction in sample size and statistical precision as a result of limiting many analyses to eyes in which DME persisted for 24 weeks. Nevertheless, bias should have been minimized because retention was more than 90%,10 visual acuity testers were masked at annual visits, and objective OCT data were used in the retreatment algorithm. Also, many outcomes were compared between and within 3 treatment groups, reducing the confidence one may place in any particular finding and increasing the possibility that some results could be owing to chance, even with the multiplicity adjustments undertaken.

There is possible selection bias in comparing eyes with persistent DME through 24 weeks by treatment group. For example, eyes that have persistent DME after 6 aflibercept injections may not be comparable with eyes with persistent DME after 6 bevacizumab injections because the eyes not responding to aflibercept may be more resistant to treatment than those not responding to bevacizumab. However, this bias would be in the opposite direction of the observed finding that resolution of chronic persistent DME through 2 years is more likely with aflibercept than bevacizumab. There is also a large treatment group imbalance in sample size in the 24-week cohort, making comparisons involving bevacizumab, such as the proportion with resolution of persistent DME over time, more likely to have lower P values than similar proportions with aflibercept because the bevacizumab group had approximately double the sample size of the other 2 groups.

Conclusions

The results presented here show that aflibercept and ranibizumab are more effective than bevacizumab in preventing persistent DME through 24 weeks and that eyes with persistent DME through 24 weeks are more likely to subsequently achieve resolution of DME by 2 years with aflibercept than bevacizumab. When following the retreatment protocol used in this trial of eyes with DME and vision impairment, improvement from baseline in visual acuity is the norm, and substantial loss of visual acuity (≥2 lines) is uncommon across all 3 anti-VEGF agents, even when DME chronically persists through 2 years. These observations were made while withholding continued anti-VEGF injections as early as 6 months for stable, persistent DME in many eyes, placing adjuvant focal/grid laser when indicated per protocol, and without administering other alternative therapies such as corticosteroids. These analyses are consistent with and strengthen similar conclusions from earlier analyses of Protocol I.2

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Article Information

Published Online: February 1, 2018. doi:10.1001/jamaophthalmol.2017.6565

Corresponding Author: Wesley T. Beaulieu, PhD, Jaeb Center for Health Research, 15310 Amberly Drive, Suite 350, Tampa, FL 33647 (drcrstat8@jaeb.org).

Accepted for Publication: December 11, 2017.

Correction: This article was corrected on March 29, 2018, to correct errors in the Abstract, Table 1, and Table 2.

Author Contributions: Drs Beaulieu and Neil M. Bressler had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: N. Bressler, S. Bressler, Jampol.

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

Drafting of the manuscript: N. Bressler, Beaulieu, Glassman, S. Bressler, Jampol.

Critical revision of the manuscript for important intellectual content: N. Bressler, Beaulieu, Blinder, S. Bressler, Jampol, Melia, Wells.

Statistical analysis: Beaulieu, Glassman, Melia.

Obtained funding: N. Bressler, Glassman, Jampol.

Administrative, technical, or material support: Glassman.

Supervision: N. Bressler, Glassman, S. Bressler, Melia.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Beaulieu reports other support from the National Eye Institute and National Institute of Diabetes and Digestive and Kidney Diseases and nonfinancial support Genentech and Regeneron during the conduct of the study. Dr Blinder reports personal fees from Regeneron Pharmaceuticals, Bausch and Lomb, and Allergan outside the submitted work. Dr Neil M. Bressler reports grants from Bayer, Genentech/Roche, Novartis, and Samsung Bioepis outside the submitted work. Dr Susan B. Bressler reports grants from Jaeb Center during the conduct of the study and grants from Bayer HealthCare Pharmacueticals Inc, Boehringer Ingelheim Pharm, Notal Vision, Novartis, Genentech, Jaeb Center, and Merck outside the submitted work; .Dr Glassman reports grants from National Institutes of Health during the conduct of the study and grants from Regeneron and Genentech outside the submitted work. Dr Jampol reports a grant from the National Eye Institute. Ms Melia reports grant support from the National Eye Institute and provision of study drug from Regeneron and Genentech during the conduct of the study. Dr Wells reports consultancy for Genentech, Iconic Pharmaceuticals, Alimera, and Alcon and grants for Genentech, Regeneron, Ophthotech, Emmes, Iconic Pharmaceuticals, Neurotech, KalVista Pharmaceuticals, Opthea, LPath, and Bayer. No other disclosures were reported.

Funding/Support: Supported through a cooperative agreement from the National Eye Institute and the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services grants EY14231, EY23207, and EY18817.

Role of the Funder/Sponsor: The funding organization 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; the collection, management, analysis, or interpretation of the data; or in the preparation of the manuscript.

Group Information: Members of the Diabetic Retinopathy Clinical Research Network who participated in the clinical trial analyzed in the present study are as follows: Charlotte Eye, Ear, Nose and Throat Association, Charlotte, North Carolina: David Browning, Andrew N. Antoszyk, Angela K. Price, Sherry L. Fredenberg, Jenna T. Herby, Christina J. Fleming, Ashley A. McClain, Sarah A. Ennis, Kelly R Gallagher, Angella S. Karow, Autumn C. Grupp, Danielle Puskas, Lynn Watson, Swann J Bojaj, Uma M. Balasubramaniam, Donna McClain, Donna R. Styles, Jeff A. Kuopus, Kathryn Kimrey, Loraine M. Clark, Lisa A. Jackson, Michael D. McOwen, Matt Dunlap, Susannah J Held. California Retina Consultants, Santa Barbara, California: Dante J. Pieramici, Ma'an A. Nasir, Alessandro A. Castellarin, Dilsher Dhoot, Sarah Fishbein, Jack Giust, Lisha Wan, Michelle S. Hanna, Melvin D. Rabena, Jerry Smith, Layne J. Bone, Kelly Avery, Matthew Giust, Aimee Walker, Aimee H. Shook, Sara Esau, Nitce L. Ruvalcaba. Palmetto Retina Center, West Columbia, South Carolina: John A. Wells, W. Lloyd Clark, David L. Johnson, John F. Payne, Tiffany R. Swinford, Mallie M. Taylor, Cassandra L. Garrison, Peggy D. Miller, Amber R. Houlahan, Charlotte A. O'Neill, Ashley Floyd, Crystal C. Parker, Courtney Sease, Tara Graham, Robin Spencer, Tiffany N. Ogbuewu, Ashley Studebaker, Tyler Huggins, Robbin Spivey, Brian Jones, Ashley Williams, Ron Petty, Erin L. Poston, G. Michael Ward. Paducah Retinal Center, Paducah, Kentucky: Carl W. Baker, Ron H. Tilford, Tracey M. Caldwell, Lynnette F. Lambert, Mary J. Palmer, Tracey R. Martin, Tana R. Williams, Samantha Kettler, Alecia B. Camp. Joslin Diabetes Center/Harvard Vanguard Medical Associates, Boston, Massachusetts: Paolo S. Silva, Paul G. Arrigg, George S. Sharuk, Sabera T. Shah, Jennifer K. Sun, Corey Westerfeld, Christopher Michael Andreoli, Lloyd Paul Aiello, Deborah Schlossman, Timothy Murtha, Hanna Kwak, Flor M. Flores, Margaret E. Stockman, Troy Kieser, Michael N. Krigman, Leila Bestourous, Elizabeth S. Weimann, Jerry D. Cavallerano, Kristen M. Hock, Mary Ann Robertson, Rita K. Kirby, Steve L. Papaconstantinou, Kylie M. Madigan, Robert W. Cavicchi, Kate A. Palitsch, Taygan Yilmaz. Retina Research Center, Austin, Texas: Brian B. Berger, Chirag D. Jhaveri, Tori Moore, Ginger J. Manhart, Rachel A. Walsh, Ivana Gunderson, Dietrich Riepen, Chelsey A. Bravenec, Ryan M. Reid, Yong Ren, Ben Ostrander, Christopher C. Stovall. Elman Retina Group, Baltimore, Maryland: Michael J. Elman, Robert A. Liss, Henry A. Leder, JoAnn Starr, Jennifer L. Belz, Charlene K. Putzulo, Dallas R. Sandler, Jennifer L. Simmons, Pamela V. Singletary, Ashley Davis, Perel M. Simpson, Teresa Coffey, Daniel J. Ketner, Terri Cain, Ashley M. Metzger, Peter Sotirakos, Michael J. Elman, Robert A. Liss, Henry A. Leder, JoAnn Starr, Jennifer L. Belz, Charlene K. Putzulo, Dallas R. Sandler, Jennifer L. Simmons, Pamela V. Singletary, Ashley Davis, Perel M. Simpson, Teresa Coffey, Daniel J. Ketner, Terri Cain, Ashley M. Metzger, Peter Sotirakos. Southeast Retina Center, Augusta, Georgia: Dennis M. Marcus, Harinderjit Singh, Courtney N. Roberts, Geri L Floyd, Siobhan O. Ortiz, Virginia Mims, L. Allison Foster, Christy Coursey, Jared C. Gardner, Ken Ivey. Retina Institute of Virginia, Richmond, Virginia: John Stewart O'Keefe, Juan A. Astruc, Bryan J. Schwent, Ali R. Tabassian, Suzette A. Rosen, David C. Vaughan, Jeffrey Michaels, Natalie J. Arndt, John J. Maziarz. Florida Retina Consultants, Lakeland, Florida: Scott M. Friedman, Nader Moinfar, Kimberly A. Williamson, Damanda F. Fagan, Katrina L. Dawson, Paige N. Walters, Allen McKinney, Steve Carlton. Retina Associates of Utah, Salt Lake City, Utah: Robert C. Kwun, Victoria L. Knudsen, Kirk E. Winward, Mano Swartz, James G. Howard, Michelle Riley, Gena Taylor, Michelle Holt, Jason G. Winward, Adam Walsh, Teresa Taylor, Daniel Walsh. Retina-Vitreous Surgeons of Central New York, Syracuse, New York: G. Robert Hampton, Jamin S. Brown, Rajeev K. Seth, Laurie J. Sienkiewycz, Deborah A. Appleton, Cindy J. Grinnell, Charity A. Cowley, Lynn M. Kwasniewski, Michelle L. Manley, Nicole E. Robarge, Stefanie R. DeSantis, Peter B. Hay, Teresa M. DeForge. Retina Consultants of Houston, Houston, Texas: Charles C. Wykoff, Tien P. Wong, Eric Chen, David M. Brown, Rosa Y. Kim, James C. Major, Amy C. Schefler, Richard H. Fish, Matthew S. Benz, Meredith Lipman, Amy Hutson, Nubia Landaverde, Ashley E. Chancey, Cassie Cone, Tressa Royse, Veronica A. Sneed, Belinda A. Almanza, Brenda Dives, Beau A. Richter, Eric N. Kegley. Casey Eye Institute, Portland, Oregon: Andreas K. Lauer, Christina J. Flaxel, Steven T. Bailey, Mitchell Schain, Ann D. Lundquist, Shelley A. Hanel, Shirley D. Ira, Susan K. Nolte, Peter N. Steinkamp, Dawn M. Ryan, Scott R. Pickell, Jocelyn T. Hui, Michelle Brix, Jordan Barth, Chris S. Howell. Retina Associates, Shawnee Mission, Kansas: Gregory M. Fox, Blake A. Cooper, Ivan R. Batlle, Lexie R. Manning, Karla A. Batlle, Holly Wyrick, Katherine Pippin, Samantha Perkins, Frank T. Yeager. Southwest Retina Specialists, Amarillo, Texas: Ryan B. Rush, Glenn R. Gardner, Christi Rush, Johnathan R. Hawkins, Brenda Dumas, Ben Ysasaga. Ophthalmic Consultants of Boston, Boston, Massachusetts: Chirag P. Shah, Michael G. Morley, Torsten W. Wiegand, Tina S. Cleary, Trexler M. Topping, Lindsey Colegrove, Katharine Bechtel, Britta Johnson, Lisa Lebedew, Natacha Lorius, Sandy G. Chong, Jennifer L. Stone, Michael Cullen Jones, Dennis Donovan, Sherry Malone, Margie Graham, Audrey Santos, Steve A. Bennett. The Retina Institute, St Louis, Missouri: Kevin J. Blinder, Bradley T. Smith, Ginny S. Nobel, Rhonda F. Weeks, Erika A. Hoehn, Maria A. Stuart, Kelly E. Pepple, Lynda K. Boyd, Brook G. Pulliam, Steve A Schremp, Stephanie L. Guevara, Jarrod Wehmeier, Timothy L. Wright, Dana L. Gabel. Retina Associates of Cleveland Inc, Beachwood, Ohio: David G. Miller, Jerome P. Schartman, Lawrence J. Singerman, Joseph M. Coney, Michael A. Novak, Llewelyn J. Rao, Susan C. Rath, Elizabeth McNamara, Larraine Stone, Veronica A. Smith, Cecelia Rykena, Kimberly A. DuBois, Mary A. Ilc, Vivian Tanner, Kim Drury, Trina M. Nitzsche, Gregg A. Greanoff, John C. DuBois. Fort Lauderdale Eye Institute, Plantation, Florida: Stuart K. Burgess, Tirso M. Lara, Noel H. Pereda, Cindy V. Fernandez, Deborah Davis, Evelyn Quinchia, Karen Workman. Wolfe Eye Clinic, West Des Moines, Iowa: Jared S. Nielsen, Jeong-Hyeon Sohn, Kyle J. Alliman, David D. Saggau, Marianne Parker, Bethany George, Carrie L. Eastvold, Kristin Sells, Tami Jo Woehl, Marilyn A. Johnson, Holly Keenan, Jennifer L. Coleman, Jamie Spillman, Shannon Freeman, Leigh S. Schmidt, Lisa M. Boender, Jill L. Partin, Bailey R. Bennett, Jay Rostvold. Western Carolina Retinal Associates, Asheville, North Carolina: Cameron McLure Stone, Lea R. Raymer, Andrea K. Menzel, Leslie D. Rickman, Barbara Campbell, Lorraine P. Sherlin, Lisa H. Hawkins, Melissa L. Buckner, Olesya N. Matsipura, Paula A. Price. National Ophthalmic Research Institute, Fort Myers, Florida: A. Thomas Ghuman, Paul A. Raskauskas, Ashish G. Sharma, Glenn Wing, Joseph P. Walker, Eileen Knips, Cheryl Kiesel, Crystal Y. Peters, Cheryl Ryan, Laura Greenhoe, Natalie N. Torres, Rebecca J. Youngblood, Danielle Turnbo, Anita H. Leslie, Etienne C. Schoeman, Raymond K. Kiesel. Dean A. McGee Eye Institute, Oklahoma City, Oklahoma: Ronald M. Kingsley, Vinay A. Shah, Robert E. Leonard, Heather R. Miller, Sonny Icks, Vanessa A. Bergman, Vanessa K. Drummond, Brittany L. Ross, Reshial D. Ellis, Tina R. Whittington, Shannon R. Almeida, Amanda M. Butt, Russ Burris. Retina Northwest, Portland, Oregon: Mark A. Peters, Michael S. Lee, Paul S. Tlucek, Colin Ma, Stephen Hobbs, Amanda C. Milliron, Stephanie L. Ho, Marcia Kopfer, Joe Logan, Christine Hoerner. Retina and Vitreous of Texas, Houston, Texas: Joseph A. Khawly, Hassan T. Rahman, Diana Abdelgani, Pam S. Miller, Debbie Fredrickson, Erica Pineda, Desiree Lopez, Donald K. Lowd, Colin Blank, Lorena R. Martinez, Jason E. Muniz. University of Wisconsin–Madison, Madison, Wisconsin: Justin Gottlieb, Michael S. Ip, Barbara A. Blodi, Kristine A. Dietzman, Kathryn F. Burke, Christopher M. Smith, Shelly R. Olson, Angela M. Wealti, Sandie L. Reed, Denise A. Krolnik, John C. Peterson. Valley Retina Institute, McAllen, Texas: Victor Hugo Gonzalez, Roberto Diaz-Rohena, Juan G. Santiago, Rohit Adyanthaya, Nehal R. Patel, Deyla Anaya, Dina Garcia, Edna E. Cruz, Crystal A. Alvarez, Ruth Iracheta, Jessica Rodriguez, Monica R. Cantu, Rebecca R. Flores, Hector Jasso, Rachel Rodriguez, Karina Miranda, Krystle R. Lozano, Maricela Garza, Lazaro Aguero, Amanda L. Sandoval, Monique Montemayor, Samuel Alonso, Santos Garza. University of Rochester, Rochester, New York: David Allen DiLoreto, Rajeev S. Ramchandran, David M. Kleinman, George W. O'Gara, Andrea M. Czubinski, Peter MacDowell, Kari M. Steinmetz, Dan A. Castillo, Yvonne F. Yu, Salina M. Tongue, Melissa S. Keim, Rachel Hollar, Brandi N. Deats, Brittany S. Richardson, Lynn Singer, Taylor A. Pannell. Bay Area Retina Associates, Walnut Creek, California: Stewart A. Daniels, Tushar M. Ranchod, Craig J. Leong, Stacey Touson, Shannon R. Earl, Melissa C. Bartlett, Christine Fernando, Djorella Factor, Jessica Garcia, Anna K. Nguyen, Betty Hom, Cathy Walker, Grace M. Marudo, Jose Carlos Suazo, Leah M. McNeil, Fred Hanamoto, Matthew D. Hughes. Retina Vitreous Center, Grand Blanc, Michigan: Robin D. Ross, Susan M. Sanford, Nicole Martini Markiewicz, Tracy M. Utley, Shannon Henderson, Joanie H. Lippincott, Patricia Streasick. Vitreo-Retinal Associates, Grand Rapids, Michigan: Louis C. Glazer, Frank W. Garber, Jeffrey D. Zheutlin, Angela D. Listerman, Christine E. Feehan, Heather L. Cruz, Donald E. Kuitula, Olivia P. Rainey, Sue Weatherbee. Southeastern Retina Associates, Knoxville, Tennessee: Joseph M. Googe, R. Keith Shuler, Nicholas G. Anderson, Stephen L. Perkins, Kristina Oliver, Nicole Grindall, Ann Arnold, Jennifer Beerbower, Cecile Hunt, Kathy L. Schulz, Sarah M. Oelrich, Jerry K. Whetstone, Justin Walsh, Chris Morris. Austin Retina Associates, Austin, Texas: Robert W. Wong, Peter A. Nixon, Jeni L. Leon, Chris A. Montesclaros, Carrie E. Leung, Phill Le, Codey L. Harborth, Margaret A. Rodriguez, Cory Mangham. Retina Specialists of Michigan, Grand Rapids, Michigan: Thomas M. Aaberg, Scott J. Westhouse, Holly L. Vincent, Rebecca Malone, Kathy L. Karsten. Raj K. Maturi, MD, Indianapolis, Indiana: Raj K. Maturi, Ashley M. Harless, Carolee K. Novak, Laura A. Bleau, Thomas Steele, Charlotte Harris, Alisha Bildner, Abby Maple. Retina and Vitreous Associates of Kentucky, Lexington, Kentucky: Thomas W. Stone, Rick D. Isernhagen, John W. Kitchens, Diana M. Holcomb, Jeanne Van Arsdall, Michelle Buck, Edward A. Slade. Eye Associates of New Mexico, Albuquerque, New Mexico: Mark T. Chiu, Ashok K. Reddy, Frank W. Wyant, Mary M. Montano-Niles, Lorraine J. Carter, Shirley Maerki, Laura Tartaglia, Paul P. Gomez, Stephen A. Maestas, Camille Shanta, Lisbrenda M. Jimenez. Georgia Retina, Atlanta, Georgia: Robert A. Stoltz, Stephanie L. Vanderveldt, Scott I. Lampert, Leslie G. Marcus, Shelly Fulbright, James P. Martin. Retina-Vitreous Associates Medical Group, Beverly Hills, California: Roger L. Novack, David S. Liao, Tammy Eileen Lo, Janet Kurokouchi, Richard Ngo, Connie V. Hoang, Julio Sierra, Adam Zamboni, Eric G. Protacio, Jeff Kessinger. University of North Carolina, Kittner Eye Center, Chapel Hill, North Carolina: Seema Garg, Odette M. Houghton, Jan Niklas Ulrich, Sai H. Chavala, Elizabeth L. DuBose, Cassandra J. Barnhart, Megha Karmalkar, Pooja D. Jani, Justin Goble, Debra Cantrell, Rona Lyn Esquejo. Retina Vitreous Center, Edmond, Oklahoma: Sandeep N. Shah, Natasha Harmon. Retina Group of Florida, Ft. Lauderdale, Florida: Mandeep S. Dhalla, Mario R. del Cid, Lawrence S. Halperin, Jaclyn A. Brady, Monica Hamlin, Monica L. Lopez, Jamie Mariano, Candace M. Neale, Rita R. Veksler, Angelica Mannarelli. Baylor Eye Physicians and Surgeons, Houston, Texas: Robert E. Coffee, Petros Euthymiou Carvounis, Pejman Hemati, Cindy J. Dorenbach, Annika S. Joshi, April Leger, Dana B. Barnett, Joseph F. Morales. Virginia Retina Center, Leesburg, Virginia: Sam E. Mansour, Cathy Choyce, Aissa L. Dirawatun, Emma A. Nagy, Jamie C Kerkstra. Loma Linda University Health Care, Department of Ophthalmology, Loma Linda, California: Joseph T. Fan, Mukesh Bhogilal Suthar, Michael E. Rauser, Gisela Santiago, Liel Marvyn Cerdenio, Brandi J Perez, Kara E. Halsey, William H. Kiernan, Jesse Knabb, Rachel Catren. Texas Retina Associates, Lubbock, Texas: Michel Shami, Brenda K. Arrington, Keri S. Neuling, Ashaki Meeks, Natalie R. Garcia, Kayla Blair, Ginger K. Rhymes, Janet Medrano. Medical College of Wisconsin, Milwaukee, Wisconsin: Judy E. Kim, David V. Weinberg, Kimberly E. Stepien, Thomas B. Connor, Vesper V. Williams, Tracy L. Kaczanowski, Krissa L. Packard, Judy Flanders, Vicki Barwick, Pat A. Winter, Joseph R. Beringer, Kathy J. Selchert. Magruder Eye Institute, Orlando, Florida: John T. Lehr, Elaine Rodriguez-Roman, Teri Jones, Martha Eileen Haddox, Mark Pena, Brenda Hernandez. Southern California Desert Retina Consultants, Palm Desert, California: Clement K. Chan, Maziar Lalezary, Steven G. Lin, Kimberly S. Walther, Tiana Gonzales, Lenise E. Myers, Kenneth M. Huff. Eyesight Ophthalmic Services, Portsmouth, New Hampshire: Richard Chace, Sunny Kallay, Kirsten Stevens, Nicole Dolbec, Ronda Baker-Hill, Janea Surette. Retina Associates of Western New York, Rochester, New York: Steven J. Rose, Brian P. Connolly, Ernest G. Guillet, Edward F. Hall, Margaret M. Yagoda, Mary Jo Doran, Mindy Burgess, Ann Reynard, Margaret Powers, Joe Territo. Retinal Consultants of San Antonio, San Antonio, Texas: Calvin E. Mein, Moises A. Chica, R. Gary Lane, Sarah Elizabeth Holy, Lita Kirschbaum, Vanessa D. Martinez, Jaynee Baker, Christa G. Kincaid, Elaine Castillo, Christopher Sean Wienecke, Sara L. Schlichting, Brenda Nakoski. Retinal Consultants of Southern California Medical Group, Inc, Westlake Village, California: Kenneth R. Diddie, Deborah M. Cadwell, Louise Van Arsdale, Taryn F. Boisvert, Joyce Galonsky, Susie O'Hayer, Melissa L. Johnson. Vitreo-Retinal Associates, Worcester, Massachusetts: Frank J. McCabe, Brad J. Baker, Melvyn H. Defrin, Marie V. Lampson, Heather Pratte, Selena A. Baron, Aundrea S. Borelli. OSU Eye Physicians and Surgeons, LLC, Columbus, Ohio: Frederick H. Davidorf, Michael B. Wells, Susie Chang, John Byron Christoforidis, Alan D. Letson, Jill A. Salerno, Jerilyn G. Perry, Stephen E. Shelley, Patrick J. Fish. Medical Associates Clinic, Dubuque, Iowa: Michael H. Scott, James A. Dixon, Shannon R. Walsh, Philomina M. Ozpirincci, Brenda L. Tebon, Marcia J. Moyle. Family Eye Group, Lancaster, Pennsylvania: Michael R. Pavlica, Noelle S. Matta, Cristina M. Brubaker, Alyson B. Backer. The Institute of Ophthalmology and Visual Science, Newark, New Jersey: Neelakshi Bhagat, Catherine Fay, Tatiana Mikheyeva, Michael Lazar, Janie D. Ellenberger, Beth Malpica. University of Pennsylvania Scheie Eye Institute, Philadelphia, Pennsylvania: Alexander J. Brucker, Benjamin J. Kim, Brian L. VanderBeek, Sheri Drossner, Joan C. DuPont, Rebecca Salvo, Stephanie B. Engelhard, Jim M. Berger, Sara Morales, Beth Serpentine. Thomas Eye Group, Sandy Springs, Georgia: Paul L. Kaufman, Jessica D. McCluskey, Kathy T. Wynne, Julian Jordan, Brandun Watson. Spokane Eye Clinic, Spokane, Washington: Robert S. Wirthlin, Eric S. Guglielmo, Eileen A. Dittman, Dylan C. Waidelich, Cristofer J. Garza, Adeline M. Stone, Ashley Nicole Oakes. Retina Associates of Florida, Tampa, Florida: Ivan J. Suner, Mark E. Hammer, Marc C. Peden, Janet R. Traynom, Rochelle DenBoer, Heidi Vargo, Susan Ramsey, Anita Kim Malzahn, Debra Jeffres. New England Retina Associates, Trumbull, Connecticut: Nauman A. Chaudhry, Sumit P. Shah, Gregory M. Haffner, Emiliya German, Shannan Moreau, Laura A. Fox, Jennifer M. Matteson, JoAnna L. Pelletier, Alison Fontecchio, Emily Morse, Greg McNamara, Marie Grace Laglivia, Marissa L. Scherf, Angela LaPre, Justin A. Cocilo. University of New Mexico Health Sciences Center, Albuquerque, New Mexico: Arup Das, Linda Friesen, Michele Franco, Johnny Lucero, Melissa Frazier, Robert Laviolette. Montefiore Medical Center, Bronx, New York: Umar Khalil Mian, Rebecca L. Riemer, Evelyn Koestenblatt, Louise V. Wolf, Christine Kim, Irina Katkovskaya, Erica Otoo, Kevin A. Ellerbe, Kenneth Boyd, Caroline Costa. Henry Ford Health System, Department of Ophthalmology and Eye Care Services, Detroit, Michigan: Paul Andrew Edwards, Hua Gao, Thomas Hessburg, Uday Desai, Janet Murphy, Mary K. Monk, Julianne Hall, Melina Mazurek, Katie M. Ventimiglia, Brian A. Rusinek, Bradley A. Stern, Kris Brouhard, Katie M. Weier, Megan Allis, Jenny Shaken, Nicole M. Massu, Tracy A. Troszak, David Burley. Retina Center, Minneapolis, Minnesota:Abdhish R. Bhavsar, Geoffrey G. Emerson, Jacob M. Jones, Tracy A. Anderson, Andrea Gilchrist, Matt D. Peloquin. Gaid Gaid, Yang Vang, Samantha Ryan, Denise Vang, Alanna C. Evans, Tonja Scherer. John-Kenyon American Eye Institute, New Albany, Indiana: Howard S. Lazarus, Debra Paige Bunch, Liana C. Davis, Kelly Booth, Margaret Trimble, Mary A. Bledsaw, Jay Moore. Macula Care New York, New York: Daniel F. Rosberger, Sandra Groeschel, Miriam A. Madry, Nikoletta DiGirolamo, Dustin Pressley, Robert Santora, Yenelda M. Gomez. Retina Vitreous Consultants, Pittsburgh, Pennsylvania: Karl R. Olsen, Robert L. Bergren, P. William Conrad, Pamela P. Rath, Avni Patel Vyas, Judy C. Liu, Lori A. Merlotti, Jennifer L. Chamberlin, Holly M. Mechling, Mary E. Kelly, Kellianne Marfisi, Kimberly A. Yeckel, Veronica L. Bennett, Christina M. Schultz, Grace A. Rigoni, Julie Walter, Missy A. Forish, Amanda Fec, Courtney L. Foreman, David Steinberg, Keith D. McBroom. Sarasota Retina Institute, Sarasota, Florida: Melvin C. Chen, Marc H. Levy, Waldemar Torres, Peggy Jelemensky, Tara L. Raphael, Joann Rich, Mark Sneath. University of Washington Medical Center, Seattle, Washington: James L. Kinyoun, Gurunadh Atmaram Vemulakonda, Susan A. Rath, Patricia K. Ernst, Juli A. Pettingill, Ronald C. Jones, Brad C. Clifton, James D. Leslie. Wilmer Eye Institute at Johns Hopkins Baltimore, Maryland: Sharon D. Solomon, Neil M. Bressler, Lisa K. Levin, Deborah Donohue, Mary Frey, Lorena Larez, Keisha Murray, Rita L. Denbow, Janis Graul, David Emmert, Charles Herring, Nick Rhoton, Joe Belz. Northwestern Medical Faculty Foundation, Chicago, Illinois: Alice T. Lyon, Rukhsana G. Mirza, Amanda M. Krug, Carmen Ramirez, Lori Kaminski, Anna Liza M. Castro-Malek, Amber N. Mills, Zuzanna Rozenbajgier, Marriner L. Skelly, Evica Simjanoski, Andrea R. Degillio. University of Illinois at Chicago Medical Center Chicago, Illinois: Jennifer I. Lim, Felix Y. Chau, Marcia Niec, Tametha Johnson, Yesenia Ovando, Mark Janowicz, Catherine Carroll. Carolina Retina Center, Columbia, South Carolina: Jeffrey G. Gross, Barron C. Fishburne, Amy M. Flowers, Riley Stroman, Christen Ochieng, Angelique SA McDowell, Ally M. Paul, Randall L. Price. Retina Associates of Hawaii, Inc, Honolulu, Hawaii: John H. Drouilhet, Erica N. Lacaden, Deborah J. Nobler. Southeastern Retina Associates Kingsport, Tennessee: Howard L. Cummings, Deanna Jo Long, Ben McCord, Jason Robinson, Jamie Swift, Julie P. Maynard. Mount Sinai School of Medicine, Department of Ophthalmology, New York, New York: Patricia J. Pahk, Hannah Palmer-Dwore, Dipali H. Dave, Mariebelle Pacheco, Barbara A. Galati, Eneil Simpson. Mayo Clinic Department of Ophthalmology, Rochester, Minnesota: Andrew J. Barkmeier, Diane L. Vogen, Karin A. Berg, Shannon L. Howard, Jean M. Burrington, Jessica Ann Morgan, Joan T. Overend, Shannon Goddard, Denise M. Lewison, Jaime L. Tesmer. Wake Forest University Eye Center, Winston-Salem, North Carolina: Craig Michael Greven, Joan Fish, Cara Everhart, Mark D. Clark, David T Miller. Emory Eye Center, Atlanta, Georgia: Andrew M. Hendrick, George Baker Hubbard, Jiong Yan, Blaine E. Cribbs, Linda T. Curtis, Judy L. Brower, Jannah L. Dobbs, Debora J. Jordan. Case Western Reserve University, Cleveland, Ohio: Baseer U. Ahmad, Suber S. Huang, Hillary M. Sedlacek, Cherie L. Hornsby, Lisa P. Ferguson, Kathy Carlton, Kelly A. Sholtis, Peggy Allchin, Claudia Clow, Mark A. Harrod, Geoffrey Pankhurst, Irit Baum-Rawraway, Stacie A. Hrvatin. The New York Eye and Ear Infirmary/Faculty Eye Practice, New York, New York:Ronald C. Gentile, Alex Yang, Wanda Carrasquillo-Boyd, Robert Masini. Ocala Eye Retina Consultants, Ocala, Florida: Chander N. Samy, Robert J. Kraut, Kathy Shirley, Linsey Corso, Karen Ely, Elizabeth Scala, Stewart Gross, Vanessa Alava. University of Nebraska Medical Center, Department of Ophthalmology, Omaha, Nebraska: Eyal Margalit, Donna G. Neely, Maria Blaiotta, Lori Hagensen. Retina Associates, Tucson, Arizona: April E. Harris, Rita L. Lennon, Denice R. Cota, Larry Wilson. Protocol Development Committee: John A. Wells, III, Lloyd P. Aiello, Roy W. Beck, Neil M. Bressler, Susan B. Bressler, Kakarla V. Chalam, Ronald P. Danis, Bambi J. Arnold-Bush, Frederick Ferris, Scott M. Friedman, Adam R. Glassman, Michael H. Scott, Jennifer K. Sun, Robert W. Wong. DRCR.net Coordinating Center: Jaeb Center for Health Research, Tampa, FL (staff as of 12/20/2017): Adam R. Glassman (Director and Principal Investigator), Roy W. Beck (Executive Director), Daphne Auza, Alyssa Baptista, Wesley T. Beaulieu, Crystal Connor, Sharon R. Constantine, Brian B. Dale, Simone S. Dupre, Julie Davis, Meagan L. Huggins, Paula A. Johnson, Brittany Kelly, Danni Liu, Brenda L. Loggins, Maureen Maguire, Michele Melia, Ilona Nemeth, Isoken Odia, Carrie Preston, Cynthia R. Stockdale. Duke Reading Center (staff as of 4/7/17): Dee Busian, Martha Fuquay, Chris Harrington, Cindy Heydary, Kally Inman, Glenn Jaffee, Adiel Mora, Justin Myers, Kelly Shields, Garrett Thompson, Katrina Winter, Ellen Young. Fundus Photograph Reading Center (staff as of 12/22/17): University of Wisconsin-Madison, Madison, WI (staff as of 4/7/17): Barbara Blodi (Principal Investigator), Matthew D. Davis, Amitha Domalpally, James Reimers, Pamela Vargo, Dawn Myers, Daniel Lawrence, James Allan, Ashley Harris, Ellie Corkery, Kristi L. Dohm, Kristine Lang; Ruth Shaw; Sheila Watson and Wendy K. Benz. DRCR.net Network Chair: Jennifer K. Sun (2018-present), Daniel F. Martin (2018-Present), Lee M. Jampol (2013-2017), Neil M. Bressler (2006-2012). DRCR.net Vice Chairs: Carl W. Baker (2011-2013, 2017-present), Chirag Jhaveri (2016 –present), Mathew MacCumber (2018- present), Andrew Antoszyk (2013-2016), Susan B. Bressler (2009-2011), Scott Friedman (2009-2012), Judy Kim (2015-2017), Ingrid U. Scott (2009-2010), Jennifer K. Sun (2012-2014), John A. Wells, III (2013- 2015). National Eye Institute: Sangeeta Bhargava (2016-current), Eleanor Schron (2009-2015), Donald F. Everett (2003-2006, 2007-2009), Päivi H. Miskala (2006-2007). Data Safety and Monitoring Committee: Gary Abrams, Deborah R. Barnbaum, Harry Flynn, Kyle D. Rudser, Sangeeta Bhargave, Ruth S. Weinstock, Charles P. Wilkinson, Stephen Wisniewski, John Connett (Chair, 2003-2015), Saul Genuth (2006-2013), Robert Frank (2006-2012). Executive Committee: Lloyd Paul Aiello (2002-present; Chair 2002 – 2005), Andrew N. Antoszyk (2009; 2013 - present), Carl W. Baker (2009-present), Roy W. Beck (2002-present), Sangeeta Bhargava (2016-present), Barbra Blodi (2014-present), Neil M. Bressler (2006-present; Chair 2006 - 2008), Susan B. Bressler (2009-Present), Matthew D. Davis (2002-present), Michael J. Elman (2006-present; Chair 2009 and 2012), Frederick L. Ferris III (2002-present), Adam R. Glassman (2005-present), Glenn J. Jaffe (2012-present), Lee M. Jampol (2012-present), Chirag D. Jhaveri (2016-present), Brandon Lujan (2017-present), Mathew MacCumber (2018-Present), Dennis M. Marcus (2011-2012, 2018-Present), Daniel F. Martin (2017-present), Raj K. Maturi (2009-2011, 2013- present), Jennifer K. Sun (2009-present). Prior Members: Abdhish Bhavsar (2007-2008, 2010-2012), Alexander J. Brucker (2009-2011), Kakarla V. Chalam (2009-2011), Ronald P. Danis (2004-2015), Donald F. Everett (2002-2009), Joan Fish (2008 - 2009), Scott Friedman (2007-2013), Joseph Googe, Jr. (2009-2011), Jeffrey G. Gross (2012-2017), Diana M. Holcomb (2011-2012), Judy E. Kim (2015-2017), Andreas Lauer (2007-2008), Ashley McClain (2013); Brandi J. Perez (2013), Eleanor Schron (2009-2015), Ingrid U. Scott (2009-2010), JoAnn Starr (2009-2011), John A. Wells, III (2012-2015).

Disclaimer: Dr Neil M. Bressler is the JAMA Ophthalmology Editor in Chief but was not involved in the review process or the acceptance of the manuscript.

Meeting Presentation: Portions of these data were presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology; May 8, 2017; Baltimore, Maryland.

Additional Contributions: Regeneron Pharmaceuticals Inc provided the aflibercept and Genentech Inc (now part of F. Hoffmann–La Roche Ltd) provided the ranibizumab for the study. Genentech Inc also provided funding for blood pressure cuffs and the collection of serum and urine that are not part of the study results reported herein. As per the DRCR.net Industry Collaboration Guidelines (available at http://www.drcr.net), the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol. Genentech Inc has provided funds restricted to DRCR.net clinical sites.

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