CLINICAL RESEARCH STUDY

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1 CLINICAL RESEARCH STUDY Efficacy and Safety of Apixaban Versus Warfarin in Patients with Atrial Fibrillation and a History of Cancer: Insights from the ARISTOTLE Trial Chiara Melloni, MD, MHS, a,b Allison Dunning, MS, a Christopher B. Granger, MD, a,b Laine Thomas, PhD, a Michel G. Khouri, MD, b David A. Garcia, MD, c Elaine M. Hylek, MD, MPH, d Michael Hanna, MD, e Lars Wallentin, MD, PhD, f Bernard J. Gersh, MB, ChB, DPhil, g Pamela S. Douglas, MD, a,b John H. Alexander, MD, MHS, a,b Renato D. Lopes, MD, MHS, PhD a,b a Duke Clinical Research Institute, Durham, NC; b Duke University School of Medicine, Durham, NC; c University of Washington School of Medicine, Seattle; d Boston University School of Medicine, Boston, Mass; e Bristol-Myers Squibb, Princeton, NJ; f Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden; g Mayo Clinic, Rochester, Minn. ABSTRACT BACKGROUND: Cancer is associated with a prothrombotic state and increases the risk of thrombotic events in patients with atrial fibrillation. We described the clinical characteristics and outcomes and assessed the safety and efficacy of apixaban versus warfarin in patients with atrial fibrillation and cancer in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. METHODS: The association between cancer and clinical outcomes was assessed using Cox regression models. At baseline, 1236 patients (6.8%) had a history of cancer; 12.7% had active cancer, and 87.3% had remote cancer. RESULTS: There were no significant associations between history of cancer and stroke/systemic embolism, major bleeding, or death. The effect of apixaban versus warfarin for the prevention of stroke/systemic embolism was consistent among patients with a history of cancer (event/100 patient-years = 1.4 vs 1.2; hazard ratio [HR], 1.09; 95% confidence interval [CI], ) and no cancer (1.3 vs 1.6; HR, 0.77; 95% CI, ) (P interaction =.37). The safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer. Apixaban was associated with a greater benefit for the composite of stroke/systemic embolism, myocardial infarction, and death in active cancer (HR, 0.30; 95% CI, ) versus without cancer (HR, 0.86; 95% CI, ), but not in remote cancer (HR, 1.46; 95% CI, ) (interaction P =.0028). CONCLUSIONS: Cancer was not associated with a higher risk of stroke. The superior efficacy and safety of apixaban versus warfarin were consistent in patients with and without cancer. Our positive findings regarding apixaban use in patients with atrial fibrillation and cancer are exploratory and promising, but warrant further evaluation Elsevier Inc. All rights reserved. The American Journal of Medicine (2017) 130, KEYWORDS: Apixaban; Atrial fibrillation; Cancer; Stroke; Systemic embolism; Warfarin Funding: This work was supported by the Duke Clinical Research Institute. The ARISTOTLE trial was supported by Bristol-Myers Squibb and Pfizer, Inc. Conflict of Interest: See last page of article. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Chiara Melloni, MD, MHS, Duke Clinical Research Institute, 2400 Pratt St, Durham, NC address: chiara.melloni@duke.edu /$ - see front matter 2017 Elsevier Inc. All rights reserved.

2 Melloni et al Cancer and Atrial Fibrillation 1441 INTRODUCTION Cancer is associated with a prothrombotic state and may further increase the risk of thrombotic events in patients with atrial fibrillation. Some chemotherapeutic agents have been associated with thromboembolic complications and increased bleeding risk. 1-3 There are no guideline recommendations for antithrombotic therapy use in patients with atrial fibrillation and concurrent cancer, which creates uncertainty about the optimal antithrombotic therapy for stroke prevention in this population. Apixaban, a factor Xa inhibitor, was shown to be superior to warfarin in preventing stroke or systemic embolism and in reducing the risk of major hemorrhage by 31% compared with warfarin in patients with atrial fibrillation in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation CLINICAL SIGNIFICANCE (ARISTOTLE) trial. 4 There are currently no data on the safety or efficacy of apixaban in patients with atrial fibrillation and concomitant cancer. With the use of ARISTOTLE data, we aimed to describe the clinical characteristics, examine the associated clinical outcomes, and assess the safety and efficacy of apixaban versus warfarin in patients with atrial fibrillation and cancer. MATERIALS AND METHODS The design and primary results of ARISTOTLE have been reported. 4,5 In brief, patients with atrial fibrillation and at least 1 risk factor for stroke (age <75 years; previous stroke, transient ischemic attack, or systemic embolism; symptomatic heart failure within the previous 3 months or left ventricular ejection fraction >40%; and diabetes or hypertension requiring pharmacologic therapy) were randomized to receive doseadjusted warfarin (target international normalized ratio of ) or apixaban 5 mg twice daily. A reduced dose of apixaban (2.5 mg twice daily) was administered in patients who met 2 or more of the following criteria: age >80 years, body weight <60 kg, or serum creatinine level >1.5 mg/dl. Cancer and atrial fibrillation frequently coexist, yet there are few data to guide care in this population. No significant associations between history of cancer and risk of stroke systemic embolism, major bleeding, or mortality were observed. The safety and efficacy of apixaban versus warfarin seem to be preserved among patients with and without active cancer. checkbox was selected on the case report form. This analysis was not predefined in the ARISTOTLE study protocol. Clinical Outcomes The primary efficacy outcome was stroke, defined as the abrupt onset of a nontraumatic, focal neurologic deficit lasting at least 24 hours, or systemic embolism, defined as symptoms consistent with acute loss of blood to a noncerebral artery confirmed by autopsy, angiography, vascular imaging, or other objective testing. Secondary end points included myocardial infarction and death. Myocardial infarction was defined as symptoms with biomarker elevation at least 2 greater than normal (creatine kinase, creatine kinase-myocardial band, or troponin) or with new Q waves in >2 contiguous leads. Death was classified as cardiovascular (stroke, systemic embolism, sudden death, heart failure, indeterminate) or noncardiovascular. The primary safety outcome was major bleeding, defined according to International Society on Thrombosis and Haemostasis criteria as clinically overt bleeding accompanied by a decrease in hemoglobin of at least 2 g/dl or transfusion of at least 2 units of packed red cells occurring at a critical site (intracranial, intraocular, intraspinal, intraarticular, intramuscular with compartment syndrome, pericardial, retroperitoneal) or resulting in death. 6 All primary and secondary outcomes were adjudicated by a clinical events committee blinded to treatment assignment. Median followup was 1.8 years. Objectives Our objectives were to assess 1) the association between cancer status and efficacy (stroke/noncentral nervous system embolism, myocardial infarction) and safety (major bleeding) outcomes in patients with atrial fibrillation; and 2) the interaction between treatment and cancer status (active and remote cancer) for efficacy and safety outcomes. Cancer History of cancer at baseline assessment was defined by the medical disease history question malignancy other than basal or squamous cell skin cancer. If cancer was selected, investigators specified the location and whether it was (1) active or treated within the past 1 year or (2) remote. No additional information on cancer stage or treatment was collected. In addition, new cancer or recurrence was not collected during the study. In this article, we will refer to patients with cancer as all patients with reported cancer history at baseline assessment, and we will specifically refer to active (or recent) cancer or remote cancer according to which Statistical Analysis Baseline characteristics of patients with atrial fibrillation and cancer were compared with patients with atrial fibrillation and no cancer, according to randomized treatment. Continuous variables are presented as medians (25th, 75th percentiles) for between-group comparisons. Student t tests were used for normally distributed data and nonparametric (Wilcoxon) tests for other data. Categoric variables are presented as counts (percentages) and compared using chi-square or Fisher exact tests where appropriate. Cox regression models were used to assess the association between cancer status and efficacy and safety

3 1442 The American Journal of Medicine, Vol 130, No 12, December 2017 outcomes (reference: noncancer group) and treatment-bycancer interaction for the association between treatment effect and efficacy and safety outcomes in patients with and without cancer (cancer overall/active and remote vs no cancer). Two Cox regression models were run for each efficacy and safety outcome of interest. The first was a univariable model to assess the unadjusted relationship between cancer status and each efficacy and safety outcome separately. The second was a baseline-adjusted model, in which adjustment variables included both prespecified and key demographic and clinical characteristics that resulted in a difference between the cancer and no cancer groups (Appendix 1, available online). Significance of P values was not corrected for multiplicity. All statistical analyses were performed using SAS version 9.4 software (SAS Institute, Inc, Cary, NC). RESULTS Baseline Characteristics Of 18,183 ARISTOTLE patients with known cancer status at baseline, 1236 (6.8%) had a history of cancer. Of these, 157 (12.7%) had active cancer or had received treatment for cancer within the past year, and 1079 (87.3%) had remote Table 1 Baseline Characteristics of Patients with Atrial Fibrillation and No History of Cancer Compared with Patients with Atrial Fibrillation with History of Cancer at Baseline Active Cancer (N = 157) Remote Cancer (N = 1079) No Cancer (N = 16,947) Age, y 74 (68, 80) 75 (69, 80) 70 (62, 76) Female sex, no. (%) 31 (19.7%) 374 (34.7%) 6005 (35.4%) Systolic BP, mm Hg 130 (120, 140) 130 (120, 140) 130 (120, 140) Diastolic BP, mm Hg 76 (70, 82) 78 (70, 84) 80 (70, 87) Weight, kg 86 (75, 97) 84 (73, 99) 82 (70, 95) Prior stroke, TIA, or SE, no. (%) 30 (19.1%) 202 (18.7%) 3305 (19.5%) Hypertension pharmacologically treated, no. (%) 132 (84.1%) 933 (86.5%) 14,838 (87.6%) HF or reduced LVEF, no. (%) 40 (25.5%) 303 (28.1%) 6101 (36.0%) CAD, no. (%) 64 (40.8%) 368 (34.2%) 5605 (33.1%) PAD, no. (%) 15 (9.6%) 68 (6.4%) 801 (4.8%) CHADS 2 score, mean (±SD) 2.2 (±1.20) 2.3 (±1.12) 2.1 (±1.10) CHADS 2 score, no. (%) 1 51 (32.5%) 292 (27.1%) 5829 (34.4%) 2 50 (31.8%) 408 (37.8%) 6053 (35.7%) 3 56 (35.7%) 379 (35.1%) 5065 (29.9%) CHA 2DS 2-VASc score, mean (±SD) 3.6 (±1.52) 3.8 (±1.42) 3.4 (±1.51) CHA 2DS 2-VASc score, no. (%) (25.5%) 191 (17.7%) 5133 (30.3%) (62.4%) 757 (70.2%) 10,231 (60.4%) >5 19 (12.1%) 131 (12.1%) 1583 (9.3%) HAS-BLED score, mean (±SD) 2.2 (±0.99) 2.2 (±1.02) 1.7 (±1.05) HAS-BLED score, no. (%) (22.3%) 239 (22.2%) 7176 (42.3%) 2 70 (44.6%) 427 (39.6%) 6067 (35.8%) 3 52 (33.1%) 413 (38.3%) 3704 (21.9%) Medications at time of randomization, no. (%) Prior use of VKA for >30 d 110 (70.1) 731 (67.7) 9553 (56.4) ACE inhibitor or ARB 105 (67.7) 708 (66.0) 12,012 (72.1) Amiodarone 13 (8.4) 82 (7.6) 1952 (11.7) Beta-blocker 98 (63.2) 714 (66.6) 10,663 (64.0) Aspirin 43 (27.4) 336 (31.1) 5248 (31.0) Clopidogrel 5 (3.2) 17 (1.6) 316 (1.9) Digoxin 46 (29.7) 327 (30.5) 5450 (32.7) Calcium channel blocker 48 (31.0) 379 (35.4) 5134 (30.8) Statin 85 (54.8) 562 (52.4) 6822 (40.9) NSAIDs 26 (16.8) 148 (13.8) 1345 (8.1) Gastric antacid drugs 33 (21.3) 290 (27.1) 3026 (18.2) Data presented as median (25th, 75th), unless otherwise indicated. See Appendix 2 (available online) for the definition of the terms CHADS 2, CHA 2DS 2-VASc and HAS-BLED. ACE = angiotensin-converting enzyme; AF = atrial fibrillation; ARB = angiotensin receptor blocker; BP = blood pressure; CAD = coronary artery disease; HF = heart failure; LVEF = left ventricular ejection fraction; NSAID = nonsteroidal anti-inflammatory drug; PAD = peripheral artery disease; SD = standard deviation; SE = systemic embolism; TIA = transient ischemic attack; VKA = vitamin K antagonist.

4 Melloni et al Cancer and Atrial Fibrillation 1443 Table 2 Type of Cancer Active Cancer (n = 157) Remote Cancer (n = 1079) Cancer (n = 1236) Bladder 14 (9%) 68 (6%) 82 (7%) Breast 17 (11%) 182 (17%) 199 (16%) Colon 12 (8%) 126 (12%) 138 (11%) Gastric 1 (1%) 28 (3%) 29 (2%) Lung 7 (4%) 30 (3%) 37 (3%) Melanoma 9 (6%) 69 (6%) 78 (6%) Others 19 (12%) 109 (10%) 128 (10%) Ovarian/uterine 3 (2%) 68 (6%) 71 (6%) Prostate 66 (42%) 290 (27%) 356 (29%) Rectal 2 (1%) 31 (3%) 33 (3%) Renal cell carcinoma 3 (2%) 43 (4%) 46 (4%) Hodgkin lymphoma 0 (0%) 6 (1%) 6 (1%) Leukemia 1 (1%) 5 (0%) 6 (0%) Lymphoma 1 (1%) 8 (1%) 9 (1%) Non-Hodgkin lymphoma 2 (1%) 13 (1%) 15 (1%) Data presented as number (%). cancer. Patients with a history of cancer were older, were more likely to have concomitant cardiovascular risk factors, and had more comorbidities with higher CHADS 2, CHA 2DS 2-VASc, and HAS-BLED scores (Table 1). During the study, patients with active cancer were more likely to permanently discontinue the study drug compared with those with remote and no cancer (29% vs 26% vs 22%). The majority of cancers were solid tumors, including prostate, breast, bladder, and colon (Table 2). Association Between Cancer Status and Clinical Outcomes Overall, no significant relationship was found between history of cancer and stroke/systemic embolism, death, or ischemic stroke. A significant relationship between cancer and increased risk of myocardial infarction was observed in the unadjusted model (hazard ratio [HR], 1.98; 95% confidence interval [CI], ; P =.0018), but this relationship was no longer significant after adjustment (HR, 1.45, 95% CI, ; P =.1047) (Table 3a). Likewise, there was a significant relationship between cancer and increased risk of major or clinically relevant nonmajor bleeding (HR, 1.25; 95% CI, ; P =.0181) and any bleeding (HR, 1.35; 95% CI, ; P <.0001) in the unadjusted model, but these associations were no longer significant after adjustment (HR, 0.96; 95% CI, ; HR, 1.10; 95% CI, ) (Table 3a). When comparing patients with active and remote cancer versus without cancer, rates of stroke/systemic embolism and death from any cause were similar. However, patients with remote cancer had a significantly higher risk of myocardial infarction compared with no cancer, even after adjustment (HR, 1.59; 95% CI, ; P =.0463) (Table 3b). Rates of ischemic events were similar between patients with active cancer and patients with remote cancer with the exception of death from any cause, which appeared to be higher in the active cancer group. In the adjusted Cox regression models, no other significant relationships between active and remote cancer, and in relation to no cancer, were found with any of the safety outcomes (Table 3b). Treatment Effect of Apixaban Versus Warfarin on Clinical Outcomes According to Cancer Status No significant interactions between cancer status and anticoagulant treatment were found for the outcomes of stroke/ systemic embolism, ischemic stroke, myocardial infarction, any of the safety outcomes, or the net composite outcomes (Table 4a). From Cox regression analyses, there was a trend for a significant interaction between cancer status and drug treatment effect only on death from any cause (P =.05), with a numerically greater reduction in death with apixaban versus warfarin in patients without cancer versus with cancer (Table 4a). When we examined active versus remote cancer and compared death from any cause with patients with no history of Table 3a Association Between Cancer Status and Outcomes Cancer (N = 1236) No Cancer (N = 16,947) Unadjusted P Value Adjusted Ischemic outcomes Stroke or SE 29 (1.3) 447 (1.4) 0.89 ( ) ( ).7104 Death from any cause 96 (4.2) 1174 (3.7) 1.13 ( ) ( ).8751 Ischemic stroke 23 (1.0) 313 (1.0) 1.01 ( ) ( ).9179 MI 24 (1.1) 168 (0.5) 1.98 ( ) ( ).1047 Bleeding outcomes ISTH major bleeding 56 (2.9) 733 (2.6) 1.09 ( ) ( ).0862 Major or CRNM bleeding 120 (6.2) 1370 (4.9) 1.25 ( ) ( ).6748 Any bleeding 449 (29.3) 4964 (21.3) 1.35 ( ) < ( ).0718 Intracranial bleeding 9 (0.4) 165 (0.6) 0.78 ( ) ( ).4769 CI = confidence interval; CRNM = clinically relevant nonmajor; HR = hazard ratio; ISTH = International Society on Thrombosis and Haemostasis; MI = myocardial infarction; SE = systemic embolism. *Event rate = events per 100 patient-years of follow up. P Value

5 1444 The American Journal of Medicine, Vol 130, No 12, December 2017 Table 3b Association Between Cancer Status (Active and Remote Versus No Cancer and Active Versus Remote) and Outcomes Adjusted Active vs No Cancer Remote vs No Cancer Active vs Remote Cancer No Cancer (n = 16,947) P Value P Value P Value Remote Cancer (n = 1079) Active Cancer (n = 157) Ischemic outcomes Stroke or SE 5 (1.9) 24 (1.2) 447 (1.4) 1.37 ( ) ( ) ( ).3549 Death from any cause 16 (5.9) 80 (3.9) 1174 (3.7) 1.62 ( ) ( ) ( ).0494 Ischemic stroke 3 (1.1) 20 (1.0) 313 (1.0) 1.14 ( ) ( ) ( ).8368 MI 1 (0.4) 23 (1.2) 168 (0.5) 0.48 ( ) ( ) ( ).2424 PE/DVT 1 (0.4) 6 (0.3) 6 (0.2) 1.80 ( ) ( ) ( ).8798 Bleeding outcomes ISTH major bleeding 6 (2.6) 50 (2.9) 733 (2.6) 0.59 ( ) ( ) ( ).5112 Major or CRNM bleeding 16 (7.2) 104 (6.1) 1370 (4.9) 1.00 ( ) ( ) ( ).8781 Any bleeding 57 (33.1) 392 (28.8) 4964 (21.3) 1.18 ( ) ( ) ( ).5710 Intracranial bleeding 2 (0.9) 7 (0.4) 165 (0.6) 1.34 ( ) ( ) ( ).4184 CI = confidence interval; CRNM = clinically relevant nonmajor; DVT = deep vein thrombosis; HR = hazard ratio; ISTH = International Society on Thrombosis and Haemostasis; MI = myocardial infarction; PE = pulmonary embolism; SE = systemic embolism. *Event rate = events pet 100 patient-years of follow up. cancer, the interaction became statistically significant (P =.013) (Table 4b). The interaction seemed to be driven mainly by patients with remote cancer, and patients receiving apixaban had higher rates of death from any cause versus warfarin (event rate/100 patient-years = 4.9 vs 3.0; HR, 1.63; 95% CI, ). An in-depth look at cause of death revealed that the increased number of deaths in the remote cancer group treated with apixaban was driven by a higher rate of noncardiovascular death versus those treated with warfarin (event rate/100 patientyears = 2.5 vs 1.3, respectively). Cardiovascular deaths were similar in the apixaban and warfarin groups (event rate/100 patient-years = 1.6 vs 1.3, respectively). Overall, the safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer with respect to each individual efficacy and safety outcome (Table 4b). Apixaban versus warfarin was associated with a numerically greater benefit in reducing thrombotic events as measured by the composite efficacy outcome in patients with active cancer (HR, 0.30; 95% CI, ) versus no cancer (HR, 0.86; 95% CI, ), but not in patients with remote cancer (HR, 1.46; 95% CI, ), as supported by a significant interaction for the composite efficacy end point (P interaction =.0028) (Table 4b). DISCUSSION Cancer and atrial fibrillation frequently coexist, yet few data guide care in this population. Our study evaluated the influence of cancer history on stroke prevention treatment with apixaban versus warfarin in patients with atrial fibrillation. Results demonstrated no significant associations between cancer history and risk of stroke/systemic embolism, major bleeding, or mortality. Overall, the superior safety and efficacy of apixaban versus warfarin were preserved among patients with and without active cancer. Compared with warfarin, apixaban seems to be associated with a greater benefit on the ischemic composite end point in patients with active cancer versus no cancer, but not in patients with remote cancer (a signal of an effect in the opposite direction was observed). The indication of an even larger efficacy in patients with active cancer is promising and warrants further evaluation. As expected, patients with atrial fibrillation and cancer history were older than those without cancer because the incidence of both increases with age. Of ARISTOTLE enrollees, 1236 (6.8%) had a history of cancer. Patients with atrial fibrillation and cancer history presented with more risk factors and comorbidities than those without cancer. Although cardiovascular treatment at baseline appeared to be similar in those without cancer, some differences were observed; particularly, a higher percentage of patients with cancer history had prior vitamin K antagonist treatment at enrollment, likely reflecting a history of thrombotic events requiring anticoagulation. Regardless of these differences, our results were carefully adjusted for key variables. Cancer has been associated with a hypercoagulable state and a 3-fold increase in thrombotic and thromboembolic risk, which further increases with the use of some chemotherapeutic

6 Melloni et al Cancer and Atrial Fibrillation 1445 Table 4a Effects of Apixaban Versus Warfarin in Patients with Atrial Fibrillation and Cancer and No Cancer Cancer (n = 1236) No Cancer (n = 16,947) Apixaban (n = 615) Warfarin (n = 621) Apixaban (n = 8493) Warfarin (n = 8454) P Value Ischemic outcomes Stroke or SE 15 (1.4) 14 (1.2) 1.09 ( ) 196 (1.3) 251 (1.6) 0.77 ( ).3671 Death from any cause 54 (4.7) 42 (3.6) 1.32 ( ) 548 (3.4) 626 (4.0) 0.87 ( ).0504 Ischemic stroke 14 (1.3) 9 (0.8) 1.59 ( ) 147 (0.9) 166 (1.1) 0.88 ( ).1807 MI 12 (1.1) 12 (1.1) 1.02 ( ) 78 (0.5) 90 (0.6) 0.86 ( ).693 PE/DVT 3 (0.3) 4 (0.4) 0.76 ( ) 27 (0.2) 33 (0.2) 0.81 ( ).9408 Bleeding outcomes ISTH major bleeding 24 (2.4) 32 (3.2) 0.76 ( ) 303 (2.1) 430 (3.1) 0.69 ( ).7227 Major or CRNM bleeding 53 (5.5) 67 (6.9) 0.80 ( ) 560 (4.0) 810 (5.9) 0.67 ( ).3682 Any bleeding 204 (26.5) 245 (32.2) 0.83 ( ) 2149 (17.6) 2815 (25.4) 0.71 ( ).1053 Intracranial bleeding 0 (0) 9 (0.9) Not estimable 52 (0.4) 113 (0.8) 0.45 ( ).9652 Net composite end point Composite efficacy end point 74 (6.6) 65 (5.7) 1.17 ( ) 734 (4.7) 841 (5.4) 0.86 ( ).0859 Composite end point 93 (8.5) 89 (8.0) 1.07 ( ) 948 (6.0) 1124 (7.3) 0.83 ( ).1033 AF = atrial fibrillation; CI = confidence interval; CRNM = clinically relevant nonmajor; DVT = deep vein thrombosis; HR = hazard ratio; ISTH = International Society on Thrombosis and Haemostasis; MI = myocardial infarction; PE = pulmonary embolism; SE = systemic embolism. *Event rate = events per 100 patient-years of follow-up. P value for the randomized treatment-by-cancer interaction. Stroke/SE, MI, and death. Stroke/SE, MI, death, and ISTH major bleeding. agents. 2 Concurrently, coagulation defects due to hematologic malignancies, chemotherapy-induced thrombocytopenia, and other factors may increase bleeding risk. 1-3 Despite the increased thrombotic and bleeding risks in the population with cancer, we found no differences in the rates of stroke/ systemic embolism, all-cause death, or ischemic stroke in patients with and without cancer. Patients with cancer were strictly followed by a cardiovascular specialist and most likely had their cardiovascular secondary prevention therapy optimized during the study, which may have influenced their risk of cardiovascular events. Ischemic event rates were comparable between patients with active and remote cancer, yet the rate of death from any cause was higher in the active cancer group. No significant differences in major bleeding were detected among the 3 groups. We did find an increase in the risk of myocardial infarction among patients with remote cancer versus no cancer. Because of the lack of information on cancer stage and treatment, we are not able to fully explain the association, and it is possible that this simply represents the play of chance. Antithrombotic therapy for stroke prevention in patients with atrial fibrillation and cancer is particularly challenging because of the complexity of this population and the lack of evidence to guide their optimal treatment. Warfarin has been the choice anticoagulant for stroke prevention in atrial fibrillation for decades and has been used extensively in patients with cancer New direct-acting oral anticoagulants are approved for stroke prevention in patients with nonvalvular atrial fibrillation. 4,11-13 Although there are no published data on the safety and efficacy of these direct-acting oral anticoagulants in patients with atrial fibrillation and cancer for preventing stroke or systemic embolism, cancer subgroup analysis in recent systematic reviews and meta-analyses of phase III studies assessing the safety and efficacy of these agents for the prevention of venous thromboembolism were concordant, showing that these drugs are safe and can be effective for prevention of venous thromboembolism in patients with cancer In ARISTOTLE, data on history of cancer were limited, but we were able to separate patients with remote cancer from those with active cancer. Describing a heterogeneous disease like cancer is complex and incomplete without staging, timing, and treatment data. The remote cancer group in our study is particularly poorly defined and may include a heterogeneous group with very different thromboembolic risk profiles. Although the safety of apixaban was preserved in this group (consistently lower rate of bleeding), we found a significant increase in the composite end point, mainly driven by increased noncardiovascular death in those with remote cancer receiving apixaban versus warfarin. The reason behind this finding (opposite of the finding in active cancer) is unknown and merits further evaluation. The active cancer group may be more clearly defined and encompasses recently diagnosed or active cancer, as well as patients who had been treated 6 months prior and were in remission at enrollment. These patients constitute a high-risk and vulnerable population, one that clinicians tend to be more cautious about treating with novel drugs. Because of the small number of patients and events in this group, these results are exploratory; yet our findings on efficacy and safety of apixaban in active cancer are promising and deserve further evaluation. Factor Xa and other procoagulant proteins have the

7 Table 4b Effects of Apixaban Versus Warfarin in Patients with Atrial Fibrillation and Cancer (Active and Remote) and No Cancer Active Cancer Remote Cancer No Cancer Apixaban (n = 76) Warfarin (n = 81) Apixaban (n = 539) Warfarin (n = 540) Apixaban (n = 8493) Warfarin (n = 8454) Ischemic outcomes Stroke or SE 0 (0) 5 (3.8) NA 15 (1.5) 9 (0.9) 1.71 ( ) 196 (1.3) 251 (1.6) 0.77 ( ).1852 Death from any cause 5 (3.7) 11 (8.1) 0.45 ( ) 49 (4.9) 31 (3.0) 1.63 ( ) 548 (3.4) 626 (4.0) 0.87 ( ).0127 Ischemic stroke 0 (0) 3 (2.3) NA 14 (1.4) 6 (0.6) 2.39 ( ) 147 (0.9) 166 (1.1) 0.88 ( ).1348 MI 0 (0) 1 (0.8) NA 12 (1.2) 11 (1.1) 1.12 ( ) 78 (0.5) 90 (0.6) 0.86 ( ).8371 PE/DVT 0 (0) 1 (0.8) NA 3 (0.3) 3 (0.3) 1.02 ( ) 27 (0.2) 33 (0.2) 0.81 ( ).9635 Bleeding outcomes ISTH major bleeding 1 (0.8) 5 (4.5) 0.19 ( ) 23 (2.7) 27 (3.1) 0.87 ( ) 303 (2.1) 430 (3.1) 0.69 ( ).3485 Major or CRNM bleeding 6 (5.2) 10 (9.5) 0.56 ( ) 47 (5.6) 57 (6.6) 0.84 ( ) 560 (4.0) 810 (5.9) 0.67 ( ).507 Any bleeding 27 (31.4) 30 (34.9) 0.93 ( ) 177 (25.9) 215 (31.8) 0.82 ( ) 2149 (17.6) 2815 (25.4) 0.71 ( ).2412 Intracranial bleeding 0 (0) 2 (1.8) NA 0 (0) 7 (0.8) 0 (0-infinity) 52 (0.4) 113 (0.8) 0.45 ( ).9991 Net composite end point Composite efficacy end point 5 (3.7) 16 (12.1) 0.30 ( ) 69 (7.1) 49 (4.8) 1.46 ( ) 734 (4.7) 841 (5.4) 0.86 ( ).0028 Composite end point 6 (4.4) 18 (13.9) 0.32 ( ) 87 (9.1) 71 (7.2) 1.26 ( ) 948 (6.0) 1124 (7.3) 0.83 ( ).0048 AF = atrial fibrillation; CI = confidence interval; CRNM = clinically relevant nonmajor; DVT = deep vein thrombosis; HR = hazard ratio; ISTH = International Society on Thrombosis and Haemostasis; MI = myocardial infarction; PE = pulmonary embolism; SE = systemic embolism. *Event rate = events per 100 patient-years of follow up. P value for the randomized treatment-by-cancer interaction. Stroke/SE, MI, and death. Stroke/SE, MI, death, and ISTH major bleeding. P Value 1446 The American Journal of Medicine, Vol 130, No 12, December 2017

8 Melloni et al Cancer and Atrial Fibrillation 1447 capacity to support the malignant process by promoting neoangiogenesis and formation of metastasis; therefore, apixaban in this population may play an important role on different biological pathways and merits additional investigation. 17 Our findings also align with a pilot study testing apixaban for prevention of thromboembolism in patients with advanced cancer receiving chemotherapy, which demonstrated that apixaban was well tolerated and, compared with placebo, did not increase the risk of major bleeding. 18 Also, the A Very Early Rehabilitation Trial is under way to explore the safety and efficacy of apixaban in preventing venous thromboembolism in patients with cancer (NCT ). Currently, there is insufficient evidence to allow specific recommendations about using direct-acting oral anticoagulants in patients with atrial fibrillation and cancer. However, considering the increasing prevalence of concurrent cancer and atrial fibrillation, there is an important need to better understand the safety and efficacy of these relatively novel anticoagulants in patients with atrial fibrillation. In the future, patients with history of cancer should not be excluded from randomized clinical trials, and sufficient details regarding cancer should be collected to better understand this highrisk group. Study Limitations Several limitations need to be considered. First, although some information on cancer status at baseline was available, we could not further characterize remote cancer in these patients. It is possible that this group encompasses a heterogeneous population and was not appropriately characterized. Patients with a very different thromboembolic risk may have balanced the differences between patients with cancer and those without. The stage, treatment details, and remission status were not available. Furthermore, information about new occurrence or recurrence of cancer was not collected. Second, this is a post hoc, secondary analysis of a randomized trial with inclusion/exclusion criteria that may have excluded patients with the most severe cancers or those with the highest bleeding risk, thus introducing a selection bias and limiting generalizability to the larger population with atrial fibrillation/cancer. Third, sample size and event rates were small, particularly in the active cancer group, limiting the robustness of the analysis and ability to explore outcomes by cancer type. Finally, residual unmeasured confounding may have affected some findings. Conclusions Among this population of patients with atrial fibrillation, no significant association between cancer and the risk of stroke or systemic embolism was observed. The superior efficacy of apixaban over warfarin on stroke and systemic embolism was consistent in patients with and without cancer. The numerically larger effect of apixaban on reducing thrombotic events in patients with active cancer warrants further evaluation in prospective studies of direct-acting oral anticoagulants in patients with cancer. References 1. Lin JT. Thromboembolic events in the cancer patient. J Womens Health. 2003;12: Suter TM, Ewer MS. Cancer drugs and the heart: importance and management. Eur Heart J. 2013;34: Farmakis D, Parissis J, Filippatos G. Insights into onco-cardiology: atrial fibrillation in cancer. J Am Coll Cardiol. 2014;63: Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365: Lopes RD, Alexander JH, Al-Khatib SM, et al. Apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010;159: Schulman S. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3: Bona RD, Sivjee KY, Hickey AD, Wallace DM, Wajcs SB. The efficacy and safety of oral anticoagulation in patients with cancer. Thromb Haemost. 1995;74: Pangilinan JM, Pangilinan PH Jr, Worden FP. Use of warfarin in the patient with cancer. J Support Oncol. 2007;5: Palareti G, Legnani C, Lee A, et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost. 2000;84: Rose AJ, Sharman JP, Ozonoff A, Henault LE, Hylek EM. Effectiveness of warfarin among patients with cancer. J Gen Intern Med. 2007;22: Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365: Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361: Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban vs warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369: Van der Hulle T, den Exter PL, Kooiman J, van der Hoeven JJ, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost. 2014;12: Sardar P, Chatterjee S, Herzog E, et al. New oral anticoagulants in patients with cancer: current state of evidence. Am J Ther. 2015;22: Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and metaanalysis. Chest. 2015;147: Falanga A, Panova-Noeva M, Russo L. Procoagulant mechanisms in tumour cells. Best Pract Res Clin Haematol. 2009;22: Levine MN, Gu C, Liebman HA, et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost. 2012;10: Conflict of Interest: CM: Institutional research grants from Amgen, AstraZeneca, GlaxoSmithKline, Ferring Degarelix, Hoffmann-LaRoche, Janssen Pharmaceuticals, Medtronic Vascular, Inc., Novartis, Roche Group, Sanofi-Aventis, The Medicines Company, and Regeneron Pharmaceuticals. AD, LT, MK: none. CBG: Institutional research grants from Armetheon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, US Food and Drug Administration, GlaxoSmithKline, Janssen Pharmaceuticals, The Medicines Company, Medtronic Foundation, Novartis, Pfizer, Sanofi Aventis, and Takeda; and consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Daiichi Sankyo, Gilead, GlaxoSmithKline, Hoffmann-LaRoche, Janssen Pharmaceuticals, The Medicines Company, Medtronic, National Institutes of Health, Novartis, Pfizer, Sanofi Aventis, and Takeda. DAG: Research grants from Incyte, Janssen, and Daiichi Sankyo; and consulting fees from Incyte, Alexion, Janssen, Pfizer, Bristol-Myers Squibb, and Boehringer Ingelheim. EMH: Consultant/

9 1448 The American Journal of Medicine, Vol 130, No 12, December 2017 advisory board for Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Armetheon, Daiichi Sankyo, Janssen, Medtronic, Pfizer, and Portola. MH: Employee of Bristol-Myers Squibb. LW: Institutional research grants, consultancy fees, lecture fees, and travel support from Bristol-Myers Squibb/ Pfizer, AstraZeneca, GlaxoSmithKline, and Boehringer Ingelheim; institutional research grants from Merck & Co. and Roche Diagnostics; and consulting fees from Abbott. BJG: Consultant/advisory board for Medtronic, Baxter Healthcare Corporation, Cardiovascular Research Foundation, St Jude Medical, Ortho-McNeil-Janssen, Teva Pharmaceuticals, Boston Scientific, Pfizer. PSD: Research grants from Heartflow and GE Healthcare. JHA: Research grants from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, CSL Behring, Sanofi, and Tenax Therapeutics; and consulting fees/honoraria from Cempra, CryoLife, CSL Behring, Pfizer, Portola Pharmaceuticals, and VasoPrep Surgical. RDL: Institutional research grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, and Pfizer; and consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, and Portola. SUPPLEMENTARY DATA Supplementary Material accompanying this article can be found in the online version at doi: /j.amjmed

10 Melloni et al Cancer and Atrial Fibrillation 1448.e1 APPENDIX 1 The following adjustment models have been explored for linearity assumption for all continuous adjustment variables, and transformations, including linear and restricted cubic splines, have been applied when necessary. The following adjustment models will be used for each end point: Stroke or systemic embolism: age, region, weight, diabetes, hypertension, moderate valvular disease, prior stroke/ transient ischemic attack/systemic embolism, type of atrial fibrillation, and prior vitamin K antagonist. Ischemic stroke: same as stroke or systemic embolism. Death from any cause: age, sex, region, systolic blood pressure, diastolic blood pressure, weight, hypertension, moderate valvular disease, left bundle branch block, prior myocardial infarction, prior stroke/transient ischemic attack/systemic embolism, anemia, smoking status, prior vitamin K antagonist, New York Heart Association, CHADS 2, renal function. Myocardial infarction: age, region, diabetes, coronary artery disease, prior myocardial infarction, New York Heart Association, renal function. International Society on Thrombosis and Haemostasis major bleeding: age, sex, region, coronary artery disease, prior myocardial infarction, prior bleeding, anemia, CHADS 2, renal function, history of fall. International Society on Thrombosis and Haemostasis major or clinically relevant nonmajor bleeding: same as International Society on Thrombosis and Haemostasis major bleeding. Any bleeding: same as International Society on Thrombosis and Haemostasis major bleeding. Intracranial bleeding: same as International Society on Thrombosis and Haemostasis major bleeding. APPENDIX 2: DEFINITION OF SCORES CHA 2 DS 2 -VASc score Condition Points C Congestive heart failure (or Left ventricular systolic dysfunction) 1 H Hypertension: blood pressure consistently above 140/90 mmhg (or treated hypertension on medication) 1 A 2 Age 75 years 2 D Diabetes Mellitus 1 S 2 Prior Stroke or TIA or thromboembolism 2 V Vascular disease (e.g. peripheral artery disease, myocardial infarction, aortic plaque) 1 A Age years 1 Sc Sex category (i.e. female sex) 1 CHADS2 score Condition Points C Congestive heart failure (or Left ventricular systolic dysfunction) 1 H Hypertension: blood pressure consistently above 140/90 mmhg (or treated hypertension on medication) 1 A 2 Age 75 years 2 D Diabetes Mellitus 1 S 2 Prior Stroke or TIA or thromboembolism 2 HAS-BLED score Condition Points H Hypertension: (uncontrolled, >160 mmhg systolic) 1 A Abnormal renal function: Dialysis, transplant, Cr >2.26 mg/dl or >200 µmol/l 1 Abnormal liver function: Cirrhosis or Bilirubin >2x Normal or AST/ALT/AP >3x Normal 1 S Stroke: Prior history of stroke 1 B Bleeding: Prior Major Bleeding or Predisposition to Bleeding 1 L Labile INR: (Unstable/high INR), Time in Therapeutic Range < 60% 1 E Elderly: Age > 65 years 1 D Prior Alcohol or Drug Usage History ( 8 drinks/week) 1 Medication Usage Predisposing to Bleeding: (Antiplatelet agents, NSAIDs) 1