Association Between Change in Visual Acuity and Change in Central Subfield Thickness During Treatment of Diabetic Macular Edema in Participants Randomized to Aflibercept, Bevacizumab, or Ranibizumab: A Post Hoc Analysis of the Protocol T Randomized Clinical Trial

Key Points

Question  What are the associations between changes in visual acuity and changes in optical coherence tomographic central subfield thickness across 3 anti–vascular endothelial growth factor medications used for diabetic macular edema?

Findings  In a post hoc analysis of 652 participants in a randomized clinical trial, changes in central subfield thickness were compared with changes in visual acuity. Analysis showed that changes in central subfield thickness accounted for only a small proportion of the total variation in changes in visual acuity.

Meaning  These findings do not support using changes in optical coherence tomography central subfield thickness as a surrogate for changes in visual acuity in phase 3 trials evaluating anti–vascular endothelial growth factor for diabetic macular edema or to guide physicians or patients about changes in visual acuity with anti–vascular endothelial growth factor treatment.

Importance  The determination of optical coherence tomography (OCT) central subfield thickness (CST) is an objective measure, and visual acuity (VA) is a subjective measure. Therefore, using OCT CST changes as a surrogate for VA changes in diabetic macular edema seems reasonable. However, studies suggest that change in OCT CST following anti–vascular endothelial growth factor (anti-VEGF) treatment for diabetic macular edema is correlated with changes in VA but varies substantially among individuals, and so may not be a good surrogate for changes in VA.

Objective  To determine associations between changes in VA and changes in OCT CST across 3 anti-VEGF agents (aflibercept, bevacizumab, or ranibizumab) used in a randomized clinical trial for diabetic macular edema.

Design, Setting, and Participants  Post hoc analyses were conducted of DRCR Retina Network Protocol T among 652 of 660 participants (98.8%) meeting inclusion criteria for this investigation. The study was conducted between August 22, 2012, and September 23, 2015. The post hoc data collection and analysis were performed from May 29 to July 11, 2018.

Interventions  Six monthly intravitreous anti-VEGF injections (unless success was achieved after 3-5 months) were administered; subsequent injections or focal/grid laser photocoagulation treatments were given as needed per protocol to achieve stability.

Main Outcomes and Measures  Association between changes in VA letter score with changes in CST at 12, 52, and 104 weeks after randomization to aflibercept, bevacizumab, or ranibizumab.

Results  Of the 652 participants, 304 were women (46.6%); median age was 61 years (interquartile range, 54-67 years). The correlation between CST and VA at the follow-up visits was 0.24 (95% CI, 0.16-0.31) in 616 patients at 12 weeks, 0.31 (95% CI, 0.24-0.38) in 609 patients at 52 weeks, and 0.23 (95% CI, 0.15-0.31) in 566 patients at 104 weeks. The correlation coefficients of change in VA vs change in OCT CST for these time intervals were 0.36 (95% CI, 0.29-0.43) at 12 weeks, 0.36 (95% CI, 0.29-0.43) at 52 weeks, and 0.33 (95% CI, 0.26-0.41) at 104 weeks.

Conclusions and Relevance  Changes in CST appear to account for only a small proportion of the total variation in changes in VA. These findings do not support using changes in OCT CST as a surrogate for changes in VA in phase 3 clinical trials evaluating anti-VEGF for diabetic macular edema or as a guide to inform the physician or patient about changes in VA after anti-VEGF treatment.

Trial Registration  ClinicalTrials.gov identifier: NCT01627249

Phase 3 randomized clinical trials evaluating anti–vascular endothelial growth factor (anti-VEGF) therapy for diabetic macular edema (DME) have used visual acuity (VA) as the primary outcome.^1-4 These trials also have used optical coherence tomography (OCT) central subfield thickness (CST) measures as a secondary outcome. Previous publications have reported that CST is the preferred OCT measurement for the central macula in DME because of its higher reproducibility and correlation with other measurements of the central macula.⁵ Some 2-year trials with 1-year extensions have used fixed dosing of anti-VEGF either monthly for 3 years or monthly for 5 months followed by every other month through 3 years,^2,4 regardless of anatomic or functional outcomes. The DRCR Retina Network trials use a treatment algorithm based on changes in either OCT CST or best-corrected VA at each follow-up visit to determine whether retreatment is indicated after 4 to 6 initial monthly injections.⁶

It seems reasonable to use OCT CST changes as a surrogate for VA changes in DME because the objective determination of OCT CST is faster to obtain and less prone to subjective aspects of VA measurement. However, in the DRCR Retina Network Protocol I in eyes treated with focal/grid laser for DME, OCT CST correlated only moderately with VA.⁷ Furthermore, in the DRCR Retina Network Protocol T, change in OCT CST after 3 anti-VEGF injections was a weak determinant of a patient’s subsequent VA outcome at 2 years when following the DRCR Retina Network anti-VEGF treatment regimen for DME.⁸ Among eyes with less than 10% vs 20% or greater CST reduction from baseline at 12 weeks, the percentage of eyes gaining 10 or more letters from baseline at 2 years appeared similar when using aflibercept, 2.0 mg, or ranibizumab, 0.3 mg, although not necessarily with bevacizumab, 1.25 mg.⁸ Furthermore, after 6 monthly injections of anti–VEGF therapy with 1 of these 3 agents, changes in VA between baseline and 2 years among eyes with persistent DME based on OCT CST were similar to changes in VA among eyes without persistent DME based on OCT CST.⁹ To extend our knowledge regarding the association of OCT CST and VA following anti-VEGF therapy for DME, this present investigation is a post hoc analysis of data from the DRCR Retina Network Protocol T trial to determine the association between changes in VA and changes in OCT CST across 3 different anti-VEGF agents evaluated in a randomized clinical trial for DME.³

Between August 22, 2012, and September 23, 2015, 660 participants were enrolled at 89 clinical sites in the United States. The study adhered to the tenets of the Declaration of Helsinki.¹⁰ Study participants provided written informed consent. The protocol and Health Insurance Portability and Accountability Act–compliant consent forms were approved by the institutional review board associated with each participating center. The institutional review boards at all sites approved the study, including collection of data for this analysis, which was performed from May 29 to July 11, 2018.

A detailed description of the methods for Protocol T has been published elsewhere³ and the complete protocol is available online.¹¹ In brief, participants were adults (≥18 years) with type 1 or type 2 diabetes, had at least 1 eye with best-corrected Electronic Early Treatment Diabetic Retinopathy Study VA letter score of 78 through 24 (approximate Snellen equivalent, 20/32-20/320) and center-involved DME on clinical examination and OCT according to instrument-specific cutoffs for CST. Each participant had 1 study eye randomly assigned to aflibercept, 2.0 mg; bevacizumab, 1.25 mg (repackaged or compounded at 1 central site); or ranibizumab, 0.3 mg.

Protocol visits were every 4 weeks through the 52-week visit and every 4, 8, or 16 weeks through the 104-week visit, depending on the course of the disease. Retreatment with intravitreous anti-VEGF through follow-up was based on protocol-specified criteria. Subsequent focal/grid laser also was given as needed per protocol starting as early as the 24-week visit.

All eyes with complete VA and OCT CST measurements at baseline were included in this analysis. To minimize the potential influence of outliers on the results, changes in VA (n = 1, 8, and 16) and changes in CST (n = 4, 8, and 12) measurements at 12, 52, and 104 weeks, respectively, were truncated to ±3 SDs from the mean using the 52-week distribution (protocol T primary outcome). The association between changes in VA letter score with changes in CST at 12, 52, and 104 weeks was summarized using the Pearson correlation coefficient. The association between changes in VA and changes in measures of fluid on OCT (subretinal fluid and cystoid spaces, defined as improved, no change, or worsened) was evaluated at 52 and 104 weeks with the nonparametric Spearman correlation coefficient. The 95% CIs of the correlation coefficients were estimated using Fisher z transformation and the magnitude of the correlation was described using Cohen terminology (r): 0.10, small; 0.30, moderate; and 0.50, large.^12,13 Generalized linear regression models were used to calculate the slope of the regression line for change in CST and the coefficient of determination (R²), adjusting for treatment group, for each visit. At 104 weeks, previously identified baseline factors (VA, treatment group interaction with VA, age, hemoglobin A_1c level, and prior panretinal photocoagulation and diabetic retinopathy severity) associated with VA changes and additional factors were included in the model.¹⁴ Additional factors included presence of subretinal fluid within 500 μm of the macula center or cystoid spaces on OCT, as well as hard exudates within 1800 μm of the macula center or hemorrhages and microaneurysms within 1800 μm of the macula center on fundus photographs. A backward stepwise procedure with entry selection criterion set at P ≤ .10 and stay criterion set at P ≤ .05 were used to select the final model. Residuals from the final models were evaluated to verify assumptions of normality and equal variance. No adjustments were made for multiplicity. All reported P values are 2-sided and all analyses were performed in SAS, version 9.4 (SAS Institute Inc).

A total of 652 eyes were included in this analysis, among which 221 eyes (33.9%) were in the aflibercept group, 216 eyes (33.1%) were in the bevacizumab group, and 215 eyes (33.0%) were in the ranibizumab group. Baseline characteristics are summarized in Table 1; 304 of 652 participants were women (46.6%), median age was 61 years (interquartile range, 54-67 years), 424 of 649 participants were white (65.3%), and 590 of 639 individuals had type 2 diabetes (92.3%).

Quiz Ref IDAt baseline (N = 652), the mean (SD) (approximate Snellen equivalent) VA letter score was 65.0 (11.1) (20/50) letters and the mean (SD) CST was 459 (128) μm. The Pearson correlation coefficient for the association between VA and OCT CST at baseline (Figure 1) was 0.36 (95% CI, 0.30-0.43). The correlation coefficient was similar among the 3 treatment groups (eFigure 1 in the Supplement; Table 2). The slope of the regression line indicated 3.2 letters (95% CI, 2.5-3.8 letters) increased VA for every 100-μm decrease in OCT CST. Central subfield thickness accounted for 13% of the total variation in VA observed. The association between VA and CST was similar (3.3 letters; 95% CI, 2.7-3.9 letters) after accounting for the hemoglobin A_1c level, which was the only other previously identified baseline variable significantly related to VA.¹⁴

Of the 652 eyes analyzed at baseline, the numbers evaluable for follow-up were 616 at 12 weeks, 609 at 52 weeks, and 566 at 104 weeks. The correlation between CST and VA was 0.24 (95% CI, 0.16-0.31) at the 12-week visit, 0.31 (95% CI, 0.24-0.38) at the 52-week visit, and 0.23 (95% CI, 0.15-0.31) at the 104-week visit (Table 2).

Quiz Ref IDeTable 1 in the Supplement provides the mean (SD) of the distributions of changes in VA and changes in CST by treatment group for each follow-up visit. At 12, 52, and 104 weeks, combining all treatment groups, the mean (SD) changes in OCT CST were −115.1 (121.2) μm at 12 weeks, −137.7 (129.4) μm at 52 weeks, and −147.5 (136.7) μm at 104 weeks, and mean (SD) VA letter score changes were 8.3 (8.7) letters at 12 weeks, 11.3 (10.2) letters at 52 weeks, and 11.7 (11.5) letters at 104 weeks. The correlation coefficients of change in VA vs change in OCT CST for these time intervals were 0.36 (95% CI, 0.29-0.43) at 12 weeks, 0.36 (95% CI. 0.29-0.43) at 52 weeks, and 0.33 (95% CI, 0.26-0.41) at 104 weeks (Table 2, Figure 2; eFigure 2 in the Supplement). The correlation coefficients of change in VA vs change in OCT CST at 12 weeks among eyes with baseline CST were 0.21 with less than 450 μm (n = 351), 0.37 with 450 to less than 650 μm (n = 211), and 0.47 with 650 μm and above (n = 54) (Figure 2). Correlation coefficients were similar across all treatment groups (range, 0.25-0.40) (eFigure 3 in the Supplement).

After adjusting for treatment group, the slope of the regression line for changes in VA vs changes in CST (for better VA letter score for every 100-μm lower OCT CST) was 2.5 (95% CI, 2.0-3.1) at 12 weeks, 2.7 (95% CI, 2.1-3.3) at 52 weeks, and 2.7 (95% CI, 2.1-3.4) at 104 weeks. The R² values for these models were 14% at 12 and 52 weeks and 12% at 104 weeks (eTable 2 in the Supplement). For the analysis of data at 104 weeks, previously identified baseline factors associated with VA changes (VA, treatment group, VA and treatment group interaction, hemoglobin A_1c level, age, and prior panretinal photocoagulation and diabetic retinopathy severity) were included in the model and this inclusion increased the R² to 29% (Table 3). There were no statistically significant interactions between treatment group and changes in CST at each visit identified (eTable 2 in the Supplement).

At the 12-, 52-, and 104-week visits, a small percentage of eyes showed presumably paradoxical improvement in VA with increased OCT CST (12 weeks, 5.7%; 52 weeks, 5.4%; 104 weeks, 5.1%) or paradoxical worsening of VA with a decrease in OCT CST (12 weeks, 9.1%; 52 weeks, 7.4%; 104 weeks, 7.6%). The correlation between changes in VA and changes in cystoid spaces (n = 594) was −0.10 at 52 weeks; the correlation of changes in VA with changes in subretinal fluid (n = 588) was −0.21 at 52 weeks (eFigure 4 and eFigure 5 in the Supplement).

Quiz Ref IDAmong eyes with DME in Protocol T at baseline, small to moderate correlations were observed between VA and OCT CST at baseline and follow-up times. A moderate correlation was observed between changes in VA and changes in CST after the DRCR Retina Network anti-VEGF retreatment regimen for DME was applied with aflibercept, bevacizumab, or ranibizumab. However, changes in CST accounted only for a small proportion (12%-14%) of the total variation in changes in VA at each follow-up visit. For any given change in OCT CST from baseline, there was a broad range of changes in VA from baseline at 12, 52, and 104 weeks. Similarly, for any given change in VA from baseline, there was a broad range of changes in OCT CST from baseline at 12, 52, and 104 weeks. The data suggested that the correlation coefficients of change in VA vs change in OCT CST at 12 weeks were greater when the baseline CST was 650 μm or more compared with greater than 350 μm but less than 450 μm. However, the correlation between change in OCT CST and change in VA was still no better than moderate (0.47) in eyes with the most pronounced thickening.

The findings in this analysis are similar to those observed when evaluating the correlation between VA and OCT CST when laser treatment was used to treat DME.⁷ The results also are consistent with findings reported regarding this association when anti-VEGF therapy was used to treat choroidal neovascularization secondary to age-related macular degeneration.¹⁵ Thus, the preponderance of data to date suggests that one should not use change in OCT CST over time as a definitive surrogate for VA changes over time. Because there is a general correlation, though, between changes in OCT CST and changes in VA that has been found consistently across study cohorts, using changes in OCT CST as a surrogate outcome for generating hypotheses regarding potential VA benefits or risks of treatments for DME in phase 1 or phase 2 trials seems reasonable.

Strengths of this analysis included limitation of the potential for selection bias with greater than 90% retention of living study participants through 2 years, masked VA examiners at annual visits, objective OCT data, and a protocol-mandated anti-VEGF retreatment algorithm. Given the post hoc nature of this investigation, the results should be viewed as exploratory and potentially applicable only to the DRCR Retina Network treatment regimen for DME. Nevertheless, the consistency of these findings across other treatments for DME, such as laser,⁷ or other macular diseases, such as neovascular age-related macular degeneration treated with anti-VEGF,¹⁵ increase the likelihood that these findings generalize to other treatment regimens for DME.

There are several limitations to this study. It is unknown if changes over time of other OCT measures, which have been correlated with VA at baseline or at follow-up in cross-sectional evaluations, also could be considered as a surrogate for changes in VA over time. For example, the height of intraretinal cystoid spaces at baseline has been shown to correlate with subsequent change in VA.¹⁶ However, that finding does not indicate that change in the height of intraretinal cystoid spaces correlates with change in VA such that this structural change could serve as a surrogate for change in VA. Similarly, there are cross-sectional studies showing that measures on OCT angiography, such as the size of the foveal avascular zone, correlate with VA.¹⁷ These cross-sectional studies do not necessarily mean that changes in the size of the foveal avascular zone over time on OCT angiography are a good surrogate for changes in VA. The DRCR Retina Network also has not yet evaluated whether other OCT features, such as changes in the disorganization of the retinal inner layers, correlate with changes in VA over time. Also, the data from this investigation do not allow us to speculate why the correlation of change in OCT CST with change in VA during anti-VEGF treatment is relatively poor, although others have speculated recently on some possibilities.¹⁸

Quiz Ref IDThese results support findings from previous studies of laser photocoagulation for DME or anti-VEGF treatment for other macular diseases, wherein there is at best a moderate correlation between changes in VA and changes in CST after anti-VEGF therapy. However, these changes in CST account for only a small proportion of the total variation in changes in VA at each follow-up visit. For any given change in OCT CST from baseline, there was a broad range of changes in VA from baseline at 12, 52, and 104 weeks. These findings do not support using changes in OCT CST in lieu of changes in VA in phase 3 clinical trials evaluating anti-VEGF treatments for DME and suggest that OCT CST changes are not typically a reliable guide to informing a physician or patient about changes in VA with anti-VEGF treatment for an individual eye.

Accepted for Publication: March 18, 2019.

Corresponding Author: Isoken Odia, OD, MPH, Jaeb Center for Health Research, 15310 Amberly Dr, Ste 350, Tampa, FL 33647 (drcrstat9@jaeb.org).

Published Online: June 27, 2019. doi:10.1001/jamaophthalmol.2019.1963

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

Concept and design: Bressler, Glassman, Jampol, Rosberger, Sun.

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

Drafting of the manuscript: Bressler, Odia, Maguire, Glassman, Jampol, Rosberger.

Critical revision of the manuscript for important intellectual content: Bressler, Odia, Maguire, Jampol, MacCumber, Shah, Rosberger, Sun.

Statistical analysis: Odia, Maguire, Glassman, Rosberger.

Obtained funding: Bressler, Glassman, Jampol.

Administrative, technical, or material support: Odia, Glassman, Rosberger.

Supervision: Bressler, Maguire, Glassman, Shah, Sun.

Conflict of Interest Disclosures: Dr Bressler reported grants from the National Eye Institute (NEI) during the conduct of the study as well as grants from Bayer, Genentech/Roche, Novartis, and Samsung Bioepis outside the submitted work. Dr Odia reported grants from the National Institutes of Health (NIH) and nonfinancial support from Regeneron and Genentech during the conduct of the study. Dr Maguire reported grants from NEI Funding through the Jaeb Center for Health Research during the conduct of the study and personal fees from Genentech/Roche outside the submitted work. Dr Glassman reported grants from NEI during the conduct of the study and grants from Genentech, Regeneron, and Allergan outside the submitted work. Dr Jampol reported grants from the NEI during the conduct of the study. Dr MacCumber reported grants from Allergan, Genentech, Aerpio, and Regeneron during the conduct of the study; personal fees from Genentech, Regeneron, Allergan, Novartis, and the NEI outside the submitted work. Dr Shah reported other support from Regeneron and other support from Genentech/Roche outside the submitted work. Dr Sun reported grants from the Jaeb Center for Health Research during the conduct of the study and nonfinancial support from Optovue, Zeiss, and Heidelberg outside the submitted work. No other disclosures were reported.

Funding/Support: The study was supported through a cooperative agreement from the NEI and the National Institute of Diabetes and Digestive and Kidney Diseases, NIH, and by US Department of Health and Human Services grants EY14231, EY23207, and EY18817.

Role of the Funder/Sponsor: The NIH participated in oversight of the conduct of the study and review of the manuscript but not directly in the design or conduct of the study, and did not participate in the collection, management, analysis, or interpretation of the data, or in the preparation of the manuscript.

Group Information: The members of the DRCR Retina Network are: Charlotte, NC: Charlotte Eye, Ear, Nose and Throat Association, PA: Justin C. Brown (I); Andrew N. Antoszyk (I); David Browning (I); Angela K. Price (C,V); Sherry L. Fredenberg (C,V); Jenna T. Herby (C,V); Merri F Walker (C,V); Christina J. Fleming (C,V); Ashley A. McClain (C,V); Angella S. Karow (V); Autumn C. Grupp (V); Kelly R Gallagher (V); Sarah A. Ennis (V); Donna McClain (P); Joan P. Mondello (P); Autumn K. Finch (P); Kathryn Kimrey (P); Loraine M. Clark (P); Lisa A. Jackson (P); Lynn Watson (P); Jeff A. Kuopus (P); Robin Kerr (P); Swann J Bojaj (P); Susannah J Held (P); Uma M. Balasubramaniam (P); Michael D. McOwen (P); Matt Dunlap (P); Baltimore, MD Elman Retina Group, PA: Michael J. Elman (I); Henry A. Leder (I); JoAnn Starr (C); Jennifer L. Belz (C); Charlene K. Putzulo (C); Dena Y. Salfer-Firestone (V); Perel M. Simpson (V); Pamela V. Singletary (V); Jennifer L. Simmons (V); Teresa Coffey (V); Dallas R. Sandler (V); Ashley Davis (V); Ashley M. Metzger (P); Peter Sotirakos (P); Terri Cain (P); Daniel J. Ketner (P); Lakeland, FL: Florida Retina Consultants: Scott M. Friedman (I); Nader Moinfar (I); Kimberly A. Williamson (C,V); Karen Sjoblom (C,V); Katrina L. Dawson (C); Damanda F. Fagan (C,V); Paige N. Walters (V); Steve Carlton (P); Allen McKinney (P); Paducah, KY: Paducah Retinal Center: Carl W. Baker (I); Ron H. Tilford (I); Tracey M. Caldwell (C); Lynnette F. Lambert (C,V); Margaret J. Orr (V); Mary J. Palmer (V); Tracey R. Martin (V); Alecia B. Camp (P); Samantha Kettler (P); Tana R. Williams (P); Augusta, GA: Southeast Retina Center, PC: Dennis M. Marcus (I); Harinderjit Singh (I); Siobhan O. Ortiz (C); Teresa J. Acklie (C); Michele Woodward (C); Courtney N. Roberts (C); Geri L Floyd (C); Judith Hendrickson (V); Lindsay Allison Foster (V); Christy Coursey (V); Virginia Mims (V); Jared C. Gardner (P); Kimbi Y. Overton (P); Ken Ivey (P); Austin, TX: Retina Research Center: Brian B. Berger (I); Chirag D. Jhaveri (I); Tori Moore (C); Ivana Gunderson (C,V); Rachel A. Walsh (C); Ginger J. Manhart (C); Jenny J. Tracy (C); Dietrich Riepen (V); Boris Corak (V); Chelsey A. Bravenec (V); Brandon Nguyen (V); Ryan M. Reid (V); Yong Ren (P); Christopher C. Stovall (P); Ben Ostrander (P); Santa Barbara, CA: California Retina Consultants: Dante J. Pieramici (I); Alessandro A. Castellarin (I); Sarah Fishbein (C,V); Michelle S. Hanna (C,V); Erica D. Morasse (C,V); Gina Hong (C,V); Jack Giust (C); Lisha Wan (C,V); Melvin D. Rabena (C); Sara Esau (C,V); Jerry Smith (V); Kelly Avery (V); Layne J. Bone (V); Aimee Walker (P); Matthew Giust (P); Nitce L. Ruvalcaba (P); Aimee H. Shook (P); Columbia, SC: Carolina Retina Center: Jeffrey G. Gross (I); Michael A. Magee (I); Barron C. Fishburne (I); Amy M. Flowers (C,V); Christen Ochieng (C,V); Rile Stroman (C,V); Angelique SA McDowell (V); Randall L. Price (P); Hunter Matthews (P); Lubbock, TX: Texas Retina Associates: Michel Shami (I); Sushma K. Vance (I); Yolanda Saldivar (C); Keri S. Neuling (C); Brenda K. Arrington (C,P,V); Ashaki Meeks (V); Natalie R. Garcia (V); Kayla Blair (P); Janet Medrano (P); Ginger K. Rhymes (P); Plantation, FL: Fort Lauderdale Eye Institute: Stuart K. Burgess (I); Tirso M. Lara (I); Noel H. Pereda (C,V); Cindy V. Fernandez (C,V); Evelyn Quinchia (V); Deborah Davis (V); Karen Workman (P); Trumbull, CT: New England Retina Associates, PC: Nauman A. Chaudhry (I); Sumit P. Shah (I); Gregory M. Haffner (I); Emiliya German (C); Laura A. Fox (C,V); JoAnna L. Pelletier (C); Jennifer M. Matteson (C); Shannan Moreau (C); Kristin E. Brown (V); Michelle Esler (V); Alison Fontecchio (V); Emily Morse (P); Marie Grace Laglivia (P); Justin A. Cocilo (P); Greg McNamara (P); Stefanie R DeSantis (P); Marissa L. Scherf (P); Angela LaPre (P); McAllen, TX: Valley Retina Institute: Victor Hugo Gonzalez (I); Nehal R. Patel (I); Rohit Adyanthaya (I); Roberto Diaz-Rohena (I); Deyla Anaya (C); Crystal A. Alvarez (C); Ruth Iracheta (C); Edna E. Cruz (C); Jessica Rodriguez (C); Gabriela Zavala (C); Kethsaly J. Salinas (C); Tabitha Trevino (V); Krystle R. Lozano (V); Karina Miranda (V); Monica R. Cantu (V); Maricela Garza (V); Hector Jasso (V); Rebecca R. Flores (V); Rachel Rodriguez (V); Samuel Alonso (P); Amanda L. Sandoval (P); Santos Garza (P); John Trevino (P); Lazaro Aguero (P); Monique Montemayor (P); Portland, OR: Retina Northwest, PC: Mark A. Peters (I); Paul S. Tlucek (I); Michael S. Lee (I); Colin Ma (I); Stephen Hobbs (C,V); Stephanie L. Ho (C,V); Amanda C. Milliron (V); Marcia Kopfer (V); Joe Logan (P); Christine Hoerner (P); San Antonio, TX: Retinal Consultants of San Antonio: Calvin E. Mein (I); R. Gary Lane (I); Moises A. Chica (I); Sarah Elizabeth Holy (I); Lita Kirschbaum (C,V); Vanessa D Martinez (C); Jaynee Baker (C); Adriana A. Lopez (C); Christa G. Kincaid (V); Sara L Schlichting (P); Brenda Nakoski (P); Christopher Sean Wienecke (P); Elaine Castillo (P); Clarissa M. Marquez (P); Worcester, MA: Vitreo-Retinal Associates, PC: Frank J. McCabe (I); Brad J. Baker (I); Melvyn H. Defrin (I); Marie V. Lampson (C); Heather Pratte (V); Selena A. Baron (V); Aundrea S. Borelli (V); Fort Myers, FL: National Ophthalmic Research Institute: A. Thomas Ghuman (I); Paul A. Raskauskas (I); Glenn Wing (I); Ashish G. Sharma (I); Joseph P. Walker (I); Eileen Knips (C,P); Natalie N. Torres (C); Crystal Y. Peters (C); Cheryl Ryan (C); Laura Greenhoe (C); Cheryl Kiesel (C); Rebecca J Youngblood (C); Anita H. Leslie (V); Danielle Turnbo (V); Etienne C. Schoeman (P); Raymond K. Kiesel (P); Houston, TX: Retina Consultants of Houston, PA: Charles C. Wykoff (I); Eric Chen (I); David M. Brown (I); Matthew S. Benz (I); Tien P. Wong (I); Amy C. Schefler (I); Richard H. Fish (I); James C. Major (I); Rosa Y. Kim (I); Meredith Lipman (C); Ashley E. Chancey (C); Amy Hutson (C); Cassie Cone (C); Stacy M. Supapo (C); Nubia Landaverde (C); Belinda A. Almanza (V); Brenda Dives (V); Veronica A. Sneed (V); Eric N. Kegley (P); Cary A. Stoever (P); Beau A Richter (P); Loma Linda, CA: Loma Linda University Health Care, Department of Ophthalmology: Joseph T. Fan (I); Mukesh Bhogilal Suthar (I); Michael E. Rauser (I); Gisela Santiago (C,V); Brandi J Perez (C,V); Liel Marvyn Cerdenio (C,V); Kara E. Halsey (C,V); William H. Kiernan (V); Raquel Hernandez (V); Diana Povero (P); Jesse Knabb (P); Portland, OR: Casey Eye Institute: Andreas K. Lauer (I); Christina J Flaxel (I); Ann D. Lundquist (C,V); Mitchell Schain (C,V); Shelley A. Hanel (C); Susan K. Nolte (V); Shirley D. Ira (V); Scott R. Pickell (P); Peter N. Steinkamp (P); Jocelyn T. Hui (P); Jordan Barth (P); Dawn M. Ryan (P); Chris S Howell (P); Michelle Brix (P); Beachwood, OH: Retina Associates of Cleveland, Inc: Michael A. Novak (I); David G. Miller (I); Llewelyn J. Rao (I); Jerome P. Schartman (I); Joseph M. Coney (I); Lawrence J. Singerman (I); Susan C. Rath (C,V); Veronica A. Smith (C); Larraine Stone (C); Elizabeth McNamara (C,V); Kimberly A. DuBois (V); Vivian Tanner (V); Mary A Ilc (V); Kim Drury (V); Cecelia Rykena (V); Trina M. Nitzsche (P); Gregg A. Greanoff (P); John C. DuBois (P); Lancaster, PA: Family Eye Group: Michael R. Pavlica (I); Noelle S Matta (C,V); Alyson B. Keene (P); Cristina M. Brubaker (P); Christine M. Keefer (P); Ocala, FL: Ocala Eye Retina Consultants: Chander N. Samy (I); Robert J. Kraut (I); Kathy Shirley (C); Linsey Corso (C); Karen Ely (V); Elizabeth Scala (P); Vanessa Alava (P); Stewart Gross (P); Ann Arbor, MI: Kellogg Eye Center, University of Michigan: Thomas W. Gardner (I); Grant M. Comer (I); Pamela S. Campbell (C,V); Lindsay M. Godsey (C,V); Linda Fournier (V); Moe Hesselgrave (V); Timothy Steffens (P); Robert Prusak (P); Hillary Bernard (P); Linda Goings (P); Alexis L. Smith (P); Grand Blanc, MI: Retina Vitreous Center: Robin D. Ross (I); Susan M. Sanford (C); Nicole Martini Markiewicz (C); Tracy M. Utley (C,V); Shannon Henderson (V); Mary D. Walker (V); Joanie H. Lippincott (P); Patricia Streasick (P); Boston, MA: Joslin Diabetes Center/Harvard Vanquard Medical Associates: Jennifer K. Sun (I); Paolo S. Silva (I); Lloyd Paul Aiello (I); Paul Arrigg (I); Margaret E. Stockman (C,V); Hanna Kwak (C); Ann Kopple (C); Jerry D. Cavallerano (V); Rita K. Kirby (P); Leila Bestourous (P); Elizabeth S. Weimann (P); Robert W. Cavicchi (P); Denver, CO: Denver Health Medical Center: Hugo Quiroz-Mercado (I); Leif S. Ryman (C); Teresa E. Rudesyle (C); Daniela Santos Canto (C); Guillermo Salcedo-Villanueva (C); Chelsea Lynn Mastin (V); Rosemary C. Rhodes (V); Carolyn J. Jackson (P); Regina Victoria (P); Indianapolis, IN: Raj K. Maturi, MD, PC: Raj K. Maturi (I); Ashley M. Harless (C,V); Carolee K. Novak (C,V); Laura A. Bleau (C,V); Nicole Ellingwood (P); Thomas Steele (P); Missy Livengood (P); Alisha Bildner (P); Abby Maple (P); Charlotte Harris (P); Jacksonville, FL: University of Florida College of Medicine, Department of Ophthalmology, Jacksonville Health Science Center: Kakarla V. Chalam (I); Ghulam Shabbir Hamdani (C); Shamim A. Haji (C); Wenhua Li (C,V); Kumar Sambhav (C,V); Ashley Cowart (C,V); Nicholas Freeman (P); Jose J. Carrion (P); Knoxville, TN: Southeastern Retina Associates, PC: Joseph M. Googe (I); Stephen L. Perkins (I); Nicholas G. Anderson (I); Kristina Oliver (C); Lisa Lovelady (C); Christy Berry (V); Cecile Hunt (V); Jennifer Beerbower (V); Ann Arnold (V); Nicole Grindall (V); Patricia Coppola (V); Kathy L. Schulz (V); Jerry K. Whetstone (P); Sarah M. Oelrich (P); Raul E. Lince (P); Justin Walsh (P); Milwaukee, WI: Medical College of Wisconsin: Judy E. Kim (I); Dennis P. Han (I); David V. Weinberg (I); William J. Wirostko (I); Thomas B. Connor (I); Vesper V. Williams (C); Krissa L. Packard (C); Tracy L. Kaczanowski (C); Judy Flanders (V); Vicki Barwick (V); Pat A. Winter (V); Dennis B. Backes (P); Mara Goldberg (P); Joseph R. Beringer (P); Kathy J. Selchert (P); San Antonio, TX: Medical Center Ophthalmology Associates: Michael A. Singer (I); Darren J. Bell (I); Catherine Ellis (C); Tamara M. Urias (C); Beatrice A. Guajardo (C); Roxanne Gomez (V); Ann-Marie Mora (V); Celia Maria Pena (P); Vincent Segovia (P); Rosa Escobar (P); Syracuse, NY: Retina-Vitreous Surgeons of Central New York, PC: G. Robert Hampton (I); Jamin S. Brown (I); Laurie J. Sienkiewycz (C); Cindy J. Grinnell (C); Lynn M. Kwasniewski (V); Michelle L. Manley (V); Nicole E. Robarge (P); Peter B. Hay (P); Teresa M. DeForge (P); West Des Moines, IA: Wolfe Eye Clinic: Jared S. Nielsen (I); Kyle J. Alliman (I); Marianne Parker (C); Bethany George (C); Jennifer L. Coleman (V); Jamie Spillman (V); Marilyn A. Johnson (V); Holly Keenan (V); Bailey R. Bennett (P); Jay Rostvold (P); Jodi Weier (P); Austin, TX: Austin Retina Associates: Robert W. Wong (I); Shelley Day (I); Peter A. Nixon (I); Chris A. Montesclaros (C); Carrie E. Leung (C); Phill Le (V); Margaret A. Rodriguez (P); Mary Laremont (P); Cory Mangham (P); Codey L. Harborth (P); Northfield, NJ: Retinal and Ophthalmic Consultants, PC: Brett T. Foxman (I); Scott G. Foxman (I); Natalie S. Mahan (C); Chastity Mendez (V); Rochester, NY: University of Rochester: David Allen DiLoreto (I); George W. O’Gara (C); Andrea M. Czubinski (C,V); Kari M. Steinmetz (C); Melissa S Keim (V); Yvonne F. Yu (V); Salina M. Tongue (V); Dan A Castillo (V); Laura Guzman (P); Lynn Singer (P); Rachel Hollar (P); Taylor A. Pannell (P); Brittany S. Richardson (P); Brandi N Deats (P); Steven DeRidder (P); TKe Long (P); Seattle, WA: University of Washington Medical Center: James L. Kinyoun (I); Gurunadh Atmaram Vemulakonda (I); Susan A. Rath (C,V); Patricia K. Ernst (C,V); Juli A. Pettingill (V); Brad C. Clifton (P); James D. Leslie (P); Ronald C. Jones (P); Spokane, WA: Spokane Eye Clinic: Robert S. Wirthlin (I); Eric S. Guglielmo (I); Eileen A. Dittman (C,V); Dylan C. Waidelich (C,V); Christina Owens (V); Vicki M. Stanton (P); Adeline M. Stone (P); Ashley Nicole Oakes (P); Cristofer J. Garza (P); Walnut Creek, CA: Bay Area Retina Associates: Stewart A. Daniels (I); Tushar M. Ranchod (I); Stacey Touson (C,V); Shannon R. Earl (C); Jessica Garcia (V); Melissa C Bartlett (V); Christine Fernando (V); Jose Carlos Suazo (P); Grace M. Marudo (P); Matthew D. Hughes (P); Fred Hanamoto (P); Cathy Walker (P); Betty Hom (P); Leah M. McNeil (P); Yesenia Cerna (P); Grand Rapids, MI: Retina Specialists of Michigan: Thomas M. Aaberg (I); Scott J. Westhouse (I); Holly L. Vincent (C,V); Rebecca Malone (V); Kristine L. VanDerKooi (P); Casey Le Roy (P); Kathy L. Karsten (P); Houston, TX: Retina and Vitreous of Texas: Joseph A. Khawly (I); H. Michael Lambert (I); Pam S. Miller (C,V); Valerie N. Lazarte (V); Debbie Fredrickson (V); Colin Blank (P); Donald K. Lowd (P); Desiree Lopez (P); Jason E. Muniz (P); Lorena R. Martinez (P); Houston, TX: Baylor Eye Physicians and Surgeons: Petros Euthymiou Carvounis (I); Robert E. Coffee (I); Pejman Hemati (C,V); Cindy J. Dorenbach (C,V); Annika S. Joshi (C,V); April Leger (V); Dana B. Barnett (P); Joseph F. Morales (P); Monroeville, PA: Retina Vitreous Consultants: Karl R. Olsen (I); P. William Conrad (I); Pamela P. Rath (I); Judy C Liu (I); Bernard H. Doft (I); Robert L. Bergren (I); Lori A. Merlotti (C); Mary E. Kelly (C); Holly M. Mechling (C); Jennifer L. Chamberlin (C); Missy A. Forish (V); Veronica L. Bennett (V); Christina M. Schultz (V); Grace A. Rigoni (V); Lois Stepansky (V); Kimberly A. Yeckel (V); Kellianne Marfisi (V); Christina R. Fulwylie (V); Julie Walter (V); Courtney L. Foreman (P); David Steinberg (P); Brandi L. Sherbine (P); Amanda Fec (P); Keith D McBroom (P); Philadelphia, PA: University of Pennsylvania Scheie Eye Institute: Alexander J. Brucker (I); Benjamin J. Kim (I); Sheri Drossner (C,V); Joan C. DuPont (C,V); Armin Farazdaghi (V); Laurel Weeney (P); Michael Bodine (P); Beth Serpentine (P); Cheryl Devine (P); Jim M. Berger (P); William Nyberg (P); Tampa, FL: Retina Associates of Florida, PA: Ivan J. Suner (I); Marc C. Peden (I); Mark E. Hammer (I); Janet R. Traynom (C); Rochelle DenBoer (C); Susan Ramsey (V); Heidi Vargo (V); Debra Jeffres (P); Anita Kim Malzahn (P); Baltimore, MD: Wilmer Eye Institute at Johns Hopkins: Sharon D. Solomon (I); Susan Bressler (I); Lisa K. Levin (C); Mary Frey (C,V); Deborah Donohue (C,V); Rita L. Denbow (V); Keisha Murray (V); David Emmert (P); Joe Belz (P); Janis Graul (P); Jacquelyn McDonald (P); Nick Rhoton (P); Bronx, NY: Montefiore Medical Center: Umar Khalil Mian (I); Rebecca L. Riemer (C); Louise V. Wolf (C); Evelyn Koestenblatt (C); Erica Otoo (V); Irina Katkovskaya (V); Christine Kim (V); Kevin A. Ellerbe (P); Caroline Costa (P); Kenneth Boyd (P); Campbell, CA: Retinal Diagnostic Center: Amr Dessouki (I); Joel M. Barra (C); Jessenia Perez (C); Rose Monahan (C); Kelly To (V); Hienmy Dang (V); Tim Kelley (P); Chicago, IL: Rush University Medical Center: Mathew W. MacCumber (I); Eileen E. Tonner (C,V); Danielle R. Carns (C); Denise L. Voskuil-Marre (C,V); Evan R. Rosenberg (V); Kisung Woo (P); Dallas, TX: Texas Retina Associates: Gary E. Fish (I); Sally Arceneaux (C,V); Karen Duignan (V); Nicholas Hesse (P); Michael Mackens (P); Glenview, IL: North Shore University Health System: Manvi P. Maker (I); Mira Shiloach (C,V); Courtney Kastler (P); Lynn Wasilewski (P); Lexington, KY: Retina Associates of Kentucky: Thomas W. Stone (I); John W. Kitchens (I); Diana M. Holcomb (C,V); Jeanne Van Arsdall (V); Edward A. Slade (P); Michelle Buck (P); Palm Desert, CA: Southern California Desert Retina Consultants, MC: Clement K. Chan (I); Maziar Lalezary (I); Kimberly S. Walther (C); Tiana Gonzales (C); Lenise E. Myers (V); Kenneth M. Huff (P); Phoenix, AZ: Retinal Consultants of Arizona: Karim N. Jamal (I); David T. Goldenber (I); Sachin Mehta (I); Scheleen R. Dickens (C); Jessica L. Miner (C); Heather Dunlap (V); Lydia Saiz (V); Dayna Bartoli (P); John J. Bucci (P); Rohana Yager (P); Sarasota, FL: Sarasota Retina Institute: Melvin Chen (I); Peggy A. Jelemensky (C); Tara L. Raphael (V); Mark Sneath (P); Evelyn Inlow (P); St. Louis, MO: The Retina Institute: Kevin J. Blinder (I); Ginny S. Nobel (C); Rhonda F. Weeks (C,V); Maria A. Stuart (V); Brook G. Pulliam (V); Kelly E. Pepple (V); Lynda K. Boyd (V); Timothy L Wright (P); Dana L Gabel (P); Jarrod Wehmeier (P); Protocol Development Committee: Jeffrey G. Gross (Protocol Chair), Lloyd Paul Aiello, Roy W. Beck, Neil M. Bressler, Susan B. Bressler, Ronald P Danis, Joseph T. Fan, Frederick Ferris, Adam R. Glassman, Dennis M. Marcus, Michael R. Pavlica, Ingrid U. Scott, Cynthia R. Stockdale, Jennifer K. Sun; DRCR.net Coordinating Center: Jaeb Center for Health Research, Tampa, FL (staff as of 5/7/2018): Adam R. Glassman (Director and Principal Investigator), Roy W. Beck (Executive Director), Daphne Auza, Alyssa Baptista, Wesley T. Beaulieu, 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, Katie Stutz; Duke Reading Center (staff as of 1/5/18): Adiel Mora, Ellen Young, Chris Harrington, Glenn Jaffe, Trina Winter, Kelly Inman, Cindy Heydary, Justin Myers, Kelly Shields, Dee Busian, Garrett Thompson, Keifer McGugan; Fundus Photograph Reading Center, University of Wisconsin-Madison, Madison, WI (staff as of 5/8/2018): Barbara Blodi (Principal Investigator), Matthew D. Davis, Amitha Domalpally, James L. 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; University of Iowa Visual Field Reading Center: (staff as of 5/08/2018): Michael Wall, Chris Johnson, Todd Shinkunas, Trina Eden, Kimberly Woodward; Data Safety and Monitoring Committee: Gary Abrams, Deborah R. Barnbaum, Harry Flynn, Kyle D. Rudser, Sangeeta Bhargava, Ruth S. Weinstock, Stephen Wisniewski, Paul Sternberg, John Connett (Chair, 2003-2015), Saul Genuth (2006-2013), Robert Frank (2006-2012); Charles P. Wilkinson (2013-2018); 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); Executive Committee: 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), 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: Lloyd Paul Aiello (2002-2018; Chair 2002–2005), Abdhish Bhavsar (2007-2008, 2010-2012), Alexander J. Brucker (2009-2011), Kakarla V. Chalam (2009-2011), Ronald P. Danis (2004-2015), Matthew D. Davis (2002-2018), 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). (I) for Study Investigator, (C) for Coordinator, (V) Visual Acuity Technician, and (P) for Photographer.

Disclaimer: Dr Bressler is the editor of JAMA Ophthalmology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

Additional Contributions: Regeneron Pharmaceuticals, Inc provided aflibercept and Genentech, Inc (now part of F. Hoffmann-La Roche Ltd) provided ranibizumab for the study. Genentech, Inc also provided funding for blood pressure cuffs and the collection of serum and urine samples, which 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.