Atrial Fibrillation Management and Outcomes in Bruton's Tyrosine Kinase Inhibitor Treated Chronic Lymphocytic Leukemia Patients
Authors: Itchaki Gilad , Razi Talish , Zoref-Lorenz Adi , Ellis Martin H. , Arbel Ronen 
Published: December 2024

Introduction
Bruton's tyrosine kinase inhibitors (BTKIs) have revolutionized the treatment of chronic lymphocytic leukemia (CLL). Covalent BTKIs improve survival but are associated with serious toxicities, including atrial fibrillation (AF) and a bleeding diathesis. Despite the widespread use of BTKIs, there are few data regarding the appropriate management of AF in this context. The aim of our study is to compare the safety and effectiveness of AF management in CLL patients with and without BTKI therapy.
Methods
We conducted a population-based cohort study using the database maintained by Clalit Health Services, which is the largest health maintenance organization in Israel with approximately 5 million members. We collected data regarding patients with a diagnosis of CLL between 2005 and 2022 and who had a first AF event after CLL diagnosis. Patients with less than 5 months of follow-up from their first AF event were excluded. Specifically, we studied CLL patients who developed AF while receiving treatment with a BTKI. The safety endpoint was bleeding events leading to hospitalization. The effectiveness endpoint was major cardiovascular events (MACE), including stroke, myocardial infarction, and all-cause mortality. We performed a multivariate time-sensitive Cox-regression analysis of event-free survival (EFS) adjusted for various sociodemographic and clinical variables.
Results
During the study period, 6,431 CLL patients were identified, of whom 632 patients had a first AF event after the CLL diagnosis. The median age at CLL diagnosis was 74 years (IQR 67-80); 57% were men. Ethnic and socioeconomic diversity were achieved in our cohort. Twenty-one percent (n=134) of patients had used a BTKI prior to developing AF. These patients were younger at CLL diagnosis (70 vs. 75 years, P&lt;0.001) and at first AF event (80 vs. 77 years, P&lt;0.001) compared to CLL patients developing AF with no prior BTKI use (79%, n=498). The CHADS2-VASC score distribution was similar between groups. There was no difference between the BTKI and non-BTKI groups regarding medications used for rate and rhythm control. Seventy-two percent of patients in the BTKI-treated group received anticoagulation, similar to the 68% in the non-BTKI treated group. However, patients in the BTKI group were more likely to be treated with direct oral anticoagulants (DOACs) (69% vs. 51%, P&lt;0.001) and less likely to be given warfarin (3% vs. 17%, P&lt;0.001).
Follow-up was similar between groups, with a median follow-up of 79 months from CLL diagnosis (IQR 47-123 months) and 19 months (IQR 4-44 months) from the first AF event. Regarding safety, there was no difference in the incidence of bleeding events that led to hospitalization between the BTKI and non-BTKI groups (8.2% vs. 10%, respectively, P=0.5). The EFS (no MACE or death events) was significantly higher in the BTKI group (38% vs. 27%, P=0.024).
In the Cox-regression analysis of EFS with the first AF event as the index case, age (HR 1.04, 95% CI: 1.02-1.05), high CHADS2-VASC score (HR 1.2, 95% CI: 1.11-1.32), and BTKI use (HR 1.4, 95% CI: 1.08-1.81) were associated with a higher risk of MACE or death. Female sex (HR 0.77, 95% CI: 0.62-0.95), the use of rate control medications (HR 0.67, 95% CI: 0.51-0.89), and DOACs (HR 0.33, 95% CI: 0.27-0.40) were protective factors. Importantly, even in BTKI-treated patients who developed AF, DOACs remained a statistically significant protective factor against MACE or death (HR 0.44, 95% CI: 0.28-0.68).
Conclusion
AF occurring in BTKI and non-BTKI-treated CLL patients have similar outcomes. DOAC treatment is safe and effective in BTKI-treated patients.