TY - JOUR

T1 - Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability

AU - Ye, Johan Z.

AU - Hansen, Finn B.

AU - Mills, Robert W.

AU - Lundby, Alicia

PY - 2021

Y1 - 2021

N2 - Background: Ibrutinib is a protein kinase inhibitor that has been widely successful in treating multiple common variations of B-cell cancers. However, an unfortunate side effect of ibrutinib is that it predisposes patients to development of atrial fibrillation. Objectives: The purpose of this study was to assess other commonly prescribed protein kinase inhibitors for similar pro-arrhythmic liability. Methods: This study comprehensively evaluated data from the U.S. Food and Drug Administration adverse events reporting system and determined the reporting of cardiac arrhythmia attributed to kinase inhibitor therapy using a multivariable logistic regression model. We evaluated 3,663,300 case reports containing 23,067 cases of atrial fibrillation and 66,262 cases of cardiac arrhythmia. In total, 32 protein kinase inhibitors were evaluated, almost all of which are oncotherapeutics. Results: Seven protein kinase inhibitors were associated with a significant increase in the odds of atrial fibrillation (ibrutinib, ponatinib, nilotinib, ribociclib, trametinib, osimertinib, and idelalisib). Assessment of broader pro-arrhythmic toxicity suggested a ventricular-specific liability for nilotinib and a bradyarrhythmia risk with alectinib and crizotinib. Conclusions: Compounds that result in the inhibition of a number of protein kinases are associated with an increased risk of cardiac rhythm disturbances. The mechanisms driving the arrhythmogenic effects remain to be discovered, but this study presents an important step in identifying and prioritizing the study of these protein kinase signaling pathways.

AB - Background: Ibrutinib is a protein kinase inhibitor that has been widely successful in treating multiple common variations of B-cell cancers. However, an unfortunate side effect of ibrutinib is that it predisposes patients to development of atrial fibrillation. Objectives: The purpose of this study was to assess other commonly prescribed protein kinase inhibitors for similar pro-arrhythmic liability. Methods: This study comprehensively evaluated data from the U.S. Food and Drug Administration adverse events reporting system and determined the reporting of cardiac arrhythmia attributed to kinase inhibitor therapy using a multivariable logistic regression model. We evaluated 3,663,300 case reports containing 23,067 cases of atrial fibrillation and 66,262 cases of cardiac arrhythmia. In total, 32 protein kinase inhibitors were evaluated, almost all of which are oncotherapeutics. Results: Seven protein kinase inhibitors were associated with a significant increase in the odds of atrial fibrillation (ibrutinib, ponatinib, nilotinib, ribociclib, trametinib, osimertinib, and idelalisib). Assessment of broader pro-arrhythmic toxicity suggested a ventricular-specific liability for nilotinib and a bradyarrhythmia risk with alectinib and crizotinib. Conclusions: Compounds that result in the inhibition of a number of protein kinases are associated with an increased risk of cardiac rhythm disturbances. The mechanisms driving the arrhythmogenic effects remain to be discovered, but this study presents an important step in identifying and prioritizing the study of these protein kinase signaling pathways.

KW - alectinib

KW - cardiac arrhythmia

KW - cardiotoxicity

KW - crizotinib

KW - ibrutinib

KW - idelalisib

KW - nilotinib

KW - osimertinib

KW - pharmacovigilance

KW - ponatinib

KW - protein kinase inhibitor

KW - ribociclib

KW - risk models

KW - trametinib U.S. Food and Drug Administration Adverse Event Reporting System

U2 - 10.1016/j.jaccao.2021.01.009

DO - 10.1016/j.jaccao.2021.01.009

M3 - Journal article

C2 - 34396309

AN - SCOPUS:85102102999

VL - 3

SP - 88

EP - 97

JO - JACC: CardioOncology

JF - JACC: CardioOncology

SN - 2666-0873

IS - 1

ER -