Background 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. Methods 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. Results 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). Conclusions 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 .).
AD - 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 Neurologicas, 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 Neuroscience Institute, University of Cincinnati Academic Health Center, Cincinnati (J.P.B.); the Division of Neurology, Department of Medicine, National University Hospital and School of Medicine, National University of Singapore, Singapore (V.K.S.); the Department of Neurology, University of Ulsan, Asan Medical Center, Seoul, South Korea (J.S.K.); the Department of Cerebrovascular Disease, People's 115 Hospital, Ho Chi Minh City, Vietnam (N.H.T.); Calgary Stroke Program, Department of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada (A.M.D.); the Stroke Division of Neurology Service, Hospital de Clinicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre (S.M.), and the Stroke Service, Neurology Division, Department of Neuroscience and Behavior, Ribeirao Preto School of Medicine, University of Sao Paulo, Sao Paulo (O.M.P.-N.) - both in Brazil; the Neurovascular Sciences Group, Neurosciences Department, Bucaramanga, Colombia (F.S.); Unita Operativa de Neurologia, USL Umbria 1, Sedi di Citta di Castello e Branca, Italy (S.R.); the Department of Neurology, Christian Medical College, Ludhiana, India (J.P.); and the Department of Epidemiology, Johns Hopkins University, Baltimore (M.W.). AN - 27161018 BT - New England Journal of Medicine. DP - NLM ET - 2016/05/11 LA - Eng LB - AUSBackground 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. Methods 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. Results 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). Conclusions 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 .).
PY - 2016 SN - 1533-4406 (Electronic)