• Lee M Jampol, Adam R Glassman, Neil M Bressler, John A Wells, Allison R Ayala, and Diabetic Retinopathy Clinical Research Network.
• Feinberg School of Medicine, Northwestern University, Chicago, Illinois.
• JAMA Ophthalmol. 2016 Dec 1; 134 (12).

ImportancePost hoc analyses from the Diabetic Retinopathy Clinical Research Network randomized clinical trial comparing aflibercept, bevacizumab, and ranibizumab for diabetic macular edema (DME) might influence interpretation of study results.ObjectiveTo provide additional outcomes comparing 3 anti-vascular endothelial growth factor (VEGF) agents for DME.Design, Setting, And ParticipantsPost hoc analyses performed from May 3, 2016, to June 21, 2016, of a randomized clinical trial performed from August 22, 2012, to September 23, 2015, of 660 participants comparing 3 anti-VEGF treatments in eyes with center-involved DME causing vision impairment.ExposuresRandomization to intravitreous aflibercept (2.0 mg), bevacizumab (1.25 mg), or ranibizumab (0.3 mg) administered up to monthly based on a structured retreatment regimen. Focal/grid laser treatment was added after 6 months for the treatment of persistent DME.Main Outcomes And MeasuresChange in visual acuity (VA) area under the curve and change in central subfield thickness (CST) within subgroups based on whether an eye received laser treatment for DME during the study.ResultsPost hoc analyses were performed for 660 participants (mean [SD] age, 61 [10] years; 47% female, 65% white, 16% black or African American, 16% Hispanic, and 3% other). For eyes with an initial VA of 20/50 or worse, VA improvement was greater with aflibercept than the other agents at 1 year but superior only to bevacizumab at 2 years. Mean (SD) letter change in VA over 2 years (area under curve) was greater with aflibercept (+17.1 [9.7]) than with bevacizumab (+12.1 [9.4]; 95% CI, +1.6 to +7.3; P < .001) or ranibizumab (+13.6 [8.5]; 95% CI, +0.7 to +6.0; P = .009). When VA was 20/50 or worse at baseline, bevacizumab reduced CST less than the other agents at 1 year, but at 2 years the differences had diminished. In subgroups stratified by baseline VA, anti-VEGF agent, and whether focal/grid laser treatment was performed for DME, the only participants to have a substantial reduction in mean CST between 1 and 2 years were those with a baseline VA of 20/50 or worse receiving bevacizumab and laser treatment (mean [SD], -55 [108] µm; 95% CI, -82 to -28 µm; P < .001).Conclusions And RelevanceAlthough post hoc analyses should be viewed with caution given the potential for bias, in eyes with a VA of 20/50 or worse, aflibercept has the greatest improvement in VA over 2 years. Focal/grid laser treatment, ceiling and floor effects, or both may account for mean thickness reductions noted only in bevacizumab-treated eyes between 1 and 2 years.Trial Registrationclinicaltrials.gov Identifier NCT01627249.

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