Abstract
IMPORTANCE: Among patients receiving ongoing intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy who experience stroke or myocardial infarction (MI), evidence is limited on the systemic safety of continuing injections and whether treatment should be paused or modified. OBJECTIVE: To evaluate whether, among patients receiving intravitreal anti-VEGF therapy who experience cardiovascular events (CVE), there exist associations between anti-VEGF treatments administered shortly before or after CVE (peri-CVE) and mortality or major functional outcomes, and to evaluate whether systemic outcomes differ by anti-VEGF agents. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study of TriNetX network deidentified electronic health records (EHR) from 2005 to 2025. This study setting was a multicenter, EHR-based network analysis including individuals with stroke or MI with established anti-VEGF history (≥3 months pre-CVE), matched between those receiving 1 or more anti-VEGF injections within 14 days before or up to 6 weeks after CVE and those with no anti-VEGF from 3 months before to 3 months after. Propensity score matching (PSM) balanced demographics, comorbidities, procedures, systemic medications, laboratory values, and anti-VEGF agent history. EXPOSURES: Exposures included intravitreal anti-VEGF during the peri-CVE window vs no peri-CVE anti-VEGF. Sensitivity analyses restricted exposure to 14 days or fewer pre-CVE and compared aflibercept, bevacizumab, or ranibizumab with other agents. MAIN OUTCOMES AND MEASURES: The primary outcomes were 3-month and 1-year all-cause mortality, poststroke neurologic deficits, and post-MI heart failure. Data were expressed in relative risks (RRs) with 95% CIs. RESULTS: A total of 6073 and 5381 individuals with stroke or MI, respectively, were included before PSM. After PSM (1526 pairs with stroke; exposure [received peristroke anti-VEGF], mean [SD] age, 72.1 [12.9] years; 822 female [53.9%]; control [did not receive peristroke anti-VEGF], 72.7 [13.3] years; 840 female [55.0%]; and 1523 pairs with MI, exposure [received peri-MI anti-VEGF], 71.4 [13.5] years; 809 male [53.1%]; control [did not receive peri-MI anti-VEGF], 71.5 [13.3] years; 798 male [52.4%]), peristroke anti-VEGF was associated with lower mortality at 3 months (RR, 0.39; 95% CI, 0.29-0.53) and 1 year (RR, 0.52; 95% CI, 0.43-0.63) and fewer neurologic deficits at 3 months (RR, 0.64; 95% CI, 0.46-0.89) but not 1 year (RR, 0.79; 95% CI, 0.62-1.01). Peri-MI exposure was associated with lower mortality at 3 months (RR, 0.34; 95% CI, 0.26-0.43) and 1 year (RR, 0.58; 95% CI, 0.49-0.68) and lower heart failure at 3 months (RR, 0.65; 95% CI, 0.46-0.93) but not 1 year (RR, 0.87; 95% CI, 0.68-1.11). Timing-restricted analyses showed similar mortality findings without differences in neurologic deficits or heart failure. In agent-specific comparisons, there were no differences across aflibercept, bevacizumab, or ranibizumab for any outcome. CONCLUSIONS AND RELEVANCE: Results of this cohort study reveal that peri-CVE anti-VEGF was not associated with increased mortality or morbidity. Outcomes did not differ among commonly used agents, supporting the safety of continuing intravitreal anti-VEGF therapy without modification during the peri-CVE period.