Anticoagulants are the mainstay for the prevention and treatment of
thrombosis. However,
bleeding complications remain a primary concern. Recent advances in understanding the contribution of
activated factor XI (FXIa) in arterial
thrombosis with a limited impact on hemostasis have led to the development of several FXIa-targeting modalities.
Injectable agents including
monoclonal antibodies and
antisense oligonucleotides against FXIa have been primarily studied in
venous thrombosis. The orally active small molecules that specifically inhibit the active site of FXIa are currently being investigated for their antithrombotic activity in both arteries and veins. This review focuses on a discussion of the potential clinical benefits of small molecule FXIa inhibitors, mainly asundexian and
milvexian, in arterial
thrombosis based on their pharmacological profiles and the compelling results of phase 2 clinical studies. The preclinical and epidemiological basis for the impact of FXIa in hemostasis and arterial
thrombosis is also addressed. In recent clinical study results, asundexian appears to reduce ischemic events in patients with
myocardial infarction and minor-to-moderate
stroke, whereas
milvexian possibly provides benefits in patients with minor
stroke or high-risk
transient ischemic attack (TIA). In addition, asundexian and
milvexian had a minor impact on hemostasis even in combination with dual-antiplatelet
therapy. Other orally active FXIa inhibitors also produce antithrombotic activity in vivo with low
bleeding risk. Therefore, FXIa inhibitors might represent a new class of
direct-acting oral anticoagulants (DOACs) for the treatment of
thrombosis, although the explicit clinical positions of asundexian and
milvexian in patients with
ischemic stroke, high-risk TIA, and
coronary artery disease require confirmation from the outcomes of ongoing phase 3 trials.