Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study

Werner Hacke, Anthony J. Furlan, Yasir Al-Rawi, Antoni Davalos, Jochen B. Fiebach, Franz Gruber, Markku Kaste, Leslie J. Lipka, Salvador Pedraza, Peter A. Ringleb, Howard A. Rowley, Dietmar Schneider, Lee H. Schwamm, Joaquin Serena Leal, Mariola Söhngen, Phil A. Teal, Karin Wilhelm-Ogunbiyi, Max Wintermark, Steven Warach

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Abstract

Background: Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). Methods: In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 μg/kg desmoteplase, 125 μg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. Findings: Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 μg/kg desmoteplase; 66 received 125 μg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10·6 cm3 and 52·5 cm3, respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 μg/kg desmoteplase, 36% (24 of 66) for 125 μg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 μg/kg desmoteplase 14·0% (0·5 cm3); 125 μg/kg desmoteplase 10·8% (0·3 cm3); placebo -10·0% (-0·9 cm3). The rates of symptomatic intracranial haemorrhage were 3·5% (2 of 57) for 90 μg/kg desmoteplase, 4·5% (3 of 66) for 125 μg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 μg/kg desmoteplase; 21% [14 of 66] for 125 μg/kg desmoteplase; and 6% [4 of 63] for placebo). Interpretation: The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. Funding: PAION Deutschland GmbH; Forest Laboratories.

Original languageEnglish (US)
Pages (from-to)141-150
Number of pages10
JournalThe Lancet Neurology
Volume8
Issue number2
DOIs
StatePublished - Feb 2009

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Diffusion Magnetic Resonance Imaging
Perfusion Imaging
Magnetic Resonance Angiography
Stroke
Placebos
National Institutes of Health (U.S.)
Intracranial Hemorrhages
salivary plasminogen activator alpha 1, Desmodus rotundus
Intention to Treat Analysis
Mortality
Plasminogen Activators

ASJC Scopus subject areas

  • Clinical Neurology

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Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2) : a prospective, randomised, double-blind, placebo-controlled study. / Hacke, Werner; Furlan, Anthony J.; Al-Rawi, Yasir; Davalos, Antoni; Fiebach, Jochen B.; Gruber, Franz; Kaste, Markku; Lipka, Leslie J.; Pedraza, Salvador; Ringleb, Peter A.; Rowley, Howard A.; Schneider, Dietmar; Schwamm, Lee H.; Leal, Joaquin Serena; Söhngen, Mariola; Teal, Phil A.; Wilhelm-Ogunbiyi, Karin; Wintermark, Max; Warach, Steven.

In: The Lancet Neurology, Vol. 8, No. 2, 02.2009, p. 141-150.

Research output: Contribution to journalArticle

Hacke, W, Furlan, AJ, Al-Rawi, Y, Davalos, A, Fiebach, JB, Gruber, F, Kaste, M, Lipka, LJ, Pedraza, S, Ringleb, PA, Rowley, HA, Schneider, D, Schwamm, LH, Leal, JS, Söhngen, M, Teal, PA, Wilhelm-Ogunbiyi, K, Wintermark, M & Warach, S 2009, 'Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study', The Lancet Neurology, vol. 8, no. 2, pp. 141-150. https://doi.org/10.1016/S1474-4422(08)70267-9
Hacke, Werner ; Furlan, Anthony J. ; Al-Rawi, Yasir ; Davalos, Antoni ; Fiebach, Jochen B. ; Gruber, Franz ; Kaste, Markku ; Lipka, Leslie J. ; Pedraza, Salvador ; Ringleb, Peter A. ; Rowley, Howard A. ; Schneider, Dietmar ; Schwamm, Lee H. ; Leal, Joaquin Serena ; Söhngen, Mariola ; Teal, Phil A. ; Wilhelm-Ogunbiyi, Karin ; Wintermark, Max ; Warach, Steven. / Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2) : a prospective, randomised, double-blind, placebo-controlled study. In: The Lancet Neurology. 2009 ; Vol. 8, No. 2. pp. 141-150.
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title = "Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study",
abstract = "Background: Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). Methods: In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 μg/kg desmoteplase, 125 μg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. Findings: Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 μg/kg desmoteplase; 66 received 125 μg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30{\%} (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10·6 cm3 and 52·5 cm3, respectively). The clinical response rates at day 90 were 47{\%} (27 of 57) for 90 μg/kg desmoteplase, 36{\%} (24 of 66) for 125 μg/kg desmoteplase, and 46{\%} (29 of 63) for placebo. The median changes in lesion volume were: 90 μg/kg desmoteplase 14·0{\%} (0·5 cm3); 125 μg/kg desmoteplase 10·8{\%} (0·3 cm3); placebo -10·0{\%} (-0·9 cm3). The rates of symptomatic intracranial haemorrhage were 3·5{\%} (2 of 57) for 90 μg/kg desmoteplase, 4·5{\%} (3 of 66) for 125 μg/kg desmoteplase, and 0{\%} for placebo. The overall mortality rate was 11{\%} (5{\%} [3 of 57] for 90 μg/kg desmoteplase; 21{\%} [14 of 66] for 125 μg/kg desmoteplase; and 6{\%} [4 of 63] for placebo). Interpretation: The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. Funding: PAION Deutschland GmbH; Forest Laboratories.",
author = "Werner Hacke and Furlan, {Anthony J.} and Yasir Al-Rawi and Antoni Davalos and Fiebach, {Jochen B.} and Franz Gruber and Markku Kaste and Lipka, {Leslie J.} and Salvador Pedraza and Ringleb, {Peter A.} and Rowley, {Howard A.} and Dietmar Schneider and Schwamm, {Lee H.} and Leal, {Joaquin Serena} and Mariola S{\"o}hngen and Teal, {Phil A.} and Karin Wilhelm-Ogunbiyi and Max Wintermark and Steven Warach",
year = "2009",
month = "2",
doi = "10.1016/S1474-4422(08)70267-9",
language = "English (US)",
volume = "8",
pages = "141--150",
journal = "The Lancet Neurology",
issn = "1474-4422",
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TY - JOUR

T1 - Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2)

T2 - a prospective, randomised, double-blind, placebo-controlled study

AU - Hacke, Werner

AU - Furlan, Anthony J.

AU - Al-Rawi, Yasir

AU - Davalos, Antoni

AU - Fiebach, Jochen B.

AU - Gruber, Franz

AU - Kaste, Markku

AU - Lipka, Leslie J.

AU - Pedraza, Salvador

AU - Ringleb, Peter A.

AU - Rowley, Howard A.

AU - Schneider, Dietmar

AU - Schwamm, Lee H.

AU - Leal, Joaquin Serena

AU - Söhngen, Mariola

AU - Teal, Phil A.

AU - Wilhelm-Ogunbiyi, Karin

AU - Wintermark, Max

AU - Warach, Steven

PY - 2009/2

Y1 - 2009/2

N2 - Background: Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). Methods: In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 μg/kg desmoteplase, 125 μg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. Findings: Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 μg/kg desmoteplase; 66 received 125 μg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10·6 cm3 and 52·5 cm3, respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 μg/kg desmoteplase, 36% (24 of 66) for 125 μg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 μg/kg desmoteplase 14·0% (0·5 cm3); 125 μg/kg desmoteplase 10·8% (0·3 cm3); placebo -10·0% (-0·9 cm3). The rates of symptomatic intracranial haemorrhage were 3·5% (2 of 57) for 90 μg/kg desmoteplase, 4·5% (3 of 66) for 125 μg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 μg/kg desmoteplase; 21% [14 of 66] for 125 μg/kg desmoteplase; and 6% [4 of 63] for placebo). Interpretation: The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. Funding: PAION Deutschland GmbH; Forest Laboratories.

AB - Background: Previous studies have suggested that desmoteplase, a novel plasminogen activator, has clinical benefit when given 3-9 h after the onset of the symptoms of stroke in patients with presumptive tissue at risk that is identified by magnetic resonance perfusion imaging (PI) and diffusion-weighted imaging (DWI). Methods: In this randomised, placebo-controlled, double-blind, dose-ranging study, patients with acute ischaemic stroke and tissue at risk seen on either MRI or CT imaging were randomly assigned (1:1:1) to 90 μg/kg desmoteplase, 125 μg/kg desmoteplase, or placebo within 3-9 h after the onset of symptoms of stroke. The primary endpoint was clinical response rates at day 90, defined as a composite of improvement in National Institutes of Health stroke scale (NIHSS) score of 8 points or more or an NIHSS score of 1 point or less, a modified Rankin scale score of 0-2 points, and a Barthel index of 75-100. Secondary endpoints included change in lesion volume between baseline and day 30, rates of symptomatic intracranial haemorrhage, and mortality rates. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, NCT00111852. Findings: Between June, 2005, and March, 2007, 193 patients were randomised, and 186 patients received treatment: 57 received 90 μg/kg desmoteplase; 66 received 125 μg/kg desmoteplase; and 63 received placebo. 158 patients completed the study. The median baseline NIHSS score was 9 (IQR 6-14) points, and 30% (53 of 179) of the patients had a visible occlusion of a vessel at presentation. The core lesion and the mismatch volumes were small (median volumes were 10·6 cm3 and 52·5 cm3, respectively). The clinical response rates at day 90 were 47% (27 of 57) for 90 μg/kg desmoteplase, 36% (24 of 66) for 125 μg/kg desmoteplase, and 46% (29 of 63) for placebo. The median changes in lesion volume were: 90 μg/kg desmoteplase 14·0% (0·5 cm3); 125 μg/kg desmoteplase 10·8% (0·3 cm3); placebo -10·0% (-0·9 cm3). The rates of symptomatic intracranial haemorrhage were 3·5% (2 of 57) for 90 μg/kg desmoteplase, 4·5% (3 of 66) for 125 μg/kg desmoteplase, and 0% for placebo. The overall mortality rate was 11% (5% [3 of 57] for 90 μg/kg desmoteplase; 21% [14 of 66] for 125 μg/kg desmoteplase; and 6% [4 of 63] for placebo). Interpretation: The DIAS-2 study did not show a benefit of desmoteplase given 3-9 h after the onset of stroke. The high response rate in the placebo group could be explained by the mild strokes recorded (low baseline NIHSS scores, small core lesions, and small mismatch volumes that were associated with no vessel occlusions), which possibly reduced the potential to detect any effect of desmoteplase. Funding: PAION Deutschland GmbH; Forest Laboratories.

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