Arterial thromboembolic events during long-term intravitreal anti-VEGF therapy: incidence, associated factors, and mortality in a retrospective cohort study

Background Repeated intravitreal anti-vascular endothelial growth factor (anti-VEGF) injections raise concern about systemic arterial thromboembolic events. We evaluated the cumulative incidence of first thromboembolic events, associated factors, and the association of incident events with all-cause mortality in a treated cohort. Methods This single-centre retrospective cohort study included 321 patients who initiated intravitreal therapy for neovascular age-related macular degeneration, diabetic macular edema, or retinal vein occlusion between April 2019 and April 2025 and were followed until September 2026. The primary outcome was the first myocardial infarction or ischemic stroke. Cumulative incidence was estimated with the Aalen–Johansen method, treating death as a competing event. Associated factors were evaluated with cause-specific Cox models with a time-updated cumulative number of injections and covariates selected a priori. Mortality was assessed with time-dependent Cox regression, with a sensitivity analysis excluding same-day deaths. Results During a median follow-up of 45.6 months, 28 patients (8.7%) had a first arterial thromboembolic event (myocardial infarction, 16; ischemic stroke, 12). The competing-risk cumulative incidence was 2.1%, 5.7%, 8.5%, and 10.1% at 12, 24, 36, and 48 months, respectively. Time-updated cumulative injection count was not significantly associated with the cause-specific hazard of thromboembolic events (hazard ratio 1.06 per five injections; 95% confidence interval 0.84–1.34). Diabetes mellitus had an imprecise association in the primary model (hazard ratio 3.18; 95% confidence interval 0.79–12.77) that was statistically significant in two sensitivity models. Diabetes duration, baseline glycated hemoglobin, and time-updated bilateral treatment were not significantly associated with thromboembolic events. Incident arterial thromboembolic events were associated with higher all-cause mortality (adjusted HR 10.61; 95% CI 3.95–28.47), with the association remaining elevated in sensitivity analysis (adjusted HR 3.80; 95% CI 1.29–11.18). Conclusions In this treated cohort, the four-year cumulative incidence of a first arterial thromboembolic event was approximately 10%. No significant association with time-updated cumulative injection count was detected, although clinically important associations cannot be excluded. Incident arterial thromboembolic events were associated with higher all-cause mortality, and this association persisted in sensitivity analysis. Without an untreated comparator, these findings cannot establish cardiovascular safety or harm attributable to intravitreal anti-VEGF therapy. Trial registration Not applicable.