Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability

Ye, Johan Ziruo; Hansen, Finn B.; Mills, Robert W.; Lundby, Alicia

doi:10.1016/j.jaccao.2021.01.009

Cited by 17 publications

(20 citation statements)

References 20 publications

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“…Oral inhibitors of ALK-positive tumors (e.g., crizotinib and ceritinib) were reported to cause sinus bradycardia. Trials on crizotinib treatment of NSCLC revealed a bradycardia frequency between 0.5% and 70%, with the average time to the lowest heart rate after 18.6 weeks [ 76 , 77 ]. However, the reported incidence of this adverse event depends on the definition of bradycardia.…”

Section: Cardiotoxicity Of Protein Kinase Inhibitorsmentioning

confidence: 99%

Cardiotoxicity Induced by Protein Kinase Inhibitors in Patients with Cancer

Grela-Wojewoda¹,

Pacholczak-Madej

Adamczyk

et al. 2022

IJMS

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Kinase inhibitors (KIs) represent a growing class of drugs directed at various protein kinases and used in the treatment of both solid tumors and hematologic malignancies. It is a heterogeneous group of compounds that are widely applied not only in different types of tumors but also in tumors that are positive for a specific predictive factor. This review summarizes common cardiotoxic effects of KIs, including hypertension, arrhythmias with bradycardia and QTc prolongation, and cardiomyopathy that can lead to heart failure, as well as less common effects such as fluid retention, ischemic heart disease, and elevated risk of thromboembolic events. The guidelines for cardiac monitoring and management of the most common cardiotoxic effects of protein KIs are discussed. Potential signaling pathways affected by KIs and likely contributing to cardiac damage are also described. Finally, the need for further research into the molecular mechanisms underlying the cardiovascular toxicity of these drugs is indicated.

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Section: Cardiotoxicity Of Protein Kinase Inhibitorsmentioning

confidence: 99%

Cardiotoxicity Induced by Protein Kinase Inhibitors in Patients with Cancer

Grela-Wojewoda¹,

Pacholczak-Madej

Adamczyk

et al. 2022

IJMS

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“…In a 2021 analysis of 3,663,300 case reports of TKIs, ibrutinib was found to have the strongest association with AF increasing the overall risk by 9-fold. 56 AF is believed to be because of off-target effect on C-terminal Src kinase. In the murine model, ibrutinib has been demonstrated to result in atrial fibrosis, atrial remodelling, and an increase in the atrial refractory period.…”

Section: Commonly Implicated Agentsmentioning

confidence: 99%

“…51 Furthermore, several have been linked to AF and a smaller number have been linked to bradyarrhythmias and ventricular arrhythmias. 52…”

Section: Commonly Implicated Agentsmentioning

confidence: 99%

Chemotherapy-Induced Arrhythmias

Essa

Dobson

Lip

2022

Journal of Cardiovascular Pharmacology

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:Cardio-oncology is a subspeciality within cardiology that has developed primarily as a consequence of the cardiovascular implications of cancer and its therapeutics. Arrhythmias are increasingly recognized as an adverse feature of many chemotherapeutic agents. This relationship is poorly defined and studied in the literature compared with other side effects of chemotherapy. In this review, we appraise the published literature on arrhythmogenic consequences of chemotherapeutic agents and summarize the available evidence. Atrial fibrillation (AF) and other supraventricular tachycardias are frequently observed in patients receiving chemotherapy. High rates of AF are seen with certain agents such as tyrosine kinase inhibitors eg, ibrutinib and the mechanism for this is poorly defined but likely related to off-target effects. The management of AF in cardio-oncology is similar to that of the noncancer patient with certain nuances. Mainly that bleeding and stroke risk stratification tools are not validated in the cancer population. In this patient cohort, treatment decisions are usually led by anecdotal evidence rather than an evidence base. This leads to treatment heterogeneity between clinicians. Furthermore, various drug interactions can limit the choice of therapy, particularly with respect to anticoagulant drugs. Many chemotherapeutic agents have been implicated in QT interval (A Measurement calculated from the start of the Q wave to the end of the T wave on the electrocardiogram approximating the time taken for ventricular relaxation.) of these, arsenic trioxide and several tyrosine kinase inhibitors are classic culprits. In patients receiving these agents, it is advisable to perform a baseline electrocardiogram and monitor the QT interval. If the (QT interval corrected for heart rate) increases by 60 milliseconds from baseline or is greater than 500 milliseconds, it is advisable to suspend treatment temporarily. Moving forward, further trials are required in the field of cardio-oncology to better understand the relationship between chemotherapeutic agents and arrhythmia.

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“…Alectinib is approved for first‐line treatment of patients with ALK‐positive advanced or metastatic NSCLC and second‐line treatment for disease progression after crizotinib 5 . As a life‐saving therapy, despite alectinib's benefits, cardiovascular complication is gaining more attention 6–8 . A study based on the pharmacovigilance database revealed the common alectinib‐associated cardiac disorders, including cardiac arrhythmias, heart failures, and pericardial and coronary artery disorders 9 .…”

Section: Introductionmentioning

confidence: 99%

High incidence and reversible bradycardia events following alectinib initiation

et al. 2022

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Background With the widespread use of alectinib in patients with anaplastic lymphoma kinase (ALK)‐positive non‐small‐cell lung cancer (NSCLC), its cardiotoxicity has gradually emerged, including new‐onset sinus bradycardia (SB). However, the incidence, timing, severity, and risk factors of alectinib‐induced bradycardia remain unknown. Methods From January 2020 to June 2022, 93 patients with ALK‐positive NSCLC treated with alectinib were enrolled in this retrospective analysis. These patients had heart rate (HR) recorded before and after alectinib administration. By reviewing electronic medical records and follow‐up, the HR changes of patients during medication were recorded. The potential risk factors associated with alectinib‐induced SB were explored. Results According to an HR cut‐off of 60 beats per minute (bpm), 47 patients (50.54%) experienced at least one recorded bradycardia. The mean HR of total participants before alectinib administration was 78.32 (standard deviation [SD], 9.48) and after was 64.88 (SD, 12.21). The median maximum change in HR (range) for all patients was 11 (−55, +4) bpm. For the bradycardia subgroup, the HR of most patients (76.60%) hovered around 50–60 bpm, and 61.70% of SB occurred within 3 months after alectinib administration. Multivariate analysis indicated that baseline HR (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.79–0.93, p < 0.001) and history of hypertension (OR 13.71, 95% CI 2.49–76.38, p = 0.003) were independent risk factors for alectinib‐related bradycardia. Conclusions Alectinib‐induced bradycardia had a high incidence, appeared relatively early, and was reversible by dose reduction or withdrawal.

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Oncotherapeutic Protein Kinase Inhibitors Associated With Pro-Arrhythmic Liability

Cited by 17 publications

References 20 publications

Cardiotoxicity Induced by Protein Kinase Inhibitors in Patients with Cancer

Cardiotoxicity Induced by Protein Kinase Inhibitors in Patients with Cancer

Chemotherapy-Induced Arrhythmias

High incidence and reversible bradycardia events following alectinib initiation

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