Journal of the American College of Cardiology 2014 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 63, No. 10, 2014 ISSN 0735-1097/$36.00 http://dx.doi.org/10.1016/j.jacc.2013.11.026
STATE-OF-THE-ART PAPER
Insights Into Onco-Cardiology Atrial Fibrillation in Cancer Dimitrios Farmakis, MD,*y John Parissis, MD,y Gerasimos Filippatos, MDy Athens, Greece Atrial fibrillation (AF) has been found to occur with an increased frequency in patients with malignancies, particularly in those undergoing cancer surgery. The occurrence of AF in cancer may be related to comorbid states or a direct tumor effect or may represent a complication of cancer surgical or medical therapy, whereas inflammation may be a common denominator for both conditions. Treating AF in patients with malignancies is a challenge, especially in terms of antithrombotic therapy, because cancer may result in an increased risk of either thrombosis or hemorrhage and an unpredictable anticoagulation response, whereas thromboembolic risk prediction scores such as CHADS2 (Cardiac Failure, Hypertension, Age, Diabetes, and Stroke [doubled]) may not be applicable. The general lack of evidence imposes an individualized approach to the management of AF in those patients, although some general recommendations based on current guidelines in noncancer patients and the existing evidence in cancer patients, where available, may be outlined. (J Am Coll Cardiol 2014;63:945–53) ª 2014 by the American College of Cardiology Foundation
Atrial fibrillation (AF) is the most common sustained arrhythmia; it affects 1.5% to 2% of the general population, and this prevalence increases to 10% at 80 years of age and to 18% at 85 years of age (1,2). In addition to aging, several cardiovascular conditions, such as hypertension, heart failure, and valvular disease, as well as noncardiovascular conditions, such as chronic pulmonary disease, diabetes, electrolyte abnormalities, thyroid dysfunction, and chronic kidney disease, predispose to the development of AF (2). Given the increasing occurrence of malignancies in the elderly and the coexistence of other conditions predisposing to AF in cancer patients, an association between those 2 conditions would be expected. On the other hand, AF confers an increased risk of cardiovascular complications, including a 5-fold risk of stroke and a 3-fold risk of heart failure, as well as a doubled mortality rate (1). Therefore, AF may present an additional factor affecting the prognosis of malignant diseases and a challenge for the therapeutic management of cancer patients. Epidemiology The bulk of epidemiological evidence on the association between AF and cancer is generally limited, with the From the *First Department of Internal Medicine, University of Athens Medical School, Athens, Greece; and the ySecond Department of Cardiology, University of Athens Medical School, Athens, Greece. This paper was partly supported by a grant from the Hellenic Cardiological Society. Dr. Farmakis is a member of the Steering Committee for a trial sponsored by Boehringer-Ingelheim Ellas. Dr. Parissis has received research grants from Abbott USA and ORION Pharma for heart failure; and has received honoraria from Servier International and Menarini International for lectures. Dr. Filippatos is a member of the Steering Committee for trials sponsored by Bayer and Corthera. Manuscript received October 7, 2013; revised manuscript received October 30, 2013, accepted November 19, 2013.
exception of AF after cancer surgery (Table 1). A large epidemiological study on 24,125 patients with newly diagnosed cancer recently shed some new light on the issue. More specifically, the prevalence of AF at baseline (i.e., at cancer diagnosis) was 2.4% (baseline AF), whereas AF developed in another 1.8% of patients after the diagnosis of cancer (new-onset AF) (3). In this study, new-onset AF was associated with a 2-fold risk of thromboembolism and a 6fold risk of heart failure, even after adjustment for known risk factors (adjusted hazard ratios [HRs]: 1.98 [p < 0.001] and 6.3 [p < 0.001], respectively) (3). The inverse approach was followed by another large population-based cohort that compared the prevalence of colorectal cancer in patients with and without AF. The authors compared 28,333 patients with AF with 283,260 matched individuals without AF; the prevalence of colorectal cancer was 0.59% in AF patients and only 0.05% in those without AF (HR: 11.8) (4). Furthermore, in a cohort of 2,339 patients admitted for surgery, AF was present with at least twice the frequency in patients admitted with a first diagnosis of colorectal or breast cancer than in those admitted for nonneoplastic surgery (3.6% vs. 1.6%) (5). In another study from the same group, patients with a first diagnosis of colorectal cancer had an approximately 3-fold higher risk of AF compared with patients admitted for nonneoplastic diseases (HR: 3.5) (6). The most frequent form of cancer-related AF is that occurring post-operatively (Table 1). AF is particularly frequent during thoracic surgery, especially pulmonary resection for lung cancer, an association that has been reported since the early 1970s (7). In a large cohort of 13,906 patients who underwent lung cancer surgery, AF occurred post-operatively in 12.6% of cases (8). Other
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by race and type of surgery, but provided no data on the impact of cancer surgery (19). On the other hand, postoperative AF complicates w25% to 30% of patients undergoing cardiac surgery such as coronary artery bypass grafting or valve surgery (20,21). However, these latter patients have established heart disease and undergo a procedure that involves direct manipulation of cardiac tissues, and therefore AF occurrence is expected to be high (19). The available evidence on the risk factors for the development of post-operative AF in cancer patients is outlined in Table 2. In contrast to the aforementioned studies, there is some evidence, derived by rather small study populations, arguing against the association between AF and cancer or the impact of AF on the prognosis of cancer patients (22). Thus, cancer was not an independent predictor of atrial arrhythmias in a cohort of 131 patients, whereas AF was not an independent predictor of survival in 175 patients with colorectal cancer (23,24). Sample size and the type and severity of cancer in previous analyses represent important factors that may account for the lack of data consistency. Another essential issue is the methodology of AF detection followed in different studies (i.e., symptoms driven, electrocardiographic monitoring) that may have crucially affected the reported frequency.
studies in patients subjected to lung cancer surgery reported incidences ranging between 6% AF = atrial fibrillation and 32% (9–16), whereas a single CRP = C-reactive protein study on a small population reHR = hazard ratio ported an incidence as high as LMWH = low molecular 60% (17). Furthermore, postweight heparin operative AF has been reported NT-proBNP = N-terminal in 4.4% of 563 patients who pro–B-type natriuretic peptide underwent elective colectomy for colorectal cancer (18), as well as in 9.2% of 207 patients who underwent esophagectomy for esophageal cancer (19). Postoperative AF seems to have a negative impact on patients’ prognosis. Thus, AF occurring during lung cancer surgery increased post-operative mortality (6.7% vs. 1.0% in patients without AF; p ¼ 0.024), hospital length of stay, and intensive care unit admissions, and it was further associated with an almost 4-fold higher long-term mortality in 5-year survivors after adjustment for other risk factors (HR: 3.75; p ¼ 0.007) (9). Whether there is a significant difference concerning post-operative AF in cancer patients compared with noncancer patients undergoing similar surgical procedures is not easy to conclude on the basis of the available evidence. A direct comparison is not available, whereas a comparison on the basis of the results of different studies is not possible given that AF prevalence is affected by and therefore should be adjusted for several factors. A single largescale retrospective observational study involving 370,447 patients undergoing major noncardiac surgery reported a 3% incidence of post-operative AF, with considerable variation Abbreviations and Acronyms
Table 1
Pathophysiology AF in cancer patients may represent a comorbid state because those patients share several factors predisposing to
Epidemiological Evidence of AF in Patients With Cancer
First Author, Year (Ref. #) Hu et al., 2012 (3)
No. of Patients 24,125
Erichsen et al., 2012 (4)
28,333 with AF and 28,3260 without AF
Guzzetti et al., 2008 (5)
1,317
Guzzetti et al., 2002 (6)
456
Onaitis et al., 2010 (8)
Condition Various types of cancer Colorectal cancer
AF Prevalence 2.4% at cancer diagnosis plus 1.8% after cancer diagnosis (new onset) Colorectal cancer: 0.59% in AF vs. 0.05% in non-AF
Colorectal or breast cancer
3.6%
Colorectal cancer
5.2%
13,906
Pulmonary resection for lung cancer
12.6%
Imperatori et al., 2012 (9)
454
Pulmonary resection for lung cancer
9.9%
Cardinale et al., 2007 (10)
400
Pulmonary resection for lung cancer
18%
Roselli et al., 2005 (11)
604
Pulmonary resection for lung cancer
19%
Nojiri et al., 2011 (13)
553
Pulmonary resection for lung cancer
5.6%
Salvatici et al., 2010 (14)
400
Pulmonary resection for lung cancer
18%
Cardinale et al., 1999 (15)
233
Pulmonary resection for lung cancer
12%
Nojiri et al., 2010 (16)
126
Pulmonary resection for lung cancer
23%
Nojiri et al., 2010 (50)
80
Pulmonary resection for lung cancer
28%
Ciszewski et al., 2013 (65)
117
Pulmonary resection for lung cancer
16%
Siu et al., 2005 (18)
563
Colectomy for colorectal cancer
4.4%
Walsh et al., 2004 (24)
174
Colectomy for colorectal cancer
5.4% (pre- and post-operatively)
Ojima et al., 2013 (66)
207
Esophagectomy for esophageal cancer
9.2%
Erichsen et al., 2011 (28)
11,887
Cancer bisphosphonates
3.2% in bisphosphonate group vs. 2.4% in controls
Wilkinson et al., 2010 (29)
20,571
Cancer bisphosphonates
18.0% in bisphosphonate group vs. 12.7% in controls
Arslan et al., 2011 (67)
124
Cancer þ bisphosphonate
Abonowara et al., 2012 (68)
136
TSH suppression for thyroid cancer
AF ¼ atrial fibrillation; TSH ¼ thyroid-stimulating hormone.
0% 10.3%
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Table 2
Risk Factors for the Development of Post-Operative Atrial Fibrillation in Patients With Cancer
Demographic Advanced age, male Clinical Advanced cancer stage, history of arterial hypertension, history of paroxysmal atrial fibrillation, physical status, post-operative tachycardia Laboratory Increased natriuretic peptides (NT-proBNP, BNP), ectopic beats on electrocardiogram, mitral E/e0 ratio >8, low heart rate variability, low mean heart rate Treatment related Increased duration of surgery, surgical complications, need for post-operative blood transfusion, extended lung resection in lung cancer, use of colon conduit in esophagectomy Based on information from multiple studies (8–11,14,16,18,50,65,66). BNP ¼ B-type natriuretic peptide; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide.
AF such as advanced age, electrolyte abnormalities, hypoxia, and metabolic disorders (22,25,26). The autonomic nervous system imbalance due to the increased sympathetic drive caused by pain or other forms of physical or emotional stress may also predispose to AF (27). AF may further result from paraneoplastic conditions including hyperparathyroidism and autoimmune reactions against atrial structures (27). AF may also represent a direct manifestation of the neoplasm in the case of primary or metastatic cardiac tumors or tumors of adjacent tissues such as the lungs and
Figure 1
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esophagus that invade the heart. Moreover, AF may be a complication of cancer therapy. As previously stated, postoperative AF occurs frequently, particularly in the case of pulmonary resection. In addition, several drugs used for the treatment of cancer have been found to induce AF (22,28–32). These drugs include most of the cytotoxic agents such as cisplatin, 5-fluorouracil, doxorubicin, paclitaxel/docetaxel, ifosfamide, gemcitabine, and mitoxantrone; high-dose corticosteroids; antiemetic agents such as ondansetron; targeted therapies; and bisphosphonates (22,28–33). A single study, however, argued against biphosphonate related-AF (35). Inflammation may be a common denominator of both conditions. It has been suggested that AF may actually represent an inflammatory complication of cancer (25). In a population-based study in 5,806 subjects followed for a median of 7.8 years, C-reactive protein (CRP) increase was associated both with the presence of AF at baseline (odds ratio for fourth vs. first CRP quartile: 1.8) and with future AF development (HR for fourth vs. first CRP quartile: 1.3) (34). An increase in CRP and other inflammatory markers such as tumor necrosis factor-a and interleukins 2, 6, and 8 has been found in AF (23,35), although an increased neutrophil count was associated with the occurrence of postoperative AF in patients who underwent surgery for colorectal cancer (18). Overall, the underlying mechanisms of AF induction in cancer patients are poorly understood and remain to be
An Overview of the Potential Pathogenetic Mechanisms Linking Cancer With Atrial Fibrillation
Cancer may cause atrial fibrillation, rarely by direct invasion of the heart and more commonly by chemotherapy and supportive therapies, surgery, chronic inflammation, autonomous nervous system (ANS) imbalance, paraneoplastic manifestation, and metabolic, electrolyte, and other abnormalities. In addition, aging and coexisting comorbid conditions may predispose both to cancer and to atrial fibrillation.
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Table 3
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Studies on the Prevention or Treatment of Post-Operative AF in Patients With Cancer
First Author, Year (Ref. #)
No.
Cancer Type
Surgery Type
Intervention
Outcome
Riber et al., 2012 (12)
254
Lung cancer
Pulmonary resection
Amiodarone
AF reduction (9% vs. 30%)
Nojiri et al., 2012 (17)
40
Lung cancer
Pulmonary resection
Atrial natriuretic peptide
AF reduction (10% vs. 60%)
117
Lung cancer
Pulmonary resection
Acebutolol or diltiazem
Nonsignificant AF reduction (5% in acebutolol, 23% in diltiazem, 20% in placebo)
Nojiri et al., 2011 (13)
30 with AF
Lung cancer
Pulmonary resection
Landiolol or verapamil þ digoxin for cardioversion
Reduction of cardioversion time (8 h vs. 11 h)
Ojima et al., 2013 (66)
19 with AF
Esophageal cancer
Transthoracic esophagectomy
Medical cardioversion (landiolol as first-line therapy)
63.2% successful cardioversion
Prevention
Ciszewski et al., 2012 (60)
Treatment
AF ¼ atrial fibrillation.
elucidated by future research. An overview of the potential pathogenetic links between cancer and AF is outlined in Figure 1. Treatment Treatment of AF in cancer patients is a challenge, particularly in terms of antithrombotic therapy for stroke prevention. On the one hand, cancer is itself a prothrombotic state, thus further increasing the risk of thromboembolic events in patients with AF. Despite that, the history of cancer has not been incorporated in the thromboembolic risk prediction scores such as CHADS2 (Cardiac Failure, Hypertension, Age, Diabetes, and Stroke [doubled]) or CHA2DS2-VASc (congestive heart failure or left ventricular dysfunction, hypertension, age 75 [doubled], diabetes, stroke [doubled]–vascular disease, age 65 to 74, sex [female]) that are currently suggested to be used to guide antithrombotic therapy (1,2). Moreover, some anticancer therapies and in particular the novel angiogenesis inhibitors have been related to thromboembolic complications (32). On the other hand, some malignancies, such as primary or metastatic intracranial tumors and hematological malignancies, pose an increased risk of hemorrhage. To complicate things Table 4
further, the response to anticoagulation may not be predictable owing to the concomitant medication or metabolic disorders associated with cancer (36). Actually, the use of vitamin K antagonists for deep venous thrombosis in patients with malignancies was associated with a 6-fold higher risk of hemorrhage compared with patients without cancer (37). In addition, there is practically no evidence to guide practice, and the recent randomized clinical trials on the novel anticoagulants dabigatran, rivaroxaban, and apixaban for stroke prevention in AF did not include cancer patients (38–40). Finally, using the established thromboembolic risk prediction scores to guide antithrombotic therapy in cancer patients may not be adequate. More specifically, in a large cohort of 24,125 patients with newly diagnosed cancer, although the CHADS2 score was predictive of thromboembolism risk in patients with baseline AF, it did not predict thromboembolic events in those with new-onset AF (i.e., AF that occurred after cancer diagnosis) (3). Therefore, the decision regarding the initiation of antithrombotic therapy in cancer patients has to be strictly individualized, weighing cautiously the benefits against the risks according to the features of each particular patient. Low molecular weight heparin (LMWH) may have a more favorable outcome than vitamin K inhibitors in
Open Issues Concerning AF in Cancer Patients
Epidemiology
Prevalence of AF in different types of cancer based on large cohorts or registries Occurrence of AF in relation to various cancer modalities, particularly novel targeted therapies Risk factors of AF Impact of AF on cancer prognosis and outcome Impact of AF on therapeutic decisions concerning cancer management
Pathogenesis
Mechanisms of AF induction
Diagnosis and assessment
Evaluation of classic and novel biomarkers for AF prediction Use of established thromboembolic risk assessment scores (i.e., CHADS2 or CHA2DS2-VASc) Evaluation of the need for cancer-specific scores
Management
Evaluation of available strategies for stroke prevention Use of novel anticoagulants for stroke prevention (dabigatran, rivaroxaban, apixaban) Use of available pharmacological therapies and other strategies for AF prevention Use of available pharmacological and interventional therapies for AF management
AF ¼ atrial fibrillation; CHADS2 ¼ cardiac failure, Hypertension, Age, Diabetes, and Stroke (doubled); CHA2DS2-VASc ¼ congestive heart failure or left ventricular dysfunction, hypertension, age 75 (doubled), diabetes, stroke (doubled)–vascular disease, age 65 to 74, sex (female).
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Table 5
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Practical Recommendations for the Screening and Management of Cancer-Related AF on the Basis of Current Guidelines in Noncancer Patients and the Existing Evidence, Where Available, in Cancer Patients
Screening
When At cancer diagnosis Perioperatively; strong evidence supports an increased occurrence, particularly in patients undergoing lung resection Before and after chemotherapy and other cancer therapies; some evidence supports the association between AF and cancer therapies, such as specific cytotoxic agents and supportive therapies such as bisphosphonates At relative symptoms (persistent palpitations, irregular rhythm) How Pulse taking followed by electrocardiography
Prevention of thromboembolism
When At AF diagnosis, regardless of type (paroxysmal or persistent/permanent) Estimation of TER High TER in the presence of previous thromboembolism; moderate TER in the presence of age 75 years, hypertension, heart failure or left ventricular ejection fraction 35%, and diabetes mellitus; validated TER assessment tools such as CHAD2DS2-VASc score may be used Consider antithrombotic therapy even in low TER patients (e.g., CHA2DS2-VASc score ¼ 0) given the additional TER associated with certain cancers (e.g., pancreatic, ovarian, lung, primary hepatic) or cancer therapies (e.g., cisplatin, gemcitabine, 5-fluorouracil, erythropoietin, granulocyte colony-stimulating factors) Estimation of BR Cancer-related high BR features such as intracranial tumor, hematological malignancies with coagulation defects, cancer therapy–induced thrombocytopenia, and severe metastatic hepatic disease may be a contraindication to antithrombotic therapy regardless of TER Validated BR assessment tools such as HAS-BLED score may be used Medication Low molecular weight heparins: weak evidence suggests beneficial effects in cancer patients Vitamin K antagonists: consider interaction with concomitant cancer therapy Aspirin: may be contraindicated because of thrombocytopenia New oral anticoagulants: no data on cancer patients
Cardioversion
Hemodynamically unstable patient Electrical cardioversion Hemodynamically stable patient Perioperatively: weak evidence favors amiodarone and landiolol Nonperioperatively: according to the presence and severity of structural heart disease; weak evidence favors ibutilide
Sinus rhythm maintenance medication
Consider perioperative prophylaxis particularly in patients undergoing lung resection; weak evidence favors amiodarone and landiolol Consider in patients with recurrent paroxysmal episodes, advanced age, cardiovascular comorbidities, and so on Consider potential interactions with concomitant cancer therapy
Rate control
Main modality in end-stage metastatic disease on palliative care No evidence for specific agents in cancer patients Consider potential interactions with concomitant cancer therapy
Catheter ablation
No evidence yet in cancer patients May be a choice in patients with symptomatic paroxysmal atrial fibrillation despite antiarrhythmic therapy Consider patient’s preferences Consider the presence of structural heart disease Consider cancer prognosis (life expectancy) Consider individual bleeding/thrombotic risks
Left atrial appendix closure/occlusion
No evidence yet in cancer patients May be a choice in patients with high TER and BR (see previous text) Consider patient’s preferences Consider cancer prognosis (life expectancy)
BR ¼ bleeding risk; HAS-BLED ¼ hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly; TER ¼ thromboembolic risk; other abbreviations as in Table 4.
patients with malignancies. Actually, dalteparin was associated with better survival than coumarin derivatives in patients with nonmetastatic solid tumors and venous thromboembolism (41). This may be related to the potential antitumor and antimetastatic effects of LMWH that have been shown to provide a survival benefit in patients with different types of cancer (42,43). As a result, the American College of Chest Physicians recommended the use of LMWH over vitamin K antagonists in cancer patients with venous thromboembolism (44). The role of LMWH in long-term anticoagulation therapy of patients with cancer and AF remains to be proven.
The decision regarding whether to begin antiarrhythmic therapy may also be difficult in cancer patients. In several cases, restoration and maintenance of sinus rhythm are necessary due to contraindications to long-term antithrombotic therapy. On the other hand, the antiarrhythmic medications that are effective in rhythm control, such as class III drugs, are associated with QT interval prolongation. Prolongation of the QT interval may also result from several drugs used in the treatment of cancer, including chemotherapeutic agents such as arsenic trioxide, targeted therapies such as angiogenic inhibitors, and supportive therapies such as ondansetron (45–47). Concomitant conditions such
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Figure 2
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Algorithm for Antithrombotic Therapy in Cancer-Related Atrial Fibrillation
A practical algorithm for antithrombotic therapy in cancer-related atrial fibrillation. *Intracranial tumor, hematologic malignancies with coagulation defects, cancer therapyinduced thrombocytopenia, severe metastatic hepatic disease etc. yHAS-BLED ¼ Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly zCHA2DS2-VASc ¼ Congestive heart failure or left ventricular dysfunction Hypertension, Age 75 (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age 65–74, Sex (female) xAntithrombotic therapy may be considered in high thromboembolic risk associated with certain cancers (e.g., pancreatic, ovarian, lung, primary hepatic) or cancer therapies (e.g., cisplatin, gemcitabine, 5-fluorouracil, erythropoietin, granulocyte colony stimulating factors).
as electrolyte disturbances that occur frequently in these patients may also have a proarrhythmic effect. Clinical evidence in this field is quite limited. A retrospective analysis of 81 cancer patients who received ibutilide for cardioversion of AF or atrial flutter at MD Anderson Cancer Center showed that the drug was effective in 75% of cases (48). In the same study, although 84% of patients received at least 1 additional drug associated with QT interval prolongation, no changes in corrected QT interval were encountered in any of the patients. Radiofrequency catheter ablation for pulmonary vein isolation has not yet been studied in cancer patients, and it may be a good option for some of these patients, particularly when rhythm control therapy has failed or there are concerns about its interaction with the background therapy (49). Nevertheless, there are several issues that need to be taken into consideration when considering this technique for cancer patients, such as the high doses of anticoagulation required during the procedure and the risk of trauma in cancer patients with a high bleeding risk or the risk of thromboembolism associated with placing intracardiac catheters in those patients with a prothrombotic tendency. Given the lack of evidence of a specific rhythm- or rate-control strategy in cancer patients with AF, the strategy followed in other chronic conditions such as heart failure may be followed, with particular attention to concomitant or planned anticancer therapies and comorbid conditions (50,51). The management of post-operative AF represents an additional challenge given its high occurrence rate, especially during surgery for lung cancer, as previously stated. Postoperative N-terminal pro–B-type natriuretic peptide (NT-proBNP)
levels may identify patients at increased risk of post-operative AF and thus guide the use of prophylactic antiarrhythmic therapy (10). More specifically, in patients undergoing thoracic surgery for lung cancer, increased NT-proBNP, according to the assay’s age-related cutoffs, either 24 h before or 1 h after surgery, was associated with a substantially higher rate of AF (64% vs. 5% in patients without increased NT-proBNP; p < 0.001) (10). Another study identified a cutoff post-operative NT-proBNP level of 182 ng/l for the prediction of post-operative AF (14), whereas a B-type natriuretic peptide level of 30 pg/ml had a high specificity of 93% for predicting AF after pulmonary resection for lung cancer (52). In addition to natriuretic peptide level, echocardiographic indexes may also be useful, particularly those indicating left ventricular diastolic dysfunction or increased left ventricular diastolic pressures. A mitral E/e0 ratio >8 was highly sensitive (90% sensitivity) for predicting post-operative AF (16). Other predictors of post-operative AF include advanced age, male sex, long duration of surgery, advanced cancer stage, occurrence of surgical complications, need for postoperative blood transfusions, and history of hypertension and pre-operative paroxysmal AF (8,9,11,18). Several drugs have been studied for the prevention or management of post-operative AF, mostly in patients undergoing cardiac surgery (Table 3). These agents included beta-blockers such as metoprolol and landiolol, statins, angiotensin-converting enzyme inhibitors, omega-3 fatty acids, and ranolazine (21,53–56). The corresponding data on cancer patients are limited. Post-operative amiodarone prophylaxis, given at 300 mg intravenously over 20 min
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immediately after surgery followed by 600 mg orally twice daily for 5 days, reduced the risk of AF by 23% in patients undergoing lung cancer surgery (12). A cost analysis of this trial showed that amiodarone was a cost-neutral way to prevent post-operative AF in lung cancer patients (57). Furthermore, landiolol, a novel, ultrashort-acting betablocker, when given in a small group of patients who experienced AF after elective pulmonary resection for lung cancer, accomplished a more profound perioperative reduction of heart rate and a quicker restoration of sinus rhythm compared with historical controls treated with verapamil and digoxin (13). In another small clinical trial, low-dose human atrial natriuretic peptide infusion during lung cancer surgery was protective against post-operative AF in patients with pre-operative B-type natriuretic peptide increase (30 pg/ml) (17). In 2 subsequent studies from the same group, human atrial natriuretic peptide effectively reduced the incidence of post-operative cardiopulmonary complications during lung cancer surgery in patients 75 years of age as well as in patients with chronic obstructive pulmonary disease (58,59). In contrast, acebutolol induced a nonsignificant reduction in the incidence of post-operative AF in patients undergoing pulmonary resection compared with diltiazem or placebo (60). Conclusions and Practical Considerations The accumulated evidence suggests that a large part of AF in cancer patients results from surgery (4). The presence of AF may affect patients’ prognosis, whereas its management, particularly in terms of antithrombotic therapy for stroke prevention, is a challenge. There are several issues that need to be addressed by future research concerning epidemiology, pathogenesis, diagnosis, prevention, and treatment, as outlined in Table 4. Given the lack of evidence, there are currently no specific guidelines for AF therapy in patients with malignancies. An approach to practical issues concerning AF management based on the current guidelines in noncancer patients (1,61) and the existing evidence in cancer patients, where available, is shown in Table 5. In what concerns antithrombotic therapy in particular, certain features like intracranial tumors, chemotherapy-induced thrombocytopenia, and coagulation defects due to hematological malignancies may predispose to bleeding and therefore may constitute contraindications to antithrombotic therapy, even in patients at high thromboembolic risk. On the other hand, certain malignant tumors such as pancreatic, ovarian, lung, and primary hepatic cancer are associated with an increased thromboembolic risk, and the same applies to several chemotherapeutic agents such as cisplatin, gemcitabine, and 5-fluorouracil and supportive therapies like erythropoietin and granulocyte-colony stimulating factors (62–64). As a result, antithrombotic prophylaxis may be needed even in patients classified as low risk by risk assessment tools such as CHA2DS2-VASc score or others. An algorithm for
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antithrombotic therapy in cancer-related AF based on cancer features and established thromboembolic and bleeding risk assessment tools (CHA2DS2-VASc and HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (age >65 years), Drugs/alcohol concomitantly], respectively) is proposed in Figure 2. It should be stressed that the particular clinical features of cancer patients render an individually tailored therapy even more crucial, especially for antithrombotic prophylaxis. Reprint requests and correspondence: Dr. Gerasimos Filippatos, Second Department of Cardiology, University of Athens Medical School, Attikon Hospital, 1 Rimini Street, Athens, Greece. E-mail: [email protected].
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15. Cardinale D, Martinoni A, Cipolla CM, et al. Atrial fibrillation after operation for lung cancer: clinical and prognostic significance. Ann Thorac Surg 1999;68:1827–31. 16. Nojiri T, Maeda H, Takeuchi Y, et al. Predictive value of preoperative tissue Doppler echocardiographic analysis for postoperative atrial fibrillation after pulmonary resection for lung cancer. J Thorac Cardiovasc Surg 2010;140:764–8. 17. Nojiri T, Yamamoto K, Maeda H, et al. Effect of low-dose human atrial natriuretic peptide on postoperative atrial fibrillation in patients undergoing pulmonary resection for lung cancer: a doubleblind, placebo-controlled study. J Thorac Cardiovasc Surg 2012; 143:488–94. 18. Siu CW, Tung HM, Chu KW, Jim MH, Lau CP, Tse HF. Prevalence and predictors of new-onset atrial fibrillation after elective surgery for colorectal cancer. Pacing Clin Electrophysiol 2005;28 Suppl 1: S120–3. 19. Bhave PD, Goldman LE, Vittinghoff E, Maselli J, Auerbach A. Incidence, predictors, and outcomes associated with postoperative atrial fibrillation after major noncardiac surgery. Am Heart J 2012;164: 918–24. 20. El-Chami MF, Kilgo P, Thourani V, et al. New-onset atrial fibrillation predicts long-term mortality after coronary artery bypass graft. J Am Coll Cardiol 2010;55:1370–6. 21. Mozaffarian D, Marchioli R, Macchia A, et al., for the OPERA Investigators. Fish oil and postoperative atrial fibrillation: the Omega-3 Fatty Acids for Prevention of Post-operative Atrial Fibrillation (OPERA) randomized trial. JAMA 2012;308:2001–11. 22. Velagapudi P, Turagam MK, Kocheril AG. Atrial fibrillation in cancer patients: an underrecognized condition. South Med J 2011;104:667–8. 23. Chung MK, Martin DO, Sprecher D, et al. C-reactive protein elevation in patients with atrial arrhythmias. Circulation 2001;104: 2886–91. 24. Walsh SR, Gladwish KM, Ward NJ, Justin TA, Keeling NJ. Atrial fibrillation and survival in colorectal cancer. World J Surg Oncol 2004; 2:40. 25. Lainscak M, Dagres N, Filippatos GS, Anker SD, Kremastinos DT. Atrial fibrillation in chronic non-cardiac disease: where do we stand? Int J Cardiol 2008;128:311–5. 26. Mann DL, Krone RJ. Cardiac disease in cancer patients: an overview. Prog Cardiovasc Dis 2010;53:80–7. 27. Guzzetti S, Costantino G, Fundarò C. Systemic inflammation, atrial fibrillation, and cancer. Circulation 2002;106:e40. 28. Erichsen R, Christiansen CF, Frøslev T, Jacobsen J, Sørensen HT. Intravenous bisphosphonate therapy and atrial fibrillation/flutter risk in cancer patients: a nationwide cohort study. Br J Cancer 2011;105: 881–3. 29. Wilkinson GS, Baillargeon J, Kuo YF, Freeman JL, Goodwin JS. Atrial fibrillation and stroke associated with intravenous bisphosphonate therapy in older patients with cancer. J Clin Oncol 2010;28: 4898–905. 30. Kaakeh Y, Overholser BR, Lopshire JC, Tisdale JE. Drug-induced atrial fibrillation. Drugs 2012;72:1617–30. 31. van der Hooft CS, Heeringa J, van Herpen G, Kors JA, Kingma JH, Stricker BH. Drug-induced atrial fibrillation. J Am Coll Cardiol 2004; 44:2117–24. 32. Suter TM, Ewer MS. Cancer drugs and the heart: importance and management. Eur Heart J 2013;34:1102–11. 33. Khouri MG, Douglas PS, Mackey JR, et al. Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues. Circulation 2012;126:2749–63. 34. Aviles RJ, Martin DO, Apperson-Hansen C, et al. Inflammation as a risk factor for atrial fibrillation. Circulation 2003;108:3006–10. 35. Guo Y, Lip GY, Apostolakis S. Inflammation in atrial fibrillation. J Am Coll Cardiol 2012;60:2263–70. 36. Lee AY. Deep vein thrombosis and cancer: survival, recurrence, and anticoagulant choices. Dis Mon 2005;51:150–7. 37. Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JGP, Büller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000;18:3078–83. 38. Connolly SJ, Ezekowitz MD, Yusuf S, et al., for the RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361:1139–51.
JACC Vol. 63, No. 10, 2014 March 18, 2014:945–53 39. Patel MR, Mahaffey KW, Garg J, et al., for the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011;365:883–91. 40. Granger CB, Alexander JH, McMurray JJ, et al., ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011;365:981–92. 41. Lee AY, Rickles FR, Julian JA, et al. Randomized comparison of low molecular weight heparin and coumarin derivatives on the survival of patients with cancer and venous thromboembolism. J Clin Oncol 2005; 23:2123–9. 42. Klerk CP, Smorenburg SM, Otten HM, et al. The effect of low molecular weight heparin on survival in patients with advanced malignancy. J Clin Oncol 2005;23:2130–5. 43. Niers TM, Klerk CP, DiNisio M, et al. Mechanisms of heparin induced anti-cancer activity in experimental cancer models. Crit Rev Oncol Hematol 2007;61:195–207. 44. Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004;126 Suppl:401S–28S. 45. Barbey JT, Pezzullo JC, Soignet SL. Effect of arsenic trioxide on QT interval in patients with advanced malignancies. J Clin Oncol 2003;21: 3609–15. 46. des Guetz G, Uzzan B, Chouahnia K, Morère JF. Cardiovascular toxicity of anti-angiogenic drugs. Target Oncol 2011;6:197–202. 47. Doggrell SA, Hancox JC. Cardiac safety concerns for ondansetron, an antiemetic commonly used for nausea linked to cancer treatment and following anaesthesia. Expert Opin Drug Saf 2013;12:421–31. 48. Bickford CL, Agarwal R, Urbauer DL, Durand JB, Lenihan DJ. Efficacy and safety of ibutilide for chemical cardioversion of atrial fibrillation and atrial flutter in cancer patients. Am J Med Sci 2013 Apr 12 [E-pub ahead of print]. 49. Efremidis M, Sideris A, Xydonas S, et al. Ablation of atrial fibrillation in patients with heart failure: reversal of atrial and ventricular remodeling. Hellenic J Cardiol 2008;49:19–25. 50. Efremidis M, Pappas L, Sideris A, Filippatos G. Management of atrial fibrillation in patients with heart failure. J Card Fail 2008;14:232–7. 51. Lip GY, Ponikowski P, Andreotti F, et al., for the ESC Task Force. Thrombo-embolism and antithrombotic therapy for heart failure in sinus rhythm. A joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis. Eur J Heart Fail 2012;14:681–95. 52. Nojiri T, Maeda H, Takeuchi Y, et al. Predictive value of B-type natriuretic peptide for postoperative atrial fibrillation following pulmonary resection for lung cancer. Eur J Cardiothorac Surg 2010;37: 787–91. 53. Skiba MA, Pick AW, Chaudhuri K, et al. Prophylaxis against atrial fibrillation after cardiac surgery: beneficial effect of postoperative metoprolol. Heart Lung Circ 2013;22:627–33. 54. Chopra V, Wesorick DH, Sussman JB, et al. Effect of postoperative statins on death, myocardial infarction, atrial fibrillation, and length of stay: a systematic review and meta-analysis. Arch Surg 2012;147: 181–9. 55. Johnston K, Stephens S. Effect of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on risk of atrial fibrillation before coronary artery bypass grafting. Ann Pharmacother 2012;46: 1239–44. 56. Simopoulos V, Tagarakis GI, Daskalopoulou SS, et al. Ranolazine enhances the antiarrhythmic activity of amiodarone by accelerating conversion of new-onset atrial fibrillation after cardiac surgery. Angiology 2013 Feb 25 [E-pub ahead of print]. 57. Riber LP, Christensen TD, Pilegaard HK. Amiodarone is a costneutral way of preventing atrial fibrillation after surgery for lung cancer. Eur J Cardiothorac Surg 2014;45:120–5. 58. Nojiri T, Inoue M, Yamamoto K, et al. Effects of low-dose human atrial natriuretic peptide for preventing post-operative cardiopulmonary complications in elderly patients undergoing pulmonary resection for lung cancer. Eur J Cardiothorac Surg 2012;41:1330–4. 59. Nojiri T, Inoue M, Maeda H, et al. Low-dose human atrial natriuretic peptide for the prevention of postoperative cardiopulmonary complications in chronic obstructive pulmonary disease patients undergoing lung cancer surgery. Eur J Cardiothorac Surg 2013;44:98–103. 60. Ciszewski P, Tyczka J, Nadolski J, Roszak M, Dyszkiewicz W. Comparative efficacy and usefulness of acebutolol and diltiazem for the
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prevention of atrial fibrillation during perioperative time in patients undergoing pulmonary resection. Thorac Cardiovasc Surg 2013;61: 365–72. Anderson JL, Halperin JL, Albert NM, et al. Management of patients with atrial fibrillation (compilation of 2006 ACCF/AHA/ESC and 2011 ACCF/AHA/HRS recommendations): a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:1935–44. Sorensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Nielsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998;338:1169–73. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ, 3rd Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000;160:809–15. Nadir Y, Hoffman R, Brenner B. Review Drug-related thrombosis in g hematologic malignancies. Rev Clin Exp Hematol 2004;8:E4.
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65. Ciszewski P, Tyczka J, Nadolski J, Roszak M, Dyszkiewicz W. Lower preoperative fluctuation of heart rate variability is an independent risk factor for postoperative atrial fibrillation in patients undergoing major pulmonary resection. Interact Cardiovasc Thorac Surg 2013;17:680–6. 66. Ojima T, Iwahashi M, Nakamori M, et al. Atrial fibrillation after esophageal cancer surgery: an analysis of 207 consecutive patients. Surg Today 2013 May 15 [E-pub ahead of print]. 67. Arslan C, Aksoy S, Dizdar O, Dede DS, Harputluoglu H, Altundag K. Zoledronic acid and atrial fibrillation in cancer patients. Support Care Cancer 2011;19:425–30. 68. Abonowara A, Quraishi A, Sapp JL, et al. Prevalence of atrial fibrillation in patients taking TSH suppression therapy for management of thyroid cancer. Clin Invest Med 2012;35:E152–6. Key Words: antithrombotic therapy chemotherapy - warfarin.
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STATE-OF-THE-ART PAPER
Insights Into Onco-Cardiology Atrial Fibrillation in Cancer Dimitrios Farmakis, MD,*y John Parissis, MD,y Gerasimos Filippatos, MDy Athens, Greece Atrial fibrillation (AF) has been found to occur with an increased frequency in patients with malignancies, particularly in those undergoing cancer surgery. The occurrence of AF in cancer may be related to comorbid states or a direct tumor effect or may represent a complication of cancer surgical or medical therapy, whereas inflammation may be a common denominator for both conditions. Treating AF in patients with malignancies is a challenge, especially in terms of antithrombotic therapy, because cancer may result in an increased risk of either thrombosis or hemorrhage and an unpredictable anticoagulation response, whereas thromboembolic risk prediction scores such as CHADS2 (Cardiac Failure, Hypertension, Age, Diabetes, and Stroke [doubled]) may not be applicable. The general lack of evidence imposes an individualized approach to the management of AF in those patients, although some general recommendations based on current guidelines in noncancer patients and the existing evidence in cancer patients, where available, may be outlined. (J Am Coll Cardiol 2014;63:945–53) ª 2014 by the American College of Cardiology Foundation
Atrial fibrillation (AF) is the most common sustained arrhythmia; it affects 1.5% to 2% of the general population, and this prevalence increases to 10% at 80 years of age and to 18% at 85 years of age (1,2). In addition to aging, several cardiovascular conditions, such as hypertension, heart failure, and valvular disease, as well as noncardiovascular conditions, such as chronic pulmonary disease, diabetes, electrolyte abnormalities, thyroid dysfunction, and chronic kidney disease, predispose to the development of AF (2). Given the increasing occurrence of malignancies in the elderly and the coexistence of other conditions predisposing to AF in cancer patients, an association between those 2 conditions would be expected. On the other hand, AF confers an increased risk of cardiovascular complications, including a 5-fold risk of stroke and a 3-fold risk of heart failure, as well as a doubled mortality rate (1). Therefore, AF may present an additional factor affecting the prognosis of malignant diseases and a challenge for the therapeutic management of cancer patients. Epidemiology The bulk of epidemiological evidence on the association between AF and cancer is generally limited, with the From the *First Department of Internal Medicine, University of Athens Medical School, Athens, Greece; and the ySecond Department of Cardiology, University of Athens Medical School, Athens, Greece. This paper was partly supported by a grant from the Hellenic Cardiological Society. Dr. Farmakis is a member of the Steering Committee for a trial sponsored by Boehringer-Ingelheim Ellas. Dr. Parissis has received research grants from Abbott USA and ORION Pharma for heart failure; and has received honoraria from Servier International and Menarini International for lectures. Dr. Filippatos is a member of the Steering Committee for trials sponsored by Bayer and Corthera. Manuscript received October 7, 2013; revised manuscript received October 30, 2013, accepted November 19, 2013.
exception of AF after cancer surgery (Table 1). A large epidemiological study on 24,125 patients with newly diagnosed cancer recently shed some new light on the issue. More specifically, the prevalence of AF at baseline (i.e., at cancer diagnosis) was 2.4% (baseline AF), whereas AF developed in another 1.8% of patients after the diagnosis of cancer (new-onset AF) (3). In this study, new-onset AF was associated with a 2-fold risk of thromboembolism and a 6fold risk of heart failure, even after adjustment for known risk factors (adjusted hazard ratios [HRs]: 1.98 [p < 0.001] and 6.3 [p < 0.001], respectively) (3). The inverse approach was followed by another large population-based cohort that compared the prevalence of colorectal cancer in patients with and without AF. The authors compared 28,333 patients with AF with 283,260 matched individuals without AF; the prevalence of colorectal cancer was 0.59% in AF patients and only 0.05% in those without AF (HR: 11.8) (4). Furthermore, in a cohort of 2,339 patients admitted for surgery, AF was present with at least twice the frequency in patients admitted with a first diagnosis of colorectal or breast cancer than in those admitted for nonneoplastic surgery (3.6% vs. 1.6%) (5). In another study from the same group, patients with a first diagnosis of colorectal cancer had an approximately 3-fold higher risk of AF compared with patients admitted for nonneoplastic diseases (HR: 3.5) (6). The most frequent form of cancer-related AF is that occurring post-operatively (Table 1). AF is particularly frequent during thoracic surgery, especially pulmonary resection for lung cancer, an association that has been reported since the early 1970s (7). In a large cohort of 13,906 patients who underwent lung cancer surgery, AF occurred post-operatively in 12.6% of cases (8). Other
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by race and type of surgery, but provided no data on the impact of cancer surgery (19). On the other hand, postoperative AF complicates w25% to 30% of patients undergoing cardiac surgery such as coronary artery bypass grafting or valve surgery (20,21). However, these latter patients have established heart disease and undergo a procedure that involves direct manipulation of cardiac tissues, and therefore AF occurrence is expected to be high (19). The available evidence on the risk factors for the development of post-operative AF in cancer patients is outlined in Table 2. In contrast to the aforementioned studies, there is some evidence, derived by rather small study populations, arguing against the association between AF and cancer or the impact of AF on the prognosis of cancer patients (22). Thus, cancer was not an independent predictor of atrial arrhythmias in a cohort of 131 patients, whereas AF was not an independent predictor of survival in 175 patients with colorectal cancer (23,24). Sample size and the type and severity of cancer in previous analyses represent important factors that may account for the lack of data consistency. Another essential issue is the methodology of AF detection followed in different studies (i.e., symptoms driven, electrocardiographic monitoring) that may have crucially affected the reported frequency.
studies in patients subjected to lung cancer surgery reported incidences ranging between 6% AF = atrial fibrillation and 32% (9–16), whereas a single CRP = C-reactive protein study on a small population reHR = hazard ratio ported an incidence as high as LMWH = low molecular 60% (17). Furthermore, postweight heparin operative AF has been reported NT-proBNP = N-terminal in 4.4% of 563 patients who pro–B-type natriuretic peptide underwent elective colectomy for colorectal cancer (18), as well as in 9.2% of 207 patients who underwent esophagectomy for esophageal cancer (19). Postoperative AF seems to have a negative impact on patients’ prognosis. Thus, AF occurring during lung cancer surgery increased post-operative mortality (6.7% vs. 1.0% in patients without AF; p ¼ 0.024), hospital length of stay, and intensive care unit admissions, and it was further associated with an almost 4-fold higher long-term mortality in 5-year survivors after adjustment for other risk factors (HR: 3.75; p ¼ 0.007) (9). Whether there is a significant difference concerning post-operative AF in cancer patients compared with noncancer patients undergoing similar surgical procedures is not easy to conclude on the basis of the available evidence. A direct comparison is not available, whereas a comparison on the basis of the results of different studies is not possible given that AF prevalence is affected by and therefore should be adjusted for several factors. A single largescale retrospective observational study involving 370,447 patients undergoing major noncardiac surgery reported a 3% incidence of post-operative AF, with considerable variation Abbreviations and Acronyms
Table 1
Pathophysiology AF in cancer patients may represent a comorbid state because those patients share several factors predisposing to
Epidemiological Evidence of AF in Patients With Cancer
First Author, Year (Ref. #) Hu et al., 2012 (3)
No. of Patients 24,125
Erichsen et al., 2012 (4)
28,333 with AF and 28,3260 without AF
Guzzetti et al., 2008 (5)
1,317
Guzzetti et al., 2002 (6)
456
Onaitis et al., 2010 (8)
Condition Various types of cancer Colorectal cancer
AF Prevalence 2.4% at cancer diagnosis plus 1.8% after cancer diagnosis (new onset) Colorectal cancer: 0.59% in AF vs. 0.05% in non-AF
Colorectal or breast cancer
3.6%
Colorectal cancer
5.2%
13,906
Pulmonary resection for lung cancer
12.6%
Imperatori et al., 2012 (9)
454
Pulmonary resection for lung cancer
9.9%
Cardinale et al., 2007 (10)
400
Pulmonary resection for lung cancer
18%
Roselli et al., 2005 (11)
604
Pulmonary resection for lung cancer
19%
Nojiri et al., 2011 (13)
553
Pulmonary resection for lung cancer
5.6%
Salvatici et al., 2010 (14)
400
Pulmonary resection for lung cancer
18%
Cardinale et al., 1999 (15)
233
Pulmonary resection for lung cancer
12%
Nojiri et al., 2010 (16)
126
Pulmonary resection for lung cancer
23%
Nojiri et al., 2010 (50)
80
Pulmonary resection for lung cancer
28%
Ciszewski et al., 2013 (65)
117
Pulmonary resection for lung cancer
16%
Siu et al., 2005 (18)
563
Colectomy for colorectal cancer
4.4%
Walsh et al., 2004 (24)
174
Colectomy for colorectal cancer
5.4% (pre- and post-operatively)
Ojima et al., 2013 (66)
207
Esophagectomy for esophageal cancer
9.2%
Erichsen et al., 2011 (28)
11,887
Cancer bisphosphonates
3.2% in bisphosphonate group vs. 2.4% in controls
Wilkinson et al., 2010 (29)
20,571
Cancer bisphosphonates
18.0% in bisphosphonate group vs. 12.7% in controls
Arslan et al., 2011 (67)
124
Cancer þ bisphosphonate
Abonowara et al., 2012 (68)
136
TSH suppression for thyroid cancer
AF ¼ atrial fibrillation; TSH ¼ thyroid-stimulating hormone.
0% 10.3%
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Table 2
Risk Factors for the Development of Post-Operative Atrial Fibrillation in Patients With Cancer
Demographic Advanced age, male Clinical Advanced cancer stage, history of arterial hypertension, history of paroxysmal atrial fibrillation, physical status, post-operative tachycardia Laboratory Increased natriuretic peptides (NT-proBNP, BNP), ectopic beats on electrocardiogram, mitral E/e0 ratio >8, low heart rate variability, low mean heart rate Treatment related Increased duration of surgery, surgical complications, need for post-operative blood transfusion, extended lung resection in lung cancer, use of colon conduit in esophagectomy Based on information from multiple studies (8–11,14,16,18,50,65,66). BNP ¼ B-type natriuretic peptide; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide.
AF such as advanced age, electrolyte abnormalities, hypoxia, and metabolic disorders (22,25,26). The autonomic nervous system imbalance due to the increased sympathetic drive caused by pain or other forms of physical or emotional stress may also predispose to AF (27). AF may further result from paraneoplastic conditions including hyperparathyroidism and autoimmune reactions against atrial structures (27). AF may also represent a direct manifestation of the neoplasm in the case of primary or metastatic cardiac tumors or tumors of adjacent tissues such as the lungs and
Figure 1
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esophagus that invade the heart. Moreover, AF may be a complication of cancer therapy. As previously stated, postoperative AF occurs frequently, particularly in the case of pulmonary resection. In addition, several drugs used for the treatment of cancer have been found to induce AF (22,28–32). These drugs include most of the cytotoxic agents such as cisplatin, 5-fluorouracil, doxorubicin, paclitaxel/docetaxel, ifosfamide, gemcitabine, and mitoxantrone; high-dose corticosteroids; antiemetic agents such as ondansetron; targeted therapies; and bisphosphonates (22,28–33). A single study, however, argued against biphosphonate related-AF (35). Inflammation may be a common denominator of both conditions. It has been suggested that AF may actually represent an inflammatory complication of cancer (25). In a population-based study in 5,806 subjects followed for a median of 7.8 years, C-reactive protein (CRP) increase was associated both with the presence of AF at baseline (odds ratio for fourth vs. first CRP quartile: 1.8) and with future AF development (HR for fourth vs. first CRP quartile: 1.3) (34). An increase in CRP and other inflammatory markers such as tumor necrosis factor-a and interleukins 2, 6, and 8 has been found in AF (23,35), although an increased neutrophil count was associated with the occurrence of postoperative AF in patients who underwent surgery for colorectal cancer (18). Overall, the underlying mechanisms of AF induction in cancer patients are poorly understood and remain to be
An Overview of the Potential Pathogenetic Mechanisms Linking Cancer With Atrial Fibrillation
Cancer may cause atrial fibrillation, rarely by direct invasion of the heart and more commonly by chemotherapy and supportive therapies, surgery, chronic inflammation, autonomous nervous system (ANS) imbalance, paraneoplastic manifestation, and metabolic, electrolyte, and other abnormalities. In addition, aging and coexisting comorbid conditions may predispose both to cancer and to atrial fibrillation.
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Table 3
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Studies on the Prevention or Treatment of Post-Operative AF in Patients With Cancer
First Author, Year (Ref. #)
No.
Cancer Type
Surgery Type
Intervention
Outcome
Riber et al., 2012 (12)
254
Lung cancer
Pulmonary resection
Amiodarone
AF reduction (9% vs. 30%)
Nojiri et al., 2012 (17)
40
Lung cancer
Pulmonary resection
Atrial natriuretic peptide
AF reduction (10% vs. 60%)
117
Lung cancer
Pulmonary resection
Acebutolol or diltiazem
Nonsignificant AF reduction (5% in acebutolol, 23% in diltiazem, 20% in placebo)
Nojiri et al., 2011 (13)
30 with AF
Lung cancer
Pulmonary resection
Landiolol or verapamil þ digoxin for cardioversion
Reduction of cardioversion time (8 h vs. 11 h)
Ojima et al., 2013 (66)
19 with AF
Esophageal cancer
Transthoracic esophagectomy
Medical cardioversion (landiolol as first-line therapy)
63.2% successful cardioversion
Prevention
Ciszewski et al., 2012 (60)
Treatment
AF ¼ atrial fibrillation.
elucidated by future research. An overview of the potential pathogenetic links between cancer and AF is outlined in Figure 1. Treatment Treatment of AF in cancer patients is a challenge, particularly in terms of antithrombotic therapy for stroke prevention. On the one hand, cancer is itself a prothrombotic state, thus further increasing the risk of thromboembolic events in patients with AF. Despite that, the history of cancer has not been incorporated in the thromboembolic risk prediction scores such as CHADS2 (Cardiac Failure, Hypertension, Age, Diabetes, and Stroke [doubled]) or CHA2DS2-VASc (congestive heart failure or left ventricular dysfunction, hypertension, age 75 [doubled], diabetes, stroke [doubled]–vascular disease, age 65 to 74, sex [female]) that are currently suggested to be used to guide antithrombotic therapy (1,2). Moreover, some anticancer therapies and in particular the novel angiogenesis inhibitors have been related to thromboembolic complications (32). On the other hand, some malignancies, such as primary or metastatic intracranial tumors and hematological malignancies, pose an increased risk of hemorrhage. To complicate things Table 4
further, the response to anticoagulation may not be predictable owing to the concomitant medication or metabolic disorders associated with cancer (36). Actually, the use of vitamin K antagonists for deep venous thrombosis in patients with malignancies was associated with a 6-fold higher risk of hemorrhage compared with patients without cancer (37). In addition, there is practically no evidence to guide practice, and the recent randomized clinical trials on the novel anticoagulants dabigatran, rivaroxaban, and apixaban for stroke prevention in AF did not include cancer patients (38–40). Finally, using the established thromboembolic risk prediction scores to guide antithrombotic therapy in cancer patients may not be adequate. More specifically, in a large cohort of 24,125 patients with newly diagnosed cancer, although the CHADS2 score was predictive of thromboembolism risk in patients with baseline AF, it did not predict thromboembolic events in those with new-onset AF (i.e., AF that occurred after cancer diagnosis) (3). Therefore, the decision regarding the initiation of antithrombotic therapy in cancer patients has to be strictly individualized, weighing cautiously the benefits against the risks according to the features of each particular patient. Low molecular weight heparin (LMWH) may have a more favorable outcome than vitamin K inhibitors in
Open Issues Concerning AF in Cancer Patients
Epidemiology
Prevalence of AF in different types of cancer based on large cohorts or registries Occurrence of AF in relation to various cancer modalities, particularly novel targeted therapies Risk factors of AF Impact of AF on cancer prognosis and outcome Impact of AF on therapeutic decisions concerning cancer management
Pathogenesis
Mechanisms of AF induction
Diagnosis and assessment
Evaluation of classic and novel biomarkers for AF prediction Use of established thromboembolic risk assessment scores (i.e., CHADS2 or CHA2DS2-VASc) Evaluation of the need for cancer-specific scores
Management
Evaluation of available strategies for stroke prevention Use of novel anticoagulants for stroke prevention (dabigatran, rivaroxaban, apixaban) Use of available pharmacological therapies and other strategies for AF prevention Use of available pharmacological and interventional therapies for AF management
AF ¼ atrial fibrillation; CHADS2 ¼ cardiac failure, Hypertension, Age, Diabetes, and Stroke (doubled); CHA2DS2-VASc ¼ congestive heart failure or left ventricular dysfunction, hypertension, age 75 (doubled), diabetes, stroke (doubled)–vascular disease, age 65 to 74, sex (female).
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Table 5
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Practical Recommendations for the Screening and Management of Cancer-Related AF on the Basis of Current Guidelines in Noncancer Patients and the Existing Evidence, Where Available, in Cancer Patients
Screening
When At cancer diagnosis Perioperatively; strong evidence supports an increased occurrence, particularly in patients undergoing lung resection Before and after chemotherapy and other cancer therapies; some evidence supports the association between AF and cancer therapies, such as specific cytotoxic agents and supportive therapies such as bisphosphonates At relative symptoms (persistent palpitations, irregular rhythm) How Pulse taking followed by electrocardiography
Prevention of thromboembolism
When At AF diagnosis, regardless of type (paroxysmal or persistent/permanent) Estimation of TER High TER in the presence of previous thromboembolism; moderate TER in the presence of age 75 years, hypertension, heart failure or left ventricular ejection fraction 35%, and diabetes mellitus; validated TER assessment tools such as CHAD2DS2-VASc score may be used Consider antithrombotic therapy even in low TER patients (e.g., CHA2DS2-VASc score ¼ 0) given the additional TER associated with certain cancers (e.g., pancreatic, ovarian, lung, primary hepatic) or cancer therapies (e.g., cisplatin, gemcitabine, 5-fluorouracil, erythropoietin, granulocyte colony-stimulating factors) Estimation of BR Cancer-related high BR features such as intracranial tumor, hematological malignancies with coagulation defects, cancer therapy–induced thrombocytopenia, and severe metastatic hepatic disease may be a contraindication to antithrombotic therapy regardless of TER Validated BR assessment tools such as HAS-BLED score may be used Medication Low molecular weight heparins: weak evidence suggests beneficial effects in cancer patients Vitamin K antagonists: consider interaction with concomitant cancer therapy Aspirin: may be contraindicated because of thrombocytopenia New oral anticoagulants: no data on cancer patients
Cardioversion
Hemodynamically unstable patient Electrical cardioversion Hemodynamically stable patient Perioperatively: weak evidence favors amiodarone and landiolol Nonperioperatively: according to the presence and severity of structural heart disease; weak evidence favors ibutilide
Sinus rhythm maintenance medication
Consider perioperative prophylaxis particularly in patients undergoing lung resection; weak evidence favors amiodarone and landiolol Consider in patients with recurrent paroxysmal episodes, advanced age, cardiovascular comorbidities, and so on Consider potential interactions with concomitant cancer therapy
Rate control
Main modality in end-stage metastatic disease on palliative care No evidence for specific agents in cancer patients Consider potential interactions with concomitant cancer therapy
Catheter ablation
No evidence yet in cancer patients May be a choice in patients with symptomatic paroxysmal atrial fibrillation despite antiarrhythmic therapy Consider patient’s preferences Consider the presence of structural heart disease Consider cancer prognosis (life expectancy) Consider individual bleeding/thrombotic risks
Left atrial appendix closure/occlusion
No evidence yet in cancer patients May be a choice in patients with high TER and BR (see previous text) Consider patient’s preferences Consider cancer prognosis (life expectancy)
BR ¼ bleeding risk; HAS-BLED ¼ hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol concomitantly; TER ¼ thromboembolic risk; other abbreviations as in Table 4.
patients with malignancies. Actually, dalteparin was associated with better survival than coumarin derivatives in patients with nonmetastatic solid tumors and venous thromboembolism (41). This may be related to the potential antitumor and antimetastatic effects of LMWH that have been shown to provide a survival benefit in patients with different types of cancer (42,43). As a result, the American College of Chest Physicians recommended the use of LMWH over vitamin K antagonists in cancer patients with venous thromboembolism (44). The role of LMWH in long-term anticoagulation therapy of patients with cancer and AF remains to be proven.
The decision regarding whether to begin antiarrhythmic therapy may also be difficult in cancer patients. In several cases, restoration and maintenance of sinus rhythm are necessary due to contraindications to long-term antithrombotic therapy. On the other hand, the antiarrhythmic medications that are effective in rhythm control, such as class III drugs, are associated with QT interval prolongation. Prolongation of the QT interval may also result from several drugs used in the treatment of cancer, including chemotherapeutic agents such as arsenic trioxide, targeted therapies such as angiogenic inhibitors, and supportive therapies such as ondansetron (45–47). Concomitant conditions such
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Figure 2
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Algorithm for Antithrombotic Therapy in Cancer-Related Atrial Fibrillation
A practical algorithm for antithrombotic therapy in cancer-related atrial fibrillation. *Intracranial tumor, hematologic malignancies with coagulation defects, cancer therapyinduced thrombocytopenia, severe metastatic hepatic disease etc. yHAS-BLED ¼ Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly zCHA2DS2-VASc ¼ Congestive heart failure or left ventricular dysfunction Hypertension, Age 75 (doubled), Diabetes, Stroke (doubled)-Vascular disease, Age 65–74, Sex (female) xAntithrombotic therapy may be considered in high thromboembolic risk associated with certain cancers (e.g., pancreatic, ovarian, lung, primary hepatic) or cancer therapies (e.g., cisplatin, gemcitabine, 5-fluorouracil, erythropoietin, granulocyte colony stimulating factors).
as electrolyte disturbances that occur frequently in these patients may also have a proarrhythmic effect. Clinical evidence in this field is quite limited. A retrospective analysis of 81 cancer patients who received ibutilide for cardioversion of AF or atrial flutter at MD Anderson Cancer Center showed that the drug was effective in 75% of cases (48). In the same study, although 84% of patients received at least 1 additional drug associated with QT interval prolongation, no changes in corrected QT interval were encountered in any of the patients. Radiofrequency catheter ablation for pulmonary vein isolation has not yet been studied in cancer patients, and it may be a good option for some of these patients, particularly when rhythm control therapy has failed or there are concerns about its interaction with the background therapy (49). Nevertheless, there are several issues that need to be taken into consideration when considering this technique for cancer patients, such as the high doses of anticoagulation required during the procedure and the risk of trauma in cancer patients with a high bleeding risk or the risk of thromboembolism associated with placing intracardiac catheters in those patients with a prothrombotic tendency. Given the lack of evidence of a specific rhythm- or rate-control strategy in cancer patients with AF, the strategy followed in other chronic conditions such as heart failure may be followed, with particular attention to concomitant or planned anticancer therapies and comorbid conditions (50,51). The management of post-operative AF represents an additional challenge given its high occurrence rate, especially during surgery for lung cancer, as previously stated. Postoperative N-terminal pro–B-type natriuretic peptide (NT-proBNP)
levels may identify patients at increased risk of post-operative AF and thus guide the use of prophylactic antiarrhythmic therapy (10). More specifically, in patients undergoing thoracic surgery for lung cancer, increased NT-proBNP, according to the assay’s age-related cutoffs, either 24 h before or 1 h after surgery, was associated with a substantially higher rate of AF (64% vs. 5% in patients without increased NT-proBNP; p < 0.001) (10). Another study identified a cutoff post-operative NT-proBNP level of 182 ng/l for the prediction of post-operative AF (14), whereas a B-type natriuretic peptide level of 30 pg/ml had a high specificity of 93% for predicting AF after pulmonary resection for lung cancer (52). In addition to natriuretic peptide level, echocardiographic indexes may also be useful, particularly those indicating left ventricular diastolic dysfunction or increased left ventricular diastolic pressures. A mitral E/e0 ratio >8 was highly sensitive (90% sensitivity) for predicting post-operative AF (16). Other predictors of post-operative AF include advanced age, male sex, long duration of surgery, advanced cancer stage, occurrence of surgical complications, need for postoperative blood transfusions, and history of hypertension and pre-operative paroxysmal AF (8,9,11,18). Several drugs have been studied for the prevention or management of post-operative AF, mostly in patients undergoing cardiac surgery (Table 3). These agents included beta-blockers such as metoprolol and landiolol, statins, angiotensin-converting enzyme inhibitors, omega-3 fatty acids, and ranolazine (21,53–56). The corresponding data on cancer patients are limited. Post-operative amiodarone prophylaxis, given at 300 mg intravenously over 20 min
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immediately after surgery followed by 600 mg orally twice daily for 5 days, reduced the risk of AF by 23% in patients undergoing lung cancer surgery (12). A cost analysis of this trial showed that amiodarone was a cost-neutral way to prevent post-operative AF in lung cancer patients (57). Furthermore, landiolol, a novel, ultrashort-acting betablocker, when given in a small group of patients who experienced AF after elective pulmonary resection for lung cancer, accomplished a more profound perioperative reduction of heart rate and a quicker restoration of sinus rhythm compared with historical controls treated with verapamil and digoxin (13). In another small clinical trial, low-dose human atrial natriuretic peptide infusion during lung cancer surgery was protective against post-operative AF in patients with pre-operative B-type natriuretic peptide increase (30 pg/ml) (17). In 2 subsequent studies from the same group, human atrial natriuretic peptide effectively reduced the incidence of post-operative cardiopulmonary complications during lung cancer surgery in patients 75 years of age as well as in patients with chronic obstructive pulmonary disease (58,59). In contrast, acebutolol induced a nonsignificant reduction in the incidence of post-operative AF in patients undergoing pulmonary resection compared with diltiazem or placebo (60). Conclusions and Practical Considerations The accumulated evidence suggests that a large part of AF in cancer patients results from surgery (4). The presence of AF may affect patients’ prognosis, whereas its management, particularly in terms of antithrombotic therapy for stroke prevention, is a challenge. There are several issues that need to be addressed by future research concerning epidemiology, pathogenesis, diagnosis, prevention, and treatment, as outlined in Table 4. Given the lack of evidence, there are currently no specific guidelines for AF therapy in patients with malignancies. An approach to practical issues concerning AF management based on the current guidelines in noncancer patients (1,61) and the existing evidence in cancer patients, where available, is shown in Table 5. In what concerns antithrombotic therapy in particular, certain features like intracranial tumors, chemotherapy-induced thrombocytopenia, and coagulation defects due to hematological malignancies may predispose to bleeding and therefore may constitute contraindications to antithrombotic therapy, even in patients at high thromboembolic risk. On the other hand, certain malignant tumors such as pancreatic, ovarian, lung, and primary hepatic cancer are associated with an increased thromboembolic risk, and the same applies to several chemotherapeutic agents such as cisplatin, gemcitabine, and 5-fluorouracil and supportive therapies like erythropoietin and granulocyte-colony stimulating factors (62–64). As a result, antithrombotic prophylaxis may be needed even in patients classified as low risk by risk assessment tools such as CHA2DS2-VASc score or others. An algorithm for
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antithrombotic therapy in cancer-related AF based on cancer features and established thromboembolic and bleeding risk assessment tools (CHA2DS2-VASc and HAS-BLED [Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (age >65 years), Drugs/alcohol concomitantly], respectively) is proposed in Figure 2. It should be stressed that the particular clinical features of cancer patients render an individually tailored therapy even more crucial, especially for antithrombotic prophylaxis. Reprint requests and correspondence: Dr. Gerasimos Filippatos, Second Department of Cardiology, University of Athens Medical School, Attikon Hospital, 1 Rimini Street, Athens, Greece. E-mail: [email protected].
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