The Cardiovascular Outcomes Difference between Acalabrutinib and Zanubrutinib: A Retrospective Cohort Study Using Real-World Data
Authors: Tang Zhiting , Aldapt Mahmood B , Chiang Cho-Han , Gong Zimu 
Published: December 2024

Background:
Zanubrutinib and acalabrutinib are next-generation Bruton's tyrosine kinase (BTK) inhibitors used in chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL). They have demonstrated lower cardiotoxicity compared to first-generation BTK inhibitor ibrutinib. However, there is limited data comparing cardiovascular outcomes between zanubrutinib and acalabrutinib. This study aims to investigate the cardiovascular risks associated with these two agents in a real-world setting.
Method:
A retrospective, propensity score-matched study was conducted using the TriNetX database, which includes de-identified electronic health records from over 101 million individuals across 70 healthcare organizations. Patients with CLL and SLL treated with either zanubrutinib or acalabrutinib were included, excluding those who received ibrutinib. The primary outcome of interest was major cardiovascular adverse events, composed of heart failure, myocardial infarction, and cardiac arrest. Other outcomes of interest were new-onset hypertension, new-onset atrial fibrillation/flutter, ventricular arrhythmia, myocardial infarction, new-onset heart failure, conduction block, and stroke within 18 months of therapy initiation. Propensity score matching accounted for demographics, comorbidities, disease status, other CLL/SLL-directed therapies, and concomitant cardiovascular agents. Relative risk and 95% confidence intervals were calculated to assess the outcomes.
Results:
A total of 907 patients treated with zanubrutinib were matched to 907 patients treated with acalabrutinib. At 18 months, the zanubrutinib group experienced 106 major cardiovascular adverse events, compared to 144 in the acalabrutinib group (RR (relative risk), 0.73 [95% CI: 0.58-0.93]; p=0.009). New-onset hypertension occurred in 35 zanubrutinib and 31 acalabrutinib patients (RR, 1.14 [95% CI: 0.72-1.82]; p=0.579). New-onset atrial fibrillation/flutter occurred in 15 zanubrutinib and 30 acalabrutinib patients (RR, 0.49 [95% CI: 0.27-0.91]; p=0.020). Ventricular arrhythmia occurred in 13 zanubrutinib and 9 acalabrutinib patients (RR, 1.44 [95% CI: 0.62-3.36]; p=0.402). Myocardial infarction occurred in 18 zanubrutinib and 25 acalabrutinib patients (RR, 0.72 [95% CI: 0.40-1.31]; p=0.286). New-onset heart failure occurred in 34 zanubrutinib and 40 acalabrutinib patients (RR, 0.82 [95% CI: 0.52-1.28]; p=0.385). Conduction block occurred in 43 zanubrutinib and 48 acalabrutinib patients (RR, 0.90 [95% CI: 0.60-1.34]; p=0.593). Stroke occurred in 20 zanubrutinib and 19 acalabrutinib patients (RR, 1.05 [95% CI: 0.57-1.96]; p=0.873).
Conclusion:
Zanubrutinib was associated with a 27% lower risk of major cardiovascular adverse events and a 51% lower risk of new-onset atrial fibrillation/flutter compared to acalabrutinib, suggesting its preference for patients with high cardiovascular risks. The risks of new-onset hypertension, ventricular arrhythmia, myocardial infarction, new-onset heart failure, conduction block, and stroke were similar between the two groups. Further studies with long-term follow-up data will be valuable for evaluating the safety of next-generation BTK inhibitors.