加拿大麦克马斯特大学Jeffrey I. Weitz联合美国俄克拉荷马大学健康科学中心Gary E. Raskob课题组在研究中取得进展。他们的最新研究探索了Osocimab在预防膝关节置换术患者静脉血栓栓塞中的作用。该研究于2020年1月14日发表于国际一流学术期刊《美国医学会杂志》上。

凝血因子XIa抑制血栓形成的疗效尚不清楚。Osocimab是一种长效的完全人源化单克隆抗体，可抑制因子XIa。

为了比较不同剂量Osocimab与依诺肝素和阿哌沙班在膝关节置换术后预防血栓形成的作用，2017年10月至2018年8月，研究组在13个国家的54家医院进行了一项随机、开放标签、试验者盲、临床2期的非劣效性试验，共招募了813名接受单侧膝关节置换术的成年患者，平均年龄为66.5岁，74.2%为女性。

将这些患者随机分组，其中107名术后单次静脉注射Osocimab 0.3mg/kg，65名注射0.6mg/kg，108名注射1.2mg/kg，106名注射1.8mg/kg；109名术前静脉注射Osocimab 0.3mg/kg，108名注射1.8mg/kg；105名每日一次皮下注射依诺肝素，105名每日口服阿哌沙班，至少为期10天。术后10-13天，采用双侧静脉造影对深静脉血栓或肺栓塞进行评估。

共有600名患者纳入最终分析。其中术后Osocimab 0.3mg/kg组中有23.7%的患者发生静脉血栓栓塞，0.6mg/kg组中有15.7%，1.2mg/kg组中有16.5%，1.8mg/kg组中有17.9%；术前Osocimab 0.3mg/kg组中有29.9%，1.8mg/kg组中有11.3%；依诺肝素组中有26.3%，阿哌沙班组中有14.5%。

与依诺肝素相比，术后给予Osocimab符合非劣效性标准，0.6mg/kg剂量的风险差异为10.6%，1.2mg/kg为9.9%，1.8mg/kg为8.4%；术前Osocimab剂量为1.8mg/kg显著优于依诺肝素，风险差异为15.1%。术后和术前Osocimab剂量为0.3mg/kg均不符合非劣效性标准，风险差异分别为2.6%和-3.6%。Osocimab组中有4.7%的患者出现严重或临床相关的非大出血，依诺肝素组为5.9%，阿哌沙班组为2%。

总之，对于接受膝关节置换术的患者，与依诺肝素相比，术后给予0.6mg/kg、1.2mg/kg和1.8mg/kg的Osocimab在术后10-13天静脉血栓栓塞方面符合非劣效性标准，而术前1.8mg/kg的Osocimab符合优势标准。仍需要进一步研究来确定Osimimb预防血栓栓塞的有效性和安全性。

附：英文原文

Title: Effect of Osocimab in Preventing Venous Thromboembolism Among Patients Undergoing Knee Arthroplasty: The FOXTROT Randomized Clinical Trial

Author: Jeffrey I. Weitz, Rupert Bauersachs, Bastian Becker, Scott D. Berkowitz, Maria C. S. Freitas, Michael R. Lassen, Carola Metzig, Gary E. Raskob

Issue&Volume: 2020/01/14

Abstract:

Importance  The efficacy of factor XIa inhibition for thromboprophylaxis is unknown. Osocimab is a long-acting, fully human monoclonal antibody that inhibits factor XIa.

Objective  To compare different doses of osocimab with enoxaparin and apixaban for thromboprophylaxis in patients who have undergone knee arthroplasty.

Design, Setting, and Participants  Randomized, open-label, adjudicator-blinded, phase 2 noninferiority trial with observer blinding for osocimab doses, conducted at 54 hospitals in 13 countries. Adult patients undergoing unilateral knee arthroplasty were randomized from October 2017 through August 2018 and followed up until January 2019.

Interventions  Single intravenous osocimab postoperative doses of 0.3 mg/kg (n = 107), 0.6 mg/kg (n = 65), 1.2 mg/kg (n = 108), or 1.8 mg/kg (n = 106); preoperative doses of 0.3 mg/kg (n = 109) or 1.8 mg/kg (n = 108); or 40 mg of subcutaneous enoxaparin once daily (n = 105) or 2.5 mg of oral apixaban twice daily (n = 105) for at least 10 days or until venography.

Main Outcomes and Measures  The primary outcome was venous thromboembolism incidence between 10 and 13 days postoperatively (assessed by mandatory bilateral venography performed 10 to 13 days after surgery or confirmed symptomatic deep vein thrombosis or pulmonary embolism). A 5% noninferiority margin compared with enoxaparin was chosen. The primary safety outcome of major or clinically relevant nonmajor bleeding was assessed until 10 to 13 days postoperatively.

Results  Of 813 randomized participants (mean [SD] age, 66.5 years [8.2 years]; body mass index, 32.7 [5.7]; and 74.2% women), 600 were included in the per-protocol population used for the primary analysis. The primary outcome occurred in 18 patients (23.7%) receiving 0.3 mg/kg, 8 (15.7%) receiving 0.6 mg/kg, 13 (16.5%) receiving 1.2 mg/kg, and 14 (17.9%) receiving 1.8 mg/kg of osocimab postoperatively; 23 (29.9%) receiving 0.3 mg/kg and 9 (11.3%) receiving 1.8 mg/kg of osocimab preoperatively; 20 (26.3%) receiving enoxaparin; and 12 (14.5%) receiving apixaban. Osocimab given postoperatively met criteria for noninferiority compared with enoxaparin with risk differences (1-sided 95% CIs) of 10.6% (95% CI, –1.2% to ∞) at the 0.6-mg/kg dose; 9.9% (95% CI, –0.9% to ∞) at the 1.2-mg/kg dose, and 8.4% (95% CI, –2.6 to ∞) at the 1.8-mg/kg dose. The preoperative dose of 1.8 mg/kg of osocimab met criteria for superiority compared with enoxaparin with a risk difference of 15.1%; 2-sided 90% CI, 4.9% to 25.2%). Postoperative and preoperative doses of 0.3 mg/kg of osocimab did not meet the prespecified criteria for noninferiority, with risk differences (1-sided 95% CIs) of 2.6% (95% CI, –8.9% to ∞) and –3.6% (95% CI, –15.5% to ∞), respectively. Major or clinically relevant nonmajor bleeding was observed in up to 4.7% of those receiving osocimab, 5.9% receiving enoxaparin, and 2% receiving apixaban.

Conclusions and Relevance  Among patients undergoing knee arthroplasty, postoperative osocimab 0.6 mg/kg, 1.2 mg/kg, and 1.8 mg/kg met criteria for noninferiority compared with enoxaparin, and the preoperative 1.8-mg/kg dose of osocimab met criteria for superiority compared with enoxaparin for the primary outcome of incidence of venous thromboembolism at 10 to 13 days postoperatively. Further studies are needed to establish efficacy and safety of osocimab relative to standard thromboprophylaxis.

DOI: 10.1001/jama.2019.20687

Source: https://jamanetwork.com/journals/jama/article-abstract/2758600