Antithrombotic Therapy for Secondary Prevention after Non-Cardioembolic Ischemic Stroke: Current Status, Limitations, and Future Directions

Ischemic stroke is increasing in frequency and results in significant morbidity and mortality. Disability due to ischemic stroke results from motor, language, and cognitive deficits with depression and nonmotor symptoms increasingly recognized as common and associated with disability and a reduced quality of life. Stroke associated with major cardiac sources makes up about one-fifth of all strokes with the remainder being non-cardioembolic. Most non-cardioembolic strokes fall into three subtypes: large artery atherosclerosis, small vessel disease, and cryptogenic. Thrombosis and thromboembolism underlie most stroke subtypes and antithrombotic therapy remains an essential component of secondary stroke prevention. Survivors of ischemic stroke have a considerable risk of disabling recurrent stroke and other major ischemic events despite advances in prevention strategies. Dual antiplatelet therapy is the standard secondary prevention strategy for short-term treatment after minor stroke or transient ischemic attack and aspirin monotherapy is used for more severe stroke and long-term thromboprophylaxis. Current antiplatelet strategies are limited by moderate efficacy and bleeding risk. Inhibition of activated factor XI (FXIa) in the intrinsic pathway of the coagulation cascade has the potential to prevent recurrent stroke by attenuating pathologic thrombosis with minimal effects on hemostasis. The first efficacy trial of FXIa inhibition for stroke prevention has been completed and shows a reduction in ischemic stroke without an increase in major hemorrhage.