Pub Date: Thursday, Jun 17, 2021
Author: Benjamin Noor, MD; Olujimi A. Ajijola, MD, PhD; Eric H. Yang, MD
Affiliation: Dr. Noor: Department of Medicine, University of California at Los Angeles; Dr. Ajijola: UCLA Arrhythmia Center, Division of Cardiology, Department of Medicine, University of California at Los Angeles, and UCLA Cardio-Oncology Program, Division of Cardiology, Department of Medicine, University of California at Los Angeles; Dr. Yang: UCLA Cardio-Oncology Program, Division of Cardiology, Department of Medicine, University of California at Los Angeles
Cardiotoxicity from cancer-directed treatments has many manifestations within the different components of the cardiovascular system. Some of the more well-known associations are the development of cardiac dysfunction from anthracycline and/or anti-HER2 exposure1, myocarditis from immune-checkpoint inhibitors2, and accelerated coronary artery disease from radiation therapy3. However, a constellation of electrophysiologic and autonomic complications from cancer treatment that warrant further discussion and investigation have been extensively reviewed in Fradley et al’s recent AHA Scientific Statement.4 Many cancer survivors develop QT interval derangements, tachy- and bradyarrhythmias, and autonomic dysfunction as a result of the physiologic changes associated with cancer biology and/or the chemotherapeutics used for treatment. Such manifestations can be long-lasting, contribute to comorbidity and early mortality, and be significantly detrimental to one’s quality of life. Yet, the mechanisms and treatment strategies of electrophysiologic complications of both historical and novel cancer treatments remain poorly understood.
Certain cancer-directed therapies can have electrophysiologic sequelae in addition to their other traditionally associated cardiotoxic properties. For example, while anthracyclines are rarely directly associated with arrhythmias, the development of left ventricular dysfunction caused by these agents can indirectly promote arrhythmogenicity.5 Additionally, hematopoietic stem cell transplant recipients are more likely to develop cardiovascular comorbidities, which predispose them to develop arrhythmias.6 These electrophysiologic complications can add an extra layer of complexity to the management of cancer and significantly affect the patients’ overall quality of life. Moreover, conduction abnormalities and autonomic dysfunction in the context of cancer are associated with an increase in all-cause mortality.7-9 This Scientific Statement provides an extensive review of identifying antineoplastic agents that are associated with electrophysiologic side-effects and describing common clinical scenarios where these adverse effects become particularly relevant to clinical practice. In addition, it provides a roadmap into the scientific wilderness of what work needs to be done in order to understand these mechanisms of toxicity, and to identify vulnerable populations at risk for such sequelae during and after cancer treatments.
Many chemoradiation techniques and novel targeting therapies are thought to cause cardiac conduction abnormalities and autonomic dysfunction either directly through cardiomyocyte toxicity or indirectly through inducing cardiac dysfunction, ischemia, myocarditis, electrolyte abnormalities, and other unknown mechanisms. For example, microtubule inhibitors are thought to cause sinus bradycardia and atrioventricular block through histamine receptor stimulation and ischemia.10 It can be exceptionally challenging to establish causality and uncover the exact pathophysiologic mechanisms behind these electrophysiologic complications given patients are on multiple agents, and sometimes may go through many lines of treatment prior to the onset of these manifestations. One reason is that the physiologic changes, inflammatory milieu, and risk factors of cancer share many features with preexisting cardiovascular diseases that predispose individuals to develop cardiac conduction disorders. Moreover, cancer-directed treatments are usually composed of multidrug regimens, which can make it difficult to identify a single culprit.
This statement also highlights one of the most challenging aspects of cardio-oncology, which is the extrapolation of evidence-based medicine to this unique patient population. For example, while cardiac-resynchronization therapy (CRT) has been studied specifically in chemotherapy-induced cardiomyopathy with the MADIT-CHIC trial, it was a small study with 30 patients, which reflects upon the difficult nature of patient recruitment in this population.12-13 Another topic of discussion warranting investigation is whether implantable cardioverter defibrillator implantation (ICD) has similar benefits to patients with cancer treatment associated cardiomyopathy compared to the general population, as many patients with cardiac dysfunction do not qualify for CRT therapy by ECG criteria.
In patients with atrial fibrillation, the CHA2DS2Vasc and HAS-BLED scores help prognosticate the risk of thromboembolic stroke and major bleeding, respectively. However, these tools do not take into account the hypercoagulable state of cancer and risk of bleeding from conditions such as brain metastases and thrombocytopenia. An additional challenge is balancing the drug-drug interactions of particular cancer treatments, especially the Bruton tyrosine kinase inhibitor ibrutinib, a drug with increasing use in chronic lymphocytic leukemia, mantle cell lymphoma and graft-versus-host disease. Aspirin, warfarin, and virtually all the direct oral anticoagulants may or will increase one’s risk of bleeding, which complicates one’s management when atrial fibrillation--also a known cardiotoxic property of ibrutinib--occurs. However, many historical and novel treatment regimens--particularly with the advent of chimeric antigen receptor T cell treatment--can cause cytokine release syndrome and other acute hemodynamic changes. This can lead to atrial arrhythmias and hemodynamic instability,14 which can make the use of medications such as beta-blockers or calcium channel blockers less favorable. Therefore, there may be a role for a prophylactic rhythm control strategy for patients at high-risk of developing atrial fibrillation on anti-arrhythmics prior to known triggers of atrial fibrillation. It is possible that many of the standard-of-care treatments for cardiovascular disease may be less efficacious when studied specifically in patients with cancer, similar to the evidence of statins and ICDs for primary prevention in patients with advanced chronic kidney disease.15-16 These factors should be considered when designing future cardio-oncology clinical trials evaluating the efficacy of arrhythmia management, as well as anticoagulation strategies.
The combination of cancer and cardiac conduction disorders often creates clinical challenges that require careful decision-making and trade-offs to optimally manage and balance the patients’ medical conditions. For example, medications such as tyrosine kinase inhibitors, BRAF inhibitors, and arsenic trioxide can cause QT prolongation which may limit their use.17-18 Patients with cancer can develop thrombocytopenia due to direct cancer invasion of the bone marrow or spleen, chemoradiation, microangiopathic disorders, or immune disorders--all which are pathophysiologically distinct entities that cannot all be quantified in a “one risk fits all” model.19 This can limit the use of anticoagulation in patients who also have or develop prothrombotic conditions such as atrial fibrillation. There can be drug-drug interactions between cardioactive medications and chemotherapy agents. For example, as previously alluded to, medications such as non-dihydropyridine calcium channel blockers, digoxin, amiodarone, and dabigatran have drug-drug interactions with ibrutinib, which can affect the metabolism of these drugs.20 When prescribing new cardiovascular medications in the setting of some of these novel treatments, prescribers should be cognizant of these interactions and any absolute or relative contraindications. In addition, should initial cancer treatments fail to be effective, future treatment strategies should be discussed in a multidisciplinary fashion in order to provide a personalized strategy of pharmacologic treatments to avoid both frequent medication changes, and potential drug-drug interactions. Identifying, and investigating solutions to these challenges will allow us to both find solutions or engage in shared decision-making with the patient to optimize their medical care.
Finally, one of the known, but poorly understood complications faced by cancer survivors is cardiovascular autonomic dysfunction. These manifestations can contribute to long term disability, decreased quality of life, and increased comorbidity and mortality. In a single-center case series, cardiovascular autonomic dysfunction in cancer survivors was seen in patients predominantly with hematologic disorders and who received vinca alkaloids, alkylating agents, and anthracyclines.21 Theoretical mechanisms of this dysautonomia can arise from alterations of the autonomic nerve fibers through chemotherapy-mediated damage, paraneoplastic syndromes, extrinsic compression or invasion by the tumors, radiation-induced fibrosis, and/or deconditioning.22 Due to imbalance between the sympathetic and parasympathetic arms of the autonomic system, patients can develop symptoms such as dizziness, palpitations, and syncope.23 Autonomic dysfunction may also manifest with symptoms from clinical entities such as postural orthostatic tachycardia syndrome, inappropriate sinus tachycardia, and orthostatic hypotension. Not only can the symptoms of cardiovascular autonomic dysfunction be particularly debilitating to the patient, but it is also associated with an increase in all-cause mortality.24 Clinicians caring for the cardio-oncology population should have a high index of suspicion in order to diagnose and appropriately treat this condition. Furthermore, investigative efforts should be directed specifically towards autonomic dysfunction in cancer survivors as this entity may respond differently to treatment when compared to other more traditional forms of autonomic dysfunction arising from neurogenerative and metabolic conditions.
As the prevalence of patients with cancer and the treatments available to them continue to grow, there will likely be more electrophysiologic issues that arise in this population. It is imperative that all members of the treatment team including oncologists, cardio-oncologists, electrophysiologists, pharmacists, and primary care doctors collaborate and maintain active and frequent avenues of communication. In particular, all those involved should be notified about anticipated changes to the patient’s medication list, potential drug-drug interactions, and upcoming treatment plans. For example, if an oncologist plans to start a new chemotherapy drug that causes gastrointestinal side-effects, the cardiovascular team may closely monitor the patient’s electrolytes to minimize the risk of developing arrhythmias. Additionally, if a medication with known QT prolongation is being started, prior medications may be adjusted to minimize the risk of any significant and/or potentially lethal arrhythmias. Thus, multidisciplinary communication and management of electrophysiologic complications associated with cancer will continue to be more and more crucial to patient care.
We are only beginning to identify and understand the electrophysiologic and autonomic issues that arise with cancer treatment. This subdomain within cardio-oncology has many avenues for growth that will ultimately impact clinical care. For example, standardizing protocols for monitoring QT interval during titration or administration of chemotherapy agents may help avoid ambiguity and adverse events.25 There may be a role for preemptive placement of left atrial appendage closure devices in patients with atrial fibrillation who are expected to develop contraindications to anticoagulation, such as thrombocytopenia which may be long lasting.26 Furthermore, patients may benefit from planned adjustments to cardiac medications in the peri-chemotherapy period, such as temporarily switching from a rate to rhythm control strategy in a treatment regimen known to cause atrial fibrillation. However, management of these complex clinical scenarios to many remain at the anecdotal level and require rigorous study. This AHA statement discusses the complex nuances that arise with arrhythmia management in the cardio-oncology patients; yet, these challenges provide opportunities to investigate whether individualized, or protocol-based management that consider the specificities of each patient, cancer, and chemotherapy regimen will ultimately be better. Ultimately, the proper management of these issues will require wide scale, randomized trials that specifically enroll patients in this population.
This AHA statement offers an essential and much needed guide into the thicket of electrophysiologic and autonomic issues faced during and after cancer treatments. Much like how arrhythmias and dysautonomias can appear perilous, chaotic, and vast with overwhelming and hostile findings--much like an uncharted wilderness--it is just as critical for us to start systematically observing, analyzing, and treating these disease states. As the number of patients living with cancer and the oncologic treatments available to them continue to expand at an exceptional rate, practitioners from all avenues of medicine will surely face many of these issues. It is imperative that multidisciplinary teams involved in cancer care at least familiarize themselves with the topics addressed in this document. Our ability to navigate these obstacles will require an anticipation of these complexities, proactive and preventative strategies, and a multi-institutional collaborative effort in the form of registries and clinical trials.
While this statement proposes future directions for research within cardio-oncology, there remains much to uncover regarding the optimal management of these issues from both a basic science and clinical perspective. Ultimately, the goal of these endeavors will be to optimize the treatments we provide, minimize the harms associated with them, and most importantly, improve the lives of patients faced with cancer. While elucidating these mechanisms may be difficult, it is necessary to pursue as it may reveal insights into the pathogenesis of arrhythmias and conduction disease that are so commonly seen in general cardiovascular practice. Furthering our understanding of these electrophysiologic and autonomic complications surrounding cancer management and survivorship will allow us to identify the patients and conditions that are highest in risk and shift cardio-oncology towards a preventative, rather than reactive science. This hopefully can be another territory of the cardio-oncology wilderness that we can finally begin charting--and clearing.
Fradley MG, Beckie TM, Brown SA, Cheng RK, Dent SF, Nohria A, Patton KK, Singh JP, Olshansky B; on behalf of the American Heart Association Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular and Stroke Nursing. Recognition, prevention, and management of arrhythmias and autonomic disorders in cardio-oncology: a scientific statement from the American Heart Association [published online ahead of print June 17, 2021]. Circulation. doi: 10.1161/CIR.0000000000000986
- Keefe DL. Anthracycline-induced cardiomyopathy. Proc. Seminars in oncology, 2001, 28:2-7: Elsevier
- Mahmood SS, Fradley MG, Cohen JV, Nohria A, Reynolds KL, et al. 2018. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 71:1755-64
- Heidenreich PA, Kapoor JR. 2009. Radiation induced heart disease. Heart 95:252-8
- Fradley MG, Beckie TM, Brown SA, Cheng RK, Dent SF, Nohria A, Patton KK, Singh JP, Olshansky B; on behalf of the American Heart Association Council on Clinical Cardiology; Council on Arteriosclerosis, Thrombosis and Vascular Biology; and Council on Cardiovascular and Stroke Nursing. Recognition, prevention, and management of arrhythmias and autonomic disorders in cardio-oncology: a scientific statement from the American Heart Association [published online ahead of print June 17, 2021]. Circulation. doi: 10.1161/CIR.0000000000000986
- Mazur M, Wang F, Hodge DO, Siontis BL, Beinborn DS, et al. 2017. Burden of Cardiac Arrhythmias in Patients With Anthracycline-Related Cardiomyopathy. JACC: Clinical Electrophysiology 3:139-50
- Armenian SH, Xu L, Ky B, Sun C, Farol LT, et al. 2016. Cardiovascular Disease Among Survivors of Adult-Onset Cancer: A Community-Based Retrospective Cohort Study. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 34:1122-30
- Escudier M, Cautela J, Malissen N, Ancedy Y, Orabona M, et al. 2017. Clinical features, management, and outcomes of immune checkpoint inhibitor–related cardiotoxicity. Circulation 136:2085-7
- Tonorezos ES, Stillwell EE, Calloway JJ, Glew T, Wessler JD, et al. 2015. Arrhythmias in the setting of hematopoietic cell transplants. Bone marrow transplantation 50:1212-6
- Salem J-E, Manouchehri A, Bretagne M, Lebrun-Vignes B, Groarke JD, et al. 2019. Cardiovascular toxicities associated with ibrutinib. J Am Coll Cardiol 74:1667-78
- Markman TM, Nazarian S. 2016. Arrhythmia and electrophysiological effects of chemotherapy: a review. Oncology 91:61-8
- Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, et al. 2005. Amiodarone or an implantable cardioverter-defibrillator for congestive heart failure. N Engl J Med 352:225-37
- Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, et al. 2009. Cardiac-resynchronization therapy for the prevention of heart-failure events. N Engl J Med 361:1329-38
- Singh JP, Solomon SD, Fradley MG, Barac A, Kremer KA, et al. 2019. Association of Cardiac Resynchronization Therapy With Change in Left Ventricular Ejection Fraction in Patients With Chemotherapy-Induced Cardiomyopathy. Jama 322:1799-805
- Ganatra S, Carver JR, Hayek SS, Ky B, Leja MJ, et al. 2019. Chimeric antigen receptor T-cell therapy for cancer and heart: JACC Council Perspectives. J Am Coll Cardiol 74:3153-63
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- Ganatra S, Sharma A, Shah S, Chaudhry GM, Martin DT, et al. 2018. Ibrutinib-associated atrial fibrillation. JACC: Clinical Electrophysiology 4:1491-500
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