Risk of non-fatal MACE in patients treated with zanubrutinib and acalabrutinib: a propensity-matched analysis

Abstract Aims The comparative cardiovascular toxicity profile of zanubrutinib versus acalabrutinib remains poorly characterised, even though it is increasingly influencing clinical decision-making regarding BTK inhibitor (BTK-I) prescription. The main aim of this study was to examine the risk of developing non-fatal MACE (composite of acute myocardial infarction, ischaemic stroke or systemic embolism and heart failure) in patients exposed to zanubrutinib compared with those exposed to acalabrutinib. Secondary endpoints included comparative risk of all-cause mortality, incident intra-cerebral haemorrhages, major bleedings, incident atrial fibrillation (AF), hypertension, and a composite of ventricular tachycardia/ventricular fibrillation/cardiac arrest (VT/VF/cardiac arrest). Methods and results Using the TriNetX research network database, a retrospective cohort of adult patients (≥18 years) previously diagnosed with a B-cell malignancy in whom a first BTK-I introduction occurred between October 31, 2017 and October 31, 2025 was established. After propensity score matching across 60 covariates, Cox proportional hazards models were used to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) to compare the 2 matched groups. Results were summarised with the use of Kaplan-Meier survival curves. Follow-up started from 1 day after first BTK-I introduction and continued over a 5-year follow-up period. During a mean follow-up of 1.7±1.4 years, no significant difference was observed in the risk of non-fatal MACE between zanubrutinib and acalabrutinib groups in the matched cohort (n=4,589 in each group; HR 0.99, 95% CI 0.898–1.093). The risks of all-cause mortality and major bleedings were significantly lower in the zanubrutinib group when compared to the acalabrutinib group (HR 0.82, 95% CI 0.737–0.915 and HR 0.93, 95% CI 0.878–0.982; respectively). No significant differences were observed in the risk of intra-cerebral haemorrhages, hypertension, AF and VT/VF/cardiac. Conclusion The risk of developing non-fatal MACE associated with zanubrutinib and acalabrutinib in patients with B-cell malignancies does not appear to diverge significantly.