Pharmapulse report—does the arrival of factor XI inhibitors mark the end of the NOAC era?

Cerebral and pulmonary infarctions due to thromboembolism are serious diseases with poor prognoses, and treatment with anticoagulants is required for their prevention. Warfarin has been used as an anticoagulant for decades, but while it prevents thrombus formation, its use significantly increases the risk of bleeding, which has troubled clinicians for many years. Specifically, Asians have a higher risk of bleeding than Caucasians. During the past decade, factor Xa inhibitors, such as rivaroxaban and apixaban, were developed as new oral anticoagulants (NOACs) to replace warfarin. Although NOACs are effective in preventing thrombus formation and are associated with a lower risk of bleeding than warfarin, bleeding remains their main side effect. Some patients refuse to take anticoagulants due to the fear of bleeding, which highlights the need for safer drugs. Previous studies have shown that factor XI (FXI), an enzyme involved in the blood coagulation cascade, plays an important role in thrombus formation, but is only partially involved in haemostasis. This suggests that inhibiting FXI activity could suppress pathological thrombus formation without increasing the risk of bleeding. A new oral anticoagulant, milvexian, is a low-molecular-weight compound that can be taken orally to inhibit the activity of FXIa, an activator of FXI. The results of AXIOMATIC-TKR, a phase II trial on milvexian for preventing venous thromboembolism (VTE) after total knee arthroplasty (TKA), were presented at an online meeting of the American Heart Association (AHA2021, 13–15 November) and a paper was published simultaneously on the New England Journal of Medicine website.1 In the trial, 1242 patients aged 50 years or older undergoing elective unilateral TKA were either assigned to receive oral milvexian (25, 50, 100, or 200 mg twice daily or 25, 50, or 200 mg once daily; seven groups in total) or subcutaneous injections of an existing anticoagulant enoxaparin (40 mg once daily) using open label randomization. The primary endpoint was VTE [which was a composite of asymptomatic deep vein thrombosis (DVT), confirmed symptomatic VTE (symptomatic DVT or non-fatal pulmonary embolism), and all-cause mortality]. The incidence of VTE was as follows—milvexian 25 mg × twice daily group: 21%; 50 mg × twice daily group: 11%; 100 mg × twice daily group: 9%; 200 mg × twice daily group: 8%; 25 mg × once daily group: 25%; 50 mg × once daily group: 24%; and 200 mg × once daily group: 7%. The incidence of VTE in the control enoxaparin group was 21%. In the groups receiving milvexian twice daily, the incidence of VTE decreased in a dose-dependent manner (P = 0.0004). Further, the incidence of VTE was significantly lower than that in the enoxaparin group when the daily milvexian dose was ≥100 mg (P < 0.014). The incidence of bleeding was 4.1% in both the milvexian and enoxaparin groups, and the proportion of patients with major or clinically significant bleeding was 1% in the milvexian group and 2% in the enoxaparin group. For milvexian to be introduced in clinical practice, its efficacy and safety need to be verified in larger clinical trials. Demonstrating that this FXIa inhibitor further reduces the risk of thrombus formation without increasing the risk of bleeding compared with NOACs in a phase III trial would drastically change physicians’ treatment options for patients requiring anticoagulation to prevent thrombotic events. Results regarding the efficacy of FXIa inhibitors in preventing stroke recurrence are also expected. Conflict of interest: none declared.