Cardiovascular Toxicity of Oral Antineoplastic Agents

Rao VU, Reeves DJ, Chugh AR, et al.
Clinical Approach to Cardiovascular Toxicity of Oral Antineoplastic Agents: JACC State-of-the-Art Review. J Am Coll Cardiol 2021;77:2693-2716.

This state-of-the-art review by Rao and colleagues synthesizes recommendations regarding the cardiovascular (CV) monitoring and management of patients undergoing treatment with oral antineoplastic agents based on Food and Drug Administration (FDA) drug labeling, protocols of the phase III clinical trials, and expert opinion. The manuscript notably includes valuable tables delineating the various oral antineoplastic agents, their associated CV toxicities, and the specific FDA guidelines for monitoring. Here are 10 key points to remember:

  1. The initial evaluation of a patient receiving an oral antineoplastic agent with the potential for CV toxicity should include a complete assessment of baseline CV risk factors.
  2. Optimization of CV risk factors is imperative at all stages of cancer treatment to decrease the risk of CV events.
  3. Patients on BCR-ABL inhibitors (nilotinib and ponatinib), as well as hormonal therapies (anastrozole, apalutamide, darolutamide, and enzalutamide) have an accelerated risk of atherosclerosis, and should be considered for aspirin and statin therapy depending on baseline factors including a lipid panel and CV imaging.
  4. For oral agents with a lower incidence of left ventricular (LV) dysfunction (<10%), a baseline LV ejection fraction (LVEF) is required. Repeat assessment should occur if the patient develops signs or symptoms of heart failure.
  5. For high-risk LV dysfunction (>10%) (e.g., BRAF inhibitors in combination with MEK inhibitors), serial LVEF assessment every 3 months throughout duration of therapy is recommended.
  6. Recognition of a decreased LVEF, even asymptomatic, is important because treatment with beta-blockers, angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers has been shown to improve cardiac function and prevent progression to heart failure.
  7. Ibrutinib has been linked to both atrial and ventricular arrhythmias. Non-dihydropyridine calcium channel blockers, digoxin, and warfarin should be avoided, given interactions with cytochrome P450 (CYP3A4), which can lead to increased concentrations of ibrutinib. Direct oral anticoagulants appear to be safe.
  8. Bradycardia is commonly associated with the anaplastic lymphoma kinase (ALK) inhibitors, crizotinib and ceritinib, which are used to treat non–small cell lung cancer, and is generally well tolerated.
  9. Nilotinib, vandetanib, and ribociclib are notable for their QT-prolonging effects. QT prolongation in this setting has not been shown to be associated with an increased risk of ventricular arrhythmias. Nonetheless, a baseline electrocardiogram (ECG), ECG at 14 days, and repeat ECG are recommended and clinically indicated in those at risk.
  10. Vascular signaling pathway (VSP) inhibitors, including vascular endothelial growth factor inhibitors, have been associated with the development or worsening of hypertension (30%-80%), which is not necessarily dose-related. The optimal agent for treatment of VSP-induced hypertension is ill-defined.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardio-Oncology, Congenital Heart Disease and Pediatric Cardiology, Dyslipidemia, Heart Failure and Cardiomyopathies, Noninvasive Imaging, Prevention, Implantable Devices, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Imaging, CHD and Pediatrics and Prevention, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Acute Heart Failure, Hypertension

Keywords: Angiotensin Receptor Antagonists, Angiotensin-Converting Enzyme Inhibitors, Anticoagulants, Antineoplastic Agents, Arrhythmias, Cardiac, Aspirin, Atherosclerosis, Bradycardia, Carcinoma, Non-Small-Cell Lung, Cardiotoxicity, Diagnostic Imaging, Drug Labeling, Electrocardiography, Heart Failure, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypertension, Lipids, Long QT Syndrome, Lung Neoplasms, Lymphoma, Large-Cell, Anaplastic, Mitogen-Activated Protein Kinase Kinases, Secondary Prevention, Stroke Volume, Vascular Endothelial Growth Factor A, Ventricular Dysfunction, Left

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