Anti-Vascular Endothelial Growth Factor Comparative Effectiveness Trial for Diabetic Macular Edema: Additional Efficacy Post Hoc Analyses of a Randomized Clinical Trial

JAMA Ophthalmol. 2016 Dec 1;134(12):10.1001/jamaophthalmol.2016.3698. doi: 10.1001/jamaophthalmol.2016.3698.


Importance: Post 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.

Objective: To provide additional outcomes comparing 3 anti-vascular endothelial growth factor (VEGF) agents for DME.

Design, setting, and participants: Post 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.

Exposures: Randomization 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 measures: Change 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.

Results: Post 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 relevance: Although 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 registration: Identifier NCT01627249.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Angiogenesis Inhibitors / administration & dosage
  • Bevacizumab / administration & dosage*
  • Diabetic Retinopathy / diagnosis
  • Diabetic Retinopathy / drug therapy*
  • Dose-Response Relationship, Drug
  • Female
  • Follow-Up Studies
  • Humans
  • Intravitreal Injections
  • Macula Lutea / pathology
  • Macular Edema / diagnosis
  • Macular Edema / drug therapy*
  • Male
  • Middle Aged
  • Ranibizumab / administration & dosage*
  • Receptors, Vascular Endothelial Growth Factor / administration & dosage*
  • Recombinant Fusion Proteins / administration & dosage*
  • Retrospective Studies
  • Tomography, Optical Coherence
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors*
  • Visual Acuity*


  • Angiogenesis Inhibitors
  • Recombinant Fusion Proteins
  • Vascular Endothelial Growth Factor A
  • aflibercept
  • Bevacizumab
  • Receptors, Vascular Endothelial Growth Factor
  • Ranibizumab

Associated data