密尔沃基用于预防静脉血栓栓塞。
Milvexian for the Prevention of Venous Thromboembolism.
机构信息
From the Thrombosis and Atherosclerosis Research Institute and McMaster University (J.I.W., R.R.) - both in Hamilton, ON, Canada; Janssen Research and Development, Raritan, NJ (J.S., R.S.N.); the University of Insubria, Varese, Italy (W.A.); Vanderbilt University Medical Center, Nashville (D.G.); Boston University School of Medicine, Boston (E.M.H.); Gildhøj Private Hospital, Copenhagen (M.R.L.); Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, Stanford, CA (K.W.M.); International Trial Expertise Advisory and Services, Amsterdam (A.S.); and Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City (G.E.R.).
出版信息
N Engl J Med. 2021 Dec 2;385(23):2161-2172. doi: 10.1056/NEJMoa2113194. Epub 2021 Nov 15.
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.).
背景
XI 因子抑制剂可预防和治疗静脉及动脉血栓栓塞，其疗效可能优于传统抗凝剂，且出血风险更低。目前仍需要更多有关米伐昔布（一种口服 XI 因子抑制剂）疗效和安全性的数据。
方法
在这项平行分组的 2 期临床试验中，我们将 1242 例接受膝关节置换术的患者随机分为 7 组，分别接受米伐昔布（每日 2 次，每次 25、50、100 或 200mg；或每日 1 次，每次 25、50 或 200mg）或依诺肝素（40mg，每日 1 次）治疗。主要疗效终点为静脉血栓栓塞（无症状深静脉血栓形成、确诊有症状静脉血栓栓塞或任何原因所致死亡的复合终点）。主要安全性终点为出血。
结果
接受米伐昔布每日 2 次治疗的患者中，25mg 组 27 例（21%）、50mg 组 14 例（11%）、100mg 组 12 例（9%）和 200mg 组 10 例（8%）发生静脉血栓栓塞；接受米伐昔布每日 1 次治疗的患者中，25mg 组 7 例（25%）、50mg 组 30 例（24%）和 200mg 组 8 例（7%）发生静脉血栓栓塞，而依诺肝素组 252 例患者中有 54 例（21%）发生静脉血栓栓塞。米伐昔布每日 2 次治疗的剂量-反应关系有统计学意义（单侧 P<0.001），每日 2 次米伐昔布治疗的静脉血栓栓塞发生率为 12%，显著低于预设的 30%界值（单侧 P<0.001）。923 例接受米伐昔布治疗的患者中有 38 例（4%）发生任何严重程度的出血，296 例接受依诺肝素治疗的患者中有 12 例（4%）发生出血；主要或临床相关非主要出血的发生率分别为 1%和 2%；严重不良事件的发生率分别为 2%和 4%。
结论
膝关节置换术后口服米伐昔布抑制 XI 因子可有效预防静脉血栓栓塞，且出血风险较低。（由 Bristol Myers Squibb 和 Janssen Research and Development 资助；AXIOMATIC-TKR ClinicalTrials.gov 编号：NCT03891524。）
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