Cardiovascular Toxicities Associated With Ibrutinib.

Abstract

BACKGROUND:

Ibrutinib has revolutionized treatment for several B-cell malignancies. However, a recent clinical trial where ibrutinib was used in a front-line setting showed increased mortality during treatment compared with conventional chemotherapy. Cardiovascular toxicities were suspected as the culprit but not directly assessed in the study.

OBJECTIVES:

The purpose of this study was to identify and characterize cardiovascular adverse drug reactions (CV-ADR) associated with ibrutinib.

METHODS:

This study utilized VigiBase (International pharmacovigilance database) and performed a disproportionality analysis using reporting odds ratios (ROR) and information component (IC) to determine whether CV-ADR and CV-ADR deaths were associated with ibrutinib. IC compares observed and expected values to find associations between drugs and adverse drug reactions using disproportionate Bayesian-reporting; IC025 (lower end of the IC 95% credibility interval) >0 is significant.

RESULTS:

This study identified 303 ibrutinib-associated cardiovascular deaths. Ibrutinib was associated with higher reporting of supraventricular arrhythmias (SVAs) (ROR: 23.1; 95% confidence interval: 21.6 to 24.7; p < 0.0001; IC025: 3.97), central nervous system (CNS) hemorrhagic events (ROR: 3.7; 95% confidence interval: 3.4 to 4.1; p < 0.0001; IC025: 1.63), heart failure (ROR: 3.5; 95% confidence interval: 3.1 to 3.8; p < 0.0001; IC025: 1.46), ventricular arrhythmias (ROR: 4.7; 95% confidence interval: 3.7 to 5.9; p < 0.0001; IC025: 0.96), conduction disorders (ROR: 3.5; 95% confidence interval: 2.7 to 4.6; p < 0.0001; IC025: 0.76), CNS ischemic events (ROR: 2.2; 95% confidence interval: 2.0 to 2.5; p < 0.0001; IC025: 0.73), and hypertension (ROR: 1.7; 95% confidence interval: 1.5 to 1.9; p < 0.0001; IC025: 0.4). CV-ADR often occurred early after ibrutinib administration. Importantly, CV-ADR were associated with fatalities that ranged from ∼10% (SVAs and ventricular arrhythmias) to ∼20% (CNS events, heart failure, and conduction disorders). Ibrutinib-associated SVA portends poor prognosis when CNS events occur concomitantly, with 28.8% deaths (15 of 52 cases).

CONCLUSIONS:

Severe and occasionally fatal cardiac events occur in patients exposed to ibrutinib. These events should be considered in patient care and in clinical trial designs. (Evaluation of Reporting of Cardio-vascular Adverse Events With Antineoplastic and Immunomodulating Agents [EROCA]; NCT03530215).

• Authors: Joe-Elie Salem, Ali Manouchehri, Marie Bretagne, Bénédicte Lebrun-Vignes, John D Groarke, Douglas B Johnson, Tao Yang, Nishitha M Reddy, Christian Funck-Brentano, Jennifer R Brown, Dan M Roden, Javid J Moslehi
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 74 Issue 13 Pg. 1667-1678 (10 01 2019) ISSN: 1558-3597 [Electronic] United States
• PMID: 31558250 (Publication Type: Journal Article, Observational Study, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Chemical References

• Piperidines
• Pyrazoles
• Pyrimidines
• ibrutinib
• Adenine

Topics

• Adenine (analogs & derivatives)
• Adverse Drug Reaction Reporting Systems (trends)
• Aged
• Aged, 80 and over
• Cardiovascular Diseases (chemically induced, diagnosis, mortality)
• Databases, Factual (trends)
• Female
• Humans
• Male
• Mortality (trends)
• Pharmacovigilance
• Piperidines
• Pyrazoles (adverse effects)
• Pyrimidines (adverse effects)
• Retrospective Studies