Asundexian versus Apixaban in Patients with Atrial Fibrillation

In this issue of our newsletter, we present the OCEANIC-AF trial, a pivotal phase 3 study comparing the factor XIa inhibitor asundexian with apixaban in patients with atrial fibrillation at risk of stroke. The manuscript titled "Asundexian versus Apixaban in Patients with Atrial Fibrillation" by Piccini et al., published in The New England Journal of Medicine, and concomitantly presented during a hotline session at the ESC Congress 2024 in London, provides intriguing insights into the evolving landscape of anticoagulation therapy1.

The OCEANIC-AF trial was designed to explore whether asundexian, an oral inhibitor of activated factor XI, could be as effective as apixaban in preventing stroke or systemic embolism while offering the advantage of a reduced bleeding risk. The study was halted prematurely due to an unexpectedly higher incidence of stroke or systemic embolism in the asundexian group (1.3%) compared to the apixaban group (0.4%), yielding a hazard ratio of 3.79. In contrast, major bleeding events occurred less frequently with asundexian (0.2%) than with apixaban (0.7%).

These findings reflect a nuanced balance between safety and efficacy. Asundexian's promise in minimizing major bleeding comes at the potential cost of insufficient thromboembolic protection, raising important questions about the suitability of factor XIa inhibition as an alternative to established anticoagulants in this high-risk population. One speculation that has emerged from this data is whether the dosage of asundexian (50 mg daily) provided adequate suppression of factor XIa to prevent thrombus formation. Previous phase 2 trials, such as PACIFIC-AF2, demonstrated a significant reduction in factor XI activity with this dose, but the OCEANIC-AF results suggest that more complete inhibition might be necessary for effective stroke prevention.

Moreover, while patients with congenital factor XI deficiency have been shown to have a lower incidence of thromboembolic events3,4, the asundexian group’s increased rates of stroke or systemic embolism suggest that escape mechanisms in atrial fibrillation may undermine the efficacy of factor XIa inhibition in certain contexts.

The implications of these results are significant for the field. While factor XIa inhibition remains an exciting avenue for reducing bleeding risks, the data from OCEANIC-AF suggest that further refinement in dosing or additional research into combined inhibition strategies may be necessary to achieve both safety and efficacy. This trial also underscores the robustness of existing DOACs, which continue to demonstrate consistent protection against thromboembolic events while maintaining a manageable bleeding profile. Trials like OCEANIC-AF offer important lessons about the complex interplay between coagulation pathways and clinical outcomes, shaping the future of stroke prevention strategies in atrial fibrillation. 

The ongoing phase III studies of factor XI/XIa inhibition will contribute to our knowledge of the net clinical benefit of the different compounds. There is a need of alternative to the existing DOACs in the increasing group of fragile patients with renal impairment and high bleeding risk. Contact surfaces-associated thrombosis, (i.e., mechanical valves, left ventricular assistant devices and thrombotic antiphospholipid syndrome) is another area where factor XI inhibition may have potential as treatment compared to VKA.