Design of a Prospective Multi-National CLOTBUST Collaboration on Reperfusion Therapies for Stroke

Author:

Saqqur Maher1,Tsivgoulis Georgios23,Molina Carlos A.4,Demchuk Andrew M.5,Garami Zsolt6,Barreto Andrew7,Spengos Konstantinos3,Forteza Alex8,Mikulik Robert9,Sharma Vijay K.10,Brunser Alex11,Martinez Patricia12,Montaner Joan4,Kohrmann Martin13,Schellinger Peter D.,Alexandrov Andrei V.2,

Affiliation:

1. Department of Medicine (Neurology), University of Alberta, Alberta, Canada

2. Comprehensive Stroke Center, University of Alabama at Birmingham Hospital, Birmingham, AL, USA

3. Department of Neurology, University of Athens School of Medicine, Athens, Greece

4. Neurovascular Unit, Neurology Department, Hospital University Vall d'Hebron, Barcelona, Spain

5. Department of Clinical Neurosciences, University of Calgary, Foothills Medical Centre, Calgary, Alberta, Canada

6. Non-invasive Cerebrovascular Study Laboratory, Methodist Hospital, Houston, TX, USA

7. Department of Neurology, University of Texas-Houston Medical School, Houston, TX, USA

8. Department of Neurology, University of Miami, Miller School of Medicine, Miami, FL, USA

9. Department of Neurology, Masaryk University, St Anne's Hospital, Brno, Czech Republic

10. Division of Neurology, Department of Medicine, National University Hospital, Singapore, Singapore

11. Department of Neurology, Clinica Alemana de Santiago, Santiago, Chile

12. Stroke Unit, Department of Neurology, La Paz University Hospital, Madrid, Spain

13. Neurologische Universitatsklinik, Schwabachanlage 6, 91054, Erlangen, Deutschland

Abstract

Background The benefit of intravenous (i.v.) tissue plasminogen activator (tPA) in acute ischemic stroke (IS) is attributable to lysis of thrombus and restoration of perfusion to ischemic but not yet infarcted brain. Aims Our multicentre collaborative group prospectively implemented a protocol for transcranial Doppler assessment of intracranial recanalization with tPA treatment based on the CLOTBUST clinical trial (CLOTBUST-PRO). We aim to determine whether early recanalization (within 1 h from tPA bolus) is independently associated with better 3-month outcome in patients with intracranial arterial occlusions and correlates to a shorter time interval elapsed from symptom onset to tPA bolus. Subjects and methods Consecutive patients with acute IS due to intracranial arterial occlusions will be treated with standard i.v.-tPA and continuously monitored with 2 MHz Transcranial Doppler for arterial recanalization. Early recanalization will be determined with the previously validated Thrombolysis in Brain Ischemia flow-grading system within 60 min after tPA bolus. Power calculations are based on the assumption of α = 0·05 (two-sided test) and probabilities of functional independence at 3 months of 0·50 and 0·35 in patients with early complete recanalization and persisting occlusion, respectively. Detection of a 15% difference with a power of 0·824 requires an estimated sample of 480 patients of whom 25% are expected to achieve early recanalization while 75% will have persisting occlusion at 1 h after tPA bolus. We also plan to test prespecified secondary hypotheses within the projected study sample. Conclusions CLOTBUST-PRO is designed to determine if the timing (within 1 h from tPA bolus) of tPA-induced arterial recanalization is an independent determinant of 3-month functional recovery. We also seek to demonstrate that the sooner the tPA is given to stroke patients, the earlier the recanalization occurs and the greater is the likelihood of functional independence at 3 months. Introduction Intravenous (i.v.) tissue plasminogen activator (tPA) remains the only approved therapy for acute ischemic stroke (IS) with faster time to treatment being associated with better outcomes at 3 months ( 1 ). Although the benefit of tPA is attributable to lysis of thrombus and restoration of perfusion to ischemic but not yet infarcted brain ( 2 ), recanalization was not documented in pivotal tPA trials. This hypothesis is supported by both animal and smaller human studies showing that the duration of impaired perfusion is associated with final infarct volume and that early recanalization correlates with smaller infarct size ( 3 – 5 ).

Publisher

SAGE Publications

Subject

Neurology

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