Study Questions
The oncotherapeutic drug ibrutinib is a protein kinase inhibitor that has been previously associated with increased risk for new-onset atrial fibrillation. Do other frequently prescribed protein kinase inhibitors have similar pro-arrhythmic liabilities?

Methods
This study¹ is an analysis of post-market drug safety surveillance data sourced from the publicly available US Food and Drug Administration (FDA) Adverse Event Reporting System, comprising both mandatory and voluntary reports. A multivariable logistic regression model assessed over 3.6 million adverse event reports containing 66,262 cases of cardiac arrhythmias associated with drug therapy. The model evaluated 32 frequently reported protein kinase inhibitors for increased reporting of arrhythmic adverse events.

Results
Controlling for Confounding Factors
The patient population with arrhythmic adverse events skews older (p < 0.001) but is more evenly distributed between the sexes (p < 0.001) than the general FDA Adverse Event Reporting System population. In addition to age and sex, the analysis of protein kinase inhibitor pro-arrhythmic liability was also controlled for the presence of comorbidities that correlate with arrhythmia. After aggregating adverse event report comorbidities by Medical Dictionary for Regulatory Activities hierarchy, 5 aggregates are significantly enriched within the reporting of new-onset atrial fibrillation (reporting odds ratio [ROR] and 95% confidence interval [CI]):

• Cardiac disorders (ROR 3.90; 95% CI, 3.83-3.98; p < 0.001)
• Vascular disorders (ROR 1.56; 95% CI, 1.53-1.60; p < 0.001)
• Respiratory disorders (ROR 1.46; 95% CI, 1.42-1.49; p < 0.001)
• Neoplasms (ROR 1.32; 95% CI, 1.30-1.34; p < 0.001)
• Metabolic disorders (ROR 1.19; 95% CI, 1.17-1.19; p < 0.001)

Within cardiac disorders, a history of arrhythmia has a significant independent enrichment among arrhythmic adverse events reporting (ROR 1.74; 95% CI, 1.67-1.80; p < 0.001) and thus was controlled for separately from the other forms of cardiac disorders.

Oncotherapeutics With Increased Reporting Odds for Arrhythmia
After controlling for the above confounding factors, 7 oncotherapeutic protein kinase inhibitors have significantly elevated reporting of atrial fibrillation adverse events:

• Ibrutinib (ROR 8.68; 95% CI, 8.14-9.26; p < 0.001)
• Ponatinib (ROR 3.03; 95% CI, 2.21-4.14; p < 0.001)
• Nilotinib (ROR 2.96; 95% CI, 2.47-3.53; p < 0.001)
• Ribociclib (ROR 2.96; 95% CI, 1.94-4.52; p < 0.001)
• Trametinib (ROR 2.37; 95% CI, 1.66-3.39; p < 0.001)
• Osimertinib (ROR 1.98; 95% CI, 1.43-2.74; p < 0.001)
• Idelalisib (ROR 1.59; 95% CI, 1.22-2.07; p = 0.017)

Additional analysis aimed to detect pro-arrhythmic liability more broadly by assessing reporting of cardiac arrhythmias in aggregate with post-hoc identification of specific arrhythmia etiologies underlying the aggregate signals. In addition to recovering most of the above signals for atrial fibrillation, this analysis also finds enriched reporting of the following:

• Nilotinib (ROR 2.02; 95% CI, 1.71-2.38; p < 0.001), primarily for ventricular arrhythmias and extrasystoles
• Alectinib (ROR 3.56; 95% CI, 2.26-5.62; p < 0.001), primarily for bradycardia
• Crizotinib (ROR 1.83; 95% CI, 1.45-2.31; p < 0.001), primarily for bradycardia

Conclusions
Nine of 32 protein kinase inhibitors evaluated are associated with an increased risk of cardiac rhythm disturbances.

Perspective
This study suggests an association between several protein kinase inhibitors and cardiac arrhythmias; however, further functional research and prospective studies are necessary to establish causal relationships and to quantify the true relative risk of these agents. The compounds identified here are directed against a handful of therapeutic targets, but these compounds have diverse additional off-target effects. This study is an important step in identifying and prioritizing the kinase signaling pathways affected by these compounds resulting in proarrhythmia. Some of the compounds (ibrutinib, ponatinib, alectinib, and crizotinib) already carry FDA label warnings for the arrhythmic liabilities detected in this study. Appropriate monitoring of patients for cardiac complications should be adhered to and adverse events reported to relevant post-market drug safety surveillance initiatives.

References

1. Ye JZ, Hansen FB, Mills RW, Lundby A. Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability. JACC CardioOncol 2021;3:88-97.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, EP Basic Science, Atrial Fibrillation/Supraventricular Arrhythmias, Cardio-Oncology

Keywords: Prospective Studies, Odds Ratio, Pharmaceutical Preparations, Protein Kinase Inhibitors, United States Food and Drug Administration, Logistic Models, Atrial Fibrillation, Bradycardia, Confidence Intervals, Factor VII, Cardiac Complexes, Premature, Metabolic Diseases, Neoplasms

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