Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability

Abstract

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.

Keywords: AF, atrial fibrillation; FAERS, FDA Adverse Event Reporting System; FDA, U.S. Food and Drug Administration; HLGT, high level group terms; HLT, high level terms; MedDRA, Medical Dictionary for Regulatory Activities; PKI, protein kinase inhibitor; PT, preferred term; ROR, reporting odds ratio; SOC, system organ classes; alectinib; cardiac arrhythmia; cardiotoxicity; crizotinib; ibrutinib; idelalisib; nilotinib; osimertinib; pharmacovigilance; ponatinib; protein kinase inhibitor; ribociclib; risk models; trametinib U.S. Food and Drug Administration Adverse Event Reporting System.

Graphical abstract

Figure 1

Identification of Confounding Effects (A to C) Summary statistics for age and sex of U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) population and subpopulations. The age distribution for the FAERS population (A) and the subpopulation that reported atrial fibrillation (AF) (B) both tend to be elderly. n indicates number of cases in each population and μ is the population mean. The age distribution for the AF population is statistically significantly different from the background FAERS population (p < 0.001, Mann-Whitney U test; ∗∗∗p < 0.001, Student’s t-test). (C) Summary statistics for sex distributions for subpopulations affected by AF or any etiology of cardiac arrhythmia differ significantly from the background FAERS population (∗∗∗p < 0.001, Chi-squared test). (D and E) Analysis of comorbidities associated with AF reporting. (D) System organ class (SOC) level terms were analyzed by Chi-squared disproportionality testing to identify terms that co-segregated with elevated AF reporting. Significantly enriched terms, included as confounding variables in the final analysis, are shown in red. (E) AF reporting odds ratio (ROR) for the SOC level term “cardiac disorders” was large compared to the other terms and was analyzed for division at the high level group term (HLGT) stratum. “Cardiac arrhythmias” is significantly enriched (shown in red) over other cardiac disorders within AF reporting. RORs and confidence intervals for all terms are presented with Bonferroni corrections for multiple testing, and marker size is the proportional total number of reports containing the term.

Figure 2

Odds Ratios for Protein Kinase Inhibitor Effect With Regards to Atrial Fibrillation Logistic regression analysis of AF in FAERS assessed the confounding effect size of comorbidities associated with increased incidence of disease, on the patient’s likelihood of developing AF (dark red). After controlling for these confounding variables, 7 protein kinase inhibitors have significantly increased likelihood of being reported for AF (red). These are: ibrutinib, ponatinib, nilotinib, ribociclib, trametinib, osimertinib, and idelalisib. The 95% confidence intervals (CIs) are skewed due to being in exponential space, and are not corrected for multiple hypothesis testing. Abbreviations as in Figure 1.

Figure 3

Odds Ratios for Protein Kinase Inhibitors With Regards to Related Arrhythmias All protein kinase inhibitors were assessed for elevated reporting of arrhythmias grouped under Medical Dictionary for Regulatory Activities (MedDRA) high level terms (HLTs): “rate and rhythm disorders” (A), “cardiac conduction disorders” (B), “ventricular arrhythmias” (C), and “supraventricular arrhythmias” (D). For each analysis, compounds with significantly elevated ROR after multiple-testing correction are presented along with confounder effects. Confounder effects with ROR < 1 does not imply a protective effect. For compounds with significantly elevated reporting, a post hoc analysis assessed for enrichment of underlying PTs to identify recurrent etiological themes. Significantly enriched or under-represented terms are labelled and shown with filled-in markers. The size of each marker is proportional to total number of reports for this form of arrhythmia for this drug. (Ai) Alectinib, nilotinib, crizotinib, and ibrutinib were associated with elevated rate and rhythm disorder reporting. The alectinib (Aii) and crizotinib (Aiii) signals were primarily driven by reporting of Bradycardia. (Bi) No protein kinase inhibitors were associated with elevated cardiac conduction disorder reporting. (Ci) Nilotinib was associated with elevated ventricular arrhythmia reporting. (Cii) This signal was primarily driven by reporting of ventricular extrasystoles and nonspecific ventricular arrhythmias. (D) With the exception of idelalisib, all other significant protein kinase inhibitors detected in the AF analysis were associated with elevated supraventricular arrhythmia reporting. Trametinib (Dii) and ibrutinib (Diii) signals were primarily driven by reporting of AF, and to a lesser extent by closely related terms (e.g., supraventricular tachycardia and atrial flutter). Abbreviations as in Figure 1.

Central Illustration

Protein Kinase Inhibitors With Elevated Reporting Odds Ratios for Various Arrhythmias Logistic regression analysis of 3,663,300 U.S. Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) reports (66,262 cardiac arrhythmia reports) that assessed the likelihood of developing arrhythmia. After controlling for confounding variables, 9 protein kinase inhibitors have significantly increased likelihood of being reported for arrhythmia, including ibrutinib, ponatinib, nilotinib, ribociclib, trametinib, osimertinib, and idelalisib for atrial fibrillation specifically. The 95% confidence intervals are skewed due to being in exponential space, and are not corrected for multiple hypothesis testing.