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N Engl J Med. 2019 May 9;380(19):1795-1803. doi: 10.1056/NEJMoa1813046.

Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke.

Collaborators (203)

Donnan GA, Davis SM, Ma H, Churilov L, Campbell BCV, Parsons MW, Yan B, Mitchell PJ, Yassi N, Sharma G, Desmond PM, Oxley TJ, Wu TY, Shah D, Zhao H, Rodrigues E, Salvaris P, Alemseged F, Ng F, Williams C, Ng JL, Tu HT, McDonald A, Jackson D, Tsoleridis J, McCoy R, Pesavento L, Weir L, Bivard A, Kleinig TJ, Patel S, Harvey J, Mahadevan J, Cheong E, Balabanski A, Waters M, Drew R, Cranefield J, Wijeratne T, Tu H, Mackey E, Celestino S, Low E, Dewey HM, Bladin CF, Loh PS, Choi PM, Coote S, Frost T, Hogan K, Ding C, McModie S, Zhang WW, Kyndt C, Moore A, Ross Z, Liu J, Miteff F, Levi CR, Ang T, Spratt N, Garcia-Esperon C, Kaauwai L, Phan T, Ly J, Singhal S, Clissold B, Wong K, Krause M, Day S, Sturm J, O'Brian W, Grimley R, Thijs V, Simpson M, Archer ML, Brodtmann A, Ng FC, Coulton B, Young D, Wong AA, Muller C, Field D, Vallat W, Maxwell V, Bailey P, Sabet A, Mishra S, Tan M, George K, Barber PA, Zhao L, Meretoja A, Curtze S, Tatlisumak T, Sibolt G, Tiainen M, Koivu M, Aarnio K, Virta J, Kasari O, Eirola S, Sun MC, Chen TC, Chuang CS, Chen YY, Lin CM, Ho SC, Hsiao PM, Tsai CH, Huang WS, Yang YW, Huang HY, Wang WC, Liu CH, Lu MK, Lu CH, Kung WL, Jiang SK, Wu YH, Huang SC, Tseng CH, Tseng LT, Guo YC, Lin D, Hsu CT, Kuan CW, Hsu JP, Tsai HT, Suzuki M, Sun Y, Chen HF, Lu CJ, Liu CH, Lin CH, Huang CC, Chu HJ, Lee CY, Chang WH, Lo YC, Lin CH, Hsu YT, Chen CH, Sung PS, Ysai CL, Jeng JS, Tang SC, Tsai LK, Yeh SJ, Lee YC, Wang YT, Chung TC, Hu CJ, Chan L, Chiou YW, Lien LM, Yeh HL, Yeh JH, Chen WH, Lau CL, Chang A, Lee IY, Huang MY, Lee JT, Peng GS, Lim JC, Hsu YD, Lin CC, Cheng CA, Yen CH, Yang FC, Hsu CH, Sung YF, Tsai CK, Tsai CL, Lee A, Hankey G, Blacker D, Gerraty R, Chen CI, Hsu CS, Cowley E, Sallaberger M, Snow B, Kolbe J, Stark R, King J, Macdonnell R, Attia J, D'Este C, Bernhardt J, Carey L, Cadilhac D, Anderson C, Hankey G, Howells D, Barber A, Connelly A, Levi C, Macleod M, O'Collins V, Wilson W, Macaulay L.

Author information

From Florey Institute of Neuroscience and Mental Health (H.M., L. Churilov, N.Y., V.T., L. Carey, A.M., G.A.D.), the Department of Medicine and Neurology, Melbourne Brain Centre at the Royal Melbourne Hospital (B.C.V.C., M.W.P., L. Churilov, S. Christensen, N.Y., G.S., A.B., B.Y., A.M., S.M.D., G.A.D.), and the Department of Radiology, Royal Melbourne Hospital (P.M.D., B.Y., P.J.M.), University of Melbourne, Parkville, the Department of Medicine, School of Clinical Science, Monash University, Clayton (H.M., T.G.P.), the Departments of Medicine and Neurology, Melbourne Medical School, University of Melbourne and Western Health, Sunshine Hospital, St. Albans (T.W.), the Department of Neurosciences, Eastern Health and Eastern Health Clinical School, Monash University, Box Hill (H.M.D., C.F.B.), the Department of Neurology, University Hospital Geelong, Deakin University, Geelong (B.C.), the Department of Neurology, Austin Hospital, Austin Health, Heidelberg (V.T.), and Occupational Therapy, School of Allied Health, College of Science, Health and Engineering, La Trobe University, Bundoora (L. Carey), VIC, the Department of Neurology, Priority Research Centre for Brain and Mental Health Research, John Hunter Hospital (C.R.L., F.M.), University of Newcastle (J.S.), Newcastle, the Department of Neurology, Westmead Hospital (N.M.), the Department of Neurology, Royal North Shore Hospital and Kolling Institute, University of Sydney (M.K.), and the Department of Neurology, St. Vincent's Hospital Sydney (R.M.), Sydney, and the Department of Neurology, Gosford Hospital, Gosford (J.S.), NSW, the Department of Neurology, Royal Adelaide Hospital (T.J.K., J.J.), the Department of Neurology, Lyell McEwin Hospital (D.F.), and the Department of Neurology, Queen Elizabeth Hospital (J.J.), Adelaide, SA, the Department of Medicine, Sunshine Coast University Hospital, Nambour (R.G.), the Department of Neurology, Royal Brisbane and Women's Hospital and the University of Queensland, Brisbane (A.A.W.), and the Department of Neurology, Gold Coast University Hospital, Southport (A.S.), and Australia and Griffith University, Gold Coast (A.S.), QLD - all in Australia; the Graduate Institute of Clinical Medical Science (C.H.) and the School of Medicine (C.-H.T.), China Medical University, and the Department of Neurology, China Medical University Hospital (C.-H.T.), Taichung, the Department of Neurology, Tri-Service General Hospital, National Defense Medical Center (J.-T.L.), the Department of Neurology, Shuang Ho Hospital (C.-J.H.), the Department of Neurology, En Chu Kong Hospital (Y.S.), the Stroke Center and Department of Neurology, National Taiwan University Hospital (J.-S.J.), and the Department of Neurology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei Medical University College of Medicine (L.-M.L.), Taipei, the Stroke Center and Department of Neurology, Changhua Christian Hospital, Changhua (M.-C.S.), the Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan (C.-H.C.), and the Department of Neurology, Kaohsiung Veterans General Hospital, Kaohsiung (C.-H.L.) - all in Taiwan; the Department of Neurology, Helsinki University Hospital, Helsinki (S. Curtze, A.M.); the Department of Neurology, Auckland City Hospital, University of Auckland, Auckland, New Zealand (P.A.B.); and the Stanford Stroke Center, Stanford University, Stanford, CA (S. Christensen).



The time to initiate intravenous thrombolysis for acute ischemic stroke is generally limited to within 4.5 hours after the onset of symptoms. Some trials have suggested that the treatment window may be extended in patients who are shown to have ischemic but not yet infarcted brain tissue on imaging.


We conducted a multicenter, randomized, placebo-controlled trial involving patients with ischemic stroke who had hypoperfused but salvageable regions of brain detected on automated perfusion imaging. The patients were randomly assigned to receive intravenous alteplase or placebo between 4.5 and 9.0 hours after the onset of stroke or on awakening with stroke (if within 9 hours from the midpoint of sleep). The primary outcome was a score of 0 or 1 on the modified Rankin scale, on which scores range from 0 (no symptoms) to 6 (death), at 90 days. The risk ratio for the primary outcome was adjusted for age and clinical severity at baseline.


After 225 of the planned 310 patients had been enrolled, the trial was terminated because of a loss of equipoise after the publication of positive results from a previous trial. A total of 113 patients were randomly assigned to the alteplase group and 112 to the placebo group. The primary outcome occurred in 40 patients (35.4%) in the alteplase group and in 33 patients (29.5%) in the placebo group (adjusted risk ratio, 1.44; 95% confidence interval [CI], 1.01 to 2.06; P = 0.04). Symptomatic intracerebral hemorrhage occurred in 7 patients (6.2%) in the alteplase group and in 1 patient (0.9%) in the placebo group (adjusted risk ratio, 7.22; 95% CI, 0.97 to 53.5; P = 0.05). A secondary ordinal analysis of the distribution of scores on the modified Rankin scale did not show a significant between-group difference in functional improvement at 90 days.


Among the patients in this trial who had ischemic stroke and salvageable brain tissue, the use of alteplase between 4.5 and 9.0 hours after stroke onset or at the time the patient awoke with stroke symptoms resulted in a higher percentage of patients with no or minor neurologic deficits than the use of placebo. There were more cases of symptomatic cerebral hemorrhage in the alteplase group than in the placebo group. (Funded by the Australian National Health and Medical Research Council and others; EXTEND numbers, NCT00887328 and NCT01580839.).

[Indexed for MEDLINE]

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