Hu Yibin, Wu Shengxian, Zhang Haixuan, Wang Kangfeng, Zhang Lijuan, Ma Yizheng, Li He
Neurology Department of the First Clinical Medical College, Shandong University of Traditional Chinese Medicine, No. 4655, Daxue Road, Changqing District, Jinan City, 250355, China.
Dongzhimen Hospital, Beijing University of Chinese Medicine, No.5 Ocean Warehouse, Dongcheng District, Beijing, 100700, China.
Neurol Ther. 2025 Apr;14(2):491-523. doi: 10.1007/s40120-024-00684-9. Epub 2024 Dec 11.
Currently, there is limited evidence on the efficacy and safety of various thrombolytic drugs at different dosages for the treatment of acute ischemic stroke (AIS). From current randomized clinical trials, the optimal type and dosage of thrombolytics for patients with AIS are unclear.
This systematic review was registered in PROSPERO (CRD42024563757). We searched four databases using a combination of keywords that contained various intravenous thrombolytics, as well as acute ischemic stroke. Only data from participants with AIS treated with various intravenous thrombolytics within the 4.5-h time window were included. Among initially identified studies, 16 met the selection criteria. Network meta-analysis was conducted for efficacy (90 day modified Rankin scale score) and safety (intracranial hemorrhage events, mortality at 90 days) using Stata 17.0 software, with a fixed-effects model. Cochrane risk of bias tool assessed all risk of bias domains, and the CINeMA Evidence Assessment Tool evaluated the level of evidence for each outcome.
A total of 9056 studies were retrieved through the literature search, and 12,792 patients screened from 16 randomized controlled trials were included in the network meta-analysis. The risk of bias in the included studies ranged from moderate to low. The network meta-analysis results indicated that reteplase at 18 + 18 mg ranked highest in efficacy, though its safety was lower compared to 0.25 mg/kg tenecteplase and alteplase. The dose of 0.25 mg/kg tenecteplase emerged as the optimal dose, demonstrating both superior efficacy and a lower risk of bleeding compared to alteplase, making it a potential alternative to alteplase. The dose of 50 mg prourokinase was associated with the highest risk of symptomatic intracranial hemorrhage and was inferior to reteplase in terms of both efficacy and safety. The CINeMA Evidence Assessment Tool identified one outcome with a high level of evidence, several with moderate levels, and the remainder with low levels.
Reteplase at 18 + 18 mg may be more suitable for patients with lower incidence of adverse events evaluated by physicians. Compared to 0.9 mg/kg alteplase, 0.25 mg/kg tenecteplase is more effective, with the lowest risk of intracranial hemorrhage. However, as tenecteplase's dosages increase (0.32 mg/kg and 0.4 mg/kg), its efficacy in improving neurological deficits decreases, while the risk of intracranial hemorrhage and death (especially at 0.4 mg/kg) increases. Clinicians are supposed to carefully assess the needs of patients with AIS and the risks then choose decent thrombolytics.
目前，关于不同剂量的各种溶栓药物治疗急性缺血性卒中（AIS）的疗效和安全性的证据有限。从目前的随机临床试验来看，AIS患者溶栓药物的最佳类型和剂量尚不清楚。
本系统评价已在国际前瞻性系统评价注册库（PROSPERO，注册号：CRD42024563757）登记。我们使用包含各种静脉溶栓药物以及急性缺血性卒中的关键词组合检索了四个数据库。仅纳入在4.5小时时间窗内接受各种静脉溶栓药物治疗的AIS参与者的数据。在最初确定的研究中，16项符合入选标准。使用Stata 17.0软件，采用固定效应模型，对疗效（90天改良Rankin量表评分）和安全性（颅内出血事件、90天死亡率）进行网络荟萃分析。Cochrane偏倚风险工具评估所有偏倚风险领域，CINeMA证据评估工具评估每个结局的证据水平。
通过文献检索共检索到9056项研究，16项随机对照试验筛选出的12792例患者纳入网络荟萃分析。纳入研究的偏倚风险从中度到低度不等。网络荟萃分析结果表明，18 + 18 mg的瑞替普酶疗效排名最高，但其安全性低于0.25 mg/kg的替奈普酶和阿替普酶。0.25 mg/kg的替奈普酶剂量成为最佳剂量，与阿替普酶相比，疗效更优且出血风险更低，使其成为阿替普酶的潜在替代药物。50 mg的普洛激酶剂量与有症状颅内出血的最高风险相关，在疗效和安全性方面均不如瑞替普酶。CINeMA证据评估工具确定一项结局证据水平高，几项为中等水平，其余为低水平。
18 + 18 mg的瑞替普酶可能更适合医生评估不良事件发生率较低的患者。与0.9 mg/kg的阿替普酶相比，0.25 mg/kg的替奈普酶更有效，颅内出血风险最低。然而，随着替奈普酶剂量增加（0.32 mg/kg和0.4 mg/kg），其改善神经功能缺损的疗效降低，而颅内出血和死亡风险（尤其是0.4 mg/kg时）增加。临床医生应仔细评估AIS患者的需求和风险，然后选择合适的溶栓药物。
