Fiessinger Jean-Noel, Huisman Menno V, Davidson Bruce L, Bounameaux Henri, Francis Charles W, Eriksson Henry, Lundström Torbjörn, Berkowitz Scott D, Nyström Per, Thorsén Mona, Ginsberg Jeffrey S
Department of Vascular Medicine, Hôpital Européen Georges Pompidou, Paris, France.
JAMA. 2005 Feb 9;293(6):681-9. doi: 10.1001/jama.293.6.681.
Ximelagatran, an oral direct thrombin inhibitor with a rapid onset of action and predictable antithrombotic effect, has the potential to be a simple therapeutic alternative to current standard treatment of acute venous thromboembolism.
To compare the efficacy and safety of ximelagatran with standard enoxaparin/warfarin treatment for the prevention of recurrent venous thromboembolism.
DESIGN, SETTING, AND PATIENTS: Randomized, double-blind, noninferiority trial (Thrombin Inhibitor in Venous Thromboembolism [THRIVE] Treatment Study) of 2489 patients with acute deep vein thrombosis, of whom approximately one third had concomitant pulmonary embolism. The study was conducted at 279 centers in 28 countries from September 2000 through December 2002.
Patients were randomized to receive 6 months of treatment with either oral ximelagatran, 36 mg twice daily, or subcutaneous enoxaparin, 1 mg/kg twice daily, for 5 to 20 days followed by warfarin adjusted to maintain an international normalized ratio of 2.0 to 3.0.
Recurrent venous thromboembolism, bleeding, and mortality.
Venous thromboembolism recurred in 26 of the 1240 patients assigned to receive ximelagatran (estimated cumulative risk, 2.1%) and in 24 of the 1249 patients assigned to receive enoxaparin/warfarin (2.0%). The absolute difference between ximelagatran and enoxaparin/warfarin was 0.2% (95% confidence interval [CI], -1.0% to 1.3%). This met the prespecified criterion for noninferiority. Corresponding values for major bleeding were 1.3% and 2.2% (difference, -1.0%; 95% CI, -2.1% to 0.1%), and for mortality were 2.3% and 3.4% (difference, -1.1%; 95% CI, -2.4% to 0.2%). Alanine aminotransferase levels increased to more than 3 times the upper limit of normal in 119 patients (9.6%) and 25 patients (2.0%) receiving ximelagatran and enoxaparin/warfarin, respectively. Increased enzyme levels were mainly asymptomatic. Retrospective analysis of locally reported adverse events showed a higher rate of serious coronary events with ximelagatran (10/1240 patients) compared with enoxaparin/warfarin (1/1249 patients).
Oral ximelagatran administered in a fixed dose without coagulation monitoring, was as effective as enoxaparin/warfarin for treatment of deep vein thrombosis with or without pulmonary embolism and showed similar, low rates of bleeding. Increased levels of liver enzymes in 9.6% of ximelagatran-treated patients require regular monitoring; the mechanism requires further evaluation. Prospective assessment of coronary events in future studies is warranted.
希美加群是一种口服直接凝血酶抑制剂，起效迅速且抗血栓作用可预测，有可能成为目前急性静脉血栓栓塞标准治疗的一种简便的替代疗法。
比较希美加群与标准的依诺肝素/华法林治疗预防复发性静脉血栓栓塞的疗效和安全性。
设计、地点和患者：对2489例急性深静脉血栓形成患者进行的随机、双盲、非劣效性试验（静脉血栓栓塞中的凝血酶抑制剂[THRIVE]治疗研究），其中约三分之一患者合并肺栓塞。该研究于2000年9月至2002年12月在28个国家的279个中心进行。
患者被随机分为接受6个月治疗，其中一组口服希美加群，每日2次，每次36mg；另一组皮下注射依诺肝素，每日2次，每次1mg/kg，持续5至20天，随后服用华法林并调整剂量以使国际标准化比值维持在2.0至3.0。
复发性静脉血栓栓塞、出血和死亡率。
在1240例接受希美加群治疗的患者中，有26例发生静脉血栓栓塞复发（估计累积风险为2.1%）；在1249例接受依诺肝素/华法林治疗的患者中，有24例复发（2.0%）。希美加群与依诺肝素/华法林之间的绝对差异为0.2%（95%置信区间[CI]，-1.0%至1.3%）。这符合预先设定的非劣效性标准。主要出血的相应值分别为1.3%和2.2%（差异为-1.0%；95%CI，-2.1%至0.1%），死亡率分别为2.3%和3.4%（差异为-1.1%；95%CI，-2.4%至0.2%）。接受希美加群和依诺肝素/华法林治疗的患者中，分别有119例（9.6%）和25例（2.0%）的丙氨酸氨基转移酶水平升高至正常上限的3倍以上。酶水平升高主要无症状。对当地报告的不良事件进行回顾性分析显示，与依诺肝素/华法林（1/1249例患者）相比，希美加群组严重冠状动脉事件的发生率更高（10/1240例患者）。
固定剂量服用且无需凝血监测的口服希美加群在治疗有或无肺栓塞的深静脉血栓形成方面与依诺肝素/华法林效果相当，且出血发生率相似且较低。9.6%接受希美加群治疗的患者肝酶水平升高，需要定期监测；其机制需要进一步评估。未来研究有必要对冠状动脉事件进行前瞻性评估。
