Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients
Extended Thromboprophylaxis with Betrixaban in Acutely Ill Medical Patients
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DOI：
10.1056/nejmoa1601747
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发表时间：
2016-08-11
影响因子：
158.5
通讯作者：
Zakai, N.
中科院分区：
文献类型：
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作者：
Cohen, Alexander T.;Harrington, Robert A.;Zakai, N.
背景患有急性内科疾病的患者长期存在静脉血栓形成的风险。方法将因急性内科疾病住院的患者随机分为两组，分别给予皮下注射依诺肝素(40 mg，每日一次)+口服倍他沙班安慰剂35~42天或皮下注射依诺肝素10+/-4天+口服倍他沙班(每日80 mg)，疗程35~42天。我们在三个预先指定的、逐步纳入的队列中进行了序贯分析：d-二聚体水平升高的患者(队列1)，d-二聚体水平升高或年龄至少75岁的患者(队列2)，以及所有入选的患者(总体人群队列)。统计分析计划规定，如果这一序列中任何一项分析的组间差异不显著，其他分析将被视为探索性分析。主要的疗效结果是无症状的近端深静脉血栓形成和症状性静脉血栓栓塞症的组合。主要的安全结果是大出血。结果共7513名患者接受了随机分组。在队列1中，接受倍他班治疗的患者和接受依诺肝素治疗的患者分别有6.9%和8.5%的患者出现了主要疗效结果(倍他班组的相对风险为0.81；95%可信区间[CI]为0.65-1.00；P=0.054)。队列2的患病率分别为5.6%和7.1%(相对危险度为0.80；95%可信区间为0.66~0.98；P=0.03)，总体人群的患病率分别为5.3%和7.0%(相对危险度为0.76；95%可信区间为0.63~0.92；P=0.006)。(由于队列1的结果，最后两项分析被认为是探索性的。)在总体人群中，倍他沙班组和依诺肝素组中发生大出血的比例分别为0.7%和0.6%(相对危险度为1.19；95%可信区间为0.67~2.12；P=0.55)。结论在d-二聚体水平升高的急性内科患者中，延长疗程的倍他卡班与依诺肝素标准方案在预先指定的主要疗效结果上没有显著差异。然而，预先指定的探索性分析提供的证据表明，倍他沙班在两个较大的队列中是有益的。(由Portola制药公司提供资金；APEX ClinicalTrials.gov编号，NCT01583218。)
BACKGROUNDPatients with acute medical illnesses are at prolonged risk for venous thrombosis. However, the appropriate duration of thromboprophylaxis remains unknown.METHODSPatients who were hospitalized for acute medical illnesses were randomly assigned to receive subcutaneous enoxaparin (at a dose of 40 mg once daily) for 10 +/- 4 days plus oral betrixaban placebo for 35 to 42 days or subcutaneous enoxaparin placebo for 10 +/- 4 days plus oral betrixaban (at a dose of 80 mg once daily) for 35 to 42 days. We performed sequential analyses in three prespecified, progressively inclusive cohorts: patients with an elevated d-dimer level (cohort 1), patients with an elevated d-dimer level or an age of at least 75 years (cohort 2), and all the enrolled patients (overall population cohort). The statistical analysis plan specified that if the between-group difference in any analysis in this sequence was not significant, the other analyses would be considered exploratory. The primary efficacy outcome was a composite of asymptomatic proximal deep-vein thrombosis and symptomatic venous thromboembolism. The principal safety outcome was major bleeding.RESULTSA total of 7513 patients underwent randomization. In cohort 1, the primary efficacy outcome occurred in 6.9% of patients receiving betrixaban and 8.5% receiving enoxaparin (relative risk in the betrixaban group, 0.81; 95% confidence interval [CI], 0.65 to 1.00; P = 0.054). The rates were 5.6% and 7.1%, respectively (relative risk, 0.80; 95% CI, 0.66 to 0.98; P = 0.03) in cohort 2 and 5.3% and 7.0% (relative risk, 0.76; 95% CI, 0.63 to 0.92; P = 0.006) in the overall population. (The last two analyses were considered to be exploratory owing to the result in cohort 1.) In the overall population, major bleeding occurred in 0.7% of the betrixaban group and 0.6% of the enoxaparin group (relative risk, 1.19; 95% CI, 0.67 to 2.12; P = 0.55).CONCLUSIONSAmong acutely ill medical patients with an elevated d-dimer level, there was no significant difference between extended-duration betrixaban and a standard regimen of enoxaparin in the prespecified primary efficacy outcome. However, prespecified exploratory analyses provided evidence suggesting a benefit for betrixaban in the two larger cohorts. (Funded by Portola Pharmaceuticals; APEX ClinicalTrials.gov number, NCT01583218.)