Skip to main content

Advertisement

SpringerLink
Log in

Perfusion-CT guided intravenous thrombolysis in patients with unknown-onset stroke: a randomized, double-blind, placebo-controlled, pilot feasibility trial

  • Interventional Neuroradiology
  • Published:
Neuroradiology Aims and scope Submit manuscript

Abstract

Introduction

Patients with unknown stroke onset are generally excluded from acute recanalisation treatments. We designed a pilot study to assess feasibility of a trial of perfusion computed tomography (PCT)-guided thrombolysis in patients with ischemic tissue at risk of infarction and unknown stroke onset.

Methods

Patients with a supratentorial stroke of unknown onset in the middle cerebral artery territory and significant volume of at-risk tissue on PCT were randomized to intravenous thrombolysis with alteplase (0.9 mg/kg) or placebo. Feasibility endpoints were randomization and blinded treatment of patients within 2 h after hospital arrival, and the correct application (estimation) of the perfusion imaging criteria.

Results

At baseline, there was a trend towards older age [69.5 (57–78) vs. 49 (44–78) years] in the thrombolysis group (n = 6) compared to placebo (n = 6). Regarding feasibility, hospital arrival to treatment delay was above the allowed 2 h in three patients (25%). There were two protocol violations (17%) regarding PCT, both underestimating the predicted infarct in patients randomized in the placebo group. No symptomatic hemorrhage or death occurred during the first 7 days. Three of the four (75%) and one of the five (20%) patients were recanalized in the thrombolysis and placebo group respectively. The volume of non-infarcted at-risk tissue was 84 (44–206) cm3 in the treatment arm and 29 (8–105) cm3 in the placebo arm.

Conclusions

This pilot study shows that a randomized PCT-guided thrombolysis trial in patients with stroke of unknown onset may be feasible if issues such as treatment delays and reliable identification of tissue at risk of infarction tissue are resolved. Safety and efficiency of such an approach need to be established.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. NINDS Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. New Engl J Med 333(24):1581–1587

    Article  Google Scholar 

  2. Hacke W, Kaste M, Bluhmki E, Brozman M, Davalos A, Guidetti D et al (2008) Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 359(13):1317–1329

    Article  PubMed  CAS  Google Scholar 

  3. Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C et al (1999) Intra-arterial prourokinase for acute ischemic stroke. The PROACT II study: a randomized controlled trial. Prolyse in Acute Cerebral Thromboembolism. JAMA 282(21):2003–2011

    Article  PubMed  CAS  Google Scholar 

  4. Ahmed N, Wahlgren N, Grond M, Hennerici M, Lees KR, Mikulik R et al (2010) Implementation and outcome of thrombolysis with alteplase 3–4.5 h after an acute stroke: an updated analysis from SITS-ISTR. Lancet Neurol 9(9):866–874

    Article  PubMed  CAS  Google Scholar 

  5. Michel P, Odier C, Rutgers M, Reichhart M, Maeder P, Meuli R et al (2010) The Acute STroke Registry and Analysis of Lausanne (ASTRAL): design and baseline analysis of an ischemic stroke registry including acute multimodal imaging. Stroke 41(11):2491–2498

    Article  PubMed  Google Scholar 

  6. Adams HP Jr, Leira EC, Torner JC, Barnathan E, Padgett L, Effron MB et al (2008) Treating patients with ‘wake-up’ stroke: the experience of the AbESTT-II trial. Stroke 39(12):3277–3282

    Article  PubMed  Google Scholar 

  7. Chemmanam T, Campbell BC, Christensen S, Nagakane Y, Desmond PM, Bladin CF et al (2010) Ischemic diffusion lesion reversal is uncommon and rarely alters perfusion-diffusion mismatch 1. Neurology 75(12):1040–1047

    Article  PubMed  CAS  Google Scholar 

  8. Tourdias T, Renou P, Sibon I, Asselineau J, Bracoud L, Dumoulin M et al (2011) Final cerebral infarct volume is predictable by MR imaging at 1 week 1. AJNR Am J Neuroradiol 32(2):352–358

    Article  PubMed  CAS  Google Scholar 

  9. Wintermark M, Reichhart M, Cuisenaire O, Maeder P, Thiran JP, Schnyder P et al (2002) Comparison of admission perfusion computed tomography and qualitative diffusion- and perfusion-weighted magnetic resonance imaging in acute stroke patients. Stroke 33(8):2025–2031

    Article  PubMed  CAS  Google Scholar 

  10. Wintermark M, Albers GW, Alexandrov AV, Alger JR, Bammer R, Baron JC et al (2008) Acute stroke imaging research roadmap. Stroke 39(5):1621–1628

    Article  PubMed  Google Scholar 

  11. Wintermark M, Flanders AE, Velthuis B, Meuli R, van Leeuwen M, Goldsher D et al (2006) Perfusion-CT assessment of infarct core and penumbra: receiver operating characteristic curve analysis in 130 patients suspected of acute hemispheric stroke. Stroke 37(4):979–985

    Article  PubMed  Google Scholar 

  12. Bivard A, McElduff P, Spratt N, Levi C, Parsons M (2011) Defining the extent of irreversible. Cerebrovascular Diseases 31(3):238–245

    Article  PubMed  Google Scholar 

  13. Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E et al (2006) Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 60(5):508–517

    Article  PubMed  Google Scholar 

  14. Davis SM, Donnan GA, Parsons MW, Levi C, Butcher KS, Peeters A et al (2008) Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 7(4):299–309

    Article  PubMed  Google Scholar 

  15. Furlan AJ, Eyding D, Albers GW, Al-Rawi Y, Lees KR, Rowley HA et al (2006) Dose Escalation of Desmoteplase for Acute Ischemic Stroke (DEDAS): evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 37(5):1227–1231

    Article  PubMed  CAS  Google Scholar 

  16. Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M et al (2005) The Desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. Stroke 36(1):66–73

    Article  PubMed  CAS  Google Scholar 

  17. Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F et al (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. Lancet Neurol 8(2):141–150

    Article  PubMed  CAS  Google Scholar 

  18. Darby DG, Barber PA, Gerraty RP, Desmond PM, Yang Q, Parsons M et al (1999) Pathophysiological topography of acute ischemia by combined diffusion-weighted and perfusion MRI. Stroke 30(10):2043–2052

    Article  PubMed  CAS  Google Scholar 

  19. Silva GS, Lima FO, Camargo EC, Smith WS, Singhal AB, Greer DM et al (2010) Wake-up stroke: clinical and neuroimaging characteristics. Cerebrovasc Dis 29(4):336–342

    Article  PubMed  Google Scholar 

  20. Schulz KF, Altman DG, Moher D (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 152(11):726–732

    PubMed  Google Scholar 

  21. Moher D, Hopewell S, Schulz KF, Montori V, Gotzsche PC, Devereaux PJ et al (2010) CONSORT 2010 Explanation and Elaboration: Updated guidelines for reporting parallel group randomised trials. J Clin Epidemiol 63(8):e1–e37

    Article  PubMed  Google Scholar 

  22. Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D et al (1998) Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet 352(9136):1245–1251

    Article  PubMed  CAS  Google Scholar 

  23. Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R et al (1995) Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA 274(13):1017–1025

    Article  PubMed  CAS  Google Scholar 

  24. Toni D, Chamorro A, Kaste M, Lees K, Wahlgren NG, Hacke W (2004) Acute treatment of ischaemic stroke. European Stroke Initiative (EUSI). Cerebrovasc Dis 17(Suppl 2):30–46

    Article  PubMed  Google Scholar 

  25. Lees KR, Bluhmki E, von Kummer R, Brott TG, Toni D, Grotta JC et al (2010) Time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ECASS, ATLANTIS, NINDS, and EPITHET trials. Lancet 375(9727):1695–1703

    Article  PubMed  CAS  Google Scholar 

  26. Mishra NK, Albers GW, Davis SM, Donnan GA, Furlan AJ, Hacke W et al (2010) Mismatch-based delayed thrombolysis: a meta-analysis. Stroke 41(1):e25–e33

    Article  PubMed  Google Scholar 

  27. Obach V, Oleaga L, Urra X, Macho J, Amaro S, Capurro S et al (2011) Multimodal CT-assisted thrombolysis in patients with acute stroke. A cohort study. Stroke 42:1129–1131

    Article  PubMed  CAS  Google Scholar 

  28. Tong DC, Adami A, Moseley ME, Marks MP (2000) Relationship between apparent diffusion coefficient and subsequent hemorrhagic transformation following acute ischemic stroke. Stroke 31(10):2378–2384

    Article  PubMed  CAS  Google Scholar 

  29. Wahlgren N, Ahmed N, Davalos A, Ford GA, Grond M, Hacke W et al (2007) Thrombolysis with alteplase for acute ischaemic stroke in the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST): an observational study. Lancet 369(9558):275–282

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

A Swiss Cardiology Foundation grant funded parts of the salaries of research personnel involved in the study.

Conflict of interest

PM receives funding from Paion and Lundbeck (research support and consulting fees) and Boehringer-Ingelheim (speaker fees, Advisory Board). MW receives funding from the National Center for Research Resources, Grant KL2 RR024130, GE Healthcare and Philips Medical Systems.

Author information

Authors and Affiliations

  1. Department of Neurology Service, Center Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

    Patrik Michel, George Ntaios & Marc Reichhart

  2. Pharmacy Department, Center Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

    Christian Schindler

  3. Genolier Swiss Medical Network, Clinique Valmont, Glion, Switzerland

    Julien Bogousslavsky

  4. Department of Radiology, Center Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland

    Philip Maeder & Reto Meuli

  5. Department of Radiology, Division of Neuroradiology, University of Virginia, Charlottesville, VA, USA

    Max Wintermark

  6. Neurology Service, Centre Hospitalier Universitaire Vaudois & University of Lausanne, Rue du Bugnon 46, 1011, Lausanne, Switzerland

    Patrik Michel

Authors
  1. Patrik Michel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. George Ntaios
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Marc Reichhart
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian Schindler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Julien Bogousslavsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Philip Maeder
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Reto Meuli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Max Wintermark
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrik Michel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Michel, P., Ntaios, G., Reichhart, M. et al. Perfusion-CT guided intravenous thrombolysis in patients with unknown-onset stroke: a randomized, double-blind, placebo-controlled, pilot feasibility trial. Neuroradiology 54, 579–588 (2012). https://doi.org/10.1007/s00234-011-0944-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00234-011-0944-1

Keywords

Search

Navigation