Introduction

Atrial fibrillation (AF) is one of the most common supraventricular arrhythmias that affects more than 33 million people in the world, with a prevalence of 2–4%, expected to increase within the next decade [1, 2]. In specific population such as oncologic patients this prevalence increase, with a reported increment rate of 20% regardless of the kind of malignancy [3,4,5,6]. Particularly AF and cancer are inextricably linked as supported by consistent literature that underlines the bidirectional nature of this relationship [7, 8] A four fouled age-adjusted increase in the likelihood of incident AF during the first year was seen after cancer diagnosis [9]. The chance of detecting new AF peaked in the first 3 months following a malignancy diagnosis, declining gradually after six months [10]. Hematological cancers, intrathoracic cancers (e.g., pulmonary and esophageal malignancy) and central nervous system cancers are also related to a greater than two-fold incidence of AF [11]. Frequency of AF in multiple myeloma seems to be higher in patients older than 35 and increased sharply with age. In patients over 50 aged, liver malignancy appears to be a strongly related to AF occurrence, whereas pulmonary cancer showed strong correlation in patients aged less than 50 [12]. Fauchier et al. found that in oncologic patients AF is a strong predictor of all-cause death [13]. Indeed, the occurrence of AF is linked to a poorer outcome, either in presence of previous history of AF and/or in case of new diagnosis within 3 years cancer detection. The latter condition could be related to the pro-arrhythmogenic effects of some cancer treatment [14]. Furthermore, Ostenfeld et al. showed that within the first three months of AF detection, there is a fivefold increased risk for malignancy [15]. Moreover, 3 months after a new diagnosis of AF, the risk of cancer tripled and resulted consistent after one year. Rahman et al. showed that women with AF had a considerably greater risk of malignancy compared with those without AF [16]. Individuals with non-valvular AF and a newly discovered malignancy were included in a study by Kim et al. [11]. In this study stomach (approximately 20%), colorectal segment (about 15%), and lung cancer (about 5%) were the most prevalent solid tumor observed. Management of patients in whom AF and cancer coexist is complicated by elevated both bleeding and thrombotic risk [17] requiring tailored therapeutic strategy and multidisciplinary discussion that involves the cardiologist, the oncologist, and the patients itself. Reasons for elevated increased hypercoagulative state are unclear but evidence suggest that cancer and AF shared increased level of circulating pro-coagulative factors (von Willebrand factor, vascular endothelial growth factor, tissue factor, microvesicles, and neutrophil extracellular traps) [18], whereas chemotherapy is a recognized independent risk factor responsible for a six-fold increment in the risk of embolic events [19]. On the other hand, the increased bleeding risk that occurs in patients with cancer recognize direct cause such as erosion and tumor invasion, and indirect treatment related factors such as tissue injury due to chemotherapy or radiation therapy. Recently, Pastori et al., in a retrospective study observed that malignancy enhanced the incidence of severe bleeding and all-cause death in people with AF [20]. Different subtypes of malignancy had different relationship with cardio-embolic stroke, being higher in pancreatic, uterine and breast cancer and lower in lung and liver cancer, leukemia, and myeloma. The risk of bleeding appeared to outweigh the hazard of thromboembolic events especially in hematologic malignancies, liver, and met-astatic cancer, where thrombocytopenia frequently occurs [20]. The aim of this review is to report latest evidence in term of pathophysiologic mechanism and management of patients with AF in the setting of cancer patients, underlining unmet issues on the topic and future direction.

Pathophysiology

Numerous pathways have been hypothesized to determine mechanism of AF in cancer. Even though epidemiological data do not demonstrate causality, they underline the strong connection and shared risk factors between the two entities. Advanced age, smoke, metabolic syndrome, diabetes, chronic obstructive pulmonary disease (COPD), alcohol abuse, cirrhosis, arterial hypertension led to both atrial remodeling and pro-inflammatory state [21]. Tumors could cause AF either directly by invading the heart with primary tumors / metastatic extension, or indirectly by inducing fluid imbalance, hypoxia, electrolyte and metabolic imbalances, infection, anemia, autonomic nerve system dysfunction and paraneoplastic symptoms. Moreover, the relationship between shared metabolic risk factors and AF was inferred by the link between inflammatory biomarkers levels such as white blood cells, C-reactive protein (CRP), and ceruloplasmin and higher chance of developing preclinical and clinical AF. Inflammation also play a significant role in the pathophysiology of AF, which is a combination of structural, electrical, and functional atrial remodeling that involves the onset of AF [22]. In Fig. 1, the possible pathophysiological mechanisms that led to AF in cancer patients are reported briefly. Cancer treatments such as surgery intervention, radiotherapy (RT) and chemotherapy (CT) result in extremely high inflammatory state and promote the development of AF [23]. Perioperative AF (POAF) is highly prevalent in people with cancer. Patients with advanced cancer stages, cardiovascular (CV) comorbidities, older age, prolonged surgical time, and significant tissue excision appear to be more likely to experience POAF. Surgery-related AF risk could be explained by mechanical stimulation of the pericardium, inflammation damage, anesthetic drugs, and post-operative electrolyte imbalances. In a meta-analysis conducted by Inoue et al. the prevalence of POAF in patient with cancer is 13,5% (95% confidence interval (CI), 11.6–15.7%) [24]. Particularly, thoracic surgery for lung cancer is a significant risk factor for the onset of POAF. In this subgroup, the rate of POAF fluctuates from 9.9% to 14.9% [25, 26]. Additionally, abdominal (6–35%) and neck surgery are also linked to an elevated hazard of POAF [27, 28]. Different prophylactic treatments have been tested to reduce the incidence of POAF. A recent trial investigated the effects of prophylactic treatment with anti-inflammatory medication (i.e., colchicine) on the incidence of POAF in patients undergoing major non-cardiac thoracic surgery. The authors did not find any benefits from the administration of colchicine, while the risk of benign non-infectious diarrhea [29] resulted increased. Wang et al. provided a meta-analysis on pharmacological intervention to prevent POAF after lung surgery, showing that prophylactic beta-blocker reduced of 87% the risk of AF with no serious adverse events reported, but with no impact on 30-days mortality. Cardinale et al. proposed to screen patients undergoing thoracic surgery by dosing NT-pro-BNP values, since elevated pre and and/or post-surgery NT-pro-BNP appeared to be associated with increased risk of POAF compared thoracic surgery by dosing NT-pro-BNP values, since elevated pre and and/or post-surgery NT-pro-BNP appeared to be associated with increased risk of POAF compared with patients with normal values (64% versus 5%; P < 0.001) [30]. In those patients with high perioperative levels of NT-pro-BNP, the prophylactic treatment with metoprolol or losartan reduced the incidence of POAF compared to controls (6%, 12% and 40% respectively) [31]. In non-cancer patients, current ESC guidelines on management of patients with AF recommend prophylactic treatment with beta-blocker or amiodarone to prevent POAF in patients at higher risk of AF onset, considering potential adverse events and ambiguous effects on major adverse events [32, 33]. In patients with cancer, although with less evidence, these recommendations do not appear to differ, especially in the context of thoracic surgery [34].

Fig. 1
figure 1

Common pathophysiologic mechanisms of atrial fibrillation in cancer patients. AF atrial fibrillation, CNS central nervous system, COPD chronic obstructive pulmonary disease, HF heart failure, ROS reactive oxygen species; SCA: acute coronary syndrome

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RT contributes to fibrosis development of the atrial tissue and raises the risk of inflammatory responses in the endothelial compartment, including the coronaries, raising the risk of the onset of AF. For these reasons, people who receive left breast radiotherapy are more likely to develop AF [35]. The cumulative amount of radiation, the body surface area exposed, and the age of the subject at the time of radiation exposure are all significant risk factors correlated with myocardial damage. Additionally, in consecutive treatment protocol, RT and CT worked together synergistically for cardiotoxicity. An elevated rate of arrhythmias was seen in individuals receiving neo-adjuvant RT and CT versus those receiving only surgery in patients affected by locally advanced esophageal squamous cell carcinoma [36]. Table 1 reports anticancer medication that could potentially induce AF as referred in the pharmacovigilance database created by the World Health Organization [37]. A meta-analysis showed an incidence of AF events of 10.3% in those patients undergoing traditional treatment such as anthracyclines, while higher risk was found in those treated with targeted treatment like Bruton tyrosine kinase inhibitors (ibrutinib: 10–19%) or with alkylating agents (Melphalan: 22.5%). However, Font et al. considered only the incidence of symptomatic AF for the analysis, not considering undetected subclinical AF, often present in cancer patients [38], thus underestimating the actual burden of AF induced by chemotherapy [39]. CT-induced AF may appear acutely (within 24 h) following drug intake (gemcitabine or cisplatin) or it could occur in days, weeks, or even months after chemotherapy (ibrutinib) [23, 40]. Proteasome inhibitors like bortezomib or carfilzomib, prescribed in hematological cancers, showed a dose-dependent toxic effect that have been linked to increased CV reactivity, vascular impairment, and myocardial oxidative stress [41, 42]. Apart from its inhibition of cardiac BTK, ibrutinib also inhibits Tec protein tyrosine kinase (TEC) off-target. These targets have been demonstrated to be formed in cardiac cells with atrial cells expressing them more during AF then sinus rhythm [43]. Ibrutinib exhibited an atrial-specific toxicity in human cardiomyocytes through significant increase in left atrial fibrosis and impairment in atrial myocyte calcium channel regulation. Furthermore, these tyrosine kinases regulate the phosphoinositide 3-kinase–Akt pathway, an essential regulator of heart protection in stressful situations and could cause inflammatory and oxidative damage by increasing reactive oxygen species (ROS) levels [43,44,45]. AF has also been linked to other supportive therapy, which can trigger cardiac arrhythmias by different modalities. Nonsteroidal anti-inflammatory drugs (NSAIDs) and opiates, which are both linked to an elevated risk of developing AF, are frequently prescribed to cancer patients, particularly to those who are affected by end stage disease [46, 47]. However, pathophysiologic pathways specific to AF in cancer are still unclear.

Table 1. Chemotherapic drugs inducing atrial fibrillation. CART chimeric antigen receptor T-cell therapy, CD cluster of differentiation, CTLA-4 cytotoxic T-lymphocyte antigen 4, eGFR epidermal growth factor, GnRH gonadotropin releasing hormone, HER-2 human epidermal growth factor receptor 2, PD-1 programmed death protein 1, VEGF vascular endothelial growth factor
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Management

Treatment of reversible AF triggers in cancer such as electrolyte disruption (due to fever or sepsis), pain and hypoxemia, is recommended considering that reversion to sinus rhythm might happen as a result in some cases. Cardiac imaging assessment can help to detect additional potential features (acute ventricular dysfunction, pulmonary thromboembolism, pericardial effusion, cardiac tamponade, tumor invasion, and endocarditis) [48] and/or marked geometrical changes (left ventricular hypertrophy, atrial enlargements) that increase the chances to detect those cancer patients at higher risk of AF. Significant left atrial (LA) remodeling is common in AF and may implies advanced state of fibrosis. Thus, preventing atrial remodeling is essential through direct targeted and specialized management of the risk factors (obesity, sleep apnea, etc.) [49]. LA strain is highly sensitive to measuring increased LA stiffness and fibrosis. LA strain has also been shown to be a significant indicator of AF recurrence following cardioversion [50], and following ablation [51]. A recent investigation on pediatric patients revealed a substantial reduction in LA strain during anthracyclines treatment [52]. In a study conducted by Yaylali et al. breast cancer individuals treated with adriamycin, cyclophosphamide, paclitaxel atrial electromechanical delay correctly predicted AF onset [53]. Therefore, cardiac imaging may help to guide the management of the patients detecting those patients who are keener to AF onset/recurrence. However, further studies are required to understand the prognostic impact of those assessment on cardiovascular outcomes in patients with cancer. Once higher risk patients have been identified, lifestyle modifications are encouraged to reduce the CV risk and concomitantly reducing the risk of AF [33].

Rhythm- or rate-control

AF should be managed by a multidisciplinary team according to patient's symptoms, age, CVD, preferences, and the ongoing cancer therapy. Individual therapeutic strategy (rate, rhythm control, ablation) should consider possible interactions between anti-arrhythmic and cancer medications, absolute contraindications to anticoagulant therapy and hemodynamic instability requiring prompt electrical cardioversion [33]. A particular care must be used in patients at risk of POAF. In patients at low CV risk a cardiac rhythm strategy could be considered, while in patients with high CV risk or in those managed by pro-arrhythmic cancer medications, a rate control management is recommended since sinus rhythm persistence is difficult to achieve. Additionally, in elderly patients and/or those with CVD or enlarged left atrium, a rate control strategy appears reasonable, particularly for those with a poor prognosis for malignancy (including patients receiving palliative therapy). For the rate control strategy beta-blockers (e.g. metoprolol considering the fewer interactions) are generally recommended. Non-dihydropyridine calcium channel blockers may be used cautiously considering the higher risk of drug interactions by CYP 3A4 pathway with different CT drugs. Moreover, when digoxin use is indicated for rate control (HF or intolerance to beta-blockers), a careful risk benefit assessment is indicated considering the competitive mechanism on P-glycoprotein, resulting in higher digoxin levels and possible toxic effects [54]. Dronedarone moderately affects both these pathways and for this reason it is not recommended. Amiodarone is often used to manage cancer-related arrhythmias, especially in individuals with concomitant CV diseases. This drug could raise the levels of other CT drugs due to actions on CYP3A4 and P-glycoprotein. The interactions between anti-arrhythmic drugs and CT medications are reported in Table 2. In non-oncologic patients ablation should be evaluated in paroxysmal or persistent AF to improve outcome and symptoms, particularly when medical treatment failed to improve clinical condition [33]. Recent trials demonstrated benefits of AF catheter ablation also in patients with heart failure with reduced ejection fraction (HFrEF) [55] and in those with end-stage heart failure (i.e., patients evaluated for heart transplantation) [56]. The indication for ablation treatment is not clearly established in individuals with AF and concomitant malignancy. When rate or rhythm management results inefficacious or detrimental (due to interactions or intolerance), catheter ablation could represent an option, subordinate to prognosis assessment discussed by the multidisciplinary teams. There are very few studies that have assessed AF ablation in cancer patients. A retrospective analysis of 15 patients with persistent AF following pneumonectomy for cancer showed that the treatment was safe and successful, with 20% recurrence after one year follow-up [57]. However, a retrospective trial comparing catheter ablation for AF in patients with and without cancer revealed that obesity but not cancer was considered an increased risk factor for recurrence at 12 months, underlining that catheter ablation in oncologic population is as safe and effective as in general population [58]. Post cardioversion anticoagulation should be continued for at least 4 weeks or more, depending on bleeding/ embolic risk and risk of recurrence (see below) [4].

Table 2. Interactions between rate control, rhythm control and chemotherapic drugs. CT chemotherapic
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Anticoagulation

Anticoagulation in cancer patients should be managed according to a detailed and individualized strategy, considering thrombotic and bleeding risk, type of cancer, potential drug interactions and patient's choice. The assessment of the patient's therapeutic objectives and preferences, current health condition, and prognosis are pivotal to re-duce adverse events and suboptimal treatment adherence. In patients with pre-existing AF managed by anticoagulants, the antithrombotic strategy should be reviewed, either for surgical reason or CT drug interactions. Cancer-related hypercoagulability may lead AF patients to thrombus development with a related fivefold risk of thromboembolism [4, 59]. Pharmacological interactions need to be examined when anticoagulation is used in patients with active cancer, through individualized considerations of the benefits and risks. While validated score for prediction of venous thromboembolic events and thromboprophylaxis in cancer patients has been tested [60,61,62,63,64], risk assessment for both thrombotic and bleeding events is slippery since common risk scores (CHADS2, CHA2DS2-VASc, HAS-BLED) do not include malignancy as a risk factor for individuals with AF. CHA2DS2-VASc score was able to predict prognosis in patients with cancer, when AF was discovered 3 years after the diagnosis, but was not accurate to predict thromboembolic events [65]. In a retrospective observational study from Spain CHA2DS2-VASc and HAS-BLED were tested on 16,056 patients with AF (7.1% of whom had previous history of cancer) as predictors of embolic and bleeding events during a period of about 5 years. The authors found that traditional scores failed to predict both embolic and bleeding events in cancer patients (Hazard Ratio—HR 1.14, 95% CI 0.98 to 1.32; p = 0.076 for CHA2DS2-VASc and HR 1.08, 95% CI 0.99 to 1.17; p = 0.070 for HAS-BLED). However, they found that in cancer patients with AF the identification of patients at low embolic risk was possible when CHA2DS2-VASc score was equal to zero, highlighting its accuracy in identifying those patients in whom anticoagulation should be avoided [65].

Therefore, the lack of evidence supporting the use of conventional risk score and a well-validated risk score specifically for patients with cancer led to an under prescription of anticoagulation treatment due to concerns regarding fatal adverse events in such a fragile population. Previous evidence found that 1/3 of individuals with cancer and AF received nontherapeutic dosages of low-molecular-weight heparins (LMWHs) whereas 1/4 of individuals did not receive any anticoagulant therapy [66]. This founding could be partially addressed by the high bleeding risk (HAS-BLED > 3) that results in in almost half (44.3%) of individuals with the standard anticoagulant indications (CHADS2-VASc > 2) and cancer as underlined by Fradley et al. [54].

Bleeding risk increases further if patients need to undergo surgical or interventional procedures or need to combine antiplatelet therapy [7], in the setting of acute coronary syndromes [67, 68]. The ABC stroke risk score [69] (age, biomarkers, and clinical history) and the HEMORR2HAGES score [70] (hepatic or renal dysfunction, alcohol, cancer, age > 75 years, platelet count, multiple bleeding events, hypertension, anemia, genetic factors, fall risk, and stroke) are tools that might be used to identify individual risk of bleeding in complex circumstances. Among the reasons of anticoagulation treatment withheld cerebral metastases, CKD, prior and current bleeding history, CT, thrombocytopenia (< 25.000 platelets, mainly in hematological malignancies) and/or simultaneous use of NSAIDs were the most frequent ones.

In patients with valvular AF or CKD, the vitamin K antagonists (VKAs) may represent the first choice [71] even though CT medications could impact coagulation profile and liver function, reducing or increasing the plasma concentration of the anticoagulant, hindering the possibility to obtain optimal therapeutic range (time of on-target INR > 65%). Fluctuation in INR values represent a challenge in the daily practice particularly in patients with high bleeding risk due to the tumor's localization (central nervous system, urinary system, upper or lower gastrointestinal tract).

Moreover, other common conditions as poor nutrition, vomiting, liver dysfunction, thrombocytopenia, and the necessity for surgery, decreases the probability of an optimal therapeutic range increasing the risk of VKAs related adverse events compared to non-oncologic patients [72]. LMWH are preferable to VKAs during active cancer treatment with better profile in terms of drug interactions and stable anticoagulation. Prolonged administration of LMWH is considered safe and efficacious, however the reduced quality of life and difficulties related to the long term subcutaneous treatment may affect its prescription, considering that many CT regimens are administered for several months. Additionally, their efficacy has never been established and the dose for the stroke prevention during AF has not been determined in the context of cancer patients, with ambiguous results in terms of prevention of embolic events and death when LMWH were compared to Direct oral anticoagulants (DOACs) [73]. Almost all the evidence about the efficacy and safety of LMWH in cancer patients refer to the setting of treatment or prophylaxis of VTE. Individuals at higher risk of bleeding, such as those with active gastrointestinal or genitourinary malignancy, gastrointestinal mucosal abnormalities, low platelet counts (between 25,000 and 50,000 × 109/mcL), gastrointestinal toxicity, or severe renal dysfunction, should be managed by LMWH at the recommended or therapeutic dosage [33, 74, 75]. Interactions of VKAs and LMWH with CT drug are summarized in Table 3.

Table 3. Interactions between vitamin K antagonists (VKAs), low molecular-weight heparins (LMWHs), direct oral anticoagulants (DOACs) and chemotherapic drugs. VEGF Vascular Endothelial Growth Factor, VEGFR Vascular Endothelial Growth Factor Receptor
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DOACs represented the first choice of oral anticoagulation in AF patients [33]. In the daily practice, DOACs are usually preferred over VKAs in the occasion of sudden withheld (invasive surgery, major bleeding), considering the pharmacokinetic profile, quick onset and offset and presence of reversal medication, despite their prescription among cancer patients remains "off-label". In fact, the randomized clinical trials assessing the safety and efficacy of DOACs compared to VKAs in AF patients were not designed to evaluate safety and efficacy in cancer population and are at least effective and safe as LMWH.

However, subgroup analyses including cancer population are available, since the diagnosis of cancer was not considered as an exclusion criteria per se and in some cases occurred during the follow up phase of the studies.

This sub analysis revealed that DOACs in patients with cancer are safer and, at least, as efficacious to VKA, with a better safety profile [76]. The number of patients with cancer in these trials and their cancer-related exclusion criteria are reported in Table 4.

Table 4. Number of patients with cancer and cancer-related exclusion criteria in DO-ACs principal trials. DOACs direct oral anticoagulants
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In the Rivaroxaban Once-daily, Oral, Direct Factor Xa Inhibition Compared with Vita-min K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF trial) [77], history of cancer was not explicitly reported among the exclusion criteria. However, concurrent disease with an estimated lifespan of less than 2 years, diseases that increase the risk of bleeding, and a number of platelets less than 90 000/mL at the screening visit were in the exclusion criteria and for this reason many cancer patients were not included. A secondary analysis [78] conducted in those patients with a history of cancer (4,5% of the participants showed “actively treated cancer”) found that there is not significant differences in the risk of ischemic stroke/ thromboembolism (IS/TE) (HR 0.86, 95% CI 0.55–1.33; P = 0.50) but greater risk of any bleeding (HR 1.30, 95% CI 1.16–1.47; P < 0.0001) compared to individual with no history of cancer. However, no significant differences were found in terms of efficacy (rate of IS/TE, HR 0.52, 95% CI 0.22– 1.21; P = 0.21) or safety outcomes (major or non-significant bleeding, HR 1.09, 95% CI 0.82–1.44; P = 0,79) between rivaroxaban and warfarin anticoagulation [78]. The Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation trial (ARISTOTLE trial) conditions with increased bleeding risk, planned major surgery, severe comorbidities with life expectancy ≤ 1 year, platelet less than 100,000/mm3 and hemoglobin level less than 9 g/dL were considered exclusion criteria like limiting the recruitment of patients with cancer [79]. Sub analysis was also available in this trial since 6,8% of the recruited patients had history of cancer either active cancer (12.7%) or previous history of cancer treatment (87.3%). A secondary analysis on these patients [80] revealed no differences in IS/TE (HR 0.93, 95% CI 0.63–1.37; P = 0,7104) and any bleeding (HR, 1.10; 95% CI, 0.99–1.22; P = 0,0718) between the individuals with background/active cancer compared to those without. Individuals with remote cancer experienced comparable incidence of ischemic events as those with active disease. However, mortality from any cause seemed to be more common in the active cancer cohort. Both cancer and non-cancer patients experienced apixaban's greater efficacy compared to warfarin in preventing IS/SE (HR 1,09; 95% CI, 0,53–2,26; P = 0,3671). In the Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation Thrombolysis in Myocardial Infarction 48 trial (EN-GAGE AF-TIMI 48 trial) [81] patients with active cancer (diagnosed within 5 years) or under anticancer therapy were excluded from the recruitment at the time of randomization. However, 5,5% of these patients have developed cancer post-randomization and a sub-analysis was conducted including these patients [82]. According to the secondary analysis of the ENGAGE AF-TIMI 48 trial [82], there was no difference in the incidences of IS/SE among individuals who had and did not have cancer (HR, 1.08; 95% CI, 0.83–1.42; P = 0.55). Furthermore, edoxaban is more efficient in IS/SE prevention in the higher dose arm (edoxaban 60 mg) compared to warfarin (HR, 0.60; 95% CI, 0.31– 1.15 vs HR, 0.89; 95% CI, 0.76–1.05; P = 0,25) and with similar efficacy of warfarin in the lower dose arm (edoxaban 30 mg) (HR, 0.87; 95% CI, 0.47–1.59 vs HR, 1.15; 95% CI, 0.99–1.34; P = 0.38), as well as having a similar safety profile. In Randomized Evaluation of Long-Term Anticoagulation Therapy trial (RELY trial) [83], likewise, patients with recent diagnosis of cancer (< 6 months) and life expectation < 3 likewise, patients with recent diagnosis of cancer (< 6 months) and life expectation < 3 years were not included and secondary analyses was not performed. However, in the Anticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Out-comes and Experience of Patients trial (ARISTOPHANES trial) 9% of the patients had active cancer and 24% of these patients use dabigatran. Individuals on dabigatran and those taking warfarin had comparable rates of IS/SE (HR 0.88; 95% CI 0.54- 1.41; P < 0,001) and major bleeding (HR 0.76; 95% CI: 0.57–1.01; P = 0,058) [84]. Furthermore, dabigatran had a similar IS/SE risk compared to apixaban and lower major bleeding compared to rivaroxaban. Moreover, in this sub-analysis apixaban was related to a decreased incidence of IS/SE and major bleeding among individuals with AF and active malignancy, while rivaroxaban was linked to comparable risks in warfarin users. Additionally, in comparison with dabigatran, patients managed by apixaban showed a reduced risk of IS/SE compared to rivaroxaban users [79]. Shah et al. also demonstrated that in patients with AF and cancer, the rate of IS is similar in patients in therapy with dabigatran compared with patients in therapy with warfarin (HR 0.89; 95% CI 0.56–1.42; P = 0,63) [85]. Furthermore, they observed that the risk of serious bleeding was analogue with dabigatran (HR 0.96, 95% CI 0.72–1.27; P = 0,75) and rivaroxaban (HR 1.09, 95% CI 0.79–1.39; P = 0,59) compared to warfarin, but significantly lower with apixaban (HR 0.37, 95% CI 0.17–0.79; P = 0,01) in patients with AF and active cancer [85]. In a meta-analysis conducted by Yang and colleagues DOACs reduce the risk of IS/SE, VTE, serious bleeding, and all-cause mortality in individuals with AF and cancer and the lowest risk of IS/SE was found in apixaban users [74]. These results were confirmed by Mariani and colleagues' recent meta-analysis, revealing that DOACs were correlated with lower incidence of any stroke (RR 0.84; 95% CI 0.74–0.95; P = 0.007) or thromboembolism (RR 0.65; 95% CI 0.52–0.81; P = 0.001), lower incidence of major bleeding (RR 0.68; 95% CI 0.50–0.92; P = 0.01), resulting to be non-inferior compared to VKAs [86] in patients with cancer and AF. A meta-analysis by Papanastasiou and colleague, found that in patients with AF receiving DOAC, the bleeding occurrence during the treatment increased the chance of cancer detection by 6 times (OR 6.12, 95% CI 4.47–8.37; P < 0,01) [87]. The P-glycoprotein (P-gp) pathway (primarily for apixaban and rivaroxaban) and the cytochrome P450 pathway (through CYP3A4) in the liver have an impact on the effects of all DOACs [70]. P-gp plays a crucial role in DOACs pharmacokinetic reducing their intestinal absorption and accelerating their liver and renal excretion. So, all DOACs must be used with caution in patients treated with drugs that strongly induce or inhibit CYP3A4 and P-gp, while the interactions by P-gp alone should only affect the patients in apixaban and rivaroxaban treatment. The interaction of DOACs with CT drugs are reported in Table 3. Less convincing data supports the security and effectiveness of DOACs as a preventative measure against stroke and thromboembolism in individuals with AF and specific active malignancy. Administration of DOACs in individuals with luminal gastrointestinal malignancies or individuals with active gastrointestinal mucosal anomalies such as ulcers, gastritis, esophagitis, or colitis, is discouraged based on significant bleeding evidence [88]. Concerning kidney function, all DOAC should be contraindicated in individuals with an estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m2, except for Dabigatran that is contraindicated with eGFR < 30 ml/min/1.73 m2. Finally, it is essential that the initial anticoagulant prescription is routinely assessed and modified according to malignancy stages, possible alterations to the CT regimen, or variations in patients bleeding/thrombotic risk balance. The choice of the anticoagulant and its dosage is summarized in Fig. 2.

Fig. 2
figure 2

Management of atrial fibrillation in cancer patients. AF atrial fibrillation, CHA2DS2VASc score (congestive heart failure/LV dysfunction, hypertension, age > 75, diabetes mellitus, stroke/TIA, vascular disease, age 65–74, sex), CKD chronic kidney disease, DOAC direct oral anticoagulant, GI gastrointestinal, GU genitourinary, HAS-BLED score (hypertension, abnormal liver or renal function, stroke, bleeding, la-bile international normalized ratio, INR, elderly with age > 65, drugs or alcohol); HF heart failure, INR international normalized ratio, LMWH, low molecular-weight heparin, LV left ventricular, LVEF left ventricular ejection fraction, PLT platelets, TEE transesophageal echocardiography, TIA transient ischemic attack, TTE, transthoracic echocardiography, VKAs vitamin K antagonists

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A web-based survey conducted on 960 physicians (82.4% cardiologist, 75.5.5 from Europe) by the Council of Cardio-Oncology of the European Society of Cardiology revealed that in 62.6% of cases DOACs were preferred over LMWH and warfarin, in all type of cancer but non-operable gastrointestinal cancer. Traditional risk score for thrombotic and bleeding risk were considered appropriate, despite concerns about the lack of validated literature for cancer patients [61].

Percutaneous left atrial appendage (LAA) closure

According to ESC guidelines [33], individuals with a high embolic hazard and conditions that exclude long-term anticoagulation (i.e., high bleeding risk) may consider percutaneous left atrial appendage closure as a secure and efficacious alternative to anticoagulant therapy. Analogously, in cancer patients who have absolute contraindication to anticoagulation, and in those who have an average lifespan of more than a year, LAA closure should be considered as a treatment option, even though there is lack of strong data to support this approach. In the context of malignancies high bleeding risk features such as intracranial metastases, thrombocytopenia (platelets count below 50,000), liver or renal dysfunction, elevated INR chemotherapy interaction (CYP system and P-glycoprotein cell transport enzyme) and active GI bleeding, may guide management decision, where LAA closure device offers efficacious and safe management solution.

based on anecdotal experience reported in literature on LAA closure in patients with cancer. In those patients in who percutaneous LAA closure is recommended focused imaging for LAA assessment is required, addressing LAA morphology and presence of thrombus apposition [89]. Transesophageal echocardiography (TEE) is estimated to be the gold standard technique for the evaluation of LAA's flow patterns related to cardioembolic cerebrovascular accidents (i.e. LAA mean flow velocities below 20 cm/Sec in atrial fibrillation and LAA, spontaneous echo-contrast), morphology and identification of LAA thrombi, with a sensitivity of 93–100% and specificity of 99–100% and minimal complications in patients with AF [90]. While 2D TEE gives higher resolution pictures for its superior frame rate, 3D TEE overcomes some disadvantages of 2D TEE (i.e. limited scanning planes, mental reconstruction), enabling navigation within cardiac chambers that allows meticulous stereotactic examination of the LAA, especially in complex anatomy [91]. Even though TEE is a generally safe procedure in experienced hand, it is not always available, and it came with absolute (i.e. esophagogastrectomy, recent upper GI surgery, active GI bleeding) and relative contraindication (i.e. history of GI surgery, esophagitis, coagulopathy) that need to be considered in the oncologic setting [92]. In presence of contraindication, inadequate imaging or in doubt cases, additional cardiac imaging examination such as cardiac computed tomography (CCT) or cardiovascular magnetic resonance (CMR) can be required. CCT has been demonstrated to be a reliable alternative to TEE offering a comprehensive morphological evaluation of the LAA in pre-operative evaluation for occlusive device implant [93], with a sensitivity of 96% and specificity of 92% for LAA thrombus identification [94]. However, CT has some disadvantages to take into consideration in cancer patients including the use of nephrotoxic contrast agent and radiation exposure. Data about CMR's capacity to identify LAA thrombi are encouraging since it enables non-invasive tissue characterization distinguishing between old (lower signal intensity) and fresh (higher signal intensity) thrombus, showing high concordance in thrombi identification compared to TEE [95]. Negative aspects about widespread use of CMR in this setting include higher costs, extended study duration, potential hazards associated with gadolinium-based contrast agent and the presence of devices incompatible with CMR.

In their recent research, Shabtaie et al. observed that LAA closure in individuals with malignancy was accomplished with good technical efficacy and provided decrease in stroke incidence or death without a higher hazard of bleeding compared to non-cancer individuals [96]. Data are confirmed in another recent study conducted in a tertiary center with follow up at 3 years following the LAA closure, showing no difference in all-cause death (HR 1.3, 95% CI 0.72–2.35; P = 0.38), serious bleeding events (HR 1.2, 95% CI 0.45–3.33; P = 0.68) or stroke (HR 0.64, 95% CI 0.19–2.21; P = 0.49) in patients with cancer compared to patients without cancer [97]. In a retrospective analysis conducted by Isogai and colleagues on more than 15,000 patients with AF who underwent LAA closure, divided by cancer history (2.4% with active cancer, 15.1% with prior history of cancer), no significant difference was found for the composite outcome (in-hospital mortality, ischemic stroke/transient ischemic attack, systemic embolism, bleeding necessitating blood transfusion, pericardial effusion/cardiac tamponade or embolized device extraction) in patients with active cancer (aOR = 0.99; 95% CI = 0.51–1.93, p = 0.973) or prior cancer (aOR = 0.94, 95% CI = 0.70 to 1.28, p = 0.704). On the other hand, active cancer was substantially linked to an increased chance of in-hospital ischemic stroke/TIA (aOR = 3.06, 95% CI = 1.17 to 8.01, p = 0.023). This observation might be explained by a possible hypercoagulability associated with active malignancy [98]. Since no data on the impact on thrombogenic state during malignancies on device related thrombosis, after LAA closure antiplatelet or short-term anticoagulation treatment (if tolerated) must be tailored on patients bleeding and thrombotic risk [99].

Conclusions

Patients with cancer are keener to experience AF, because of shared risk factors (inflammatory state) and detrimental effects of some cancer treatments (surgery, CT, RT). Rate/rhythm control strategy have to be tailored based on the clinical context (patient's symptoms, age, CVD, and possible interactions with the ongoing cancer therapy). Risk assessment for thromboembolic and bleeding events is puzzling since malignancy is not taken into consideration as predisposing risk factors in the shared risk stratification scores like CHA2DS2VASc and HASBLED, currently applied in cancer population. For a more accurate assessment of the thrombotic and bleeding hazard, an individual stratification tool is required, and further studies are required for clinical validation. The choice of anticoagulant treatment shows additional difficulties because of the absence of dedicated literature. Recently randomize trial on efficacy and safety of switching frail patients with AF from VKA to DOACs fail to reduce thromboembolic events at the expense of higher risk of bleeding events in those who were switch to DOAC treatment [100] puzzling furtherly the management of anticoagulation treatment in frail populations.

Drug interactions and specific clinical conditions like thrombocytopenia, renal and liver dysfunction, are features that frequently come along with malignancies and need to be addressed when anticoagulation is required. In individuals with a high embolic hazard and conditions that exclude long-term anticoagulation consider percutaneous left atrial appendage closure as a secure and efficacious alternative. In conclusion, AF results in a rise in their comorbidity and mortality, mining the potential benefit on the outcome of recent anticancer treatment, making the management of this condition a pivotal aspect towards which high efforts in research should be spent to determine evidence-based recommendation and to enhance tailored management.