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AHA 2021: Oral factor XIa inhibitor shows promise for venous thromboembolism.
Postoperative factor XIa inhibition with oral milvexian in patients undergoing knee arthroplasty has been found to be effective for the prevention of venous thromboembolism and is associated with a low risk of bleeding, as per the results of AXIOMATIC-TKR trial that were presented at AHA 2021 this week and simultaneously published in NEJM.
Oral anticoagulants are a mainstay for the prevention and treatment of venous and arterial thromboembolism. Although direct oral anticoagulants have replaced vitamin K antagonists for many indications, bleeding remains the major side effect.
Rationale behind Factor XI inhibition:
Factor XI is an important driver of thrombus growth but plays a subsidiary part in hemostasis. Thus, patients with congenital factor XI deficiency are at lower risk for venous thromboembolism and ischemic stroke than those with normal factor XI levels but rarely have spontaneous bleeding. This makes it a promising target for the development of safer anticoagulants.
In this proof-of-principle phase 2 trial, Weitz et al 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.
Milvexian significantly reduced the incidence of venous thromboembolism after elective knee arthroplasty in a dose-dependent manner with both twice-daily and once-daily regimens.
The incidence of venous thromboembolism was significantly lower with daily milvexian doses of 100 mg or more than that with enoxaparin. Although the incidence of any bleeding was 4% with both milvexian and enoxaparin, the incidence of the composite of major bleeding and clinically relevant nonmajor bleeding was low across total daily doses of milvexian that ranged from 25 to 400 mg.
Therefore, postoperative factor XIa inhibition with milvexian was effective for preventing venous thromboembolism and was associated with a low risk of clinically relevant bleeding.
Despite the dose-dependent increase in the activated partial-thromboplastin time ratio, no dose–response relationship was seen with respect to bleeding, a finding consistent with the poor correlation between the extent of prolongation of the activated partial-thromboplastin time and the propensity for bleeding in patients with congenital factor XI deficiency.
"This dissociation probably reflects the fact that factor XI activation is essential for clot formation in the activated partial-thromboplastin time assay but is mostly dispensable for hemostasis", point out authors in discussion.
Further studies are needed to determine whether oral anticoagulants that target factor XIa can dissociate thrombosis from hemostasis.
Source: NEJM: DOI: 10.1056/NEJMoa2113194
MBBS, MD , DM Cardiology
Dr Abhimanyu Uppal completed his M. B. B. S and M. D. in internal medicine from the SMS Medical College in Jaipur. He got selected for D. M. Cardiology course in the prestigious G. B. Pant Institute, New Delhi in 2017. After completing his D. M. Degree he continues to work as Post DM senior resident in G. B. pant hospital. He is actively involved in various research activities of the department and has assisted and performed a multitude of cardiac procedures under the guidance of esteemed faculty of this Institute. He can be contacted at editorial@medicaldialogues.in.
Dr Kamal Kant Kohli-MBBS, DTCD- a chest specialist with more than 30 years of practice and a flair for writing clinical articles, Dr Kamal Kant Kohli joined Medical Dialogues as a Chief Editor of Medical News. Besides writing articles, as an editor, he proofreads and verifies all the medical content published on Medical Dialogues including those coming from journals, studies,medical conferences,guidelines etc. Email: drkohli@medicaldialogues.in. Contact no. 011-43720751