From the Departments of Neurology (S.L., H.L., X.W., Yilong Wang, Z.L., X.M., X.Z., L.L., Yongjun Wang) and Clinical Trial Center (S.L., H.L., X.W., Yilong Wang, Z.L., X.M., X.Z., L.L., Yongjun Wang), and the China National Clinical Research Center for Neurologic Diseases (S.L., H.-Q.G., H.L., X.W., A.J., Yilong Wang, Z.L., X.M., X.Z., L.L., Yongjun Wang), Beijing Tiantan Hospital, Capital Medical University, Beijing, the Emergency Department, Linfen Central Hospital, Linfen (S.G.), the Department of Neurology, Ke shi ke teng Banner Traditional Chinese Medicine and Mongolian Medical Hospital, Chifeng (G.L.), the Department of Neurology, Linyi People’s Hospital, Linyi (F.C.), the Department of Neurology, Xianyang Hospital of Yan’an University, Xianyang (W.W.), and the Department of Neurology, Halison International Peace Hospital, Hengshui (Y. Wei) - all in China. Dr. Yongjun Wang can be contacted at yongjunwang@ncrcnd.org.cn or at Beijing Tiantan Hospital, No. 119 South 4th Ring West Rd., Fengtai District, Beijing 100070, China. 来自神经内科（S.L.， H.L.， X.W.， Yilong Wang， Z.L.， X.M.， X.Z.， L.L.， Yongjun Wang）和临床试验中心（S.L.， H.L.， X.W.， Yilong Wang， Z.L.， X.M.， X.Z.， L.L.， Yongjun Wang）和中国国家神经疾病临床医学研究中心（S.L.， H.-Q.G.， H.L.， X.W.， A.J.， 王一龙， Z.L.， X.M.， X.Z.， L.L.）， 北京首都医科大学附属北京天坛医院， 临汾市中心医院急诊科 临汾 （S.G.）， 神经内科， 柯世克腾旗中医科 和 赤峰蒙古医学医院 （G.L.）， 神经内科， 临沂市临沂市人民医院 （F.C.）、延安大学咸阳医院神经内科 （W.W.） 和衡水市哈利森国际和平医院神经内科 （Y. Wei） - 均在中国。王永军医生的联系方式是 yongjunwang@ncrcnd.org.cn 或北京天坛医院，地址：北京市丰台区南四环西路 119 号，邮编：100070。
*A list of the RAISE investigators and committee members is provided in the Supplementary Appendix, available at NEJM.org. *RAISE 研究人员和委员会成员的名单在补充附录中提供，可在 NEJM.org 上获得。
Drs. S. Li and Gu contributed equally to this article. S. Li 博士和 Gu 博士对本文做出了同样的贡献。
This article was published on June 14, 2024, at NEJM.org. 本文发表于 2024 年 6 月 14 日，NEJM.org。
Alteplase is the standard agent used in early reperfusion therapy, but alternative thrombolytic agents are needed. The efficacy and safety of reteplase as compared with alteplase in patients with acute ischemic stroke are unclear. 阿替普酶是早期再灌注治疗中使用的标准药物，但需要替代溶栓药物。与阿替普酶相比，瑞替普酶在急性缺血性卒中患者中的疗效和安全性尚不清楚。
METHODS 方法
We randomly assigned patients with ischemic stroke within 4.5 hours after symptom onset in a 1:1 ratio to receive intravenous reteplase (a bolus of 18 mg followed 30 minutes later by a second bolus of 18 mg ) or intravenous alteplase ( 0.9 mg per kilogram of body weight; maximum dose, 90 mg ). The primary efficacy outcome was an excellent functional outcome, defined as a score of 0 or 1 on the modified Rankin scale (range, 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]) at 90 days. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after symptom onset. 我们以 1：1 的比例将症状出现后 4.5 小时内的缺血性卒中患者随机分配接受静脉注射瑞替普酶（推注 18 mg，30 分钟后第二次推注 18 mg）或静脉注射阿替普酶（每公斤体重 0.9 mg;最大剂量，90 mg）。主要疗效结局是出色的功能结局，定义为 90 天时改良 Rankin 量表评分 0 或 1 分（范围，0 [无神经功能缺损、无症状或完全康复] 至 6 [死亡]）。主要安全性结局为症状出现后 36 小时内出现症状性颅内出血。
RESULTS 结果
A total of 707 patients were assigned to receive reteplase, and 705 were assigned to receive alteplase. An excellent functional outcome occurred in 79.5%79.5 \% of the patients in the reteplase group and in 70.4%70.4 \% of those in the alteplase group (risk ratio, 1.13; 95% confidence interval [CI], 1.05 to 1.21; P<0.001 for noninferiority and P=0.002\mathrm{P}=0.002 for superiority). Symptomatic intracranial hemorrhage within 36 hours after disease onset was observed in 17 of 700 patients ( 2.4%2.4 \% ) in the reteplase group and in 14 of 699 ( 2.0%2.0 \% ) of those in the alteplase group (risk ratio, 1.21; 95% CI, 0.54 to 2.75). The incidence of any intracranial hemorrhage at 90 days was higher with reteplase than with alteplase ( 7.7%7.7 \% vs. 4.9%4.9 \%; risk ratio, 1.59 ; 95%95 \% CI, 1.00 to 2.51 ), as was the incidence of adverse events ( 91.6%91.6 \% vs. 82.4%82.4 \%; risk ratio, 1.11; 95% CI, 1.03 to 1.20). 共有 707 例患者被分配接受瑞替普酶，705 例被分配接受阿替普酶。瑞替普酶组和 70.4%70.4 \% 阿替普酶组患者功能结局 79.5%79.5 \% 极佳 （风险比，1.13;95% 置信区间 [CI]，1.05 至 1.21;P<0.001 为非劣效性和 P=0.002\mathrm{P}=0.002 优效性）。瑞替普酶组 700 例患者中有 17 例 （ 2.4%2.4 \% ） 和阿替普酶组 699 例患者中有 14 例 （ 2.0%2.0 \% ） 在发病后 36 小时内观察到有症状的颅内出血 （风险比，1.21;95% CI，0.54 至 2.75）。瑞替普酶组 90 天颅内出血的发生率高于阿替普酶组 （ 7.7%7.7 \% vs. 4.9%4.9 \% ;风险比，1.59 ; 95%95 \% CI，1.00 至 2.51），不良事件的发生率也是如此 （ 91.6%91.6 \% vs. 82.4%82.4 \% ;风险比，1.11;95% CI，1.03 至 1.20）。
CONCLUSIONS 结论
Among patients with ischemic stroke within 4.5 hours after symptom onset, reteplase was more likely to result in an excellent functional outcome than alteplase. (Funded by China Resources Angde Biotech Pharma and others; RAISE ClinicalTrials.gov number, NCT05295173.) 在症状出现后 4.5 小时内的缺血性卒中患者中，瑞替普酶比阿替普酶更有可能导致出色的功能结局。（由华润昂德生物制药等资助;RAISE ClinicalTrials.gov number， NCT05295173.）
REPERFUSION THERAPY IS AN EVIDENCEbased intervention for ischemic stroke. ^(1,2){ }^{1,2} Intravenous alteplase is the internationally approved standard thrombolytic agent for acute ischemic stroke within 4.5 hours after symptom onset. ^(3-5){ }^{3-5} Recent studies have shown that tenecteplase, a genetically modified form of alteplase given as a single bolus, delivers clinical benefits similar to those of alteplase. ^(6,7){ }^{6,7} Some guidelines have recommended either alteplase or tenecteplase for patients with acute ischemic stroke within 4.5 hours after known onset. ^(8-10){ }^{8-10} 再灌注疗法是一种针对缺血性卒中的循证干预措施。 ^(1,2){ }^{1,2} 静脉注射阿替普酶是国际批准的急性缺血性卒中症状发作后 4.5 小时内的标准溶栓剂。 ^(3-5){ }^{3-5} 最近的研究表明，替奈普酶是一种转基因形式的阿替普酶，以单次推注给药，具有与阿替普酶相似的临床益处。 ^(6,7){ }^{6,7} 一些指南建议急性缺血性卒中患者在已知发作后 4.5 小时内使用阿替普酶或替奈普酶。 ^(8-10){ }^{8-10}
The demand for intravenous thrombolysis in acute ischemic stroke has increased substantially with the continuous improvement in the quality of stroke care. ^(11){ }^{11} From 2015 to 2019, the use of intravenous thrombolysis grew by 60.3%60.3 \%, reaching 22.9%22.9 \% among patients treated within 4.5 hours after symptom onset. ^(12){ }^{12} The development of diverse, effective, and affordable thrombolytic agents is still needed. 随着卒中护理质量的不断提高，急性缺血性卒中对静脉溶栓的需求大幅增加。 ^(11){ }^{11} 从 2015 年到 2019 年，静脉溶栓的使用在症状出现后 4.5 小时内接受 22.9%22.9 \% 治疗的患者中增长 60.3%60.3 \% 。 ^(12){ }^{12} 仍然需要开发多样化、有效且负担得起的溶栓剂。
Reteplase is a recombinant plasminogen activator that is characterized by a double-bolus approach (the boluses are separated by 30 minutes) with a fixed dose regimen. ^(13-16){ }^{13-16} Reteplase was approved for the treatment of acute myocardial infarction in many geographic regions. ^(15-18){ }^{15-18} A metaanalysis that compared reteplase with alteplase in patients with acute myocardial infarction showed no significant differences between the two treatments in terms of mortality or the incidence of disabling stroke. ^(19){ }^{19} 瑞替普酶是一种重组纤溶酶原激活剂，其特征是采用固定剂量方案的双推注方法（推注间隔 30 分钟）。 ^(13-16){ }^{13-16} 瑞替普酶在许多地区被批准用于治疗急性心肌梗死。 ^(15-18){ }^{15-18} 一项比较急性心肌梗死患者瑞替普酶与阿替普酶的荟萃分析显示，两种治疗在死亡率或致残性卒中发生率方面没有显著差异。 ^(19){ }^{19}
In a phase 2, randomized, controlled trial, the proportion of patients with an excellent functional outcome was higher with two 18-mg18-\mathrm{mg} doses of reteplase than with two 12-mg12-\mathrm{mg} doses or with alteplase at a dose of 0.9 mg per kilogram of body weight, and the higher dose of reteplase was not associated with an increased risk of fatal bleeding. ^(20){ }^{20} We conducted the Reteplase versus Alteplase for Acute Ischemic Stroke (RAISE) trial to compare reteplase at a double-bolus dose of 18 mg plus 18 mg (with a 30-minute interval) and standard alteplase with respect to the functional outcome in patients with acute ischemic stroke who were eligible for intravenous thrombolysis within 4.5 hours after symptom onset. 在一项 2 期随机对照试验中，两 18-mg18-\mathrm{mg} 剂瑞替普酶组具有出色功能结果的患者比例高于两 12-mg12-\mathrm{mg} 剂或阿替普酶（剂量为每公斤体重 0.9 毫克），并且较高剂量的瑞替普酶与致命性出血风险增加无关。 ^(20){ }^{20} 我们进行了瑞替普酶与阿替普酶治疗急性缺血性卒中 （RAISE） 试验，以比较 18 mg 加 18 mg 双倍推注剂量的瑞替普酶与标准阿替普酶在症状出现后 4.5 小时内有资格接受静脉溶栓的急性缺血性卒中患者的功能结局。
METHODS 方法
TRIAL DESIGN AND OVERSIGHT 试验设计和监督
The RAISE trial was a phase 3, multicenter, prospective, open-label, noninferiority, randomized RAISE 试验为 3 期、多中心、前瞻性、开放标签、非劣效性、随机
trial with blinded end-point assessment; the trial was conducted at 62 sites in China. The participating sites are listed in the Supplementary Appendix, available with the full text of this article at NEJM.org. The trial protocol has been published previously ^(21){ }^{21} and is available at NEJM. org. The open-label design was implemented because of the unavailability of placebo and to avoid potential delay in the administration of thrombolytic agents. The trial was approved by the institutional review board at the Beijing Tiantan Hospital and at each participating site. Written informed consent was provided by all the patients or their representatives. An independent data and safety monitoring committee monitored the progress of the trial, with regular assessment of safety outcomes, overall trial integrity, and trial conduct. Intracranial hemorrhage, other clinically significant hemorrhage events, and death from any cause were evaluated by an independent clinical event committee whose members were unaware of the trial-group assignments. Local investigators vouched for the accuracy and completeness of the other serious adverse events. 盲法终点评估试验;该试验在中国的 62 个地点进行。参与研究中心列在补充附录中，本文全文可在 NEJM.org 上获得。试验方案之前已发布 ^(21){ }^{21} ，可在 NEJM 上获得。组织。实施开放标签设计是因为安慰剂不可用，并避免了溶栓药物给药的潜在延迟。该试验得到了北京天坛医院和每个参与地点的机构审查委员会的批准。所有患者或其代表均提供书面知情同意书。一个独立的数据和安全性监测委员会监测试验的进展，定期评估安全性结果、整体试验完整性和试验实施。颅内出血、其他有临床意义的出血事件和任何原因导致的死亡由独立的临床事件委员会进行评估，该委员会的成员不知道试验组分配。当地调查人员为其他严重不良事件的准确性和完整性提供了保证。
The trial drugs (reteplase and alteplase) were provided free of charge to the trial sites by China Resources Angde Biotech Pharma, which provided funding for the trial but did not have any role in data analysis or interpretation. The investigators were responsible for data collection and the conduct of the trial. The Pharmaron (Nanjing) Clinical Service, an independent contract research organization, was responsible for the data management and statistical analysis. The last author designed the trial. The first two authors wrote the first draft of the manuscript. All the authors made the decision to submit the manuscript for publication and vouch for the completeness and accuracy of the reported data and for the fidelity of the trial to the protocol. 试验药物（瑞替普酶和阿替普酶）由华润昂德生物制药公司免费提供给试验地点，该公司为试验提供资金，但在数据分析或解释方面没有任何作用。研究人员负责数据收集和试验的进行。康龙化成（南京）临床服务有限公司是一家独立的合同研究机构，负责数据管理和统计分析。最后一位作者设计了该试验。前两位作者撰写了手稿的初稿。所有作者都决定提交手稿以供发表，并保证报告数据的完整性和准确性以及试验对方案的忠实度。
TRIAL PATIENTS 试验患者
Patients were eligible if they were 18 to 80 years of age, could receive intravenous thrombolysis within 4.5 hours after the time that they had last been known to be well, had excellent functional status before the onset of their stroke (defined by a score of <= 1\leq 1 on the modified Rankin scale, with scores ranging from 0 [no neurologic deficit, no symptoms, or completely recovered] to 6 [death]), and had a disabling ischemic stroke with a National Institutes of Health Stroke Scale 如果患者年龄在 18 至 80 岁之间，可以在最后一次已知身体健康后 4.5 小时内接受静脉溶栓，在中风发作前具有良好的功能状态（定义为改良 Rankin 量表的评分 <= 1\leq 1 ，评分范围为 0 [无神经功能缺损， 无症状，或完全康复] 至 6 [死亡]），并且患有致残性缺血性中风，且美国国立卫生研究院卒中量表
A Quick Take is available at NEJM.org Quick Take 可在 NEJM.org
(NIHSS) score of 4 to 25 (range, 0 [no neurologic deficit] to 42 [death]). The eligibility for thrombolysis in this trial was based on Chinese guideline recommendations, ^(5){ }^{5} which are consistent with other national guidelines, including those in the United States ^(3){ }^{3} and Europe. ^(4){ }^{4} Ischemic stroke is typically diagnosed by means of noncontrast computed tomography or magnetic resonance imaging in patients with symptoms of neurologic impairment. Patients were excluded from participation if they had previously undergone or were planned to undergo endovascular thrombectomy. Additional information on inclusion and exclusion criteria is provided in the Supplementary Appendix and the protocol. （NIHSS） 评分为 4 至 25（范围，0 [无神经功能缺损] 至 42 [死亡]）。该试验中的溶栓合格性基于中国指南推荐， ^(5){ }^{5} 这些推荐与其他国家指南一致，包括美国 ^(3){ }^{3} 和欧洲的指南。 ^(4){ }^{4} 对于有神经功能损害症状的患者，缺血性卒中通常通过平扫计算机断层扫描或磁共振成像进行诊断。如果患者之前接受过或计划接受血管内血栓切除术，则他们被排除在参与之外。补充附录和方案中提供了有关纳入和排除标准的其他信息。
TREATMENT 治疗
Eligible patients were randomly assigned in a 1:11: 1 ratio to receive intravenous reteplase or intravenous alteplase. The randomization process was conducted with the use of an interactive Webresponse system (Randomization and Trial Supply Management eBalance [version 5.3], Zhejiang Taimei Medical Technology) with a variable block length. 符合条件的患者按 1:11: 1 比例随机分配接受静脉注射瑞替普酶或静脉注射阿替普酶。随机化过程是使用具有可变块长度的交互式 Webresponse 系统（随机化和试验供应管理 eBalance [5.3 版]，浙江泰美医疗科技有限公司）进行的。
The intravenous thrombolytic treatment was conducted in an open-label manner. Reteplase was given as two intravenous 18-mg18-\mathrm{mg} bolus doses, each administered over a period of 2 minutes; the first dose was administered immediately after randomization and the second 30 minutes later. Alteplase was administered at a dose of 0.9 mg per kilogram (maximum dose, 90 mg ), with 10%10 \% of the dose delivered as a bolus within 1 minute; the remaining dose was infused intravenously during the subsequent 60 minutes. All other treatments followed standard practice for the management of ischemic stroke. 静脉溶栓治疗以开放标签方式进行。瑞替普酶以两次静脉 18-mg18-\mathrm{mg} 推注给药，每次给药时间为 2 分钟;第一剂在随机分组后立即给药，第二剂在 30 分钟后给药。阿替普酶以每公斤 0.9 毫克的剂量（最大剂量，90 毫克）给药， 10%10 \% 剂量在 1 分钟内推注给药;剩余剂量在随后的 60 分钟内静脉输注。所有其他治疗均遵循缺血性卒中的标准做法。
OUTCOMES 结果
The primary efficacy outcome was an excellent functional outcome, defined as a modified Rankin scale score of 0 or 1 at 90 days. The secondary efficacy outcomes included a good functional outcome (defined as a modified Rankin scale score of 0 to 2 at 90 days), the ordinal distribution of the modified Rankin scale score at 90 days, early dramatic recovery with respect to the NIHSS score (defined as a decrease of >= 4\geq 4 points or a score of <= 1\leq 1 at 24 hours and at 7 days), and a Barthel Index score of at least 95 (range, 0 to 100, with 主要疗效结局是出色的功能结局，定义为 90 天时改良 Rankin 量表评分为 0 或 1。次要疗效结局包括良好的功能结局（定义为 90 天时改良 Rankin 量表评分为 0 至 2），90 天时改良 Rankin 量表评分的顺序分布，相对于 NIHSS 评分的早期戏剧性恢复（定义为 24 小时和 7 天 <= 1\leq 1 时 >= 4\geq 4 分数下降或评分下降）， 以及 Barthel 指数评分至少为 95（范围为 0 到 100，其中
higher scores indicating better independent function) at 90 days. 分数越高表示独立功能越好）。
The primary safety outcome was symptomatic intracranial hemorrhage, as defined by the European Cooperative Acute Stroke Study III (ECASS III), ^(2){ }^{2} within 36 hours. Other safety outcomes included symptomatic intracranial hemorrhage, as defined by ECASS III, within 7 days; parenchymal hemorrhage type 2, as defined by the Safe Implementation of Thrombolysis in Stroke-Monitoring Study, ^(22){ }^{22} within 36 hours; any intracranial hemorrhage; major hemorrhage and clinically relevant nonmassive hemorrhage according to the International Society on Thrombosis and Haemostasis criteria ^(23,24){ }^{23,24}; death from any cause within 7 days and 90 days; and adverse events and serious adverse events occurring within 90 days after disease onset. Detailed definitions of these outcomes are provided in the Supplementary Appendix. 主要安全性结局是 36 小时内出现症状性颅内出血，如欧洲急性卒中合作研究 III （ECASS III ^(2){ }^{2} ） 所定义。其他安全性结局包括 7 天内 ECASS III 定义的症状性颅内出血;2 型实质出血，如中风监测研究中 ^(22){ }^{22} 安全实施溶栓定义的，在 36 小时内;任何颅内出血;根据国际血栓形成和止血学会标准 ^(23,24){ }^{23,24} ，大出血和临床相关的非大出血;在 7 天和 90 天内因任何原因死亡;以及发病后 90 天内发生的不良事件和严重不良事件。这些结局的详细定义见补充附录。
The clinical assessments were conducted at 30 days and 90 days by neurologists who were unaware of the trial-group assignments and who had received specialized training and certification. The modified Rankin scale score at 90 days was obtained either through face-to-face interviews or telephone conversations. The clinical event committee adjudicated the end-point events on the basis of clinical symptoms, laboratory tests, and imaging data. Adverse events and serious adverse events were classified according to standardized terminology. 临床评估在 30 天和 90 天由神经科医生进行，他们不知道试验组分配并且接受过专门培训和认证。90 天时改良的 Rankin 量表评分是通过面对面访谈或电话交谈获得的。临床事件委员会根据临床症状、实验室检查和影像学数据对终点事件进行裁决。不良事件和严重不良事件根据标准化术语进行分类。
STATISTICAL ANALYSIS 统计分析
On the basis of previous alteplase trials ^(1,2){ }^{1,2} and the phase 2 trial comparing reteplase with alteplase, ^(20){ }^{20} we assumed that a modified Rankin scale score of 0 or 1 would be achieved by 62.5%62.5 \% of the patients in the alteplase group. We estimated that a sample size of 1412 patients would provide the trial with 85%85 \% power, at a one-sided significance level of 0.025 , to show the noninferiority of reteplase to alteplase with respect to an excellent functional outcome, with the lower limit of the 95%95 \% confidence interval of the risk ratio being higher than 0.93, assuming a real efficacy risk ratio of 1.05 and a dropout rate of 3%3 \%. The noninferiority margin of 0.93 was defined to preserve at least 50%50 \% of the most conservative estimate of the efficacy of alteplase as compared with placebo, which was based on a lower limit 根据先前的阿替普酶试验 ^(1,2){ }^{1,2} 和比较瑞替普酶与阿替普酶的 2 期试验， ^(20){ }^{20} 我们假设阿替普酶组患者的改良 Rankin 量表评分为 62.5%62.5 \% 0 或 1。我们估计 1412 名患者的样本量将为试验提供 85%85 \% 力量，单侧显着性水平为 0.025 ，以显示瑞替普酶在出色的功能结果方面的非劣效性，风险比置 95%95 \% 信区间的下限高于 0.93，假设实际疗效风险比为 1.05 且退出率为 3%3 \% 。与安慰剂相比，0.93 的非劣效性边际定义为至少 50%50 \% 保留了对阿替普酶疗效的最保守估计，该估计基于下限
