Cardiac adverse event signals of Bruton’s tyrosine kinase inhibitors as primary suspect and in co-reported regimens: a large-scale FAERS pharmacovigilance study

Background Bruton’s tyrosine kinase inhibitors (BTKis) have improved outcomes in B-cell malignancies, but cardiac toxicity remains a clinically relevant concern, particularly with newer-generation agents and co-reported regimens. We aimed to characterize real-world cardiac adverse event signals associated with BTKis as primary suspect (PS) agents and in co-reported regimens. Methods We conducted a pharmacovigilance study using the FDA Adverse Event Reporting System from the fourth quarter of 2013 to the first quarter of 2025. We evaluated BTKi regimens (ibrutinib, acalabrutinib, and zanubrutinib as primary suspect agents) and three specific BTKi-based co-reported combination subgroups (BTKi + anti-CD20 monoclonal antibodies, BTKi + venetoclax, and BTKi + lenalidomide). Cardiac adverse events were defined by the Medical Dictionary for Regulatory Activities “Cardiac disorders” system organ class. Disproportionality signals were assessed using four algorithms, and time-to-onset and fatal-case phenotypes were evaluated. Results A total of 8,266 BTKi-associated cardiac adverse event reports were identified. “Cardiac disorders” showed consistent disproportionality signals across BTKis. Ibrutinib had the broadest cardiac signal spectrum, whereas acalabrutinib and zanubrutinib showed fewer but earlier-onset cardiac events. Median reported time-to-onset was 150 days for ibrutinib, 72.5 days for acalabrutinib, and 66 days for zanubrutinib. Among co-reported regimens, BTKi plus lenalidomide showed the strongest disproportional reporting signal for atrial fibrillation. Reports with fatal cardiac outcome were more frequently reported among males, patients older than 85 years, and events occurring within 30 days of treatment initiation. Conclusion BTKis exhibit distinct real-world cardiac safety profiles. Early cardiovascular surveillance may be particularly important for newer-generation BTKis and BTKi-lenalidomide co-reported regimens, especially in patients with risk factors associated with higher reporting proportions.