Thompson G Robinson1, Xia Wang1, Hisatomi Arima1, Philip M Bath1, Laurent Billot1, Joseph P Broderick1, Andrew M Demchuk1, Geoffery A Donnan1, Jong S Kim1, Pablo M Lavados1, Tsong-Hai Lee1, Richard I Lindley1, Sheila C O Martins1, Veronica V Olavarria1, Jeyaraj D Pandian1, Mark W Parsons1, Octavio M Pontes-Neto1, Stefano Ricci1, Shoichiro Sato1, Vijay K Sharma1, Thang H Nguyen1, Ji-Guang Wang1, Mark Woodward1, John Chalmers1, Craig S Anderson2. 1. From the Department of Cardiovascular Sciences, National Institute for Health Research Biomedical Research Unit, University of Leicester, (T.G.R.); George Institute for Global Health, Neurological and Mental Health Division (X.W., H.A., L.B., R.I.L., M.W., J.C., C.S.A.), Faculty of Medicine, University of New South Wales (X.W., H.A., L.B., M.W., J.C., C.S.A.), and Department of Geriatric Medicine, Westmead Clinical School (R.I.L.), University of Sydney, Australia; Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, United Kingdom (P.M.B.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati Neuroscience Institute (J.P.B.); Departments of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary, Canada (A.M.D.); Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia (G.A.D.); Department of Neurology, Asan Medical Center, University of Ulsan, Seoul, Korea (J.S.K.); Department of Neurology and Psychiatry, Clinica Alemana de Santiago, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Chile (P.M.L., V.V.O.); Departamento de Ciencias Neurológicas, Facultad de Medicina, Universidad de Chile, Santiago (P.M.L.); Department of Neurology, Stroke Center, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan (T.-H.L.); Stroke Division of Neurology Service, Hospital de Clinicas de Porto Alegre, University of Rio Grande do Sul, Brazil (S.C.O.M.); Department of Neurology, Christian Medical College, Ludhiana, Punjab, India (J.D.P.); Department of Neurology, John Hunter Hospital, University of Newcastle, Australia (M.W.P.); Department of Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Brazil (O.M.P.-N.); Uo Neurologia, USL Umbria 1, Sedi di Citta di Castello e Branca, Italy (S.R.); Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (S.S.); Yong Loo Lin School of Medicine, National University of Singapore (V.K.S.); Division of Neurology, National University Hospital, Singapore (V.K.S.); Department of Cerebrovascular Disease, 115 People's Hospital, Ho Chi Minh City, Vietnam (T.H.N.); The Shanghai Institute for Hypertension, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, China (J.-G.W.); Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.); George Institute for Global Health, University of Oxford, United Kingdom (M.W.); Department of Neurology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.S.A.); and The George Institute China, Peking University Health Sciences Center, Beijing (C.S.A.). 2. From the Department of Cardiovascular Sciences, National Institute for Health Research Biomedical Research Unit, University of Leicester, (T.G.R.); George Institute for Global Health, Neurological and Mental Health Division (X.W., H.A., L.B., R.I.L., M.W., J.C., C.S.A.), Faculty of Medicine, University of New South Wales (X.W., H.A., L.B., M.W., J.C., C.S.A.), and Department of Geriatric Medicine, Westmead Clinical School (R.I.L.), University of Sydney, Australia; Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, United Kingdom (P.M.B.); Department of Neurology and Rehabilitation Medicine, University of Cincinnati Neuroscience Institute (J.P.B.); Departments of Clinical Neurosciences and Radiology, Hotchkiss Brain Institute, University of Calgary, Canada (A.M.D.); Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia (G.A.D.); Department of Neurology, Asan Medical Center, University of Ulsan, Seoul, Korea (J.S.K.); Department of Neurology and Psychiatry, Clinica Alemana de Santiago, Facultad de Medicina, Clinica Alemana Universidad del Desarrollo, Chile (P.M.L., V.V.O.); Departamento de Ciencias Neurológicas, Facultad de Medicina, Universidad de Chile, Santiago (P.M.L.); Department of Neurology, Stroke Center, Linkou Chang Gung Memorial Hospital and College of Medicine, Chang Gung University, Taoyuan, Taiwan (T.-H.L.); Stroke Division of Neurology Service, Hospital de Clinicas de Porto Alegre, University of Rio Grande do Sul, Brazil (S.C.O.M.); Department of Neurology, Christian Medical College, Ludhiana, Punjab, India (J.D.P.); Department of Neurology, John Hunter Hospital, University of Newcastle, Australia (M.W.P.); Department of Neurosciences and Behavioral Sciences, Ribeirao Preto Medical School, University of Sao Paulo, Brazil (O.M.P.-N.); Uo Neurologia, USL Umbria 1, Sedi di Citta di Castello e Branca, Italy (S.R.); Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan (S.S.); Yong Loo Lin School of Medicine, National University of Singapore (V.K.S.); Division of Neurology, National University Hospital, Singapore (V.K.S.); Department of Cerebrovascular Disease, 115 People's Hospital, Ho Chi Minh City, Vietnam (T.H.N.); The Shanghai Institute for Hypertension, Rui Jin Hospital, Shanghai Jiaotong University School of Medicine, China (J.-G.W.); Department of Epidemiology, Johns Hopkins University, Baltimore, MD (M.W.); George Institute for Global Health, University of Oxford, United Kingdom (M.W.); Department of Neurology, Royal Prince Alfred Hospital, Sydney, New South Wales, Australia (C.S.A.); and The George Institute China, Peking University Health Sciences Center, Beijing (C.S.A.). canderson@georgeinstitute.org.au.
Abstract
BACKGROUND AND PURPOSE: Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS: Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2-6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria. RESULTS: There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01; 95% confidence interval [CI], 0.81-1.26; P=0.953), 3 to 6 (OR, 0.95; 95% CI, 0.75-1.20; P=0.662), or ordinal mRS shift (OR, 1.03; 95% CI, 0.87-1.21; P=0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82; 95% CI, 1.00-3.30; P=0.051) according to the safe implementation of thrombolysis in stroke-monitoring study definition. Although not significant (P-trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2-6; OR, 0.84; 95% CI, 0.62-1.12 versus OR, 1.16; 95% CI, 0.99-1.36). CONCLUSIONS:Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic stroke patients on prior APT, but this requires further evaluation in a randomized controlled trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616.
RCT Entities:
BACKGROUND AND PURPOSE: Many patients receiving thrombolysis for acute ischemic stroke are on prior antiplatelet therapy (APT), which may increase symptomatic intracerebral hemorrhage risk. In a prespecified subgroup analysis, we report comparative effects of different doses of intravenous alteplase according to prior APT use among participants of the international multicenter ENCHANTED study (Enhanced Control of Hypertension and Thrombolysis Stroke Study). METHODS: Among 3285 alteplase-treated patients (mean age, 66.6 years; 38% women) randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 hours of symptom onset, 752 (22.9%) reported prior APT use. Primary outcome at 90 days was the combined end point of death or disability (modified Rankin Scale [mRS] scores, 2-6). Other outcomes included mRS scores 3 to 6, ordinal mRS shift, and symptomatic intracerebral hemorrhage by various standard criteria. RESULTS: There were no significant differences in outcome between patients with and without prior APT after adjustment for baseline characteristics and management factors during the first week; defined by mRS scores 2 to 6 (adjusted odds ratio [OR], 1.01; 95% confidence interval [CI], 0.81-1.26; P=0.953), 3 to 6 (OR, 0.95; 95% CI, 0.75-1.20; P=0.662), or ordinal mRS shift (OR, 1.03; 95% CI, 0.87-1.21; P=0.770). Alteplase-treated patients on prior APT had higher symptomatic intracerebral hemorrhage (OR, 1.82; 95% CI, 1.00-3.30; P=0.051) according to the safe implementation of thrombolysis in stroke-monitoring study definition. Although not significant (P-trend, 0.053), low-dose alteplase tended to have better outcomes than standard-dose alteplase in those on prior APT compared with those not using APT (mRS scores of 2-6; OR, 0.84; 95% CI, 0.62-1.12 versus OR, 1.16; 95% CI, 0.99-1.36). CONCLUSIONS: Low-dose alteplase may improve outcomes in thrombolysis-treated acute ischemic strokepatients on prior APT, but this requires further evaluation in a randomized controlled trial. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01422616.
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