Intravenous tenecteplase increases reperfusion in patients with salvageable brain tissue on perfusion imaging and might have advantages over alteplase as a thrombolytic for ischaemic stroke. We aimed to assess the non-inferiority of tenecteplase versus alteplase on clinical outcomes in patients selected by use of perfusion imaging. This international, multicentre, open-label, parallel-group, randomised, clinical non-inferiority trial enrolled patients from 35 hospitals in eight countries. Participants were aged 18 years or older, within 4·5 h of ischaemic stroke onset or last known well, were not being considered for endovascular thrombectomy, and met target mismatch criteria on brain perfusion imaging. Patients were randomly assigned (1:1) by use of a centralised web server with randomly permuted blocks to intravenous tenecteplase (0·25 mg/kg) or alteplase (0·90 mg/kg). The primary outcome was the proportion of patients without disability (modified Rankin Scale 0–1) at 3 months, assessed via masked review in both the intention-to-treat and per-protocol populations. We aimed to recruit 832 participants to yield 90% power (one-sided alpha=0·025) to detect a risk difference of 0·08, with an absolute non-inferiority margin of −0·03. The trial was registered with the Australian New Zealand Clinical Trials Registry, ACTRN12613000243718, and the European Union Clinical Trials Register, EudraCT Number 2015-002657-36, and it is completed. Recruitment ceased early following the announcement of other trial results showing non-inferiority of tenecteplase versus alteplase. Between March 21, 2014, and Oct 20, 2023, 680 patients were enrolled and randomly assigned to tenecteplase (n=339) and alteplase (n=341), all of whom were included in the intention-to-treat analysis (multiple imputation was used to account for missing primary outcome data for five patients). Protocol violations occurred in 74 participants, thus the per-protocol population comprised 601 people (295 in the tenecteplase group and 306 in the alteplase group). Participants had a median age of 74 years (IQR 63–82), baseline National Institutes of Health Stroke Scale score of 7 (4–11), and 260 (38%) were female. In the intention-to-treat analysis, the primary outcome occurred in 191 (57%) of 335 participants allocated to tenecteplase and 188 (55%) of 340 participants allocated to alteplase (standardised risk difference [SRD]=0·03 [95% CI −0·033 to 0·10], one-tailed p=0·031). In the per-protocol analysis, the primary outcome occurred in 173 (59%) of 295 participants allocated to tenecteplase and 171 (56%) of 306 participants allocated to alteplase (SRD 0·05 [−0·02 to 0·12], one-tailed p=0·01). Nine (3%) of 337 patients in the tenecteplase group and six (2%) of 340 in the alteplase group had symptomatic intracranial haemorrhage (unadjusted risk difference=0·01 [95% CI −0·01 to 0·03]) and 23 (7%) of 335 and 15 (4%) of 340 died within 90 days of starting treatment (SRD 0·02 [95% CI −0·02 to 0·05]). The findings in our study provide further evidence to strengthen the assertion of the non-inferiority of tenecteplase to alteplase, specifically when perfusion imaging has been used to identify reperfusion-eligible stroke patients. Although non-inferiority was achieved in the per-protocol population, it was not reached in the intention-to-treat analysis, possibly due to sample size limtations. Nonetheless, large-scale implementation of perfusion CT to assist in patient selection for intravenous thrombolysis in the early time window was shown to be feasible. Australian National Health Medical Research Council; Boehringer Ingelheim.

中文翻译：

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替奈普酶与阿替普酶在缺血性卒中 （TASTE） 发作后 4·5 小时内使用灌注成像选择的患者溶栓：一项多中心、随机、对照、3 期非劣效性试验


静脉注射替奈普酶可增加灌注成像上可挽救脑组织的患者的再灌注，并且在缺血性卒中中溶栓方面可能优于阿替普酶。我们旨在评估替奈普酶与阿替普酶对使用灌注成像选择的患者临床结局的非劣效性。这项国际性、多中心、开放标签、平行组、随机、临床非劣效性试验招募了来自 8 个国家 35 家医院的患者。参与者年龄在 18 岁或以上，缺血性卒中发作后 4·5 小时内或最后一次已知良好，未考虑进行血管内血栓切除术，并且符合脑灌注成像的目标错配标准。通过使用带有随机排列块的集中式 Web 服务器将患者随机分配 （1：1） 静脉注射替奈普酶 （0·25 mg/kg） 或阿替普酶 （0·90 mg/kg）。主要结果是 3 个月时无残疾患者 （改良 Rankin 量表 0-1） 的比例，通过盲法审查在意向治疗人群和按方案人群中进行评估。我们的目标是招募 832 名参与者，以产生 90% 的功效 （单侧 alpha=0·025） 以检测 0·08 的风险差异，绝对非劣效性边际为 -0·03。该试验已在澳大利亚新西兰临床试验注册中心（Australian New Zealand Clinical Trials Registry， ACTRN12613000243718）和欧盟临床试验注册库（EudraCT）注册，EudraCT编号为2015-002657-36，并已完成。在宣布其他试验结果显示替奈普酶与阿替普酶的非劣效性后，招募提前停止。 在 2014 年 3 月 21 日至 2023 年 10 月 20 日期间，680 例患者入组并随机分配到替奈普酶 （n=339） 和阿替普酶 （n=341） 组，所有这些患者都被纳入意向性治疗分析（多重插补用于解释 5 例患者的主要结局数据缺失）。违反方案发生在 74 名参与者中，因此符合方案的人群包括 601 人（替奈普酶组 295 人，阿替普酶组 306 人）。参与者的中位年龄为 74 岁 （IQR 63-82），基线美国国立卫生研究院卒中量表评分为 7 （4-11），260 名 （38%） 为女性。在意向治疗分析中，主要结局发生在 335 名替奈普酶参与者中的 191 名 （57%） 和阿替普酶组的 340 名参与者中的 188 名 （55%） （标准化风险差 [SRD]=0·03 [95% CI -0·033 至 0·10]，单尾 p=0·031）。在符合方案的分析中，主要结局发生在 295 名参与者中的 59% 和阿替普酶组的 306 名参与者中的 171 名 （56%） （SRD 0·05 [-0·02 至 0·12]，单尾 p=0·01）。替奈普酶组 337 例患者中有 9 例 （3%），阿替普酶组 340 例患者中有 6 例 （2%） 有症状性颅内出血（未校正风险差 = 0·01 [95% CI -0·01 至 0·03]），335 例中有 23 例 （7%） 和 340 例中有 15 例 （4%） 在开始治疗后 90 天内死亡（SRD 0·02 [95% CI -0·02 至 0·05]）。我们研究的结果提供了进一步的证据，以加强替奈普酶不劣于阿替普酶的断言，特别是当灌注成像已被用于识别符合再灌注条件的中风患者时。 尽管在符合方案的人群中实现了非劣效性，但在意向治疗分析中未达到非劣效性，可能是由于样本量限制。尽管如此，大规模实施灌注 CT 以协助患者在早期选择静脉溶栓已被证明是可行的。澳大利亚国家健康医学研究委员会;勃林格殷格翰。