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

EXTEND Investigators, Graeme Hankey

Research output: Contribution to journalArticle

Abstract

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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 ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

Original languageEnglish
Pages (from-to)1795-1803
Number of pages9
JournalThe New England Journal of Medicine
Volume380
Issue number19
DOIs
Publication statusPublished - 9 May 2019

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Perfusion Imaging
Stroke
Tissue Plasminogen Activator
Placebos
Odds Ratio
Cerebral Hemorrhage
Brain
Confidence Intervals
Neurologic Manifestations
Publications
Biomedical Research
Sleep
Randomized Controlled Trials

Cite this

@article{977044624dfe4f558e28a1e0bd2ad3bf,
title = "Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke",
abstract = "BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: 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 ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).",
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author = "{EXTEND Investigators} and Henry Ma and Campbell, {Bruce C V} and Parsons, {Mark W} and Leonid Churilov and Levi, {Christopher R} and Chung Hsu and Kleinig, {Timothy J} and Tissa Wijeratne and Sami Curtze and Dewey, {Helen M} and Ferdinand Miteff and Chon-Haw Tsai and Jiunn-Tay Lee and Phan, {Thanh G} and Neil Mahant and Mu-Chien Sun and Martin Krause and Jonathan Sturm and Rohan Grimley and Chih-Hung Chen and Chaur-Jong Hu and Wong, {Andrew A} and Deborah Field and Yu Sun and Barber, {P Alan} and Arman Sabet and Jim Jannes and Jiann-Shing Jeng and Benjamin Clissold and Romesh Markus and Ching-Huang Lin and Li-Ming Lien and Bladin, {Christopher F} and S{\o}ren Christensen and Nawaf Yassi and Gagan Sharma and Andrew Bivard and Desmond, {Patricia M} and Bernard Yan and Mitchell, {Peter J} and Vincent Thijs and Leeanne Carey and Atte Meretoja and Davis, {Stephen M} and Donnan, {Geoffrey A} and Graeme Hankey",
year = "2019",
month = "5",
day = "9",
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Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke. / EXTEND Investigators ; Hankey, Graeme.

In: The New England Journal of Medicine, Vol. 380, No. 19, 09.05.2019, p. 1795-1803.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Thrombolysis Guided by Perfusion Imaging up to 9 Hours after Onset of Stroke

AU - EXTEND Investigators

AU - Ma, Henry

AU - Campbell, Bruce C V

AU - Parsons, Mark W

AU - Churilov, Leonid

AU - Levi, Christopher R

AU - Hsu, Chung

AU - Kleinig, Timothy J

AU - Wijeratne, Tissa

AU - Curtze, Sami

AU - Dewey, Helen M

AU - Miteff, Ferdinand

AU - Tsai, Chon-Haw

AU - Lee, Jiunn-Tay

AU - Phan, Thanh G

AU - Mahant, Neil

AU - Sun, Mu-Chien

AU - Krause, Martin

AU - Sturm, Jonathan

AU - Grimley, Rohan

AU - Chen, Chih-Hung

AU - Hu, Chaur-Jong

AU - Wong, Andrew A

AU - Field, Deborah

AU - Sun, Yu

AU - Barber, P Alan

AU - Sabet, Arman

AU - Jannes, Jim

AU - Jeng, Jiann-Shing

AU - Clissold, Benjamin

AU - Markus, Romesh

AU - Lin, Ching-Huang

AU - Lien, Li-Ming

AU - Bladin, Christopher F

AU - Christensen, Søren

AU - Yassi, Nawaf

AU - Sharma, Gagan

AU - Bivard, Andrew

AU - Desmond, Patricia M

AU - Yan, Bernard

AU - Mitchell, Peter J

AU - Thijs, Vincent

AU - Carey, Leeanne

AU - Meretoja, Atte

AU - Davis, Stephen M

AU - Donnan, Geoffrey A

AU - Hankey, Graeme

PY - 2019/5/9

Y1 - 2019/5/9

N2 - BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: 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 ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

AB - BACKGROUND: 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.METHODS: 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.RESULTS: 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.CONCLUSIONS: 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 ClinicalTrials.gov numbers, NCT00887328 and NCT01580839.).

KW - Aged

KW - Aged, 80 and over

KW - Brain/diagnostic imaging

KW - Brain Ischemia/diagnostic imaging

KW - Cerebral Hemorrhage/chemically induced

KW - Computed Tomography Angiography

KW - Female

KW - Fibrinolytic Agents/adverse effects

KW - Humans

KW - Infusions, Intravenous

KW - Magnetic Resonance Angiography

KW - Male

KW - Middle Aged

KW - Nervous System Diseases/epidemiology

KW - Perfusion Imaging

KW - Stroke/diagnostic imaging

KW - Therapeutic Equipoise

KW - Time-to-Treatment

KW - Tissue Plasminogen Activator/adverse effects

U2 - 10.1056/NEJMoa1813046

DO - 10.1056/NEJMoa1813046

M3 - Article

VL - 380

SP - 1795

EP - 1803

JO - The New England Journal of Medicine

JF - The New England Journal of Medicine

SN - 0028-4793

IS - 19

ER -