Intravitreal Aflibercept for Retinal Nonperfusion in Proliferative Diabetic Retinopathy

Abstract Purpose Evaluate the impact of intravitreal aflibercept (Eylea, Regeneron, Tarrytown, NY) on retinal non-perfusion (RNP) in eyes with proliferative diabetic retinopathy (PDR). Design Prospective, randomized clinical trial. Subjects Eyes with treatment-naive PDR and extensive RNP without diabetic macular edema. Methods Patients were randomized 1:1 to intravitreal 2-mg aflibercept every-4-weeks (Monthly) or every-12-weeks (Quarterly). Main Outcome Measures The primary outcome measure was change in total RNP area (mm2) from baseline to year 1. Secondary outcomes included ischemic index (ISI), neovascularization area, diabetic retinopathy severity scale (DRSS) scores, visual acuity, central retinal thickness, visual function questionnaire score, and adverse events. Mean and 95% confidence interval (CI) were calculated for each outcome. Results Through 1-year, the Monthly (n=20) & Quarterly (n=20) cohorts received 11.0 & 3.95 mean aflibercept injections, & DRSS scores improved ≥2 steps in 74% & 67% of patients, respectively. Among all patients through 1-year, mean total area of RNP increased from 235 mm2 (CI, 183-288) to 266 mm2 (CI, 299-303; P=0.18) and ISI increased from 25.8% (CI, 20.9-30.7) to 31.9% (CI, 27.6-36.3; P=0.004). RNP outcomes favored monthly-dosing. Mean total RNP increased from 207 mm2 (CI, 143-270) at baseline to 268 mm2 (CI, 212-324; P=0.01) at 1-year in the Quarterly cohort, and remained stable at 264 mm2 at baseline (CI, 176-351) and 1-year (CI, 209-318; P=0.70) in the Monthly cohort (P=0.05, Monthly vs. Quarterly cohorts), with a difference of 56.8 mm2 in total RNP (CI: -47.8-161; P=0.28) at baseline and -4.19 mm2 (CI: -79.4-71.0; P=0.91) at 1-year between the Monthly and Quarterly cohorts. While many eyes demonstrated increased areas of RNP longitudinally (24, 66.7%), this was more common with Quarterly dosing (14, 77.8%), and a proportion of eyes (12, 33.3%) demonstrated localized areas of apparent reperfusion of non-perfused retina, more commonly in the Monthly cohort (8, 44.4%). Conclusions Widespread evidence of retinal reperfusion with aflibercept-dosing of PDR eyes with extensive RNP was not identified, and therefore the primary outcome of RECOVERY was not met; nevertheless, zones of apparent reperfusion were detected in some patients and a dose-response was identified with a reduction of RNP progression with monthly compared to quarterly dosing.