Eriksson Bengt I, Arfwidsson Ann-Christin, Frison Lars, Eriksson Ulf G, Bylock Anders, Kälebo Peter, Fager Gunnar, Gustafsson David
Department of Orthopaedic Surgery, Sahlgrenska University Hospital/Ostra, Göteborg, Sweden.
Thromb Haemost. 2002 Feb;87(2):231-7.
The novel, oral direct thrombin inhibitor, ximelagatran (formerly H 376/95), represents an advance in antithrombotic therapy through its oral availability. After oral administration, ximelagatran is converted to its active form, melagatran. Melagatran can also be administered subcutaneously (s.c.). The results from the first clinical study with ximelagatran are reported. In this randomized, parallel-group, controlled study, 103 patients scheduled for elective total hip or total knee replacement received s.c. melagatran (1, 2 or 4 mg bid) for 2 days commencing immediately before surgery, followed by oral ximelagatran (6, 12 or 24 mg bid) for 6-9 days. Another 33 patients received dalteparin 5000 IU s.c. once daily, started the evening before surgery, for 8-11 days. At bilateral venography, deep vein thrombosis was found in 20.5% (16/78) of patients who had received s.c. melagatran and oral ximelagatran and in 18.5% (5/27) of patients in the dalteparin group. The study did not evaluate a dose-response for efficacy, and no differences between the three dose levels of melagatran and ximelagatran were shown. No pulmonary embolism was diagnosed during treatment. Total bleeding in the s.c. melagatran plus oral ximelagatran groups showed no dose-response and was similar to that seen in the dalteparin group. The pharmacokinetic properties of melagatran in the surgery patients were consistent with those observed for healthy subjects, and the APTT ratio, which increased non-linearly with plasma melagatran concentration, showed a consistent concentration-effect relationship during the treatment period. Ximelagatran and melagatran were well tolerated. In conclusion, ximelagatran and its active form melagatran appear to be promising agents for the prevention of venous thromboembolism following orthopaedic surgery.
新型口服直接凝血酶抑制剂希美加群（原称H 376/95）因其口服可用性，在抗血栓治疗方面取得了进展。口服给药后，希美加群转化为其活性形式美拉加群。美拉加群也可皮下注射。本文报告了希美加群的首个临床研究结果。在这项随机、平行组、对照研究中，103例计划接受择期全髋关节或全膝关节置换术的患者在手术前即刻开始接受皮下注射美拉加群（1、2或4 mg，每日两次），持续2天，随后口服希美加群（6、12或24 mg，每日两次），持续6 - 9天。另外33例患者在手术前一晚开始接受皮下注射达肝素5000 IU，每日一次，持续8 - 11天。在双侧静脉造影中，接受皮下注射美拉加群和口服希美加群的患者中有20.5%（16/78）发生深静脉血栓形成，达肝素组患者中有18.5%（5/27）发生深静脉血栓形成。该研究未评估疗效的剂量反应，美拉加群和希美加群的三个剂量水平之间未显示出差异。治疗期间未诊断出肺栓塞。皮下注射美拉加群加口服希美加群组的总出血情况未显示出剂量反应，且与达肝素组相似。手术患者中美拉加群的药代动力学特性与健康受试者观察到的一致，活化部分凝血活酶时间（APTT）比值随血浆美拉加群浓度呈非线性增加，在治疗期间显示出一致的浓度 - 效应关系。希美加群和美拉加群耐受性良好。总之，希美加群及其活性形式美拉加群似乎是预防骨科手术后静脉血栓栓塞的有前景的药物。
