Key Points
- Selective XIa inhibitor Asundexian may innovate the field of oral anticoagulation by finally uncoupling hemostasis from thrombosis and potentially allowing similar protection from thromboembolic events without increasing bleeding risk among patients with atrial fibrillation.
- The Phase 2 dose-finding PACIFIC-AF trial (n=755) compared Asundexian 20 mg, Asundexian 50 mg and apixaban among patients with atrial fibrillation followed for 14 weeks. While Asundexian 50 mg showed a significant reduction in major and non-major clinically relevant bleeding, the low bleeding rate and resulting wide confidence intervals suggests more data are needed to better understand the comparative effectiveness and safety of this novel agent versus DOACs.
Since the early 2010s, DOACs have revolutionized the field of atrial fibrillation by providing a safer and more effective anticoagulation option compared to vitamin K antagonists like warfarin. While DOACs reduce the risk of bleeding compared to warfarin, they still carry a 2-3% major bleeding risk based on randomized clinical trials, which may be as high as 6-8% in real-world registries and can lead to adverse outcomes and/or ultimately the need to discontinue anticoagulation.1 This is due to the fact that DOAC-mediated Factor Xa inhibition prevents the formation of pathological thrombi, but also blocks the tissue factor pathway, which in turns prevents the formation of thrombin-mediated “beneficial clots” that are needed in routine homeostasis of blood vessels around the body. This status quo, however, may be revolutionized with the introduction of selective Factor XIa inhibitors, which would be capable of preventing the formation of pathological thrombi while still allowing activation of the tissue factor pathway and thus the formation of “beneficial clots”.
This hypothesis led to the development of oral XIa inhibitor Asundexian. In-vivo animal data already showed that Asundexian led to antithrombotic effects without a significant increase in bleeding time. Importantly, this agent did not show significant interaction with clopidogrel, impact on CYP3A4, or food interaction. Asundexian was well-tolerated in Phase 1 trials, generating sufficient safety and efficacy data to launch the dose-finding phase 2 study against apixaban, the most commonly prescribed DOAC – which may also have a lower bleeding risk compared to rivaroxaban and the other commercially-available DOACs.
During the 2022 American College of Cardiology Conference, Dr. Manesh Patel presented the results of the PACIFIC-AF trial (NCT04218266). This multicenter, randomized, active comparator-controlled, double-blind, double-dummy, parallel group trial enrolled 755 patients with atrial fibrillation and randomized them to Asundexian 20 mg (n=251), Asundexian 50 mg (n=254 mg) or apixaban (n=250) and followed them for 14 weeks (12 weeks of treatment plus 2 weeks of observation period). Importantly, patients with another requirement for chronic anticoagulation, or on antiplatelet therapy (apart from up to 100 mg aspirin) were excluded from the study. Patients were elderly (mean age 73 years), 40% female, with a mean CHA2DS2-VASc score of 4 (with 8.5% with a prior stroke); overall, only 3% had a prior major bleeding event (slightly unbalanced, with up to 5.5% in the Asundexian 50 mg group), and 28% had chronic kidney disease (slightly unbalanced, with only 21% in the Asundexian 20 mg group).
There was a significant reduction in the primary bleeding endpoint (ISTH major bleeding plus clinically-relevant non-major bleeding) with Asundexian 50 mg compared to apixaban (CIR 0.16, 90% CI 0.01-0.99) and when pooling Asundexian 20 and 50 mg compared to apixaban (CIR 0.33, 90% CI 0.09-0.97). The wide confidence intervals, as well as the selection of a 90% rather than 95% CI, suggests that there may have been insufficient events to reach enough power – as explained by the authors, there were very few bleeding events observed during the trial (48 participants with bleeding events in total), generating a bleeding rate (2.4%) that was lower than expected (4%). There were very few ischemic events, and a pre-specified exploratory analysis did not identify any major differences between the three arms.
In conclusion, selective XIa inhibitor Asundexian may innovate the field of oral anticoagulation by finally uncoupling hemostasis from thrombosis and potentially allowing similar protection from thromboembolic events without increasing bleeding risk among patients with atrial fibrillation. Larger Phase 3 trial data, however, are needed in order to have a more definitive understanding of the efficacy and safety of this novel agent against traditional DOACs.
1. Ferro EG, Kazi DS, Zimetbaum PJ. Informing the Choice of Direct Oral Anticoagulant Therapy in Patients With Atrial Fibrillation. JAMA. 2021 Dec 21;326(23):2372-2374. PMID: 34932097.