Factor XI inhibitors and atrial fibrillation: imminent breakthrough or false start?

Atrial fibrillation (AF) is a common cardiac arrhythmia associated with a high risk of thrombo-embolic events, such as ischaemic stroke and systemic embolism, which require anticoagulant treatment. Vitamin K antagonists and direct oral anticoagulants represent the current therapeutic standards, but they are limited by the risk of bleeding. In this scenario, factor XI (FXI) inhibitors are emerging as a new therapeutic option, potentially capable of reducing bleeding risk while maintaining antithrombotic efficacy. Molecules such as abelacimab, asundexian, and milvexian are under investigation for the prevention of thrombo-embolic events in patients with AF. Although preliminary data on these compounds suggest a favourable safety profile, the results regarding efficacy do not yet appear convincing. The phase 2 AZALEA-TIMI 71 trial was prematurely terminated after demonstrating a clear reduction in the incidence of major bleeding with abelacimab compared to rivaroxaban, whereas the phase 3 OCEANIC-AF study on asundexian was stopped due to inferiority compared to apixaban. Ongoing trials, such as LILAC-TIMI 76 and LIBREXIA-AF, are crucial to confirm the efficacy and safety of this therapeutic class. While FXI inhibitors represent a potential breakthrough in the treatment of AF, further data are needed to determine their definitive role in clinical practice.