Davis Stephen M, Donnan Geoffrey A, Parsons Mark W, Levi Christopher, Butcher Kenneth S, Peeters Andre, Barber P Alan, Bladin Christopher, De Silva Deidre A, Byrnes Graham, Chalk Jonathan B, Fink John N, Kimber Thomas E, Schultz David, Hand Peter J, Frayne Judith, Hankey Graeme, Muir Keith, Gerraty Richard, Tress Brian M, Desmond Patricia M
Department of Neurology, Royal Melbourne Hospital, University of Melbourne, Australia.
Lancet Neurol. 2008 Apr;7(4):299-309. doi: 10.1016/S1474-4422(08)70044-9. Epub 2008 Feb 28.
Whether intravenous tissue plasminogen activator (alteplase) is effective beyond 3 h after onset of acute ischaemic stroke is unclear. We aimed to test whether alteplase given 3-6 h after stroke onset promotes reperfusion and attenuates infarct growth in patients who have a mismatch in perfusion-weighted MRI (PWI) and diffusion-weighted MRI (DWI).
We prospectively and randomly assigned 101 patients to receive alteplase or placebo 3-6 h after onset of ischaemic stroke. PWI and DWI were done before and 3-5 days after therapy, with T2-weighted MRI at around day 90. The primary endpoint was infarct growth between baseline DWI and the day 90 T2 lesion in mismatch patients. Major secondary endpoints were reperfusion, good neurological outcome, and good functional outcome. Patients, caregivers, and investigators were unaware of treatment allocations. Primary analysis was per protocol. This study is registered with ClinicalTrials.gov, number NCT00238537.
We randomly assigned 52 patients to alteplase and 49 patients to placebo. Mean age was 71.6 years, and median score on the National Institutes of Health stroke scale was 13. 85 of 99 (86%) patients had mismatch of PWI and DWI. The geometric mean infarct growth (exponential of the mean log of relative growth) was 1.24 with alteplase and 1.78 with placebo (ratio 0.69, 95% CI 0.38-1.28; Student's t test p=0.239); the median relative infarct growth was 1.18 with alteplase and 1.79 with placebo (ratio 0.66, 0.36-0.92; Wilcoxon's test p=0.054). Reperfusion was more common with alteplase than with placebo and was associated with less infarct growth (p=0.001), better neurological outcome (p<0.0001), and better functional outcome (p=0.010) than was no reperfusion.
Alteplase was non-significantly associated with lower infarct growth and significantly associated with increased reperfusion in patients who had mismatch. Because reperfusion was associated with improved clinical outcomes, phase III trials beyond 3 h after treatment are warranted.
急性缺血性卒中发病3小时后静脉注射组织型纤溶酶原激活剂（阿替普酶）是否有效尚不清楚。我们旨在测试卒中发病3 - 6小时后给予阿替普酶是否能促进再灌注并减轻灌注加权磁共振成像（PWI）与扩散加权磁共振成像（DWI）不匹配患者的梗死灶扩大。
我们前瞻性随机分配101例患者在缺血性卒中发病3 - 6小时后接受阿替普酶或安慰剂治疗。在治疗前及治疗后3 - 5天进行PWI和DWI检查，在90天左右进行T2加权磁共振成像检查。主要终点是不匹配患者基线DWI与90天T2病灶之间的梗死灶扩大情况。主要次要终点是再灌注、良好的神经功能结局和良好的功能结局。患者、护理人员和研究人员均不知晓治疗分配情况。主要分析按方案进行。本研究已在ClinicalTrials.gov注册，编号为NCT00238537。
我们随机分配52例患者接受阿替普酶治疗，49例患者接受安慰剂治疗。平均年龄为71.6岁，美国国立卫生研究院卒中量表中位数评分为13分。99例患者中有85例（86%）存在PWI与DWI不匹配。阿替普酶组梗死灶扩大的几何均值（相对生长均值对数的指数）为1.24，安慰剂组为1.78（比值0.69，95%置信区间0.38 - 1.28；学生t检验p = 0.239）；阿替普酶组梗死灶相对生长中位数为1.1与安慰剂组为1.79（比值0.66，0.36 - 0.92；Wilcoxon检验p = 0.054）。与安慰剂相比，阿替普酶组再灌注更常见，且与梗死灶扩大较少（p = 0.001）、神经功能结局更好（p < 0.0001）和功能结局更好（p = 0.010）相关，而非再灌注情况则相反。
阿替普酶与不匹配患者梗死灶生长降低无显著关联，但与再灌注增加显著相关。由于再灌注与临床结局改善相关，因此有必要开展治疗后3小时以上的III期试验。
