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

Autor:	van der Steen W; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands. Electronic address: w.vandersteen@erasmusmc.nl., van de Graaf RA; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands., Chalos V; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Public Health, Erasmus MC University Medical Center, Rotterdam, Netherlands., Lingsma HF; Department of Public Health, Erasmus MC University Medical Center, Rotterdam, Netherlands., van Doormaal PJ; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands., Coutinho JM; Department of Neurology, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., Emmer BJ; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., de Ridder I; Department of Neurology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands., van Zwam W; Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands., van der Worp HB; Department of Neurology and Neurosurgery, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands., van der Schaaf I; Department of Radiology, Brain Center, University Medical Center Utrecht, Utrecht, Netherlands., Gons RAR; Department of Neurology, Catharina Hospital, Eindhoven, Netherlands., Yo LSF; Department of Radiology, Catharina Hospital, Eindhoven, Netherlands., Boiten J; Department of Neurology, Haaglanden Medical Centre, The Hague, Netherlands., van den Wijngaard I; Department of Neurology, Haaglanden Medical Centre, The Hague, Netherlands; Department of Radiology, Haaglanden Medical Centre, The Hague, Netherlands., Hofmeijer J; Department of Neurology, Rijnstate Hospital, Arnhem, Netherlands., Martens J; Department of Radiology and Nuclear Medicine, Rijnstate Hospital, Arnhem, Netherlands., Schonewille W; Department of Neurology, St Antonius Hospital, Nieuwegein, Netherlands., Vos JA; Department of Radiology, St Antonius Hospital, Nieuwegein, Netherlands., Tuladhar AM; Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands., de Laat KF; Department of Neurology, HagaZiekenhuis, The Hague, Netherlands., van Hasselt B; Department of Radiology, Isala, Zwolle, Netherlands., Remmers M; Department of Neurology, Amphia Hospital, Breda, Netherlands., Vos D; Department of Radiology, Amphia Hospital, Breda, Netherlands., Rozeman A; Department of Neurology, Albert Schweitzer Hospital, Dordrecht, Netherlands., Elgersma O; Department of Radiology, Albert Schweitzer Hospital, Dordrecht, Netherlands., Uyttenboogaart M; Department of Neurology, University Medical Center Groningen, Groningen, Netherlands; Department of Radiology, Medical Imaging Center, University Medical Center Groningen, Groningen, Netherlands., Bokkers RPH; Department of Radiology, Medical Imaging Center, University Medical Center Groningen, Groningen, Netherlands., van Tuijl J; Department of Neurology, Elisabeth-TweeSteden Hospital, Tilburg, Netherlands., Boukrab I; Department of Radiology, Elisabeth-TweeSteden Hospital, Tilburg, Netherlands., van den Berg R; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., Beenen LFM; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., Roosendaal SD; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., Postma AA; Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands., Krietemeijer M; Department of Radiology, Catharina Hospital, Eindhoven, Netherlands., Lycklama G; Department of Radiology, Haaglanden Medical Centre, The Hague, Netherlands., Meijer FJA; Department of Medical Imaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands., Hammer S; Department of Radiology, HagaZiekenhuis, The Hague, Netherlands., van der Hoorn A; Department of Radiology, Medical Imaging Center, University Medical Center Groningen, Groningen, Netherlands., Yoo AJ; Texas Stroke Institute, Dallas-Fort Worth, TX, USA., Gerrits D; Medisch Spectrum Twente, Enschede, Netherlands., Truijman MTB; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands., Zinkstok S; Tergooi, Hilversum, Netherlands., Koudstaal PJ; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands., Manschot S; Department of Neurology, Haaglanden Medical Centre, The Hague, Netherlands., Kerkhoff H; Department of Neurology, Albert Schweitzer Hospital, Dordrecht, Netherlands., Nieboer D; Department of Public Health, Erasmus MC University Medical Center, Rotterdam, Netherlands., Berkhemer O; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., Wolff L; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands., van der Sluijs PM; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands., van Voorst H; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands; Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., Tolhuisen M; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands; Department of Biomedical Engineering and Physics, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., Roos YBWEM; Department of Neurology, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., Majoie CBLM; Department of Radiology & Nuclear Medicine, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands., Staals J; Department of Neurology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands., van Oostenbrugge RJ; Department of Neurology, Maastricht University Medical Centre, Cardiovascular Research Institute Maastricht, Maastricht, Netherlands., Jenniskens SFM; Department of Medical Imaging, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands., van Dijk LC; Department of Radiology, HagaZiekenhuis, The Hague, Netherlands., den Hertog HM; Department of Neurology, Isala, Zwolle, Netherlands., van Es ACGM; Department of Radiology, Leiden University Medical Center, Leiden, Netherlands., van der Lugt A; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands., Dippel DWJ; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands., Roozenbeek B; Department of Neurology, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Radiology and Nuclear Medicine, Erasmus MC University Medical Center, Rotterdam, Netherlands.
Jazyk:	angličtina
Zdroj:	Lancet (London, England) [Lancet] 2022 Mar 12; Vol. 399 (10329), pp. 1059-1069. Date of Electronic Publication: 2022 Feb 28.
DOI:	10.1016/S0140-6736(22)00014-9
Abstrakt:	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. Competing Interests: Declaration of interests 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. (Copyright © 2022 Elsevier Ltd. All rights reserved.)
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