Ibrutinib is associated with a higher risk of symptomatic atrial fibrillation (AF) than newer Bruton’s tyrosine kinase inhibitors (BTKis), a large study of real-world data has shown.
The French study of B-cell malignancy patients showed that the risk of AF leading to hospitalisation with ibrutinib was three times higher than with acalabrutinib, seven times higher than with zanubrutinib, and nine times higher than with venetoclax.
Ibrutinib also elevated the risk of outpatient AF events, while acalabrutinib and zanubrutinib showed a similar cardiac toxicity profile to venetoclax.
The study “supports the preferential use of second-generation BTKi or venetoclax in patients with elevated AF risk,” wrote the authors, led by Dr Yoann Zelmat of the University of Toulouse.
“Our results underscore the need for cardiovascular assessment before treatment initiation, enhanced rhythm monitoring during therapy with ibrutinib and multidisciplinary collaboration between haematologists and cardiologists,” they added.
The study, published in the British Journal of Haematology [link here], analysed real-world outcomes of patients in a French national health database who were newly treated with a BTKi (ibrutinib [n=16 375], acalabrutinib [n=2,431] or zanubrutinib [n=1,116]) or venetoclax (n=6,471), excluding those with prior AF or non-overlapping BTKi indications..
Patients were most commonly diagnosed with chronic lymphocytic leukaemia (47.0%), followed by Waldenström macroglobulinaemia (9.0%), mantle cell lymphoma (8.3%) and marginal zone B-cell lymphoma (1.5%).
Median age at treatment initiation was higher in the acalabrutinib and zanubrutinib cohorts (both 76 years) compared to ibrutinib (72 years) and venetoclax (70 years), and patients who received second-generation BTKis had more comorbidities overall.
The cumulative one-year incidence of AF requiring hospitalisation was highest for ibrutinib (2.3%), followed by acalabrutinib (0.9%), zanubrutinib (0.7%) and venetoclax (0.5%).
“Remarkably, in the present study, the outcome of AF requiring hospitalization closely mirrored severe (grade ≥3 according to CTCAE) AF rates from pivotal clinical trials (ibrutinib 3–5%, acalabrutinib 0–5%, zanubrutinib 0–3%),” the authors noted.
For AF including hospitalisations and outpatient diagnoses, the incidence remained highest for ibrutinib (5.5%), compared to acalabrutinib (1.6%), zanubrutinib (0.4%) and venetoclax (0.7%).
Following weighting, ibrutinib was associated with a significantly higher risk of AF requiring hospitalisation compared to acalabrutinib (three-fold higher), zanubrutinib (eight-fold higher) and venetoclax (nine-fold higher).
Ibrutinib also showed a significantly higher risk of inpatient and outpatient AF compared to venetoclax (HR 9.93), while the risk with acalabrutinib and zanubrutinib was similar to venetoclax.
Several cardiovascular comorbidities, including valvular heart disease (OR 2.40), heart failure (OR 2.28) and hypertension (OR 1.29), also significantly elevated the risk of AF requiring hospitalisation.
“Longer follow-up is needed to refine AF risk estimates for zanubrutinib and the cardiovascular safety profile of next-generation BTKi such as pirtobrutinib remains to be evaluated in real-world settings,” the authors wrote.
“These findings complement randomised trial evidence by extending AF risk estimates to a broader, more comorbid real-world population that remains largely underrepresented in pivotal clinical trials,” they concluded.