Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial.

BACKGROUND

Whether thrombectomy alone is equally as effective as intravenous alteplase plus thrombectomy remains controversial. We aimed to determine whether thrombectomy alone would be non-inferior to intravenous alteplase plus thrombectomy in patients presenting with acute ischaemic stroke.

METHODS

In this multicentre, randomised, open-label, blinded-outcome trial in Europe and Canada, we recruited patients with stroke due to large vessel occlusion confirmed with CT or magnetic resonance angiography admitted to endovascular centres. Patients were randomly assigned (1:1) via a centralised web server using a deterministic minimisation method to receive stent-retriever thrombectomy alone or intravenous alteplase plus stent-retriever thrombectomy. In both groups, thrombectomy was initiated as fast as possible with any commercially available Solitaire stent-retriever revascularisation device (Medtronic, Irvine, CA, USA). In the combined treatment group, intravenous alteplase (0·9 mg/kg bodyweight, maximum dose 90 mg per patient) was administered as early as possible after randomisation for 60 min with 10% of the calculated dose given as an initial bolus. Personnel assessing the primary outcome were masked to group allocation; patients and treating physicians were not. The primary binary outcome was a score of 2 or less on the modified Rankin scale at 90 days. We assessed the non-inferiority of thrombectomy alone versus intravenous alteplase plus thrombectomy in all randomly assigned and consenting patients using the one-sided lower 95% confidence limit of the Mantel-Haenszel risk difference, with a prespecified non-inferiority margin of 12%. The main safety endpoint was symptomatic intracranial haemorrhage assessed in all randomly assigned and consenting participants. This trial is registered with ClinicalTrials.gov, NCT03192332, and is closed to new participants.

FINDINGS

Between Nov 29, 2017, and May 7, 2021, 5215 patients were screened and 423 were randomly assigned, of whom 408 (201 thrombectomy alone, 207 intravenous alteplase plus thrombectomy) were included in the primary efficacy analysis. A modified Rankin scale score of 0-2 at 90 days was reached by 114 (57%) of 201 patients assigned to thrombectomy alone and 135 (65%) of 207 patients assigned to intravenous alteplase plus thrombectomy (adjusted risk difference -7·3%, 95% CI -16·6 to 2·1, lower limit of one-sided 95% CI -15·1%, crossing the non-inferiority margin of -12%). Symptomatic intracranial haemorrhage occurred in five (2%) of 201 patients undergoing thrombectomy alone and seven (3%) of 202 patients receiving intravenous alteplase plus thrombectomy (risk difference -1·0%, 95% CI -4·8 to 2·7). Successful reperfusion was less common in patients assigned to thrombectomy alone (182 [91%] of 201 vs 199 [96%] of 207, risk difference -5·1%, 95% CI -10·2 to 0·0, p=0·047).

INTERPRETATION

Thrombectomy alone was not shown to be non-inferior to intravenous alteplase plus thrombectomy and resulted in decreased reperfusion rates. These results do not support omitting intravenous alteplase before thrombectomy in eligible patients.

FUNDING

Medtronic and University Hospital Bern.

Informations de copyright

Copyright © 2022 Elsevier Ltd. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests UF reports financial support for the present study from Medtronic; research grants from Medtronic BEYOND SWIFT registry, the Swiss National Science Foundation, and the Swiss Heart Foundation; consulting fees from Medtronic, Stryker, and CSL Behring (fees paid to institution); has membership of a data safety monitoring board for the IN EXTREMIS trial and the TITAN trial; was on the advisory board for Portola (Alexion; fees paid to institution); and is Vice President of the Swiss Neurological Society. JK reports financial support from Medtronic for the BEYOND SWIFT registry (fees paid to institution); and research grants from the Swiss National Science Foundation supporting the TECNO trial (fees paid to institution), Swiss Academy of Medical Sciences supporting MRI research (fees paid to institution), and Swiss Heart Foundation supporting cardiac MRI in the aetiological work-up of stroke patients (fees paid to institution). CC reports consulting fees from Medtronic. PMo reports research funding (fees paid to institution) from the Swiss National Science Foundation, the Swiss Heart Foundation, and Medtronic. GM reports consulting fees from Stryker Neurovascular; and was paid for lectures for Medtronic and Microvention Europe. IS reports consulting fees from Sanofi Synthé-Labo, Servier, Boheringer Ingelheim, AstraZeneca, Novonordisk, and Medtronic; and payment or honoraria from Sanofi Synthé-Labo, Medtronic, Boheringer Ingelheim, AstraZeneca, and BMS—Pfizer. ON reports funding from a Stryker Research grant; and payment or honoraria for lectures for Phenox and Stryker. MR reports consulting fees from Medtronic, Stryker, Cerenovus, Philips, and Apta Targets; payment or honoraria from Ischemia View; participates on a data safety monitoring board or advisory board of Sensome; and has stock or stock options in Anaconda Biomed, CVAid, and Methinks. EC reports grants from the Swiss Heart Foundation and Swiss National Science Foundation, not related to the present study. ARL reports grants from the University of Zurich, the LOOP Zurich, and P&K Pühringer Foundation; consulting fees from Bayer; and a lecture honorarium from Moleac Pte, Singapore. WP reports grants from the German Research Foundation, LOEWE (research funding of the federal state of Hesse); royalties or licenses from the Stroke Team Training (Laerdal Medical); payment or honoraria from Laerdal Medical, Alexion, Pfizer—BMS, and Stryker Neurovascular; and support for attending meetings or travel from Laerdal Medical, Alexion, Pfizer—BMS, and Stryker Neurovascular. MA reports honoraria for lectures from AstraZeneca, Bayer, Covidien, Medtronic, and Sanofi; and participates on scientific advisory boards of Amgen, Bayer, BMS, Daiichi Sankyo, Medtronic, and Pfizer. AHS reports being a coinvestigator for the US National Institutes of Health (1R01EB030092-01); is mentor for the Carol W Harvey Chair of Research and Sharon Epperson Chair of Research at the Brain Aneurysm Foundation; receipt of consulting fees from Amnis Therapeutics, Apellis Pharmaceuticals, Boston Scientific, Canon Medical Systems USA, Cardinal Health 200, Cerebrotech Medical Systems, Cerenovus, Cerevatech Medical, Cordis, Corindus, Endostream Medical, Imperative Care, InspireMD, Integra, IRRAS AB, Medtronic, MicroVention, Minnetronix Neuro, Peijia Medical, Penumbra, Q’Apel Medical, Rapid Medical, Serenity Medical, Silk Road Medical, StimMed, Stryker Neurovascular, Three Rivers Medical, VasSol, and Viz.ai; is Secretary of the Board of the Society of NeuroInterventional Surgery 2020–2021 (unpaid); is Chair of the Cerebrovascular Section of the AANS/CNS 2020–2021 (unpaid); has stock or stock options in Adona Medical, Amnis Therapeutics, Bend IT Technologies, BlinkTBI, Cerebrotech Medical Systems, Cerevatech Medical, Cognition Medical, CVAID, E8, Endostream Medical, Galaxy Therapeutics, Imperative Care, InspireMD, Instylla, International Medical Distribution Partners, Launch NY, NeuroRadial Technologies, NeuroTechnology Investors, Neurovascular Diagnostics, Peijia Medical, PerFlow Medical, Q’Apel Medical, QAS.ai, Radical Catheter Technologies, Rebound Therapeutics (purchased 2019 by Integra Lifesciences), Rist Neurovascular, (purchased 2020 by Medtronic), Sense Diagnostics, Serenity Medical, Silk Road Medical, Sim & Cure, SongBird Therapy, Spinnaker Medical, StimMed, Synchron, Three Rivers Medical, Truvic Medical, Tulavi Therapeutics, Vastrax, VICIS, and Viseon; and other financial or non-financial interests: national principal investigator or steering committees for Cerenovus EXCELLENT and ARISE II Trial; Medtronic SWIFT PRIME, VANTAGE, EMBOLISE and SWIFT DIRECT Trials; MicroVention FRED Trial and CONFIDENCE Study; MUSC POSITIVE Trial; Penumbra 3D Separator Trial, COMPASS Trial, INVEST Trial, MIVI neuroscience EVAQ Trial; Rapid Medical SUCCESS Trial; and InspireMD C-GUARDIANS IDE Pivotal Trial. MTF reports research grants from Medtronic, Siemens, Genentech, Idorsia, and Vesalio; consulting fees from Genentech, Balt USA, CereNovus, and Oculus Imaging; and participates on a data safety monitoring board or advisory board for Balt USA, Jacobs Institute, and Imperative Care. MW reports a grant from Stryker Neurovascular; consulting fees from Stryker Neurovascular; payment or honoraria from Stryker Neurovascular and Bracco Imaging; is board member for the German Society of Neuroradiology (no payments); and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Ab medica, Acandis, Bracco Imaging, Cerenovus, Kaneka Pharmaceuticals, Medtronic, Mentice, Phenox, and Stryker Neurovascular (support to institution). PMa reports grants from the Swiss National Science Foundation; consulting fees from Medtronic and Stryker; payment or honoraria from Medtronic and Stryker; and participated on a data safety monitoring board or advisory board of MicroVention. H-CD reports honoraria for participation in clinical trials, contribution to advisory boards, or oral presentations from Abbott, BMS, Boehringer Ingelheim, Daiichi-Sankyo, Novo-Nordisk, Pfizer, Portola, and WebMD Global; financial support for research projects from Boehringer Ingelheim; received research grants from the German Research Council and German Ministry of Education and Research; serves as Editor of Neurologie up2date, InFo Neurologie & Psychiatrie, Arzneimitteltherapie, and coeditor of Cephalalgia; and is on the editorial board of The Lancet Neurology and Drugs. MM reports payment or honoraria from Boehringer Ingelheim. DSL reports consulting fees from Cerenovus, Genentech, Medtronic, Stryker, and Rapid Medical as imaging core laboratory. JLS reports funding for the present study from Medtronic; consulting fees from Cerenovus; participates on a data safety monitoring board or advisory board for MIVI and Phillips; and has stock or stock options in Rapid Medical. JG reports a Swiss National Funds grant for MRI in stroke. All other authors declare no competing interests.