This editorial refers to ‘Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial’, by J. Steffel et al., on page doi:10.1093/eurheartj/ehv201. Stroke prevention using oral anticoagulation is a highly effective intervention to improve outcomes among patients with atrial fibrillation (AF), the most common cardiac arrhythmia in the population.1,2 Compared with placebo, the use of vitamin K antagonists reduces the risk of stroke by 64% in patients with AF, but significantly increases the risk of major and life-threatening bleeding.3 In recent years, new oral anticoagulants with a more favourable risk–benefit profile have been developed and tested in large randomized trials, further improving anticoagulation treatment among patients with AF. One of these studies was the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial, a large randomized trial comparing the efficacy and safety of two dosing regimens of edoxaban with warfarin among AF patients at increased risk of stroke. Compared with warfarin, this trial established the non-inferiority of both regimens with regard to prevention of stroke and systemic embolism, with the advantage of significantly lower rates of major bleeding associated with both dosing strategies.4 However, the low-dose edoxaban strategy was associated with …