Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-year Results from a Comparative Effectiveness Randomized Clinical Trial

[ ABSTRACT ]

Purpose Provide 2-year efficacy, safety and treatment results comparing three anti-vascular endothelial growth factor (anti-VEGF) agents for center-involved diabetic macular edema (DME) utilizing a standardized follow-up and retreatment regimen. Design Randomized clinical trial. Participants 660 participants with DME causing visual acuity (VA) impairment. Methods Randomization to 2.0-mg aflibercept, 1.25-mg repackaged (compounded) bevacizumab, or 0.3-mg ranibizumab intravitreous injections performed as frequently as monthly utilizing a protocol-specific follow-up and retreatment regimen. Focal/grid laser was added if DME persisted and was not improving at 6 months or later. Visits occurred every 4 weeks during year 1, and were extended up to every 4 months thereafter when VA and macular thickness were stable and injections were deferred. Main Outcome Measures Change in VA (efficacy), ocular/systemic adverse events (safety), retreatment frequency. Results Median numbers of injections in year 2 were 5, 6, 6 and over 2 years were 15, 16, 15 in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P=0.08). Focal/grid laser was administered in 41%, 64%, and 52%, respectively (aflibercept-bevacizumab: P<0.001, aflibercept-ranibizumab: P=0.04, bevacizumab-ranibizumab: P=0.01). From baseline to 2 years, mean VA letter score improved by 12.8 with aflibercept, 10.0 with bevacizumab, and 12.3 with ranibizumab. Treatment group differences varied by baseline VA (interaction P=0.02). With worse baseline VA (20/50-20/320), mean improvement was 18.3, 13.3, and 16.1 letters, respectively (aflibercept-bevacizumab: P=0.02, aflibercept-ranibizumab: P=0.18, ranibizumab-bevacizumab: P=0.18). With baseline VA 20/32-20/40, mean improvement was 7.8, 6.8, and 8.6 letters, respectively (P>0.10 for pairwise comparisons). Anti-Platelet Trialists’ Collaboration (APTC) events occurred in 5% with aflibercept, 8% with bevacizumab, and 12% with ranibizumab (global P=0.047: aflibercept-bevacizumab: P=0.34, aflibercept-ranibizumab: P=0.047, ranibizumab-bevacizumab: P=0.20; global P=0.09 adjusted for potential confounders). Conclusion All 3 anti-VEGF groups had visual acuity improvement at 2 years with a decreased number of injections in year 2. VA outcomes were similar among treatment groups for eyes with baseline VA 20/32-20/40. Among eyes with worse baseline VA, aflibercept, on average, had superior 2-year VA outcomes compared with bevacizumab, but superiority of aflibercept over ranibizumab, noted at 1 year, was no longer identified. Higher APTC event rates with ranibizumab over 2 years warrants continued evaluation in future trials.