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
Authors: Chalos Vicky , A. van de Graaf Rob , Roozenbeek Bob , C. G. M. van Es Adriaan , M. den Hertog Heleen , Staals Julie , van Dijk Lukas , F.M. Jenniskens Sjoerd , J. van Oostenbrugge Robert , H. van Zwam Wim , B.W.E.M. Roos Yvo , B.L.M. Majoie Charles , F. Lingsma Hester , van der Lugt Aad , W.J. Dippel Diederik ,   on behalf of the MR CLEAN-MED investigators, Dippel Diederik , van der Lugt Aad , Roozenbeek Bob , Chalos Vicky , van de Graaf Rob , van der Steen Wouter , van Es Adriaan , Coutinho Jonathan , Emmer Bart , de Ridder Inger , van Zwam Wim , van der Worp Bart , Lo Rob , Keizer Koos , Gons Rob , Yo Lonneke , Boiten Jelis , van den Wijngaard Ido , Hofmeijer Jeanette , Martens Jasper , Schonewille Wouter , Vos Jan Albert , Tuladhar Anil M. , Jenniskens Sjoerd , de Laat Karlijn , van Dijk Lukas , den Hertog Heleen , van Hasselt Boudewijn , Brouwers Paul , Sturm Emiel , Remmers Michel , de Jong Thijs , Rozeman Anouk , Elgersma Otto , Uyttenboogaart Maarten , Bokkers Reinoud P. H. , van Tuijl Julia , Boukrab Issam , Staals Julie , Roos Yvo , Majoie Charles , van Oostenbrugge Robert , Rothwell Peter , Molyneux Andrew , Moschandreas Joanna , Nieboer Daan , del Zoppo Gregory , van Nuland Rick , Postma Alida Annechien , van den Berg René , Beenen Ludo , van Doormaal Pieter-Jan , Lycklama Geert , Yoo Albert , Hammer Sebastiaan , Roosendaal Stefan , Meijer Anton , Krietemeijer Menno , van der Hoorn Anouk , Gerrits Dick , Jansen Ben , Manschot Sanne , Kerkhoff Henk , Koudstaal Peter , Lingsma Hester , Berkhemer Olvert , Versteeg Adriaan , Wolff Lennard , Su Jiahang , ten Cate Hugo , de Maat Moniek , Donkel Samantha , van Beusekom Heleen , Taha Aladdin , Treurniet Kilian , van den Berg Sophie , LeCouffe Natalie , Goldhoorn Robert-Jan , Hinsenveld Wouter , Pirson Anne , Sondag Lotte , Kappelhof Manon , Reinink Rik , Tolhuisen Manon , Brouwer Josje , Collette Sabine , Venema Simone Uniken , Olthuis Susan , Pinkaers Floor , Sterrenberg Martin , El Ghannouti Naziha , Verheesen Sabrina , Sprengers Rita , Pellikaan Wilma , Drabbe Yvonne , de Meris Joke , Simons Michelle , Bongenaar Hester , van Loon Anja , Ponjee Eva , Eilander Rieke , Kooij Suze , de Jong Marieke , Santegoets Esther , van der Minne Friedus , Heiligers Leontien , Martens Yvonne 
Published: July 2020

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.