Safety and efficacy of aspirin, unfractionated heparin, both, or neither during endovascular stroke treatment (MR CLEAN-MED): an open-label, multicentre, randomised controlled trial

Wouter van der Steen*, Rob A. van de Graaf, MR CLEAN-MED investigators, Vicky Chalos, Hester F. Lingsma, Pieter Jan van Doormaal, Jonathan M. Coutinho, Bart J. Emmer, Inger de Ridder, Wim van Zwam, H. Bart van der Worp, Irene van der Schaaf, Rob A.R. Gons, Lonneke S.F. Yo, Jelis Boiten, Ido van den Wijngaard, Jeannette Hofmeijer, Jasper Martens, Wouter Schonewille, Jan Albert VosAnil Man Tuladhar, Karlijn F. de Laat, Boudewijn van Hasselt, Michel Remmers, Douwe Vos, Anouk Rozeman, Otto Elgersma, Maarten Uyttenboogaart, Reinoud P.H. Bokkers, Julia van Tuijl, Issam Boukrab, René van den Berg, Ludo F.M. Beenen, Stefan D. Roosendaal, Alida Annechien Postma, Menno Krietemeijer, Geert Lycklama, Frederick J.A. Meijer, Sebastiaan Hammer, Anouk van der Hoorn, Albert J. Yoo, DIck Gerrits, MTB Truijman, Sanne M. Zinkstok, Peter J. Koudstaal, Sanne Manschot, Henk Kerkhoff, Daan Nieboer, Olvert Berkhemer, Lennard Wolff, Matthijs van der Sluijs, Henk van Voorst, ML Tolhuisen, Bwem Roos, Charles B.L.M. Majoie, Julie Staals, Robert J. van Oostenbrugge, Sjoerd F.M. Jenniskens, Lukas C. van Dijk, Heleen M. den Hertog, Adriaan C.G.M. van Es, Aad van der Lugt, Diederik W.J. Dippel, Bob Roozenbeek

*Corresponding author for this work

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Abstract

Background: Aspirin and unfractionated heparin are often used during endovascular stroke treatment to improve reperfusion and outcomes. However, the effects and risks of anti-thrombotics for this indication are unknown. We therefore aimed to assess the safety and efficacy of intravenous aspirin, unfractionated heparin, both, or neither started during endovascular treatment in patients with ischaemic stroke. Methods: We did an open-label, multicentre, randomised controlled trial with a 2 × 3 factorial design in 15 centres in the Netherlands. We enrolled adult patients (ie, ≥18 years) with ischaemic stroke due to an intracranial large-vessel occlusion in the anterior circulation in whom endovascular treatment could be initiated within 6 h of symptom onset. Eligible patients had a score of 2 or more on the National Institutes of Health Stroke Scale, and a CT or MRI ruling out intracranial haemorrhage. Randomisation was done using a web-based procedure with permuted blocks and stratified by centre. Patients were randomly assigned (1:1) to receive either periprocedural intravenous aspirin (300 mg bolus) or no aspirin, and randomly assigned (1:1:1) to receive moderate-dose unfractionated heparin (5000 IU bolus followed by 1250 IU/h for 6 h), low-dose unfractionated heparin (5000 IU bolus followed by 500 IU/h for 6 h), or no unfractionated heparin. The primary outcome was the score on the modified Rankin Scale at 90 days. Symptomatic intracranial haemorrhage was the main safety outcome. Analyses were based on intention to treat, and treatment effects were expressed as odds ratios (ORs) or common ORs, with adjustment for baseline prognostic factors. This trial is registered with the International Standard Randomised Controlled Trial Number, ISRCTN76741621. Findings: Between Jan 22, 2018, and Jan 27, 2021, we randomly assigned 663 patients; of whom, 628 (95%) provided deferred consent or died before consent could be asked and were included in the modified intention-to-treat population. On Feb 4, 2021, after unblinding and analysis of the data, the trial steering committee permanently stopped patient recruitment and the trial was stopped for safety concerns. The risk of symptomatic intracranial haemorrhage was higher in patients allocated to receive aspirin than in those not receiving aspirin (43 [14%] of 310 vs 23 [7%] of 318; adjusted OR 1·95 [95% CI 1·13–3·35]) as well as in patients allocated to receive unfractionated heparin than in those not receiving unfractionated heparin (44 [13%] of 332 vs 22 [7%] of 296; 1·98 [1·14–3·46]). Both aspirin (adjusted common OR 0·91 [95% CI 0·69–1·21]) and unfractionated heparin (0·81 [0·61–1·08]) led to a non-significant shift towards worse modified Rankin Scale scores. Interpretation: Periprocedural intravenous aspirin and unfractionated heparin during endovascular stroke treatment are both associated with an increased risk of symptomatic intracranial haemorrhage without evidence for a beneficial effect on functional outcome. Funding: The Collaboration for New Treatments of Acute Stroke consortium, the Brain Foundation Netherlands, the Ministry of Economic Affairs, Stryker, Medtronic, Cerenovus, and the Dutch Heart Foundation.

Original languageEnglish
Pages (from-to)1059-1069
Number of pages11
JournalThe Lancet
Volume399
Issue number10329
DOIs
Publication statusPublished - 12 Mar 2022

Bibliographical note

Funding Information:
This study was funded by the Collaboration for New Treatments of Acute Stroke (CONTRAST) consortium, which acknowledges the support from the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation (CVON2015-01: CONTRAST); the Brain Foundation Netherlands (HA2015.01.06); the Ministry of Economic Affairs, by means of the public–private partnerships Allowance made available by Top Sector Life Sciences & Health to stimulate public–private partnerships (LSHM17016); and in part through unrestricted funding by Stryker, Medtronic, and Cerenovus. We are grateful to the Scientific Advisory Board and to the members of the Data Safety Monitoring Board (names disclosed in the appendix [p3]) for their dedication and advice.

Funding Information:
This study was funded by the Collaboration for New Treatments of Acute Stroke (CONTRAST) consortium, which acknowledges the support from the Netherlands Cardiovascular Research Initiative, an initiative of the Dutch Heart Foundation (CVON2015-01: CONTRAST); the Brain Foundation Netherlands (HA2015.01.06); the Ministry of Economic Affairs, by means of the public–private partnerships Allowance made available by Top Sector Life Sciences & Health to stimulate public–private partnerships (LSHM17016); and in part through unrestricted funding by Stryker, Medtronic, and Cerenovus. We are grateful to the Scientific Advisory Board and to the members of the Data Safety Monitoring Board (names disclosed in the appendix [p3] ) for their dedication and advice.

Funding Information:
BR and DWJD report financial support for the current manuscript from the CONTRAST consortium, all paid to their institution. AvdL, BR, HBvdW, CBLMM, DWJD, and MU report funding from the Dutch Heart Foundation, all paid to their institution. AvdL and DWJD report funding from the Dutch Brain foundation paid to their institution. AvdL, BJE, DWJD, and MU report funding from Health Holland Top Sector Life Sciences & Health, all paid to their institution. AvdH, BJE, BR, DWJD, JAV, JMC, and RvdB report grants from the Netherlands Organisation for Health Research and Development, all paid to their institution. AvdL, AJY, HBvdW, CBLMM, and DWJD report funding from Stryker, all paid to their institution. AvdL, AJY, DWJD, and RPHB report funding from Cerenovus, all paid to their institution. AvdL, AJY, DWJD, and JMC report funding from Medtronic, all paid to their institution. AvdL, AJY, and DWJD report funding from Penumbra, all paid to their institution. AvdL and DWJD report funding from Thrombolytic Science paid to their institution. AJY, CBLMM and YBWEMR are minor shareholders of Nicolab. AJY reports funding from Genentech paid to his institution; consulting fees from Penumbra, Cerenovus, Philips, and Vesalio paid to himself; participates in an advisory board of Philips, Nicolab, XCath, and HCA; is part of the endovascular safety monitor of the NIH MOST trial; is an associate editor of the Stroke: Vascular and Interventional Neurology journal; and is a stock owner of Insera. AAP reports institutional grants from Siemens Healthineers and Bayer Healthcare. FJAM reports reimbursements for lectures for Speaker Bureau and Canon Medical Systems. AMT reports being a junior staff member of the Dutch Heart Foundation. BJE reports being a delegate of the Netherlands in the European Union of Medical Specialists Neuroradiology. HBvdW reports grants from the European Union, and participation in an advisory board of Bayer Healthcare and LivaNova, all paid to their institution. CBLMM received funds from the European Commission, TWIN foundation, and Health Evaluation Netherlands, all paid to their institution. JMC reports funding from the Dutch Thrombosis Society and the Dr CJ Vaillant Foundation; consulting fees from Bayer Healthcare, Boehringer, and Portola, all paid to their institution; a fellowship from the European Stroke Organisation; and is a member of the writing committee of the European Stroke Organisation guideline on cerebral venous thrombosis, both unpaid. WvZ reports consulting and speaker fees from Philips, Stryker, Cerenovus, and NicoLab, all paid to their institution; and participation in advisory boards of WeTrust (Philips), Solonda (Anaconda), and InExtremis (CHU Montpellier). All other authors declare no competing interests.

Publisher Copyright:
© 2022 Elsevier Ltd

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