Novel horizons in anticoagulation: the emerging role of factor XI inhibitors across different settings

Abstract

Anticoagulants have long been fundamental in preventing and treating thromboembolic disorders, with a recent shift of focus towards direct oral anticoagulants, thanks to their ease of use, efficacy, and safety. Despite these advancements, bleeding complications remain a major concern with any anticoagulant, highlighting the need for safer drugs. Factor XI (FXI) inhibitors have emerged as promising agents in this regard, offering a novel approach by targeting upstream factors in the coagulation system. Phase II trials have shown encouraging outcomes, indicating a reduced bleeding risk compared to that associated with traditional anticoagulants, particularly in the context of cardiovascular disease management when combined with antiplatelet therapy. However, the variability in findings and limited efficacy data call for a cautious interpretation pending insights from phase III trials. These trials are essential for validating the potential of FXI inhibitors to balance bleeding risk reduction and maintain anticoagulant efficacy. This review explores the pharmacology, potential indications, clinical data, and future directions of FXI inhibitors, providing a perspective on their evolving role in anticoagulant therapy. It also provides a detailed analysis of data from published clinical trials on FXI inhibitors in various indications. Preliminary data from ongoing trials are also outlined. As the field moves forward, a cautiously optimistic outlook can be expected, focusing on comprehensive data from phase III trials to define the role of FXI inhibitors in various clinical scenarios.

Figure 1.

Differentiating thrombosis from hemostasis for safer anticoagulation. Differentiating thrombosis from hemostasis is vital for safer anticoagulation. Hemostasis stops bleeding through a local plug, while thrombosis can obstruct blood flow, risking organ damage. The contact pathway, less involved in hemostasis but more in thrombosis, appears to offer a safer target for new anticoagulants. Inhibition of this pathway is less likely to cause bleeding than drugs affecting multiple coagulation factors or the common pathways. Targeted agents include antisense oligonucleotides, monoclonal antibodies and small molecules, focusing on factor XI to enhance safety profiles. HK: high molecular weight kininogen; PKK: prekallikrein; F: factor; VKA: vitamin K antagonists; PL: phospholipids; DOAC: direct oral anticoagulants; LMWH: low molecular weight heparins; DTI: direct thrombin inhibitors; ASO: antisense oligonucleotides.