Author + information
- Received May 31, 2016
- Revision received July 11, 2016
- Accepted August 18, 2016
- Published online February 20, 2017.
- Matylda Mazur, MDa,
- Feilong Wang, MDa,
- David O. Hodge, MSb,
- Brittany L. Siontis, MDc,
- Douglas S. Beinborna,
- Hector R. Villarraga, MDa,
- Amir Lerman, MDa,
- Paul A. Friedman, MDa and
- Joerg Herrmann, MDa,∗ ()
- aDivision of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota
- bDepartment of Health Sciences Research, Mayo Clinic, Jacksonville, Florida
- cDepartment of Internal Medicine, Mayo Clinic, Rochester, Minnesota
- ↵∗Address for correspondence:
Dr. Joerg Herrmann, Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905.
Objectives The objective of this study was to determine the incidence of arrhythmias and device (internal cardiac defibrillator/cardiac resynchronization therapy defibrillator) therapies in patients with a diagnosis of cardiomyopathy and anthracycline exposure.
Background The burden of arrhythmias in adult cancer survivors with anthracycline-related cardiomyopathy has not been studied, but might have important implications for clinical management and outcomes.
Methods Retrospective cohort study of all patients with left ventricular dysfunction (LVD) who underwent internal cardiac defibrillator/cardiac resynchronization therapy defibrillator implantation at the Mayo Clinic from 1990 to 2012. Ninety-five patients were cancer survivors (on average, 5 years), 23 of which had anthracycline-related cardiomyopathy (CA-ACM) and 72 of which had non–anthracycline-related cardiomyopathy (CA-NACM). A second control group of 68 noncancer patients with ischemic heart disease-related LVD or dilated cardiomyopathy (ischemic heart disease [IHD]/DCM) was age- and gender-matched to patients with CA-ACM. All patients were followed for arrhythmias and appropriate ICD therapies, total mortality, heart transplantation, and left ventricular ejection fraction.
Results More than 5.5 ± 3.0 years after device implantation, nonsustained ventricular tachycardia was the most common arrhythmia in patients with CA-ACM followed by atrial fibrillation and sustained ventricular tachycardia or fibrillation (73.9%, 56.6%, and 30.4%, respectively), which was not significantly different from CA-NACM and IHD/DCM. The 5-year rate of ICD therapies was 19.9% in the CA-ACM group versus 22.1% in the CA-NACM group and 32.6% in the IHD/DCM group (p = NS for both). Device therapy–free, heart transplantation–free, and/or overall survival as well as cardiac function dynamics over time were not different in patients with CA-ACM than in patients with CA-NACM and IHD/DCM.
Conclusions This study indicates that the burden of arrhythmia in patients with anthracycline-related cardiomyopathy is not different from cancer and non-cancer patients with IHD-related LVD or DCM.
Cancer therapy–induced cardiomyopathy has gained increasing importance with the remarkable improvement in overall cancer survival during the past decade (1,2). The most concerning subtype relates to anthracyclines because it can develop late after completion of treatment and can take a relentless course (3,4). In fact, anthracycline-related cardiomyopathy may carry one of the worst prognoses of all types of cardiomyopathy (5). Whether this relates to progressive ventricular dysfunction or a higher incidence of malignant arrhythmias remains unknown.
A pro-arrhythmic effect of anthracyclines was noted in cultured cardiomyocytes and rodent models (6–8). Similarly, electrocardiographic abnormalities and arrhythmias are mainly observed in patients during or shortly after the acute phase of anthracycline treatment (9–11). On the contrary, there have been only a few studies noting QT dispersion, sudden cardiac deaths, and cardiac arrhythmias in childhood cancer survivors (3,12–15). The adult cancer population remains even less well-characterized, and there has not been a comprehensive analysis of arrhythmias in any cohort with anthracycline-related cardiomyopathy. Thus, there is uncertainty regarding the burden of arrhythmias and need for device therapy (i.e., internal cardiac defibrillator [ICD]/cardiac resynchronization therapy defibrillator [CRT-D]) in cancer survivors with left ventricular systolic dysfunction (LVD) (16,17). A very recent study (18) indicated that cancer patients may have a higher burden of ventricular arrhythmias with an increase noted after diagnosis.
The current study was designed to determine the burden of arrhythmias in long-term adult cancer survivors with anthracycline-related cardiomyopathy who underwent ICD or CRT-D implantation at the Mayo Clinic, Rochester, in comparison with cancer survivors who developed non–anthracycline-related cardiomyopathy and noncancer patients with ischemic heart disease (IHD)-related LVD or dilated cardiomyopathy (DCM) and to corroborate these data with clinical outcomes and cardiac function dynamics.
The current retrospective cohort study was approved by the Mayo Clinic institutional review board and included only patients who provided research authorization. The study was based on the centralized Mayo Clinic ICD registry, which prospectively collects clinical information, device characteristics, and postimplantation arrhythmic events and therapy delivery pertaining to all patients implanted at or followed by Mayo Clinic Heart Rhythm Services. Data are collected at all Mayo clinic visits; device interrogations during outpatient visits, emergency room visits and hospitalizations; and remote device interrogations. For this comparative retrospective cohort analysis, all patients enrolled in the Mayo Clinic ICD registry from 1990 until the end of 2012 were cross-matched with the Mayo Clinic cancer database to identify patients with a history of cancer, chemotherapy, new LVD (defined as left ventricular ejection fraction [LVEF] ≤50%), and presence of an ICD. Patients not meeting these criteria or with a lack of device interrogations on file or lack of follow-up evaluations were excluded. Medical records of patients meeting the inclusion criteria were thoroughly reviewed to extract patients characteristics, including age, gender, preexisting cardiovascular risk factors; echocardiographic parameters, including LVEF by use of modified biplane Simpson method, end-diastolic diameter, end-systolic diameter, right ventricular systolic pressure; cancer type and stage, chemotherapy regimen, dose and duration of agent; and indication for ICD implantation. Number of arrhythmic events and number and type of ICD therapies were followed by review of all available device interrogation reports. Vital status and death date information were queried using an institutionally approved fee-based Internet research and location service (Accurint, LexisNexis, Irvine, California). Heart transplant status was obtained from the comprehensive Mayo Clinic integrated medical record. Cardiac function (LVEF) dynamics were followed over time by review of serial echocardiograms.
All patients with a history of cancer, cardiomyopathy, and ICD/CRT-D implantation identified were further designated as anthracycline exposed (CA-ACM, n = 23) or anthracycline non-exposed (CA-NACM, n = 72). For a second comparison analysis, patients with CA-ACM were matched 3:1 to noncancer patients with IHD-related LVD (n = 23) or DCM (n = 45) (IHD/DCM, n = 68) from the Mayo ICD database based on age and gender. The diagnostic classification of cardiomyopathy was based on professional societal recommendations (19,20). IHD-related LVD was diagnosed based on a history of myocardial infarction, coronary revascularization, or objective evidence of coronary artery disease by stress testing and/or coronary angiography (21).
Definition of arrhythmic and cardiac events
Data from ICD interrogations were reviewed by electrophysiologists or specially trained electrophysiology nurses. ICD therapy (antitachycardia pacing or shock) was considered appropriate if it were preceded by ventricular tachycardia (VT) or ventricular fibrillation (VF) documented by stored episode data. Therapy was considered inappropriate if preceded by heart rates exceeding the programmed threshold, supraventricular or atrial arrhythmias, or device malfunction. ICD programming was determined by the implanting clinician.
Continuous data were presented as the mean ± SD. Categorical data were presented as frequency (percentage). Two-sample t tests were used to compare continuous variables. Categorical variables were compared using a chi-square test. Standardized differences for the comparison of the distribution of baseline covariates between the CA-ACM group and the comparison group were calculated as the differences in the mean of a variable between the 2 groups divided by an estimate of the standard deviation of that variable. Follow-up events were estimated using the Kaplan-Meier method and group comparisons were made using the log-rank test. The proportional hazards assumption was assessed for the individual variables and was found to be satisfied. A p value <0.05 was considered statistically significant for all analyses. All analyses were completed using SAS version 9.4 (SAS Institute, Inc., Cary, North Carolina).
Patients with cancer were derived almost exclusively from three malignancies: lymphoma, breast cancer, and renal or pelvis cancer. Lymphoma was more common in CA-ACM, renal or pelvis cancer in CA-NACM, and breast cancer was equally common in about one third (Table 1). Details regarding the chemotherapeutics are outlined in Online Table 1. Patients with CA-ACM did not differ significantly in their cardiovascular risk factor profile from patients with CA-NACM or IHD/DCM; IHD, however, was less frequent in patients with CA-ACM than in patients with CA-NACM (Table 1). In agreement, patients with CA-ACM were less frequently on antiplatelet therapy compared with CA-NACM (Table 1). Patients with CA-ACM had similar cardiac function and dimensions as well as New York Heart Association functional class when compared with patients with CA-ACM or IHD/DCM (Table 1). Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy was used less often in patients with CA-ACM in comparison with patients with IHD/DCM but not with patients with CA-NACM (Table 1). Amiodarone use tended to be lower in CA-ACM than in NA-NACM and sotalol use was higher in CA-ACM than IHD/DCM (Table 1). CRT-D constituted one-half of the devices in CA-ACM and IHD/DCM and about one-third in CA-NACM (Table 2). The average time interval from cardiomyopathy diagnosis to device implantation was not different between CA-ACM patients and patients with CA-NACM or IHD/DCM (Table 2).
Arrhythmia burden and ICD therapies
The most common rhythm abnormality in CA-ACM was nonsustained VT, twice as common as VF and sustained VT (Figure 1, Table 2). The 5-year rate of ICD therapies was 19.9% in the CA-ACM group versus 22.1% in the CA-NACM group (p = 0.93) and 32.6% in the IHD/DCM group (p = 0.14). Survival free of ICD therapy of patients with CA-ACM was not different from patients with CA-NACM or IHD/DCM (Figures 2 and 3⇓⇓). In separate analyses restricted to patients with events (i.e., only if occurring), patients with CA-ACM had more VF episodes and more appropriate shock therapies than patients with CA-NACM or IHD/DCM (Table 2).
The second most common arrhythmia in patients with CA-ACM was atrial fibrillation/flutter similar to patients with CA-NACM or IHD/DCM (Figure 1). Of all patients with CA-ACM with atrial fibrillation/flutter, 69% were on anticoagulation compared with 31.4% in CA-NACM (p = 0.02) and 59.5% in IHD/DCM (p = 0.53). Pacemaker dependency during ICD interrogation was noted in 17.4% of patients with CA-ACM, similar to 13.9% of patients with CA-NACM and 23.5% of patients with IHD/DCM. ICD therapies were actively disabled in 1 patient (4.4%) on hospice care in the CA-ACM group compared with 11.1% and 11.8% of patients with CA-NACM and IHD/DCM, respectively.
Heart failure progression, heart transplantation, and LVEF dynamics
Over the follow-up period, the average New York Heart Association functional class in the CA-ACM group remained relatively unchanged (from 2.3 ± 0.8 to 2.4 ± 1.1), similar to CA-NACM (from 2.1 ± 0.9 to 2.4 ± 1.0) and IHD/DCM (from 2.4 ± 0.9 to 2.3 ± 0.9). Heart transplantation/left ventricular assist device implantation was performed in 3 patients with CA-ACM (5-year rate 12.9%) compared with 5 patients with CA-NACM (5-year rate 7.0%, p = 0.37) and 4 patients with IHD/DCM (5-year rate 5.4%, p = 0.36). Survival free of heart transplantation/left ventricular assist device implantation was not different in patients with CA-ACM compared with patients with CA-NACM or IHD/DCM (Figures 2 and 3). The LVEF dynamics are outlined in the Online Appendix.
Over the follow-up period, 7 patients with CA-ACM died (5-year mortality rate, 13.5%) compared with 36 patients with CA-NACM (5-year mortality rate, 31.8%; p = 0.44) and 23 patients with IHD/DCM (5-year mortality rate, 19.7%; p = 0.32) (Figures 2 and 3). The outcomes did not change when patients with a history of myocardial infarction or coronary revascularization were excluded from the CA-ACM cohort (Online Figures 2 and 3). Stratifying the control groups accordingly, patients with IHD fared worse in the CA-NACM and noncancer groups, and survival outcomes of patients with CA-ACM was similar to those with DCM (Figures 4 and 5⇓⇓).
No patient in this study died from malignancy within 1 year of device implantation. Among patients with CA-ACM, 1 developed recurrent cancer and another 1 developed a secondary malignancy; 2 were admitted to hospice care (1 for recurrent cancer and 1 for heart failure). In the CA-NACM group, 15 patients had cancer recurrence/progression and 6 developed a secondary malignancy; a total of 7 patients were admitted to hospice care, 3 because of their malignancy, 3 for progressive heart failure, and 1 for combined cancer and end-stage heart failure. Among patients with IHD/DCM, 4 were admitted to a hospice program for heart failure.
The current study provides the first comprehensive analysis of arrhythmias in long-term adult cancer survivors with cardiomyopathy and corroborated clinical outcomes and cardiac function dynamics. The incidence and types of arrhythmias and appropriate device therapies were similar in patients with anthracycline-related cardiomyopathy compared with cancer patients with nonanthracycline-related cardiomyopathy and noncancer patients with IHD-related LVD and DCM. Furthermore, following ICD or CRT-D implantation, there was no difference in cardiomyopathy outcome parameters over time. Of importance, in this cohort study, overall survival of long-term adult cancer survivors with cardiomyopathy after anthracycline exposure was similar to DCM, and IHD-related LVD yielded the worst prognosis.
Arrhythmic events and ICD therapies
Anthracyclines generate a pro-arrhythmic effect in cultured cardiomyocytes that is responsive to beta-blocker (6). In rodent models, the administration of doxorubicin can induce QRS and QT prolongation, premature ventricular contractions, and VT (7,8). In keeping with these experimental observations, electrocardiograph abnormalities are not infrequently observed during the acute phase of anthracycline treatment (9). Conducted before and soon after doxorubicin treatment, 24-h Holter monitoring identified new-onset paroxysmal atrial fibrillation in 3 of the 29 patients (10%) and supraventricular tachycardia in another patient (3%); 1 patient required pacemaker implantation (10). On the contrary, VT and VF have been rarely observed and documented with anthracyclines (11,22).
Although these data refer to those undergoing active therapy with anthracycline, there is relative paucity of data on long-term cancer survivors. Only 1 study used 24-h Holter monitoring in pediatric and adolescent cancer survivors, 3 months to 21 years (mean 5 years) out from therapy (82% anthracyclines) and noticed supraventricular tachycardia in 2% and nonsustained VT in 3% of the patients (15). Of note, nonsustained VT was only noted in those with chest radiation (15). Moreover, all of these individuals had normal cardiac function, and dynamics may be different among those with documented cardiomyopathy. Indeed, prior studies on childhood cancer survivors indicated that although 20% developed a notable change of systolic cardiac function on echocardiography, it was only in 20% of these patients that clinical consequences emerged, including heart failure, conduction abnormalities, and arrhythmias (3). One-third of these patients developed sudden cardiac death with documentation of cardiac arrhythmias as the cause of death in 2 (3). In an extended analysis of 15 patients with childhood cancer with anthracycline-induced cardiomyopathy, VT and VF were noted in 4, all with cumulative anthracycline doses of 480 mg/m2 doxorubicin and reduced LVEF (14). Thus, there might be an ill-defined burden of malignant arrhythmias in cancer survivors with anthracycline-induced cardiomyopathies.
The current first-time comprehensive long-term analysis points out that nonsustained VT and atrial fibrillation are, indeed, the 2 most commonly noted rhythm abnormalities in adult cancer survivors with cardiomyopathy and anthracycline exposure similar to other cancer and noncancer patients with cardiomyopathy who underwent device implantation. Intriguingly, a number of cancer survivors with atrial fibrillation do not receive appropriate, guideline-recommended anticoagulation therapy for reasons unknown (23). Imbalances were furthermore noted in the utilization of antiarrhythmics, which, however, did not correlate with ICD therapy. Overall, nearly one-third of patients with CA-ACM had VT/VF episodes, and while not more common on a cohort level, malignant arrhythmias could be noted more commonly on an individual patient level. These findings would argue that cancer survivors with anthracycline-related cardiomyopathy should undergo device implantation in keeping with current guidelines (16,17).
Heart failure progression and heart transplantation
Progression of heart failure to the point of medical therapy refractoriness has been best described in childhood cancer survivors with anthracycline-induced cardiomyopathy (24,25). As mentioned previously, some studies in these cohorts also indicated that arrhythmias are mainly noted in those with overt cardiac dysfunction (3,14). The relationship between progression of heart failure and arrhythmias is 2-sided: arrhythmias may aggravate existing heart failure, and vice versa, heart failure progression may render the myocardium more vulnerable. Furthermore, the malignant disease process itself may lead to cardiac dysfunction and its complications (26).
In the current study, patients with anthracycline-related cardiomyopathy did not develop refractory heart failure significantly more frequently than patients with cancer with non–anthracycline-related cardiomyopathy and noncancer patients with IHD-related LVD or DCM. An important aspect to emphasize is that these patients were, on average, more than 4 years out from cancer diagnosis by the time of ICD implantation and are thus representative of cancer survivors. Prior studies have suggested that the outcomes of mechanical circulation support device therapy or heart transplantation are reportedly quite favorable in these patient cohorts with a low risk of recurrent malignancies and cancer-related deaths (27,28). The same was noted here, and cancer was a reason for hospice care referral in only 4% of the patients, as common as progressive heart failure in these and noncancer patients.
Malignant arrhythmias and progressive heart failure are the leading mechanisms of mortality in patients with cardiomyopathy. However, it has remained unknown if these 2 mechanisms explain the poor survival of anthracycline-related cardiomyopathy, which, in fact, is thought to carry one of the worst prognoses among the various types of cardiomyopathy (5). In keeping with the aforementioned lack of differences in arrhythmias and heart failure progression, cancer survivors with anthracycline-related cardiomyopathy did not have a survival that was worse than that of cancer survivors with cardiomyopathy unrelated to anthracycline exposure and noncancer patients with IHD-related LVD or DCM. In fact, this study indicates that their overall survival prognosis is similar to patients with DCM, whereas those with IHD-related LVD fare the worst. One may argue that patients with anthracycline-related cardiomyopathy in this study may represent a cohort with more favorable outcome characteristics (29,30). However, these patients already developed cardiomyopathy 4 years out from cancer therapy to the point of requiring optimal heart failure therapy, and therefore may not represent a low-risk group. Further, the time interval from cancer to ICD implantation and follow-up covers exactly the time window of anthracycline-induced cardiomyopathy in an adult breast cancer population (31). One may therefore conclude that the cohort of patients with cancer with cardiomyopathy and anthracycline exposure is not misrepresentative and the outcome data obtained here are relevant for clinical practice. Even more, that long-term cancer survivors were included reduces the impact of malignancy on survival outcomes and thus allows for a better comparison by cardiomyopathy type. Indeed, in both cancer groups, only 4% of patients were admitted to a hospice program because of their primary or secondary malignancy. Progressive heart failure was equally as common a reason for hospice referral as it was in those without cancer but advanced cardiomyopathy.
Cardiac function dynamics
The prevailing view of anthracycline-induced cardiomyopathy has been that of an unrelenting disease process with a gradual, progressive decline in cardiac function (32). Improvement of cardiac function may occur early on and yet ultimately fail (14). Time to diagnosis and treatment has been identified as an important factor for cardiac function dynamics (33,34). Furthermore, stressors later in life such as acute viral infection may lead to depression of cardiac function and episodes of decompensation followed by recovery (30). Thus, cancer survivors with anthracycline-induced cardiomyopathy may have a more variable (dynamic) pattern of their cardiac function that conventionally thought, which could influence clinical presentations and arrhythmias.
Accordingly, we analyzed the pattern of cardiac function over time. Indeed, a variable (dynamic) pattern was the one most commonly noted in patients with anthracycline-related cardiomyopathy, supporting recommendations for cardiac function monitoring in exposed cancer survivors (35). Of further note, the fraction of patients with anthracycline-related cardiomyopathy who experienced recovery of their cardiac function was similar to cancer patients with non-anthracycline-related cardiomyopathy and non-cancer patients with IHD-related LVD and DCM. These observations challenge the view of an unrelenting disease course of anthracycline-related cardiomyopathy and should stimulate further larger scale studies in the current era of heart failure therapies.
The current study is limited by the small number of patients. However, one has to state that these patients are not easy to identify and to characterize, and the setup of the current study allowed for an unrestricted review of data obtained at a single institution with consistent practice patterns. Also, the number and average age of patients with CA-ACM is not significantly different from previous publications on the clinical course of patients with this and other types of cardiomyopathy (5). Confining the current analysis to CA-ACM patients with devices may introduce a selection bias toward those with better projected outcomes. To address this concern, comparisons were made with cancer patients and non-anthracycline-related cardiomyopathy who also underwent ICD implantation. The key advantage of including device patients is the ability to capture clinically relevant arrhythmias over a long period of time. It also allows for a common time point for outcome comparisons of different patient populations. From then on, if a particular type of cardiomyopathy has a universally “malignant” phenotype, it should eventually become apparent. The goal of this study was not to provide final conclusive statements on the benefit of device therapy in patients with cancer. Also, it is important to emphasize that the current findings were obtained in an essentially exclusively adult cancer population. They may thus not fully characterize the incidence or types of arrhythmias in all patients with anthracycline-induced cardiomyopathies, especially childhood cancer survivors who represent a large and distinct group of patients with anthracycline-induced cardiomyopathy (36).
The current study provides evidence that the burden of arrhythmias in long-term adult cancer survivors with anthracycline-related cardiomyopathy is not significantly different from other cancer or non-cancer patients with other types of cardiomyopathy. In combination with favorable clinical outcome data, the current data may suggest that long-term adult cancer survivors with anthracycline-related cardiomyopathy warrant standard guideline-directed device therapies.
COMPETENCY IN MEDICAL KNOWLEDGE: The burden of arrhythmias in patients with anthracycline-related cardiomyopathy is similar to cancer and non-cancer patients with other types of cardiomyopathy. ICD/CRT-D therapy should not be withheld from cancer survivors with cardiomyopathy, even anthracycline-related cardiomyopathy, because they derive similar benefit than noncancer patients.
TRANSLATIONAL OUTLOOK: A universally higher burden of arrhythmias cannot explain the previously reported worse survival outcome of cancer survivors with anthracycline-related cardiomyopathy compared with patients with DCM and IHD. Whether survival outcomes of cancer survivors with anthracycline-related cardiomyopathy are improved in the current era and by use of ICD/CRT-D therapy requires further studies.
This study was supported by research funding of the Division of Cardiovascular Diseases, Mayo Clinic, Rochester. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Drs. Mazur and Wang contributed equally to this work.
All authors attest they are in compliance with human studies committees and animal welfare regulations of the authors' institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Clinical Electrophysiology author instructions page.
- Abbreviations and Acronyms
- anthracycline-related cardiomyopathy
- non–anthracycline-related cardiomyopathy
- cardiac resynchronization therapy defibrillator
- dilated cardiomyopathy
- internal cardiac defibrillator
- ischemic heart disease
- left ventricular dysfunction
- left ventricular ejection fraction
- ventricular fibrillation
- ventricular tachycardia
- Received May 31, 2016.
- Revision received July 11, 2016.
- Accepted August 18, 2016.
- 2017 American College of Cardiology Foundation
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