Factor XI Inhibitors in Atrial Fibrillation: Insights and Implications from Recent Trials

Stroke prevention remains a cornerstone of the management of atrial fibrillation (AF) given the increased risk of thromboembolic events. While direct oral anticoagulants (DOACs) have significantly advanced stroke prophylaxis in AF, bleeding risks remain a challenge and preclude use in some populations. Furthermore, evidence indicates significant undertreatment in AF, with up to 40% of patients receiving incorrect anticoagulant dosing or no anticoagulation at all, further elevating their stroke risk. Novel anticoagulants targeting factor (F)XI are emerging as a promising alternative, offering the potential to reduce thromboembolic events whilst minimizing bleeding risks. Inhibitors under development include small molecules, monoclonal antibodies, and antisense oligonucleotides. These agents have demonstrated favorable safety profiles when compared to DOACs in early phase and some late phase trials. For example abelacimab, an anti-FXI monoclonal antibody, demonstrated superior safety with lower bleeding rates when compared to rivaroxaban in patients with AF. However, the efficacy of these drugs remains uncertain. However, the OCEANIC-AF trial, which studied the small molecule FXI inhibitor asundexian, was terminated early due to lack of efficacy as there was an increased rate of stroke and systematic embolism compared to the DOAC apixaban, raising new concerns about the utility of targeting FXI. However, many FXI inhibitors are currently undergoing phase 3 trials, and as such the true efficacy of the full class of FXI inhibitors remains to be elucidated. This review aims to provide a comprehensive synopsis of the landscape of FXI inhibitors in development for AF, their advantages, challenges, and known utility with a focus on how they may be applied to future anticoagulation therapy for AF.