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Select wisely: the ethical challenge of defining large core with perfusion in the early time window
  1. Ashutosh P Jadhav1,
  2. Werner Hacke2,
  3. Diederik W J Dippel3,
  4. Claus Ziegler Simonsen4,
  5. Vincent Costalat5,
  6. Jens Fiehler6,
  7. Goetz Thomalla7,
  8. Martin Bendszus8,
  9. Tommy Andersson9,10,
  10. Heinrich Paul Mattle11,
  11. Thabele M Leslie-Mazwi12,
  12. Maxim Mokin13,
  13. Albert J Yoo14,
  14. Osama O Zaidat15,
  15. Sunil A Sheth16,
  16. Tudor G Jovin17,
  17. David Liebeskind18
  1. 1 Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
  2. 2 Neurology, University of Heidelberg, Heidelberg, Germany
  3. 3 Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
  4. 4 Neurology, Aarhus University Hospital, Aarhus, Denmark
  5. 5 Department of Neuroradiology, Hôpital Gui de Chauliac, Montpellier University Medical Center, Montepellier, France
  6. 6 Department of Neuroradiology, University Medical Center Hamburg Eppendorf, Hamburg, Germany
  7. 7 Neurology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
  8. 8 Department of Neuroradiology, University of Heidelberg, Heidelberg, Germany
  9. 9 Departments of Radiology and Neurology, AZ Groeninge, Kortrijk, Belgium
  10. 10 Department of Neuroradiology; Department of Clinical Neuroscience, Karolinska University Hospital; Karolinska Institutet, Stockholm, Sweden
  11. 11 Neurology, Inselspital, University of Bern, Bern, Switzerland
  12. 12 Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, USA
  13. 13 Neurosurgery, University of South Florida, Tampa, Florida, USA
  14. 14 Neurointervention, Texas Stroke Institute, Plano, Texas, USA
  15. 15 Neuroscience, St Vincent Mercy Hospital, Toledo, Ohio, USA
  16. 16 Neurology, University of Texas Health Science Center at Houston, Houston, Texas, USA
  17. 17 Neurology, Cooper University Hospital, Camden, New Jersey, USA
  18. 18 Neurology, UCLA, Los Angeles, California, USA
  1. Correspondence to Dr Ashutosh P Jadhav, Neurology, Barrow Neurological Institute, Phoenix, AZ 85013, USA; jadhav.library{at}

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The pivotal stroke trials published in 2015 provided indisputable evidence of the benefit of thrombectomy in early window (0–6 hours) patients with anterior circulation emergent large vessel occlusion (ELVO) and small infarcts on non-contrast CT (NCCT), measured by ASPECTS 6–10.1–5 Since then, endovascular treatment of this population has been standard guideline-based care.6 Efforts, similar to the late window trials,7 8 are now directed at further expanding thrombectomy indications. Five trials are underway investigating the role of thrombectomy in patients with ELVO with ASPECTS <6, the 'large core' population for whom formal level I evidence is lacking (TENSION (NCT03094715); IN EXTREMIS-LASTE (NCT03811769); TESLA (NCT03805308); SELECT 2 (NCT03876457); and RESCUE-Japan LIMIT (NCT03702413)). Of these studies, all define large core using ASPECTS alone, except for one (SELECT 2). This study defines large core using ASPECTS or CT perfusion (CTP), and in doing so includes patients with poor NCCT ASPECTS (score <6) and also those with NCCT ASPECTS 6–10 with CTP-estimated ischemic core volumes ≥50 mL. Because the pivotal trials show unequivocally that patients with ASPECTS 6–10 and ELVO benefit from endovascular treatment in the 0–6-hour time window, we believe that this subgroup in SELECT 2 withholds proven class I treatment from eligible patients, raising concern for patient harm.

As its name implies, CTP provides a measure of cerebral perfusion or, in the case of stroke, the strength of the collateral circulation.9 Even if one accepts the proposition that CTP can provide an accurate measure of cerebral blood flow (CBF),10 basic physiologic experiments and clinical studies have demonstrated that the progression from reversible ischemia to infarction is dependent on both CBF and the duration of ischemia.11–13 Taken together, the idea that one can accurately identify the region of irreversible injury (the core) from a threshold applied to a single snapshot …

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  • Twitter @ashupjadhav, @clauszsimonsen, @Fie0815

  • Contributors All authors contributed to the drafting and final approval of the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests WH reports consultancy fees from Neuravi and fees for DSMB work by Phenox. DWJD reports funding from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences & Health, and unrestricted grants from Penumbra, Stryker European Operations BV, Medtronic, Thrombolytic Science, LLC and Cerenovus for research, all paid to institution. CZS reports research grants from Novo Nordisk Foundation and Health Research Foundation of Central Denmark Region. JF reports research support from the German Ministry of Science and Education (BMBF and BMWi), German Research Foundation (DFG), European Union (EU), Hamburgische Investitions- und Förderbank (IFB), Medtronic, Microvention, Philips, Stryker, and consultancy fees from Acandis, Boehringer Ingelheim, Cerenovus, Covidien, Evasc Neurovascular, MD Clinicals, Medtronic, Medina, Microvention, Penumbra, Route92, Stryker, Transverse Medical. GT reports personal fees from Acandis, grants and personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers-Squibb/Pfizer, personal fees from Portola, and personal fees from Stryker outside the submitted work, and is Neurological Co-Principal Investigator of the TENSION study, which receives funding from the European Union’s Horizon 2020 research and innovation program under grant agreement number 754640. TA reports consultancy fees from Amnis Therapeutics, Anaconda, Cerenovus/Neuravi, Rapid Medical and Stryker. MM is a member of the TESLA steering committee and local principal investigator. He reports research support from the NIH and consultancy fees from Medtronic and Cerenovus as well as stock options in Serenity Medical, Synchron and Endostream. AJY is the co-Principal Investigator for TESLA and reports research funding from Medtronic, Cerenovus, Penumbra and Stryker. He reports consultancy fees from Penumbra, Cerenovus, Vesalio and Zoll Circulation. He has equity interests in Insera Therapeutics. SAS reports research support from the NIH, American Academy of Neurology and Society for Vascular and Interventional Neurology, and consultancy fees from Penumbra and Cerenovus. OOZ is the co-Principal Investigator for TESLA and reports consultancy fees from Cerenovus, Stryker, Penumbra and Medtronic. TGJ reports consultancy fees from Cerenovus and Contego, and research support from Stryker. DL reports consultancy fees from Cerenovus, Genentech, Medtronic, and Stryker outside the submitted work.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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