Targeting angiogenesis, unmasking coronary risk: incidence, predictors, and outcomes of coronary events with VEGFR tyrosine kinase inhibitors

Coronary events are an emerging concern in cancer patients treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFRI TKIs), yet their incidence, predictors, and clinical implications remain poorly defined.

We aimed to characterize the burden, risk factors, and outcomes of new coronary events in patients receiving VEGFRI therapy.

We retrospectively reviewed 290 cancer patients treated with axitinib, cabozantinib, lenvatinib, or pazopanib between 2015–2023. Patients were stratified by the presence or absence of a new coronary event occurring during VEGFRI therapy or within one year of treatment completion. Coronary events included ST-elevation myocardial infarction (STEMI), non–ST-elevation myocardial infarction (NSTEMI), and myocardial injury. Univariate and multivariate analyses were performed to assess risk factors and clinical outcomes.

New coronary events occurred in 32 patients (11%) at a median of 492 days following VEGFRI initiation (IQR 264–977). Events included 4 STEMI, 12 NSTEMI, and 16 myocardial injury presentations. Five patients required percutaneous coronary intervention with drug-eluting stent placement, while the remainder were managed medically. Patients experiencing coronary events were significantly more likely to develop new-onset heart failure compared with those without events (34% vs 14%, p = 0.0087). All-cause mortality was similar between cohorts at three-year follow-up, and Kaplan–Meier analysis demonstrated no significant difference in survival (p = 0.056).

Baseline demographics were similar between groups. On univariate analysis, patients with coronary events were more likely to have pre-existing hyperlipidemia (69% vs 48%, p = 0.041). Other cardiovascular comorbidities and baseline cardiac medications were comparable. Patients with coronary events were less likely to have prior anthracycline exposure (6% vs 23%, p = 0.047). While overall VEGFRI exposure duration did not differ significantly, patients with coronary events had longer immune checkpoint inhibitor exposure (749 vs 334 days, p = 0.041).

On multivariate analysis adjusting for age, sex, race, comorbidities, and oncologic exposures, hyperlipidemia independently predicted coronary events (OR 3.16, 95% CI 1.14–9.22, p = 0.03), while prior anthracycline exposure was independently protective (OR 0.22, 95% CI 0.03–0.83, p = 0.049). The model demonstrated good discrimination (AUC = 0.744).

New coronary events represent a clinically meaningful toxicity of VEGFRI therapy and are frequently accompanied by subsequent heart failure. Hyperlipidemia identifies patients at increased risk, while the protective association of anthracycline exposure may reflect treatment selection or survivor bias. These findings underscore the importance of cardiovascular risk stratification, lipid management, and longitudinal surveillance in patients receiving VEGFRI TKIs.

Kaplan Meier Survival Analysis