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. 2021 Feb 15;22(1):141.
doi: 10.1186/s13063-021-05063-5.

MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial

Kilian M Treurniet #  1 , Natalie E LeCouffe #  1   2 , Manon Kappelhof #  1 , Bart J Emmer  1 , Adriaan C G M van Es  3 , Jelis Boiten  4 , Geert J Lycklama  5 , Koos Keizer  6 , Lonneke S F Yo  7 , Hester F Lingsma  8 , Wim H van Zwam  9 , Inger de Ridder  10 , Robert J van Oostenbrugge  10 , Aad van der Lugt  11 , Diederik W J Dippel  12 , Jonathan M Coutinho  2 , Yvo B W E M Roos #  2 , Charles B L M Majoie #  13 ; MR CLEAN-NO IV Investigators
Affiliations

MR CLEAN-NO IV: intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion-study protocol for a randomized clinical trial

Kilian M Treurniet et al. Trials. .

Abstract

Background: Endovascular treatment (EVT) has greatly improved the prognosis of acute ischemic stroke (AIS) patients with a proximal intracranial large vessel occlusion (LVO) of the anterior circulation. Currently, there is clinical equipoise concerning the added benefit of intravenous alteplase administration (IVT) prior to EVT. The aim of this study is to assess the efficacy and safety of omitting IVT before EVT in patients with AIS caused by an anterior circulation LVO.

Methods: MR CLEAN-NO IV is a multicenter randomized open-label clinical trial with blinded outcome assessment (PROBE design). Patients ≥ 18 years of age with a pre-stroke mRS < 3 with an LVO confirmed on CT angiography/MR angiography eligible for both IVT and EVT are randomized to receive either IVT (0.9 mg/kg) followed by EVT, or direct EVT in a 1:1 ratio. The primary objective is to assess superiority of direct EVT. Secondarily, non-inferiority of direct EVT compared to IVT before EVT will be explored. The primary outcome is the score on the modified Rankin Scale at 90 days. Ordinal regression with adjustment for prognostic variables will be used to estimate treatment effect. Secondary outcomes include reperfusion graded with the eTICI scale after EVT and stroke severity (National Institutes of Health Stroke Scale) at 24 h. Safety outcomes include intracranial hemorrhages scored according to the Heidelberg criteria. A total of 540 patients will be included.

Discussion: IVT prior to EVT might facilitate early reperfusion before EVT or improved reperfusion rates during EVT. Conversely, among other potential adverse effects, the increased risk of bleeding could nullify the beneficial effects of IVT. MR CLEAN-NO IV will provide insight into whether IVT is still of added value in patients eligible for EVT.

Trial registration: www.isrctn.com : ISRCTN80619088 . Registered on 31 October 2017.

Keywords: Endovascular treatment; Intravenous alteplase; Ischemic stroke.

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Conflict of interest statement

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

YR reports that he is a shareholder of Nico.lab

JMC reports that Amsterdam UMC received research support from Medtronic.

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.

DD and AvdL report 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 Organization for Health Research and Development, Health Holland Top Sector Life Sciences & Health, Stryker, Thrombolytic Science, LLC, and Cerenovus.

All other authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
MR CLEAN-NO IV logo
Fig. 2
Fig. 2
Patient flow in MR CLEAN-NO IV. Abbreviations: CTA, CT angiography; EVT, endovascular treatment; IVT, intravenous alteplase administration; MRI, magnetic resonance imaging; MRA, magnetic resonance angiography; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale
Fig. 3
Fig. 3
Timing of all procedures in MR CLEAN-NO IV. Abbreviations: EVT, endovascular treatment; IVT, intravenous alteplase administration; MRI, magnetic resonance imaging; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale
Fig. 4
Fig. 4
Flow of informed consent procedure in MR CLEAN-NO IV. Abbreviations: ER, emergency room; EVT, endovascular treatment; IVT, intravenous thrombolysis; MR CLEAN-NO IV: Intravenous treatment followed by endovascular treatment versus direct endovascular treatment for acute ischemic stroke caused by a proximal intracranial occlusion
Fig. 5
Fig. 5
Flow of patients in the 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. *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
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