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Figure 1.
Percentage of Eyes With Gain of 10 Letters or More, Stratified by Baseline VA and CST
Percentage of Eyes With Gain of 10 Letters or More, Stratified by Baseline VA and CST

A, Worse visual acuity (VA) and thicker central subfield thickness (CST). B, Worse VA and thinner CST. C, Better VA and thicker CST. D, Better VA and thinner CST. All CST values were translated2 to a Stratus optical coherence tomography equivalent thickness. All available data shown at each visit; numbers shown for 52-week visit.

Figure 2.
Mean Change in VA Over Time by Baseline VA and CST
Mean Change in VA Over Time by Baseline VA and CST

A, Worse visual acuity (VA) and thicker central subfield thickness (CST). B, Worse VA and thinner CST. C, Better VA and thicker CST. D, Better VA and thinner CST. All CST values were translated2 to a Stratus optical coherence tomography equivalent thickness. All available data shown at each visit; numbers shown for 52-week visit.

Table 1.  
Visual Acuity Outcomes at 1 Year by Baseline CSTa and Visual Acuity
Visual Acuity Outcomes at 1 Year by Baseline CSTa and Visual Acuity
Table 2.  
Treatment Group Comparisons of Change in VA and CST From Baseline to 1 Yeara,b
Treatment Group Comparisons of Change in VA and CST From Baseline to 1 Yeara,b
Table 3.  
Optical Coherence Tomography CST Outcomes by Baseline CST and Visual Acuitya
Optical Coherence Tomography CST Outcomes by Baseline CST and Visual Acuitya
Supplement 2.

eAppendix. Institutional Review Boards That Approved the Protocol

eFigure 1. Scatter Plot of the Distribution of Baseline Visual Acuity and Baseline Optical Coherence Tomography Central Subfield Thickness

eFigure 2. Percentage of Eyes With VA 84 (20/20) or Better Stratified by Baseline VA and CST

eFigure 3. Percentage of Eyes With 15 or More Letter Score Improvement Stratified by Baseline Visual Acuity and Central Subfield Thickness Subgroup

eFigure 4. Percentage of Eyes With Visual Acuity Letter Score of 84 or Better (Approximate Snellen Equivalent 20/20 or Better) Stratified by Baseline Visual Acuity (VA) Approximate Snellen Equivalent

eFigure 5. Percentage of Eyes That Achieved a Visual Acuity Letter Score of 84 or Better (Approximately 20/20 or Better) Stratified by Baseline Central Subfield Thickness (CST)

eFigure 6. Percentage of Eyes With 10 or More Letter Score Improvement Stratified by Baseline Central Subfield Thickness (CST)

eFigure 7. Percentage of Eyes With 15 or More Letter Score Improvement Stratified by Baseline Central Subfield Thickness (CST)

eFigure 8. Mean Change in Visual Acuity Over Time by Baseline Central Subfield Thickness (CST)

eTable 1. Baseline Characteristics: Stratified by Baseline Visual Acuity and Central Subfield Thickness Subgroups; Worse and Thicker and Worse and Thinner

eTable 2. Baseline Characteristics: Stratified by Baseline Visual Acuity and Central Subfield Thickness Subgroups; Better and Thicker and Better and Thinner

eTable 3. Treatment for Diabetic Macular Edema Prior to the 1-Year Visit: Baseline Visual Acuity 20/50 or Worse (Letter Score <69)

eTable 4. Treatment for Diabetic Macular Edema Prior to the 1-Year Visit: Baseline Visual Acuity 20/32 to 20/40 (Letter Score 78-69)

eTable 5. Treatment for Diabetic Macular Edema Prior to the 1-Year Visit: Baseline Central Subfield Thickness ≥400 microns

eTable 6. Treatment for Diabetic Macular Edema Prior to the 1-Year Visit: Baseline Central Subfield Thickness <400 microns

eTable 7. Detailed Distribution of Visual Acuity at 1 Year and Visual Acuity Change from Baseline to 1 Year According to Baseline Visual Acuity Subgroup

eTable 8. Detailed Distribution of Visual Acuity at 1 Year and Visual Acuity Change from Baseline to 1 Year According to Baseline Central Subfield Thickness Subgroup

1.
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.PubMedArticle
2.
Bressler  SB, Edwards  AR, Chalam  KV,  et al; Diabetic Retinopathy Clinical Research Network Writing Committee.  Reproducibility of spectral-domain optical coherence tomography retinal thickness measurements and conversion to equivalent time-domain metrics in diabetic macular edema.  JAMA Ophthalmol. 2014;132(9):1113-1122.PubMedArticle
3.
Spiegelman  D, Hertzmark  E.  Easy SAS calculations for risk or prevalence ratios and differences.  Am J Epidemiol. 2005;162(3):199-200.PubMedArticle
Original Investigation
February 2016

Association of Baseline Visual Acuity and Retinal Thickness With 1-Year Efficacy of Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema

Author Affiliations
  • 1Palmetto Retina Center, West Columbia, South Carolina
  • 2Jaeb Center for Health Research, Tampa, Florida
  • 3Feinberg School of Medicine, Northwestern University, Chicago, Illinois
  • 4Beetham Eye Institute, Joslin Diabetes Center, Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts
  • 5Charlotte Eye, Ear, Nose and Throat Associates, PA, Charlotte, North Carolina
  • 6Paducah Retinal Center, Paducah, Kentucky
  • 7Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
  • 8Editor, JAMA Ophthalmology
  • 9Elman Retina Group, Baltimore, Maryland
  • 10National Eye Institute, National Institutes of Health, Bethesda, Maryland
  • 11Florida Retina Consultants, Winter Haven
  • 12California Retina Consultants, Santa Barbara
JAMA Ophthalmol. 2016;134(2):127-134. doi:10.1001/jamaophthalmol.2015.4599
Abstract

Importance  Comparisons of the relative effect of 3 anti–vascular endothelial growth factor agents to treat diabetic macular edema warrant further assessment.

Objective  To provide additional outcomes from a randomized trial evaluating 3 anti–vascular endothelial growth factor agents for diabetic macular edema within subgroups based on baseline visual acuity (VA) and central subfield thickness (CST) as evaluated on optical coherence tomography.

Design, Setting, and Participants  Post hoc exploratory analyses were conducted of randomized trial data on 660 adults with diabetic macular edema and decreased VA (Snellen equivalent, approximately 20/32 to 20/320). The original study was conducted between August 22, 2012, and August 28, 2013. Analysis was conducted from January 7 to June 2, 2015.

Interventions  Repeated 0.05-mL intravitreous injections of 2.0 mg of aflibercept (224 eyes), 1.25 mg of bevacizumab (218 eyes), or 0.3 mg of ranibizumab (218 eyes) as needed per protocol.

Main Outcomes and Measures  One-year VA and CST outcomes within prespecified subgroups based on both baseline VA and CST thresholds, defined as worse (20/50 or worse) or better (20/32 to 20/40) VA and thicker (≥400 µm) or thinner (250 to 399 µm) CST.

Results  In the subgroup with worse baseline VA (n = 305), irrespective of baseline CST, aflibercept showed greater improvement than bevacizumab or ranibizumab for several VA outcomes. In the subgroup with better VA and thinner CST at baseline (61-73 eyes across 3 treatment groups), VA outcomes showed little difference between groups; mean change was +7.2, +8.4, and +7.6 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively. However, in the subgroup with better VA and thicker CST at baseline (31-43 eyes), there was a suggestion of worse VA outcomes in the bevacizumab group; mean change from baseline to 1 year was +9.5, +5.4, and +9.5 letters in the aflibercept, bevacizumab, and ranibizumab groups, respectively, and VA letter score was greater than 84 (approximately 20/20) in 21 of 33 (64%), 7 of 31 (23%), and 21 of 43 (49%) eyes, respectively. The adjusted differences and 95% CIs were 39% (17% to 60%) for aflibercept vs bevacizumab, 25% (5% to 46%) for ranibizumab vs bevacizumab, and 13% (–8% to 35%) for aflibercept vs ranibizumab.

Conclusions and Relevance  These post hoc secondary findings suggest that for eyes with better initial VA and thicker CST, some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups. Given the exploratory nature of these analyses and the small sample size within subgroups, caution is suggested when using the data to guide treatment considerations for patients.

Trial Registration  clinicaltrials.gov Identifier: NCT01627249.

Introduction

The Diabetic Retinopathy Clinical Research Network (DRCR.net) conducted a comparative effectiveness randomized clinical trial with 660 participants to compare treatment outcomes with intravitreous aflibercept, bevacizumab, or ranibizumab in eyes with center-involving diabetic macular edema associated with best-corrected visual acuity (VA) of 20/32 to 20/320.1 A standardized treatment protocol that limited investigator discretion was used with treatment decisions based on VA and central subfield thickness (CST) evaluated by optical coherence tomography (OCT) at each study visit.

Mean improvement in VA was seen at 1 month with each anti–vascular endothelial growth factor (VEGF) agent, and substantial improvement, on average, was noted at the 1-year primary outcome for all 3 drugs.1 For the primary outcome at 1 year for the entire cohort, average improvement was 2 to 3 letters greater with aflibercept than ranibizumab or bevacizumab; however, the magnitude of aflibercept’s greater effect depended on the patient’s initial VA. The worse the initial VA was, the greater the relative advantage of aflibercept was compared with the other 2 agents on VA outcomes. When the initial VA was a Snellen equivalent of 20/32 to 20/40, which represented about half the study eyes, on average there was little difference in 1-year change in VA from baseline among the 3 agents. The relative treatment effect on VA also varied according to initial CST; the worse the initial CST was, the greater the relative advantage of aflibercept was compared with the other 2 agents.1 These findings prompted evaluation of other clinically relevant post hoc, exploratory analyses including outcomes within subgroups combining baseline VA and CST and additional outcomes and treatments administered that were not previously reported within the subgroups with worse and better initial VA.

Box Section Ref ID

At a Glance

  • When comparing aflibercept, bevacizumab, and ranibizumab for diabetic macular edema, the average visual acuity (VA) gain was statistically significantly greater with aflibercept than bevacizumab or ranibizumab at 1 year for the primary outcome.

  • Prespecified subgroup analyses showed statistically significant interactions with worse baseline VA, or the thicker the baseline central subfield thickness (CST) on optical coherence tomography, the greater the treatment benefit, on average, of aflibercept over bevacizumab or ranibizumab.

  • Post hoc analyses were pursued to evaluate outcomes in eyes with worse baseline VA but thinner baseline CST, as well as eyes with better baseline VA but thicker baseline CST.

  • In the worse VA subgroup, irrespective of CST, aflibercept showed greater improvement than bevacizumbab or ranibizumab for several VA outcomes.

  • For eyes with better VA and thicker CST, some VA outcomes might be worse with bevacizumab than the other agents.

Methods

The study procedures and statistical methods have been reported1 and are only summarized briefly herein. The study adhered to the tenets of the Declaration of Helsinki. The study is accessible on http://www.clinicaltrials.gov (NCT01627249) and the protocol is available on the DRCR.net website (http://drcrnet.jaeb.org/) (Supplement 1). The protocol and Health Insurance Portability and Accountability Act–compliant informed consent forms were approved by multiple institutional review boards (eAppendix in Supplement 2).

The study, conducted between August 22, 2012, and August 28, 2013, included 660 individuals 18 years or older. Each participant had only 1 eye included in the study, with best-corrected VA letter score of 78 to 24 (approximate Snellen equivalent of 20/32 to 20/320) owing to diabetic macular edema, with CST equivalent to 250 µm or greater on Stratus time domain OCT (Carl Zeiss Meditec). Central subfield thickness values were usually obtained via spectral domain OCT scan (1246 of 1277 scan [97.6%]) and translated2 to Stratus OCT–equivalent thickness values based on a validated conversion equation. Analysis was conducted from January 7 to June 2, 2015.

Prespecified subgroups for baseline VA included eyes with letter score 78 to 69 (20/32 to 20/40, defined as the better VA subgroup) or 68 to 24 (20/50 to 20/320, defined as the worse VA subgroup), while subgroups for baseline CST included eyes with thicknesses of 400 µm or more (defined as the thicker subgroup) and 250 to 399 µm (defined as the thinner subgroup). The subgroups were defined based on prestudy anticipated median VA of 20/50 and median CST of approximately 400 µm. Among the 660 participants, 329 (49.8%) eyes were in the worse VA subgroup and 331 (50.2%) were in the better VA subgroup. Eight eyes had missing baseline CST values; 299 (45.9%) and 353 (54.1%) of 652 eyes were in the thicker and thinner subgroups, respectively. Among the 323 eyes with available CST values in the worse VA group, 185 were in the thicker group, composing 57.2% of the subgroup, and 138 were in the thinner group, composing 42.7% of the subgroup. Among the 329 eyes with available CST values in the better VA group, 114 were in the thicker group, composing 34.7% of the subgroup, and 215 were in the thinner group, composing 65.3% of the subgroup (eFigure 1 in Supplement 2).

The study eyes were assigned randomly to receive 0.05-mL intravitreous injections of 2.0 mg of aflibercept (n = 224), 1.25 mg of bevacizumab (n = 218), or 0.3 mg of ranibizumab (n = 218). Injections were given at baseline and 4 weeks. Subsequent injections were performed every 4 weeks unless 1 or more of the following occurred: (1) before the 24-week visit, VA letter score was 84 or more (20/20 or better) with CST less than 250 µm by use of time-domain OCT or equivalent cutoff on spectral-domain OCT (thinner than the eligibility threshold) and no improvement (a gain of at least 5 letters or at least a 10% reduction in CST) from the last 2 injections, referred to as treatment success, or (2) starting at the 24-week visit, no improvement and no worsening (at least a 5-letter change or 10% change in CST) after 2 consecutive injections, referred to as stability. Injections were resumed following deferral of treatment if VA or CST subsequently worsened. For persistent diabetic macular edema at or after the 24-week visit, focal/grid photocoagulation was added if there were thickened areas to treat within the macula and if the CST was 250 µm or more, or there was edema threatening the fovea and VA, or CST did not improve from the last 2 consecutive injections. Retreatment with focal/grid photocoagulation was performed unless 1 of the following criteria were met: (1) less than 13 weeks had passed since the last focal/grid treatment, (2) in the investigator’s judgment, complete treatment with focal/grid photocoagulation had been performed, (3) the CST was less than 250 µm and there was no edema threatening the fovea seen on clinical examination, or (4) the eye had improved since the last focal/grid treatment.

Statistical Analysis

Analyses included only participants with 1-year outcome data (aflibercept, n = 208 [92.5%]; bevacizumab, n = 206 [94.5%]; ranibizumab, n = 206 [94.5%]). Outlying changes in VA were truncated to 3 SDs from the mean (SD) change (11 [11]) in VA at 1 year. Area under the curve for change in VA from baseline up to 1 year was calculated using the trapezoidal rule. Mean change in VA, CST, and area under the curve from baseline to 1 year were estimated and compared among treatment groups using an analysis of covariance model and binary VA outcomes were analyzed using a binomial regression model.3 Analyses of VA and CST included adjustment for baseline VA; baseline CST; the 3-way interaction of baseline VA, baseline CST, and treatment; and all 2-way interactions. When both VA and CST and the interactions with treatment were included in the model of mean change in VA, the treatment effect still varied according to the initial VA (P = .006 for interaction with VA) but there was less confidence in the interaction with CST (P = .11; P = .82 for the 3-way interaction of VA, CST, and treatment group). For the model of mean change in CST, the treatment effect still varied according to baseline CST (P < .001), but neither a 2-way interaction of treatment and baseline VA nor the 3-way interaction of treatment, CST, and VA were identified (P = .84 and P = .92, respectively). Differences in least-squares means or binary proportions with corresponding 95% CIs are reported for the models, including 3-way and all lower-order interactions.

Means are reported with SDs because all analyses were considered exploratory. All reported P values are 2-sided and no corrections were made for multiple comparisons unless otherwise stated in the table footnotes. Analyses used SAS, version 9.4 (SAS Institute).

Results

Baseline characteristics within the VA and OCT subgroups are given in eTable 1 and eTable 2 in Supplement 2. eFigure 1 in Supplement 2 provides a scatterplot of the distribution of baseline VA and baseline CST values. Eyes in the worse VA subgroup were slightly more likely to be in the thicker CST subgroup than in the thinner subgroup while eyes in the better VA subgroup were more likely to be in the thinner CST subgroup than in the thicker subgroup (r = –0.36; P < .001). Regardless, there still were many eyes with thinner CST and worse VA (lower right quadrant of eFigure 1) or thicker CST and better VA (upper left quadrant of eFigure 1 in Supplement 2).

VA and CST Outcomes by Baseline VA and Baseline CST Subgroups

Table 1 and Table 2 provide VA outcomes at 1 year stratified by baseline VA and baseline CST. Figure 1 and Figure 2 and eFigure 2 and eFigure 3 in Supplement 2 show VA outcomes within the 4 subgroups over time. As shown in Tables 1 and 2, for eyes in the worse baseline VA subgroup, for both thicker (aflibercept, n = 61; bevacizumab, n = 61; and ranibizumab, n = 50) and thinner baseline CST (aflibercept, n = 40; bevacizumab, n = 39; and ranibizumab, n = 49), mean VA letter score change from baseline was greater in eyes treated with aflibercept than in those treated with bevacizumab or ranibizumab. The difference in the area under the curve (essentially, the average VA letter score change during the 1-year study) was also greater in eyes treated with aflibercept than in those threated with bevacizumab or ranibizumab. Comparing area under the curve of ranibizumab with that of bevacizumab within the worse VA subgroup at baseline, slight differences were noted in favor of ranibizumab with thicker but not thinner CST at baseline.

In the subgroup with better baseline VA and thicker baseline CST (aflibercept, n = 33; bevacizumab, n = 31; and ranibizumab, n = 43), there was a suggestion of less improvement in the bevacizumab group than in the other 2 groups on several VA outcome measures, especially the percentage of eyes with VA letter score of 84 or more (Snellen equivalent of 20/20) at 1 year (aflibercept, 21 eyes [63.6%]; bevacizumab, 7 eyes [22.6%]; and ranibizumab, 21 eyes [48.8%]). In the subgroup with better baseline VA and thinner CST (aflibercept, n = 72; bevacizumab, n = 73; and ranibizumab, n = 61), differences among the 3 anti-VEGF agents in VA outcomes were small, with the mean (SD) change from baseline to 1 year in VA letter score of 7.2 (7.2), 8.4 (6.6), and 7.6 (6.8) in the aflibercept, bevacizumab, and ranibizumab groups, respectively (Table 1).

Outcomes based on change in findings on OCT scan at 1 year for the 4 subgroups were in the same direction as those seen for VA (Table 2 and Table 3). In general, the reduction in retinal thickening from baseline to 1 year was greater in the aflibercept and ranibizumab groups compared with the bevacizumab group (mean differences, –123 [95% CI, –155 to –91] and –99 [–133 to –66] µm, respectively) among the thicker eyes with worse VA at baseline (Table 2). As demonstrated in Table 2, the reductions in retinal thickening among the thinner eyes with worse or better VA were less in the bevacizumab group, but these treatment differences could not be considered to be definitively different because the lower limit of the 95% CIs crossed 0 except for aflibercept vs bevacizumab, in which the upper limit of the difference approached 0 (–3 µm) in the better VA subgroup.

Outcomes Stratified by Either Baseline VA or CST Subgroups

Treatment for diabetic macular edema by VA subgroup is presented in eTable 3 and eTable 4 in Supplement 2 and by CST subgroup in eTable 5 and eTable 6 in Supplement 2. Visual acuity outcomes by baseline VA subgroups, including percentage of eyes achieving 20/20 VA, full distribution of 1-year VA letter scores and changes in VA letters, and area under the curve are presented in eTable 7 and eFigure 4 in Supplement 2; eFigures 5 through eFigure 8 and eTable 8 in Supplement 2 present VA outcomes by baseline CST.

Discussion

In a comparative effectiveness trial evaluating 3 different anti-VEGF agents for diabetic macular edema, treatment with aflibercept resulted in greater mean improvements in VA than did treatment with bevacizumab or ranibizumab. However, a significant interaction between treatment group and baseline VA showed that the worse the initial VA was, the greater the relative advantage of aflibercept was compared with the other 2 agents for VA outcomes.1 Although there were separate interactions of baseline VA with treatment group and baseline CST with treatment group, when both 2-way interactions were included in the model, the interaction with CST was no longer significant. This finding suggests that baseline VA is more effective than baseline CST at explaining the differences in VA outcomes across the 3 anti-VEGF agents at 1 year. The post hoc findings in this report support the initial publication that the worse the initial VA is, the greater the relative advantage is of aflibercept on VA outcomes at 1 year.1 These superior outcomes with aflibercept, on average, were neither owing to a greater number of intravitreous injections in that arm nor to an increased number of injections in the fellow eye, which theoretically could have caused a crossover effect on the study eye.1 An additional finding in this report among eyes in the subgroup of patients with better baseline VA and thicker CST (albeit based on a relatively small sample size of 31 to 43 eyes across the 3 anti-VEGF agents) was less improvement in several VA outcome measures in the bevacizumab group than with the other agents, particularly in the percentage of eyes with a VA letter score of 84 or more (approximately 20/20 or better) at 1 year (63.6%, 22.6%, and 48.8% in the aflibercept, bevacizumab, and ranibizumab groups, respectively).

These findings need to be interpreted with caution. The strengths of this study include the randomized study design and the standardized retreatment protocol that incorporated the principle of visits every 4 weeks in the first year to assess whether anti-VEGF treatment should be repeated or focal/grid photocoagulation should be performed. However, given the post hoc nature of these exploratory analyses and wide 95% CIs that result from variability of the measurements and limited number of participants within subgroups, there is a limit to the confidence in the differences reported herein. When considering applications of these data to clinical practice, one also should consider that adjustments were not made for the multiple analyses undertaken. Also, while the study participants and personnel at the OCT reading center were masked to treatment assignment at all visits, and VA and OCT examiners were masked at least at the 1-year visit, the treating ophthalmologists were not masked. While most of the treatment protocol decisions were based on VA and CST that avoided investigator discretion, biases may have been introduced when making subjective determinations, for example, whether complete focal/grid treatment had been given.

Conclusions

These post hoc secondary findings suggest that for eyes with better initial VA and thicker CST, some VA outcomes may be worse in the bevacizumab group than in the aflibercept and ranibizumab groups. In view of the exploratory nature of these analyses and the small sample sizes, particularly in the analyses stratified by VA and CST, caution is suggested when using the data to guide treatment considerations for patients.

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Article Information

Correction: This article was corrected on March 10, 2016, to fix an error in Table 3.

Submitted for Publication: June 19, 2015; accepted September 30, 2015.

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

Published Online: November 25, 2015. doi:10.1001/jamaophthalmol.2015.4599.

Author Contributions: Mr Glassman and Ms Connor 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.

Study concept and design: Wells, Glassman, Jampol, Aiello, Baker, Bressler, Elman, Ferris, Sun, Beck.

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

Drafting of the manuscript: Wells, Glassman, Jampol, Bressler, Connor, Pieramici, Beck.

Critical revision of the manuscript for important intellectual content: Wells, Jampol, Aiello, Antoszyk, Baker, Bressler, Browning, Connor, Elman, Ferris, Friedman, Melia, Pieramici, Sun, Beck.

Statistical analysis: Glassman, Melia, Pieramici.

Obtained funding: Glassman, Jampol, Bressler.

Administrative, technical, or material support: Glassman, Aiello, Bressler, Browning, Elman, Ferris.

Study supervision: Wells, Glassman, Aiello, Baker, Bressler, Elman, Ferris, Melia, Sun, Beck.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflict of Interest. Dr Wells reported receiving clinical or laboratory research grants from Regeneron and Genentech. Mr Glassman reported receiving grants from the National Institutes of Health, Genentech/Roche, and Regeneron. Dr Jampol conducted data monitoring for Janssen/QLT. Dr Aiello served as a consultant for Genentech. Dr Antoszyk reported receiving a grant from Allegro; a grant, personal fees, and nonfinancial support from Allergan; a grant and nonfinancial support from Regeneron; a grant, personal fees, and nonfinancial support from Genentech; a grant and personal fees from Alimera; a grant from Quark; and personal fees from Valeant and Novartis. Dr Baker reported receiving clinical or laboratory research grants from Genentech. Dr Bressler reported working for Northwestern University on a subcontract from the National Eye Institute and receiving clinical or laboratory research grants from Genentech/Roche, Lumenis, Bayer, Novartis, and Regeneron. Dr Browning reported receiving clinical or laboratory research grants from Alcon, Pfizer, Aerpio, Regeneron, and Novartis; personal fees from Alimera; and royalties from Springer. Dr Friedman reported receiving grants from Alson, Allergan, Regeneron, and Genentech. Ms Melia reported receiving a grant from the National Eye Institute and serving on the Data and Safety Monitoring Board for Alimera Sciences. Dr Pieramici reported serving as a consultant for and receiving clinical or laboratory research grants and other nonclinical or laboratory research grants from Genentech and Regeneron. Dr Sun reported receiving clinical or laboratory research grants from Genentech. Dr Beck reported receiving nonfinancial support and provision of a study drug from Genentech and Regeneron and receiving a grant from the National Institutes of Health. No other conflicts were reported.

Funding/Support: This study was 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, US Department of Health and Human Services (grants EY14231, EY23207, and EY18817 from the National Institutes of Health). Regeneron Pharmaceutical provided the aflibercept and Genentech provided the ranibizumab for the study. Genentech also provided funding for blood pressure cuffs and the collection of serum and urine that are not part of the main study results reported herein.

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; the collection, management, analysis, or interpretation of the data; preparation of the manuscript; or the decision to submit the manuscript for publication. As described in the DRCR.net Industry Collaboration Guidelines (available at http://www.drcr.net), the DRCR.net had complete control over 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.

Disclaimer: Dr Bressler is the Editor of JAMA Ophthalmology. He was not involved in the editorial evaluation or decision to accept this article for publication.

References
1.
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.PubMedArticle
2.
Bressler  SB, Edwards  AR, Chalam  KV,  et al; Diabetic Retinopathy Clinical Research Network Writing Committee.  Reproducibility of spectral-domain optical coherence tomography retinal thickness measurements and conversion to equivalent time-domain metrics in diabetic macular edema.  JAMA Ophthalmol. 2014;132(9):1113-1122.PubMedArticle
3.
Spiegelman  D, Hertzmark  E.  Easy SAS calculations for risk or prevalence ratios and differences.  Am J Epidemiol. 2005;162(3):199-200.PubMedArticle
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