Hacke Werner, Furlan Anthony J, Al-Rawi Yasir, Davalos Antoni, Fiebach Jochen B, Gruber Franz, Kaste Markku, Lipka Leslie J, Pedraza Salvador, Ringleb Peter A, Rowley Howard A, Schneider Dietmar, Schwamm Lee H, Leal Joaquin Serena, Söhngen Mariola, Teal Phil A, Wilhelm-Ogunbiyi Karin, Wintermark Max, Warach Steven
Department of Neurology, University of Heidelberg, Heidelberg, Germany.
Lancet Neurol. 2009 Feb;8(2):141-50. doi: 10.1016/S1474-4422(08)70267-9. Epub 2008 Dec 25.
Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI).
In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 microg/kg desmoteplase, 125 microg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852.
Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 microg/kg desmoteplase; 66 received 125 microg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10.6 cm(3) and 52.5 cm(3), respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 microg/kg desmoteplase, 36% (24 of 66) for 125 microg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 microg/kg desmoteplase 14.0% (0.5 cm(3)); 125 microg/kg desmoteplase 10.8% (0.3 cm(3)); placebo -10.0% (-0.9 cm(3)). The rates of symptomatic intracranial haemorrhage were 3.5% (2 of 57) for 90 microg/kg desmoteplase, 4.5% (3 of 66) for 125 microg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 microg/kg desmoteplase; 21% [14 of 66] for 125 microg/kg desmoteplase; and 6% [4 of 63] for placebo).
The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase.
PAION Deutschland GmbH; Forest Laboratories.
既往研究表明，新型纤溶酶原激活剂去氨普酶在经磁共振灌注成像（PI）和弥散加权成像（DWI）确定有假定风险组织的中风患者症状发作后3 - 9小时给药具有临床益处。
在这项随机、安慰剂对照、双盲、剂量范围研究中，急性缺血性中风且在MRI或CT成像上显示有风险组织的患者在中风症状发作后3 - 9小时内被随机分配（1:1:1）接受90微克/千克去氨普酶、125微克/千克去氨普酶或安慰剂治疗。主要终点是90天时的临床反应率，定义为美国国立卫生研究院卒中量表（NIHSS）评分改善8分或更多或NIHSS评分为1分或更低、改良Rankin量表评分为0 - 2分以及Barthel指数为75 - 100的综合指标。次要终点包括基线至30天时病变体积的变化、有症状性颅内出血的发生率和死亡率。分析采用意向性治疗。本研究已在ClinicalTrials.gov注册，注册号为NCT00111852。
在2005年6月至2007年3月期间，193例患者被随机分组，186例患者接受了治疗：57例接受90微克/千克去氨普酶治疗；66例接受125微克/千克去氨普酶治疗；63例接受安慰剂治疗。158例患者完成了研究。基线NIHSS评分中位数为9分（四分位间距6 - 14分），30%（179例中的53例）患者在就诊时有可见血管闭塞。核心病变和不匹配体积较小（中位数体积分别为10.6立方厘米和52.5立方厘米）。90微克/千克去氨普酶组90天时的临床反应率为47%（57例中的27例），125微克/千克去氨普酶组为36%（66例中的24例），安慰剂组为46%（63例中的29例）。病变体积的中位数变化为：90微克/千克去氨普酶组为14.0%（0.5立方厘米）；125微克/千克去氨普酶组为10.8%（0.3立方厘米）；安慰剂组为 - 10.0%（ - 0.9立方厘米）。有症状性颅内出血的发生率在90微克/千克去氨普酶组为3.5%（57例中的2例），125微克/千克去氨普酶组为4.5%（66例中的3例），安慰剂组为0%。总体死亡率为11%（90微克/千克去氨普酶组为5%[57例中的3例]；125微克/千克去氨普酶组为21%[66例中的14例]；安慰剂组为6%[63例中的4例]）。
DIAS - 2研究未显示中风发作后3 - 9小时给予去氨普酶有获益。安慰剂组的高反应率可能是由于记录的中风症状较轻（基线NIHSS评分低、核心病变小以及与无血管闭塞相关的不匹配体积小）导致，这可能降低了检测去氨普酶任何效应的可能性。
PAION Deutschland GmbH；Forest Laboratories。
