Safety and efficacy of sonothrombolysis for acute ischaemic
stroke: a multicentre, double-blind, phase 3, randomised
controlled trial

J 2019

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial

ALEXANDROV, Andrei, V., Martin KOHRMANN, Lauri SOINNE, Georgios TSIVGOULIS, Andrew D. BARRETO et. al.

Basic information

Original name

Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial

Authors

ALEXANDROV, Andrei, V. (840 United States of America, guarantor), Martin KOHRMANN (276 Germany), Lauri SOINNE (246 Finland), Georgios TSIVGOULIS (300 Greece), Andrew D. BARRETO (840 United States of America), Andrew M. DEMCHUK (124 Canada), Vijay K. SHARMA (702 Singapore), Robert MIKULÍK (203 Czech Republic, belonging to the institution), Keith W. MUIR (826 United Kingdom of Great Britain and Northern Ireland), Gordon BRANDT (840 United States of America), John ALLEMAN (840 United States of America), James C. GROTTA (840 United States of America), Christopher R. LEVI (36 Australia), Carlos A. MOLINA (724 Spain), Maher SAQQUR (124 Canada), Dimitris MAVRIDIS (300 Greece), Theodora PSALTOPOULOU (300 Greece), Milan VOSKO (40 Austria), Jochen B. FIEBACH (276 Germany), Pitchaiah MANDAVA (840 United States of America), Thomas A. KENT (840 United States of America), Anne W. ALEXANDROV (840 United States of America) and Peter D. SCHELLINGER (276 Germany)

Edition

Lancet Neurology, London, UK, Elsevier, 2019, 1474-4422

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30103 Neurosciences

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 30.039

RIV identification code

RIV/00216224:14110/19:00112519

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1016/S1474-4422(19)30026-2

UT WoS

000461169400011

Keywords in English

ULTRASOUND-ENHANCED THROMBOLYSIS; TISSUE-PLASMINOGEN ACTIVATOR; ALTEPLASE; DEVICE

Abstract

V originále

Background Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. Methods We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score >= 10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4.5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov , number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. Findings Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1.05 (95% CI 0.77-1.45; p=0.74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1.24, 95% CI 0 .80-1. 92; 13=0.37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1.12, 0.79-1.60; p=0.53). Interpretation Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. Copyright (C) 2019 Elsevier Ltd. All rights reserved.

Citovat

ALEXANDROV, Andrei, V., Martin KOHRMANN, Lauri SOINNE, Georgios TSIVGOULIS, Andrew D. BARRETO, Andrew M. DEMCHUK, Vijay K. SHARMA, Robert MIKULÍK, Keith W. MUIR, Gordon BRANDT, John ALLEMAN, James C. GROTTA, Christopher R. LEVI, Carlos A. MOLINA, Maher SAQQUR, Dimitris MAVRIDIS, Theodora PSALTOPOULOU, Milan VOSKO, Jochen B. FIEBACH, Pitchaiah MANDAVA, Thomas A. KENT, Anne W. ALEXANDROV and Peter D. SCHELLINGER. Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Neurology. London, UK: Elsevier, 2019, vol. 18, No 4, p. 338-347. ISSN 1474-4422. Available from: https://dx.doi.org/10.1016/S1474-4422(19)30026-2.

@article{1605637,
   author = {Alexandrov, Andrei, V. and Kohrmann, Martin and Soinne, Lauri and Tsivgoulis, Georgios and Barreto, Andrew D. and Demchuk, Andrew M. and Sharma, Vijay K. and Mikulík, Robert and Muir, Keith W. and Brandt, Gordon and Alleman, John and Grotta, James C. and Levi, Christopher R. and Molina, Carlos A. and Saqqur, Maher and Mavridis, Dimitris and Psaltopoulou, Theodora and Vosko, Milan and Fiebach, Jochen B. and Mandava, Pitchaiah and Kent, Thomas A. and Alexandrov, Anne W. and Schellinger, Peter D.},
   article_location = {London, UK},
   article_number = {4},
   doi = {http://dx.doi.org/10.1016/S1474-4422(19)30026-2},
   keywords = {ULTRASOUND-ENHANCED THROMBOLYSIS; TISSUE-PLASMINOGEN ACTIVATOR; ALTEPLASE; DEVICE},
   language = {eng},
   issn = {1474-4422},
   journal = {Lancet Neurology},
   title = {Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial},
   url = {http://dx.doi.org/10.1016/S1474-4422(19)30026-2},
   volume = {18},
   year = {2019}
}

TY  - JOUR
ID  - 1605637
AU  - Alexandrov, Andrei, V. - Kohrmann, Martin - Soinne, Lauri - Tsivgoulis, Georgios - Barreto, Andrew D. - Demchuk, Andrew M. - Sharma, Vijay K. - Mikulík, Robert - Muir, Keith W. - Brandt, Gordon - Alleman, John - Grotta, James C. - Levi, Christopher R. - Molina, Carlos A. - Saqqur, Maher - Mavridis, Dimitris - Psaltopoulou, Theodora - Vosko, Milan - Fiebach, Jochen B. - Mandava, Pitchaiah - Kent, Thomas A. - Alexandrov, Anne W. - Schellinger, Peter D.
PY  - 2019
TI  - Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial
JF  - Lancet Neurology
VL  - 18
IS  - 4
SP  - 338-347
EP  - 338-347
PB  - Elsevier
SN  - 14744422
KW  - ULTRASOUND-ENHANCED THROMBOLYSIS
KW  - TISSUE-PLASMINOGEN ACTIVATOR
KW  - ALTEPLASE
KW  - DEVICE
UR  - http://dx.doi.org/10.1016/S1474-4422(19)30026-2
L2  - http://dx.doi.org/10.1016/S1474-4422(19)30026-2
N2  - Background Pulsed-wave ultrasound increases the exposure of an intracranial thrombus to alteplase (recombinant tissue plasminogen activator), potentially facilitating early reperfusion. We aimed to ascertain if a novel operator-independent transcranial ultrasound device delivering low-power high-frequency ultrasound could improve functional outcome in patients treated with alteplase after acute ischaemic stroke. Methods We did a multicentre, double-blind, phase 3, randomised controlled trial (CLOTBUST-ER) at 76 medical centres in 14 countries. We included patients with acute ischaemic stroke (National Institutes of Health Stroke Scale score >= 10) who received intravenous thrombolysis (alteplase bolus) within 3 h of symptom onset in North America and within 4.5 h of symptom onset in all other countries. Participants were randomly allocated (1:1) via an interactive web response system to either active ultrasound (2 MHz pulsed-wave ultrasound for 120 min [sonothrombolysis]; intervention group) or sham ultrasound (control group). Ultrasound was delivered using an operator-independent device, which had to be activated within 30 min of the alteplase bolus. Participants, investigators, and those assessing outcomes were unaware of group assignments. The primary outcome was improvement in the modified Rankin Scale score at 90 days in patients enrolled within 3 h of symptom onset, assessed in the intention-to-treat population as a common odds ratio (cOR) using ordinal logistic regression shift analysis. This trial is registered with ClinicalTrials.gov , number NCT01098981. The trial was stopped early by the funder after the second interim analysis because of futility. Findings Between August, 2013, and April, 2015, 335 patients were randomly allocated to the intervention group and 341 patients to the control group. Compared with the control group, the adjusted cOR for an improvement in modified Rankin Scale score at 90 days in the intervention group was 1.05 (95% CI 0.77-1.45; p=0.74). 51 (16%) of 317 patients in the intervention group and 44 (13%) of 329 patients in the control group died (unadjusted OR 1.24, 95% CI 0 .80-1. 92; 13=0.37) and 83 (26%) and 79 (24%), respectively, had serious adverse events (1.12, 0.79-1.60; p=0.53). Interpretation Sonothrombolysis delivered by an operator-independent device to patients treated with alteplase after acute ischaemic stroke was feasible and most likely safe, but no clinical benefit was seen at 90 days. Sonothrombolysis could be further investigated either in randomised trials undertaken in stroke centres that are dependent on patient transfer for endovascular reperfusion therapies or in countries where these treatments cannot yet be offered as the standard of care. Copyright (C) 2019 Elsevier Ltd. All rights reserved.
ER  -

ALEXANDROV, Andrei, V., Martin KOHRMANN, Lauri SOINNE, Georgios TSIVGOULIS, Andrew D. BARRETO, Andrew M. DEMCHUK, Vijay K. SHARMA, Robert MIKULÍK, Keith W. MUIR, Gordon BRANDT, John ALLEMAN, James C. GROTTA, Christopher R. LEVI, Carlos A. MOLINA, Maher SAQQUR, Dimitris MAVRIDIS, Theodora PSALTOPOULOU, Milan VOSKO, Jochen B. FIEBACH, Pitchaiah MANDAVA, Thomas A. KENT, Anne W. ALEXANDROV and Peter D. SCHELLINGER. Safety and efficacy of sonothrombolysis for acute ischaemic stroke: a multicentre, double-blind, phase 3, randomised controlled trial. \textit{Lancet Neurology}. London, UK: Elsevier, 2019, vol.~18, No~4, p.~338-347. ISSN~1474-4422. Available from: https://dx.doi.org/10.1016/S1474-4422(19)30026-2.

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