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.

2nd Department of Neurology 'Attikon' University Hospital School of Medicine National and Kapodistrian University of Athens Athens Greece

Center for Stroke Research Berlin Charité University Medicine Berlin Berlin Germany

Cerevast Therapeutics Inc Redmond WA USA

Department of Hygiene Epidemiology and Medical Statistics Medical School National and Kapodistrian University of Athens Athens Greece

Department of Medicine University of Alberta Edmonton Alberta Canada

Department of Neurology 2 Med Campus 3 Kepler University Hospital Linz Austria

Department of Neurology Helsinki University Hospital and Clinical Neurosciences Neurology University of Helsinki Helsinki Finland

Department of Neurology John Hunter Hospital University of Newcastle Newcastle Australia

Department of Neurology Universitaetsklinikum Erlangen Erlangen Germany

Department of Neurology University of Tennessee Health Science Center 855 Monroe Avenue Suite 415 Memphis TN 38163 USA

Department of Neurology University of Tennessee Health Science Center Memphis TN USA

Department of Neurology University of Texas Health Science Center at Houston Houston TX USA

Department of Primary Education School of Education University of Ioannina Ioannina Greece

Departments of Neurology and Neurogeriatry John Wesling Medical Center Minden Ruhr University Bochum Minden Germany

Institute of Neuroscience and Psychology University of Glasgow Queen Elizabeth University Hospital Glasgow UK

International Clinical Research Centre and Department of Neurology St Anne's University Hospital in Brno and Medical Faculty Masaryk University Brno Czech Republic

Stroke Outcomes Laboratory Department of Neurology Baylor College of Medicine Houston TX USA

Stroke Unit Department of Neurology Vall d'Hebron University Hospital Vall d'Hebron Research Institute Autonomous University of Barcelona Barcelona Spain

Yong Loo Lin School of Medicine National University of Singapore and Division of Neurology Department of Medicine National University Hospital Singapore Singapore

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