Anticoagulation is the fundamental priority for the prevention of stroke in patients with atrial fibrillation, yet enthusiasm for use among patients at highest thromboembolic risk is often tempered by concern for increased bleeding. In one of the earliest studies evaluating vitamin K antagonists (VKA) in atrial fibrillation, Askey and Cherry noted in 1950 that anticoagulant use for thromboembolic prophylaxis requires “a reasonable assurance that the benefit will justify the bother and expense of control and the dangers of the drug,” and predicted that “safer anticoagulant drugs will be available eventually.”1 It would take another 60 years to realize that prophesy: the first direct-acting oral anticoagulant (DOAC) entered the US market in 2010, followed by 3 more DOACs over the next 5 years. Each DOAC approval was based on randomized clinical trials that demonstrated greater, equivalent, or noninferior reduction in ischemic stroke and similar or lower bleeding compared with VKA.