Purpose: Controversy exists regarding the systemic safety of intravitreal VEGF inhibitors in the treatment of neovascular age-related macular degeneration (nAMD). We aimed to investigate the potential impact of VEGF inhibitor treatment on the risk of all-cause mortality and cardiovascular disease (CVD) among patients with nAMD. Design: A nationwide register-based cohort study with 16 years follow-up. Participants: Patients with nAMD exposed with VEGF inhibitors (n = 37 733) and unexposed individuals without nAMD (n = 1 897 073) aged ≥ 65 years residing in Denmark between January 1, 2007, and December 31, 2022. Methods: Cox proportional hazards analysis was conducted to assess the effect of intravitreal VEGF inhibitor treatment on all-cause mortality and incident CVD. Main Outcome Measures: In a predefined analysis plan we defined primary outcomes as hazard ratios (HRs) of all-cause mortality and a composite CVD endpoint in patients with nAMD treated with VEGF inhibitors compared with individuals without nAMD. The secondary outcomes encompassed analyses that explored the impact of the number of doses and the association between exposure and outcome over a specific time period. Results: Overall, 63.7% of patients with nAMD were women with an average age of 69.9 years (interquartile range 65.0–76.0 years). Patients exposed to VEGF inhibitors demonstrated a reduced risk of all-cause mortality compared with individuals without nAMD (HR, 0.79; 95% confidence interval [CI], 0.78–0.81), and an increased risk of composite CVD (HR, 1.04; 95% CI, 1.01–1.07). The decreased risk of all-cause mortality persisted, but there was no significant association between VEGF inhibitor treatment and CVD when patients with nAMD were grouped by the number of doses or considered exposed within 60 days postinjection. Conclusions: Our study revealed a decreased risk of all-cause mortality and a 4% increased risk of CVD among patients with nAMD exposed with VEGF inhibitors. The decreased risk of mortality is unlikely to be directly pathophysiologically related to VEGF inhibitor treatment. Instead, we speculate that patients undergoing VEGF inhibitor treatment are, on average, individuals in good health with adequate personal resources. Therefore, they also have a higher likelihood of overall survival. These findings strongly support the safety of VEGF inhibitor treatment in terms of all-cause mortality and CVD among patients with nAMD. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
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