PMID- 32665035 OWN - NLM STAT- MEDLINE DCOM- 20210513 LR - 20240329 IS - 1745-6215 (Electronic) IS - 1745-6215 (Linking) VI - 21 IP - 1 DP - 2020 Jul 14 TI - 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. PG - 644 LID - 10.1186/s13063-020-04514-9 [doi] LID - 644 AB - 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 x 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. FAU - Chalos, Vicky AU - Chalos V AD - Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. AD - Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. AD - Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands. FAU - A van de Graaf, Rob AU - A van de Graaf R AD - Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. AD - Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. FAU - Roozenbeek, Bob AU - Roozenbeek B AUID- ORCID: 0000-0002-8320-8303 AD - Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. b.roozenbeek@erasmusmc.nl. AD - Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. b.roozenbeek@erasmusmc.nl. FAU - C G M van Es, Adriaan AU - C G M van Es A AD - Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. FAU - M den Hertog, Heleen AU - M den Hertog H AD - Department of Neurology, Isala, Zwolle, The Netherlands. FAU - Staals, Julie AU - Staals J AD - Department of Neurology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands. FAU - van Dijk, Lukas AU - van Dijk L AD - Department of Radiology & Nuclear Medicine, HagaZiekenhuis, Radiology, Den Haag, The Netherlands. FAU - F M Jenniskens, Sjoerd AU - F M Jenniskens S AD - Department of Radiology & Nuclear Medicine, Radboud University Medical Center, Nijmegen, The Netherlands. FAU - J van Oostenbrugge, Robert AU - J van Oostenbrugge R AD - Department of Neurology, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands. FAU - H van Zwam, Wim AU - H van Zwam W AD - Department of Radiology & Nuclear Medicine, Cardiovascular Research Institute Maastricht, Maastricht University Medical Center, Maastricht, The Netherlands. FAU - B W E M Roos, Yvo AU - B W E M Roos Y AD - Department of Neurology, Amsterdam UMC, University of Amsterdam, location AMC, Amsterdam, The Netherlands. FAU - B L M Majoie, Charles AU - B L M Majoie C AD - Department of Radiology & Nuclear Medicine, Amsterdam UMC, University of Amsterdam, location AMC, Amsterdam, The Netherlands. FAU - F Lingsma, Hester AU - F Lingsma H AD - Department of Public Health, Erasmus MC University Medical Center, Rotterdam, The Netherlands. FAU - van der Lugt, Aad AU - van der Lugt A AD - Department of Radiology & Nuclear Medicine, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands. FAU - W J Dippel, Diederik AU - W J Dippel D AD - Department of Neurology, Erasmus MC University Medical Center, Rotterdam, The Netherlands. CN - MR CLEAN-MED investigators LA - eng PT - Clinical Trial Protocol PT - Journal Article DEP - 20200714 PL - England TA - Trials JT - Trials JID - 101263253 RN - 9005-49-6 (Heparin) RN - R16CO5Y76E (Aspirin) SB - IM MH - Adult MH - Aspirin/*therapeutic use MH - Brain Ischemia/*drug therapy MH - *Endovascular Procedures MH - Heparin/*therapeutic use MH - Humans MH - Ischemic Stroke/*drug therapy MH - Multicenter Studies as Topic MH - Prospective Studies MH - Randomized Controlled Trials as Topic MH - Thrombectomy MH - Treatment Outcome PMC - PMC7362523 OTO - NOTNLM OT - Acetylsalicylic acid OT - Cerebrovascular disorders OT - Endovascular treatment OT - Heparin OT - Ischemic stroke OT - Periprocedural OT - Randomized controlled trial OT - Thrombectomy COIS- WvZ: reports that Maastricht University Medical Center received compensation from Stryker(R) and Cerenovus(R) 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(R); 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(R), 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(R), 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. FIR - Dippel, Diederik IR - Dippel D FIR - van der Lugt, Aad IR - van der Lugt A FIR - Roozenbeek, Bob IR - Roozenbeek B FIR - Chalos, Vicky IR - Chalos V FIR - van de Graaf, Rob IR - van de Graaf R FIR - van der Steen, Wouter IR - van der Steen W FIR - van Es, Adriaan IR - van Es A FIR - Coutinho, Jonathan IR - Coutinho J FIR - Emmer, Bart IR - Emmer B FIR - de Ridder, Inger IR - de Ridder I FIR - van Zwam, Wim IR - van Zwam W FIR - van der Worp, Bart IR - van der Worp B FIR - Lo, Rob IR - Lo R FIR - Keizer, Koos IR - Keizer K FIR - Gons, Rob IR - Gons R FIR - Yo, Lonneke IR - Yo L FIR - Boiten, Jelis IR - Boiten J FIR - van den Wijngaard, Ido IR - van den Wijngaard I FIR - Hofmeijer, Jeanette IR - Hofmeijer J FIR - Martens, Jasper IR - Martens J FIR - Schonewille, Wouter IR - Schonewille W FIR - Vos, Jan Albert IR - Vos JA FIR - Tuladhar, Anil M IR - Tuladhar AM FIR - Jenniskens, Sjoerd IR - Jenniskens S FIR - de Laat, Karlijn IR - de Laat K FIR - van Dijk, Lukas IR - van Dijk L FIR - den Hertog, Heleen IR - den Hertog H FIR - van Hasselt, Boudewijn IR - van Hasselt B FIR - Brouwers, Paul IR - Brouwers P FIR - Sturm, Emiel IR - Sturm E FIR - Remmers, Michel IR - Remmers M FIR - de Jong, Thijs IR - de Jong T FIR - Rozeman, Anouk IR - Rozeman A FIR - Elgersma, Otto IR - Elgersma O FIR - Uyttenboogaart, Maarten IR - Uyttenboogaart M FIR - Bokkers, Reinoud P H IR - Bokkers RPH FIR - van Tuijl, Julia IR - van Tuijl J FIR - Boukrab, Issam IR - Boukrab I FIR - Staals, Julie IR - Staals J FIR - Roos, Yvo IR - Roos Y FIR - Majoie, Charles IR - Majoie C FIR - van Oostenbrugge, Robert IR - van Oostenbrugge R FIR - Rothwell, Peter IR - Rothwell P FIR - Molyneux, Andrew IR - Molyneux A FIR - Moschandreas, Joanna IR - Moschandreas J FIR - Nieboer, Daan IR - Nieboer D FIR - Del Zoppo, Gregory IR - Del Zoppo G FIR - van Nuland, Rick IR - van Nuland R FIR - Postma, Alida Annechien IR - Postma AA FIR - van den Berg, Rene IR - van den Berg R FIR - Beenen, Ludo IR - Beenen L FIR - van Doormaal, Pieter-Jan IR - van Doormaal PJ FIR - Lycklama, Geert IR - Lycklama G FIR - Yoo, Albert IR - Yoo A FIR - Hammer, Sebastiaan IR - Hammer S FIR - Roosendaal, Stefan IR - Roosendaal S FIR - Meijer, Anton IR - Meijer A FIR - Krietemeijer, Menno IR - Krietemeijer M FIR - van der Hoorn, Anouk IR - van der Hoorn A FIR - Gerrits, Dick IR - Gerrits D FIR - Jansen, Ben IR - Jansen B FIR - Manschot, Sanne IR - Manschot S FIR - Kerkhoff, Henk IR - Kerkhoff H FIR - Koudstaal, Peter IR - Koudstaal P FIR - Lingsma, Hester IR - Lingsma H FIR - Berkhemer, Olvert IR - Berkhemer O FIR - Versteeg, Adriaan IR - Versteeg A FIR - Wolff, Lennard IR - Wolff L FIR - Su, Jiahang IR - Su J FIR - Ten Cate, Hugo IR - Ten Cate H FIR - de Maat, Moniek IR - de Maat M FIR - Donkel, Samantha IR - Donkel S FIR - van Beusekom, Heleen IR - van Beusekom H FIR - Taha, Aladdin IR - Taha A FIR - Treurniet, Kilian IR - Treurniet K FIR - van den Berg, Sophie IR - van den Berg S FIR - LeCouffe, Natalie IR - LeCouffe N FIR - Goldhoorn, Robert-Jan IR - Goldhoorn RJ FIR - Hinsenveld, Wouter IR - Hinsenveld W FIR - Pirson, Anne IR - Pirson A FIR - Sondag, Lotte IR - Sondag L FIR - Kappelhof, Manon IR - Kappelhof M FIR - Reinink, Rik IR - Reinink R FIR - Tolhuisen, Manon IR - Tolhuisen M FIR - Brouwer, Josje IR - Brouwer J FIR - Collette, Sabine IR - Collette S FIR - Venema, Simone Uniken IR - Venema SU FIR - Olthuis, Susan IR - Olthuis S FIR - Pinkaers, Floor IR - Pinkaers F FIR - Sterrenberg, Martin IR - Sterrenberg M FIR - El Ghannouti, Naziha IR - El Ghannouti N FIR - Verheesen, Sabrina IR - Verheesen S FIR - Sprengers, Rita IR - Sprengers R FIR - Pellikaan, Wilma IR - Pellikaan W FIR - Drabbe, Yvonne IR - Drabbe Y FIR - de Meris, Joke IR - de Meris J FIR - Simons, Michelle IR - Simons M FIR - Bongenaar, Hester IR - Bongenaar H FIR - van Loon, Anja IR - van Loon A FIR - Ponjee, Eva IR - Ponjee E FIR - Eilander, Rieke IR - Eilander R FIR - Kooij, Suze IR - Kooij S FIR - de Jong, Marieke IR - de Jong M FIR - Santegoets, Esther IR - Santegoets E FIR - van der Minne, Friedus IR - van der Minne F FIR - Heiligers, Leontien IR - Heiligers L FIR - Martens, Yvonne IR - Martens Y EDAT- 2020/07/16 06:00 MHDA- 2021/05/14 06:00 PMCR- 2020/07/14 CRDT- 2020/07/16 06:00 PHST- 2020/02/07 00:00 [received] PHST- 2020/06/15 00:00 [accepted] PHST- 2020/07/16 06:00 [entrez] PHST- 2020/07/16 06:00 [pubmed] PHST- 2021/05/14 06:00 [medline] PHST- 2020/07/14 00:00 [pmc-release] AID - 10.1186/s13063-020-04514-9 [pii] AID - 4514 [pii] AID - 10.1186/s13063-020-04514-9 [doi] PST - epublish SO - Trials. 2020 Jul 14;21(1):644. doi: 10.1186/s13063-020-04514-9.