Abstract
To Editor,
Atrial fibrillation (AFib) is a common arrhythmia marked by rapid, irregular atrial activity leading to an irregular ventricular rhythm. Its pathogenesis is multifactorial, often involving stretch-induced fibrosis, chronic inflammation, epicardial adipose tissue, autonomic nervous system (ANS) imbalance, and genetic mutations. 1 AFib is frequently asymptomatic; when present, symptoms may include palpitations, dizziness, chest pain, or lightheadedness. Assessment can follow the 4S-AF scheme: stroke risk (St), symptoms (Sy), severity of burden (Sb), and substrate (Su). 2
According to Global Burden of Disease (GBD) 2019, AFib and atrial flutter (AFL) affect an estimated 59.7 million people and contribute to 8.39 million disability-adjusted life years (DALYs). 3 Continuous cardiac monitoring found AFib in 12.1% to 30% of stroke patients in a study by Tsao et al. 4 Thus, reducing stroke risk is key in AFib management, achieved through rate/rhythm control and anticoagulation. Previously, warfarin was used for this purpose, but the latest guidelines by the American Heart Association (AHA) recommend direct oral anticoagulants (DOACs). 5 Commonly used ones include factor Xa inhibitors (apixaban, edoxaban, and rivaroxaban) and factor IIa inhibitors (dabigatran). Compared to warfarin, DOACs showed superiority to warfarin in preventing stroke in AFib (except in moderate to severe mitral stenosis [MS] and mechanical heart valve) with significantly lower major bleeding and intracranial hemorrhage (ICH) risks, but the risk for significant gastrointestinal (GI) bleeding was higher except in apixaban, where it showed no significant increase. 6
Considering the significant stroke risk in atrial fibrillation, anticoagulants are central in AFib management but pose a bleeding risk, as they disrupt both normal hemostasis and pathological thrombosis by targeting multiple coagulation factors. One solution here lies in the manipulation of factor XI, which plays a minor role in hemostasis but significantly increases pathological thrombosis by mediating the amplification phase, leading to thrombus growth. 6 Asundexian is a novel oral small molecule factor XIa inhibitor that is being developed and tested to compete with DOACs for AFib by providing a targeted approach to stroke prevention. Early clinical data showed that asundexian inhibited factor XIa with high potency and selectivity 7 and was well tolerated in healthy individuals with a predictable pharmacokinetic/pharmacodynamic profile. 8
The PACIFIC-Stroke trial, evaluated the efficacy and safety of asundexian (10, 20, and 50 mg once daily doses) in patients with acute non-cardioembolic ischemic stroke who were receiving antiplatelet therapy. 9 Although the study did not demonstrate a significant dose-response relationship for the primary efficacy outcome, a numerical reduction in recurrent symptomatic ischemic stroke was observed at the highest dose of asundexian. However, this reduction did not reach statistical significance, most likely due to smaller population size. 9 These findings highlight the need for further large-scale trials to more definitively assess the therapeutic potential of asundexian in this patient population. 9 Building upon previous research, the phase 3 OCEANIC-AF trial, evaluated asundexian (10, 25, 50, and 100 mg once daily doses) versus apixaban for stroke prevention in high-risk patients with atrial fibrillation. In this trial, asundexian was associated with a higher incidence of stroke or embolism compared to apixaban (1.3% vs 0.4%), raising significant concerns about its efficacy. Nonetheless, the incidence of major bleeding was markedly lower with asundexian (0.2% vs 0.7%), suggesting a favorable bleeding risk profile. 10 Considering these 2 trials, an evolving perspective on the clinical profile of asundexian is presented. While the data suggest a favorable safety profile, particularly with respect to reduced bleeding risk, uncertainties surrounding its efficacy in stroke prevention remain. To more definitively characterize the therapeutic potential of asundexian, especially in terms of efficacy, further large-scale, multicenter studies are essential.
As the above-mentioned studies demonstrated, asundexian may be inferior to conventional DOAC therapy in terms of the prevention of stroke but offers a better safety profile. However, a few questions still remain unanswered: Can asundexian be a good choice at higher doses like 75 or 100 mg? As dose-dependent FXIa activity inhibition and activated partial thromboplastin time prolongation were observed in some studies. 8 suggesting a clear pharmacodynamic response to asundexian. However, it remains unclear whether doses higher than 50 mg yield further therapeutic benefit. In the PACIFIC studies, numerous cases demonstrated that higher doses of asundexian (20 mg vs 50 mg) were associated with improved efficacy in preventing stroke. These findings raise the possibility of a dose-dependent relationship, where increased levels of the drug might enhance its antithrombotic effect without necessarily increasing bleeding risk. However, this hypothesis requires further investigation in appropriately powered clinical studies to determine whether higher doses translate into meaningful clinical benefit. Also, the previous studies were conducted in high-risk populations, and we need more studies demonstrating the effect of asundexian in moderate-to-low-risk populations (having fewer risk factors for AFib, ie, lower age group, non-hypertensive, non-diabetic, no family history of AFib, etc.). Given its favorable safety profile, this drug has the potential to be a game changer for patients with a low risk of embolism but an elevated risk of bleeding. Therefore, we emphasize the urgent need for targeted research across diverse and larger clinical settings to further evaluate the potential benefits of various doses of asundexian in various patient populations.
To conclude, asundexian represents a promising evolution and potential treatment option for the prevention of stroke in patients with atrial fibrillation. It can effectively mitigate the incidence of cardioembolic events while carrying a lower risk of major or clinically significant bleeding, thereby offering a viable therapeutic alternative for patients with an elevated bleeding risk associated with conventional DOACs. Further clinical trials and ongoing research involving diverse patient populations and varying doses of asundexian are essential to fully elucidate its therapeutic role.
