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Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study
IJCA-26805; No of Pages 6 International Journal of Cardiology xxx (2018) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study Maria Cristina Vedovati a,⁎,1, Michela Giustozzi a,1, Paolo Verdecchia b,1, Lucia Pierpaoli c,1, Serenella Conti d,1, Melina Verso a,1, Francesco Di Filippo c,1, Emanuela Marchesini a,1, Giulio Bogliari a,1, Giancarlo Agnelli a,1, Cecilia Becattini a,1 a
Internal and Cardiovascular Medicine - Stroke Unit, University of Perugia, Perugia, Italy Department of Medicine, Hospital of Assisi, Assisi, Italy c Emergency Medicine, S. Maria Delle Croci Hospital, Ravenna, Italy d Division of Cardiology, S. Matteo degli Infermi Hospital, Spoleto, Italy b
a r t i c l e
i n f o
Article history: Received 25 April 2018 Received in revised form 19 June 2018 Accepted 27 July 2018 Available online xxxx Keywords: Dabigatran Rivaroxaban Apixaban Atrial fibrillation Cancer Anticoagulants
a b s t r a c t Background: Limited data are available on the use of direct oral anticoagulants (DOACs) in patients with cancer and atrial fibrillation (AF). Methods: Consecutive patients with non-valvular AF treated with DOACs were enrolled in a prospective cohort with the aim of evaluating thromboembolic (ischemic stroke or transient ischemic attack or systemic embolism) and major bleeding (MB) events according to presence and type of cancer. The risk of study outcomes over time was compared using Kaplan-Meier method and log-rank test or Cox proportional hazards regression. Results: 2304 patients with non-valvular AF receiving DOACs were enrolled and 16 excluded: 2288 analysed of whom 289 (12.6%) had cancer. Gastrointestinal (21%), genitourinary (15%), prostate (15%), haematological (14%), breast (13%), and lung (8%) were the more frequent sites of cancer. After a mean follow-up of 451 days, thromboembolic events occurred in 2.1% and 0.8% patient-year of cancer and non-cancer patients (adjusted-HR 2.58, 95% CI 1.08–6.16, p = 0.033). The rate of MB was 6.6% and 3.0% patientyear in cancer and non-cancer patients (adjusted-HR 2.02, 95% CI 1.25–3.27, p = 0.004). The differences in bleeding were mainly accounted for by bleeding at gastrointestinal and genitourinary sites. No significant differences were found concerning the rates of non-cancer-related mortality, fatal bleeding or fatal thrombotic events. Conclusions: In this study, the higher bleeding risk found in cancer compared to non-cancer patients was mainly due to an excess of bleeding at gastrointestinal and at genitourinary sites. Larger studies on the optimal management of cancer patients with AF are needed. © 2018 Published by Elsevier B.V.
1. Introduction Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and an important risk factor for stroke, heart failure and dementia [1–3]. The incidence of AF is known to be related to ageing, cardiovascular conditions (such as hypertension, heart failure, valvular disease) and non-cardiovascular conditions (such as diabetes, thyroid dysfunction, chronic pulmonary or kidney diseases). More recently, a correlation has been reported between AF and cancer [4,5]. The prevalence of a concomitant history of cancer was reported up to 20% of AF patients in recent registries or cohort studies [6,7].
⁎ Corresponding author at: Internal and Cardiovascular Medicine - Stroke Unit, University of Perugia, Via G Dottori 1, 06129 Perugia, Italy. E-mail address: [email protected] (M.C. Vedovati). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
For several decades, vitamin K antagonists (VKAs) have been used in patients with AF to reduce the incidence of stroke or systemic embolism. Direct oral anticoagulants (DOACs) are being increasingly prescribed and are now recommended as the first choice anticoagulant agents in patients with non-valvular AF. In patients affected by both AF and cancer, antithrombotic treatment is challenging. Cancer patients are at high risk of both thromboembolic and bleeding events for the direct interaction of cancer with the coagulation system and for the effect of chemotherapy [5]. Clinically relevant data on antithrombotic treatment in cancer patients with AF are limited and only a position paper examines this topic [8]. Indeed, only a few number of cancer patients (those with presumed long life expectancy) were included in the DOAC phase III trials on AF. Post-hoc analyses from these studies led to inconclusive results concerning the thrombotic and bleeding risks of cancer and non-cancer patients as well as in cancer patients receiving DOACs or VKAs [9,10]. A retrospective analysis of a Danish cohort of AF patients on oral anticoagulant treatment showed a similar rate of
https://doi.org/10.1016/j.ijcard.2018.07.138 0167-5273/© 2018 Published by Elsevier B.V.
Please cite this article as: M.C. Vedovati, et al., Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.138
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thromboembolic and bleeding complications in cancer and non-cancer patients [7]. However, among cancer patients thrombotic and bleeding risks also differ according to the status of the neoplastic disease. The aim of this study was to prospectively evaluate the risk of thromboembolic and bleeding events according to presence and type of cancer in patients with non-valvular AF treated with DOACs.
survival analysis (Kaplan-Meier method and log-rank test or Cox proportional hazards regression). Analyses were adjusted for significant differences among the two population. Patients were analysed according to presence of cancer or absence of cancer. Patients were also analysed according to cancer type: history of cancer and active cancer. Patients with active cancer were further categorized according to: active cancer at baseline or incidental cancer. Statistical analysis was performed with SPSS software (version 20) and values b 0.05 were considered statistically significant.
2. Methods 2.1. Study design, setting and patients Consecutive in- and out-patients with confirmed non-valvular AF who were prescribed with DOACs in four Italian hospitals from August 2013 to March 2017 were enrolled in a prospective cohort study. These patients could be either anticoagulation naïve or switched from prior treatment with VKAs. The choice of the individual DOACs was in charge of the attending physician. Exclusion criteria were refusal of informed consent and a valvular AF. AF was defined ‘valvular’ if it was related to rheumatic valvular disease (predominantly moderate or severe mitral stenosis) or associated with prosthetic heart valves [11]. The study period started at the time of the DOAC prescription. Patients included in the study were categorized as it follows: i) non-cancer patients those without clinical evidence of cancer; ii) cancer patients. Cancer patients were categorized as iii) patients with active cancer, at time of inclusion in the study, in presence of a diagnosis of cancer or any anti-cancer treatment within 6 months before the study inclusion, or recurrent locally advanced or metastatic cancer; iv) patients with history of cancer, at time of inclusion in the study, those with a cancer not satisfying the criteria for active disease. Patients with a cancer diagnosed during the study period, i.e. v) incidental cancer, were subsequently included in the group of active cancer patients. The study was approved by the Ethical Committee and/or Institutional Review Boards of the participating centres. 2.2. Study outcomes The primary outcomes of the study were thromboembolic events (ischemic stroke, transient ischemic attack [TIA] or systemic embolism) and major bleeding all occurring while on treatment with DOACs. Major bleeding was defined according to the ISTH criteria [12]. Ischemic stroke was defined as a new, focal neurological deficit of sudden onset, lasting at least 24 h, that is not due to a readily identifiable non-vascular cause (i.e., brain tumor, trauma). All strokes during the study had to be assessed by imaging or autopsy and classified as primary hemorrhagic, non-hemorrhagic, infarction with hemorrhagic conversion, or unknown, as defined by the American College of Cardiology (ACC) [13]. Additional outcomes were: 1) clinically relevant non-major bleeding (CRNMB), defined as overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of DOAC; 2) clinically relevant bleeding, defined as the composite of major and of clinically relevant non-major bleedings; 3) acute myocardial infarction (AMI) defined as an appropriate clinical situation suggestive of a myocardial infarction (e.g., abnormal history, physical examination) and/or or new ECG changes and/or elevation of Troponin T or I ≥ 2 × ULN; 4) all cause mortality; 5) non-cancer related mortality; 6) the composite of fatal bleeding and fatal thrombotic events. 2.3. Data collection For all included patients the following data were collected: age, gender, comorbidities (hypertension, congestive heart failure, diabetes, previous stroke, vascular diseases, renal or liver failure, previous major bleeding), type and dose of DOACs, date of DOAC prescription, concomitant medications (non-steroidal anti-inflammatory and antiplatelet agents) and creatinine clearance (estimated by Cockcroft–Gault formula) [14]. Risks for stroke and bleeding were assessed according to CHADS2, CHA2DS2VASc and HAS-BLED scores, respectively [11]. In patients with cancer, data on cancer site, date of diagnosis, anticancer therapy, the presence of metastases, locally advanced disease and cancer recurrence were also collected. All patients entered a scheduled follow-up program with medical visit or, if not possible, by phone calls every 6 months or whenever clinical issues occurred. At each follow-up visit, data on clinical outcomes as thromboembolic and bleeding events were collected as well as any adverse events, occurrence of cancer and treatment adherence. Thrombotic and bleeding risks were reassessed at each contact. All the events were locally adjudicated. 2.4. Statistical analysis Main basal characteristics and outcome events of patients with cancer and of those with non-cancer were compared. Categorical data were reported as frequencies and continuous data as mean ± standard deviation (SD). Categorical data were compared with the use of χ2 test and continuous data with the use of t-test. The reported p-values were based on two sided tests. Outcome event rates were reported as proportions of patient-year. Patients remained in the analysis until death, or the first between withdrawal of anticoagulant treatment or occurrence of a study outcome event (thromboembolic event or major bleeding). The risk of study outcomes over time in cancer and non-cancer patients was compared using
3. Results Overall, 2304 patients were considered for the analysis, of whom 16 were excluded and 2288 were finally included in the analysis of baseline features (eFigure 1). Nine-hundred and fifty-two patients (41.6%) were switched from prior treatment with VKAs to DOACs. Dabigatran, rivaroxaban and apixaban were prescribed in 30, 35 and 35% of patients, respectively. Overall, 289 patients had cancer (12.6%): active cancer in 104 (4.5%) and history of cancer in 185 (8.1%). An active cancer was present at time of DOAC prescription in 68 patients (2.9%): 13 had the diagnosis made in the 6 months before DOAC was started, 33 were on anti-cancer therapy, 18 had a metastatic disease and 8 had a recurrence of cancer. Four out of these patients had more than one criteria for active cancer. In 36 patients (1.6%), cancer was diagnosed during the study period (12 patients with metastatic disease). The mean time from study inclusion to cancer diagnosis was 238 ± 141 days. Thirty-three patients (92%) received the cancer diagnosis in the first year from inclusion (16 patients in the first 6 months). The occurrence of major gastrointestinal bleeding led to cancer diagnosis in 6 patients. In the cancer group, sites of cancer were gastrointestinal (20.8%), genitourinary (15.2%), prostatic (15.2%), haematological (13.8%), breast (13.1%), lung (8.0%), skin (3.5%), pancreas (2.4%), brain (1.7%), thyroid (1.4%), liver (1.4%) and other (3.5%). Cancer site among patients with incidental cancer was as it follow: gastrointestinal in 33.3%, genitourinary in 16.7%, lung in 16.7%, haematological in 11.1%, pancreas in 8.3%, liver in 5.5% and prostatic, skin and brain in 2.8% each (eFigure 2). Male gender and age ≥ 75 years were more frequent in cancer compared to non-cancer patients. No other significant difference was observed. Baseline features of cancer and non-cancer patients are detailed in Table 1. Baseline features among different cancer groups are reported in eTable 1. 3.1. Outcome events Complete outcome data were available in 2200 patients of whom 280 with cancer (eFigure 1). The mean follow-up was 451.2 days: 441.3 ± 267.6 in cancer and 452.6 ± 254.8 in non-cancer patients (p = 0.49). The incidence of thromboembolic events during treatment with DOACs was 2.1% patient-year (95% CI 1.0 to 4.2) in cancer and 0.8% patient-year (95% CI 0.5 to 1.3) in non-cancer patients (adjusted-HR 2.58, 95% CI 1.08 to 6.16) Fig. 1a. Individual components of the outcome data according to cancer and non-cancer are reported in Table 2. The incidence of major bleeding was 6.6% patient-year (95% CI 4.4 to 9.8) in cancer and 3.0% patient-year (95% CI 2.4 to 3.8) in non-cancer patients (adjusted-HR 2.02, 95% CI 1.25 to 3.27) Fig. 1b. The rate of clinically relevant bleeding was significantly higher in cancer (18.2% patient-year, 95% CI 14.4 to 22.9) compared to non-cancer patients (10.6% patient-year, 95% CI 9.5 to 12.0): adjusted-HR 1.65, 95% CI 1.23 to 2.19. In the non-cancer group, 16 patients experienced an AMI (0.7% patient-year, 95% CI 0.4 to 1.1), one patient in the cancer cohort experienced a venous thromboembolic event (0.3% patient-year, 95% CI 0.1 to 1.7). As expected, overall mortality was higher in cancer compared to non-cancer patients (10.9 vs 4.5% patient-year, adjusted-HR 2.25, 95% CI 1.55 to 3.28). Non-cancer-related mortality was non-significantly
Please cite this article as: M.C. Vedovati, et al., Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.138
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Table 1 Baseline features.
Age years, mean ± SD (range) Age ≥ 75, n (%) Female, n (%) CHF, n (%) Systemic hypertension, n (%) Diabetes, n (%) Previous stroke, n (%) Vascular disease, n (%) Previous MB, n (%) BMI kg/m2, mean ± SD Liver failure, n (%) Clearance creat. ≤ 50 ml/min, n (%)a CHADS2, mean ± SD CHADS2 ≥ 2, n (%) CHA2DS2VASC, mean ± SD CHA2DS2VASC ≥ 3, n (%) HASBLED, mean ± SD HASBLED ≥ 2, n (%) DOAC reduced dose, n (%)
Overall (n = 2288)
Cancer (n = 289)
Non-cancer (n = 1999)
p
77.9 ± 9.0 (38–99) 1586 (69.3) 1121 (49.0) 486 (21.3) 2001 (87.5) 459 (20.1) 620 (27.1) 615 (26.9) 233 (10.2) 26.9 ± 4.8 35 (1.5) 572 (25.5) 2.5 ± 1.2 1849 (80.8) 4.2 ± 1.5 1999 (87.4) 2.5 ± 1.2 1750 (76.5) 985 (43.1)
78.9 ± 7.9 (52–96) 217 (75.1) 123 (42.6) 70 (24.2) 259 (89.6) 53 (18.3) 75 (26.0) 72 (24.9) 28 (9.7) 26.6 ± 4.3 4 (1.4) 82 (28.9) 2.6 ± 1.2 238 (82.4) 4.2 ± 1.5 257 (88.9) 2. 6 ± 1.2 227 (78.5) 121 (41.9)
77.8 ± 9.1 (38–99) 1369 (68.5) 998 (49.9) 416 (20.8) 1742 (87.2) 406 (20.3) 545 (27.3) 543 (27.2) 205 (10.3) 26.9 ± 4.9 31 (1.6) 490 (25.0) 2.5 ± 1.2 1611 (80.6) 4.2 ± 1.6 1742 (87.1) 2.5 ± 1.2 1523 (76.2) 864 (43.2)
0.04 0.02 0.02 0.19 0.23 0.43 0.64 0.42 0.76 0.34 0.83 0.16 0.30 0.47 0.85 0.39 0.38 0.37 0.66
CHF = chronic heart failure; MB = major bleeding; BMI = body mass index; DOAC = direct oral anticoagulant. a Creatinine clearance calculated according to the Cockcroft–Gault formula available in 2243 patients.
higher in cancer compared to non-cancer patients (5.9 vs 4.5% patientyear, adjusted-HR 1.22, 95% CI 0.76 to 1.97); rates of fatal bleeding and fatal thrombotic events were similar in the two groups (0.9 vs 0.8% patient-year, adjusted-HR 0.98, 95% CI 0.29 to 3.33). Among patients with cancer, the incidence of thromboembolic events was higher in those with active cancer (3.6% patient-year, 95% CI 1.4 to 8.8) compared to patients with non-cancer (0.8% patientyear, 95% CI 0.5 to 1.3; adjusted-HR 4.03, 95% CI 1.35 to 12.03) Fig. 2a. As well major bleeding occurred more frequently in patients with active cancer (12.8% patient-year, 95% CI 7.8 to 20.4) compared to those without cancer (3.0% patient-year, 95% CI 2.4 to 3.8; adjusted-HR 3.87, 95% CI 2.16 to 6.94) Fig. 2b. No differences in thromboembolic or bleeding events were observed between patients with history of cancer and patients without cancer. Similar rates of non-cancer-related death were observed in patients with active cancer, history of cancer and noncancer. As well, no significant differences were observed for fatal bleeding or fatal thrombosis among these three groups. Outcome events according to cancer type and site are reported in eTables 2 and 3.
3.2. Site of bleeding events The incidence of major gastrointestinal bleeding was significantly higher in cancer (4.5% patient-year, 95% CI 2.8 to 7.3) compared to non-cancer patients (1.3% patient-year, 95% CI 0.9 to 1.9): OR 3.6, 95% CI 1.9 to 6.7, p b 0.001. Non-significant differences were found for the other sites in terms of major bleedings. Clinically relevant bleeding rates at gastrointestinal and at genitourinary site were significantly higher in cancer compared to non-cancer patients (OR 2.6, 95% CI 1.7 to 4.2, p b 0.001, and OR 3.2, 95% CI 1.7 to 6.0, p b 0.001, respectively). No significant differences were found for other bleeding site in cancer and non-cancer groups (eFigure 3). Bleeding sites according to cancer type are reported in eFigure 4. Fatal bleeding occurred in 2 patients with and in 13 patients without cancer (0.6% patient-year, 95% CI 0.2 to 2.1 and 0.6% patient year, 95% CI 0.3 to 0.9, respectively, p = 0.919). Fatal intracranial haemorrhages were observed in 7 non-cancer patients (of whom 3 were posttraumatic) and none in cancer patients.
Fig. 1. Thromboembolic (a) and major bleeding (b) events in cancer and non-cancer patients.
Please cite this article as: M.C. Vedovati, et al., Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.138
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Table 2 Outcome events in cancer and in non-cancer patients.
Thromboembolic events Ischemic stroke/TIA Systemic embolism Major Bleeding CRNMB Clinically relevant bleeding AMI All cause death Non-cancer related death Fatal bleeding or fatal thrombosis
Cancer 280, n (% pts/year, 95% CI) Non-cancer 1920, n (% pts/year, 95% CI) HR
95% CI
p
Adj-HRa 95% CI
p
7 (2.1, 1.0–4.2) 6 (1.8, 0.8–3.8) 1 (0.3, 0.1–1.7) 22 (6.6, 4.4–9.8) 38 (11.8, 8.7–15.7) 58 (18.2, 14.4–22.9) 0 37 (10.9, 8.0–14.7) 20 (5.9, 3.9–9.0) 3 (0.9, 0.3–2.6)
1.10–6.21 1.10–7.31 0.20–15.78 1.35–3.52 1.07–2.15 1.30–2.30 – 1.67–3.52 0.81–2.11 0.32–3.70
0.030 0.031 0.612 0.001 0.020 b0.001 – b0.001 0.268 0.885
2.58 2.76 1.87 2.02 1.46 1.65 – 2.25 1.22 0.98
0.033 0.036 0.575 0.004 0.036 0.001 _ b0.001 0.418 0.975
19 (0.8, 0.5–1.3) 15 (0.6, 0.4–1.0) 4 (0.2, 0.1–0.4) 71 (3.0, 2.4–3.8) 183 (7.9, 6.9–9.1) 246 (10.6, 9.5–12.0) 16 (0.7, 0.4–1.1) 107 (4.5, 3.7–5.4) 107 (4.5, 3.7–5.4) 19 (0.8, 0.5–1.3)
2.61 2.83 1.76 2.18 1.51 1.73 – 2.42 1.31 1.09
1.08–6.16 1.07–7.15 0.21–16.86 1.25–3.27 1.03–2.07 1.23–2.19 – 1.55–3.28 0.76–1.97 0.29–3.33
AMI = acute myocardial infarction; CRNMB = clinically relevant non-major bleeding; TIA = transient ischemic attack. a Adjusted-HR for age ≥ 75 years and gender.
Bleeding site was the same as cancer site in 23 out of the 55 clinically relevant bleedings (41.8%): 5 (21.8%), 3 (13.0%) and 15 (65.2%) events occurred in patients with history, active and incidental cancer, respectively. 4. Discussion In this prospective cohort of patients with non-valvular AF receiving DOACs, about two fold higher rates of major and clinically relevant non major bleedings were observed in cancer compared to non-cancer patients. Most of the excess of bleeding was accounted for by the events which occurred in patients with active cancer. As well, the thromboembolic risk was doubled in cancer compared to non-cancer patients. The highest thromboembolic risk was observed in patients with incidental cancer. In this study, the prevalence of cancer in patients with AF receiving DOACs is not negligible (12.6%). Lower rates were observed in phase III trials on DOACs (6.8% in ARISTOTLE and 5.5% in ENGAGE-AF) [9,10]. In a Danish cohort, the prevalence of cancer was 17 and 20% in AF patients prescribed with VKAs or DOACs, respectively, in clinical practice [7]. Similarly to ours, cancer patients from the Danish cohort were older than non-cancer patients. However, Ording et al. observed a similar overall thromboembolic complication rate in cancer and non-cancer patients. No differences in terms of stroke or systemic embolism were also found in patients with and without cancer included in the post-hoc analyses from ENGAGE-AF or ARISTOTLE trials [9,10].
We found a rate of major bleeding of 6.6% patient-year in patients with cancer, which is higher than those observed in other studies. In a cohort of 163 cancer patients with AF receiving rivaroxaban major bleedings was reported in 1.2% [15]. The rate of major bleeding in cancer patients reported in post-hoc analyses from ARISTOTLE were 2.4% [9]. Similarly to our findings, in the ENGAGE-AF, major bleedings occurred in 7.9% of cancer patients receiving high dose of edoxaban [10]. These differences could be explained by different features among the study populations. The high thromboembolic and bleeding risks observed in our cohort of patients with cancer are probably due to the proportion of patients with active cancer. Indeed, when patients with a history of cancer were compared to those without cancer, similar incidences in terms of major bleedings (3.6% vs 3.0% patient-year) and of thromboembolic events (1.3% vs 0.8% patient-year) were found. The increased incidence of thromboembolic and bleeding events reported in our study in cancer, compared to non-cancer patients, could be a consequence of the cancer-related but also of the anticancer treatment-related prothrombotic state [5]. Cancer cells can promote activation of blood coagulation directly by generating thrombin, or indirectly by stimulating endothelial cells and circulating mononuclear cells to synthesize and express several procoagulant factors [16]. Moreover, some anticancer therapies (novel angiogenesis inhibitors, taxanes and platinum compounds) have been related to thromboembolic complications through both the amplification of the cancerrelated prothrombotic state and direct damage to the vessel walls [5,16]. On the other hand, cancer and anti-cancer treatment are
Fig. 2. Thromboembolic (a) and major bleeding (b) events in history of cancer, active cancer and non-cancer patients.
Please cite this article as: M.C. Vedovati, et al., Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.138
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associated with an increased risk of bleeding either at cancer or noncancer sites beyond the conventional bleeding scores [17]. Therefore, the European Society of Cardiology suggests an individualized approach for decision making concerning initiation of anticoagulation in AF cancer patients based on the balance of thrombotic and bleeding risks; a strict follow-up is recommended in AF patients with cancer who are initiated on anticoagulant treatment [8]. In a recent retrospective cohort of 2037 patients with cancer and pre-existing AF, the CHADS2 and CHA2DS2-VASc scores were found to be predictors of stroke and of death [18]. However, cancer is not included in the CHA2DS2VASc score or in other scores for the assessment of thromboembolic risk in AF patients. The predictive role of cancer beyond the CHADS2VASc score appears to be limited for in-hospital cerebrovascular accidents [19], but could be not negligible for long term events. In a Danish cohort of 122,053 patients with incident AF not receiving anticoagulant therapy and a follow-up of 2 years, the CHA2DS2VASc score was associated with thromboembolic and bleeding events in both patients with and patients without cancer [20]. However, compared with non-cancer patient, those with recent cancer were at greater risk of thromboembolism at CHA2DS2VASc score 1 (HR 1.6%, 95% CI 1.2 to 2.1, versus HR 4.1%, 95% CI 2.8 to 6.1, respectively), and at greater risk of bleeding irrespective of the CHA2DS2VASc score. It is conceivable that in the low-CHA2DS2VASc patients the risk of thromboembolic events associated with cancer and cancer therapy overwhelms the risk predicted based on conventional risk factors [21]. Our study included only patients receiving DOACs and no comparison to VKAs can be made. Data from ARISTOTLE or ENGAGE-AF subanalyses on cancer patients showed non-significant differences in terms of thromboembolic events or major bleedings, between the study DOAC and warfarin [9,10]. A retrospective study in Korean AF patients and newly diagnosed cancer showed a significantly lower incidence of ischemic stroke/systemic embolism, major bleeding and allcause death in patients receiving DOACs compared to propensity score matched patients receiving warfarin (p b 0.001 for all comparisons) [22]. Data from an insurance database of 16,096 patients with active cancer who initiated oral anticoagulant therapy for nonvalvular AF showed similar rates of ischemic stroke in patients receiving different anticoagulants. Compared with warfarin, rates of bleeding were similar in rivaroxaban (HR 1.09 95% CI 0.79 to 1.39) and dabigatran (HR 0.96, 95% CI 0.72 to 1.27) users, whereas apixaban users experienced lower rates (HR 0.37, 95% CI 0.17 to 0.79) [23]. As expected, we found that all cause death was significantly higher in cancer compared to non-cancer patients. Similar results were reported in the post-hoc analysis from the ENGAGE-AF: 12% patientyear in cancer vs 3.6% patient-year in non-cancer patients (HR 3.3, 95% CI 3.0–3.7) [10]. We found that this difference was mainly driven by cancer-related mortality. In fact, a non-significant difference was found for non-cancer related death between the two groups: 5.9% patient-year in cancer and 4.5% patient-year in non-cancer groups. No differences between the two groups were found for fatal bleedings and fatal thrombosis. In our cohort a low rate of venous thromboembolic event was experienced (0.3% patient-year). This low rate is probably related to ongoing anticoagulant treatment. We observed a significantly higher rate of major gastrointestinal bleeding in cancer compared to non-cancer patients. This is probably due to the high proportion of patients with gastrointestinal cancer. Similarly to our observation, the increase in gastrointestinal major bleeding observed in the SELECT-D and Hokusai-cancer trials occurred mainly in patients with gastrointestinal cancer [24,25]. Management of AF in cancer patients can be challenging given the possible drug–drug interactions between anticancer therapies and anticoagulants. In these patients, a careful evaluation of the antithrombotic strategy with the best efficacy/safety profile is needed [16]. If potential major interactions and laboratory changes (thrombocytopenia, renal impairment) are expected, treatment with VKAs is questionable.
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DOACs should be preferred but limited evidence exists on this population. A multidisciplinary approach (oncologists/hematologists, cardiologists and coagulation experts) is advised [16]. Some limitations of this study should be considered. The sample size of cancer patients is relatively small and this might have affected the results of subgroup analyses. Decision for type and dosage of DOAC was in charge of the attending physician and information on type of chemotherapy were not collected. No comparisons between DOACs and VKAs can be provided. Patients with incidental cancer were included in the group of patients with cancer. This approach may be debatable. However, the majority of patients received a diagnosis of cancer in the first months after the prescription of DOACs and they were supposed to have had cancer at time of inclusion in the study. In order to make this point clearer, separate analyses have been provided according to the type of cancer. At last, 3.8% of patients were lost to follow-up. Despite these limitations, the prospective data collection and the consecutiveness of the population provides a real-life picture of the performance of DOACs in patients with cancer. Our results confirm some previous findings and add original information as the data concerning bleeding site and on cancer type. We conclude that this study suggests that the prevalence of cancer in patients with AF receiving DOACs is not negligible. The higher bleeding risk found in cancer compared to non-cancer patients was mainly due to an excess of bleeding at gastrointestinal and at genitourinary sites. Patients with cancer receiving DOACs have a higher thromboembolic risk compared to non-cancer patients although fatal bleeding and fatal thrombotic rates seemed comparable. Acknowledgment Vedovati M.C., Giustozzi M., Agnelli G. and Becattini C. made a substantial contributions to conception of the work, to the acquisition, analysis, and interpretation of data for the work, drafting of the work and revising it critically for important intellectual content, final approval of the version to be published, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy. Verdecchia P., Pierpaoli L., Conti S., Verso M., Di Filippo F., Marchesini E. and Bogliari G. made a substantial contributions to conception of the work, drafting of the work and revising it critically for important intellectual content, final approval of the version to be published, agreed to be accountable for all aspects of the work in ensuring that questions related to integrity of any part of the work are appropriately investigated and resolved. Vedovati M.C., Giustozzi M. and Becattini C. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Disclosures None to declare for this study. Support/funding No financial support was received for this study. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2018.07.138. References [1] M.A. Khan, F. Ahmed, L. Neyses, M.A. Mamas, Atrial fibrillation in heart failure: the sword of Damocles revisited, World J. Cardiol. 5 (7) (2013) 215–227. [2] J. Schmitt, G. Duray, B.J. Gersh, S.H. Hohnloser, Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications, Eur. Heart J. 30 (9) (2009) 1038–1045.
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Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study Maria Cristina Vedovati a,⁎,1, Michela Giustozzi a,1, Paolo Verdecchia b,1, Lucia Pierpaoli c,1, Serenella Conti d,1, Melina Verso a,1, Francesco Di Filippo c,1, Emanuela Marchesini a,1, Giulio Bogliari a,1, Giancarlo Agnelli a,1, Cecilia Becattini a,1 a
Internal and Cardiovascular Medicine - Stroke Unit, University of Perugia, Perugia, Italy Department of Medicine, Hospital of Assisi, Assisi, Italy c Emergency Medicine, S. Maria Delle Croci Hospital, Ravenna, Italy d Division of Cardiology, S. Matteo degli Infermi Hospital, Spoleto, Italy b
a r t i c l e
i n f o
Article history: Received 25 April 2018 Received in revised form 19 June 2018 Accepted 27 July 2018 Available online xxxx Keywords: Dabigatran Rivaroxaban Apixaban Atrial fibrillation Cancer Anticoagulants
a b s t r a c t Background: Limited data are available on the use of direct oral anticoagulants (DOACs) in patients with cancer and atrial fibrillation (AF). Methods: Consecutive patients with non-valvular AF treated with DOACs were enrolled in a prospective cohort with the aim of evaluating thromboembolic (ischemic stroke or transient ischemic attack or systemic embolism) and major bleeding (MB) events according to presence and type of cancer. The risk of study outcomes over time was compared using Kaplan-Meier method and log-rank test or Cox proportional hazards regression. Results: 2304 patients with non-valvular AF receiving DOACs were enrolled and 16 excluded: 2288 analysed of whom 289 (12.6%) had cancer. Gastrointestinal (21%), genitourinary (15%), prostate (15%), haematological (14%), breast (13%), and lung (8%) were the more frequent sites of cancer. After a mean follow-up of 451 days, thromboembolic events occurred in 2.1% and 0.8% patient-year of cancer and non-cancer patients (adjusted-HR 2.58, 95% CI 1.08–6.16, p = 0.033). The rate of MB was 6.6% and 3.0% patientyear in cancer and non-cancer patients (adjusted-HR 2.02, 95% CI 1.25–3.27, p = 0.004). The differences in bleeding were mainly accounted for by bleeding at gastrointestinal and genitourinary sites. No significant differences were found concerning the rates of non-cancer-related mortality, fatal bleeding or fatal thrombotic events. Conclusions: In this study, the higher bleeding risk found in cancer compared to non-cancer patients was mainly due to an excess of bleeding at gastrointestinal and at genitourinary sites. Larger studies on the optimal management of cancer patients with AF are needed. © 2018 Published by Elsevier B.V.
1. Introduction Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and an important risk factor for stroke, heart failure and dementia [1–3]. The incidence of AF is known to be related to ageing, cardiovascular conditions (such as hypertension, heart failure, valvular disease) and non-cardiovascular conditions (such as diabetes, thyroid dysfunction, chronic pulmonary or kidney diseases). More recently, a correlation has been reported between AF and cancer [4,5]. The prevalence of a concomitant history of cancer was reported up to 20% of AF patients in recent registries or cohort studies [6,7].
⁎ Corresponding author at: Internal and Cardiovascular Medicine - Stroke Unit, University of Perugia, Via G Dottori 1, 06129 Perugia, Italy. E-mail address: [email protected] (M.C. Vedovati). 1 This author takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
For several decades, vitamin K antagonists (VKAs) have been used in patients with AF to reduce the incidence of stroke or systemic embolism. Direct oral anticoagulants (DOACs) are being increasingly prescribed and are now recommended as the first choice anticoagulant agents in patients with non-valvular AF. In patients affected by both AF and cancer, antithrombotic treatment is challenging. Cancer patients are at high risk of both thromboembolic and bleeding events for the direct interaction of cancer with the coagulation system and for the effect of chemotherapy [5]. Clinically relevant data on antithrombotic treatment in cancer patients with AF are limited and only a position paper examines this topic [8]. Indeed, only a few number of cancer patients (those with presumed long life expectancy) were included in the DOAC phase III trials on AF. Post-hoc analyses from these studies led to inconclusive results concerning the thrombotic and bleeding risks of cancer and non-cancer patients as well as in cancer patients receiving DOACs or VKAs [9,10]. A retrospective analysis of a Danish cohort of AF patients on oral anticoagulant treatment showed a similar rate of
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Please cite this article as: M.C. Vedovati, et al., Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.138
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thromboembolic and bleeding complications in cancer and non-cancer patients [7]. However, among cancer patients thrombotic and bleeding risks also differ according to the status of the neoplastic disease. The aim of this study was to prospectively evaluate the risk of thromboembolic and bleeding events according to presence and type of cancer in patients with non-valvular AF treated with DOACs.
survival analysis (Kaplan-Meier method and log-rank test or Cox proportional hazards regression). Analyses were adjusted for significant differences among the two population. Patients were analysed according to presence of cancer or absence of cancer. Patients were also analysed according to cancer type: history of cancer and active cancer. Patients with active cancer were further categorized according to: active cancer at baseline or incidental cancer. Statistical analysis was performed with SPSS software (version 20) and values b 0.05 were considered statistically significant.
2. Methods 2.1. Study design, setting and patients Consecutive in- and out-patients with confirmed non-valvular AF who were prescribed with DOACs in four Italian hospitals from August 2013 to March 2017 were enrolled in a prospective cohort study. These patients could be either anticoagulation naïve or switched from prior treatment with VKAs. The choice of the individual DOACs was in charge of the attending physician. Exclusion criteria were refusal of informed consent and a valvular AF. AF was defined ‘valvular’ if it was related to rheumatic valvular disease (predominantly moderate or severe mitral stenosis) or associated with prosthetic heart valves [11]. The study period started at the time of the DOAC prescription. Patients included in the study were categorized as it follows: i) non-cancer patients those without clinical evidence of cancer; ii) cancer patients. Cancer patients were categorized as iii) patients with active cancer, at time of inclusion in the study, in presence of a diagnosis of cancer or any anti-cancer treatment within 6 months before the study inclusion, or recurrent locally advanced or metastatic cancer; iv) patients with history of cancer, at time of inclusion in the study, those with a cancer not satisfying the criteria for active disease. Patients with a cancer diagnosed during the study period, i.e. v) incidental cancer, were subsequently included in the group of active cancer patients. The study was approved by the Ethical Committee and/or Institutional Review Boards of the participating centres. 2.2. Study outcomes The primary outcomes of the study were thromboembolic events (ischemic stroke, transient ischemic attack [TIA] or systemic embolism) and major bleeding all occurring while on treatment with DOACs. Major bleeding was defined according to the ISTH criteria [12]. Ischemic stroke was defined as a new, focal neurological deficit of sudden onset, lasting at least 24 h, that is not due to a readily identifiable non-vascular cause (i.e., brain tumor, trauma). All strokes during the study had to be assessed by imaging or autopsy and classified as primary hemorrhagic, non-hemorrhagic, infarction with hemorrhagic conversion, or unknown, as defined by the American College of Cardiology (ACC) [13]. Additional outcomes were: 1) clinically relevant non-major bleeding (CRNMB), defined as overt bleeding that did not meet the criteria for major bleeding but was associated with medical intervention, unscheduled contact with a physician, interruption or discontinuation of DOAC; 2) clinically relevant bleeding, defined as the composite of major and of clinically relevant non-major bleedings; 3) acute myocardial infarction (AMI) defined as an appropriate clinical situation suggestive of a myocardial infarction (e.g., abnormal history, physical examination) and/or or new ECG changes and/or elevation of Troponin T or I ≥ 2 × ULN; 4) all cause mortality; 5) non-cancer related mortality; 6) the composite of fatal bleeding and fatal thrombotic events. 2.3. Data collection For all included patients the following data were collected: age, gender, comorbidities (hypertension, congestive heart failure, diabetes, previous stroke, vascular diseases, renal or liver failure, previous major bleeding), type and dose of DOACs, date of DOAC prescription, concomitant medications (non-steroidal anti-inflammatory and antiplatelet agents) and creatinine clearance (estimated by Cockcroft–Gault formula) [14]. Risks for stroke and bleeding were assessed according to CHADS2, CHA2DS2VASc and HAS-BLED scores, respectively [11]. In patients with cancer, data on cancer site, date of diagnosis, anticancer therapy, the presence of metastases, locally advanced disease and cancer recurrence were also collected. All patients entered a scheduled follow-up program with medical visit or, if not possible, by phone calls every 6 months or whenever clinical issues occurred. At each follow-up visit, data on clinical outcomes as thromboembolic and bleeding events were collected as well as any adverse events, occurrence of cancer and treatment adherence. Thrombotic and bleeding risks were reassessed at each contact. All the events were locally adjudicated. 2.4. Statistical analysis Main basal characteristics and outcome events of patients with cancer and of those with non-cancer were compared. Categorical data were reported as frequencies and continuous data as mean ± standard deviation (SD). Categorical data were compared with the use of χ2 test and continuous data with the use of t-test. The reported p-values were based on two sided tests. Outcome event rates were reported as proportions of patient-year. Patients remained in the analysis until death, or the first between withdrawal of anticoagulant treatment or occurrence of a study outcome event (thromboembolic event or major bleeding). The risk of study outcomes over time in cancer and non-cancer patients was compared using
3. Results Overall, 2304 patients were considered for the analysis, of whom 16 were excluded and 2288 were finally included in the analysis of baseline features (eFigure 1). Nine-hundred and fifty-two patients (41.6%) were switched from prior treatment with VKAs to DOACs. Dabigatran, rivaroxaban and apixaban were prescribed in 30, 35 and 35% of patients, respectively. Overall, 289 patients had cancer (12.6%): active cancer in 104 (4.5%) and history of cancer in 185 (8.1%). An active cancer was present at time of DOAC prescription in 68 patients (2.9%): 13 had the diagnosis made in the 6 months before DOAC was started, 33 were on anti-cancer therapy, 18 had a metastatic disease and 8 had a recurrence of cancer. Four out of these patients had more than one criteria for active cancer. In 36 patients (1.6%), cancer was diagnosed during the study period (12 patients with metastatic disease). The mean time from study inclusion to cancer diagnosis was 238 ± 141 days. Thirty-three patients (92%) received the cancer diagnosis in the first year from inclusion (16 patients in the first 6 months). The occurrence of major gastrointestinal bleeding led to cancer diagnosis in 6 patients. In the cancer group, sites of cancer were gastrointestinal (20.8%), genitourinary (15.2%), prostatic (15.2%), haematological (13.8%), breast (13.1%), lung (8.0%), skin (3.5%), pancreas (2.4%), brain (1.7%), thyroid (1.4%), liver (1.4%) and other (3.5%). Cancer site among patients with incidental cancer was as it follow: gastrointestinal in 33.3%, genitourinary in 16.7%, lung in 16.7%, haematological in 11.1%, pancreas in 8.3%, liver in 5.5% and prostatic, skin and brain in 2.8% each (eFigure 2). Male gender and age ≥ 75 years were more frequent in cancer compared to non-cancer patients. No other significant difference was observed. Baseline features of cancer and non-cancer patients are detailed in Table 1. Baseline features among different cancer groups are reported in eTable 1. 3.1. Outcome events Complete outcome data were available in 2200 patients of whom 280 with cancer (eFigure 1). The mean follow-up was 451.2 days: 441.3 ± 267.6 in cancer and 452.6 ± 254.8 in non-cancer patients (p = 0.49). The incidence of thromboembolic events during treatment with DOACs was 2.1% patient-year (95% CI 1.0 to 4.2) in cancer and 0.8% patient-year (95% CI 0.5 to 1.3) in non-cancer patients (adjusted-HR 2.58, 95% CI 1.08 to 6.16) Fig. 1a. Individual components of the outcome data according to cancer and non-cancer are reported in Table 2. The incidence of major bleeding was 6.6% patient-year (95% CI 4.4 to 9.8) in cancer and 3.0% patient-year (95% CI 2.4 to 3.8) in non-cancer patients (adjusted-HR 2.02, 95% CI 1.25 to 3.27) Fig. 1b. The rate of clinically relevant bleeding was significantly higher in cancer (18.2% patient-year, 95% CI 14.4 to 22.9) compared to non-cancer patients (10.6% patient-year, 95% CI 9.5 to 12.0): adjusted-HR 1.65, 95% CI 1.23 to 2.19. In the non-cancer group, 16 patients experienced an AMI (0.7% patient-year, 95% CI 0.4 to 1.1), one patient in the cancer cohort experienced a venous thromboembolic event (0.3% patient-year, 95% CI 0.1 to 1.7). As expected, overall mortality was higher in cancer compared to non-cancer patients (10.9 vs 4.5% patient-year, adjusted-HR 2.25, 95% CI 1.55 to 3.28). Non-cancer-related mortality was non-significantly
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Table 1 Baseline features.
Age years, mean ± SD (range) Age ≥ 75, n (%) Female, n (%) CHF, n (%) Systemic hypertension, n (%) Diabetes, n (%) Previous stroke, n (%) Vascular disease, n (%) Previous MB, n (%) BMI kg/m2, mean ± SD Liver failure, n (%) Clearance creat. ≤ 50 ml/min, n (%)a CHADS2, mean ± SD CHADS2 ≥ 2, n (%) CHA2DS2VASC, mean ± SD CHA2DS2VASC ≥ 3, n (%) HASBLED, mean ± SD HASBLED ≥ 2, n (%) DOAC reduced dose, n (%)
Overall (n = 2288)
Cancer (n = 289)
Non-cancer (n = 1999)
p
77.9 ± 9.0 (38–99) 1586 (69.3) 1121 (49.0) 486 (21.3) 2001 (87.5) 459 (20.1) 620 (27.1) 615 (26.9) 233 (10.2) 26.9 ± 4.8 35 (1.5) 572 (25.5) 2.5 ± 1.2 1849 (80.8) 4.2 ± 1.5 1999 (87.4) 2.5 ± 1.2 1750 (76.5) 985 (43.1)
78.9 ± 7.9 (52–96) 217 (75.1) 123 (42.6) 70 (24.2) 259 (89.6) 53 (18.3) 75 (26.0) 72 (24.9) 28 (9.7) 26.6 ± 4.3 4 (1.4) 82 (28.9) 2.6 ± 1.2 238 (82.4) 4.2 ± 1.5 257 (88.9) 2. 6 ± 1.2 227 (78.5) 121 (41.9)
77.8 ± 9.1 (38–99) 1369 (68.5) 998 (49.9) 416 (20.8) 1742 (87.2) 406 (20.3) 545 (27.3) 543 (27.2) 205 (10.3) 26.9 ± 4.9 31 (1.6) 490 (25.0) 2.5 ± 1.2 1611 (80.6) 4.2 ± 1.6 1742 (87.1) 2.5 ± 1.2 1523 (76.2) 864 (43.2)
0.04 0.02 0.02 0.19 0.23 0.43 0.64 0.42 0.76 0.34 0.83 0.16 0.30 0.47 0.85 0.39 0.38 0.37 0.66
CHF = chronic heart failure; MB = major bleeding; BMI = body mass index; DOAC = direct oral anticoagulant. a Creatinine clearance calculated according to the Cockcroft–Gault formula available in 2243 patients.
higher in cancer compared to non-cancer patients (5.9 vs 4.5% patientyear, adjusted-HR 1.22, 95% CI 0.76 to 1.97); rates of fatal bleeding and fatal thrombotic events were similar in the two groups (0.9 vs 0.8% patient-year, adjusted-HR 0.98, 95% CI 0.29 to 3.33). Among patients with cancer, the incidence of thromboembolic events was higher in those with active cancer (3.6% patient-year, 95% CI 1.4 to 8.8) compared to patients with non-cancer (0.8% patientyear, 95% CI 0.5 to 1.3; adjusted-HR 4.03, 95% CI 1.35 to 12.03) Fig. 2a. As well major bleeding occurred more frequently in patients with active cancer (12.8% patient-year, 95% CI 7.8 to 20.4) compared to those without cancer (3.0% patient-year, 95% CI 2.4 to 3.8; adjusted-HR 3.87, 95% CI 2.16 to 6.94) Fig. 2b. No differences in thromboembolic or bleeding events were observed between patients with history of cancer and patients without cancer. Similar rates of non-cancer-related death were observed in patients with active cancer, history of cancer and noncancer. As well, no significant differences were observed for fatal bleeding or fatal thrombosis among these three groups. Outcome events according to cancer type and site are reported in eTables 2 and 3.
3.2. Site of bleeding events The incidence of major gastrointestinal bleeding was significantly higher in cancer (4.5% patient-year, 95% CI 2.8 to 7.3) compared to non-cancer patients (1.3% patient-year, 95% CI 0.9 to 1.9): OR 3.6, 95% CI 1.9 to 6.7, p b 0.001. Non-significant differences were found for the other sites in terms of major bleedings. Clinically relevant bleeding rates at gastrointestinal and at genitourinary site were significantly higher in cancer compared to non-cancer patients (OR 2.6, 95% CI 1.7 to 4.2, p b 0.001, and OR 3.2, 95% CI 1.7 to 6.0, p b 0.001, respectively). No significant differences were found for other bleeding site in cancer and non-cancer groups (eFigure 3). Bleeding sites according to cancer type are reported in eFigure 4. Fatal bleeding occurred in 2 patients with and in 13 patients without cancer (0.6% patient-year, 95% CI 0.2 to 2.1 and 0.6% patient year, 95% CI 0.3 to 0.9, respectively, p = 0.919). Fatal intracranial haemorrhages were observed in 7 non-cancer patients (of whom 3 were posttraumatic) and none in cancer patients.
Fig. 1. Thromboembolic (a) and major bleeding (b) events in cancer and non-cancer patients.
Please cite this article as: M.C. Vedovati, et al., Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.138
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Table 2 Outcome events in cancer and in non-cancer patients.
Thromboembolic events Ischemic stroke/TIA Systemic embolism Major Bleeding CRNMB Clinically relevant bleeding AMI All cause death Non-cancer related death Fatal bleeding or fatal thrombosis
Cancer 280, n (% pts/year, 95% CI) Non-cancer 1920, n (% pts/year, 95% CI) HR
95% CI
p
Adj-HRa 95% CI
p
7 (2.1, 1.0–4.2) 6 (1.8, 0.8–3.8) 1 (0.3, 0.1–1.7) 22 (6.6, 4.4–9.8) 38 (11.8, 8.7–15.7) 58 (18.2, 14.4–22.9) 0 37 (10.9, 8.0–14.7) 20 (5.9, 3.9–9.0) 3 (0.9, 0.3–2.6)
1.10–6.21 1.10–7.31 0.20–15.78 1.35–3.52 1.07–2.15 1.30–2.30 – 1.67–3.52 0.81–2.11 0.32–3.70
0.030 0.031 0.612 0.001 0.020 b0.001 – b0.001 0.268 0.885
2.58 2.76 1.87 2.02 1.46 1.65 – 2.25 1.22 0.98
0.033 0.036 0.575 0.004 0.036 0.001 _ b0.001 0.418 0.975
19 (0.8, 0.5–1.3) 15 (0.6, 0.4–1.0) 4 (0.2, 0.1–0.4) 71 (3.0, 2.4–3.8) 183 (7.9, 6.9–9.1) 246 (10.6, 9.5–12.0) 16 (0.7, 0.4–1.1) 107 (4.5, 3.7–5.4) 107 (4.5, 3.7–5.4) 19 (0.8, 0.5–1.3)
2.61 2.83 1.76 2.18 1.51 1.73 – 2.42 1.31 1.09
1.08–6.16 1.07–7.15 0.21–16.86 1.25–3.27 1.03–2.07 1.23–2.19 – 1.55–3.28 0.76–1.97 0.29–3.33
AMI = acute myocardial infarction; CRNMB = clinically relevant non-major bleeding; TIA = transient ischemic attack. a Adjusted-HR for age ≥ 75 years and gender.
Bleeding site was the same as cancer site in 23 out of the 55 clinically relevant bleedings (41.8%): 5 (21.8%), 3 (13.0%) and 15 (65.2%) events occurred in patients with history, active and incidental cancer, respectively. 4. Discussion In this prospective cohort of patients with non-valvular AF receiving DOACs, about two fold higher rates of major and clinically relevant non major bleedings were observed in cancer compared to non-cancer patients. Most of the excess of bleeding was accounted for by the events which occurred in patients with active cancer. As well, the thromboembolic risk was doubled in cancer compared to non-cancer patients. The highest thromboembolic risk was observed in patients with incidental cancer. In this study, the prevalence of cancer in patients with AF receiving DOACs is not negligible (12.6%). Lower rates were observed in phase III trials on DOACs (6.8% in ARISTOTLE and 5.5% in ENGAGE-AF) [9,10]. In a Danish cohort, the prevalence of cancer was 17 and 20% in AF patients prescribed with VKAs or DOACs, respectively, in clinical practice [7]. Similarly to ours, cancer patients from the Danish cohort were older than non-cancer patients. However, Ording et al. observed a similar overall thromboembolic complication rate in cancer and non-cancer patients. No differences in terms of stroke or systemic embolism were also found in patients with and without cancer included in the post-hoc analyses from ENGAGE-AF or ARISTOTLE trials [9,10].
We found a rate of major bleeding of 6.6% patient-year in patients with cancer, which is higher than those observed in other studies. In a cohort of 163 cancer patients with AF receiving rivaroxaban major bleedings was reported in 1.2% [15]. The rate of major bleeding in cancer patients reported in post-hoc analyses from ARISTOTLE were 2.4% [9]. Similarly to our findings, in the ENGAGE-AF, major bleedings occurred in 7.9% of cancer patients receiving high dose of edoxaban [10]. These differences could be explained by different features among the study populations. The high thromboembolic and bleeding risks observed in our cohort of patients with cancer are probably due to the proportion of patients with active cancer. Indeed, when patients with a history of cancer were compared to those without cancer, similar incidences in terms of major bleedings (3.6% vs 3.0% patient-year) and of thromboembolic events (1.3% vs 0.8% patient-year) were found. The increased incidence of thromboembolic and bleeding events reported in our study in cancer, compared to non-cancer patients, could be a consequence of the cancer-related but also of the anticancer treatment-related prothrombotic state [5]. Cancer cells can promote activation of blood coagulation directly by generating thrombin, or indirectly by stimulating endothelial cells and circulating mononuclear cells to synthesize and express several procoagulant factors [16]. Moreover, some anticancer therapies (novel angiogenesis inhibitors, taxanes and platinum compounds) have been related to thromboembolic complications through both the amplification of the cancerrelated prothrombotic state and direct damage to the vessel walls [5,16]. On the other hand, cancer and anti-cancer treatment are
Fig. 2. Thromboembolic (a) and major bleeding (b) events in history of cancer, active cancer and non-cancer patients.
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associated with an increased risk of bleeding either at cancer or noncancer sites beyond the conventional bleeding scores [17]. Therefore, the European Society of Cardiology suggests an individualized approach for decision making concerning initiation of anticoagulation in AF cancer patients based on the balance of thrombotic and bleeding risks; a strict follow-up is recommended in AF patients with cancer who are initiated on anticoagulant treatment [8]. In a recent retrospective cohort of 2037 patients with cancer and pre-existing AF, the CHADS2 and CHA2DS2-VASc scores were found to be predictors of stroke and of death [18]. However, cancer is not included in the CHA2DS2VASc score or in other scores for the assessment of thromboembolic risk in AF patients. The predictive role of cancer beyond the CHADS2VASc score appears to be limited for in-hospital cerebrovascular accidents [19], but could be not negligible for long term events. In a Danish cohort of 122,053 patients with incident AF not receiving anticoagulant therapy and a follow-up of 2 years, the CHA2DS2VASc score was associated with thromboembolic and bleeding events in both patients with and patients without cancer [20]. However, compared with non-cancer patient, those with recent cancer were at greater risk of thromboembolism at CHA2DS2VASc score 1 (HR 1.6%, 95% CI 1.2 to 2.1, versus HR 4.1%, 95% CI 2.8 to 6.1, respectively), and at greater risk of bleeding irrespective of the CHA2DS2VASc score. It is conceivable that in the low-CHA2DS2VASc patients the risk of thromboembolic events associated with cancer and cancer therapy overwhelms the risk predicted based on conventional risk factors [21]. Our study included only patients receiving DOACs and no comparison to VKAs can be made. Data from ARISTOTLE or ENGAGE-AF subanalyses on cancer patients showed non-significant differences in terms of thromboembolic events or major bleedings, between the study DOAC and warfarin [9,10]. A retrospective study in Korean AF patients and newly diagnosed cancer showed a significantly lower incidence of ischemic stroke/systemic embolism, major bleeding and allcause death in patients receiving DOACs compared to propensity score matched patients receiving warfarin (p b 0.001 for all comparisons) [22]. Data from an insurance database of 16,096 patients with active cancer who initiated oral anticoagulant therapy for nonvalvular AF showed similar rates of ischemic stroke in patients receiving different anticoagulants. Compared with warfarin, rates of bleeding were similar in rivaroxaban (HR 1.09 95% CI 0.79 to 1.39) and dabigatran (HR 0.96, 95% CI 0.72 to 1.27) users, whereas apixaban users experienced lower rates (HR 0.37, 95% CI 0.17 to 0.79) [23]. As expected, we found that all cause death was significantly higher in cancer compared to non-cancer patients. Similar results were reported in the post-hoc analysis from the ENGAGE-AF: 12% patientyear in cancer vs 3.6% patient-year in non-cancer patients (HR 3.3, 95% CI 3.0–3.7) [10]. We found that this difference was mainly driven by cancer-related mortality. In fact, a non-significant difference was found for non-cancer related death between the two groups: 5.9% patient-year in cancer and 4.5% patient-year in non-cancer groups. No differences between the two groups were found for fatal bleedings and fatal thrombosis. In our cohort a low rate of venous thromboembolic event was experienced (0.3% patient-year). This low rate is probably related to ongoing anticoagulant treatment. We observed a significantly higher rate of major gastrointestinal bleeding in cancer compared to non-cancer patients. This is probably due to the high proportion of patients with gastrointestinal cancer. Similarly to our observation, the increase in gastrointestinal major bleeding observed in the SELECT-D and Hokusai-cancer trials occurred mainly in patients with gastrointestinal cancer [24,25]. Management of AF in cancer patients can be challenging given the possible drug–drug interactions between anticancer therapies and anticoagulants. In these patients, a careful evaluation of the antithrombotic strategy with the best efficacy/safety profile is needed [16]. If potential major interactions and laboratory changes (thrombocytopenia, renal impairment) are expected, treatment with VKAs is questionable.
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DOACs should be preferred but limited evidence exists on this population. A multidisciplinary approach (oncologists/hematologists, cardiologists and coagulation experts) is advised [16]. Some limitations of this study should be considered. The sample size of cancer patients is relatively small and this might have affected the results of subgroup analyses. Decision for type and dosage of DOAC was in charge of the attending physician and information on type of chemotherapy were not collected. No comparisons between DOACs and VKAs can be provided. Patients with incidental cancer were included in the group of patients with cancer. This approach may be debatable. However, the majority of patients received a diagnosis of cancer in the first months after the prescription of DOACs and they were supposed to have had cancer at time of inclusion in the study. In order to make this point clearer, separate analyses have been provided according to the type of cancer. At last, 3.8% of patients were lost to follow-up. Despite these limitations, the prospective data collection and the consecutiveness of the population provides a real-life picture of the performance of DOACs in patients with cancer. Our results confirm some previous findings and add original information as the data concerning bleeding site and on cancer type. We conclude that this study suggests that the prevalence of cancer in patients with AF receiving DOACs is not negligible. The higher bleeding risk found in cancer compared to non-cancer patients was mainly due to an excess of bleeding at gastrointestinal and at genitourinary sites. Patients with cancer receiving DOACs have a higher thromboembolic risk compared to non-cancer patients although fatal bleeding and fatal thrombotic rates seemed comparable. Acknowledgment Vedovati M.C., Giustozzi M., Agnelli G. and Becattini C. made a substantial contributions to conception of the work, to the acquisition, analysis, and interpretation of data for the work, drafting of the work and revising it critically for important intellectual content, final approval of the version to be published, agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy. Verdecchia P., Pierpaoli L., Conti S., Verso M., Di Filippo F., Marchesini E. and Bogliari G. made a substantial contributions to conception of the work, drafting of the work and revising it critically for important intellectual content, final approval of the version to be published, agreed to be accountable for all aspects of the work in ensuring that questions related to integrity of any part of the work are appropriately investigated and resolved. Vedovati M.C., Giustozzi M. and Becattini C. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Disclosures None to declare for this study. Support/funding No financial support was received for this study. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.ijcard.2018.07.138. References [1] M.A. Khan, F. Ahmed, L. Neyses, M.A. Mamas, Atrial fibrillation in heart failure: the sword of Damocles revisited, World J. Cardiol. 5 (7) (2013) 215–227. [2] J. Schmitt, G. Duray, B.J. Gersh, S.H. Hohnloser, Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications, Eur. Heart J. 30 (9) (2009) 1038–1045.
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Please cite this article as: M.C. Vedovati, et al., Patients with cancer and atrial fibrillation treated with doacs: A prospective cohort study, Int J Cardiol (2018), https://doi.org/10.1016/j.ijcard.2018.07.138