Reversal of the Anticoagulant Effect of Milvexian by 4-Factor PCC and rFVIIa in Healthy Participants: A Two-Part, Randomized, Crossover Study.

Milvexian is a selective, oral factor XIa inhibitor. Individuals receiving anticoagulation may require prompt reversal of anticoagulative effects. This study assessed reversal of milvexian's anticoagulant effects by recombinant human factor VIIa (rFVIIa) and 4-factor prothrombin complex concentrate (4F-PCC) in healthy participants. This was a 2-part, randomized, crossover study. In part A, milvexian (100 or 500 mg single doses) was followed by rFVIIa (30 μg/kg) or placebo 4 hours later. In part B, milvexian 200 mg was administered q12h for 3 consecutive days, with 4F-PCC (50IU/kg) or placebo given 4 hours after last dose in the morning of day 4. Anticoagulation was assessed through activated partial thromboplastin time (aPTT) and thrombin generation [endogenous thrombin potential (ETP), peak thrombin] using 2 activators: kaolin [intrinsic pathway (IP) effects] and tissue factor [extrinsic pathway (EP) effects]. rFVIIa partially reversed milvexian's effects on aPTT (milvexian 100 mg: ∼18%; 500 mg: ∼15%), IP-induced ETP (milvexian-induced ETP reversal; 100 mg: ∼50%; 500 mg: ∼80%) and peak thrombin, and EP-induced peak thrombin but not ETP. Milvexian 200 mg prolonged aPTT, strongly inhibited IP-induced ETP/peak thrombin, and mildly inhibited EP-induced ETP. 4F-PCC partially reversed milvexian's effect on aPTT (∼17%) and IP-induced ETP/peak thrombin; it reversed milvexian's effect on EP-initiated ETP (∼68% increase). Reversal was rapid (15 minutes) and long-lasting (≥8 hours). Milvexian pharmacokinetics were unchanged by reversal agents. Regimens were generally safe and well tolerated. In conclusion, milvexian's anticoagulant effect was partially reversed by rFVIIa and 4F-PCC. These results may offer clinicians options in situations where reversal of milvexian might be considered.