Department of Vascular Medicine, Academic Medical Centre, Amsterdam, Netherlands.
Lancet. 2012 Jan 14;379(9811):123-9. doi: 10.1016/S0140-6736(11)61505-5. Epub 2011 Nov 28.
Treatment of pulmonary embolism with low-molecular-weight heparin and vitamin K antagonists, such as warfarin, is not ideal. We aimed to assess non-inferiority of idrabiotaparinux, a reversible longlasting indirect inhibitor of activated factor X, to warfarin in patients with acute symptomatic pulmonary embolism.
In our randomised, double-blind, double-dummy, non-inferiority trial, we enrolled adults with objectively documented acute symptomatic pulmonary embolism attending 291 centres in 37 countries. We excluded patients who were pregnant, had active bleeding, kidney failure, or malignant hypertension, or were at high risk of death, bleeding, or adverse reactions to study drugs. We randomly allocated patients to receive 5-10 days' enoxaparin 1·0 mg/kg twice daily followed by subcutaneous idrabiotaparinux (starting dose 3·0 mg) or adjusted-dose warfarin (target international normalised ratio 2·0-3·0); regimens lasted 3 months or 6 months dependent on clinical presentation. Block randomisation was done with a central interactive computerised system, stratified by study centre and intended treatment duration. The primary efficacy outcome was recurrent venous thromboembolism at 99 days after randomisation. We estimated the odds ratio and 95% CI with a Mantel-Haenzsel χ(2) analysis (non-inferiority margin 2·0) in the intention-to-treat population. The main safety outcome was clinically relevant bleeding (major or non-major) in all patients at day 99. This study is registered with ClinicalTrials.gov, number NCT00345618.
Between Aug 1, 2006, and Jan 31, 2010, we enrolled 3202 patients aged 18-96 years. 34 (2%) of 1599 patients randomly allocated to receive enoxaparin-idrabiotaparinux and 43 (3%) of 1603 patients randomly allocated to receive enoxaparin-warfarin had recurrent venous thromboembolism (odds ratio 0·79, 95% CI 0·50-1·25; p(non-inferiority)=0·0001). 72 (5%) of 1599 patients in the enoxaparin-idrabiotaparinux group and 106 (7%) of 1603 patients in the enoxaparin-warfarin group had clinically relevant bleeding (0·67, 0·49-0·91; p(superiority)=0·0098). We noted similar differences in outcomes in those patients treated to 6 months.
Idrabiotaparinux could provide an attractive alternative to warfarin for the long-term treatment of pulmonary embolism, and seems to be associated with reduced bleeding.
Sanofi-Aventis (Paris, France).
低分子肝素和维生素 K 拮抗剂（如华法林）治疗肺栓塞并不理想。我们旨在评估可逆性长效间接 Xa 因子抑制剂伊达肝素钠在急性有症状肺栓塞患者中的非劣效性优于华法林。
在我们的随机、双盲、双模拟、非劣效性试验中，我们招募了 291 个中心来自 37 个国家的 3202 名有客观记录的急性有症状肺栓塞成年患者。我们排除了怀孕、有活动性出血、肾衰竭或恶性高血压或有死亡、出血或对研究药物不良反应高风险的患者。我们随机分配患者接受 5-10 天的依诺肝素 1.0mg/kg 每日两次皮下注射伊达肝素钠（起始剂量 3.0mg）或调整剂量的华法林（目标国际标准化比值 2.0-3.0）；方案持续 3 个月或 6 个月，取决于临床表现。采用中央交互式计算机化系统进行块随机化，按研究中心和预期治疗时间分层。主要疗效终点为随机分组后 99 天的复发性静脉血栓栓塞。我们使用 Mantel-Haenzsel χ2 分析（非劣效性边界 2.0）在意向治疗人群中估计优势比和 95%CI。主要安全性终点为所有患者在第 99 天的临床相关出血（主要或非主要）。这项研究在 ClinicalTrials.gov 注册，编号为 NCT00345618。
在 2006 年 8 月 1 日至 2010 年 1 月 31 日期间，我们招募了 3202 名 18-96 岁的患者。在随机分配接受依诺肝素-伊达肝素钠治疗的 1599 名患者中，有 34 名（2%）和随机分配接受依诺肝素-华法林治疗的 1603 名患者中，有 43 名（3%）出现复发性静脉血栓栓塞（优势比 0.79，95%CI 0.50-1.25；p（非劣效性）=0.0001）。在依诺肝素-伊达肝素钠组的 1599 名患者中，有 72 名（5%）和在依诺肝素-华法林组的 1603 名患者中，有 106 名（7%）发生了临床相关出血（0.67，0.49-0.91；p（优效性）=0.0098）。我们注意到在治疗 6 个月的患者中，结局也有类似的差异。
伊达肝素钠可能为肺栓塞的长期治疗提供一种有吸引力的华法林替代方案，并且似乎与出血减少相关。
赛诺菲-安万特（法国巴黎）。
