Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study)

Purpose: Assess follow-up treatment and clinical outcomes at 5 years in eyes initially treated with anti-VEGF therapy for center-involved diabetic macular edema (CI-DME) in a 2-year randomized clinical trial. Design: Multicenter cohort study. Participants: Participants with diabetic macular edema (DME) and visual acuity (VA) 20/32 to 20/320 enrolled in DRCR.net Protocol T with visits 5 years after randomization (3 years after Protocol T completion). Methods: Participants were assigned randomly to aflibercept, bevacizumab, or ranibizumab with protocol-defined follow-up and re-treatment for 2 years. Thereafter, participants were managed at clinician discretion and recalled for a 5-year visit. Main Outcome Measures: Anti-vascular endothelial growth factor (VEGF) treatment, VA letter score, and central subfield thickness (CST). Results: Sixty-eight percent (317/463) of eligible participants completed the 5-year visit. Between years 2 and 5, 68% (217/317) of study eyes received at least 1 anti-VEGF treatment (median, 4; interquartile range [IQR], 0–12). At 5 years, mean VA improved from baseline by 7.4 letters (95% confidence interval [CI], 5.9–9.0) but decreased by 4.7 letters (95% CI, 3.3–6.0) between 2 and 5 years. When baseline VA was 20/50 to 20/320, mean 5-year VA was 11.9 letters (95% CI, 9.3–14.5) better than baseline but 4.8 letters (95% CI, 2.5–7.0) worse than 2 years. When baseline VA was 20/32 to 20/40, mean 5-year VA was 3.2 letters (95% CI, 1.4–5.0) better than baseline but 4.6 letters (95% CI, 3.1–6.1) worse than 2 years. Mean CST decreased from baseline to 5 years by 154 μm (95% CI, 142–166) and was stable between 2 and 5 years (−1 μm; 95% CI, −12 to 9). Conclusions: Among the two-thirds of eligible Protocol T participants who completed a 5-year visit, mean VA improved from baseline to 5 years without protocol-defined treatment after follow-up ended at 2 years. Although mean retinal thickness was similar at 2 and 5 years, mean VA worsened during this period. Additional investigation into strategies to improve long-term outcomes in eyes with DME seems warranted to determine if VA can be better maintained with different management approaches.