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Figure 1.
Mean Visual Acuity Letter Score Over Time
Mean Visual Acuity Letter Score Over Time

A, Within the aflibercept group, the mean difference in the monthly minus treat-and-extend treatment group over months 7 through 12 was 2.67 (95% CI, −2.17 to 7.52; P = .28). B, Within the bevacizumab group, the mean difference in the monthly minus treat-and-extend treatment groups over months 7 to 12 was 0.65 (95% CI, −3.46 to 4.77; P = .75). Both images show means before and after the randomization at 6 months.

Figure 2.
Visual Acuity Letter Score Mean Change in Months 7 Through 12
Visual Acuity Letter Score Mean Change in Months 7 Through 12

A and B both depict means from months 7 through 12. Each mean line is surrounded by a shaded area depicting pointwise 95% CIs about the means. The overlap between the shaded areas roughly depicts times when the means do not statistically differ.

Figure 3.
Mean Central Subfield Thickness
Mean Central Subfield Thickness

A, Within the aflibercept group, the mean difference between monthly minus treat-and-extend treatment groups over months 7 through 12 was −12.29 (95% CI, −28.28 to 3.69; P = .13). B, Within the bevacizumab group, the mean difference between monthly minus treat-and-extend treatment effect over months 7 through 12 was −14.77 (95% CI, −40.33 to 10.79; P = .26). Both images show means before and after secondary randomization at 6 months.

Figure 4.
Central Subfield Thickness Mean Change in Months 7 Through 12
Central Subfield Thickness Mean Change in Months 7 Through 12

A and B both depict means from months 7 through 12 only. Each mean line is surrounded by a shaded area depicting pointwise 95% CIs about the means. The overlap between the shaded areas roughly depicts times when the means do not statistically differ.

Table.  
Visual Acuity and Central Subfield Thickness Outcomes
Visual Acuity and Central Subfield Thickness Outcomes
1.
Brown  DM, Campochiaro  PA, Singh  RP,  et al; CRUISE Investigators.  Ranibizumab for macular edema following central retinal vein occlusion: six-month primary end point results of a phase III study.  Ophthalmology. 2010;117(6):1124-1133.e1.PubMedGoogle ScholarCrossref
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Boyer  D, Heier  J, Brown  DM,  et al.  Vascular endothelial growth factor Trap-Eye for macular edema secondary to central retinal vein occlusion: six-month results of the phase 3 COPERNICUS study.  Ophthalmology. 2012;119(5):1024-1032.PubMedGoogle ScholarCrossref
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Holz  FG, Roider  J, Ogura  Y,  et al.  VEGF Trap-Eye for macular oedema secondary to central retinal vein occlusion: 6-month results of the phase III GALILEO study.  Br J Ophthalmol. 2013;97(3):278-284.PubMedGoogle ScholarCrossref
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Scott  IU, VanVeldhuisen  PC, Ip  MS,  et al; SCORE2 Investigator Group.  Effect of bevacizumab vs aflibercept on visual acuity among patients with macular edema due to central retinal vein occlusion: the SCORE2 randomized clinical trial.  JAMA. 2017;317(20):2072-2087.PubMedGoogle ScholarCrossref
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Scott  IU, VanVeldhuisen  PC, Ip  MS,  et al; SCORE2 Investigator Group.  SCORE2 Report 2: study design and baseline characteristics.  Ophthalmology. 2017;124(2):245-256.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.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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Kitchens  JW, Do  DV, Boyer  DS,  et al.  Comprehensive review of ocular and systemic safety events with intravitreal aflibercept injection in randomized controlled trials.  Ophthalmology. 2016;123(7):1511-1520.PubMedGoogle ScholarCrossref
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Heier  JS, Clark  WL, Boyer  DS,  et al.  Intravitreal aflibercept injection for macular edema due to central retinal vein occlusion: two-year results from the COPERNICUS study.  Ophthalmology. 2014;121(7):1414-1420.e1.PubMedGoogle ScholarCrossref
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Campochiaro  PA, Brown  DM, Awh  CC,  et al.  Sustained benefits from ranibizumab for macular edema following central retinal vein occlusion: twelve-month outcomes of a phase III study.  Ophthalmology. 2011;118(10):2041-2049.PubMedGoogle ScholarCrossref
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Brown  DM, Campochiaro  PA, Bhisitkul  RB,  et al.  Sustained benefits from ranibizumab for macular edema following branch retinal vein occlusion: 12-month outcomes of a phase III study.  Ophthalmology. 2011;118(8):1594-1602.PubMedGoogle ScholarCrossref
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Martin  DF, Maguire  MG, Ying  GS, Grunwald  JE, Fine  SL, Jaffe  GJ; CATT Research Group.  Ranibizumab and bevacizumab for neovascular age-related macular degeneration.  N Engl J Med. 2011;364(20):1897-1908.PubMedGoogle ScholarCrossref
13.
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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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
April 2018

Comparison of Monthly vs Treat-and-Extend Regimens for Individuals With Macular Edema Who Respond Well to Anti–Vascular Endothelial Growth Factor Medications: Secondary Outcomes From the SCORE2 Randomized Clinical Trial

Author Affiliations
  • 1Department of Ophthalmology, Penn State College of Medicine, Hershey, Pennsylvania
  • 2Department of Public Health Sciences, Penn State College of Medicine, Hershey, Pennsylvania
  • 3The Emmes Corporation, Rockville, Maryland
  • 4Doheny Eye Institute, University of California, Los Angeles
  • 5University of Wisconsin Fundus Photograph Reading Center, University of Wisconsin, Madison
  • 6Department of Ophthalmology and Visual Science, University of Wisconsin, Madison
  • 7The Retina Group of Washington, Fairfax, Virginia
JAMA Ophthalmol. 2018;136(4):337-345. doi:10.1001/jamaophthalmol.2017.6843
Key Points

Question  Does a treat-and-extend regimen of aflibercept or bevacizumab injections have outcomes similar to monthly injections in participants with macular edema associated with central retinal vein occlusion or hemiretinal vein occlusion who have exhibited a good response to 6 months of monthly injections?

Findings  In this secondary analysis of a randomized clinical trial, meaningful visual acuity differences at 12 months were not present in comparisons of participants who had received a treat-and-extend regimen vs patients who received monthly injections between months 6 and 12.

Meaning  Because of the wide confidence intervals on visual acuity differences between the monthly and the treat-and-extend groups, caution is warranted before concluding that the 2 regimens are associated with similar vision outcomes.

Abstract

Importance  Comparisons of monthly vs treat-and-extend anti–vascular endothelial growth factor (anti-VEGF) regimens for macular edema from central retinal vein occlusion or hemiretinal vein occlusion is needed.

Objective  To compare visual acuity letter score and central subfield thickness outcomes of participants in the Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) trial who then received either monthly injections or treat-and-extend (TAE) regimens of aflibercept or bevacizumab after a good response at month 6.

Design, Setting, and Participants  This randomized clinical trial enrolled participants from 66 private practice or academic centers in the United States. All participants had macular edema associated with central retinal vein occlusion or hemiretinal vein occlusion, had enrolled in the SCORE2 trial, and had a protocol-defined good response to monthly injections in the first 6 months of the trial. Participants initially assigned to receive monthly aflibercept were randomized to aflibercept on a monthly or TAE schedule, and participants initially assigned to receive monthly injections of bevacizumab were randomized to receive bevacizumab on a monthly or TAE schedule. The first participant was randomized in the SCORE2 trial on September 17, 2014, and the last month 12 visit occurred on October 24, 2016.

Main Outcomes and Measures  Change from month 6 to month 12 in best–corrected electronic visual acuity letter score (per the Early Treatment Diabetic Retinopathy Study).

Results  The 293 participants had a mean (SD) age of 68.9 (11.9) years; 127 (43.3%) were female. Of these, 79 were randomized to aflibercept on a monthly schedule, 80 to aflibercept on a TAE schedule, 67 to monthly bevacizumab, and 67 to bevacizumab on a TAE schedule. Mean treatment group difference (the change in visual acuity letter score in the monthly group minus the change in the TAE group) from month 6 to month 12 was 1.88 (97.5% CI, −1.07 to 4.83; P = .15) for aflibercept and 1.98 (97.5% CI, −1.08 to 5.03; P = .15) for bevacizumab. In the aflibercept arm, the mean number of injections between months 6 and 11 was 5.8 in the monthly injection group (95% CI, 5.6 to 5.9) and 3.8 in the TAE group (95% CI, 3.5 to 4.1; P < .001); in the bevacizumab arm, the mean number of injections was 5.8 (95% CI, 5.6 to 5.9) in the monthly group and 4.5 in the TAE group (95% CI, 4.2 to 4.8; P < .001).

Conclusions and Relevance  One to 2 fewer injections of aflibercept or bevacizumab were given to the TAE groups than the monthly groups in months 6 to 12 for macular edema associated with central retinal or hemiretinal vein occlusion. Because of wide confidence intervals on the differences between the groups, caution is warranted before concluding that the regimens are associated with similar vision outcomes.

Trial Registration  www.clinicaltrials.gov identifier: NCT01969708

Introduction

Several clinical trials have demonstrated efficacy of monthly intravitreal anti–vascular endothelial growth factor (anti-VEGF) therapy for the treatment of macular edema associated with central retinal vein occlusion (CRVO).1-4 The Study of Comparative Treatments for Retinal Vein Occlusion 2 (SCORE2) trial demonstrated that, among participants with macular edema associated with CRVO or hemiretinal vein occlusion (HRVO), monthly intravitreal bevacizumab was noninferior to monthly intravitreal aflibercept with respect to visual acuity after 6 months of treatment.4 We are not aware of prior studies comparing monthly vs treat-and-extend (TAE) injections of anti-VEGF therapy for macular edema associated with retinal vein occlusion after initial successful treatment with anti-VEGF therapy for 6 months. The purpose of the current study was to compare monthly dosing with TAE dosing of aflibercept or bevacizumab from months 6 to 12 with respect to visual acuity and central subfield thickness at month 12 in participants in the SCORE2 trial who had a protocol-defined good response at month 6.

Methods

The SCORE2 design and methods have been described in detail5 and are summarized here. The study adhered to the tenets of the Declaration of Helsinki6 and is registered at https://www.clinicaltrials.gov (identifier: NCT01969708). Institutional review board approval of the protocol was obtained at each of the 66 centers via either a site-specific or a centralized institutional review board, and written informed consent was obtained from all participants before eligibility screening and again before randomization into the study.

The study drug aflibercept (Eylea) was provided by Regeneron Pharmaceuticals and labeled for study use in single-use vials designed to deliver a 2.0-mg dose. Bevacizumab (Avastin) was purchased and repackaged by the University of Pennsylvania Investigational Drug Service into smaller, single-use vials labeled for the study and designed to deliver a 1.25-mg dose.

Major eligibility criteria for SCORE2 included a best-corrected electronic Early Treatment Diabetic Retinopathy Study (e-ETDRS)7 visual acuity letter score (VALS) between 19 and 73, a diagnosis on clinical examination of center-involved macular edema as a result of CRVO or HRVO, and central retinal thickness on spectral-domain optical coherence tomography (SD-OCT), defined as central subfield thickness (CST) of 300 μm or greater if measured with a Carl Zeiss Meditec Cirrus OCT machine or 320 μm or greater if measured with a Heidelberg Spectralis OCT machine.

The study enrolled 362 participants at 66 private practice or academic centers within the United States between September 17, 2014, and November 18, 2015. All were randomly assigned to receive injections of aflibercept (n = 180) or bevacizumab (n = 182). A total of 159 of 174 participants (91.4%) in the aflibercept arm and 134 of 173 participants (77.5%) in the bevacizumab arm had a protocol-defined good response at month 6 (χ21 = 12.8; P < .001) and were randomly assigned to continue treatment with the originally assigned drug on either a monthly schedule or a TAE schedule (eFigure 1 in the Supplement). The remaining participants, who had a protocol-defined poor response at month 6, were switched to an alternative treatment and are excluded from this analysis.

A good response was defined as either (1) a VALS of 58 or more (20/80 or better) and a VALS improvement of 5 or more letters from baseline; or (2) CST of less than 300 μm as measured by SD-OCT (or a CST of less than 320 μm on Heidelberg Spectralis) and neither intraretinal nor subretinal fluid on investigator assessment. Participants assigned to monthly injections were scheduled to receive 6 monthly injections of the originally assigned drug (aflibercept or bevacizumab) from month 6 to month 11. Participants assigned to either the aflibercept-TAE group or the bevacizumab-TAE group in months 6 through 11 were scheduled to receive an injection of the originally assigned drug at month 6. Then, those participants whose eyes did not have persistent retinal thickness at month 6 (defined as CST of greater than 300 μm as measured by SD-OCT or 320 μm as measured with Heidelberg Spectralis), intraretinal cystoid spaces on OCT, or subretinal fluid on OCT (on investigator assessment) were scheduled for a subsequent visit interval 2 weeks longer than the prior interval. For example, if a participant who was evaluated at a 6-week interval was without persistent retinal thickness, intraretinal cystoid spaces, or subretinal fluid, then treatment was provided and the next visit was scheduled to occur 8 weeks later. Visit intervals could be extended out to a maximum of 10 weeks through month 12. In contrast, participants whose eyes had any persistent retinal thickness, intraretinal cystoid spaces, or subretinal fluid on OCT were treated and then scheduled to return in 4 weeks. At each study visit, participants had visual acuity in both eyes assessed by the e-ETDRS method,7 intraocular pressure measurement, slit-lamp and dilated ophthalmoscopic examinations, and SD-OCT imaging.

Study participants were masked to the primary treatment assignment (ie, aflibercept or bevacizumab) through month 12. At month 6 and at month 12, visual acuity examiners, SD-OCT technicians, and reading center personnel were masked to primary treatment assignments. Masking the participant and clinical site staff to the dosing schedule (ie, monthly vs TAE) in the secondary randomization arms from month 6 to month 12 was not possible because of the varying visit schedules.

Statistical Analyses

The primary outcome was the difference in best-corrected VALS from the month 6 visit and the month 12 visit. Secondary outcomes included the mean change from month 6 to month 12 in CST, changes in VALS and CST from month 6 to all other post–month 6 visits, mean VALS and CST outcomes at the month 12 visit, and the percentage of participants whose eyes had resolution of macular edema at visits between month 7 and 12 (defined as CST of less than 300 μm, no subretinal or intraretinal fluid, and no cystoid spaces within the Early Treatment Diabetic Retinopathy Study7 grid on reading center evaluation). Statistical comparisons between the monthly and TAE arms were based on a contrast at month 12 from a normal repeated-measures regression (or, for resolution of macular edema, a logistic repeated-measures regression) that took into account secondary treatment assignment (ie, monthly or TAE groups), all visits the participant attended from month 7 to month 12, and the interaction between assignment and visit number. Furthermore, these models also provided statistical tests and P values for the unweighted mean across 6 months between months 7 and 12 of the estimated treatment effect at each month, comparing the monthly schedule with the TAE schedule.

To construct the visit number covariate, which was categorical in the models, a TAE visit was mapped to the integer month that was nearest to the month from randomization, but constrained to be between month 7 and month 11. Non-TAE visit covariates were taken to be the actual visit number. Temporal autocorrelations were modeled to decline exponentially with the temporal distance between the irregularly spaced actual visit dates. Any participant who attended a month 12 visit was considered to have completed the study.

The primary outcome involved 2 statistical tests of each monthly regimen and each TAE regimen, 1 for the aflibercept arm and 1 for the bevacizumab arm. We controlled for multiple testing for these 2 statistical tests by comparing the P value with .025 (ie, .05/2) and presenting 97.5% confidence intervals. For all secondary outcomes, we performed 25 statistical tests and therefore considered any P value less than .002 (.05/25) to be statistically significant. Confidence intervals for secondary outcomes were uncorrected for multiple testing and are intended only to describe the uncertainty in the estimates. Statistical analyses were conducted with SAS, versions 9.3 and 9.4 (SAS Institute). Analyses included data available as of July 10, 2017.

Results

At month 6, 79 participants were randomly assigned to the monthly group and 80 participants to the TAE group of the aflibercept arm, and 67 participants were randomly assigned to each of the monthly and TAE groups of the bevacizumab arm. The treatment groups were well balanced with respect to participant and ocular characteristics measured at the initial randomization (eTable 1 in the Supplement). The mean number of anti-VEGF treatments between randomization and month 6 was similar across the groups (eTable 1 in the Supplement). At month 6, before randomization to the monthly vs TAE groups, the mean (SD) VALS was 72.0 (16.3), with an approximate Snellen of 20/40, in the aflibercept arm, and the mean (SD) VALS was 74.1 (12.6), with an approximate Snellen of 20/32, in the bevacizumab arm (Table). Further, the mean (SD) CST prior to secondary randomization at month 6 was approximately 224 (45) μm in the aflibercept arm and 256 (75) μm in the bevacizumab arm (the Table presents treatment-specific means and standard deviations). Completion of the month 12 visits was between 95% and 99% across all participants in the monthly and TAE groups in the aflibercept and bevacizumab arms (eFigure 1 in the Supplement).

During the period between month 6 through month 12, more anti-VEGF injections were administered to study participants in the monthly group compared with the TAE group for both the aflibercept arm (monthly mean, 5.8; 95% CI, 5.6 to 5.9; vs TAE mean, 3.8; 95% CI, 3.5 to 4.1; P < .001) and the bevacizumab arm (monthly mean, 5.8; 95% CI, 5.6 to 5.9; vs TAE mean, 4.5; 95% CI, 4.2 to 4.8; P < .001) (eTable 2 in the Supplement). The mean number of days between successive injections for participants with 2 or more injections was approximately 17 days longer in the aflibercept–TAE group (mean, 46.8; 95% CI, 42.6 to 51.0) than in the aflibercept monthly group (mean, 29.6; 95% CI, 29.0 to 30.5; P < .001) and 10 days longer in the bevacizumab–TAE group (mean, 39.6; 95% CI, 37.5 to 41.7) than in the bevacizumab monthly group (mean, 29.4; 95% CI, 28.1 to 30.1; P < .001; eTable 2 in the Supplement). Extending the TAE schedules throughout the month 6 to month 12 period occurred in 45 participants receiving aflibercept (56%) and 21 participants receiving bevacizumab (31%), although the difference was not significant after correction for multiple testing. Compliance with the TAE and monthly injection schedules was high, with more than 90% of all injections occurring within 7 days of the target injection date for participants receiving aflibercept or bevacizumab (eTable 2 in the Supplement).

At month 12 for the aflibercept arm, the mean VALS was 72.7 in the monthly group and 71.6 for the TAE group (Figure 1), with a small improvement in VALS of 0.8 from month 6 to month 12 in the monthly group and a small decrease of 1.2 in the TAE group (eTable 3 in the Supplement). The estimated difference between treatment groups (monthly minus TAE) in the mean change in VALS from month 6 to month 12 was 1.88 (97.5% CI, −1.07 to 4.83; P = .15). For the bevacizumab arm, the mean VALS at month 12 was 75.2 in the monthly group and 74.0 for the TAE group, which represented a mean VALS decrease of 1.6 from month 6 to month 12 in the monthly group and a mean VALS decrease of 0.4 in the TAE group (eTable 3 in the Supplement). The estimated difference between treatment groups (monthly minus TAE) in the mean change in VALS from month 6 to month 12 was 1.98 (97.5% CI, −1.08 to 5.03; P = .15) (Table). The trends in VALS observed at month 12 in the monthly and TAE groups for both the aflibercept and bevacizumab arms was consistent with other visits before month 12 (eTable 3 in the Supplement, Figure 1 and Figure 2).

In the aflibercept arm, the mean CST measured by SD-OCT at month 12 was 237 μm in the monthly group and 238 μm in the TAE group (Figure 3). Both the monthly and TAE groups for the aflibercept arm had small increases (worsening) in CST as measured by SD–OCT from month 6 to month 12 (12.5 μm and 15.1 μm, respectively) (Figure 4; eTable 4 in the Supplement). The estimated difference between treatment groups (monthly minus TAE) in mean CST change from month 6 to month 12 was −5.2 μm (95% CI, −26.7 to 16.5; P = .64). Further, 38 participants in the monthly group (52%) and 28 in the TAE group (38%) had resolution of macular edema at month 12, although the odds of resolution of macular edema, averaged over months 7 to 12, was 2.32 times higher in the monthly group compared with the TAE group, which is statistically significant after correction for multiple testing (95% CI, 1.38 to 3.90; P = .002; eFigure 2 in the Supplement).

For the participants receiving bevacizumab, the mean CST measured by SD-OCT at month 12 was 245 μm in the monthly group and 268 μm in the TAE group (Figure 3). The monthly group in the bevacizumab arm had a small decrease (improvement) in CST as measured by SD-OCT from month 6 to month 12, of 16.2 μm; the TAE group of the bevacizumab arm experienced a small increase (worsening) in CST as measured by SD-OCT at month 12, of 17.1 μm (Figure 4; eTable 4 in the Supplement). The estimated difference in mean CST change by treatment groups (monthly minus TAE) from month 6 to month 12 was −35.0 μm, which was not significant after correction for multiple testing. The odds of resolution of macular edema did not significantly differ between the monthly and TAE arms (Table, eFigure 2 in the Supplement).

Between month 6 and month 12, ocular adverse events of interest in the study eye were rare (eTable 5 in the Supplement). One case of infectious endophthalmitis occurred in a participant in the monthly group taking aflibercept, and 1 case of culture-negative endophthalmitis occurred in a participant in the monthly group taking bevacizumab. Five or fewer participants across the 4 groups had intraocular pressure higher than 10 mm Hg over baseline. A nonfatal cerebrovascular accident occurred in 1 aflibercept-TAE participant (1.3%), and a non-fatal cerebrovascular accident and 2 deaths (caused by cardiorespiratory arrest and sepsis) occurred between months 6 and 12 in the aflibercept-TAE arm.

Discussion

In participants with macular edema secondary to CRVO or HRVO and a protocol-defined good response to 6 monthly injections of either aflibercept or bevacizumab, subsequent TAE dosing resulted in an average of 1 to 2 fewer injections over 6 months than monthly dosing. Meaningful visual acuity differences at 12 months were not present between TAE and monthly schedules. This is important as the TAE regimen is commonly used in clinical practice. However, because of the widths of the confidence intervals on the visual acuity differences between the monthly and TAE arms, caution is warranted before concluding that the 2 dosing regimens are associated with similar vision outcomes.

Similarly, no clinically meaningful differences were noted for CST outcomes between the monthly and TAE schedules in the aflibercept and bevacizumab arms, although the proportion of participants with resolution of their macular edema between months 7 to 12 was significantly higher with a monthly regimen compared with a TAE regimen in the aflibercept arm. This finding may be associated with the monthly aflibercept group having a mean of 2 additional injections in the period between month 6 and month 12 compared with the TAE aflibercept group.

While the mean number of injections administered from month 6 to month 12 was significantly lower in the TAE groups than in monthly injection groups in both the aflibercept and the bevacizumab arms (eTable 2 in the Supplement), the difference in the mean number of injections between TAE and monthly regimens is larger, and the proportion of visits extended was higher, in the aflibercept arm than in the bevacizumab arm. These findings are consistent with the better anatomic outcomes observed with aflibercept compared to bevacizumab reported previously.4

Although this study was not powered to identify differences between the monthly and TAE groups in rare adverse events, no new safety concerns associated with anti-VEGF therapy were identified. Rates of adverse events in the current study are consistent with those observed in the first 6 months of SCORE24 and those reported in other phase 3 trials evaluating anti-VEGF therapy for retinal vein occlusion,1-3,8-11 neovascular age-related macular degeneration,8,12 and diabetic macular edema.8,13,14

Strengths of the current study include a comparison, based on a secondary randomization at month 6, of a monthly schedule with a TAE regimen that is consistent with clinical practice. In addition, the study had limited loss to follow-up and excellent adherence to the protocol.

Limitations

Study limitations include the inability to make comparisons of VALS and CST outcomes across study drug groups, because more participants in the aflibercept group than those in the bevacizumab group were good responders at month 6, so aflibercept-bevacizumab comparisons would be based on a nonrandomized subset of the SCORE2 population. Another limitation is that the month 6 to 12 period may be too short to fully implement a TAE dosing schedule and thus too short to expect major differences between monthly and TAE groups. Longer follow-up may have found increased differences between the monthly and TAE groups. In addition, the study compared monthly dosing only with TAE dosing and not with other flexible dosing regimens, such as a pro re nata (as needed) schedule. Lastly, the sample sizes for the monthly with TAE comparisons were determined by the number of SCORE2 participants classified as good responders at month 6, which impacted precision and statistical power. Thus, there is lack of evidence to conclude that there is no difference between the monthly and TAE groups in the bevacizumab group, as the 97.5% confidence limits around the estimate of difference in VALS at month 12 included a clinically meaningful difference of 5 letters.

Conclusions

In sum, an average of 1 to 2 fewer injections were administered to the TAE compared with the monthly groups during the 6 months following administration of 6 monthly injections. Because of the widths of the confidence intervals on the visual acuity differences between the monthly and TAE dosing groups, caution is warranted before concluding that the 2 regimens are associated with similar vision outcomes at month 12.

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Article Information

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

Accepted for Publication: December 16, 2017.

Published Online: February 24, 2018. doi:10.1001/jamaophthalmol.2017.6843

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

Study concept and design: Scott, VanVeldhuisen, Ip, Blodi, Berinstein.

Acquisition, analysis, or interpretation of data: Scott, VanVeldhuisen, Ip, Blodi, Oden, Altaweel.

Drafting of the manuscript: Scott, VanVeldhuisen, Oden.

Critical revision of the manuscript for important intellectual content: Ip, Blodi, Altaweel, Berinstein.

Statistical analysis: VanVeldhuisen, Ip, Oden.

Obtained funding: Scott, VanVeldhuisen, Blodi.

Administrative, technical, or material support: VanVeldhuisen, Ip, Altaweel.

Study supervision: Scott, VanVeldhuisen, Ip, Blodi.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Scott serves on the Data Safety and Monitoring Committee for a clinical trial sponsored by Thrombogenics. Dr Ip reports personal fees from Genentech. No other disclosures were reported.

Funding/Support: This study was supported by National Eye Institute grants U10EY023529, U10EY023533, and U10EY023521. In-kind support was provided by Regeneron, Inc, and Allergan, Inc, through donations of investigational drugs. This work was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc to the University of Wisconsin–Madison Department of Ophthalmology and Visual Sciences.

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 preparation of the manuscript. Research to Prevent Blindness had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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

Meeting Presentation: This study was presented at the 41st Annual Macula Society Meeting; February 24, 2018; Beverly Hills, California.

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