Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy.

Key Points: Question: In patients with nonproliferative diabetic retinopathy (NPDR) and good vision but without center-involved diabetic macular edema (CI-DME), does early aflibercept reduce disease progression and improve long-term visual acuity compared with initial observation and treatment only if disease worsens? Findings: This study presents 4-year primary outcomes of a randomized clinical trial that included 328 patients (399 eyes), randomized to 2.0 mg aflibercept injections or sham injections. Among those receiving aflibercept, proliferative diabetic retinopathy or CI-DME developed in 33.9% vs 56.9% among those who received sham—a difference that was statistically significant. Change in visual acuity was −2.7 vs −2.4 letters, a difference that was not statistically significant. Meaning: At 4 years, treatment of NPDR with aflibercept vs sham treatment resulted in statistically significant anatomic improvement, but no improvement in visual acuity. Importance: Anti–vascular endothelial growth factor (VEGF) injections in eyes with nonproliferative diabetic retinopathy (NPDR) without center-involved diabetic macular edema (CI-DME) reduce development of vision-threatening complications from diabetes over at least 2 years, but whether this treatment has a longer-term benefit on visual acuity is unknown. Objective: To compare the primary 4-year outcomes of visual acuity and rates of vision-threatening complications in eyes with moderate to severe NPDR treated with intravitreal aflibercept compared with sham. The primary 2-year analysis of this study has been reported. Design, Setting, and Participants: Randomized clinical trial conducted at 64 clinical sites in the US and Canada from January 2016 to March 2018, enrolling 328 adults (399 eyes) with moderate to severe NPDR (Early Treatment Diabetic Retinopathy Study [ETDRS] severity level 43-53; range, 0 [worst] to 100 [best]) without CI-DME. Interventions: Eyes were randomly assigned to 2.0 mg aflibercept (n = 200) or sham (n = 199). Eight injections were administered at defined intervals through 2 years, continuing quarterly through 4 years unless the eye improved to mild NPDR or better. Aflibercept was given in both groups to treat development of high-risk proliferative diabetic retinopathy (PDR) or CI-DME with vision loss. Main Outcomes and Measures: Development of PDR or CI-DME with vision loss (≥10 letters at 1 visit or ≥5 letters at 2 consecutive visits) and change in visual acuity (best corrected ETDRS letter score) from baseline to 4 years. Results: Among participants (mean age 56 years; 42.4% female; 5% Asian, 15% Black, 32% Hispanic, 45% White), the 4-year cumulative probability of developing PDR or CI-DME with vision loss was 33.9% with aflibercept vs 56.9% with sham (adjusted hazard ratio, 0.40 [97.5% CI, 0.28 to 0.57]; P <.001). The mean (SD) change in visual acuity from baseline to 4 years was −2.7 (6.5) letters with aflibercept and −2.4 (5.8) letters with sham (adjusted mean difference, −0.5 letters [97.5% CI, −2.3 to 1.3]; P =.52). Antiplatelet Trialists' Collaboration cardiovascular/cerebrovascular event rates were 9.9% (7 of 71) in bilateral participants, 10.9% (14 of 129) in unilateral aflibercept participants, and 7.8% (10 of 128) in unilateral sham participants. Conclusions and Relevance: Among patients with NPDR but without CI-DME at 4 years treatment with aflibercept vs sham, initiating aflibercept treatment only if vision-threatening complications developed, resulted in statistically significant anatomic improvement but no improvement in visual acuity. Aflibercept as a preventive strategy, as used in this trial, may not be generally warranted for patients with NPDR without CI-DME. Trial Registration: ClinicalTrials.gov Identifier: NCT02634333 This randomized clinical trial analyzes the effects of aflibercept injections vs sham for reducing disease progression and improving long-term visual acuity in patients with nonproliferative diabetic retinopathy. [ABSTRACT FROM AUTHOR]