Drug class dynamics of tyrosine kinase inhibitor-induced cardiotoxicity: a 20-year large-scale real-world pharmacovigilance study

Tyrosine kinase inhibitors (TKIs) are targeted anticancer agents that suppress oncogenic signalling by blocking tyrosine kinases. While inhibiting tumour receptor tyrosine kinases (RTKs), TKIs disrupt physiological RTK signalling in healthy tissues, causing receptor-specific toxicity. TKIs have changed the treatment landscape of various malignancies. Nevertheless, the potential cardiotoxicity of TKIs may be underappreciated. This retrospective pharmacovigilance cohort study retrieved TKI-related adverse event reports from the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) database spanning from January 2004 to September 2025. To evaluate TKI-related cardiotoxicity signals, we used both the reporting odds ratio (ROR) and the information component (IC). Descriptive statistics, Bayesian modelling and temporal analysis further characterized TKI-associated cardiotoxicity. In real-world settings, we identified 31,911 reports of TKI-related cardiotoxicity. Cardiotoxicity signals varied across TKIs. Specifically, Bruton’s tyrosine kinase (BTK) TKIs showed the strongest association with atrial fibrillation, whereas BCR-ABL TKIs were linked to arterial ischaemic events. Anaplastic lymphoma kinase (ALK) TKIs and neurotrophic tyrosine receptor kinase (NTRK) TKIs were most strongly linked to pericardial effusion and myocarditis, whereas vascular endothelial growth factor receptor (VEGFR) TKIs were linked to hypertension. Among epidermal growth factor receptor (EGFR) TKIs, osimertinib exhibited the broadest cardiotoxicity profile. Temporal analysis revealed three cardiotoxicity phenotypes across TKI classes: acute/subacute for VEGFR and mitogen-activated extracellular signal-regulated kinase (MEK) TKIs, delayed/persistent for BCR-ABL and BTK TKIs, and a biphasic early onset pattern for ALK and EGFR TKIs. TKI-associated cardiotoxicity shows distinct drug-specific and temporal dynamics, providing clinically relevant insights for the development of individualized cardiovascular monitoring frameworks.