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Atrial fibrillation in cancer patients: Hindsight, insight and foresight
International Journal of Cardiology 240 (2017) 196–202
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Atrial fibrillation in cancer patients: Hindsight, insight and foresight Benoîte Mery a,⁎, Jean-Baptiste Guichard b, Jean-Baptiste Guy c, Alexis Vallard c, Jean-Claude Barthelemy d, Antoine Da Costa b, Nicolas Magné c, Laurent Bertoletti e,f,g a
Department of Medical Oncology, Lucien Neuwirth Cancer Institute, St Priest en Jarez, France Division of Cardiology, Jean Monnet University, Saint-Etienne, France Radiotherapy Department, Lucien Neuwirth Cancer Institute, St Priest en Jarez, France d Laboratory SNA-EPIS EA4607, Department of Physiology, University hospital of Saint-Etienne, PRES Lyon, France e Department of Vascular and Therapeutic Medicine, University Hospital of Saint-Etienne, France f INSERM, CIC1408, Saint-Etienne, France g INSERM, U1059, Vascular Dysfunction and Homeostasis, Saint-Etienne, France b c
a r t i c l e
i n f o
Article history: Received 16 January 2017 Received in revised form 21 March 2017 Accepted 28 March 2017 Available online 6 April 2017 Keywords: Atrial fibrillation Cancer patients Onco-cardiology Therapeutic management
a b s t r a c t An increase of atrial fibrillation (AF) incidence in cancer patients has recently been pointed out, with complex interrelationships between these two entities on top of surgery factors. Most of present knowledge comes from retrospective studies or data from registries but the underlying mechanisms of the association between atrial fibrillation and cancer are still unclear. An increased risk of AF in cancer patients could represent a major public health problem although scarce information is available for the challenging management of such patients with distinctive features, especially in terms of antithrombotic therapy. Elaborate evidence-based approaches are thus required. This review provides an insight into AF among cancer patients through an overview of the underlying mechanisms, epidemiology evidence and future therapeutic challenges. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Atrial fibrillation (AF) concerns more than 33 million people, with an increasing incidence, and is associated to morbidity and mortality such as, for instance, systemic embolic complications (including ischemic stroke), heart failure, cognitive dysfunction and death. Beside AF of patients with cardiovascular diseases, AF can occur in a wide variety of conditions such as thyroid disorder, obstructive sleep apnea, chronic obstructive pulmonary disease and sepsis [1]. Recent data pointed out an increase of AF incidence among cancer patients, raising substantial concerns, notably regarding prognosis and treatment of cancer as AF may represent a major hindrance to cancer management [2]. An increased risk of AF in cancer patients could represent a major public health problem as cancer will affect one in two people by 2020 partly due to an aging population (which is also a major risk factor for both AF and AF-related complications as stroke). The improvements in cancer therapy have led to an increase in survival, but also in oncologists' concerns about medium and long-term complications [3,4]. It seems that inflammatory conditions, which are critical components of the neoplastic process may promote AF and be the common denominator for both entities, along with the autonomic nervous system impairment [5,6]. Thereby, more in-depth knowledge ⁎ Corresponding author at: Department of Medical Oncology, Lucien Neuwirth Cancer Institute, 42270 Saint Priest en Jarez, France. E-mail address: [email protected] (B. Mery).
http://dx.doi.org/10.1016/j.ijcard.2017.03.132 0167-5273/© 2017 Elsevier B.V. All rights reserved.
about pathogenesis and epidemiologic links between AF and cancer are required in order to improve therapeutic management of cancer patients with new onset AF, which remains another major issue. As a matter of fact, there are currently no available clinical guidelines in the management of AF following cancer diagnosis, notably in terms of antithrombotic treatment choice [4]. If AF remains a common reason for chronic warfarin use, it seems that cancer patients, who receive warfarin for deep venous thrombosis (DVT) and/or pulmonary embolism (PE), have worse anticoagulation control and worse outcomes in comparison with cancer-free patients [7]. Besides, the role and safety of direct oral anticoagulants (DOACS) in patients with cancer remains to be clarified as well as the CHA2DS2-VASc and HAS-BLED scores which have not been validated in this category of patients [4]. Clinical relevant data on treatment, duration, risk of embolic events and particularly ischemic strokes in cancer patients with AF are scarce in the literature. This review provides an insight into AF among cancer patients, and its substantial characteristics through an overview of underlying mechanisms, epidemiological evidence and future therapeutic challenges. 2. AF in cancer patients: intricacies and epidemiological grounds The epidemiological evidence for an association between AF and cancer is relatively recent and mainly relies on scarce data. Early research studies on this subject, dating from the mid-nineties, primarily mentioned an increased risk of AF after oncologic thoracic surgery,
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making postoperative AF, a highly explored entity now well-known [8, 9]. Indeed, beyond thoracic surgery, the occurrence of AF after surgery has been afterwards reported for colorectal cancer or esophageal cancer with substantial prevalence ranging respectively between 4% and 10% [10,11]. On the strength of these findings, additional studies confirmed that AF had a negative impact on prognosis, especially after pulmonary resection for lung cancer, with higher rates of morbi-mortality [12]. However, if the initial link between AF and cancer was mostly based on cancer surgery and its consequences, it has gradually become clearer that patients with cancer at the time of diagnosis, prior to any treatment, were at higher risk to develop AF and that AF could also occur postoperatively. Close links between AF and cancer outside the postoperative period have been reported by several case-control studies and support the argument that cancer in itself may be a comorbid state predisposing to AF. In a case-control study investigating the risk of colon cancer among 12,304 veterans taking nonsteroidal anti-inflammatory drugs, Muller et al. were the first to note a positive association between AF and cancer, as AF was more commonly found in veterans with colon cancer (odds ratio, 1.34 [95% CI, 1.16–1.55]) [13].Other case controlstudies among non-surgical populations have led to similar findings in different types of cancers, such as colorectal, kidney, breast or ovary cancers and also focused on persons with recent cancer diagnoses or patients who were admitted to hospital for cancer treatment, suggesting that cancer itself is a comorbid condition that predisposes to AF instead of a postoperative complication [14–17]. Indeed, as associations between surgery or chemotherapy and AF were avoided, thus suppressing possible confounding factors, a sharper distinction must be drawn between two main situations: a pre-existing AF before cancer diagnosis and a new-onset AF occurring after the diagnosis of cancer with possibly respective etiopathogenis. Epidemiological data of AF in cancer patients are summarized in Table 1.
3. Interconnections between AF and cancer: towards a new paradigm? Over the past three years, large cohort studies, working from these epidemiological retrospective premises, significantly enhanced the
197
aforementioned findings. So far, it appears that cancer increases the risk of AF, but leaves unexplained the hypothesis that AF could be a marker of occult cancer and thus if cancer screening in patients with new-onset AF should be considered. To this end, a cohort study of 269,742 patients based on Danish registry data, highlighted that patients who were diagnosed with AF had a 5 times increased risk of cancer diagnosis in the first 3 months of their AF diagnosis, which represents a 2.5% absolute risk of cancer diagnosis (95% CI, 2.4%–2.5%). The relative risk of cancer diagnosis was clearly high for all types of cancer within 3 months after AF diagnosis, but was even more pronounced for lung, kidney and colon cancers. Consequently, the authors underline the potential role of AF as a marker for occult cancer, and question the interest of an extensive cancer screening at AF diagnosis in selected patients, as a way to improve prognosis [18]. The interconnection of both entities has also been investigated by Conen et al., in a long-term prospective cohort study of 34,691 women aged 45 or older. Women were followed up between 1993 and 2013 for incident AF and malignant cancer within the Women's Health Study, a randomized clinical trial of aspirin and vitamin E for preventing cardiovascular diseases and cancer. The findings published in 2016 showed that women with new-onset AF had a significantly increased risk of incident cancer during subsequent follow-up, even after extensive adjustment for age (hazard ratio, 1.58 [95% CI, 1.34–1.87]) and other potential cofounders including cardiovascular diseases, diabetes, smoking, and alcohol consumption (hazard ratio, 1.48 [95% CI, 1.25–1.75]). The risk of cancer was 3-fold higher within 3 months of AF diagnosis (hazard ratio, 3.54 [95% CI, 2.05–6.1]) and remained significant beyond 1 year (hazard ratio, 1.42 [95% CI, 1.18–1.71]). Of the examined cancer subtypes, AF was most strongly associated with colon cancer, probably due to the use of anticoagulants among patients with AF and occult colon cancer that may have led to bleeding and then, earlier detection. In contrast, the risk of incident AF after cancer diagnosis was 20% higher in the first 3 months, but not beyond. The authors also highlight that cancer and AF do share risk factors which might underlie their interrelation and subsequently, this study could not exclude that possibility. A number of coexisting comorbidities including smoking, obesity and alcoholism as well as aging are known to predispose both
Table 1 Epidemiological evidence of AF in cancer patients. Type of study, year
First author
Type of cancer
Number of patients
HR
OR
SIRs
AF prevalence
95% CI
References
Prospective single-center study 2005 Prospective single-center study 2012 Retrospective study 2005 Prospective single-center study 2013 Case-control study 1994 Case-control study 2002 Prospective single-center study 2008 Case-control study 2012 Cohort study 2012 Cohort study 2014 Cohort study 2016
Roselli et al.
Lung cancer resection
604
UK
UK
UK
19%
UK
[9]
Imperatori et al.
Lung cancer resection
454
UK
UK
UK
9.9%
UK
[12]
Siu et al.
563
UK
UK
UK
4.4%
UK
[10]
207
UK
UK
UK
9.2%
UK
[11]
Muller AD et al.
Elective surgery for colorectal cancer Esophagealcancer resection Colon cancer
12,304
1.34
UK
UK
UK
1.16–1.55
[13]
Guzzetti et al.
Colorectal cancer
456
UK
3.5
UK
5.2%
1.6–7.2
[14]
Guzzetti et al.
1317
UK
3.3
UK
3,6%
1.67–6.61
[15]
Erichsen et al.
Colorectal or breast cancer Colorectal cancer
28,333
UK
7
UK
0.59%
6.3–7.8
[16]
Hu et al.
All cancers combined
24,125
UK
UK
UK
UK
[17]
Ostenfeld et al.
All cancers combined
UK
UK
5.11
4.99–5.24
[18]
Conen et al.
All cancers combined
269,742 with new-onset AF 34,961
2.4% at cancer diagnosis/1.8% after cancer diagnosis UK
1.58
UK
UK
4.2%
1.34–1.87
[2]
SIRs: standardized incidence ratios. HR: hazard ratio. OR: odds ratio. UK: unknown data.
Ojima et al.
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to AF and cancer making unidirectional the association between these two entities. Pre-existing or new-onset AF may be both promote by shared risk factors. Finally, if AF appears to be a risk marker for cancer in these non-experimental observational studies, through common pathogenesis or co-morbidities in part, mechanisms underlying this association should be fleshed out by stronger evidence so as to determine for instance whether the presence of new-onset AF should prompt a search for occult cancer [2]. 4. New-onset and pre-existing AF in cancer patients: anchorage points of underlying mechanisms Several hypotheses beyond anatomic loco-regional factors of cancer progression could explain the increased prevalence of new-onset AF among cancer patients. At first glance, cancer-related comorbidities including hypoxia, metabolic disorders, sepsis, major surgery, and electrolyte abnormalities could foster the occurrence of new-onset AF in cancer patients, as a side effect of cancer therapy with intercurrent events that complicate the course of cancer patients [4]. However, if such predominant factors may largely contribute to transient AF, and especially through opportunistic infections enhanced by immunosuppressive anti-cancer drugs, alterations of the autonomic nervous system are often described in cancer patients and may play a causal role in the long term development of AF. Some of the potential mechanisms leading to autonomic impairment have been notably described in breast cancer and include antineoplastic therapy, psychosocial stress, sleep disturbances, weight gain, metabolic dysregulation, and low cardiorespiratory fitness that may share a common cholinergic mechanism of dysfunction [19]. An excess of sympathetic activity has been described as inductor of cancer, notably in gastric cancer cells [20]. Long-term α1B-adrenergic receptor stimulation shortens lifespan while α1Aadrenergic receptor stimulation prolongs it in association with a decrease in cancer incidence [21]. Activation of Src by β-adrenoreceptors is a key switch for tumor metastasis as in bone cancer cells and, conversely, carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src [22–24]. In women with ovarian cancer, the use of non-selective beta blockers increased significantly overall survival [25]. Concerning breast cancer, survival was significantly improved (HR: 0.44; 95%CI: 0.26–0.73) in those taking beta blockers, giving epidemiological evidence [26]. On another note, it is well known that autonomic nervous system activation can result in significant changes of atrial electrophysiology and is able to induce AF by both reentry and triggered activity, through calcium-mediated mechanisms. Thus, new-onset AF in cancer patients may be a direct consequence of autonomic activity disequilibrium [27]. AF has been described as a consequence of disequilibrium in autonomic tone both from vagal or sympathetic influences [28]. Elevated M2-muscarinic and β1 adrenergic receptor autoantibody levels are associated with atrial fibrillation and these cardiac autoantibody levels predict recurrence following pulmonary vein isolation in atrial paroxysmal fibrillation [29–30]. M2-muscarinic acetylcholine receptor autoantibody level is an independent predictor of left atrial fibrosis severity in man [31]. β1 adrenergic and M2 muscarinic autoantibodies also facilitate induction of atrial fibrillation in experimental settings. Recently, some population cells have been identified as the melanocytes-like cells localized in atrial tissue at sites from which AF triggers commonly originate [32]. These cells are located in close apposition to autonomic nerve terminals. Mutations at their level determine more susceptibility to atrial arrhythmias and it appears that the cardiac melanocyte itself can be responsible for atrial arrhythmogenesis. The involvement of the immune system has also been hypothesized as autoimmune paraneoplastic syndromes sustained by antibodies directed against tumor antigens have been observed and may lead to immune reaction against atrial structures and thus trigger the arrhythmia [33]. It has notably been described in the field of neurology with autoantibodies directed against ionic channels and acetylcholine receptors
[34]. Regarding cancer treatments, surgery, chemotherapy and radiotherapy can provoke AF, more especially in the long term, and represent in that sense, a double-edged sword; most of the cytotoxic agents including alkylating agents (cisplatin, cyclophosphamide, ifosfamide, melphalan), anthracyclines, antimetabolites, taxanes and topoisomerase II inhibitors have been found to largely induce AF through cardiotoxicity, as well as tyrosine kinase inhibitors, high-dose corticosteroids and antiemetic agents. Besides, left ventricular dysfunction and heart failure are relatively common and serious side effects of chemotherapy and radiotherapy. Finally, diastolic dysfunction which is common in cancer patients probably because of frequent changes in their volume status may also contribute to the occurrence of AF [35] [36]. Concerning surgery, intrathoracic resection for cancer is associated to a major incidence of post-operative AF whereas a lower percentage is reported for non-thoracic cancer surgeries [37]. As to the issue of radiotherapy, the risk of AF is the highest in patients who undergo both left breast radiotherapy and cardiotoxic chemotherapy through myocardial fibrosis and a synergistic cardiac toxicity [4]. Concurrently, inflammation is a critical component of tumor progression and the tumor microenvironment is largely orchestrated by inflammatory cells which increase the production of reactive oxygen species, leading to oxidative DNA damage and permanent genomic alterations. In addition, oxidative stress and excessive production of reactive oxygen species are involved in the pathogenesis of AF through structural and electrical changes. Inflammation is involved in several AF-related pathological processes including oxidative stress and fibrosis. Thereby, oxidative stress through inflammatory cells is another common link between AF and cancer [38–39]. If CRP elevation has been detected in both colon and breast cancer higher levels of inflammatory markers as well as elevated neutrophil and lymphocyte ratio have also been reported in patients with AF in comparison with those in sinus rhythm [40–42]. Similarly, increased CRP levels have been shown to predict the occurrence of AF in several prospective cohorts. Elevated plasma CRP was robustly associated with increased risk of persistent and severe AF as an association between markers of inflammation and stroke risk in AF patients was also reported [43–44]. Even more to the point, a significant decrease in CRP levels after cardioversion was noted, making the relationship between inflammation and persistence of atrial fibrillation clearer [45]. At last, atrial and ventricular biopsies of patients with lone AF have displayed the presence of inflammatory infiltrates. Furthermore, AF-related thrombogenesis and inflammation are intimately linked as increased CRP-levels in AF patients are associated with left atrial thrombus formation and dense spontaneous echo contrast. Atrial fibrosis appears to be a major potential contributor to the substrate for AF maintenance [46]. Such data underscore the fact that a persistent inflammatory state with the presence of oxygen species released from inflammatory cells as found in cancer, can promote AF and its thromboembolic complications. Besides, pre-existing AF shortly before cancer diagnosis may result from persistent and chronic inflammation when cancer is in early sub-clinical development without any possibility of properly screening. These physiopathological hypotheses are summarized in Fig. 1. 5. Current challenges of cancer patients with AF: therapeutic hints Important dilemmas in the treatment of patients with pre-existing AF who develop cancer or new-onset AF occurring during cancer course remain the choice of the therapeutic strategy and more particularly, of the antithrombotic therapy. In a retrospective cohort study, Hu et al. have shed new light on the fact that AF is related to poor prognosis in cancer patients and that both treatment and prevention might be of paramount importance as cancer patients with new-onset AF had greater likelihood of thromboembolism and heart failure with, however, higher mortality. Poor prognosis might mainly result from AF related cardiac dysfunction that occurs in frail and immunocompromised cancer patients [17]. In contrast, a more recent observational cohort study
B. Mery et al. / International Journal of Cardiology 240 (2017) 196–202
199
Chronic inflammation of carcinogenesis Invasiveness of cancer and direct loco-regional factors
Oxidative stress Electrical and structural atrial remodeling Thrombogenesis
Pre-existing AF
Mediastinal/pericardial area Pericardial effusion Cardiac tumors
Shared risk factors
Paraneoplastic syndromes Thyroid disorder Auto-immunity
Carcinogens (smoking, alcohol) Aging, obesity
Cancer treatments
New-onset AF
Thoracic surgery Chemotherapy Radiotherapy Steroids, targeted agents, bisphosphonates
Intrinsic characteristics of cancer patient Electrolyte and metabolic disorders Autonomic nervous system impairement
Fig. 1. Underlying physiological mechanisms of AF in cancer patients.
found that a pre-existing diagnosis of cancer is associated with increased 30-day mortality among patients diagnosed with new-onset AF and that active cancer is an independent predictor of 30-day mortality [47]. Cancer in itself promotes a pro-thrombotic state through release of procoagulant and fibrinolytic agents, production of proinflammatory cytokines as well as alteration of vascular endothelium and subsequently may increase the risk of thromboembolic events in patients with AF. If on the one hand, cancer can be considered as an acquired thrombophilic condition with increased incidence of venous and arterial thromboembolic complications, AF is also associated with a hypercoagulated and prothrombotic state that confers a significant increased risk of thromboembolic stroke. Abnormalities of blood flow, vessel wall changes and variations in blood components underlie the higher risk of arterial thromboembolism in patients with AF [48–49]. However, scores for thromboembolic risk prediction in AF such as CHA2DS2-Vasc do not include cancer as a variable and may not be suitable for these patients [17]. The thromboembolic risks of AF in cancer patients may be higher and the need to systematically use anticoagulant medication in these patients should be discussed. Furthermore, despite the fact that vitamin K antagonists (VKAs) have constituted the main oral anticoagulant therapy for AF and VTE for decades, their use in cancer patients with AF in particular is not as obvious as it seems [50]. In clinical practice, low molecular weight heparins (LMWH) are used preferentially to VKAs for this category of patients due to their supposed lower risk of drug interaction with anti-cancer treatments even if no sufficient data support the relevance of such a therapeutic management. Indeed, the benefit/risk balance associated to the use of VKAs in cancer patients has been studied solely in the specific context of VTE; as significant increased risks of thromboembolic recurrence and bleeding were reported with VKAs, the use of LMWH is recommended in the VTE setting, at least for the first three months of treatment, whereas no data is currently available in the AF setting [51]. Moreover, using VKA may be problematic in cancer patients as they display specific features such as unpredictable anticoagulant response and higher bleeding risks as well as frequent changes in renal or hepatic functions, hence the need of specific guidelines for the therapeutic management of AF in this unique set of patients [52]. Recently, Ambrus et al. showed that a new cancer diagnosis significantly worsens warfarin control in the six-month period following diagnosis in
comparison to the cancer-free cohort among 122,875 veterans who have been receiving warfarin for AF prior to cancer diagnosis. Besides, regarding the outcomes, anticoagulation control appears to be a major step in the causal pathway to anticoagulation-related outcomes as a significant increase in rate of major hemorrhage was found among patients with active cancer who were receiving
Table 2 Drug-drug interactions between antiarrhythmic drugs, anticoagulants and anticancer therapies through specific interactions. Metabolic interference Oncology drugs • Vinca alkaloids • Taxanes • Antimetabolites (methotrexate) • Topoisomerase inhibitors • Anthracyclines (doxorubicin) • Alkylating agents (ifosfamide, busulfan) • Platinum-based agents • Tyrosine kinase inhibitors • Hormonal agents (tamoxifen, flutamide, enzalutamide, abiraterone) Vitamin K antagonists • Warfarin • Acenocoumarol • Fluindione New oral anticoagulants • Dabigatran • Apixaban • Rivaroxaban Antiarrhythmic drugs • Amiodarone • Digoxin • Diltiazem • Dronedarone • Quinidine • Verapamil +++, strong interaction. ++, moderate interaction. +, weak interaction. *, an interaction has been documented.
P-glycoprotein CYP3A4 CYP2C9 interaction interaction interaction * * * * *
* *
+++ +++ +++ +++ +++
+++ +++
+
+++ +++ +++ ++ +++ +++ +++ +++ +++
+++ +++
+ +++ +
+++ +++ +++
200
B. Mery et al. / International Journal of Cardiology 240 (2017) 196–202
Ageing
Longer survival Pre-existing AF
CANCER Mid and long term complications
New-onset AF
Which impact on cancer prognosis and outcome?
Which underlying mechanisms beyond inflammation?
Increased incidence of AF in cancer patients
Cancer related-specificities: Metabolic disorders Higher bleeding risk Concomitant medication Worse anticoagulation control
Which available strategies for stroke prevention?
Which impact on cancer therapeutic decisions?
No specific thromboembolic risk prediction score
Fig. 2. Current issues of AF in cancer patients.
warfarin for AF. The authors also pointed out that this issue is all the more crucial given the fact that patients anticoagulated for AF are more than 2.5 times as numerous as patients anticoagulated for venous thromboembolism [7]. Meanwhile, DOACS are being increasingly prescribed for patients with AF and it is now recommended to use them in first intention for common population. It is thus expected that a growing number of patients with newly diagnosed malignancy will be undergoing such treatment. Thereby, one may wonder if it is safe to continue DOACS in patients with a newly diagnosed cancer. Their use for the prevention and management of thrombotic disorders in cancer patients might present considerable benefits as laboratory monitoring is not required, due to their wide therapeutic window. Nevertheless, no data concerning DOACS in cancer patients with AF are available yet. Besides, although the DOACS seem to display less drug-drug interactions than Vitamin K antagonists, drugs that affect the CYP3A4 enzyme could alter the plasma concentrations of DOACS and lead to worse anticoagulation effects. It is of utmost importance as several chemotherapy drugs induce or inhibit the activity of CYP3A4. Even if drugs with mild interactions have a low propensity for significant drug interactions with the DOACS, chemotherapeutic agents are often used in combination and thus accurate interactions are still unknown. Furthermore, the risk of bleeding is higher in digestive cancers, making DOACS impossible to use in that particular case, as there is no specific antidote [52–53]. Above all, the large clinical trials of dabigatran, apixaban, and rivaroxaban for stroke prevention in AF have excluded patients with active cancer [54–56]. Therefore, even if Larsen et al. have showed a beneficial effect of DOACS for the treatment of venous thromboembolism in cancer patients, in terms of efficacy and safety, statistical evidence was not reached [57]. Consequently, there is still no strong evidence to guide practice and interventional studies are required. Finally, DOACS may also have beneficial effects in AF that go beyond simply clot formation as it has been recently shown that inhibitors of thrombin or FXa could contribute to the inhibition of the AF substrate and thus directly impact its main underlying mechanism [58]. Drug-drug interactions between antiarrhytmic, anticoagulation drugs and cancer-related therapies are presented in Table 2.
6. Conclusion The emerging entity of AF in cancer patients seems to be based on recent detailed epidemiological evidence that need to be enhanced by additional large-scale randomized clinical trials, which are the main framework for progress. There is a crucial need for more epidemiological studies focusing on the link between AF and cancer in order to establish specific cancers at risk for AF. Both aspects including epidemiology, pathogenesis and treatment still have to be elucidated as it could become a major public health problem over the next years, because of the rising incidence of both conditions. If progress in cancer therapy has led to longer survival, we should be able to properly manage concomitant pathologies such as AF, with accurate therapeutic strategies, particularly given that the presence of AF may affect patients' prognosis. The optimization of treatment and preventive strategies for better patient outcomes is of particular importance and has to be explored as current guidelines do not address the specific issue of AF in cancer patients. Ultimately, the question of cancer screening secondarily to new-onset AF discovery is still unresolved and may induce radical reform of our working practices. Current issues of pre-existing and new onset AF in cancer patients are presented in Fig. 2. Conflicts of interest Laurent Bertoletti reports receiving consulting or lecture fees from Bayer, Bristol-Myers Squibb, Pfizer, Daichii-Sankyo, LEO Pharma and Sanofi Avantis. He was principal investigator, Coordinator or investigator of clinical studies promoted by Bayer, Bristol-Myers Squibb, Pfizer, Daichii-Sankyo, Portola. The other authors report no relationships that could be construed as a conflict of interest. References [1] T. Wilke, A. Groth, S. Mueller, M. Pfannkuche, F. Verheyen, R. Linder, U. Maywald, R. Bauersachs, G. Breithardt, Incidence and prevalence of atrial fibrillation: an analysis based on 8.3 million patients, Europace 15 (2013) 486–493.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Atrial fibrillation in cancer patients: Hindsight, insight and foresight Benoîte Mery a,⁎, Jean-Baptiste Guichard b, Jean-Baptiste Guy c, Alexis Vallard c, Jean-Claude Barthelemy d, Antoine Da Costa b, Nicolas Magné c, Laurent Bertoletti e,f,g a
Department of Medical Oncology, Lucien Neuwirth Cancer Institute, St Priest en Jarez, France Division of Cardiology, Jean Monnet University, Saint-Etienne, France Radiotherapy Department, Lucien Neuwirth Cancer Institute, St Priest en Jarez, France d Laboratory SNA-EPIS EA4607, Department of Physiology, University hospital of Saint-Etienne, PRES Lyon, France e Department of Vascular and Therapeutic Medicine, University Hospital of Saint-Etienne, France f INSERM, CIC1408, Saint-Etienne, France g INSERM, U1059, Vascular Dysfunction and Homeostasis, Saint-Etienne, France b c
a r t i c l e
i n f o
Article history: Received 16 January 2017 Received in revised form 21 March 2017 Accepted 28 March 2017 Available online 6 April 2017 Keywords: Atrial fibrillation Cancer patients Onco-cardiology Therapeutic management
a b s t r a c t An increase of atrial fibrillation (AF) incidence in cancer patients has recently been pointed out, with complex interrelationships between these two entities on top of surgery factors. Most of present knowledge comes from retrospective studies or data from registries but the underlying mechanisms of the association between atrial fibrillation and cancer are still unclear. An increased risk of AF in cancer patients could represent a major public health problem although scarce information is available for the challenging management of such patients with distinctive features, especially in terms of antithrombotic therapy. Elaborate evidence-based approaches are thus required. This review provides an insight into AF among cancer patients through an overview of the underlying mechanisms, epidemiology evidence and future therapeutic challenges. © 2017 Elsevier B.V. All rights reserved.
1. Introduction Atrial fibrillation (AF) concerns more than 33 million people, with an increasing incidence, and is associated to morbidity and mortality such as, for instance, systemic embolic complications (including ischemic stroke), heart failure, cognitive dysfunction and death. Beside AF of patients with cardiovascular diseases, AF can occur in a wide variety of conditions such as thyroid disorder, obstructive sleep apnea, chronic obstructive pulmonary disease and sepsis [1]. Recent data pointed out an increase of AF incidence among cancer patients, raising substantial concerns, notably regarding prognosis and treatment of cancer as AF may represent a major hindrance to cancer management [2]. An increased risk of AF in cancer patients could represent a major public health problem as cancer will affect one in two people by 2020 partly due to an aging population (which is also a major risk factor for both AF and AF-related complications as stroke). The improvements in cancer therapy have led to an increase in survival, but also in oncologists' concerns about medium and long-term complications [3,4]. It seems that inflammatory conditions, which are critical components of the neoplastic process may promote AF and be the common denominator for both entities, along with the autonomic nervous system impairment [5,6]. Thereby, more in-depth knowledge ⁎ Corresponding author at: Department of Medical Oncology, Lucien Neuwirth Cancer Institute, 42270 Saint Priest en Jarez, France. E-mail address: [email protected] (B. Mery).
http://dx.doi.org/10.1016/j.ijcard.2017.03.132 0167-5273/© 2017 Elsevier B.V. All rights reserved.
about pathogenesis and epidemiologic links between AF and cancer are required in order to improve therapeutic management of cancer patients with new onset AF, which remains another major issue. As a matter of fact, there are currently no available clinical guidelines in the management of AF following cancer diagnosis, notably in terms of antithrombotic treatment choice [4]. If AF remains a common reason for chronic warfarin use, it seems that cancer patients, who receive warfarin for deep venous thrombosis (DVT) and/or pulmonary embolism (PE), have worse anticoagulation control and worse outcomes in comparison with cancer-free patients [7]. Besides, the role and safety of direct oral anticoagulants (DOACS) in patients with cancer remains to be clarified as well as the CHA2DS2-VASc and HAS-BLED scores which have not been validated in this category of patients [4]. Clinical relevant data on treatment, duration, risk of embolic events and particularly ischemic strokes in cancer patients with AF are scarce in the literature. This review provides an insight into AF among cancer patients, and its substantial characteristics through an overview of underlying mechanisms, epidemiological evidence and future therapeutic challenges. 2. AF in cancer patients: intricacies and epidemiological grounds The epidemiological evidence for an association between AF and cancer is relatively recent and mainly relies on scarce data. Early research studies on this subject, dating from the mid-nineties, primarily mentioned an increased risk of AF after oncologic thoracic surgery,
B. Mery et al. / International Journal of Cardiology 240 (2017) 196–202
making postoperative AF, a highly explored entity now well-known [8, 9]. Indeed, beyond thoracic surgery, the occurrence of AF after surgery has been afterwards reported for colorectal cancer or esophageal cancer with substantial prevalence ranging respectively between 4% and 10% [10,11]. On the strength of these findings, additional studies confirmed that AF had a negative impact on prognosis, especially after pulmonary resection for lung cancer, with higher rates of morbi-mortality [12]. However, if the initial link between AF and cancer was mostly based on cancer surgery and its consequences, it has gradually become clearer that patients with cancer at the time of diagnosis, prior to any treatment, were at higher risk to develop AF and that AF could also occur postoperatively. Close links between AF and cancer outside the postoperative period have been reported by several case-control studies and support the argument that cancer in itself may be a comorbid state predisposing to AF. In a case-control study investigating the risk of colon cancer among 12,304 veterans taking nonsteroidal anti-inflammatory drugs, Muller et al. were the first to note a positive association between AF and cancer, as AF was more commonly found in veterans with colon cancer (odds ratio, 1.34 [95% CI, 1.16–1.55]) [13].Other case controlstudies among non-surgical populations have led to similar findings in different types of cancers, such as colorectal, kidney, breast or ovary cancers and also focused on persons with recent cancer diagnoses or patients who were admitted to hospital for cancer treatment, suggesting that cancer itself is a comorbid condition that predisposes to AF instead of a postoperative complication [14–17]. Indeed, as associations between surgery or chemotherapy and AF were avoided, thus suppressing possible confounding factors, a sharper distinction must be drawn between two main situations: a pre-existing AF before cancer diagnosis and a new-onset AF occurring after the diagnosis of cancer with possibly respective etiopathogenis. Epidemiological data of AF in cancer patients are summarized in Table 1.
3. Interconnections between AF and cancer: towards a new paradigm? Over the past three years, large cohort studies, working from these epidemiological retrospective premises, significantly enhanced the
197
aforementioned findings. So far, it appears that cancer increases the risk of AF, but leaves unexplained the hypothesis that AF could be a marker of occult cancer and thus if cancer screening in patients with new-onset AF should be considered. To this end, a cohort study of 269,742 patients based on Danish registry data, highlighted that patients who were diagnosed with AF had a 5 times increased risk of cancer diagnosis in the first 3 months of their AF diagnosis, which represents a 2.5% absolute risk of cancer diagnosis (95% CI, 2.4%–2.5%). The relative risk of cancer diagnosis was clearly high for all types of cancer within 3 months after AF diagnosis, but was even more pronounced for lung, kidney and colon cancers. Consequently, the authors underline the potential role of AF as a marker for occult cancer, and question the interest of an extensive cancer screening at AF diagnosis in selected patients, as a way to improve prognosis [18]. The interconnection of both entities has also been investigated by Conen et al., in a long-term prospective cohort study of 34,691 women aged 45 or older. Women were followed up between 1993 and 2013 for incident AF and malignant cancer within the Women's Health Study, a randomized clinical trial of aspirin and vitamin E for preventing cardiovascular diseases and cancer. The findings published in 2016 showed that women with new-onset AF had a significantly increased risk of incident cancer during subsequent follow-up, even after extensive adjustment for age (hazard ratio, 1.58 [95% CI, 1.34–1.87]) and other potential cofounders including cardiovascular diseases, diabetes, smoking, and alcohol consumption (hazard ratio, 1.48 [95% CI, 1.25–1.75]). The risk of cancer was 3-fold higher within 3 months of AF diagnosis (hazard ratio, 3.54 [95% CI, 2.05–6.1]) and remained significant beyond 1 year (hazard ratio, 1.42 [95% CI, 1.18–1.71]). Of the examined cancer subtypes, AF was most strongly associated with colon cancer, probably due to the use of anticoagulants among patients with AF and occult colon cancer that may have led to bleeding and then, earlier detection. In contrast, the risk of incident AF after cancer diagnosis was 20% higher in the first 3 months, but not beyond. The authors also highlight that cancer and AF do share risk factors which might underlie their interrelation and subsequently, this study could not exclude that possibility. A number of coexisting comorbidities including smoking, obesity and alcoholism as well as aging are known to predispose both
Table 1 Epidemiological evidence of AF in cancer patients. Type of study, year
First author
Type of cancer
Number of patients
HR
OR
SIRs
AF prevalence
95% CI
References
Prospective single-center study 2005 Prospective single-center study 2012 Retrospective study 2005 Prospective single-center study 2013 Case-control study 1994 Case-control study 2002 Prospective single-center study 2008 Case-control study 2012 Cohort study 2012 Cohort study 2014 Cohort study 2016
Roselli et al.
Lung cancer resection
604
UK
UK
UK
19%
UK
[9]
Imperatori et al.
Lung cancer resection
454
UK
UK
UK
9.9%
UK
[12]
Siu et al.
563
UK
UK
UK
4.4%
UK
[10]
207
UK
UK
UK
9.2%
UK
[11]
Muller AD et al.
Elective surgery for colorectal cancer Esophagealcancer resection Colon cancer
12,304
1.34
UK
UK
UK
1.16–1.55
[13]
Guzzetti et al.
Colorectal cancer
456
UK
3.5
UK
5.2%
1.6–7.2
[14]
Guzzetti et al.
1317
UK
3.3
UK
3,6%
1.67–6.61
[15]
Erichsen et al.
Colorectal or breast cancer Colorectal cancer
28,333
UK
7
UK
0.59%
6.3–7.8
[16]
Hu et al.
All cancers combined
24,125
UK
UK
UK
UK
[17]
Ostenfeld et al.
All cancers combined
UK
UK
5.11
4.99–5.24
[18]
Conen et al.
All cancers combined
269,742 with new-onset AF 34,961
2.4% at cancer diagnosis/1.8% after cancer diagnosis UK
1.58
UK
UK
4.2%
1.34–1.87
[2]
SIRs: standardized incidence ratios. HR: hazard ratio. OR: odds ratio. UK: unknown data.
Ojima et al.
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to AF and cancer making unidirectional the association between these two entities. Pre-existing or new-onset AF may be both promote by shared risk factors. Finally, if AF appears to be a risk marker for cancer in these non-experimental observational studies, through common pathogenesis or co-morbidities in part, mechanisms underlying this association should be fleshed out by stronger evidence so as to determine for instance whether the presence of new-onset AF should prompt a search for occult cancer [2]. 4. New-onset and pre-existing AF in cancer patients: anchorage points of underlying mechanisms Several hypotheses beyond anatomic loco-regional factors of cancer progression could explain the increased prevalence of new-onset AF among cancer patients. At first glance, cancer-related comorbidities including hypoxia, metabolic disorders, sepsis, major surgery, and electrolyte abnormalities could foster the occurrence of new-onset AF in cancer patients, as a side effect of cancer therapy with intercurrent events that complicate the course of cancer patients [4]. However, if such predominant factors may largely contribute to transient AF, and especially through opportunistic infections enhanced by immunosuppressive anti-cancer drugs, alterations of the autonomic nervous system are often described in cancer patients and may play a causal role in the long term development of AF. Some of the potential mechanisms leading to autonomic impairment have been notably described in breast cancer and include antineoplastic therapy, psychosocial stress, sleep disturbances, weight gain, metabolic dysregulation, and low cardiorespiratory fitness that may share a common cholinergic mechanism of dysfunction [19]. An excess of sympathetic activity has been described as inductor of cancer, notably in gastric cancer cells [20]. Long-term α1B-adrenergic receptor stimulation shortens lifespan while α1Aadrenergic receptor stimulation prolongs it in association with a decrease in cancer incidence [21]. Activation of Src by β-adrenoreceptors is a key switch for tumor metastasis as in bone cancer cells and, conversely, carvedilol suppresses migration and invasion of malignant breast cells by inactivating Src [22–24]. In women with ovarian cancer, the use of non-selective beta blockers increased significantly overall survival [25]. Concerning breast cancer, survival was significantly improved (HR: 0.44; 95%CI: 0.26–0.73) in those taking beta blockers, giving epidemiological evidence [26]. On another note, it is well known that autonomic nervous system activation can result in significant changes of atrial electrophysiology and is able to induce AF by both reentry and triggered activity, through calcium-mediated mechanisms. Thus, new-onset AF in cancer patients may be a direct consequence of autonomic activity disequilibrium [27]. AF has been described as a consequence of disequilibrium in autonomic tone both from vagal or sympathetic influences [28]. Elevated M2-muscarinic and β1 adrenergic receptor autoantibody levels are associated with atrial fibrillation and these cardiac autoantibody levels predict recurrence following pulmonary vein isolation in atrial paroxysmal fibrillation [29–30]. M2-muscarinic acetylcholine receptor autoantibody level is an independent predictor of left atrial fibrosis severity in man [31]. β1 adrenergic and M2 muscarinic autoantibodies also facilitate induction of atrial fibrillation in experimental settings. Recently, some population cells have been identified as the melanocytes-like cells localized in atrial tissue at sites from which AF triggers commonly originate [32]. These cells are located in close apposition to autonomic nerve terminals. Mutations at their level determine more susceptibility to atrial arrhythmias and it appears that the cardiac melanocyte itself can be responsible for atrial arrhythmogenesis. The involvement of the immune system has also been hypothesized as autoimmune paraneoplastic syndromes sustained by antibodies directed against tumor antigens have been observed and may lead to immune reaction against atrial structures and thus trigger the arrhythmia [33]. It has notably been described in the field of neurology with autoantibodies directed against ionic channels and acetylcholine receptors
[34]. Regarding cancer treatments, surgery, chemotherapy and radiotherapy can provoke AF, more especially in the long term, and represent in that sense, a double-edged sword; most of the cytotoxic agents including alkylating agents (cisplatin, cyclophosphamide, ifosfamide, melphalan), anthracyclines, antimetabolites, taxanes and topoisomerase II inhibitors have been found to largely induce AF through cardiotoxicity, as well as tyrosine kinase inhibitors, high-dose corticosteroids and antiemetic agents. Besides, left ventricular dysfunction and heart failure are relatively common and serious side effects of chemotherapy and radiotherapy. Finally, diastolic dysfunction which is common in cancer patients probably because of frequent changes in their volume status may also contribute to the occurrence of AF [35] [36]. Concerning surgery, intrathoracic resection for cancer is associated to a major incidence of post-operative AF whereas a lower percentage is reported for non-thoracic cancer surgeries [37]. As to the issue of radiotherapy, the risk of AF is the highest in patients who undergo both left breast radiotherapy and cardiotoxic chemotherapy through myocardial fibrosis and a synergistic cardiac toxicity [4]. Concurrently, inflammation is a critical component of tumor progression and the tumor microenvironment is largely orchestrated by inflammatory cells which increase the production of reactive oxygen species, leading to oxidative DNA damage and permanent genomic alterations. In addition, oxidative stress and excessive production of reactive oxygen species are involved in the pathogenesis of AF through structural and electrical changes. Inflammation is involved in several AF-related pathological processes including oxidative stress and fibrosis. Thereby, oxidative stress through inflammatory cells is another common link between AF and cancer [38–39]. If CRP elevation has been detected in both colon and breast cancer higher levels of inflammatory markers as well as elevated neutrophil and lymphocyte ratio have also been reported in patients with AF in comparison with those in sinus rhythm [40–42]. Similarly, increased CRP levels have been shown to predict the occurrence of AF in several prospective cohorts. Elevated plasma CRP was robustly associated with increased risk of persistent and severe AF as an association between markers of inflammation and stroke risk in AF patients was also reported [43–44]. Even more to the point, a significant decrease in CRP levels after cardioversion was noted, making the relationship between inflammation and persistence of atrial fibrillation clearer [45]. At last, atrial and ventricular biopsies of patients with lone AF have displayed the presence of inflammatory infiltrates. Furthermore, AF-related thrombogenesis and inflammation are intimately linked as increased CRP-levels in AF patients are associated with left atrial thrombus formation and dense spontaneous echo contrast. Atrial fibrosis appears to be a major potential contributor to the substrate for AF maintenance [46]. Such data underscore the fact that a persistent inflammatory state with the presence of oxygen species released from inflammatory cells as found in cancer, can promote AF and its thromboembolic complications. Besides, pre-existing AF shortly before cancer diagnosis may result from persistent and chronic inflammation when cancer is in early sub-clinical development without any possibility of properly screening. These physiopathological hypotheses are summarized in Fig. 1. 5. Current challenges of cancer patients with AF: therapeutic hints Important dilemmas in the treatment of patients with pre-existing AF who develop cancer or new-onset AF occurring during cancer course remain the choice of the therapeutic strategy and more particularly, of the antithrombotic therapy. In a retrospective cohort study, Hu et al. have shed new light on the fact that AF is related to poor prognosis in cancer patients and that both treatment and prevention might be of paramount importance as cancer patients with new-onset AF had greater likelihood of thromboembolism and heart failure with, however, higher mortality. Poor prognosis might mainly result from AF related cardiac dysfunction that occurs in frail and immunocompromised cancer patients [17]. In contrast, a more recent observational cohort study
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199
Chronic inflammation of carcinogenesis Invasiveness of cancer and direct loco-regional factors
Oxidative stress Electrical and structural atrial remodeling Thrombogenesis
Pre-existing AF
Mediastinal/pericardial area Pericardial effusion Cardiac tumors
Shared risk factors
Paraneoplastic syndromes Thyroid disorder Auto-immunity
Carcinogens (smoking, alcohol) Aging, obesity
Cancer treatments
New-onset AF
Thoracic surgery Chemotherapy Radiotherapy Steroids, targeted agents, bisphosphonates
Intrinsic characteristics of cancer patient Electrolyte and metabolic disorders Autonomic nervous system impairement
Fig. 1. Underlying physiological mechanisms of AF in cancer patients.
found that a pre-existing diagnosis of cancer is associated with increased 30-day mortality among patients diagnosed with new-onset AF and that active cancer is an independent predictor of 30-day mortality [47]. Cancer in itself promotes a pro-thrombotic state through release of procoagulant and fibrinolytic agents, production of proinflammatory cytokines as well as alteration of vascular endothelium and subsequently may increase the risk of thromboembolic events in patients with AF. If on the one hand, cancer can be considered as an acquired thrombophilic condition with increased incidence of venous and arterial thromboembolic complications, AF is also associated with a hypercoagulated and prothrombotic state that confers a significant increased risk of thromboembolic stroke. Abnormalities of blood flow, vessel wall changes and variations in blood components underlie the higher risk of arterial thromboembolism in patients with AF [48–49]. However, scores for thromboembolic risk prediction in AF such as CHA2DS2-Vasc do not include cancer as a variable and may not be suitable for these patients [17]. The thromboembolic risks of AF in cancer patients may be higher and the need to systematically use anticoagulant medication in these patients should be discussed. Furthermore, despite the fact that vitamin K antagonists (VKAs) have constituted the main oral anticoagulant therapy for AF and VTE for decades, their use in cancer patients with AF in particular is not as obvious as it seems [50]. In clinical practice, low molecular weight heparins (LMWH) are used preferentially to VKAs for this category of patients due to their supposed lower risk of drug interaction with anti-cancer treatments even if no sufficient data support the relevance of such a therapeutic management. Indeed, the benefit/risk balance associated to the use of VKAs in cancer patients has been studied solely in the specific context of VTE; as significant increased risks of thromboembolic recurrence and bleeding were reported with VKAs, the use of LMWH is recommended in the VTE setting, at least for the first three months of treatment, whereas no data is currently available in the AF setting [51]. Moreover, using VKA may be problematic in cancer patients as they display specific features such as unpredictable anticoagulant response and higher bleeding risks as well as frequent changes in renal or hepatic functions, hence the need of specific guidelines for the therapeutic management of AF in this unique set of patients [52]. Recently, Ambrus et al. showed that a new cancer diagnosis significantly worsens warfarin control in the six-month period following diagnosis in
comparison to the cancer-free cohort among 122,875 veterans who have been receiving warfarin for AF prior to cancer diagnosis. Besides, regarding the outcomes, anticoagulation control appears to be a major step in the causal pathway to anticoagulation-related outcomes as a significant increase in rate of major hemorrhage was found among patients with active cancer who were receiving
Table 2 Drug-drug interactions between antiarrhythmic drugs, anticoagulants and anticancer therapies through specific interactions. Metabolic interference Oncology drugs • Vinca alkaloids • Taxanes • Antimetabolites (methotrexate) • Topoisomerase inhibitors • Anthracyclines (doxorubicin) • Alkylating agents (ifosfamide, busulfan) • Platinum-based agents • Tyrosine kinase inhibitors • Hormonal agents (tamoxifen, flutamide, enzalutamide, abiraterone) Vitamin K antagonists • Warfarin • Acenocoumarol • Fluindione New oral anticoagulants • Dabigatran • Apixaban • Rivaroxaban Antiarrhythmic drugs • Amiodarone • Digoxin • Diltiazem • Dronedarone • Quinidine • Verapamil +++, strong interaction. ++, moderate interaction. +, weak interaction. *, an interaction has been documented.
P-glycoprotein CYP3A4 CYP2C9 interaction interaction interaction * * * * *
* *
+++ +++ +++ +++ +++
+++ +++
+
+++ +++ +++ ++ +++ +++ +++ +++ +++
+++ +++
+ +++ +
+++ +++ +++
200
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Ageing
Longer survival Pre-existing AF
CANCER Mid and long term complications
New-onset AF
Which impact on cancer prognosis and outcome?
Which underlying mechanisms beyond inflammation?
Increased incidence of AF in cancer patients
Cancer related-specificities: Metabolic disorders Higher bleeding risk Concomitant medication Worse anticoagulation control
Which available strategies for stroke prevention?
Which impact on cancer therapeutic decisions?
No specific thromboembolic risk prediction score
Fig. 2. Current issues of AF in cancer patients.
warfarin for AF. The authors also pointed out that this issue is all the more crucial given the fact that patients anticoagulated for AF are more than 2.5 times as numerous as patients anticoagulated for venous thromboembolism [7]. Meanwhile, DOACS are being increasingly prescribed for patients with AF and it is now recommended to use them in first intention for common population. It is thus expected that a growing number of patients with newly diagnosed malignancy will be undergoing such treatment. Thereby, one may wonder if it is safe to continue DOACS in patients with a newly diagnosed cancer. Their use for the prevention and management of thrombotic disorders in cancer patients might present considerable benefits as laboratory monitoring is not required, due to their wide therapeutic window. Nevertheless, no data concerning DOACS in cancer patients with AF are available yet. Besides, although the DOACS seem to display less drug-drug interactions than Vitamin K antagonists, drugs that affect the CYP3A4 enzyme could alter the plasma concentrations of DOACS and lead to worse anticoagulation effects. It is of utmost importance as several chemotherapy drugs induce or inhibit the activity of CYP3A4. Even if drugs with mild interactions have a low propensity for significant drug interactions with the DOACS, chemotherapeutic agents are often used in combination and thus accurate interactions are still unknown. Furthermore, the risk of bleeding is higher in digestive cancers, making DOACS impossible to use in that particular case, as there is no specific antidote [52–53]. Above all, the large clinical trials of dabigatran, apixaban, and rivaroxaban for stroke prevention in AF have excluded patients with active cancer [54–56]. Therefore, even if Larsen et al. have showed a beneficial effect of DOACS for the treatment of venous thromboembolism in cancer patients, in terms of efficacy and safety, statistical evidence was not reached [57]. Consequently, there is still no strong evidence to guide practice and interventional studies are required. Finally, DOACS may also have beneficial effects in AF that go beyond simply clot formation as it has been recently shown that inhibitors of thrombin or FXa could contribute to the inhibition of the AF substrate and thus directly impact its main underlying mechanism [58]. Drug-drug interactions between antiarrhytmic, anticoagulation drugs and cancer-related therapies are presented in Table 2.
6. Conclusion The emerging entity of AF in cancer patients seems to be based on recent detailed epidemiological evidence that need to be enhanced by additional large-scale randomized clinical trials, which are the main framework for progress. There is a crucial need for more epidemiological studies focusing on the link between AF and cancer in order to establish specific cancers at risk for AF. Both aspects including epidemiology, pathogenesis and treatment still have to be elucidated as it could become a major public health problem over the next years, because of the rising incidence of both conditions. If progress in cancer therapy has led to longer survival, we should be able to properly manage concomitant pathologies such as AF, with accurate therapeutic strategies, particularly given that the presence of AF may affect patients' prognosis. The optimization of treatment and preventive strategies for better patient outcomes is of particular importance and has to be explored as current guidelines do not address the specific issue of AF in cancer patients. Ultimately, the question of cancer screening secondarily to new-onset AF discovery is still unresolved and may induce radical reform of our working practices. Current issues of pre-existing and new onset AF in cancer patients are presented in Fig. 2. Conflicts of interest Laurent Bertoletti reports receiving consulting or lecture fees from Bayer, Bristol-Myers Squibb, Pfizer, Daichii-Sankyo, LEO Pharma and Sanofi Avantis. He was principal investigator, Coordinator or investigator of clinical studies promoted by Bayer, Bristol-Myers Squibb, Pfizer, Daichii-Sankyo, Portola. The other authors report no relationships that could be construed as a conflict of interest. References [1] T. Wilke, A. Groth, S. Mueller, M. Pfannkuche, F. Verheyen, R. Linder, U. Maywald, R. Bauersachs, G. Breithardt, Incidence and prevalence of atrial fibrillation: an analysis based on 8.3 million patients, Europace 15 (2013) 486–493.
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