Breaking BTK, Not Hearts: Cardiac Safety Review With Covalent and Non-Covalent BTK Inhibitors

INTRODUCTION: CLL is the most common leukemia in older adults and increasingly treated with targeted therapies that are generally better tolerated than conventional chemoimmunotherapy. Pirtobrutinib, a non-covalent Bruton tyrosine kinase inhibitor (BTKi), was recently FDA approved for relapsed/refractory CLL/SLL after prior covalent BTKi therapy and may demonstrate a more favorable cardiovascular safety profile compared with covalent BTK inhibitors.

AIM: To characterize and compare reported cardiac adverse events among BTK inhibitors used in CLL using the FDA Adverse Event Reporting System (FAERS) database.

METHOD: A pharmacovigilance review was conducted using FAERS data from 2013–2026. Individual drug reports for ibrutinib, acalabrutinib, zanubrutinib, and pirtobrutinib were filtered to include adult patients (≥18 years) with CLL as the reported indication. Cardiac adverse events and serious outcomes were analyzed and compared across agents.

CONCLUSION: Covalent BTK inhibitors demonstrated a substantially greater cardiac adverse event reporting burden compared with pirtobrutinib. These findings should be interpreted cautiously given pirtobrutinib’s more recent introduction and shorter real-world exposure duration. Continued post-marketing surveillance is needed to better define the long-term cardiovascular side effects.