木瓜直播

A selective factor XIa inhibitor could make for an effective anticoagulant with a good safety profile, according to a phase II study in elective knee arthroplasty.

Larger doses of oral milvexian corresponded with better prevention of postoperative venous thromboembolism (VTE) -- defined as asymptomatic deep-vein thrombosis on venography, symptomatic VTE, and all-cause deaths -- up to 6 weeks after surgery. Milvexian ≥100 mg daily significantly reduced VTE compared with enoxaparin (Lovenox), reported Jeffrey Weitz, MD, of McMaster University in Hamilton, Ontario.

Milvexian was associated with a 12% incidence of VTE across various twice-daily dosing regimens tested in AXIOMATIC-TKR, which was significantly lower than the trial's prespecified benchmark of 30% (one-sided P<0.001), Weitz noted during the American Heart Association (AHA) virtual meeting.

The study, which was simultaneously published in the , "provides proof of principle that milvexian is an effective antithrombotic agent," the study authors concluded.

The factor XIa inhibitor is rapidly absorbed after oral administration and has a half-life of approximately 12 hours. It is metabolized in the liver with <20% renal clearance, according to Weitz.

The milvexian and enoxaparin groups in AXIOMATIC-TKR experienced similarly low rates of bleeding (4% for both), with major bleeding occurring in 1% and 2%, respectively. The incidence of serious adverse events was 2% versus 4%.

"In our trial, oral milvexian reduced the risk of postoperative thromboembolism among patients undergoing knee arthroplasty in a dose-dependent manner without increasing the risk of bleeding as compared with enoxaparin. Further studies are needed to determine whether oral anticoagulants that target factor XIa can dissociate thrombosis from hemostasis," the authors wrote.

"Although direct oral anticoagulants [DOACs] have replaced vitamin K antagonists for many indications, bleeding remains the major side effect. Fear of bleeding contributes to the underuse of anticoagulants in eligible patients with atrial fibrillation and to the inappropriate use of low-dose DOAC regimens. Therefore, the need for safer oral anticoagulants persists," they noted.

Other factor XI inhibitors under investigation for VTE prevention include and an antisense oligonucleotide.

Use of these inhibitors is supported by scientific evidence that shows that high levels of factor XI are associated with more than doubled risk of VTE, whereas factor XI deficiency is associated with lower risk of thrombotic complications and milder bleeding, said AHA session discussant Tracy Wang, MD, MHS, MSc, of Duke University in Durham, North Carolina.

As small molecules, monoclonal antibodies, or antisense oligonucleotides, "factor XI inhibitor options will vary in appeal to different patients and healthcare settings," she added.

was conducted from 2019 to 2021 in 118 centers across several continents. Weitz and colleagues included 1,242 people undergoing unilateral knee arthroplasty randomized to various doses of milvexian -- ranging from 25 mg to 200 mg once or twice daily -- or enoxaparin 40 mg daily.

Study participants had a median age of around 68 years, and approximately 70% were women.

The trial's modest sample was further limited by patients who missed their follow-up venograms or had venograms that could not be evaluated (14% of the milvexian group and 15% of the enoxaparin group).

Additionally, Weitz noted that the trial was open-label with respect to milvexian versus enoxaparin assignments.

For now, orthopedic surgeons will need more convincing on milvexian's safety and efficacy, as aspirin is still commonly used in low-risk patients, and DOACs may be preferred over enoxaparin, Wang suggested.

She listed important remaining questions about milvexian: Does it have a bleeding advantage over other factor XI inhibitors? What is its optimal timing and duration of use? Can it be used in people with severe renal insufficiency or high bleeding risk? And what about its role in areas outside total knee replacement?

Comment