Extract

Comment on the article ‘Asundexian versus Apixaban in Patients with Atrial Fibrillation’ presented at the ESC Congress 2024 and published in The New England Journal of Medicine; https://doi.org/10.1056/NEJMoa2407105.

Comment

It is not unusual for phase-3 trials of new drugs targeting a novel molecular target to fail the expectations raised by a promising pathophysiologic hypothesis and supported by limited phase-2 dose-finding studies. Animal studies and studies of patients with genetic deficiency of the coagulation factor XI had suggested that this factor is more important for thrombosis than for haemostasis and raised the expectation that drugs targeting factor XI would provide safer anticoagulation as compared to direct oral anticoagulants (DOACs), while ensuring comparable antithrombotic efficacy.3 As a result, at least 10 different anti-factor XI agents are currently in clinical development, including antisense oligonucleotides, monoclonal antibodies, small molecules (such as asundexian), and natural inhibitors.3

The clinical development of new anticoagulants typically begins in patients undergoing joint replacement surgery, such as total knee arthroplasty (TKA). This procedure is associated with a high risk of post-operative venous thromboembolism (VTE), particularly asymptomatic deep vein thrombosis, which can be readily detected on venography.3 Four anti-FXI agents (including a small molecule, milvexian) evaluated in these phase-2 trials provided proof-of-concept for dose-dependent efficacy, at least non-inferior to enoxaparin in preventing VTE in patients undergoing TKA with low bleeding risk.3

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