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Arrhythmia prevention and device management: Before cancer therapy
KEY POINTS
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All patients with cancer should be evaluated for the presence and risk of developing arrhythmias because these can significantly complicate treatments and outcomes
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The intake should include preexisting atrial fibrillation, QTc prolongation, and cardiac device status
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In patients with cancer who have atrial fibrillation, rhythm control strategies to maintain sinus rhythm can be challenging and drug-drug interactions must be anticipated even when a rate-controlling approach is used (beta-blocker often first-line therapy)
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Anticoagulation decisions in patients with cancer who have atrial fibrillation must be considered in the context of planned cancer therapeutics, comorbid conditions, including cytopenias, and drug-drug interactions
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It is essential to minimize the potential for QT prolongation and risk of torsades prior to the initiation of cancer therapy; this includes monitoring of electrolyte abnormalities and drug interactions
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Cardiac implantable device status should be assessed in all cancer cases and managed proactively in patients undergoing chest surgery with (electro-) cauterization or chest radiation therapy
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Whereas cardiac device malfunction is rare and repositioning prior to cancer therapy is rarely necessary, routine device interrogation before and after is recommended
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Cardiac device reprogramming into a “safe mode” should be considered in those patients who are expected to be at higher risk of developing device malfunction (i.e., mainly those who receive a higher absorbed dose of radiation and higher energy photons)
With the aging population, a significant number of patients with newly diagnosed cancer will also have coexisting cardiovascular (CV) diseases. Additionally, many different cancer therapeutics from traditional cytotoxic chemotherapies to the newer targeted and immunotherapies can themselves be cardiotoxic. As such, optimizing patients from a CV standpoint prior to the initiation of cancer treatment can help to prevent serious complications or treatment disruption. Although preventative strategies have often focused on heart failure and left ventricular dysfunction, patients with underlying arrhythmias may also benefit from aggressive pretreatment evaluation and management. The broad scope of arrhythmias that have been reported with cancer therapeutics is outlined in Table 10.1 .
TABLE 10.1
Types of Arrhythmia Reported With the Use of Cancer Therapeutics
| THERAPY CLASS | AGENT NAME (TARGET) | AF | SVT | BRADYCARDIA | AV BLOCK | QTch | TdP | VT/VF | SCD |
|---|---|---|---|---|---|---|---|---|---|
| Miscellaneous | Arsenic trioxide | ++ | ++ | – | + | +++ | ++ | – | + |
| Alkylating agents | Anthracyclines (acute) | x | – | x | x | x | – | x | |
| Busulfan | x | x | – | x | – | – | – | x | |
| Cyclophosphamide | x | – | – | x | x | – | x | – | |
| Ifosfamide | x | – | x | – | – | – | x | x | |
| Melphalan | x | x | – | – | – | – | x | ||
| Antimetabolites | 5-Fluorouracil | x | x | x | x | – | x | x | |
| Capecitabine | ++ | – | ++ | – | + | – | – | + | |
| Clofarabine | x | x | x | – | – | – | – | – | |
| Cytarabine | x | x | – | – | – | – | – | ||
| Gemcitabine | + | + | – | – | – | – | – | – | |
| Microtubule-binding agents | Paclitaxel | + | + | ++ | + | – | – | + | – |
| Platinum drugs | Cisplatin | + | + | + | + | – | – | + | – |
| Immunomodulatory drugs | Thalidomide | + | + | – | – | – | – | – | |
| Lenalidomide | x | x | x | – | – | – | – | – | |
| Proteasome inhibitors | Bortezomib | x | – | x | x | x | x | x | x |
| Carfilzomib | x | x | x | x | – | – | – | x | |
| HDAC inhibitors | Romidepsin | + | ++ | – | – | ++ | + | ++ | + |
| Vorinostat | – | – | – | – | ++ | – | – | – | |
| Panobinostat | – | – | – | – | ++ | – | – | – | |
| CDK4/CDK6 inhibitors | Ribociclib | – | – | – | – | ++ | – | – | – |
| mTOR inhibitors | Everolimus | ++ | – | – | – | – | – | – | – |
| Monoclonal antibodies | Alemtuzumab (anti-CD52) | ++ | – | ++ | – | – | – | + | + |
| Cetuximab (anti-EGFR/HER1) | + | + | – | – | – | + | + | ||
| Necitumumab (anti-EGFR/HER1) | – | + | – | – | – | – | – | ++ | |
| Pertuzumab (anti-EGFR/HER1) | + | + | + | – | – | – | + | + | |
| Rituximab (anti-CD20) | + | + | + | + | + | + | + | + | |
| Trastuzumab (anti-HER2/ERBB2) | ++ | ++ | + | – | – | – | + | – | |
| Multi-targeted kinase Inhibitors | Lenvatinib (VEGFR) | – | – | – | – | ++ | – | – | – |
| Sunitinib (VEGFR) | – | – | + | – | + | + | – | – | |
| Sorafenib (VEGFR) | + | – | + | + | + | + | – | – | |
| Pazopanib (VEGFR) | – | – | +++ | – | ++ | – | – | – | |
| Vandetanib (VEGFR) | – | – | – | – | +++ | – | + | + | |
| Lapatinib (HER2/ERBB2) | + | + | – | – | + | – | – | – | |
| Bosutinib (BCR–ABL1) | – | – | + | – | ++ | – | – | – | |
| Dasatinib (BCR–ABL1) | + | + | – | – | + | – | + | + | |
| Imatinib (BCR–ABL1) | + | + | – | – | – | – | – | – | |
| Nilotinib (BCR–ABL1) | ++ | ++ | ++ | ++ | – | – | + | ||
| Ponatinib (BCR–ABL1) | ++ | + | + | + | + | – | + | ||
| Ibrutinib (BTK) | +++ | – | – | – | – | – | + | + | |
| Alectinib (ALK) | – | – | +++ | – | + | – | – | – | |
| Ceritinib (ALK) | – | – | + | – | ++ | – | – | – | |
| Crizotinib (ALK) | – | – | +++ | – | + | – | – | – | |
| Brigatinib (ALK) | – | – | ++ | – | – | – | – | – | |
| Lorlatinib (ALK) | – | – | – | + | – | – | – | – | |
| Osimertinib (EGFR/HER1) | – | – | – | – | ++ | – | – | – | |
| Encorafenib (BRAF) | – | – | – | – | + | – | – | – | |
| Vemurafenib (BRAF) | ++ | + | – | +++ | + | – | – | ||
| Gilteritinib (FTL3) | – | – | – | – | ++ | – | – | – | |
| Trametinib (MEK) | – | – | ++ | – | ++ | – | – | – | |
| Ruxolitinib (JAK) | – | – | + | – | + | – | – | – | |
| Immune checkpoint inhibitors | Ipilimumab (anti-CTLA4) | + | – | + | + | – | – | + | + |
| Nivolumab (anti-PD1) | + | – | + | + | – | – | + | + | |
| Pembrolizumab (anti-PD1) | + | – | + | + | – | – | + | + |
Frequency not always defined for the individual entities, but when available: +, uncommon (<1%); ++, common (1% to 10%); +++, very common (>10%); x, frequency not defined.
AF , Atrial fibrillation; CTLA4 , cytotoxic T lymphocyte antigen 4; HDAC , histone deacetylase; JAK , Janus kinase; mTOR, mechanistic target of rapamycin; NA , not applicable; PD1 , programmed cell death protein 1; SCD , sudden cardiac death; SVT , supraventricular tachycardia; TdP, torsades de pointes, VEGF , vascular endothelial growth factor; VEGFR , vascular endothelial growth factor receptor; VF , ventricular fibrillation; VT , ventricular tachycardia.
Atrial fibrillation and other atrial arrhythmias
Atrial fibrillation (AF) is an especially common arrhythmia in older individuals. In fact, the lifetime risk of developing AF after age 40 for individuals of European descent is 26% for men and 23% for women. In addition to age, risk factors for developing AF include hypertension, obesity, obstructive sleep apnea, thyroid disease, alcohol use, and underlying cardiovascular disease. In addition, patients with cancer are at increased risk for developing AF, and some cancer therapeutics are particularly arrhythmogenic. These scenarios are well illustrated in patients with chronic lymphocytic leukemia (CLL), who are at a two-fold higher risk of AF, further increased at least three-fold in patients on ibrutinib ( Fig. 10.1 ). , AF risk prediction models were developed for patients with CLL and remain applicable for patients on ibrutinib (see Fig. 10.1 ). Given that many patients with newly diagnosed cancer will have preexisting AF, it is especially important to optimize their treatment prior to the initiation of therapy in order to minimize potential complications. Both, preexisting and newly developing AF are prognostic implications for thromboembolism, heart failure (esp., newly developing) and mortality (esp., preexisting AF; Fig. 10.2 ).
Management of AF in patients with newly diagnosed cancer should follow the same algorithms as the general population ( Fig. 10.3 ). For asymptomatic individuals, a rate control strategy is most appropriate, with a goal resting heart rate of less than 110 beats per minute (bpm). In general, patients with cancer are more likely to develop tachycardia as a manifestation of autonomic dysfunction. Conversely, it is also important to recognize that some cancer therapeutics may lead to heart rate slowing—particularly crizotinib, an anaplastic lymphoma kinase inhibitor used for non-small-cell lung cancer, as well as taxanes, a class of chemotherapies with broad applicability. Additionally, certain cancer therapeutics may affect the metabolism of nodal blocking agents. For example, non-dihydropyridine calcium channel blockers should be avoided with treatments that affect the cytochrome P450 system, including vascular endothelial growth factor (VEGF) inhibitors and the antiandrogen, abiraterone, can increase levels of certain beta blockers. As such, cardio-oncologists should be prepared to adjust pharmacologic therapy if necessary.
In symptomatic patients a rhythm control strategy may be necessary; however, patients with cancer pose unique management challenges. Although cardioversion can lead to a rapid resolution of an atrial arrhythmia, it often fails to have long-term durability, particularly if the primary stressor is still present, as is the case in patients with active cancer undergoing treatment. Antiarrhythmic medications must be used with caution in patients with cancer, given frequent drug-drug interactions, which can lead to serious issues, including QT prolongation and ventricular arrhythmias. As such they often require dose adjustment or cessation. Catheter ablation may be an option for more durable rhythm control for select patients. Success rates for AF ablation ranges from 60% to 80% in the general population. It should be noted that patients must be able to tolerate anticoagulation for a minimum of 3 months after ablation regardless of CHA 2 DS 2 -VASc score (see Fig. 31.1 ). Therefore, patients who are expected to develop a contraindication to anticoagulation in the first three months after an ablation should not be referred for this procedure. Moreover, it should be noted that catheter ablation is not considered protective against stroke and decision for long-term anticoagulation should be determined based on the patient’s CHA 2 DS 2 -VASc score. Finally, catheter ablation has not been specifically studied in patients with cancer. The success of ablation in patients with active cancer or in those receiving arrhythmogenic cancer therapies is not established.
Both AF and atrial flutter are known to increase the risk of stroke and systemic thromboembolism. Anticoagulation is the mainstay of therapy to minimize this risk. In the general population, the CHA 2 DS 2 -VASc score is a validated system to help guide anticoagulation decisions. Recent guidelines suggest utilization of direct oral anticoagulants (DOACs) in men with a CHA 2 DS 2 -VASc of 2 or greater or in women with a CHA 2 DS 2 -VASc of 3 or greater to reduce the risk of thromboembolism in the absence of significant contraindications. It is not clear, however, if the CHA 2 DS 2 -VASc score is truly predictive of adverse events in patients with cancer based on data from several large studies. , Furthermore, it is advisable to weigh the benefits of anticoagulation against the risk of bleeding. This is commonly done by utilizing the HAS-BLED (Hypertension, Abnormal renal and liver function, Stroke, Bleeding, Labile INR, Elderly, Drugs or alcohol) score (see Chapter 31 , Fig. 31.1 ), but this score model is also not validated in patients with cancer. Recommendations on anticoagulation in patients with cancer with atrial fibrillation thus remain conceptual (see Fig. 31.2 ).
Although DOACs are preferred in most scenarios in patients without cancer, the choice of anticoagulant in patients with cancer remains challenging (see Fig. 31.3). Warfarin is often avoided owing to drug-drug interactions and difficulties maintaining a therapeutic window; however, it may be necessary if patients also possess mechanical prosthetic valves. Low-molecular-weight heparin (LMWH) has traditionally been the anticoagulant of choice for patients with cancer who have venous thromboembolism (VTE), given the results from the CLOT (Randomized Comparison of Low-Molecular-Weight Heparin Versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients With Cancer) trial ; however, the mechanism of thrombus formation in AF is different and the superiority of LMWH for this disease process is not established. This being said, LMWH may be preferred when drug-drug interactions and cytopenias are of concern and/or unpredictable. Recently several studies have demonstrated the efficacy and safety of DOACs in the treatment of cancer-associated VTE , ; however, dedicated studies evaluating DOACs to prevent atrial thrombus formation in patients with AF and cancer is lacking because patients with cancer have generally been excluded or underrepresented in the seminal DOAC trials. Nevertheless, a subanalysis of the ARISTOTLE (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation) trial demonstrated greater protection from thromboembolism with apixaban than warfarin in patients with active cancer when compared with patients without cancer. Similar findings were reported in a sub study of the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48) trial with edoxaban. A retrospective analysis of more than 16,000 patients with cancer suggested similar reduction in ischemic stroke with the different DOACs, and lower rates of bleeding with apixaban.
Multiple issues ranging from limited life expectancy to increased bleeding from hematologic abnormalities or intracerebral metastases may prevent long-term anticoagulant use in patients receiving cancer therapy. Furthermore, the benefits of thromboembolism reduction must be balanced with the potential for bleeding complications. For example, ibrutinib is associated with increased bleeding owing to the effects on the glycogen VI collagen activation pathway. Studies have demonstrated increased rates of intracerebral bleeds with the concomitant use of ibrutinib and vitamin K antagonists. As a result warfarin is generally avoided with this drug, although DOACs appear to be relatively safe. Moreover, multiple cancer therapeutics can interact with anticoagulants, especially warfarin and the DOACs, leading to increased bleeding and/or decreased efficacy. Dabigatran is particularly susceptible to interactions with p-glycoprotein, whereas apixaban and rivaroxaban are both metabolized via the cytochrome P450 3A4 system. As such, their efficacy is affected by both inducers and inhibitors of this system. For example, enzalutamide, a non-steroidal antiandrogen used for prostate cancer can increase levels of apixaban and rivaroxaban and therefore the concomitant use of these DOACs should be avoided. ,
In patients who are at very high risk for stroke but in whom anticoagulation is likely to be contraindicated, left atrial appendage occlusion devices may be an option, however they have not been specifically evaluated in patients with cancer. It is also important to note that current recommendations require short-term anticoagulation with warfarin followed by long-term treatment with antiplatelets. For patients who are not candidates for short-term oral anticoagulation, the ASAP-TOO trial is currently enrolling patients to determine the safety and efficacy of the Watchman left atrial appendage closure device without postprocedural anticoagulation. If the device arm demonstrates favorable results, this could become an important option to protect newly diagnosed cancer cases in patients with AF who may not be candidates for anticoagulation.
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