Insights from survival analyses during 12 years of anti-VEGF therapy for neovascular age-related macular degeneration

Importance: While multiple imputation models for missing data and use of mixed effects models generally provide better outcome estimates than using only observed data or last observation carried forward in clinical trials, such approaches usually cannot be applied to visual outcomes from retrospective analyses of clinical practice settings, so-called real-world outcomes. Objective: To explore potential utility of survival analysis techniques for retrospective clinical practice visual outcomes. Design: Retrospective cohort study with 12-year observation period. Setting: A tertiary eye center. Participants: Of 10,744 eyes with neovascular AMD receiving anti-VEGF therapy between October 2008 and February 2020, 7802 eyes met study criteria (treatment-naïve, first-treated eyes starting anti-VEGF therapy). Main outcome measures: Kaplan-Meier estimates and Cox proportional hazards modelling were used to consider: VA reaching ETDRS (Early Treatment Diabetic Retinopathy Study) letter score 70 (Snellen equivalent 20/40) or better; duration VA sustained at or better than 70 (20/40); and VA declining to 35 (20/200) or worse. Results: The median time to attaining VA letter score ≥ 70 (20/40) was 2.0 years (95% CI 1.87 - 2.32) after the first anti-VEGF injection. Predictive features were baseline VA (HR 1.43 per 5 ETDRS letter score or 1 line [95% CI 1.40 - 1.46]), baseline age (HR 0.88 per 5 years [95% CI 0.86 - 0.90]), and injection number (HR 1.123 [95% CI 1.101 - 1.15]). Of the 56% attaining this outcome, median time sustained at 70 (20/40) or better was 1.1 years (95% CI 1.1 - 1.2). Conclusions and relevance: Survival analysis potentially addresses key limitations of retrospective clinical practice (real-world) data by accounting for variable observation time-points and follow-up durations. Modelling with multiple covariates reveals factors that may help inform the likely visual trajectory of an individual. We demonstrate the utility of our proposed analyses by showing that patients with neovascular AMD beginning anti-VEGF therapy are more likely to experience positive visual outcomes within the first 2.9 years, typically maintaining this for 1.1 years, but then deteriorating to poor vision within 8.7 years. We believe that this dataset, combined with our statistical approach for retrospective analyses, may provide long-term prognostic information for patients newly diagnosed with this condition