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

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.

• Authors: Wouter van der Steen, Rob A van de Graaf, 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 Vos, Anil 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, Martine T B Truijman, Sanne Zinkstok, Peter J Koudstaal, Sanne Manschot, Henk Kerkhoff, Daan Nieboer, Olvert Berkhemer, Lennard Wolff, P Matthijs van der Sluijs, Henk van Voorst, Manon Tolhuisen, Yvo B W E M 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, MR CLEAN-MED investigators
• Journal: Lancet (London, England) (Lancet) Vol. 399 Issue 10329 Pg. 1059-1069 (03 12 2022) ISSN: 1474-547X [Electronic] England
• PMID: 35240044 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: Copyright © 2022 Elsevier Ltd. All rights reserved.

Chemical References

• Heparin
• Aspirin

Topics

• Adult
• Aspirin (therapeutic use)
• Brain Ischemia (therapy)
• Heparin (adverse effects)
• Humans
• Magnetic Resonance Imaging
• Stroke (etiology)
• Treatment Outcome