Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial
Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial
复制标题
DOI：
10.1016/s1474-4422(17)30253-3
复制
发表时间：
2017-10-01
期刊：
影响因子：
48
通讯作者：
Thomassen, Lars
中科院分区：
文献类型：
--
作者：
Logallo, Nicola;Novotny, Vojtech;Thomassen, Lars
研究背景替替普酶是一种较新的溶栓剂，与阿替普酶相比具有一定的药理优势。先前替替普酶治疗急性缺血性卒中的2期试验已经显示了令人振奋的结果。目的比较替替普酶与阿替普酶在符合静脉溶栓条件的急性卒中患者中的安全性和有效性。方法这项3期随机、开放、盲目终点、优势试验在挪威的13个卒中单元进行。我们招募了疑似急性缺血性卒中的成年人，他们有资格接受溶栓治疗，并在症状出现后4.5h内或有症状醒来后4.5h内入院，或符合血栓切除前桥接治疗的条件。患者被随机分配(1：1)接受替替普酶0.4 mg/kg(最多40 mg)或阿替普酶0.9 mg/kg(最多90 mg)的静脉注射，按纳入中心分层。患者不被告知治疗分配；治疗医生知道治疗分配，但评估主要和次要终点的医生不知道。主要结果是3个月时按改良Rankin评分(MRS)0~1分定义的极好的功能结果。主要分析是未调整的、非分层的意向治疗分析，最后一次观察用于缺失数据的归因。这项研究在ClinicalTrials.gov注册，编号NCT01949948。在2012年9月1日至2016年9月30日期间，1107名患者符合纳入标准，7名患者因撤回知情同意或重新考虑是否有资格接受溶栓治疗而被排除在外。1100例患者随机分为替替普酶组(n=549)和阿替普酶组(n=551)。参与者的中位年龄为77岁(智商-79)，基线时美国国立卫生研究院卒中量表得分中位数为4分(智商2-8)。替替普组99名患者(18%)和阿替普组91名患者(17%)被确诊为非缺血性中风或短暂性脑缺血发作。替替普组354例(%)和阿替普斯组345例(63%)患者获得了初步结果(优势比1.08，95%可信区间0.84~1.38；p=0.52)。到3个月时，替替普组有29名患者(5%)死亡，而阿替普酶组有26名患者(5%)死亡。两组间严重不良事件的发生率相似(替替普组145例[26%]，阿替普酶组141例[26%]；p=0.74)。替替普酶并不优于阿替普酶，表现出相似的安全性。在这项研究中登记的大多数患者都有轻度中风。还需要进一步的试验来确定在严重中风患者中的安全性和有效性，以及替替普酶是否不逊于阿替普酶。
Background Tenecteplase is a newer thrombolytic agent with some pharmacological advantages over alteplase. Previous phase 2 trials of tenecteplase in a(c)ute ischaemic stroke have shown promising results. We aimed to investigate the safety and efficacy of tenecteplase versus alteplase in patients with acute stroke who were eligible for intravenous thrombolysis.Methods This phase 3, randomised, open-label, blinded endpoint, superiority trial was done in 13 stroke units in Norway. We enrolled adults with suspected acute ischaemic stroke who were eligible for thrombolysis and admitted within 4.5 h of symptom onset or within 4.5 h of awakening with symptoms, or who were eligible for bridging therapy before thrombectomy. Patients were randomly assigned (1: 1) to receive intravenous tenecteplase 0.4 mg/kg (to a maximum of 40 mg) or alteplase 0.9 mg/kg (to a maximum of 90 mg), via a block randomisation schedule stratified by centre of inclusion. Patients were not informed of treatment allocation; treating physicians were aware of treatment allocation but those assessing the primary and secondary endpoints were not. The primary outcome was excellent functional outcome defined as modified Rankin Scale (mRS) score 0-1 at 3 months. The primary analysis was an unadjusted and non-stratified intention-to-treat analysis with last observation carried forward for imputation of missing data. This study is registered with ClinicalTrials.gov, number NCT01949948.Findings Between Sept 1, 2012, and Sept 30, 2016, 1107 patients met the inclusion criteria and seven patients were excluded because informed consent was withdrawn or eligibility for thrombolytic treatment was reconsidered. 1100 patients were randomly assigned to the tenecteplase (n=549) or alteplase (n=551) groups. The median age of participants was 77 years (IQR 64-79) and the median National Institutes of Health Stroke Scale score at baseline was 4 points (IQR 2-8). A final diagnosis other than ischaemic stroke or transient ischaemic attack was found in 99 (18%) patients in the tenecteplase group and 91 (17%) patients in the alteplase group. The primary outcome was achieved by 354 (64%) patients in the tenecteplase group and 345 (63%) patients in the alteplase group (odds ratio 1.08, 95% CI 0.84-1.38; p=0.52). By 3 months, 29 (5%) patients had died in the tenecteplase group compared with 26 (5%) in the alteplase group. The frequency of serious adverse events was similar between groups (145 [26%] in the tenecteplase group vs 141 [26%] in the alteplase group; p=0.74).Interpretation Tenecteplase was not superior to alteplase and showed a similar safety profile. Most patients enrolled in this study had mild stroke. Further trials are needed to establish the safety and efficacy in patients with severe stroke and whether tenecteplase is non-inferior to alteplase.