Urs Fischer1, Johannes Kaesmacher2, Daniel Strbian3, Omer Eker4, Christoph Cognard5, Patricia S Plattner6, Lukas Bütikofer7, Pasquale Mordasini2, Sandro Deppeler6, Vitor M Pereira8, Jean François Albucher9, Jean Darcourt5, Romain Bourcier10, Guillon Benoit11, Chrysanthi Papagiannaki12, Ozlem Ozkul-Wermester13, Gerli Sibolt3, Marjaana Tiainen3, Benjamin Gory14, Sébastien Richard15, Jan Liman16, Marielle Sophie Ernst17, Marion Boulanger18, Charlotte Barbier19, Laura Mechtouff20, Liqun Zhang21, Gaultier Marnat22, Igor Sibon23, Omid Nikoubashman24, Arno Reich25, Arturo Consoli26, Bertrand Lapergue26, Marc Ribo27, Alejandro Tomasello28, Suzana Saleme29, Francisco Macian30, Solène Moulin31, Paolo Pagano32, Guillaume Saliou33, Emmanuel Carrera34, Kevin Janot35, María Hernández-Pérez36, Raoul Pop37, Lucie Della Schiava38, Andreas R Luft39, Michel Piotin40, Jean Christophe Gentric41, Aleksandra Pikula42, Waltraud Pfeilschifter43, Marcel Arnold44, Adnan H Siddiqui45, Michael T Froehler46, Anthony J Furlan47, René Chapot48, Martin Wiesmann24, Paolo Machi49, Hans-Christoph Diener50, Zsolt Kulcsar51, Leo H Bonati52, Claudio L Bassetti44, Mikael Mazighi53, David S Liebeskind54, Jeffrey L Saver54, Jan Gralla2. 1. Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland. Electronic address: urs.fischer@usb.ch. 2. University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 3. Department of Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. 4. Department of Neuroradiology, Hospices Civils de Lyon, Lyon, France. 5. Department of Diagnostic and Therapeutic Neuroradiology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. 6. Neuro Clinical Trial Unit, Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 7. CTU Bern, University of Bern, Bern, Switzerland. 8. Division of Neurosurgery, Department of Surgery and Medical Imaging, St Michael's Hospital, University of Toronto, Toronto, ON, Canada. 9. Department of Neurology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France. 10. Department of Diagnostic and Interventional Neuroradiology, Centre Hospitalier Universitaire de Nantes, Nantes Université, Nantes, France. 11. Department of Neurology, Centre Hospitalier Universitaire de Nantes, Nantes Université, Nantes, France. 12. Department of Radiology, CHU Rouen, Rouen, France. 13. Department of Neurology, CHU Rouen, Rouen, France. 14. Department of Diagnostic and Therapeutic Neuroradiology, INSERM U1254, CHRU-Nancy, Université de Lorraine, Nancy, France. 15. Department of Neurology, Stroke Unit, INSERM U1116, CHRU-Nancy, Université de Lorraine, Nancy, France. 16. Department of Neurology, University Medical Center Goettingen, Goettingen, Germany. 17. Department of Neuroradiology, University Medical Center Goettingen, Goettingen, Germany. 18. Department of Neurology, CHU Caen Normandie, University Caen Normandie, INSERM U1237, Caen, France. 19. Department of Neuroradiology, CHU Caen Normandie, University Caen Normandie, INSERM U1237, Caen, France. 20. Department of Vascular Neurology, Hospices Civils de Lyon, Lyon, France. 21. Department of Neurology, St George's University Hospital NHS Foundation Trust, London, UK. 22. Department of Interventional and Diagnostic Neuroradiology, CHU Bordeaux, University of Bordeaux, Bordeaux, France. 23. Stroke Unit, CHU Bordeaux, University of Bordeaux, Bordeaux, France. 24. Department of Neuroradiology, University Hospital RWTH Aachen, Aachen, Germany. 25. Department of Neurology, University Hospital RWTH Aachen, Aachen, Germany. 26. Department of Stroke and Diagnostic and Interventional Neuroradiology, Foch Hospital, Suresnes, France. 27. Stroke Unit, Department of Neurology, Hospital Vall d'Heborn, Barcelona, Spain. 28. Interventional Neuroradiology, Department of Radiology, Hospital Vall d'Heborn, Barcelona, Spain. 29. Department of Neuroradiology, University Hospital of Limoges, Limoges, France. 30. Department of Neurology, University Hospital of Limoges, Limoges, France. 31. Department of Neurology, CHU Reims, Reims, France. 32. Department of Neuroradiology, CHU Reims, Reims, France. 33. Service of Interventional and Diagnostic Radiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland. 34. Department of Neurology, Hôpitaux Universitaires de Genève, Geneva, Switzerland. 35. Department of Diagnostic and Interventional Neuroradiology, Tours University Hospital, Tours, France. 36. Stroke Unit, Department of Neurosciences, University Hospital Germans Trias i Pujol, Barcelona, Spain. 37. Department of Interventional Neuroradiology, Strasbourg University Hospitals, Strasbourg, France. 38. Department of Neurology, Lille University Hospital, Lille, France. 39. Department of Neurology, University Hospital of Zurich, Zurich, Switzerland; Cereneo, Center for Neurology and Rehabilitation, Vitznau, Switzerland. 40. Department of Interventional Neuroradiology, Fondation Rothschild Hospital, Paris, France. 41. Department of Neuroradiology, Brest University Hospital, Brest, France; GETBO, INSERM Unit UMR 1034, Brest, France. 42. Division of Neurology, Department of Medicine, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada. 43. Department of Neurology, University Hospital Frankfurt, Frankfurt, Germany. 44. Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. 45. Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, New York, NY, USA. 46. Vanderbilt Cerebrovascular Program, Vanderbilt University Medical Center, Nashville, TN, USA. 47. School of Medicine, Case Western Reserve University, Cleveland, OH, USA. 48. Department of Intracranial Endovascular Therapy, Alfried Krupp Krankenhaus Essen, Essen, Germany. 49. Department of Neuroradiology, Hôpitaux Universitaires de Genève, Geneva, Switzerland. 50. Department of Neuroepidemiology, Institute for Medical Informatics, Biometry and Epidemiology IMIBE), Essen, Germany. 51. Department of Neuroradiology, University Hospital of Zurich, Zurich, Switzerland. 52. Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland. 53. Department of Neurology, Lariboisière Hospital, University of Paris, FHU NeuroVasc, INSERM 1148, Paris, France; Department of Interventional Neuroradiology, Adolphe de Rothschild Hospital Foundation, University of Paris, FHU NeuroVasc, INSERM 1148, Paris, France. 54. Department of Neurology and Comprehensive Stroke Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
Abstract
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.
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.