Factor Xi Inhibitors as the Next Generation of Anticoagulants: A Comprehensive Pharmacological Review of Asundexian, Milvexian, Abelacimab, Fesomersen, and the Decoupling of Thrombosis From Hemostasis

Anticoagulant therapy remains one of the most important and most challenging therapeutic interventions in cardiovascular medicine, with current direct oral anticoagulants (DOACs) — apixaban, rivaroxaban, edoxaban, dabigatran — and vitamin K antagonists offering effective thromboprophylaxis but at the cost of clinically significant bleeding, particularly intracranial and major gastrointestinal hemorrhage. The recognition that congenital factor XI (FXI) deficiency produces minimal spontaneous bleeding despite impaired thrombus formation, that FXI participates preferentially in pathological thrombus amplification rather than primary hemostasis, and that high FXI levels are associated with venous and arterial thrombosis has motivated development of FXI-targeting anticoagulants with the promise of decoupling antithrombotic efficacy from bleeding risk. This review provides a comprehensive pharmacological analysis of the FXI inhibitor class, which encompasses small-molecule oral inhibitors (asundexian, milvexian), monoclonal antibodies (abelacimab, osocimab, frunexian/MAA868), and antisense oligonucleotides (fesomersen). We examine FXI/FXIa biology and the contact pathway, the safety-efficacy rationale, pivotal clinical trial evidence including the AXIOMATIC-TKR phase 2 results, the AZALEA-TIMI 71 trial demonstrating reduced bleeding with abelacimab versus rivaroxaban in atrial fibrillation, the OCEANIC-AF trial in which asundexian failed to demonstrate non-inferiority to apixaban (terminated November 2023), and the ongoing development across multiple indications including venous thromboembolism prevention, atrial fibrillation stroke prevention, secondary stroke prevention, hemodialysis circuit thrombosis, and cancer-associated thrombosis. The review also addresses the Indian context including atrial fibrillation prevalence, venous thromboembolism epidemiology, DOAC access, and the prospective role of FXI inhibitors in low-resource settings. Future directions include reversal agent development, special populations, and the integration of FXI biology into broader anticoagulation strategies.