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.)

IMPORTANCE Panretinal photocoagulation (PRP) is standard treatment for reducing severe visual loss from proliferative diabetic retinopathy (PDR). However, PRP can damage the retina, resulting in peripheral vision loss or worsening diabetic macular edema (DME). OBJECTIVE Compare ranibizumab versus PRP for PDR. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial (55 U.S. sites) assessing non-inferiority of ranibizumab compared with PRP for vision outcomes; 305 adults with PDR enrolled February-December 2012 (mean age 52, 44% female, 52% white). Both eyes enrolled for 89 participants totaling 394 study eyes. The final 2-year visit was completed January 2015. INTERVENTIONS Ranibizumab group (N=191 eyes): intravitreous 0.5-mg ranibizumab and, PRP if treatment failed; ranibizumab as needed for DME. PRP group (N=203 eyes): PRP; ranibizumab as needed for DME. MAIN OUTCOMES AND MEASURES Primary: mean visual acuity change at 2 years (5-letter non-inferiority margin; intention-to-treat analysis). Secondary: visual acuity area under the curve, peripheral visual field loss, DME development, neovascularization, vitrectomy, and safety. RESULTS Mean visual acuity letter improvement at 2 years was +2.8 in the ranibizumab group versus +0.2 in the PRP group (difference +2.2, 95% confidence interval [CI]: −0.5 to +5.0, non-inferiority P<0.001). Mean treatment group difference in visual acuity area under the curve over 2 years was +4.2 (95% CI: +3.0 to +5.4, P<0.001). Visual field sensitivity loss was worse (mean dB difference 372; 95% CI: 213 to 531, P<0.001), vitrectomy more frequent (15% versus 4%, difference 9%, 95% CI: 4% to 15%, P<0.001), and DME development more frequent (28% versus 9%, difference 19%, 95% CI: 10% to 28%, P<0.001) in the PRP versus ranibizumab group, respectively. Eyes with neither active nor regressed neovascularization at 2 years was similar (35% [ranibizumab group] versus 30% [PRP group], difference 3%, 95% CI: −7% to 12%, P=0.58). One eye (ranibizumab group) developed endophthalmitis. No significant differences between groups in rates of major cardiovascular events were identified. CONCLUSION Among eyes with PDR, treatment with ranibizumab resulted in visual acuity that was non-inferior to (not worse than) PRP treatment at two years. Although longer term follow-up is needed, ranibizumab may be a reasonable treatment alternative, at least through 2 years, for patients with PDR.

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.

; for the DRCR Retina Network IMPORTANCE Intravitreous injections of antivascular endothelial growth factor agents are effective for treating diabetic macular edema (DME) involving the center of the macula (center-involved DME [CI-DME]) with visual acuity impairment (20/32 or worse). The best approach to treating patients with CI-DME and good visual acuity (20/25 or better) is unknown. OBJECTIVE To compare vision loss at 2 years among eyes initially managed with aflibercept, laser photocoagulation, or observation. DESIGN, SETTING, AND PARTICIPANTS Randomized clinical trial conducted at 91 US and Canadian sites among 702 adults with type 1 or type 2 diabetes. Participants had 1 study eye with CI-DME and visual acuity of 20/25 or better. The first participant was randomized on November 8, 2013, and the final date of follow-up was September 11, 2018. INTERVENTIONS Eyes were randomly assigned to 2.0 mg of intravitreous aflibercept (n = 226) as frequently as every 4 weeks, focal/grid laser photocoagulation (n = 240), or observation (n = 236). Aflibercept was required for eyes in the laser photocoagulation or observation groups that had decreased visual acuity from baseline by at least 10 letters (Ն 2 lines on an eye chart) at any visit or by 5 to 9 letters (1-2 lines) at 2 consecutive visits. MAIN OUTCOMES AND MEASURES The primary outcome was at least a 5-letter visual acuity decrease from baseline at 2 years. Antiplatelet Trialists' Collaboration adverse events (defined as myocardial infarction, stroke, or vascular or unknown death) were reported. RESULTS Among 702 randomized participants (mean age, 59 years; 38% female [n=264]), 625 of 681 (92% excluding deaths) completed the 2-year visit. For eyes with visual acuity that decreased from baseline, aflibercept was initiated in 25% (60/240) and 34% (80/236) in the laser photocoagulation and observation groups, respectively. At 2 years, the percentage of eyes with at least a 5-letter visual acuity decrease was 16% (33/205), 17% (36/212), and 19% (39/208

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