Background

Tenecteplase has potential benefits over alteplase, the standard agent for intravenous thrombolysis in acute ischaemic stroke, because it is administered as a single bolus and might have superior efficacy. The ATTEST-2 trial investigated whether tenecteplase was non-inferior or superior to alteplase within 4·5 h of onset.

Methods

We undertook a prospective, randomised, parallel-group, open-label trial with masked endpoint evaluation in 39 UK stroke centres. Previously independent adults with acute ischaemic stroke, eligible for intravenous thrombolysis less than 4·5 h from last known well, were randomly assigned 1:1 to receive intravenous alteplase 0·9 mg/kg or tenecteplase 0·25 mg/kg, by use of a telephone-based interactive voice response system. The primary endpoint was the distribution of the day 90 modified Rankin Scale (mRS) score and was analysed using ordinal logistic regression in the modified intention-to-treat population. We tested the primary outcome for non-inferiority (odds ratio for tenecteplase vs alteplase non-inferiority limit of 0·75), and for superiority if non-inferiority was confirmed. Safety outcomes were mortality, symptomatic intracranial haemorrhage, radiological intracranial haemorrhage, and major extracranial bleeding. The trial was prospectively registered on ClinicalTrials.gov (NCT02814409).

Findings

Between Jan 25, 2017, and May 30, 2023, 1858 patients were randomly assigned to a treatment group, of whom 1777 received thrombolytic treatment and were included in the modified intention-to-treat population (n=885 allocated tenecteplase and n=892 allocated alteplase). The mean age of participants was 70·4 (SD 12·9) years and median National Institutes of Health Stroke Scale was 7 (IQR 5–13) at baseline. Tenecteplase was non-inferior to alteplase for mRS score distribution at 90 days, but was not superior (odds ratio 1·07; 95% CI 0·90–1·27; p value for non-inferiority<0·0001; p=0·43 for superiority). 68 (8%) patients in the tenecteplase group compared with 75 (8%) patients in the alteplase group died, symptomatic intracerebral haemorrhage (defined by SITS-MOST criteria) occurred in 20 (2%) versus 15 (2%) patients, parenchymal haematoma type 2 occurred in 37 (4%) versus 26 (3%) patients, post-treatment intracranial bleed occurred in 94 (11%) versus 78 (9%) patients, significant extracranial haemorrhage occurred in 13 (1%) versus six (1%) patients, respectively, and angioedema occurred in six (1%) participants in both groups.

Interpretation

Tenecteplase 0·25 mg/kg was non-inferior to 0·9 mg/kg alteplase within 4·5 h of symptom onset in acute ischaemic stroke. Easier administration of tenecteplase, especially in the context of interhospital transfers, indicates that tenecteplase should be preferred to alteplase for thrombolysis in acute ischaemic stroke. The ATTEST-2 population was large and representative of thrombolysis-eligible patients in the UK and, together with findings from other trials, provides robust evidence supporting the introduction of tenecteplase in preference to alteplase.

Funding

The Stroke Association and British Heart Foundation.

中文翻译：

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替奈普酶与阿替普酶治疗发病后 4·5 小时内的急性卒中 （ATTEST-2）：一项随机、平行组、开放标签试验

 背景

替奈普酶比阿替普酶具有潜在益处，阿替普酶是急性缺血性卒中静脉溶栓的标准药物，因为它以单次推注给药，可能具有更好的疗效。ATTEST-2 试验调查了替奈普酶在发病后 4·5 小时内是否不劣于或优于阿替普酶。

 方法

我们在英国 39 个卒中中心进行了一项前瞻性、随机、平行组、开放标签试验，并进行了盲法终点评估。先前独立的急性缺血性卒中成人，有资格在距最后一个已知井不到 4·5 小时的情况下进行静脉溶栓，以 1：1 的比例随机分配接受静脉注射阿替普酶 0·9 mg/kg 或替奈普酶 0·25 mg/kg，通过使用基于电话的交互式语音应答系统。主要终点是第 90 天改良 Rankin 量表 （mRS） 评分的分布，并在改良的意向治疗人群中使用顺序 logistic 回归进行分析。我们测试了非劣效性（替奈普酶与阿替普酶非劣效性限度的比值比为 0·75）和优效性（如果确认了非劣效性），则测试了优效性的主要结局。安全性结局为死亡率、症状性颅内出血、放射学颅内出血和严重颅外出血。该试验于 ClinicalTrials.gov （NCT02814409） 前瞻性注册。

 发现

在 2017 年 1 月 25 日至 2023 年 5 月 30 日期间，1858 例患者被随机分配到治疗组，其中 1777 例接受溶栓治疗并被纳入改良意向治疗人群 （n=885 分配替奈普酶，n=892 分配阿替普酶）。参与者的平均年龄为 70·4 （SD 12·9） 岁，基线时美国国立卫生研究院卒中量表的中位数为 7 （IQR 5-13）。替奈普酶在 90 天 mRS 评分分布方面不劣于阿替普酶，但不优于阿替普酶（比值比 1·07;95% CI 0·90–1·27;非劣效性 p 值<0·0001;优效性 p=0·43）。替奈普酶组 68 例 （8%） 患者与阿替普酶组 75 例 （8%） 患者死亡，症状性脑出血（由 SITS-MOST 标准定义）发生于 20 例 （2%） 与 15 例 （2%） 患者，2 型实质血肿发生于 37 例 （4%） 对 26 例 （3%） 患者，治疗后颅内出血发生于 94 例 （11%） 对 78 例 （9%） 患者，显著颅外出血发生于 13 例 （1%） 对 6 例 （1%） 患者， 分别，两组的 6 名 （1%） 参与者发生血管性水肿。

 解释

在急性缺血性卒中症状出现后 4·5 小时内，替奈普酶 0·25 mg/kg 不劣于 0·9 mg/kg 阿替普酶。替奈普酶更容易给药，尤其是在院间转移的情况下，表明在急性缺血性卒中，替奈普酶应优于阿替普酶。ATTEST-2 人群庞大，代表了英国符合溶栓条件的患者，与其他试验的结果一起，提供了强有力的证据，支持优先引入替奈普酶而不是阿替普酶。

 资金

中风协会和英国心脏基金会。