From the Department of Vascular Medicine, Academic Medical Center, University of Amsterdam (H.R.B.), and International Trial Expertise Advisory and Services (ITREAS) (A.S.) - both in Amsterdam; Isis Pharmaceuticals, Carlsbad, CA (C.B., S.B., B.P.M.); Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville (D.G.); University of Oklahoma Health Sciences Center, College of Public Health, Oklahoma City (G.E.R.); KU Leuven Department of Cardiovascular Sciences, Vascular Medicine and Hemostasis, Leuven, Belgium (P.V.); and the Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton, ON, Canada (J.I.W.).
N Engl J Med. 2015 Jan 15;372(3):232-40. doi: 10.1056/NEJMoa1405760. Epub 2014 Dec 7.
Experimental data indicate that reducing factor XI levels attenuates thrombosis without causing bleeding, but the role of factor XI in the prevention of postoperative venous thrombosis in humans is unknown. FXI-ASO (ISIS 416858) is a second-generation antisense oligonucleotide that specifically reduces factor XI levels. We compared the efficacy and safety of FXI-ASO with those of enoxaparin in patients undergoing total knee arthroplasty.
In this open-label, parallel-group study, we randomly assigned 300 patients who were undergoing elective primary unilateral total knee arthroplasty to receive one of two doses of FXI-ASO (200 mg or 300 mg) or 40 mg of enoxaparin once daily. The primary efficacy outcome was the incidence of venous thromboembolism (assessed by mandatory bilateral venography or report of symptomatic events). The principal safety outcome was major or clinically relevant nonmajor bleeding.
Around the time of surgery, the mean (±SE) factor XI levels were 0.38±0.01 units per milliliter in the 200-mg FXI-ASO group, 0.20±0.01 units per milliliter in the 300-mg FXI-ASO group, and 0.93±0.02 units per milliliter in the enoxaparin group. The primary efficacy outcome occurred in 36 of 134 patients (27%) who received the 200-mg dose of FXI-ASO and in 3 of 71 patients (4%) who received the 300-mg dose of FXI-ASO, as compared with 21 of 69 patients (30%) who received enoxaparin. The 200-mg regimen was noninferior, and the 300-mg regimen was superior, to enoxaparin (P<0.001). Bleeding occurred in 3%, 3%, and 8% of the patients in the three study groups, respectively.
This study showed that factor XI contributes to postoperative venous thromboembolism; reducing factor XI levels in patients undergoing elective primary unilateral total knee arthroplasty was an effective method for its prevention and appeared to be safe with respect to the risk of bleeding. (Funded by Isis Pharmaceuticals; FXI-ASO TKA ClinicalTrials.gov number, NCT01713361.).
实验数据表明，降低因子 XI 水平可减轻血栓形成而不引起出血，但因子 XI 在预防人类术后静脉血栓形成中的作用尚不清楚。FXI-ASO（ISIS 416858）是一种第二代反义寡核苷酸，可特异性降低因子 XI 水平。我们比较了 FXI-ASO 与依诺肝素在接受全膝关节置换术的患者中的疗效和安全性。
在这项开放标签、平行组研究中，我们将 300 名接受择期单侧初次全膝关节置换术的患者随机分配至接受 200mg 或 300mg FXI-ASO 或每日一次 40mg 依诺肝素治疗。主要疗效终点是静脉血栓栓塞事件（通过强制性双侧静脉造影或有症状事件报告评估）的发生率。主要安全性终点是重大或临床相关非重大出血。
手术时，200mg FXI-ASO 组、300mg FXI-ASO 组和依诺肝素组的平均（±SE）因子 XI 水平分别为 0.38±0.01 单位/毫升、0.20±0.01 单位/毫升和 0.93±0.02 单位/毫升。200mg FXI-ASO 组 134 例患者中有 36 例（27%）和 300mg FXI-ASO 组 71 例患者中有 3 例（4%）发生主要疗效终点事件，而依诺肝素组 69 例患者中有 21 例（30%）发生该事件。200mg 方案非劣效于依诺肝素，300mg 方案优于依诺肝素（P<0.001）。三组患者的出血发生率分别为 3%、3%和 8%。
本研究表明因子 XI 有助于术后静脉血栓栓塞形成；降低接受择期单侧初次全膝关节置换术患者的因子 XI 水平是预防血栓形成的有效方法，且似乎不会增加出血风险。（由 ISIS 制药公司资助；FXI-ASO TKA ClinicalTrials.gov 编号，NCT01713361。）
