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

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Thrombectomy alone versus intravenous alteplase plus thrombectomy in patients with stroke: an open-label, blinded-outcome, randomised non-inferiority trial
The Lancet ( IF 168.9 ) Pub Date : 2022-07-07 , DOI: 10.1016/s0140-6736(22)00537-2
Urs Fischer ₁ , Johannes Kaesmacher ₂ , Daniel Strbian ₃ , Omer Eker ₄ , Christoph Cognard ₅ , Patricia S Plattner ₆ , Lukas Bütikofer ₇ , Pasquale Mordasini ₂ , Sandro Deppeler ₆ , Vitor M Pereira ₈ , Jean François Albucher ₉ , Jean Darcourt ₅ , Romain Bourcier ₁₀ , Guillon Benoit ₁₁ , Chrysanthi Papagiannaki ₁₂ , Ozlem Ozkul-Wermester ₁₃ , Gerli Sibolt ₃ , Marjaana Tiainen ₃ , Benjamin Gory ₁₄ , Sébastien Richard ₁₅ , Jan Liman ₁₆ , Marielle Sophie Ernst ₁₇ , Marion Boulanger ₁₈ , Charlotte Barbier ₁₉ , Laura Mechtouff ₂₀ , Liqun Zhang ₂₁ , Gaultier Marnat ₂₂ , Igor Sibon ₂₃ , Omid Nikoubashman ₂₄ , Arno Reich ₂₅ , Arturo Consoli ₂₆ , Bertrand Lapergue ₂₆ , Marc Ribo ₂₇ , Alejandro Tomasello ₂₈ , Suzana Saleme ₂₉ , Francisco Macian ₃₀ , Solène Moulin ₃₁ , Paolo Pagano ₃₂ , Guillaume Saliou ₃₃ , Emmanuel Carrera ₃₄ , Kevin Janot ₃₅ , María Hernández-Pérez ₃₆ , Raoul Pop ₃₇ , Lucie Della Schiava ₃₈ , Andreas R Luft ₃₉ , Michel Piotin ₄₀ , Jean Christophe Gentric ₄₁ , Aleksandra Pikula ₄₂ , Waltraud Pfeilschifter ₄₃ , Marcel Arnold ₄₄ , Adnan H Siddiqui ₄₅ , Michael T Froehler ₄₆ , Anthony J Furlan ₄₇ , René Chapot ₄₈ , Martin Wiesmann ₂₄ , Paolo Machi ₄₉ , Hans-Christoph Diener ₅₀ , Zsolt Kulcsar ₅₁ , Leo H Bonati ₅₂ , Claudio L Bassetti ₄₄ , Mikael Mazighi ₅₃ , David S Liebeskind ₅₄ , Jeffrey L Saver ₅₄ , Jan Gralla ₂ ,

Affiliation

Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.
University Institute of Diagnostic and Interventional Neuroradiology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Department of Neurology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
Department of Neuroradiology, Hospices Civils de Lyon, Lyon, France.
Department of Diagnostic and Therapeutic Neuroradiology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
Neuro Clinical Trial Unit, Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
CTU Bern, University of Bern, Bern, Switzerland.
Division of Neurosurgery, Department of Surgery and Medical Imaging, St Michael's Hospital, University of Toronto, Toronto, ON, Canada.
Department of Neurology, Centre Hospitalier Universitaire de Toulouse, Toulouse, France.
Department of Diagnostic and Interventional Neuroradiology, Centre Hospitalier Universitaire de Nantes, Nantes Université, Nantes, France.
Department of Neurology, Centre Hospitalier Universitaire de Nantes, Nantes Université, Nantes, France.
Department of Radiology, CHU Rouen, Rouen, France.
Department of Neurology, CHU Rouen, Rouen, France.
Department of Diagnostic and Therapeutic Neuroradiology, INSERM U1254, CHRU-Nancy, Université de Lorraine, Nancy, France.
Department of Neurology, Stroke Unit, INSERM U1116, CHRU-Nancy, Université de Lorraine, Nancy, France.
Department of Neurology, University Medical Center Goettingen, Goettingen, Germany.
Department of Neuroradiology, University Medical Center Goettingen, Goettingen, Germany.
Department of Neurology, CHU Caen Normandie, University Caen Normandie, INSERM U1237, Caen, France.
Department of Neuroradiology, CHU Caen Normandie, University Caen Normandie, INSERM U1237, Caen, France.
Department of Vascular Neurology, Hospices Civils de Lyon, Lyon, France.
Department of Neurology, St George's University Hospital NHS Foundation Trust, London, UK.
Department of Interventional and Diagnostic Neuroradiology, CHU Bordeaux, University of Bordeaux, Bordeaux, France.
Stroke Unit, CHU Bordeaux, University of Bordeaux, Bordeaux, France.
Department of Neuroradiology, University Hospital RWTH Aachen, Aachen, Germany.
Department of Neurology, University Hospital RWTH Aachen, Aachen, Germany.
Department of Stroke and Diagnostic and Interventional Neuroradiology, Foch Hospital, Suresnes, France.
Stroke Unit, Department of Neurology, Hospital Vall d'Heborn, Barcelona, Spain.
Interventional Neuroradiology, Department of Radiology, Hospital Vall d'Heborn, Barcelona, Spain.
Department of Neuroradiology, University Hospital of Limoges, Limoges, France.
Department of Neurology, University Hospital of Limoges, Limoges, France.
Department of Neurology, CHU Reims, Reims, France.
Department of Neuroradiology, CHU Reims, Reims, France.
Service of Interventional and Diagnostic Radiology, Centre Hospitalier Universitaire Vaudois and University of Lausanne, Lausanne, Switzerland.
Department of Neurology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
Department of Diagnostic and Interventional Neuroradiology, Tours University Hospital, Tours, France.
Stroke Unit, Department of Neurosciences, University Hospital Germans Trias i Pujol, Barcelona, Spain.
Department of Interventional Neuroradiology, Strasbourg University Hospitals, Strasbourg, France.
Department of Neurology, Lille University Hospital, Lille, France.
Department of Neurology, University Hospital of Zurich, Zurich, Switzerland; Cereneo, Center for Neurology and Rehabilitation, Vitznau, Switzerland.
Department of Interventional Neuroradiology, Fondation Rothschild Hospital, Paris, France.
Department of Neuroradiology, Brest University Hospital, Brest, France; GETBO, INSERM Unit UMR 1034, Brest, France.
Division of Neurology, Department of Medicine, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
Department of Neurology, University Hospital Frankfurt, Frankfurt, Germany.
Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.
Department of Neurosurgery, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, New York, NY, USA.
Vanderbilt Cerebrovascular Program, Vanderbilt University Medical Center, Nashville, TN, USA.
School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Department of Intracranial Endovascular Therapy, Alfried Krupp Krankenhaus Essen, Essen, Germany.
Department of Neuroradiology, Hôpitaux Universitaires de Genève, Geneva, Switzerland.
Department of Neuroepidemiology, Institute for Medical Informatics, Biometry and Epidemiology IMIBE), Essen, Germany.
Department of Neuroradiology, University Hospital of Zurich, Zurich, Switzerland.
Department of Neurology, University Hospital Basel, University of Basel, Basel, Switzerland.
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.
Department of Neurology and Comprehensive Stroke Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

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.

中文翻译：

卒中患者单独血栓切除术与静脉阿替普酶联合血栓切除术：一项开放标签、双盲结果、随机非劣效性试验

背景

单独血栓切除术是否与静脉阿替普酶联合血栓切除术同样有效仍存在争议。我们的目的是确定在出现急性缺血性卒中的患者中，单纯血栓切除术是否不劣于静脉阿替普酶联合血栓切除术。

方法

在这项在欧洲和加拿大进行的多中心、随机、开放标签、盲法结果试验中，我们招募了因大血管闭塞而入院血管内治疗中心并经 CT 或磁共振血管造影证实的卒中患者。通过中央网络服务器使用确定性最小化方法将患者随机分配 (1:1)，接受单独的支架取栓术或静脉阿替普酶联合支架取栓术。在两组中，使用任何市售的 Solitaire 支架取栓器血运重建装置（美敦力公司，尔湾市，加利福尼亚州，美国）尽快开始血栓切除术。在联合治疗组中，静脉阿替普酶（0·9 mg/kg 体重，最大剂量（每位患者 90 mg）在随机化 60 分钟后尽早给药，初始推注为计算剂量的 10%。评估主要结果的人员对分组分配设盲；患者和主治医生则不然。主要二元结果是 90 天时改良 Rankin 量表得分为 2 分或更低。我们使用 Mantel-Haenszel 风险差异的单侧 95% 置信下限评估了单独血栓切除术与静脉阿替普酶联合血栓切除术的非劣效性，预设的非劣效性界值为 12%。主要安全终点是在所有随机分配和同意的参与者中评估的症状性颅内出血。该试验已在 ClinicalTrials.gov 注册，NCT03192332，

发现

2017 年 11 月 29 日至 2021 年 5 月 7 日期间，筛选了 5215 名患者，随机分配了 423 名患者，其中 408 名（201 名单独血栓切除术，207 名静脉阿替普酶加血栓切除术）被纳入主要疗效分析。201 名接受单独血栓切除术的患者中有 114 名 (57%) 和接受静脉阿替普酶加血栓切除术的 207 名患者中有 135 名 (65%) 达到 90 天时的改良 Rankin 量表评分为 0–2（调整后的风险差异 -7·3 %，95% CI -16·6 至 2·1，单侧 95% CI 下限 -15·1%，跨越 -12% 的非劣效性界值。201 名接受单独血栓切除术的患者中有 5 名 (2%) 发生有症状的颅内出血，202 名接受静脉阿替普酶加血栓切除术的患者中有 7 名 (3%) 发生有症状的颅内出血（风险差异 -1·0%，95% CI -4·8 至 2·7 ).对比207 人中的 199 [96%]，风险差异 -5·1%，95% CI -10·2 至 0·0，p=0·047）。