Endovascular treatment for acute ischemic stroke; the use of periprocedural heparin or antiplatelet agents

ISRCTN	ISRCTN76741621
DOI	https://doi.org/10.1186/ISRCTN76741621
EudraCT/CTIS number	2017-001466-21
Secondary identifying numbers	NL61364.078.17

Submission date: 01/11/2017
Registration date: 06/12/2017
Last edited: 13/02/2025

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Circulatory System

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English Summary

Background and study aims
When a blood clot blocks the flow of blood to the brain an ischemic stroke occurs. When this happens, the bloodstream leading to the blocked brain arteries can be entered using very small tubes (catheters) and mechanical devices (retrievable stents). By means of this procedure (intra-arterial treatment; IAT) the clot can be removed and the blocked brain areas can be reopened. This procedure has been proven safe and effective when performed within 6 hours after onset. However, despite clot removal a considerable proportion of patients do not recover. This is for a major part due to a disturbed circulation of the capillaries (Incomplete microvascular reperfusion; IMR). Antiplatelet drugs and heparin may reduce IMR. The aim of this study is to assess the effect of acetylsalicylic acid (ASA) and unfractionated heparin (UFH), alone or in combination, in patients with a stroke undergoing IAT.

Who can participate?
Patients aged 18 or older with acute ischemic stroke undergoing IAT

What does the study involve?
Participants are randomly allocated to be treated with either ASA, UFH, both or neither. When a patient is allocated to receive ASA a loading dose (a large initial dose) is given. When allocated to UFH, patients receive a loading dose and either a low or moderate continuous infusion for 6 hours. Every participant undergoes a brain scan of the cerebral vessels to assess the rate of recanalization (restoration of blood flow) at 24 hours and at 5-7 days to assess final infarct volume (the dead tissue resulting from lack of blood supply). During the hospital stay several blood samples are taken to look for blood clotting abnormalities. After 90 days, participants are contacted by telephone to check on their general condition.

What are the possible benefits and risks of participating?
There is a potential benefit of an improved functional outcome and a low risk, which includes the risk of bleeding inside the skull. The potential benefits of ASA and UFH are expected to outweigh the limited risks of harm of these study treatments.

Where is the study run from?
The study will run in about 19 stroke intervention centers in the Netherlands. The lead center is the Erasmus Medical Center.

When is the study starting and how long is it expected to run for?
May 2017 to April 2022

Who is funding the study?
1. Dutch Heart Foundation (Netherlands)
2. Dutch Brain Foundation (Netherlands)
3. Stryker (USA)

Who is the main contact?
Rob van de Graaf, MD

Study website

Contact information

Mr Rob van de Graaf
Scientific

Erasmus MC, University Medical Center
's Gravendijkwal 230
Departments of Neurology and Radiology
Room Ee 2240.
Rotterdam
3000 CA
Netherlands

Study information

Study design	Multicenter phase III clinical trial with randomized treatment allocation, open-label treatment and blinded endpoint assessment (PROBE), with a 2x3 factorial design
Primary study design	Interventional
Secondary study design	Randomised controlled trial
Study setting(s)	Hospital
Study type	Treatment
Participant information sheet	Not available in web format yet, please use the contact details to request a patient information sheet.
Scientific title	Multicenter Randomized CLinical trial of Endovascular treatment for Acute ischemic stroke in the Netherlands: the effect of periprocedural MEDication: heparin, antiplatelet agents, both or neither
Study acronym	MR CLEAN-MED
Study hypothesis	The use of unfractionated heparin and acetylsalicylic acid, alone, or in combination increases functional outcome within 3 months in patients who undergo intra-arterial treatment for an acute ischemic stroke caused by a confirmed intracranial large vessel occlusion of the anterior circulation.
Ethics approval(s)	Medisch Ethische Toetsings Commissie Erasmus MC (Medical Ethical Committee Erasmus MC), 09/10/2017, ref: MEC-2017-366
Condition	Acute ischemic stroke due to an intracranial large vessel occlusion of the anterior circulation
Intervention	Patients will be randomized either to receive acetylsalicylic acid, unfractionated heparin, both or none during intra-arterial treatment. The randomization procedure will be computer- and web-based, permuted blocks. Backup by telephone. Randomization will take place according to the 2x3 factorial PROBE design. Acetylsalicylic acid will be administered intravenously, in a loading dose of 300 mg. Unfractionated heparin will be administered intravenously in a low dose (loading dose of 5000 IU followed by 500 IU/hour x 6 hours) or moderate dose (loading dose of 5000 IU followed by 1250 IU/hour x 6 hours). Both the IV acetylsalicylic acid and heparin treatment should be started prior to groin puncture when no IVT is administered or directly after/when the IV alteplase has been stopped. Every participant will undergo a brain scan of the cerebral vessels to assess rate of recanalization at 24 hours and at 5-7 days to assess final infarct volume. During hospital stay several blood samples will be drawn to look for blood clotting abnormalities. After 90 days, participants are approached by telephone to check on their general condition.
Intervention type	Drug
Pharmaceutical study type(s)	Not Applicable
Phase	Phase III
Drug / device / biological / vaccine name(s)	Unfractionated heparin, acetylsalicylic acid
Primary outcome measure	Functional outcome, measured by the modified Rankin Scale (mRS) at 90 days. Assessment of outcome on the mRS will be performed by independent assessors, blinded to the allocated and actually received treatment. Their assessment will be based on standardized reports of a telephone interview by trained research personnel who are not aware of treatment allocation.
Secondary outcome measures	1. Reperfusion grade, measured by the extended treatment in cerebral ischaemia (eTICI) score on final angiography of IAT 2. Symptomatic intra-cranial hemorrhage, according to the Heidelberg criteria 3. Clinical stroke severity, measured by the National Institutes of Health Stroke Scale score at 24 hours, and 5-7 days after randomization, or at discharge 4. Final infarct volume, measured on cranial non-contrast CT or MRI in a subset of 600 patients at 5-7 days after randomization. Infarct size at day 5-7 will be compared with plain CT and perfusion CT results (if available) at baseline 5. Dichotomization of functional outcome, measured by the modified Rankin Scale (mRS) at 90 days 6. Mortality at 90 days
Overall study start date	01/05/2017
Overall study end date	30/04/2022

Eligibility

Participant type(s)	Patient
Age group	Adult
Lower age limit	18 Years
Sex	Both
Target number of participants	1500
Total final enrolment	663
Participant inclusion criteria	1. A clinical diagnosis of acute ischemic stroke 2. Caused by a intracranial large vessel occlusion of the anterior circulation: distal intracranial carotid artery or middle (M1/proximal M2) cerebral artery, confirmed by neuro-imaging (CTA or MRA) 3. CT or MRI ruling out intracranial hemorrhage 4. Intra-arterial treatment (groin puncture) possible within 0-6 hours 5. A score of at least 2 on the NIH Stroke Scale 6. Age of 18 years or older 7. Written informed consent (deferred)
Participant exclusion criteria	1. Pre-stroke disability which interferes with the assessment of functional outcome at 90 days, i.e. mRS >2 2. Treatment with IV alteplase despite the following contra-indications for IV alteplase: 2.1. Cerebral infarction in the previous 6 weeks with residual neurological deficit or signs of recent infarction on neuroimaging 2.2. Previous intracerebral hemorrhage within the previous 3 months 2.3. INR exceeding 1.7 2.4. Prior use of direct oral anticoagulant (DOAC) 2.5. IV alteplase infusion >4.5 hours after symptom onset 3. Contra-indications for ASA/unfractionated heparin, for instance: allergy, recent surgery, heparin induced thrombocytopenia 4. INR exceeding 3.0 5. Thrombocyte count <100^9/L 6. Participation in trials other than current and MR ASAP
Recruitment start date	01/11/2017
Recruitment end date	01/11/2021

Locations

Countries of recruitment

Netherlands

Study participating centres

Erasmus MC, University Medical Center

Rotterdam
3000 CA
Netherlands

Academic Medical Center

Amsterdam
1005 AZ
Netherlands

University Medical Center Utrecht

Utrecht
3508 GA
Netherlands

Maastricht University Medical Center

Maastricht
6202 AZ
Netherlands

Sponsor information

Erasmus MC, University Medical Center
Charity

Erasmus MC, University Medical Center
Department of Neurology
Room Ee2240
Rotterdam
3000 CA
Netherlands

"ROR"	https://ror.org/018906e22

Funders

Funder type

Charity

Hartstichting
Private sector organisation / Trusts, charities, foundations (both public and private)

Alternative name(s): Heart Foundation
Location: Netherlands

Hersenstichting
Private sector organisation / Trusts, charities, foundations (both public and private)

Alternative name(s): Hersenstichting Nederland, Nederlandse Hersenstichting
Location: Netherlands

Stryker
Private sector organisation / For-profit companies (industry)

Alternative name(s): Stryker Corporation
Location: United States of America

Results and Publications

Intention to publish date	01/11/2023
Individual participant data (IPD) Intention to share	No
IPD sharing plan summary	Data sharing statement to be made available at a later date
Publication and dissemination plan	Additional documents (study protocol/statistical analysis plan) will be available approximately 1 year after the first patient’s inclusion. Planned publication of results in a high-impact peer reviewed journal.
IPD sharing plan	The data sharing plans for the current study are unknown and will be made available at a later date.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		28/02/2022	04/03/2022	Yes	No
Other publications	Study progress abstract European Stroke Organisation Conference 2021	03/09/2021	29/03/2023	Yes	No
Protocol article		14/07/2020	13/02/2025	Yes	No

Editorial Notes

13/02/2025: Publication reference added.
29/03/2023: Abstract added.
04/03/2022: The following changes have been made:
1. Publication reference added.
2. The total final enrolment number has been added from the reference.
16/02/2021: Publication reference added.