背景:静脉替奈普酶增加了灌注成像可挽救的脑组织患者的再灌注,作为缺血性卒中的溶栓药物,可能优于阿替普酶。我们旨在评估替奈普酶与阿替普酶对通过灌注成像选择的患者的临床结局的非劣效性。
方法:这个国际,多中心,开放标签,平行组,随机化,临床非劣效性试验纳入了来自8个国家35家医院的患者.参与者年龄在18岁或以上,在缺血性卒中发作或最后一次已知的4·5小时内,没有考虑血管内血栓切除术,并满足脑灌注成像的目标不匹配标准。通过使用集中式网络服务器将患者随机分配(1:1),并随机排列块,以静脉注射替奈普酶(0·25mg/kg)或阿替普酶(0·90mg/kg)。主要结果是3个月时无残疾患者的比例(改良Rankin量表0-1),在意向治疗人群和符合方案人群中通过掩盖审查进行评估。我们的目标是招募832名参与者,以产生90%的能力(单侧α=0·025),以检测0·08的风险差异,绝对非劣效性为-0·03。该试验已在澳大利亚新西兰临床试验注册中心注册,ACTRN12613000243718和欧盟临床试验注册,EudraCT编号2015-002657-36,已完成。
结果: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日之间,共纳入680例患者,并随机分配给替奈普酶(n=339)和阿替普酶(n=341)。所有患者均被纳入意向治疗分析(5例患者的主要结局数据缺失采用多重插补).74名参与者违反了议定书,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).参与者的平均年龄为74岁(IQR63-82),基线美国国立卫生研究院卒中量表得分为7分(4-11分),260人(38%)为女性。在意向治疗分析中,主要结局发生在分配给替奈普酶的335名参与者中的191名(57%)和分配给阿替普酶的340名参与者中的188名(55%)(标准化风险差异[SRD]=0·03[95%CI-0·033至0·10],单尾伪劣=0·031)。在符合方案的分析中,主要结局发生在分配给替奈普酶的295名参与者中的173名(59%)和分配给阿替普酶的306名参与者中的171名(56%)(SRD0·05[-0·02至0·12],单尾伪劣=0·01)。替奈普酶组的337例患者中有9例(3%)和阿替普酶组的340例患者中有6例(2%)有症状性颅内出血(未调整的风险差异=0·01[95%CI-0·01至0·03])在开始治疗90天内死亡(SRD0·02[95%CI-0·05]0。
结论:我们的研究结果为加强替奈普酶对阿替普酶的非劣效性提供了进一步的证据,特别是当灌注成像用于识别符合再灌注条件的卒中患者时。尽管在符合方案的人群中实现了非劣效性,在意向治疗分析中没有达到,可能是由于样本量的限制。尽管如此,在早期时间窗内大规模实施灌注CT以协助患者选择静脉溶栓被证明是可行的.
背景:澳大利亚国家健康医学研究委员会;勃林格键英格尔海姆。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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 pnon-inferiority=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 pnon-inferiority=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]).
CONCLUSIONS: 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.
BACKGROUND: Australian National Health Medical Research Council; Boehringer Ingelheim.