Background—Anticoagulation 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 Results—The 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). Conclusions—In 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.
Bibliographical noteFunding Information:
The ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) trial was funded from a research grant by Daiichi Sankyo. No support was provided for the current publication. The TIMI Study Group has received significant research grant support from Amgen, Astra-Zeneca, Athera, Beckman Coulter, BG Medicine, Bristol-Myers Squibb, Buhlmann Laboratories, Daiichi Sankyo, Eli Lilly and Co, Eisai, GlaxoSmithKline, Johnson & Johnson, Merck and Company, Nanosphere, Novartis Pharmaceuticals, Ortho-Clinical Diagnostics, Pfizer, Randox, Roche Diagnostics, Sanofi-Aventis, Siemens, and Singulex.
Babilonia has no relevant disclosures. Sritara has no relevant disclosures. Mercuri was an employee of Daiichi Sankyo. Kamphuisen reports research grant support from Daiichi Sankyo and Boehringer Ingelheim. Antman is a member of the TIMI Study Group and reports grant support through his institution from Daiichi Sankyo. Braunwald is a member of the TIMI Study Group and reports other support from Merck during the conduct of the study, and personal fees from Daiichi-Sankyo, Sanofi Aventis, The Medicines Company, Menarini International, Bayer, and Medscape. Giugliano is a member of the TIMI Study Group, reports that his institution received research grant support from Daiichi Sankyo for his role as Principal Investigator of the ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction Study 48) trial, and that he has received honoraria for continuing medical education lectures and/or consulting from Bristol Myers Squibb, Daiichi Sankyo, Janssen, Pfizer, and Portola. The remaining authors have no disclosures to report.
- Atrial fibrillation