Pharmacovigilance analysis of cardiac risks associated with Bruton tyrosine kinase inhibitors

ABSTRACT

Background

Bruton tyrosine kinase inhibitors (BTKIs) can be associated with several cardiac risks.

Research design and methods

The study was conducted based on records from a large spontaneous reporting database, the Food and Drug Administration Adverse Event Reporting System, for cardiac events reported for several BTKI agents. Reporting odds ratio and information components based on statistical shrinkage transformation were utilized to measure disproportionality.

Results

The final number of records for BTKI-related cardiac events was 10 320. Death or life-threatening events occurred in 17.63% of all associated cardiac records. Significant reporting was captured between BTKI (total/specific) and cardiac events, with the strongest association for ibrutinib. A total of 47 positive signals were evacuated for ibrutinib, with atrial fibrillation being the most commonly reported one. Concomitantly, cardiac failure, congestive, cardiac disorder, arrhythmia, pericardial effusion, and atrial flutter were also noticed for relatively stronger signal and disproportionality. Atrial fibrillation was over-reported in the three groups (ibrutinib, acalabrutinib, and zanubrutinib), and acalabrutinib had statistically significant lower reporting compared with ibrutinib.

Conclusions

Receiving ibrutinib, acalabrutinib, or zanubrutinib might increase the chance of cardiac complications, with ibrutinib posing the highest risk. The type of cardiotoxicity involved in ibrutinib was highly variable.

KEYWORDS:

• Bruton tyrosine kinase inhibitors
• ibrutinib
• acalabrutinib
• zanubrutinib
• cardiac safety
• FAERS database
• disproportionality analysis

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Authors’ contributions

Conception and design of the work: Y. Zhai, F. Hu. Acquisition, analysis, or interpretation of data for the work: Y. Zhai, F. Hu, W. Shi. Drafting the work: Y. Zhai. Administrative or technical support: X. Ye, J. He, F. Xu. Critical revision of the manuscript: All authors. All authors contributed to the article and approved the submitted version.

Abbreviations

AE	=	adverse event;
BTKI	=	Bruton tyrosine kinase inhibitor;
FDA	=	Food and Drug Administration;
FAERS	=	Food and Drug Administration adverse event reporting system;
HLGT	=	high-level group term;
HLT	=	high-level term;
IC	=	information component;
IQR:	=	interquartile range;
MedDRA	=	Medical Dictionary for Regulatory Activities;
PT	=	preferred term;
ROR	=	reporting odds ratio;
SOC:	=	system organ class;
Time to onset	=	TTO

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/14740338.2023.2204226.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Data availability statement

All the data used in this study are available in the FAERS database at https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.

Additional information

Funding

This manuscript was funded by the National Nature Science Foundation of China (No. 82073671), the Leading Talents of Public Health in Shanghai (No. GWV-10.2-XD22), the Shanghai Municipal Commission of Health and Family Planning Fund for Excellent Young Scholars (No. 2018YQ47) and the Excellent Young Scholars of Public Health in Shanghai (No. GWV-10.2-YQ33), three-year Action Program of Shanghai Municipality for Strengthening the Construction of Public Health System (No. GWV-10.1-XK05), Big Data and Artificial Intelligence Application, Military Key Discipline Construction Project (Health Service-Naval Health Service Organization and Command) (No.03), and Medical and Health Project of Zhoushan Municipal Health Commission (No. 2022JYB05).