脑卒中的溶栓治疗:静脉注射替奈普酶时代

M. Abdoli, Pegah Mohammadi, A. Mowla
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Another study revealed that EVT within 6 to 16 h after onset of AIS symptom could decrease the length hospital stay and improve patient functional outcome [13]. Alteplase is an intravenous recombinant tissue plasminogen activator (rTPA) with a short half-life that needs continuous infusion for about 1 h [14]. Infusion of alteplase as a bridge prior to EVT is still a treatment option for eligible AIS patients with intracranial large vessel occlusions [15-17]. Thus far, alteplase is the only FDA-approved pharmacological treatment for AIS [1, 5, 18]; however, infusion of alteplase has a relatively low rate of recanalization and reperfusion of the large vessel occlusions prior to EVT; hence, it might not be the ideal treatment option [15, 19]. Tenecteplase is a modified form of alteplase with 14-fold more fibrin specificity and enhanced ability for thrombolysis. It also has a longer half-life and 80 times greater resistance to plasminogen activator inhibitor-1 compared to the alteplase; as such, it can be used as an intravenous bolus rather than a bolus followed by 1 h infusion as with alteplase [20]. Single bolus infusion of tenecteplase can give practical benefits to AIS patients who need transportation between hospitals to access EVT [15]. Single bolus infusion of tenecteplase can also reduce the time to receive EVT after the onset of stroke symptoms [16]. Furthermore, according to the information available on drugs.com, in the USA, tenecteplase would cost much less when compared with the alteplase [20]. To the best of our knowledge, at least five randomized clinical trials that compared alteplase with tenecteplase in the treatment of AIS have shown no significant differences in the mortality rate or in the chance of neurological recovery between these two options [15]. Parson et al [18], in a randomized clinical trial on AIS patients who received thrombolytic therapy, found that tenecteplase was superior to alteplase concerning the angiographic outcomes, rate of reperfusion, and also neurological improvement in 24 h. They also showed lower rate of severe disability at 90 days [18]. Campbell et al [15] studied tenecteplase 0.25 mg/kg versus the standard dose of alteplase for patients with AIS within 4.5 h of symptom onset prior to EVT. They reported significantly greater chance of reperfusion of the occluded vessel along with meaningfully better chance of 3-month functional outcome [15, 20]. Concerning the safety outcomes, two of the most recent meta-analyses comparing the efficacy and safety of the both treatment options for AIS, found no statistically significant difference in the rates of intracerebral hemorrhage between the two, but there were tendency toward lower rate of intracerebral hemorrhage with tenecteplase (odds ratio (OR): 0.81, 95% confidence interval (CI): 0.56 1.17; P = 0.26) [14, 21]. When it comes to the administration of the tenecteplase, current evidences advocate that 0.25 mg/kg (maximum 25 mg) is the most appropriate dose. The 0.1 mg/kg dose was not as effective as 0.25 mg/kg dose in the study by Parsons et al [18], and the 0.4 mg/kg dose may result in higher rates of intracerebral hemorrhage as shown by Haley et al [22]. In conclusion, tenecteplase is shown to be as effective as alteplase with respect to functional outcome after treatment of AIS. 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引用次数: 1

摘要

急性缺血性脑卒中(AIS)是一种世界性的健康负担,也是成人致残的主要原因。AIS的管理正在迅速发展。目前,美国食品和药物管理局(FDA)批准的两种AIS治疗方案是在AIS症状出现后4.5小时内使用阿替普酶静脉溶栓(IVT),以及在症状出现后24小时内对颅内大血管中有闭塞血栓的患者进行血管内治疗(EVT),这取决于脑组织的可挽救性[1-10]。一些研究表明,在AIS症状出现后的最初16至24小时内,如果有有利的半暗带而没有大的梗死核心,EVT的潜在益处[11,12]。另一项研究显示,在AIS症状出现后6 ~ 16h内进行EVT可缩短住院时间,改善患者功能预后[13]。阿替普酶是一种静脉注射重组组织型纤溶酶原激活剂(rTPA),半衰期短,需要持续输注约1小时[14]。在EVT前输注阿替普酶作为桥梁仍然是符合条件的AIS颅内大血管闭塞患者的治疗选择[15-17]。迄今为止,阿替普酶是fda批准的唯一治疗AIS的药物[1,5,18];然而,在EVT前输注阿替普酶对大血管闭塞的再通和再灌注率相对较低;因此,它可能不是理想的治疗选择[15,19]。Tenecteplase是阿替普酶的修饰形式,具有14倍的纤维蛋白特异性和增强的溶栓能力。与阿替普酶相比,它的半衰期更长,对纤溶酶原激活物抑制剂-1的抗性高80倍;因此,它可以作为静脉注射剂使用,而不是像阿替普酶那样,先给药1小时后输注[20]。单次输注替奈普酶对需要在医院之间运输才能获得EVT的AIS患者具有实际益处[15]。单次滴注替奈普酶也可缩短卒中症状出现后接受EVT的时间[16]。此外,根据drugs.com上的信息,在美国,与阿替普酶相比,tenecteplase的成本要低得多[20]。据我们所知,至少有五项比较阿替普酶与替奈普酶治疗AIS的随机临床试验显示,这两种治疗方案在死亡率或神经系统恢复机会方面没有显著差异[15]。Parson等[18]在一项接受溶栓治疗的AIS患者的随机临床试验中发现,在血管造影结果、再灌注率和24 h内神经系统改善方面,替奈普酶优于阿替普酶。在90天内,他们的严重残疾率也更低[18]。Campbell等[15]研究了在EVT前症状出现4.5小时内,替普酶0.25 mg/kg与标准剂量替普酶对AIS患者的影响。他们报告闭塞血管再灌注的机会显著增加,3个月功能预后的机会显著增加[15,20]。关于安全性结果,最近的两项荟萃分析比较了两种治疗方案对AIS的疗效和安全性,发现两种治疗方案在脑出血发生率方面没有统计学上的显著差异,但tenecteplase的脑出血发生率有较低的趋势(优势比(OR): 0.81, 95%可信区间(CI): 0.56 1.17;P = 0.26)[14,21]。当涉及到替奈普酶的给药时,目前的证据表明0.25 mg/kg(最大25 mg)是最合适的剂量。在Parsons等[18]的研究中,0.1 mg/kg剂量不如0.25 mg/kg剂量有效,而在Haley等[22]的研究中,0.4 mg/kg剂量可能导致更高的脑出血发生率。总之,就AIS治疗后的功能结果而言,tenecteplase被证明与阿替普酶一样有效。此外,它可以作为静脉注射剂使用,而不是像阿替普酶那样在1小时内注射,这使得它更方便管理,并且与阿替普酶相比,出血风险更低。它也更便宜。卫生保健提供者应考虑在推荐剂量下使用替奈普酶而不是阿替普酶治疗AIS。
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Thrombolytic Therapy for Stroke: Intravenous Tenecteplase Era
Acute ischemic stroke (AIS) is a worldwide health burden and the leading cause of disability in adults. The management of AIS is developing rapidly. Currently, the two Food and Drug Administration (FDA)-approved treatment options for AIS are intravenous thrombolysis (IVT) with alteplase within the first 4.5 h of the AIS symptom onset and endovascular treatment (EVT) in patients with an occlusive clot in one of the intracranial large vessels within the first 24 h of symptom onset depending on the salvageability of the brain tissue [1-10]. Some studies have shown the potential benefit of EVT during the first 16 to 24 h from the AIS symptom onset if there is a favorable penumbra without a large infarct core [11, 12]. Another study revealed that EVT within 6 to 16 h after onset of AIS symptom could decrease the length hospital stay and improve patient functional outcome [13]. Alteplase is an intravenous recombinant tissue plasminogen activator (rTPA) with a short half-life that needs continuous infusion for about 1 h [14]. Infusion of alteplase as a bridge prior to EVT is still a treatment option for eligible AIS patients with intracranial large vessel occlusions [15-17]. Thus far, alteplase is the only FDA-approved pharmacological treatment for AIS [1, 5, 18]; however, infusion of alteplase has a relatively low rate of recanalization and reperfusion of the large vessel occlusions prior to EVT; hence, it might not be the ideal treatment option [15, 19]. Tenecteplase is a modified form of alteplase with 14-fold more fibrin specificity and enhanced ability for thrombolysis. It also has a longer half-life and 80 times greater resistance to plasminogen activator inhibitor-1 compared to the alteplase; as such, it can be used as an intravenous bolus rather than a bolus followed by 1 h infusion as with alteplase [20]. Single bolus infusion of tenecteplase can give practical benefits to AIS patients who need transportation between hospitals to access EVT [15]. Single bolus infusion of tenecteplase can also reduce the time to receive EVT after the onset of stroke symptoms [16]. Furthermore, according to the information available on drugs.com, in the USA, tenecteplase would cost much less when compared with the alteplase [20]. To the best of our knowledge, at least five randomized clinical trials that compared alteplase with tenecteplase in the treatment of AIS have shown no significant differences in the mortality rate or in the chance of neurological recovery between these two options [15]. Parson et al [18], in a randomized clinical trial on AIS patients who received thrombolytic therapy, found that tenecteplase was superior to alteplase concerning the angiographic outcomes, rate of reperfusion, and also neurological improvement in 24 h. They also showed lower rate of severe disability at 90 days [18]. Campbell et al [15] studied tenecteplase 0.25 mg/kg versus the standard dose of alteplase for patients with AIS within 4.5 h of symptom onset prior to EVT. They reported significantly greater chance of reperfusion of the occluded vessel along with meaningfully better chance of 3-month functional outcome [15, 20]. Concerning the safety outcomes, two of the most recent meta-analyses comparing the efficacy and safety of the both treatment options for AIS, found no statistically significant difference in the rates of intracerebral hemorrhage between the two, but there were tendency toward lower rate of intracerebral hemorrhage with tenecteplase (odds ratio (OR): 0.81, 95% confidence interval (CI): 0.56 1.17; P = 0.26) [14, 21]. When it comes to the administration of the tenecteplase, current evidences advocate that 0.25 mg/kg (maximum 25 mg) is the most appropriate dose. The 0.1 mg/kg dose was not as effective as 0.25 mg/kg dose in the study by Parsons et al [18], and the 0.4 mg/kg dose may result in higher rates of intracerebral hemorrhage as shown by Haley et al [22]. In conclusion, tenecteplase is shown to be as effective as alteplase with respect to functional outcome after treatment of AIS. Furthermore, it can be used as an intravenous bolus rather than a bolus followed by 1 h infusion as with alteplase which makes it more convenient to administer and may have lower bleeding risks when compared to alteplase. It is also cheaper. Health care providers should contemplate using tenecteplase rather than alteplase for the treatment of AIS at the recommended dose if available in their centers.
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