CardioNerds (Dr. Daniel Ambinder, Dr. Giselle Suero Abreu, Dr. Kahtan Fadah, and Dr. Colin Blumenthal) discuss arrhythmias in CardioOncology with Dr. Michael Fradley.

In this episode, Dr. Michael Fradley joins us in the CardioNerds CardioOncology clinic where he uses his unique dual training in cardio-oncology and electrophysiology to walk us through the complex interplay and management of these disorders. We discuss the incidence and pathophysiology of these arrhythmias, including the link with various cancer treatments, screening and detection, and complex management including rate vs rhythm control in atrial fibrillation, need for anticoagulation, effects on the QTc and so much more. Given the unique challenges with this population we also delve into how this affects their oncology care and how to approach changes to their cancer treatment.

Show notes were drafted by Dr. Kahtan Fadah and episode audio was edited by student Dr. Tina Reddy.

This episode is supported by a grant from Pfizer Inc.

This CardioNerds Cardio-Oncology series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Giselle Suero Abreu, Dr. Dinu Balanescu, and Dr. Teodora Donisan. 

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1. Arrhythmias are common in cancer patients due to shared risk factors and bi-directional risk between cardiac and oncologic disorders. Many cancer therapeutics can be directly arrhythmogenic or lead to cardiotoxicities that pre-dispose to arrhythmias.
   
2. Though incidence of arrhythmia can be significant increased with some cancer therapeutics (e.g. ibrutinib), there is not specific data to support proactive ambulatory monitoring for arrhythmia without evidence of clear symptoms.
   
3. Atrial fibrillation is the most common arrhythmia in cancer patients and management of atrial fibrillation, as well as other tachyarrhythmias, is unchanged from management in non-cancer patients. General principles of when to start anticoagulation or rate vs rhythm control are not significantly different (e.g. still use CHA₂DS₂-VAsC, monitor for symptoms etc), but providers should be more mindful of drug-drug interactions with cancer therapeutics.
   
4. Cancer therapeutics as well as common medications used to treat side effects or complications (e.g. antiemetics, antibiotics, etc) can prolong the QT interval and increase risk of Torsades de pointes (TdP). The QTc should be monitored with an ECG for patients on these medications. If a patient does develop a serious arrhythmia like TdP, management is similar to that in non-cancer patients.
   
5. The goal of arrhythmia management in cardio-oncology is to prevent cardiovascular disease from becoming a barrier to appropriate cancer therapy. Though cancer therapeutics should be temporarily or permanently discontinued in potentially fatal events (e.g TdP from QTc prolonging meds), the overall goal is to manage the arrhythmias appropriately to allow cancer therapeutics to be continued or restarted.
   

What is the prevalence of arrhythmias in patients with cancer?

Arrhythmias are common in patients with cancer due to a multitude of factors. Atrial fibrillation is the most common arrhythmia in this population and occurs in approximately 5% of patients with cancer. The driving forces are multifactorial and include the direct arrhythmogenic effects of cancer therapeutics and cardiotoxicities of cancer therapeutics that make arrhythmogenesis more likely. Additionally, there is a bi-directional link between cancer and cardiac disorders. For example, not only is atrial fibrillation more common in patients with cancer, but there is also a higher incidence of cancer in patients with atrial fibrillation, likely due to shared risk factors. Risk factors in patients with cancer that make arrhythmias more likely include advanced age, metabolic disturbances, electrolyte abnormalities, and elevated levels of inflammation and catecholamines.

(How) Do cancer therapeutics increase the risk of arrhythmias?

Many cancer therapies are either directly or indirectly arrhythmogenic. Though therapies like the BTK inhibitor ibrutinib have a direct link to an increase incidence of atrial fibrillation, other medications like immune checkpoint inhibitors can cause myocarditis, reduce cardiac function, and predispose to arrhythmias. The following table includes broad categories of cancer therapeutics that are linked to arrhythmia:

What is the appropriate arrhythmia monitoring strategy for patients receiving cancer therapy?

Though there is a clear increased risk of arrhythmia in many patients with cancer receiving specific therapeutics, there is not specific data to support proactive monitoring in these patients. One meta-analysis showed that when compared to alternative regimens, ibrutinib increased the risk of incident AF compared to alternative therapies (RR 3.9, 95% CI 2.0-7.5, P <0.0001), with overall AF incidence of 3.3 per 100 person-years compared to 0.84 per 100 person-years in the ibrutinib and non-ibrutinib groups, respectively. Though proactive monitoring might lead to more or earlier detection of AF in this population, there is a lack of data to support improved outcomes with monitoring asymptomatic patients. Additionally, the clinical relevance of subclinical and/or short episodes of atrial fibrillation remains uncertain. Because of this, there are no current recommendations for broad proactive monitoring, though monitoring should be considered in patients with signs or symptoms that could be consistent with arrhythmia.

What is the management of arrhythmias in patients with cancer?

Management of arrhythmias in patients with cancer is similar to general management in non-cancer patients. For AF, a rhythm control strategy is preferred for patients with paroxysmal AF and in patients who are symptomatic. For other patients who are asymptomatic, a rate control strategy is reasonable. One notable exception is when control of the AF becomes a barrier to the oncology team. In these situations, more aggressive rhythm control is preferred to facility oncologic care. Anticoagulation is also approached in a similar way to non-cancer patients. Patients with a CHA₂DS₂-VAsC score >2 for men and >3 for women warrant anticoagulation. Many patients with cancer are anemic, thrombocytopenic, or prone to bleeding, which should also be taken into account when prescribing anticoagulation. Left atrial appendage closure may be a consideration for select patients.

As for medications that cause QT prolongation, malignant arrhythmias are quite rare and mostly occur in patients with QTc > 500 ms. This can be multifactorial as many patients with cancer may have episodic metabolic or electrolyte abnormalities in addition to cancer therapeutics or symptom/complication management medications (e.g. antiemetics, antibiotics, etc) which can prolong the QTc or lower the threshold for arrhythmogenesis. Life threatening arrhythmias like Torsades de pointes (TdP) are treated similar to that in non-cancer patients, which can include magnesium, increasing HR with isoproterenol or transvenous pacing, anti-arrhythmic drugs, or cardioversion in addition to addressing the underlying cause.

Balancing arrhythmia risk with cancer therapeutics

An important goal in cardio-oncology is to prevent cardiovascular disease from becoming a barrier for a patient to receive appropriate cancer therapy. The goal is to facilitate the treatment plan that the oncologist thinks is optimal for their cancer, not to protect the heart at the expense of appropriate oncologic care. This is a difficult balancing act and, in the case of serious or potentially fatal events (e.g. Torsades from QTc prolonging meds, vasospasm with ischemia from 5FU, severe myocarditis from immune checkpoint inhibitors etc.), it is often necessary to discontinue the cancer therapeutic temporarily or permanently. Ideally, the arrhythmia should be treated and controlled allowing the patient to continue therapy while minimizing the cardiac symptoms and side effects.

1. Leiva O, AbdelHameid D, Connors JM, Cannon CP, Bhatt DL. Common Pathophysiology in Cancer, Atrial Fibrillation, Atherosclerosis, and Thrombosis: JACC: CardioOncology State-of-the-Art Review. JACC CardioOncol. 2021;3(5):619-634. doi:10.1016/j.jaccao.2021.08.011
   
2. Fradley MG, Beckie TM, Brown SA, et al. Recognition, Prevention, and Management of Arrhythmias and Autonomic Disorders in Cardio-Oncology: A Scientific Statement From the American Heart Association. Circulation. 2021;144(3):e41-e55. doi:10.1161/CIR.0000000000000986
   
3. Leong DP, Caron F, Hillis C, et al. The risk of atrial fibrillation with ibrutinib use: a systematic review and meta-analysis. Blood. 2016;128(1):138-140. doi:10.1182/blood-2016-05-712828
   

International Cardio-Oncology Society ( IC-OS). IC-OS exits to advance cardiovascular care of cancer patients and survivors by promoting collaboration among researchers, educators and clinicians around the world. Learn more at https://ic-os.org/.