Comparative Risk of Adverse Cardiovascular Outcomes With Zanubrutinib Versus Ibrutinib in B-Cell Malignancies: A Large Real-World Propensity-Matched Analysis.

Bruton tyrosine kinase inhibitors (BTKis) are foundational therapies for B-cell malignancies but are associated with clinically important cardiovascular toxicities. Ibrutinib has been linked to atrial fibrillation/flutter (AF/AFL), bleeding, and ventricular arrhythmias, whereas second-generation BTKis such as Zanubrutinib may confer improved cardiovascular safety. In this study, we aimed to compare adverse cardiovascular outcomes between zanubrutinib and ibrutinib in a large real-world cohort. We conducted a retrospective, multicenter cohort study using the TriNetX Global Collaborative Network. Adults aged ≥18 years with chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, follicular lymphoma, waldenström macroglobulinemia, or marginal zone lymphoma initiating a BTKi were included. Patients with AF/flutter before starting BTKi were excluded. Propensity score matching (1:1) was done across 41 covariates. Outcomes were assessed within 12 months of beginning the BTKi. The Cox-proportional model was used to calculate hazard ratios (HR), and a p-value <0.05 was considered significant. Propensity matching yielded 3,447 balanced pairs. The mean age was 71 years, with 40% females in each cohort. Compared to Ibrutinib users, Zanubrutinib users experienced significantly lower risks of incident AF/AFL (HR = 0.47; 95% CI: 0.38 to 0.58; p <0.001), major bleeding (HR = 0.79; 95% CI: 0.68 to 0.91; p = 0.001), and all-cause mortality (HR = 0.27; 95% CI: 0.15 to 0.48; p <0.001). There was no significant difference between the 2 cohorts in terms of intracranial hemorrhage, ischemic stroke, myocardial infarction, ventricular arrhythmias, incident heart failure, and incident hypertension. In conclusion, Zanubrutinib was associated with a lower risk of AF/AFL, major bleeding, and all-cause mortality compared with Ibrutinib. These findings support the preferential use of Zanubrutinib when cardiovascular safety is a key consideration in patients with B-cell malignancies.