Efficacy and Safety of Edoxaban in Patients With Active Malignancy and Atrial Fibrillation: Analysis of the ENGAGE AF‐TIMI 48 Trial

Abstract

BackgroundAnticoagulation in patients with malignancy and atrial fibrillation is challenging because of enhanced risks for thrombosis and bleeding and the frequent need for invasive procedures. Data on direct oral antagonists in such patients are sparse.Methods and ResultsThe ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) trial randomized 21 105 patients with atrial fibrillation to edoxaban or warfarin. Patients with malignancy, defined as a postrandomization new diagnosis or recurrence of remote cancer, were followed up over a median of 2.8 years. Adjusted Cox proportional hazard models were used to evaluate the safety and efficacy of edoxaban versus warfarin. Over a median of 495 days (interquartile range, 230–771 days), 1153 patients (5.5%) were diagnosed with new or recurrent malignancy, most commonly involving the gastrointestinal tract (20.6%), prostate (13.6%), and lung (11.1%). Malignancy was associated with increased risk of death (adjusted hazard ratio [HR], 3.12; 95% confidence interval [CI], 2.78–3.50) and major bleeding (adjusted HR, 2.45; 95% CI, 2.07–2.89), but not stroke/systemic embolism (adjusted HR, 1.08; 95% CI, 0.83–1.42). Relative outcomes with higher‐dose edoxaban versus warfarin were consistent regardless of malignancy status for stroke/systemic embolism (HR, 0.60 [95% CI, 0.31–1.15] for malignancy versus HR, 0.89 [95% CI, 0.76–1.05] for no malignancy; interaction P=0.25) and major bleeding (HR, 0.98 [95% CI, 0.69–1.40] for malignancy versus HR, 0.79 [95% CI, 0.69–1.05] for no malignancy; interaction P=0.31). There was, however, a significant treatment interaction for the composite ischemic end point (ischemic stroke/systemic embolism/myocardial infarction), with greater efficacy of higher‐dose edoxaban versus warfarin in patients with malignancy (HR, 0.54; 95% CI, 0.31–0.93) compared with no malignancy (HR, 1.02; 95% CI, 0.88–1.18; interaction P=0.026).ConclusionsIn patients with atrial fibrillation who develop malignancy, the efficacy and safety profile of edoxaban relative to warfarin is preserved, and it may represent a more practical alternative.

Anticoagulation of cancer patients with non‐valvular atrial fibrillation receiving chemotherapy: Guidance from the SSC of the ISTH

“…In the ATRISTOLE study, the safety and efficacy advantages of apixaban over warfarin in patients without a history of cancer were preserved in those with a cancer history . Similarly, a recent analysis of the ENGAGE AF‐TIMI 48 trial identified 1153 patients who developed new or recurrent malignancy after randomization and revealed that edoxaban was as effective and safe as warfarin in this subgroup …”

Oral anticoagulation in patients with active cancer and atrial fibrillation: current challenges

“…A post-hoc substudy of the ENGAGE AF-TIMI48, which randomized patients with AF to edoxaban or warfarin, compared the two drugs in patients with active cancer developed (or recurring) after randomization. The incidence of stroke and systemic embolism in each treatment arm was similar in patients with cancer and no cancer (1.43%/year and 1.58%/year, respectively, in the high-dose edoxaban arm and 2.38%/year and 1.77%/year, respectively, in the warfarin arm) [51].…”

“…Efficacy data with both classes of agents in patients with cancer largely come from retrospective studies and post-hoc subanalyses of randomized trials in the general population [50,51,76,77] while safety data is also available from randomized trials for cancer-associated VTE [78][79][80][81]. Overall, both VKA and DOACs increase bleeding risk and appear to be similarly efficacious for stroke prevention in patients with cancer [9,25,39,[49][50][51]76,77,82]. However, this comparative data is limited by the study designs.…”

“…Ultimately, with the limitations of the available data, DOACs and VKA have similar efficacy and safety results [22,47,48,50,51,76,77,87]. The two classes have differential features (convenience, half-life, use in kidney failure, availability of reversal agents, drug interaction profile) that should be used to find the optimal agent for each patient.…”

The Impending Epidemic of Cardiovascular Diseases in Patients With Cancer in Japan

“…A pooled collaborative analysis of 86,593 participants in 12 Australian and New Zealand cohorts identified 12 ,070 incident and 4,350 fatal cancer cases over a median follow-up of 15.1 years; untreated and treated hypertension, compared with normotension, was associated with an increased risk of cancer with an increased risk of all-cause death and major bleeding, but not stroke or systemic embolic event. 65 Patients with cancer have concerns of increased bleeding and thrombotic risks, rapid changes in renal and hepatic functions, and hematologic abnormalities. 59,63,64 To avoid critical bleeding, choosing the appropriate anticoagulant agent, 63,65,66 cotherapy with proton pump inhibitors in patients with risk of upper gastrointestinal tract bleeding, 67 endoscopic and/ or surgical management of bleeding points, and regular follow-up by both laboratory tests and imaging are important.…”