Carotid endarterectomy or stenting or best medical treatment alone for moderate-to-severe asymptomatic carotid artery stenosis: 5-year results of a multicentre, randomised controlled trial,The Lancet Neurology

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Carotid endarterectomy or stenting or best medical treatment alone for moderate-to-severe asymptomatic carotid artery stenosis: 5-year results of a multicentre, randomised controlled trial
The Lancet Neurology ( IF 48.0 ) Pub Date : 2022-09-14 , DOI: 10.1016/s1474-4422(22)00290-3
Tilman Reiff ₁ , Hans-Henning Eckstein ₂ , Ulrich Mansmann ₃ , Olav Jansen ₄ , Gustav Fraedrich ₅ , Harald Mudra ₆ , Dittmar Böckler ₇ , Michael Böhm ₈ , E Sebastian Debus ₉ , Jens Fiehler ₁₀ , Klaus Mathias ₁₁ , Erich B Ringelstein ₁₂ , Jürg Schmidli ₁₃ , Robert Stingele ₁₄ , Ralf Zahn ₁₅ , Thomas Zeller ₁₆ , Wolf-Dirk Niesen ₁₇ , Kristian Barlinn ₁₈ , Andreas Binder ₁₉ , Jörg Glahn ₂₀ , Werner Hacke ₁ , Peter Arthur Ringleb ₁ ,

Affiliation

Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany.
Department for Vascular and Endovascular Surgery, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany.
Department of Radiology and Neuroradiology, UKSH Campus Kiel, Kiel, Germany.
Department of Vascular Surgery, University Hospital of Innsbruck, Innsbruck, Austria.
Department of Cardiology, München Klinik, Klinikum Neuperlach, Munich, Germany.
Department of Vascular and Endovascular Surgery, University Hospital of Heidelberg, Heidelberg, Germany.
Department of Internal Medicine, University Hospital of Homburg/Saar, Homburg, Germany.
Department of Vascular Surgery, University Hospital of Hamburg, Hamburg, Germany.
Department of Neuroradiology, University Hospital of Hamburg, Hamburg, Germany.
Department of Radiology, Klinikum Dortmund, Dortmund, Germany.
Department of Neurology, University Hospital of Münster, Münster, Germany.
Department of Vascular Surgery, University Hospital of Bern, Bern, Switzerland.
Department of Neurology, DRK-Kliniken Berlin, Berlin, Germany.
Department of Internal Medicine, Klinikum Ludwigshafen, Ludwigshafen, Germany.
Department of Angiology, University Heart-Center Freiburg-Bad Krozingen, Bad Krozingen, Germany.
Department of Neurology, University Hospital Freiburg, Freiburg, Germany.
Department of Neurology, University Hospital of Dresden, Dresden, Germany.
Department of Neurology, UKSH Campus Kiel, Kiel, Germany.
Department of Neurology, Johannes Wesling Klinikum, Minden, Germany.

Background

The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only.

Methods

SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50–85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017.

Findings

513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6–60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0–5·8) with CEA plus BMT, 4·4% (2·2–8·6) with CAS plus BMT, and 3·1% (1·0–9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22–3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41–5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group.

Interpretation

CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution.

Funding

German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

中文翻译：

颈动脉内膜切除术或支架置入术或单独最佳药物治疗中度至重度无症状颈动脉狭窄：一项多中心随机对照试验的 5 年结果

背景

无症状颈动脉狭窄患者的最佳治疗方案仍在争论中。由于最佳药物治疗 (BMT) 随着时间的推移有所改善，颈动脉内膜切除术 (CEA) 或颈动脉支架置入术 (CAS) 的益处尚不清楚。没有比较 CEA 和 CAS 与单独 BMT 效果的随机数据。我们的目的是直接比较 CEA 加 BMT 与 CAS 加 BMT 以及两者仅与 BMT。

方法

SPACE-2 是一项在奥地利、德国和瑞士的 36 个研究中心进行的多中心、随机、对照试验。根据欧洲颈动脉手术试验标准，我们招募了年龄在 50-85 岁之间且颈总动脉远端或颈内动脉颅外段狭窄至少 70% 的无症状颈动脉狭窄的参与者。最初设计为三臂试验，包括一组单独进行 BMT（随机分配比例为 2·9:2·9:1），SPACE-2 研究设计被修改（由于招募缓慢）成为两个子研究用两个臂分别比较 CEA 加 BMT 与单独的 BMT (SPACE-2a) 和 CAS 加 BMT 与单独的 BMT (SPACE-2b)；在每种情况下都是 1:1 随机化。参与者和临床医生未对分配设盲。主要疗效终点是 30 天内任何卒中或任何原因死亡或 5 年内任何同侧缺血性卒中的累积发生率。主要安全终点是 CEA 或 CAS 后 30 天内的任何中风或任何原因死亡。主要分析是通过意向性治疗进行的，其中包括 SPACE-2、SPACE-2a 和 SPACE-2b 中所有随机分配的患者，使用个体患者数据的荟萃分析进行分析。我们进行了两步分层测试，首先显示 CEA 和 CAS 优于单独的 BMT，然后评估 CAS 对 CEA 的非劣效性。原计划招募3640名患者；然而，由于招募不足，该研究不得不提前停止。本报告介绍了 5 年随访的主要分析。该试验已在 ISRCTN 注册，编号为 ISRCTN78592017。

发现

在 2009 年 7 月 9 日至 2019 年 12 月 12 日期间招募和调查了 SPACE-2、SPACE-2a 和 SPACE-2b 的 513 名患者，其中 203 名 (40%) 被分配到 CEA 加 BMT，197 名 (38%)到 CAS 加 BMT，113 (22%) 单独到 BMT。中位随访时间为 59·9 个月 (IQR 46·6–60·0)。使用 CEA 加 BMT，30 天内任何中风或任何原因死亡或 5 年内任何同侧缺血性中风（主要疗效终点）的累积发生率为 2·5%（95% CI 1·0–5·8），4 ·4% (2·2–8·6) CAS 加 BMT，3·1% (1·0–9·4) 单独 BMT。Cox 比例风险测试显示 CEA 加 BMT 与单独 BMT 的主要疗效终点风险没有差异（风险比 [HR] 0·93，95% CI 0·22–3·91；p=0·93）或CAS 加 BMT 对比单独的 BMT (1·55, 0·41–5·85; p=0·52)。未显示 CEA 或 CAS 优于 BMT，因此未进行非劣效性测试。在 CEA 组和 CAS 组中，手术后 30 天内均发生了 5 次中风，没有人死亡。在 5 年的随访期间，CAS 加 BMT 组和单独 BMT 组均发生了 3 次同侧卒中，CEA 加 BMT 组没有发生。