BACKGROUND The relative efficacy and safety of intravitreous aflibercept, bevacizumab, and ranibizumab in the treatment of diabetic macular edema are unknown. METHODS At 89 clinical sites, we randomly assigned 660 adults (mean age, 61±10 years) with diabetic macular edema involving the macular center to receive intravitreous aflibercept at a dose of 2.0 mg (224 participants), bevacizumab at a dose of 1.25 mg (218 participants), or ranibizumab at a dose of 0.3 mg (218 participants). The study drugs were administered as often as every 4 weeks, according to a protocol-specified algorithm. The primary outcome was the mean change in visual acuity at 1 year. RESULTS From baseline to 1 year, the mean visual-acuity letter score (range, 0 to 100, with higher scores indicating better visual acuity; a score of 85 is approximately 20/20) improved by 13.3 with aflibercept, by 9.7 with bevacizumab, and by 11.2 with ranibizumab. Although the improvement was greater with aflibercept than with the other two drugs (P<0.001 for aflibercept vs. bevacizumab and P = 0.03 for aflibercept vs. ranibizumab), it was not clinically meaningful, because the difference was driven by the eyes with worse visual acuity at baseline (P<0.001 for interaction). When the initial visual-acuity letter score was 78 to 69 (equivalent to approximately 20/32 to 20/40) (51% of participants), the mean improvement was 8.0 with aflibercept, 7.5 with bevacizumab, and 8.3 with ranibizumab (P>0.50 for each pairwise comparison). When the initial letter score was less than 69 (approximately 20/50 or worse), the mean improvement was 18.9 with aflibercept, 11.8 with bevacizumab, and 14.2 with ranibizumab (P<0.001 for aflibercept vs. bevacizumab, P = 0.003 for aflibercept vs. ranibizumab, and P = 0.21 for ranibizumab vs. bevacizumab). There were no significant differences among the study groups in the rates of serious adverse events (P = 0.40), hospitalization (P = 0.51), death (P = 0.72), or major cardiovascular events (P = 0.56). CONCLUSIONS Intravitreous aflibercept, bevacizumab, or ranibizumab improved vision in eyes with center-involved diabetic macular edema, but the relative effect depended on baseline visual acuity. When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups. At worse levels of initial visual acuity, aflibercept was more effective at improving vision. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT01627249.)

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.

Objective To report 5-year results from a previously reported trial evaluating intravitreal 0.5-mg ranibizumab with prompt versus deferred (for ≥24 weeks) focal/grid laser treatment for diabetic macular edema (DME). Design Multicenter randomized clinical trial. Participants Among participants from the trial with 3 years of follow-up who subsequently consented to a 2-year extension and survived through 5 years, 124 (97%) and 111 (92%) completed the 5-year visit, in the prompt and deferred groups, respectively. Methods Random assignment to ranibizumab every 4 weeks until no longer improving (with resumption if worsening) and either prompt or deferred (>= 24 weeks) focal/grid laser treatment. Main Outcome Measures Best-corrected visual acuity at the 5-year visit. Results The mean change in visual acuity letter score from baseline through the 5-year visit was +7.2 letters in the prompt laser group compared with +9.8 letters in the deferred laser group (mean difference -2.6 letters, 95% confidence interval -5.5 to +0.4 letters, P = 0.09). At the 5-year visit in the prompt vs. deferred laser groups respectively, there was vision loss of ≥10 letters in 9% vs. 8%, an improvement of ≥10 letters in 46% vs. 58%, and an improvement of >15 letters in 27% vs. 38% of participants. From baseline through 5 years, 56% of participants in the deferred group did not receive laser. The median number of injections was 13 vs. 17 in the prompt and deferral groups, including 54% and 45% receiving no injections during year 4 and 62% and 52% receiving no injections during year 5, respectively. Conclusions Five-year results suggest focal/grid laser treatment at the initiation of intravitreal ranibizumab is no better than deferring laser treatment for ≥24 weeks in eyes with DME involving the central macula with vision impairment. While over half of eyes where laser treatment is deferred may avoid laser for at least 5 years, such eyes may require more injections to achieve these results when following this protocol. Most eyes treated with ranibizumab and either prompt or deferred laser maintain vision gains obtained by the first year through 5 years with little additional treatment after 3 years.

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Descemet stripping automated endothelial keratoplasty success in the early and entire postoperative period is more likely when the donor did not have diabetes and was without operative complications and in the long-term postoperative period in recipients with Fuchs dystrophy compared with those with PACE. Mechanisms whereby diabetic donors and PACE recipients reduce the rate of graft success after DSAEK warrant further study.