Sugg Rebecca M, Pary Jennifer K, Uchino Ken, Baraniuk Sarah, Shaltoni Hashem M, Gonzales Nicole R, Mikulik Robert, Garami Zsolt, Shaw Sandi G, Matherne Dawn E, Moyé Lemuel A, Alexandrov Andrei V, Grotta James C
Department of Neurology, University of Texas-Houston Medical School, 6431 Fannin, Houston, TX 77030, USA.
Arch Neurol. 2006 Aug;63(8):1057-62. doi: 10.1001/archneur.63.8.1057.
The benefit of intravenous recombinant tissue plasminogen activator (rtPA) in acute stroke is linked to clot lysis and artery recanalization. Argatroban is a direct thrombin inhibitor that safely augments the benefit of rtPA in animal stroke models. There are no human data on this combination.
We report the first phase of the Argatroban tPA Stroke Study, an ongoing prospective, open-label, dose-escalation, safety and activity study of argatroban and rtPA in patients with ischemic stroke. The primary outcome was incidence of intracerebral hemorrhage; secondary outcome, complete recanalization at 2 hours. After standard-dose intravenous rtPA administration, a 100-mug/kg bolus of argatroban followed by infusion of 1 mug/kg per minute for 48 hours was adjusted to a target partial thromboplastin time of 1.75 times that of the control group.
Fifteen patients (including 10 men) were enrolled, with a mean +/- SD age of 61 +/- 13 years. All patients had middle cerebral artery occlusions. Baseline median National Institute of Health Stroke Scale score was 14 (range, 4-25). The mean +/- SD time from symptom onset to argatroban bolus administration was 172 +/- 53 minutes. Symptomatic intracerebral hemorrhage occurred in 2 patients, including 1 with parenchymal hemorrhage type 2. Asymptomatic bleeding occurred in 1 patient and there was 1 death. Recanalization was complete in 6 patients and partial in another 4, and reocclusion occurred in 3 within 2 hours of rtPA bolus administration.
The safety of low-dose argatroban combined with intravenous rtPA may be within acceptable limits, and its efficacy for producing fast and complete recanalization is promising, but a larger cohort of patients is required to confirm these preliminary observations.
静脉注射重组组织型纤溶酶原激活剂（rtPA）治疗急性卒中的益处与血栓溶解和动脉再通有关。阿加曲班是一种直接凝血酶抑制剂，在动物卒中模型中可安全增强rtPA的益处。目前尚无关于这种联合用药的人体数据。
我们报告了阿加曲班tPA卒中研究的第一阶段，这是一项正在进行的前瞻性、开放标签、剂量递增、关于阿加曲班和rtPA治疗缺血性卒中患者的安全性和活性研究。主要结局是脑出血的发生率；次要结局是2小时时的完全再通。在静脉注射标准剂量rtPA后，给予100μg/kg阿加曲班静脉推注，随后以每分钟1μg/kg的速度输注48小时，将活化部分凝血活酶时间调整至对照组的1.75倍。
共纳入15例患者（包括10例男性），平均年龄为61±13岁。所有患者均为大脑中动脉闭塞。基线时美国国立卫生研究院卒中量表评分中位数为14分（范围4 - 25分）。从症状发作到给予阿加曲班静脉推注的平均时间为172±53分钟。2例患者发生有症状脑出血，其中1例为2型实质内出血。1例患者发生无症状出血，1例患者死亡。6例患者实现完全再通，另外4例部分再通，3例在rtPA静脉推注后2小时内发生再闭塞。
低剂量阿加曲班联合静脉rtPA的安全性可能在可接受范围内，其快速实现完全再通的疗效很有前景，但需要更大规模的患者队列来证实这些初步观察结果。
