Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke

Werner Hacke; Markku Kaste; Erich Bluhmki; Miroslav Brozman; Antoni Dávalos; Donata Guidetti; Vincent Larrue; Kennedy R Lees; Zakaria Medeghri; Thomas Machnig; Dietmar Schneider; Rüdiger von Kummer; Nils Wahlgren; Danilo Toni; ECASS Investigators; Helle Klingenberg Iversen

doi:10.1056/NEJMoa0804656

Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke

Werner Hacke, Markku Kaste, Erich Bluhmki, Miroslav Brozman, Antoni Dávalos, Donata Guidetti, Vincent Larrue, Kennedy R Lees, Zakaria Medeghri, Thomas Machnig, Dietmar Schneider, Rüdiger von Kummer, Nils Wahlgren, Danilo Toni, ECASS Investigators, Helle Klingenberg Iversen

Institut for Klinisk Medicin

4394 Citationer (Scopus)

Abstract

BACKGROUND: Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.

METHODS: After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.

RESULTS: We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.

CONCLUSIONS: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)

Originalsprog	Engelsk
Tidsskrift	New England Journal of Medicine
Vol/bind	359
Udgave nummer	13
Sider (fra-til)	1317-29
Antal sider	13
ISSN	0028-4793
DOI	https://doi.org/10.1056/NEJMoa0804656
Status	Udgivet - 25 sep. 2008

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10.1056/NEJMoa0804656

Citationsformater

Hacke, W., Kaste, M., Bluhmki, E., Brozman, M., Dávalos, A., Guidetti, D., Larrue, V., Lees, K. R., Medeghri, Z., Machnig, T., Schneider, D., von Kummer, R., Wahlgren, N., Toni, D., ECASS Investigators, & Iversen, H. K. (2008). Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. New England Journal of Medicine, 359(13), 1317-29. https://doi.org/10.1056/NEJMoa0804656

Hacke, W, Kaste, M, Bluhmki, E, Brozman, M, Dávalos, A, Guidetti, D, Larrue, V, Lees, KR, Medeghri, Z, Machnig, T, Schneider, D, von Kummer, R, Wahlgren, N, Toni, D, ECASS Investigators & Iversen, HK 2008, 'Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke', New England Journal of Medicine, bind 359, nr. 13, s. 1317-29. https://doi.org/10.1056/NEJMoa0804656

@article{18f1ae8ba38f44f28e825c20d266c860,

title = "Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke",

abstract = "BACKGROUND: Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.METHODS: After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.RESULTS: We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.CONCLUSIONS: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)",

keywords = "Acute Disease, Adult, Aged, Brain Ischemia, Double-Blind Method, Drug Administration Schedule, Female, Fibrinolytic Agents, Humans, Infusions, Intravenous, Intracranial Hemorrhages, Logistic Models, Male, Middle Aged, Odds Ratio, Stroke, Time Factors, Tissue Plasminogen Activator, Treatment Outcome",

author = "Werner Hacke and Markku Kaste and Erich Bluhmki and Miroslav Brozman and Antoni D{\'a}valos and Donata Guidetti and Vincent Larrue and Lees, {Kennedy R} and Zakaria Medeghri and Thomas Machnig and Dietmar Schneider and {von Kummer}, R{\"u}diger and Nils Wahlgren and Danilo Toni and {ECASS Investigators} and Iversen, {Helle Klingenberg}",

note = "2008 Massachusetts Medical Society",

year = "2008",

month = sep,

day = "25",

doi = "10.1056/NEJMoa0804656",

language = "English",

volume = "359",

pages = "1317--29",

journal = "New England Journal of Medicine",

issn = "0028-4793",

publisher = "Massachusetts Medical Society",

number = "13",

}

TY - JOUR

T1 - Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke

AU - Hacke, Werner

AU - Kaste, Markku

AU - Bluhmki, Erich

AU - Brozman, Miroslav

AU - Dávalos, Antoni

AU - Guidetti, Donata

AU - Larrue, Vincent

AU - Lees, Kennedy R

AU - Medeghri, Zakaria

AU - Machnig, Thomas

AU - Schneider, Dietmar

AU - von Kummer, Rüdiger

AU - Wahlgren, Nils

AU - Toni, Danilo

AU - ECASS Investigators

AU - Iversen, Helle Klingenberg

N1 - 2008 Massachusetts Medical Society

PY - 2008/9/25

Y1 - 2008/9/25

N2 - BACKGROUND: Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.METHODS: After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.RESULTS: We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.CONCLUSIONS: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)

AB - BACKGROUND: Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.METHODS: After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.RESULTS: We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.CONCLUSIONS: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)

KW - Acute Disease

KW - Adult

KW - Aged

KW - Brain Ischemia

KW - Double-Blind Method

KW - Drug Administration Schedule

KW - Female

KW - Fibrinolytic Agents

KW - Humans

KW - Infusions, Intravenous

KW - Intracranial Hemorrhages

KW - Logistic Models

KW - Male

KW - Middle Aged

KW - Odds Ratio

KW - Stroke

KW - Time Factors

KW - Tissue Plasminogen Activator

KW - Treatment Outcome

U2 - 10.1056/NEJMoa0804656

DO - 10.1056/NEJMoa0804656

M3 - Journal article

C2 - 18815396

SN - 0028-4793

VL - 359

SP - 1317

EP - 1329

JO - New England Journal of Medicine

JF - New England Journal of Medicine

IS - 13

ER -

Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke

Abstract

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