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

Abstract

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.

Figure 1.

Distribution of office visits and diabetic macular edema (DME) treatments for follow-up study participants from baseline to 5 years after initial randomization into a 2-year clinical trial on anti-vascular endothelial growth factor (VEGF) treatment for eyes with DME (Protocol T). Each row along the vertical axis represents a timeline for a follow-up study participant. Symbols indicate office visits and DME treatments in the study eye (only one study eye per participant). Participants are ordered along the vertical axis by randomized treatment group assignment and the time of the last observed DME treatment.

Figure 2.

Distribution of the number of anti-vascular endothelial growth factor (VEGF) injections received between 3 to 5 years after initial randomization into a 2-year clinical trial on anti-VEGF treatment for diabetic macular edema (Protocol T).

Figure 3.

Mean change in visual acuity over time for all eyes (A) and stratified by baseline visual acuity of 68 to 24 letters (approximate Snellen equivalent 20/50 to 20/320) (B) and 78 to 69 letters (approximal Snellen equivalent 20/32 to 20/40) (C) among follow-up study participants from a 2-year clinical trial on anti-vascular endothelial growth factor treatment for eyes with diabetic macular edema (Protocol T). Change in visual acuity was truncated to the mean ± 3 standard deviations of the change from baseline to 5 years (7.12 ± 3 × 16.04). Eyes missing visual acuity at the 5-year visit were excluded.

Figure 4.

Distribution of visual acuity (approximate Snellen equivalent) categories at annual visits among follow-up study participants from a 2-year clinical trial on anti-vascular endothelial growth factor treatment for eyes with diabetic macular edema (Protocol T).

Figure 5.

Mean change in optical coherence tomography central subfield thickness over time among follow-up study participants from a 2-year clinical trial on anti-vascular endothelial growth factor treatment for eyes with diabetic macular edema (Protocol T). Change in central subfield thickness was truncated to the mean ± 3 standard deviations of central subfield thickness change from baseline to 5 years (−154.5 ± 3 × 154.81). Eyes missing central subfield thickness at the 5-year visit were excluded.