.2020 Jul 14;21(1):644.

doi: 10.1186/s13063-020-04514-9.

Multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke. The effect of periprocedural medication: acetylsalicylic acid, unfractionated heparin, both, or neither (MR CLEAN-MED). Rationale and study design

Vicky Chalos^{1 2 3}, Rob A van de Graaf^{1 2}, Bob Roozenbeek^{4 5}, Adriaan C G M van Es², Heleen M den Hertog⁶, Julie Staals⁷, Lukas van Dijk⁸, Sjoerd F M Jenniskens⁹, Robert J van Oostenbrugge⁷, Wim H van Zwam¹⁰, Yvo B W E M Roos¹¹, Charles B L M Majoie¹², Hester F Lingsma³, Aad van der Lugt², Diederik W J Dippel¹; MR CLEAN-MED investigators

Collaborators, Affiliations

Collaborators

MR CLEAN-MED investigators:
Diederik Dippel, Aad van der Lugt, Bob Roozenbeek, Vicky Chalos, Rob van de Graaf, Wouter van der Steen, Adriaan van Es, Jonathan Coutinho, Bart Emmer, Inger de Ridder, Wim van Zwam, Bart van der Worp, Rob Lo, Koos Keizer, Rob Gons, Lonneke Yo, Jelis Boiten, Ido van den Wijngaard, Jeanette Hofmeijer, Jasper Martens, Wouter Schonewille, Jan Albert Vos, Anil M Tuladhar, Sjoerd Jenniskens, Karlijn de Laat, Lukas van Dijk, Heleen den Hertog, Boudewijn van Hasselt, Paul Brouwers, Emiel Sturm, Michel Remmers, Thijs de Jong, Anouk Rozeman, Otto Elgersma, Maarten Uyttenboogaart, Reinoud P H Bokkers, Julia van Tuijl, Issam Boukrab, Julie Staals, Yvo Roos, Charles Majoie, Robert van Oostenbrugge, Peter Rothwell, Andrew Molyneux, Joanna Moschandreas, Daan Nieboer, Gregory Del Zoppo, Rick van Nuland, Alida Annechien Postma, René van den Berg, Ludo Beenen, Pieter-Jan van Doormaal, Geert Lycklama, Albert Yoo, Sebastiaan Hammer, Stefan Roosendaal, Anton Meijer, Menno Krietemeijer, Anouk van der Hoorn, Dick Gerrits, Ben Jansen, Sanne Manschot, Henk Kerkhoff, Peter Koudstaal, Hester Lingsma, Olvert Berkhemer, Adriaan Versteeg, Lennard Wolff, Jiahang Su, Hugo Ten Cate, Moniek de Maat, Samantha Donkel, Heleen van Beusekom, Aladdin Taha, Kilian Treurniet, Sophie van den Berg, Natalie LeCouffe, Robert-Jan Goldhoorn, Wouter Hinsenveld, Anne Pirson, Lotte Sondag, Manon Kappelhof, Rik Reinink, Manon Tolhuisen, Josje Brouwer, Sabine Collette, Simone Uniken Venema, Susan Olthuis, Floor Pinkaers, Martin Sterrenberg, Naziha El Ghannouti, Sabrina Verheesen, Rita Sprengers, Wilma Pellikaan, Yvonne Drabbe, Joke de Meris, Michelle Simons, Hester Bongenaar, Anja van Loon, Eva Ponjee, Rieke Eilander, Suze Kooij, Marieke de Jong, Esther Santegoets, Friedus van der Minne, Leontien Heiligers, Yvonne Martens

Affiliations

¹ Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
² Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
³ Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁴ Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. b.roozenbeek@erasmusmc.nl.
⁵ Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. b.roozenbeek@erasmusmc.nl.
⁶ Department of Neurology, Isala, Zwolle, The Netherlands.
⁷ Department of Neurology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
⁸ Department of Radiology & Nuclear Medicine, HagaZiekenhuis, Radiology, Den Haag, The Netherlands.
⁹ Department of Radiology & Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰ Department of Radiology & Nuclear Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
¹¹ Department of Neurology, Amsterdam UMC, University of Amsterdam, location AMC, Amsterdam, The Netherlands.
¹² Department of Radiology & Nuclear Medicine, Amsterdam UMC, University of Amsterdam, location AMC, Amsterdam, The Netherlands.

PMID:32665035
PMCID: PMC7362523
DOI: 10.1186/s13063-020-04514-9

Multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke. The effect of periprocedural medication: acetylsalicylic acid, unfractionated heparin, both, or neither (MR CLEAN-MED). Rationale and study design

Vicky Chalos et al. Trials.2020.

.2020 Jul 14;21(1):644.

doi: 10.1186/s13063-020-04514-9.

Authors

Collaborators

MR CLEAN-MED investigators:
Diederik Dippel, Aad van der Lugt, Bob Roozenbeek, Vicky Chalos, Rob van de Graaf, Wouter van der Steen, Adriaan van Es, Jonathan Coutinho, Bart Emmer, Inger de Ridder, Wim van Zwam, Bart van der Worp, Rob Lo, Koos Keizer, Rob Gons, Lonneke Yo, Jelis Boiten, Ido van den Wijngaard, Jeanette Hofmeijer, Jasper Martens, Wouter Schonewille, Jan Albert Vos, Anil M Tuladhar, Sjoerd Jenniskens, Karlijn de Laat, Lukas van Dijk, Heleen den Hertog, Boudewijn van Hasselt, Paul Brouwers, Emiel Sturm, Michel Remmers, Thijs de Jong, Anouk Rozeman, Otto Elgersma, Maarten Uyttenboogaart, Reinoud P H Bokkers, Julia van Tuijl, Issam Boukrab, Julie Staals, Yvo Roos, Charles Majoie, Robert van Oostenbrugge, Peter Rothwell, Andrew Molyneux, Joanna Moschandreas, Daan Nieboer, Gregory Del Zoppo, Rick van Nuland, Alida Annechien Postma, René van den Berg, Ludo Beenen, Pieter-Jan van Doormaal, Geert Lycklama, Albert Yoo, Sebastiaan Hammer, Stefan Roosendaal, Anton Meijer, Menno Krietemeijer, Anouk van der Hoorn, Dick Gerrits, Ben Jansen, Sanne Manschot, Henk Kerkhoff, Peter Koudstaal, Hester Lingsma, Olvert Berkhemer, Adriaan Versteeg, Lennard Wolff, Jiahang Su, Hugo Ten Cate, Moniek de Maat, Samantha Donkel, Heleen van Beusekom, Aladdin Taha, Kilian Treurniet, Sophie van den Berg, Natalie LeCouffe, Robert-Jan Goldhoorn, Wouter Hinsenveld, Anne Pirson, Lotte Sondag, Manon Kappelhof, Rik Reinink, Manon Tolhuisen, Josje Brouwer, Sabine Collette, Simone Uniken Venema, Susan Olthuis, Floor Pinkaers, Martin Sterrenberg, Naziha El Ghannouti, Sabrina Verheesen, Rita Sprengers, Wilma Pellikaan, Yvonne Drabbe, Joke de Meris, Michelle Simons, Hester Bongenaar, Anja van Loon, Eva Ponjee, Rieke Eilander, Suze Kooij, Marieke de Jong, Esther Santegoets, Friedus van der Minne, Leontien Heiligers, Yvonne Martens

Affiliations

¹ Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
² Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands.
³ Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
⁴ Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. b.roozenbeek@erasmusmc.nl.
⁵ Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. b.roozenbeek@erasmusmc.nl.
⁶ Department of Neurology, Isala, Zwolle, The Netherlands.
⁷ Department of Neurology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
⁸ Department of Radiology & Nuclear Medicine, HagaZiekenhuis, Radiology, Den Haag, The Netherlands.
⁹ Department of Radiology & Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands.
¹⁰ Department of Radiology & Nuclear Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands.
¹¹ Department of Neurology, Amsterdam UMC, University of Amsterdam, location AMC, Amsterdam, The Netherlands.
¹² Department of Radiology & Nuclear Medicine, Amsterdam UMC, University of Amsterdam, location AMC, Amsterdam, The Netherlands.

PMID:32665035
PMCID: PMC7362523
DOI: 10.1186/s13063-020-04514-9

Abstract

Background: Despite evidence of a quite large beneficial effect of endovascular treatment (EVT) for ischemic stroke caused by anterior circulation large vessel occlusion, many patients do not recover even after complete recanalization. To some extent, this may be attributable to incomplete microvascular reperfusion, which can possibly be improved by antiplatelet agents and heparin. It is unknown whether periprocedural antithrombotic medication in patients treated with EVT improves functional outcome. The aim of this study is to assess the effect of acetylsalicylic acid (ASA) and unfractionated heparin (UFH), alone, or in combination, given to patients with an ischemic stroke caused by an intracranial large vessel occlusion in the anterior circulation during EVT.

Methods: MR CLEAN-MED is a multicenter phase III trial with a prospective, 2 × 3 factorial randomized, open label, blinded end-point (PROBE) design, which aims to enroll 1500 patients. The trial is designed to evaluate the effect of intravenous ASA (300 mg), UFH (low or moderate dose), both or neither as adjunctive therapy to EVT. We enroll adult patients with a clinical diagnosis of stroke (NIHSS ≥ 2) and with a confirmed intracranial large vessel occlusion in the anterior circulation on CTA or MRA, when EVT within 6 h from symptom onset is indicated and possible. The primary outcome is the score on the modified Rankin Scale (mRS) at 90 days. Treatment effect on the mRS will be estimated with ordinal logistic regression analysis, with adjustment for main prognostic variables. Secondary outcomes include stroke severity measured with the NIHSS at 24 h and at 5-7 days, follow-up infarct volume, symptomatic intracranial hemorrhage (sICH), and mortality.

Discussion: Clinical equipoise exists whether antithrombotic medication should be administered during EVT for a large vessel occlusion, as ASA and/or UFH may improve functional outcome, but might also lead to an increased risk of sICH. When one or both of the study treatments show the anticipated effect on outcome, we will be able to improve outcome of patients treated with EVT by 5%. This amounts to more than 50 patients annually in the Netherlands, more than 1800 in Europe, and more than 1300 in the USA.

Trial registration: ISRCT, ISRCTN76741621 . Dec 6, 2017.

Keywords: Acetylsalicylic acid; Cerebrovascular disorders; Endovascular treatment; Heparin; Ischemic stroke; Periprocedural; Randomized controlled trial; Thrombectomy.

PubMed Disclaimer

Conflict of interest statement

WvZ: reports that Maastricht University Medical Center received compensation from Stryker® and Cerenovus® for consultations by WvZ;

YR: reports that he is a shareholder of Nicolab

CM: reports that Amsterdam UMC received research grants form CVON/Dutch Heart Foundation, European Commission, TWIN Foundation and Stryker®; he is a shareholder of Nico-Lab.

AvdL: reports that Erasmus MC received research grants from Dutch Heart Foundation, Dutch Brain Foundation, AngioCare BV, Covidien/EV3®, MEDAC Gmbh/LAMEPRO, Penumbra Inc., Stryker, and Top Medical/Concentric, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences & Health, Stryker European Operations BV, Thrombolytic Science, LLC, and Cerenovus; he also reports that Erasmus MC received compensation from Stryker for activities of AvdL as a consultant outside the submitted work.

DD: reports that Erasmus MC received research grants from Dutch Heart Foundation, Dutch Brain Foundation, AngioCare BV, Covidien/EV3®, MEDAC Gmbh/LAMEPRO, Penumbra Inc., Stryker, and Top Medical/Concentric, The Netherlands Organisation for Health Research and Development, Health Holland Top Sector Life Sciences & Health, Stryker European Operations BV, Thrombolytic Science, LLC, and Cerenovus.

All other authors: declare that they have no competing interests.

Figures

**Fig. 2**
Flow of patients in the MR CLEAN-MED—in first approved protocol version.Abbreviations: ASA, intravenous acetylsalicylic acid; CTA, computed tomography angiogram; UFH, intravenous unfractionated heparin; EVT, endovascular treatment; LD, low dose; MD, moderate dose; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography; NCCT, non-contrast computed tomography; NIHSS, National Institutes of Health Stroke Scale.Captions: *Only to be performed if imaging at 24 hour was acquired with CT; **Blood sample drawn only in case of regular outpatient clinic appointment within 2-6 months after intervention

**Fig. 3**
SPIRIT figureAbbreviations: MR CLEAN-MED, Multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke. The effect of periprocedural medication: acetylsalicylic acid, unfractionated heparin, both or neither; ASA, intravenous acetylsalicylic acid; UFH, intravenous unfractionated heparin; DSA, digital subtraction angiography; NCCT, non-contract computed tomography; CTA, computed tomography angiography; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography; NIHSS, National Institutes of Health Stroke Scale; (s)ICH, symptomatic intracranial hemorrhage; mRS, modified Rankin Scale.Captions: *See trial protocol on https://www.mrclean-med.nl for more information about the patient flow, enrollment, interventions, and assessments; **t₁ = within 1 hour before groin puncture, after randomization; t₂ = after groin puncture/during EVT; t₃ = after EVT; t₄ = 24 hours after EVT; t₅ = 5-7 days after EVT or at discharge; t₆ = 90 days after EVT; ***Informed consent: as early as deemed possible after EVT; ****ASA/UFA loading dose administered directly after groin puncture, or prior to groin puncture in case no recombinant tissue plasminogen activator has been given, UFH continuous infusion until 6 hours after EVT; *****Blood samples: within 1 hour before groin puncture, within 1 hour after EVT, at 24 hours after EVT, if applicable 2-6 months after EVT; ******Recanalization grade on DSA at t₂, and CTA or MRA at t₄

**Fig. 4**
Flow of informed consent procedure in the MR CLEAN-MED.Abbreviations: MR CLEAN-MED, multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke. The effect of periprocedural medication: acetylsalicylic acid, unfractionated heparin, both or neither; ED, emergency department; EVT, endovascular treatment; ASA, intravenous acetylsalicylic acid; UFH, intravenous unfractionated heparin. *Captions:* *The patient or representative will be asked to provide consent as early as deemed appropriate and reasonable after hospital admission, ideally before upcoming study procedures after EVT and ultimately before final outcome assessment

**Fig. 5**
Flow of patients in the acute stroke trials of the Collaboration for New Treatments of Acute Stroke (CONTRAST) consortium.Abbreviations: MR ASAP, Multicentre Randomised trial of Acute Stroke treatment in the Ambulance with a nitroglycerin Patch; ED, emergency department; DIST pilot study, Dutch Intracerebral Hemorrhage Surgery Trial - pilot study; minimally-invasive endoscopy-guided surgery for spontaneous intracerebral hemorrhage; LVO, large vessel occlusion; IVT, intravenous thrombolysis with alteplase; MR CLEAN-MED, multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke. The effect of periprocedural medication: acetylsalicylic acid, unfractionated heparin, both or neither; MR CLEAN-NO IV, intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion; MR CLEAN-LATE: Multicenter Randomized Clinical Trial of Endovascular Stroke treatment in The Netherlands for Late arrivals. *Captions:* *Considerations: The CONTRAST trials are independent clinical trials. Patients included in MR ASAP may also be included in one of the other trials. We will perform pre-specified subgroup analyses to test for interaction between the different study treatments. At the first ED (i.e., primary stroke center or participating EVT center), all patients with a probable diagnosis of acute stroke will undergo non-invasive imaging to differentiate between cerebral infarction or intracranial hemorrhage and to assess an intracranial LVO in the anterior circulation. When the first ED is a primary stroke center and the patient could be eligible for DIST pilot study, MR CLEAN-MED, or MR CLEAN-LATE, the patient should be transferred to a participating EVT center. Patients arriving at a primary stroke center first will generally not be eligible for MR CLEAN-NO IV, since IVT cannot be withheld until after patient transfer to the EVT center, unless the perceived contraindications for IVT are not present anymore upon arrival at the EVT center. Then, inclusion in MR CLEAN-NO IV will have priority over inclusion in other trials. Competition between the three MR CLEAN trials will not occur

**Fig. 6**
Flow of patients in the MR CLEAN-MED—modification after the recommendation of the DSMB to stop recruiting patients for moderate-dose unfractionated heparin.Abbreviations: ASA, intravenous acetylsalicylic acid; CTA, computed tomography angiogram; UFH, intravenous unfractionated heparin; EVT, endovascular treatment; LD, low dose; MD, moderate dose; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography; NCCT, non-contrast computed tomography; NIHSS, National Institutes of Health Stroke Scale. *Captions:**Only to be performed if imaging at 24 hour was acquired with CT; **Blood sample drawn only in case of regular outpatient clinic appointment within 2-6 months after intervention

See this image and copyright information in PMC

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Multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke. The effect of periprocedural medication: acetylsalicylic acid, unfractionated heparin, both, or neither (MR CLEAN-MED). Rationale and study design

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Multicenter randomized clinical trial of endovascular treatment for acute ischemic stroke. The effect of periprocedural medication: acetylsalicylic acid, unfractionated heparin, both, or neither (MR CLEAN-MED). Rationale and study design

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