Direct oral anticoagulants (DOACs) have transformed the prevention and treatment of thromboembolic disease, offering predictable pharmacokinetics, fewer interactions, and improved safety compared with vitamin K antagonists. Over the past decade, DOACs have become the preferred oral anticoagulants for most patients with atrial fibrillation and venous thromboembolism; yet, important gaps remain in their optimal implementation across diverse clinical scenarios. Despite strong evidence supporting their efficacy and safety, DOACs continue to be underutilized and sometimes inappropriately dosed, particularly among patients at elevated thrombotic risk and in populations historically underrepresented in randomized trials. This American College of Cardiology Scientific Statement provides a comprehensive, evidence-based overview of established and emerging indications for DOAC therapy in primary and secondary prevention of thrombotic events. Key domains include anticoagulation in atrial fibrillation, acute and extended treatment of venous thromboembolism, management in special populations (including patients with chronic kidney disease, liver dysfunction, cancer, obesity, frailty, prior bleeding, and valvular heart disease), periprocedural anticoagulation, and antithrombotic strategies following stroke, left atrial appendage closure, and catheter ablation. The document also addresses practical considerations such as drug selection, dosing strategies, duration of therapy, bleeding risk assessment, management of anticoagulant-related bleeding, drug-drug interactions, adherence, and cost-related barriers to care. This statement is intended to complement existing clinical practice guidelines by synthesizing evolving data, clarifying areas of uncertainty, and supporting individualized, patient-centered decision making. By addressing both evidence and implementation challenges, this document aims to improve the appropriate and equitable use of DOACs across the spectrum of thrombotic disease.
