From the George Institute for Global Health (C.S.A., R.I.L., H.A., X.C., L.B., M.W., Q.L., X.W., J.C.) and Sydney Medical School (C.S.A., R.I.L., H.A., X.C., L.B., M.W., Q.L., J.C.), University of Sydney, and the Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners (C.S.A.), Sydney, the Neurology Department, John Hunter Hospital, and Hunter Medical Research Institute, University of Newcastle, Newcastle, NSW (M.W.P., C.L.), and the Florey Institute of Neuroscience and Mental Health, Parkville, VIC (G.A.D.) - all in Australia; the George Institute China, Peking University (C.S.A.), and the Department of Neurology, Peking University First Hospital (Y.H.), Beijing, the Department of Neurology, Xuzhou Central Hospital, Xuzhou (G.C.), the Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou (Y.C.), and the Shanghai Institute of Hypertension, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai (J.W.) - all in China; the University of Leicester, Department of Cardiovascular Sciences and National Institute of Health Research Biomedical Research Unit, Leicester (T.R.), the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham (P.M.B.), the Department of Neurosciences, Royal Stoke University Hospital, Stoke-on-Trent (C.R.), and the George Institute for Global Health, University of Oxford, Oxford (M.W.) - all in the United Kingdom; the Department of Preventive Medicine and Public Health, Faculty of Medicine, Fukuoka University, Fukuoka, Japan (H.A.); Clinica Alemana de Santiago, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo (P.M.L., V.V.O.), and Departamento de Ciencias Neurológicas, Facultad de Medicina, Universidad de Chile (P.M.L.), Santiago, Chile; the Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan (T.-H.L.); the Departments of Neurology and Rehabilitation Medicine and Radiology, University of Cincinnati Neur
N Engl J Med. 2016 Jun 16;374(24):2313-23. doi: 10.1056/NEJMoa1515510. Epub 2016 May 10.
Thrombolytic therapy for acute ischemic stroke with a lower-than-standard dose of intravenous alteplase may improve recovery along with a reduced risk of intracerebral hemorrhage.
Using a 2-by-2 quasi-factorial open-label design, we randomly assigned 3310 patients who were eligible for thrombolytic therapy (median age, 67 years; 63% Asian) to low-dose intravenous alteplase (0.6 mg per kilogram of body weight) or the standard dose (0.9 mg per kilogram); patients underwent randomization within 4.5 hours after the onset of stroke. The primary objective was to determine whether the low dose would be noninferior to the standard dose with respect to the primary outcome of death or disability at 90 days, which was defined by scores of 2 to 6 on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]). Secondary objectives were to determine whether the low dose would be superior to the standard dose with respect to centrally adjudicated symptomatic intracerebral hemorrhage and whether the low dose would be noninferior in an ordinal analysis of modified Rankin scale scores (testing for an improvement in the distribution of scores). The trial included 935 patients who were also randomly assigned to intensive or guideline-recommended blood-pressure control.
The primary outcome occurred in 855 of 1607 participants (53.2%) in the low-dose group and in 817 of 1599 participants (51.1%) in the standard-dose group (odds ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; the upper boundary exceeded the noninferiority margin of 1.14; P=0.51 for noninferiority). Low-dose alteplase was noninferior in the ordinal analysis of modified Rankin scale scores (unadjusted common odds ratio, 1.00; 95% CI, 0.89 to 1.13; P=0.04 for noninferiority). Major symptomatic intracerebral hemorrhage occurred in 1.0% of the participants in the low-dose group and in 2.1% of the participants in the standard-dose group (P=0.01); fatal events occurred within 7 days in 0.5% and 1.5%, respectively (P=0.01). Mortality at 90 days did not differ significantly between the two groups (8.5% and 10.3%, respectively; P=0.07).
This trial involving predominantly Asian patients with acute ischemic stroke did not show the noninferiority of low-dose alteplase to standard-dose alteplase with respect to death and disability at 90 days. There were significantly fewer symptomatic intracerebral hemorrhages with low-dose alteplase. (Funded by the National Health and Medical Research Council of Australia and others; ENCHANTED ClinicalTrials.gov number, NCT01422616.).
急性缺血性脑卒中采用低于标准剂量的静脉注射阿替普酶溶栓治疗可能会改善恢复情况，同时降低脑出血的风险。
采用 2×2 类析因开放标签设计，我们将 3310 名符合溶栓治疗条件的患者（中位年龄 67 岁；63%为亚洲人）随机分为低剂量组（0.6mg/公斤体重）和标准剂量组（0.9mg/公斤体重）；患者在卒中发病后 4.5 小时内进行随机分组。主要终点是确定低剂量是否不劣于标准剂量，以 90 天的主要结局（定义为改良 Rankin 量表评分为 2-6 分[范围 0（无症状）至 6（死亡）]）来衡量死亡率和残疾率。次要终点是确定低剂量是否优于标准剂量，以确定症状性颅内出血的发生率；以及低剂量是否在改良 Rankin 量表评分的有序分析中不劣效（用于评估评分分布的改善）。该试验包括 935 名随机分配到强化或指南推荐的血压控制组的患者。
低剂量组 1607 名参与者中有 855 名（53.2%）和标准剂量组 1599 名参与者中有 817 名（51.1%）发生主要结局（比值比，1.09；95%置信区间[CI]，0.95 至 1.25；上限超过 1.14 的非劣效性边界；P=0.51 表示非劣效性）。低剂量阿替普酶在改良 Rankin 量表评分的有序分析中不劣效（未调整的共同比值比，1.00；95%CI，0.89 至 1.13；P=0.04 表示非劣效性）。低剂量组发生主要症状性颅内出血的比例为 1.0%，标准剂量组为 2.1%（P=0.01）；两组在 7 天内分别有 0.5%和 1.5%的患者发生致死性事件（P=0.01）。90 天死亡率在两组间无显著差异（分别为 8.5%和 10.3%；P=0.07）。
这项涉及主要为亚洲急性缺血性脑卒中患者的试验未显示低剂量阿替普酶与标准剂量阿替普酶在 90 天的死亡率和残疾率方面具有非劣效性。低剂量阿替普酶的症状性颅内出血明显减少。（由澳大利亚国家卫生与医学研究委员会等资助；ENCHANTED ClinicalTrials.gov 编号，NCT01422616。）
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