FXIa inhibition for secondary stroke prevention: current evidence

Ashkan Shoamanesh, MD, McMaster University, Hamilton, Canada, discusses the evidence supporting Factor XIa (FXIa) inhibition for secondary stroke prevention. FXIa has a role in thrombus formation and propagation, but a smaller role in hemostasis. Therefore, it has been proposed that inhibition of FXIa could stop thromboembolic events by blocking clot generation, without increasing the number of clinically relevant bleeds. Clinical evidence supporting this hypothesis includes observations of lower risk of ischemic stroke and venous thromboembolism (VTE) in populations with deficiencies in FXIa (e.g. hemophilia C), compared to the general population. Evidence from Mendelian randomization analyses also shows that increased levels of FXIa are linked to VTE and ischemic stroke, but not major bleeding. There are currently several Phase II clinical trials investigating FXIa inhibition, which are demonstrating that FXIa can stop thrombus propagation and formation without affecting bleeding. In patients undergoing knee surgery, milvexian, a first-in-class oral inhibitor of FXIa, has been shown to stop thromboembolism more effectively than enoxaparin, while in patients with atrial fibrillation, the use of asundexian has been associated with less bleeding than the current widely used oral anticoagulant apixaban. For secondary stroke prevention two Phase II clinical trials have been conducted; the PACIFIC-STROKE trial (NCT04304508) and the AXIOMATIC-SSP trial (NCT03766581), investigating the FXIa inhibitors asundexian and milvexian respectively, which have shown similar positive results to previous studies. Currently, Dr Shoamanesh’s group are conducting the OCEANIC-STROKE trial (NCT05686070), which is being undertaken to investigate the effect of 50 mg of asundexian, taken daily, in patients with non-cardioembolic ischemic stroke who are enriched for baseline atherosclerotic disease. This interview took place during the European Stroke Organisation Conference (ESOC) in Munich, Germany.
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