Background

Intravenous thrombolysis with alteplase bolus followed by infusion is a global standard of care for patients with acute ischaemic stroke. We aimed to determine whether tenecteplase given as a single bolus might increase reperfusion compared with this standard of care.

Methods

In this multicentre, open-label, parallel-group, registry-linked, randomised, controlled trial (AcT), patients were enrolled from 22 primary and comprehensive stroke centres across Canada. Patients were eligible for inclusion if they were aged 18 years or older, with a diagnosis of ischaemic stroke causing disabling neurological deficit, presenting within 4·5 h of symptom onset, and eligible for thrombolysis per Canadian guidelines. Eligible patients were randomly assigned (1:1), using a previously validated minimal sufficient balance algorithm to balance allocation by site and a secure real-time web-based server, to either intravenous tenecteplase (0·25 mg/kg to a maximum of 25 mg) or alteplase (0·9 mg/kg to a maximum of 90mg; 0·09 mg/kg as a bolus and then a 60 min infusion of the remaining 0·81 mg/kg). The primary outcome was the proportion of patients who had a modified Rankin Scale (mRS) score of 0–1 at 90–120 days after treatment, assessed via blinded review in the intention-to-treat (ITT) population (ie, all patients randomly assigned to treatment who did not withdraw consent). Non-inferiority was met if the lower 95% CI of the difference in the proportion of patients who met the primary outcome between the tenecteplase and alteplase groups was more than –5%. Safety was assessed in all patients who received any of either thrombolytic agent and who were reported as treated. The trial is registered with ClinicalTrials.gov, NCT03889249, and is closed to accrual.

Findings

Between Dec 10, 2019, and Jan 25, 2022, 1600 patients were enrolled and randomly assigned to tenecteplase (n=816) or alteplase (n=784), of whom 1577 were included in the ITT population (n=806 tenecteplase; n=771 alteplase). The median age was 74 years (IQR 63–83), 755 (47·9%) of 1577 patients were female and 822 (52·1%) were male. As of data cutoff (Jan 21, 2022), 296 (36·9%) of 802 patients in the tenecteplase group and 266 (34·8%) of 765 in the alteplase group had an mRS score of 0–1 at 90–120 days (unadjusted risk difference 2·1% [95% CI – 2·6 to 6·9], meeting the prespecified non-inferiority threshold). In safety analyses, 27 (3·4%) of 800 patients in the tenecteplase group and 24 (3·2%) of 763 in the alteplase group had 24 h symptomatic intracerebral haemorrhage and 122 (15·3%) of 796 and 117 (15·4%) of 763 died within 90 days of starting treatment

Interpretation

Intravenous tenecteplase (0·25 mg/kg) is a reasonable alternative to alteplase for all patients presenting with acute ischaemic stroke who meet standard criteria for thrombolysis.

Funding

Canadian Institutes of Health Research, Alberta Strategy for Patient Oriented Research Support Unit.

中文翻译：

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静脉替奈普酶与阿替普酶在加拿大治疗急性缺血性卒中 (AcT) 的比较：一项实用的、多中心的、开放标签的、登记相关的、随机的、对照的、非劣效性试验

背景

阿替普酶推注静脉溶栓后输注是急性缺血性卒中患者的全球标准治疗。我们的目的是确定与这种护理标准相比，单次推注替奈普酶是否会增加再灌注。

方法

在这项多中心、开放标签、平行组、注册关联、随机、对照试验 (AcT) 中，患者来自加拿大 22 个初级和综合性卒中中心。符合入选条件的患者年龄在 18 岁或以上，被诊断为导致致残性神经功能缺损的缺血性中风，在症状发作后 4·5 小时内就诊，并且符合加拿大指南的溶栓条件。符合条件的患者被随机分配 (1:1)，使用先前经过验证的最小足够平衡算法来平衡按站点分配和基于安全的实时网络服务器，静脉注射替奈普酶（0·25 mg/kg 至最大25 mg）或阿替普酶（0·9 mg/kg 至最大 90 mg；0·09 mg/kg 推注，然后 60 分钟输注剩余的 0·81 mg/kg）。主要结局是治疗后 90-120 天改良 Rankin 量表 (mRS) 评分为 0-1 的患者比例，通过盲法评估意向治疗 (ITT) 人群（即所有患者随机分配给未撤回同意的治疗）。如果替奈普酶组和阿替普酶组之间满足主要结局的患者比例差异的较低 95% CI 大于 –5%，则满足非劣效性。在所有接受任何一种溶栓剂和被报告为已治疗的患者中评估了安全性。该试验已在 ClinicalTrials.gov 注册，编号为 NCT03889249，并且已停止累积。所有随机分配接受治疗但未撤回同意的患者）。如果替奈普酶组和阿替普酶组之间满足主要结局的患者比例差异的较低 95% CI 大于 –5%，则满足非劣效性。在所有接受任何一种溶栓剂和被报告为已治疗的患者中评估了安全性。该试验已在 ClinicalTrials.gov 注册，编号为 NCT03889249，并且已停止累积。所有随机分配接受治疗但未撤回同意的患者）。如果替奈普酶组和阿替普酶组之间满足主要结局的患者比例差异的较低 95% CI 大于 –5%，则满足非劣效性。在所有接受任何一种溶栓剂和被报告为已治疗的患者中评估了安全性。该试验已在 ClinicalTrials.gov 注册，编号为 NCT03889249，并且已停止累积。

发现

在 2019 年 12 月 10 日至 2022 年 1 月 25 日期间，招募了 1600 名患者并随机分配给替奈普酶 (n=816) 或阿替普酶 (n=784)，其中 1577 名患者被纳入 ITT 人群（n=806 替奈普酶；n =771 阿替普酶）。中位年龄为 74 岁 (IQR 63-83)，1577 名患者中有 755 名 (47·9%) 为女性，822 名 (52·1%) 为男性。截至数据截止（2022 年 1 月 21 日），替奈普酶组 802 名患者中的 296 名（36·9%）和阿替普酶组 765 名患者中的 266 名（34·8%）在 90-90 分时的 mRS 评分为 0-1 120 天（未调整的风险差异 2·1% [95% CI – 2·6 至 6·9]，达到预先指定的非劣效性阈值）。在安全分析中，

解释

对于所有符合溶栓标准的急性缺血性卒中患者，静脉注射替奈普酶 (0·25 mg/kg) 是替代阿替普酶的合理选择。

资金

加拿大卫生研究院，艾伯塔省以患者为导向的研究战略支持单位。