Comparative atrial fibrillation risk across Bruton's tyrosine kinase inhibitors in B-cell malignancies: A nationwide population-based study.

Bruton's tyrosine kinase inhibitors (BTKi) are widely used in B-cell malignancies. Ibrutinib is associated with atrial fibrillation (AF), but comparative real-world evidence on AF risk across BTKi remains limited. We conducted a nationwide new-user population study using the French national health insurance database (2015-2024). Adults initiating ibrutinib, acalabrutinib, zanubrutinib or venetoclax were included, excluding those with prior AF or non-overlapping BTKi indications. The primary outcome was AF requiring hospitalization. Hazard ratios (HRs) were estimated using Cox models with inverse probability of treatment weighting (IPTW). Among 26 393 patients, median follow-up ranged from 167 days in the zanubrutinib cohort to 526 days in the ibrutinib cohort. One-year incidence of hospitalized AF was highest with ibrutinib (2.3%) versus acalabrutinib (0.9%), zanubrutinib (0.7%) and venetoclax (0.5%). Ibrutinib was associated with a significantly higher AF risk versus acalabrutinib (HR 3.03, 95% confidence interval [CI] 1.84-5.00), zanubrutinib (HR 7.58, 95% CI 2.05-28.06) and venetoclax (HR 9.04, 95% CI 5.81-14.04). No significant differences in AF risk were observed between second-generation BTKi and venetoclax. Ibrutinib was associated with a substantially higher risk of hospitalized AF than second-generation BTKi, supporting closer cardiac monitoring in ibrutinib-treated patients.