Antithrombotic therapy in patients with atrial fibrillation: unresolved issues and future directions

Antithrombotic therapy is highly effective for stroke prevention in patients with atrial fibrillation (AF) but increases bleeding. Direct oral anticoagulants are preferred over vitamin K antagonists for many patients with AF because they provide similar stroke protection with less intracranial bleeding, and greater convenience, yet important knowledge gaps remain. In this review, we examine the limitations of current AF risk scores for predicting stroke, bleeding, and net benefit; identify AF populations in whom vitamin K antagonists remain preferred over direct oral anticoagulants, including those with mechanical heart valves, antiphospholipid antibody syndrome, or rheumatic mitral stenosis; and describe patient groups in whom the net benefit of oral anticoagulation is uncertain, including those with advanced kidney disease and survivors of intracranial bleeding. We address emerging challenges such as AF detected by implanted devices or consumer wearables and anticoagulation management after successful AF ablation. We highlight the substantial residual risk of stroke despite guideline-recommended anticoagulation and the high risk of recurrent stroke in patients with breakthrough events while anticoagulated and summarize ongoing trials that evaluate intensified pharmacologic or combined pharmacologic and mechanical approaches, including left atrial appendage closure and implantable carotid filters. Finally, we review the burden of bleeding associated with current antithrombotic therapies and the promise of improved safety with a new class of anticoagulants that target coagulation factor XI. Together, these data underscore the need for more accurate risk stratification and for safer, more effective approaches to stroke prevention in patients with AF.