Department of Neurology, Centre for Neurovascular Diseases, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Department of Neurology, Centre for Neurovascular Diseases, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway.
Lancet Neurol. 2017 Oct;16(10):781-788. doi: 10.1016/S1474-4422(17)30253-3. Epub 2017 Aug 2.
Tenecteplase is a newer thrombolytic agent with some pharmacological advantages over alteplase. Previous phase 2 trials of tenecteplase in acute 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.
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.
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Sept 30, 2016, 1107 patients met the inclusion criteria and seven patients were excluded because informed consent was withdrawn or eligibility for thrombolytic treatment was reconsidered. 1100 patients were randomly assigned to the tenecteplase (n=549) or alteplase (n=551) groups.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).
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.
Research Council of Norway.
替奈普酶是一种新型溶栓药物，在药理学方面优于阿替普酶。之前替奈普酶治疗急性缺血性脑卒中的 2 期临床试验结果令人鼓舞。我们旨在研究适合静脉溶栓的急性脑卒中患者中替奈普酶与阿替普酶的安全性和有效性。
这是一项在挪威 13 个卒中单元进行的 3 期、随机、开放标签、盲终点、优效性试验。我们招募了疑似急性缺血性脑卒中且适合溶栓治疗的成年人，发病时间在症状出现后 4.5 小时内或醒来后出现症状后 4.5 小时内，或在接受血栓切除术前适合桥接治疗的患者。患者以 1:1 的比例随机分配（分层为纳入中心）接受静脉注射替奈普酶 0.4mg/kg（最大剂量 40mg）或阿替普酶 0.9mg/kg（最大剂量 90mg）。患者不知道治疗分配；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。主要结局是 3 个月时改良 Rankin 量表（mRS）评分 0-1 的良好功能结局。主要分析是未调整和非分层意向治疗分析，对缺失数据进行最后观察值结转。这项研究在 ClinicalTrials.gov 注册，编号为 NCT01949948。
2012 年 9 月 1 日至 2016 年 9 月 30 日期间，符合纳入标准的 1107 例患者中，有 7 例因撤回知情同意或重新考虑溶栓治疗的适应证而被排除。1100 例患者被随机分配至替奈普酶（n=549）或阿替普酶（n=551）组。参与者的中位年龄为 77 岁（IQR 64-79），基线时国立卫生研究院卒中量表评分中位数为 4 分（IQR 2-8）。替奈普酶组有 99（18%）例患者最终诊断为缺血性卒中和短暂性脑缺血发作以外的其他疾病，阿替普酶组有 91（17%）例患者。替奈普酶组 354 例（64%）患者达到主要结局，阿替普酶组 345 例（63%）患者达到主要结局（比值比 1.08，95%CI 0.84-1.38；p=0.52）。替奈普酶组 29 例（5%）患者在 3 个月时死亡，阿替普酶组 26 例（5%）患者死亡。两组严重不良事件的发生率相似（替奈普酶组 145 例[26%]，阿替普酶组 141 例[26%]；p=0.74）。
替奈普酶并不优于阿替普酶，且安全性特征相似。这项研究纳入的大多数患者病情较轻。还需要进一步的试验来确定替奈普酶在病情严重的脑卒中患者中的安全性和有效性，以及替奈普酶是否不劣于阿替普酶。
挪威研究理事会。
