Factor XI antisense oligonucleotide for prevention of venous thrombosis.
Factor XI antisense oligonucleotide for prevention of venous thrombosis.
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DOI：
10.1056/nejmoa1405760
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发表时间：
2015-01-15
期刊：
影响因子：
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通讯作者：
FXI-ASO TKA Investigators
中科院分区：
文献类型：
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作者：
Büller HR;Bethune C;Bhanot S;Gailani D;Monia BP;Raskob GE;Segers A;Verhamme P;Weitz JI;FXI-ASO TKA Investigators
实验数据表明，降低因子XI水平可减弱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与依诺肝素在全膝关节置换术患者中的有效性和安全性。在这项开放标签、平行组研究中，我们将300例接受择期初次单侧全膝关节置换术的患者随机分配接受两种剂量的FXI-ASO（200 mg或300 mg）或40 mg依诺肝素每日一次。主要疗效结局是静脉血栓栓塞的发生率（通过强制性双侧静脉造影或症状性事件报告进行评估）。主要安全性结局为严重或临床相关非严重出血。手术前后，200 mg FXI-ASO组、300 mg FXI-ASO组和依诺肝素组的因子XI水平均值（±SE）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。接受200 mg剂量FXI-ASO的134例患者中有36例（27%）和接受300 mg剂量FXI-ASO的71例患者中有3例（4%）发生主要疗效结局，而接受依诺肝素的69例患者中有21例（30%）发生主要疗效结局。200 mg方案非劣效于依诺肝素，300 mg方案上级优于依诺肝素（P<0.001）。三个研究组中分别有3%、3%和8%的患者发生出血。这项研究表明，因子XI有助于术后静脉血栓栓塞;降低择期初次单侧全膝关节置换术患者的因子XI水平是预防其发生的有效方法，并且在出血风险方面似乎是安全的。（由Isis Pharmaceuticals资助; FXI-ASO TKA ClinicalTrials.gov编号，NCT 01713361。）
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.)