BACKGROUND: Factor XIa inhibitors for the prevention and treatment of venous and 
arterial thromboembolism may be more effective and result in less bleeding than 
conventional anticoagulants. Additional data are needed regarding the efficacy 
and safety of milvexian, an oral factor XIa inhibitor.
METHODS: In this parallel-group, phase 2 trial, we randomly assigned 1242 
patients undergoing knee arthroplasty to receive one of seven postoperative 
regimens of milvexian (25 mg, 50 mg, 100 mg, or 200 mg twice daily or 25 mg, 50 
mg, or 200 mg once daily) or enoxaparin (40 mg once daily). The primary efficacy 
outcome was venous thromboembolism (which was a composite of asymptomatic 
deep-vein thrombosis, confirmed symptomatic venous thromboembolism, or death 
from any cause). The principal safety outcome was bleeding.
RESULTS: Among the patients receiving milvexian twice daily, venous 
thromboembolism developed in 27 of 129 (21%) taking 25 mg, in 14 of 124 (11%) 
taking 50 mg, in 12 of 134 (9%) taking 100 mg, and in 10 of 131 (8%) taking 200 
mg. Among those receiving milvexian once daily, venous thromboembolism developed 
in 7 of 28 (25%) taking 25 mg, in 30 of 127 (24%) taking 50 mg, and in 8 of 123 
(7%) taking 200 mg, as compared with 54 of 252 patients (21%) taking enoxaparin. 
The dose-response relationship with twice-daily milvexian was significant 
(one-sided P<0.001), and the 12% incidence of venous thromboembolism with 
twice-daily milvexian was significantly lower than the prespecified benchmark of 
30% (one-sided P<0.001). Bleeding of any severity occurred in 38 of 923 patients 
(4%) taking milvexian and in 12 of 296 patients (4%) taking enoxaparin; major or 
clinically relevant nonmajor bleeding occurred in 1% and 2%, respectively; and 
serious adverse events were reported in 2% and 4%, respectively.
CONCLUSIONS: Postoperative factor XIa inhibition with oral milvexian in patients 
undergoing knee arthroplasty was effective for the prevention of venous 
thromboembolism and was associated with a low risk of bleeding. (Funded by 
Bristol Myers Squibb and Janssen Research and Development; AXIOMATIC-TKR 
ClinicalTrials.gov number, NCT03891524.).