Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

for the CLOTBUST-ER Trial Investigators

Research output: Contribution to journalArticle

Abstract

Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.

Original languageEnglish (US)
JournalTherapeutic Advances in Neurological Disorders
Volume12
DOIs
StatePublished - Jul 1 2019

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Phase III Clinical Trials
Randomized Controlled Trials
Stroke
Odds Ratio
Intention to Treat Analysis
National Institutes of Health (U.S.)
Random Allocation
Patient Selection
Reperfusion
boldenone undecylenate
Clinical Trials
Glucose
Equipment and Supplies
Therapeutics
Serum
Population

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Neurology
  • Clinical Neurology

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Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke. / for the CLOTBUST-ER Trial Investigators.

In: Therapeutic Advances in Neurological Disorders, Vol. 12, 01.07.2019.

Research output: Contribution to journalArticle

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title = "Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke",
abstract = "Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95{\%} CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95{\%} CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95{\%} CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.",
author = "{for the CLOTBUST-ER Trial Investigators} and Alexandrov, {Andrei V.} and Georgios Tsivgoulis and Martin K{\"o}hrmann and Katsanos, {Aristeidis H.} and Lauri Soinne and Barreto, {Andrew D.} and Travis Rothlisberger and Sharma, {Vijay K.} and Robert Mikulik and Muir, {Keith W.} and Levi, {Christopher R.} and Molina, {Carlos A.} and Maher Saqqur and Dimitris Mavridis and Theodora Psaltopoulou and Vosko, {Milan R.} and Fiebach, {Jochen B.} and Pitchaiah Mandava and Kent, {Thomas A.} and Alexandrov, {Anne W.} and Schellinger, {Peter D.}",
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T1 - Endovascular equipoise shift in a phase III randomized clinical trial of sonothrombolysis for acute ischemic stroke

AU - for the CLOTBUST-ER Trial Investigators

AU - Alexandrov, Andrei V.

AU - Tsivgoulis, Georgios

AU - Köhrmann, Martin

AU - Katsanos, Aristeidis H.

AU - Soinne, Lauri

AU - Barreto, Andrew D.

AU - Rothlisberger, Travis

AU - Sharma, Vijay K.

AU - Mikulik, Robert

AU - Muir, Keith W.

AU - Levi, Christopher R.

AU - Molina, Carlos A.

AU - Saqqur, Maher

AU - Mavridis, Dimitris

AU - Psaltopoulou, Theodora

AU - Vosko, Milan R.

AU - Fiebach, Jochen B.

AU - Mandava, Pitchaiah

AU - Kent, Thomas A.

AU - Alexandrov, Anne W.

AU - Schellinger, Peter D.

PY - 2019/7/1

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N2 - Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.

AB - Background: Results of our recently published phase III randomized clinical trial of ultrasound-enhanced thrombolysis (sonothrombolysis) using an operator-independent, high frequency ultrasound device revealed heterogeneity of patient recruitment among centers. Methods: We performed a post hoc analysis after excluding subjects that were recruited at centers reporting a decline in the balance of randomization between sonothrombolysis and concurrent endovascular trials. Results: From a total of 676 participants randomized in the CLOTBUST-ER trial we identified 52 patients from 7 centers with perceived equipoise shift in favor of endovascular treatment. Post hoc sensitivity analysis in the intention-to-treat population adjusted for age, National Institutes of Health Scale score at baseline, time from stroke onset to tPA bolus and baseline serum glucose showed a significant (p < 0.01) interaction of perceived endovascular equipoise shift on the association between sonothrombolysis and 3 month functional outcome [adjusted common odds ratio (cOR) in centers with perceived endovascular equipoise shift: 0.22, 95% CI 0.06–0.75; p = 0.02; adjusted cOR for centers without endovascular equipoise shift: 1.20, 95% CI 0.89–1.62; p = 0.24)]. After excluding centers with perceived endovascular equipoise shift, patients randomized to sonothrombolysis had higher odds of 3 month functional independence (mRS scores 0–2) compared with patients treated with tPA only (adjusted OR: 1.53; 95% CI 1.01–2.31; p = 0.04). Conclusion: Our experience in CLOTBUST-ER indicates that increasing implementation of endovascular therapies across major academic stroke centers raises significant challenges for clinical trials aiming to test noninterventional or adjuvant reperfusion strategies.

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