David G. Sherman Lecture: The Eternal Quest for Optimal Stroke Prevention.

Despite decades of clinical trial activity in stroke prevention, critical gaps remain in the evidence base guiding management of symptomatic carotid and intracranial stenosis and the quality of anticoagulation care delivered to patients with atrial fibrillation (AF). This article synthesizes recent evidence and ongoing research efforts addressing 2 enduring challenges: demonstrating the value of intensive medical therapy relative to interventional approaches and improving the quality of stroke prevention care in AF. Previous trials focused on intracranial stenosis established that aggressive, protocol-driven medical management substantially reduces recurrent vascular events. In the realm of carotid stenosis, landmark trials conducted >3 decades ago no longer reflect modern pharmacological capabilities. Emerging evidence from plaque imaging, particularly intraplaque hemorrhage on magnetic resonance imaging, suggests that stenosis severity alone is an insufficient determinant of treatment strategy. Simultaneously, strokes related to AF continue to rise in the United States, driven by demographic aging, and large vessel occlusion strokes attributable to undertreated AF represent a preventable burden on the health system. Patient-centered, precision stroke prevention requires contemporary prospective data, integration of advanced vascular imaging biomarkers, and systematic improvements in preventative therapies for patients with AF. Targeting these areas holds promise for improving stroke prevention in the coming decades.