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Review
. 2026 Jan;26(1):21-34.
doi: 10.1007/s40256-025-00757-6. Epub 2025 Aug 28.

Cardiovascular Safety of Bruton Tyrosine Kinase Inhibitors: From Ibrutinib to Next-Generation Agents

Luigi Spadafora #  1   2 , Federico Russo #  3   4 , Ewelina Bukowska-Olech  5 , Giorgia Panichella  6 , Manuel Garofalo  6 , Stefano Cacciatore  7   8 , Pierre Sabouret  9 , Gianmarco Sarto  10 , Beatrice Simeone  10 , Erica Rocco  10 , Attilio Lauretti  11 , Francesco Versaci  11 , Giuseppe Biondi Zoccai  12   13 , Iginio Colaiori  11 , Valentina Valenti  12   13 , Sebastiano Sciarretta  12   14 , Marco Bernardi  12   11
Affiliations
Review

Cardiovascular Safety of Bruton Tyrosine Kinase Inhibitors: From Ibrutinib to Next-Generation Agents

Luigi Spadafora et al. Am J Cardiovasc Drugs. 2026 Jan.

Abstract

Bruton tyrosine kinase (BTK) plays a pivotal role in B-cell receptor signaling, making it a key therapeutic target in hematologic malignancies. Bruton tyrosine kinase inhibitors (BTKIs) have revolutionized the treatment landscape, improving survival outcomes in conditions such as chronic lymphocytic leukemia and mantle cell lymphoma. However, despite their clinical efficacy, BTKIs-particularly first-generation agents such as ibrutinib-are associated with significant cardiovascular toxicity, including atrial fibrillation, hypertension, bleeding, and, in rare cases, ventricular arrhythmias and heart failure. This narrative review explores the evolving landscape of BTKI-related cardiovascular toxicity, from first-generation drugs to next-generation agents that have improved safety profiles. We summarize current evidence on the incidence, mechanisms, and risk factors of BTKI-induced cardiovascular events and highlight potential predictive tools and mitigation strategies. Given the increasing use of these agents, a comprehensive understanding of their cardiovascular impact is essential for optimizing treatment selection and patient outcomes. Future research should focus on refining risk stratification models and developing cardioprotective strategies to ensure the long-term safety of BTKI therapy.

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Conflict of interest statement

Declarations. Funding: Open access funding provided by Università degli Studi di Roma La Sapienza within the CRUI-CARE Agreement. This work was partially supported by a grant from Sapienza University of Rome (RD12318AAABE3A08). Conflicts of interest: GBZ has consulted for Aleph, Amarin, Balmed, Cardionovum, Crannmedical, Endocore Lab, Eukon, Guidotti, Innovheart, Meditrial, Menarini, Microport, Opsens Medical, Terumo, and Translumina, outside the present work. PS has received consulting fees from Axis-TV, AstraZeneca, BMS, Les Laboratoires Servier, Novartis, Menarini, and Sanofi, outside the submitted work. LS, FR, EBO, GP, MG, SC, GS, BS, ER, AL, FV, IC, VV, SS, and MB have no conflicts of interest. Author contributions: LS conceived the manuscript, drafted the initial version, and coordinated the responses to reviewers. FR and EB-O contributed to the manuscript drafting and literature review, alongside GP and MG. SC, PS, GS, BS, ER, AL, FV, GBZ, IC, VV, and SS provided critical internal review and supervision throughout the writing process. MB oversaw the project and provided final supervision and critical appraisal. All authors reviewed and approved the final version of the manuscript. Data availability statement: Data sharing is not applicable as no datasets were generated for this review article. Ethics approval: Not applicable. Code availability: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable.

Figures

Fig. 1
Fig. 1
Proposed cardiovascular monitoring plan for patients receiving Bruton tyrosine kinase inhibitor therapy. NT-proBNP, N-terminal pro-B-type natriuretic peptide
See this image and copyright information in PMC

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