Advertisement

Editor's Choice – Overview of Primary and Secondary Analyses From 20 Randomised Controlled Trials Comparing Carotid Artery Stenting With Carotid Endarterectomy

Open ArchivePublished:September 03, 2019DOI:https://doi.org/10.1016/j.ejvs.2019.06.003

      Objectives

      The aim of this review was to carry out primary and secondary analyses of 20 randomised controlled trials (RCTs) comparing carotid endarterectomy (CEA) with carotid artery stenting (CAS).

      Methods

      A systematic review and meta-analysis of data from 20 RCTs (126 publications) was carried out.

      Results

      Compared with CEA, the 30 day death/stroke rate was significantly higher after CAS in seven RCTs involving 3467 asymptomatic patients (odds ratio [OR] 1.64, 95% confidence interval [CI] 1.02–2.64) and in 10 RCTs involving 5797 symptomatic patients (OR 1.71, 95% CI 1.38–2.11). Excluding procedural risks, late ipsilateral stroke was about 4% at 9 years for both CEA and CAS, i.e., CAS was durable. Reducing procedural death/stroke after CAS may be achieved through better case selection, e.g., performing CEA in (i) symptomatic patients aged > 70 years; (ii) interventions within 14 days of symptom onset; and (iii) situations where stroke risk after CAS is predicted to be higher (segmental/remote plaques, plaque length > 13 mm, heavy burden of white matter lesions [WMLs], where two or more stents might be needed). New WMLs were significantly more common after CAS (52% vs. 17%) and were associated with higher rates of late stroke/transient ischaemic attack (23% vs. 9%), but there was no evidence that new WMLs predisposed towards late cognitive impairment. Restenoses were more common after CAS (10%) but did not increase late ipsilateral stroke. Restenoses (70%–99%) after CEA were associated with a small but significant increase in late ipsilateral stroke (OR 3.87, 95% CI 1.96–7.67; p < .001).

      Conclusions

      CAS confers higher rates of 30 day death/stroke than CEA. After 30 days, ipsilateral stroke is virtually identical for CEA and CAS. Key issues to be resolved include the following: (i) Will newer stent technologies and improved cerebral protection allow CAS to be performed < 14 days after symptom onset with risks similar to CEA? (ii) What is the optimal volume of CAS procedures to maintain competency? (iii) How to deliver better risk factor control and best medical treatment? (iv) Is there a role for CEA/CAS in preventing/reversing cognitive impairment?

      Keywords

      This paper provides an overview of primary/secondary outcome data from 20 randomised controlled trials comparing carotid endarterectomy (CEA) with carotid artery stenting (CAS) in symptomatic and asymptomatic patients, including meta-analyses for peri-operative risks and late ipsilateral stroke. Secondary analyses include (i) risk factors for stroke after CEA/CAS; (ii) the effect of peri-operative stroke or myocardial infarction on long term survival; (iii) non-stroke complications; (iv) the significance of new white matter lesions on late stroke and cognitive impairment; and (v) whether asymptomatic 70%–99% restenoses increase the risk of ipsilateral stroke after CEA and CAS.

      Introduction

      Twenty randomised controlled trials (RCTs) have compared carotid endarterectomy (CEA) with carotid angioplasty (CA) or carotid artery stenting (CAS), resulting in 126 publications in 36 medical/surgical journals between 1998 and 2019.
      • Naylor A.R.
      • Bolia A.
      • Abbott R.J.
      • Pye I.
      • Smith J.L.
      • Lennard N.
      • et al.
      Randomised trial of carotid endarterectomy versus carotid angioplasty: a stopped trial.
      CAVATAS investigators
      Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.
      • McCabe D.J.H.
      • Pereira A.C.
      • Clifton A.
      • Bland M.
      • Brown M.M.
      CAVATAS investigators
      Restenosis after carotid angioplasty, stenting, or endarterectomy in the carotid and vertebral artery transluminal angioplasty study (CAVATAS).
      • Coward L.J.
      • McCabe D.J.
      • Ederle J.
      • Featherstone R.L.
      • Clifton A.
      • Brown M.M.
      CAVATAS Investigators
      Long-term outcome after angioplasty and stenting for symptomatic vertebral artery stenosis compared with medical treatment in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.
      • Bonati L.
      • Ederle J.
      • McCabe D.J.H.
      • Dobson J.
      • Featherstone L.
      • Gaines P.A.
      • et al.
      Long-term risk of carotid restenosis in patients randomly assigned to endovascular treatment or endarterectomy in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): long-term follow-up of a randomised trial.
      • Ederle J.
      • Bonati L.H.
      • Dobson J.
      • Featherstone R.L.
      • Gaines P.A.
      • Beard J.D.
      • et al.
      Endovascular treatment with angioplasty or stenting versus endarterectomy in patients with carotid artery stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): long-term follow-up of a randomised trial.
      • Bonati L.H.
      • Ederle J.
      • Dobson J.
      • Engelter S.
      • Featherstone R.L.
      • Gaines P.A.
      • et al.
      CAVATAS Investigators
      Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.
      • Alberts M.J.
      Results of a multicenter prospective randomized trial of carotid artery stenting vs carotid endarterectomy.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.C.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.L.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy for treatment of asymptomatic carotid stenosis: a randomised trial in a community hospital.
      • Brooks W.H.
      • Jones M.R.
      • Gisler P.
      • McClure R.R.
      • Coleman T.C.
      • Breathitt L.
      • et al.
      Carotid angioplasty with stenting versus endarterectomy: 10-year randomized trial in a community hospital.
      • Yadav J.S.
      • Wholey M.H.
      • Kuntz R.E.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • et al.
      Protected carotid-artery stenting versus endarterectomy in high-risk patients.
      • Gurm H.S.
      • Yadav J.S.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • Bajwa T.K.
      • et al.
      Long-term results of carotid stenting versus endarterectomy in high-risk patients.
      • Stolker J.M.
      • Mahoney E.M.
      • Safley D.M.
      • Pomposelli F.B.
      • Yadav J.S.
      • Cohen D.J.
      • et al.
      Health-related quality of life following carotid stenting versus endarterectomy: results from the SAPPHIRE (Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy) trial.
      • Mahoney E.M.
      • Greenberg D.
      • Lavelle T.A.
      • Natarajan A.
      • Berezin R.
      • Ishak K.J.
      • et al.
      Costs and cost-effectiveness of carotid stenting versus endarterectomy for patients at increased surgical risk: results from the SAPPHIRE trial.
      EVA-3S Investigators
      Carotid angioplasty and stenting with and without cerebral protection clinical alert from the endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis (EVA-3S) trial.
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      • Mas J.-L.
      • Trinquart L.
      • Leys D.
      • Albucher J.-F.
      • Rousseau H.
      • Viguier A.
      • et al.
      Endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial.
      • Arquizan C.
      • Trinquart L.
      • Touboul P.-J.
      • Long A.
      • Feasson S.
      • Terriat B.
      • et al.
      Restenosis is more frequent after carotid stenting than after endarterectomy: the EVA-3S study.
      • Naggara O.
      • Touze E.
      • Beyssen B.
      • Trinquart L.
      • Chatellier G.
      • Meder J.-F.
      • et al.
      Anatomical and technical factors associated with stroke or death during carotid angioplasty and stenting results from the endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis (EVA-3S) trial and systematic review.
      • Mas J.-L.
      • Arquizan C.
      • Calvet D.
      • Viguier A.
      • Albucher J.-F.
      • Piquet P.
      • et al.
      Long-term follow-up study of endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis trial.
      The SPACE Collaborative Group
      30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
      • Eckstein H.H.
      • Ringleb P.
      • Allenberg J.R.
      • Berger J.
      • Fraedrich G.
      • Hacke W.
      • et al.
      Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial.
      • Fiehler J.
      • Jansen O.
      • Berger J.
      • Eckstein H.H.
      Differences in complication rates among the centre in the SPACE study.
      • Stingele R.
      • Berger J.
      • Alfk K.
      • Eckstein H.H.
      • Fraedrich G.
      • Allenberg J.
      • et al.
      Clinical and angiographic risk factors for stroke and death within 30 days after carotid endarterectomy and stent protected angioplasty: a sub-analysis of the SPACE study.
      • Jansen O.
      • Fiehler J.
      • Hartmann M.
      • Bruckmann H.
      Protection or non-protection in carotid stent angioplasty: the influence of interventional techniques on outcome data from the SPACE trial.
      • Demirel S.
      • Attigah N.
      • Bruijjnen H.
      • Ringleb P.
      • Eckstein H.H.
      • Fraedrich G.
      • et al.
      Multicenter experience on eversion versus conventional carotid endarterectomy in symptomatic carotid artery stenosis: observations from the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE-1) trial.
      • Eckstein H.H.
      • Reiff T.
      • Ringleb P.
      • Jansen O.
      • Mansmann U.
      • Hacke W.
      • et al.
      SPACE-2: a missed opportunity to compare carotid endarterectomy, carotid stenting, and best medical treatment in patients with asymptomatic carotid stenoses.
      • Reiff T.
      • Eckstein H.H.
      • Mansman U.
      • Jansen O.
      • Fraedrich G.
      • Mudra H.
      • et al.
      Angioplasty in asymptomatic carotid artery stenosis vs endarterectomy compared to best medical therapy: one year interim results of SPACE-2.
      International Carotid Stenting Study Investigators
      Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.
      • Bonati L.H.
      • Jongen L.M.
      • Haller S.
      • Flach H.Z.
      • Dobson J.
      • Nederkoorn P.J.
      • et al.
      New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a substudy of the International Carotid Stenting Study (ICSS).
      • Altinbas A.
      • van Zandvoort M.J.E.
      • van den Berg E.
      • Jongen L.M.
      • Algra A.
      • Moll F.L.
      • et al.
      Cognition after carotid endarterectomy or stenting: a randomized comparison.
      • Altinbas A.
      • Algra A.
      • Brown M.M.
      • Featherstone R.L.
      • Kappelle J.
      • de Borst G.J.
      • et al.
      Effects of carotid endarterectomy or stenting on blood pressure in the International Carotid Stenting Study (ICSS).
      • Altinbas A.
      • Algra A.
      • Brown M.M.
      • Featherstone R.L.
      • Kappelle L.J.
      • de Borst G.J.
      • et al.
      Effects of carotid endarterectomy or stenting on hemodynamic complications in the International Carotid Stenting Study: a randomized comparison.
      • Altinbas A.
      • van Zandvoort M.J.E.
      • van den Berg E.
      • Algra A.
      • de Borst G.J.
      • Hendrickse J.
      • et al.
      The effect of white matter lesions on cognition after carotid revascularization.
      • Ederle J.
      • Davagnanam I.
      • van der Worp H.B.
      • Venables G.S.
      • Lyrer P.A.
      • Featherstone R.L.
      • et al.
      Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial.
      • Gensicke H.
      • Zumbrunn T.
      • Jongen L.
      • Nederkoorn P.J.
      • MacDonald S.
      • Gaines P.A.
      • et al.
      Characteristics of ischemic brain lesions after stenting or endarterectomy for symptomatic carotid artery stenosis: results from the International Carotid Stenting Study–Magnetic Resonance Imaging Substudy.
      • Reichmann B.L.
      • Hellings W.E.
      • van der Worp H.B.
      • Nederkoorn P.J.
      • Algra A.
      • Brown M.M.
      • et al.
      Interprocedural comparison of changes in natural flow velocity patterns in the internal carotid artery following CAS or CEA.
      • Reichman B.L.
      • Hellings W.E.
      • van der Worp H.B.
      • Algra A.
      • Brown M.M.
      • Mali W.P.
      • et al.
      Flow velocities in the external carotid artery following carotid revascularization.
      ,
      • Reichman B.L.
      • Hellings W.E.
      • van der Worp H.B.
      • Algra A.
      • Brown M.M.
      • Mali W.P.
      • et al.
      Flow velocities in the external carotid artery following carotid revascularization.
      • Rostamzadeh A.
      • Zumbrunn T.
      • Jongen L.
      • Nederkoorn P.J.
      • MacDonald S.
      • Lyrer P.A.
      • et al.
      Predictors of acute and persisting ischemic brain lesions in patients randomized to carotid stenting or endarterectomy.
      • Altinbas A.
      • Hendrickse J.
      • Algra A.
      • van Zandvoort M.J.E.
      • Brown M.M.
      • Bonati L.H.
      • et al.
      Ipsilateral foetal-type posterior cerebral artery is associated with cognitive decline after carotid revascularisation.
      • Altinbas A.
      • Algra A.
      • Bonati L.H.
      • Brown M.M.
      • Kappelle J.
      • de Borst G.J.
      • et al.
      Periprocedural hemodynamic depression is associated with a higher number of new ischemic brain lesions after stenting in the International Carotid Stenting Study-MRI Substudy.
      • Bost R.B.C.
      • Hendrickse J.
      • Algra A.
      • de Borst G.J.
      • Kappelle J.
      • Jongem L.M.
      • et al.
      Effects of carotid endarterectomy or stenting on arterial diameters in the circle of Willis.
      • Burow A.
      • Lyrer P.A.
      • Nederkoorn P.J.
      • Brown M.M.
      • Szatjel R.
      • Engelter S.T.
      • et al.
      Echographic risk index and cerebral ischemic brain lesions in patients randomized to stenting versus endarterectomy for symptomatic carotid artery stenosis.
      • Doig D.
      • Turner E.L.
      • Dobson J.
      • Featherstone R.L.
      • de Borst G.J.
      • Brown M.M.
      • et al.
      Incidence, impact and predictors for cranial nerve palsy and haematoma following carotid endarterectomy in the International Carotid Stenting Study.
      • Doig D.
      • Turner E.L.
      • Dbson J.
      • Featherstone R.L.
      • de Borst G.J.
      • Stansby G.
      Risk factors for stroke, myocardial infarction, or death following carotid endarterectomy: results from the International Carotid Stenting Study.
      • Huibers A.
      • Calvet D.
      • Kennedy F.
      • Czuriga-Kovacs K.R.
      • Featherstone R.L.
      • Moll F.L.
      • et al.
      Mechanism of procedural stroke following carotid endarterectomy or carotid artery stenting within the International Carotid Stenting Study (ICSS) randomised trial.
      • Gensicke H.
      • van der Worp H.B.
      • Nederkoorn P.J.
      • Macdonald S.
      • Gaines P.A.
      • van der Lugt A.
      • et al.
      Ischaemic brain lesions after carotid artery stenting increase future cerebrovascular risk.
      • Bonati L.H.
      • Dobson J.
      • Featherstone R.L.
      • Ederle J.
      • van der Worp H.B.
      • de Borst G.J.
      • et al.
      Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomized trial.
      • Bonati L.H.
      • Dobson J.
      • Featherstone R.L.
      • Ederle J.
      • Bart van der Worp H.
      • de Borst G.J.
      • et al.
      Supplementary material: long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial.
      • Doig D.
      • Hobson B.M.
      • Muller M.
      • Jager H.R.
      • Featherstone R.L.
      • Brown M.M.
      Carotid anatomy does not predict the risk of new ischaemic brain lesions on diffusion-weighted imaging after carotid artery stenting in the ICSS-MRI substudy.
      • Doig D.
      • Turner E.L.
      • Dobson J.
      • Featherstone R.L.
      • Lo R.T.
      • Gaines P.A.
      • et al.
      Prediction of stroke, myocardial infarction or death within 30-days of carotid artery stenting: results from the International Carotid Stenting Study.
      • Featherstone R.L.
      • Dobson J.
      • Ederle J.
      • Doig D.
      • Bonati L.H.
      • Morris S.
      • et al.
      Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): a randomised controlled trial with cost-effectiveness analysis.
      • Muller M.D.
      • Ahlhelm F.J.
      • von Hessling A.
      • Doig D.
      • Nederkoorn P.J.
      • MacDonald S.
      Vascular anatomy predicts the risk of cerebral ischemia in patients randomized to carotid stenting versus endarterectomy.
      • Huibers A.
      • Hendrickse J.
      • Brown M.M.
      • Pegge S.A.
      • Arnold M.
      • Moll F.L.
      • et al.
      Upper extremity blood pressure difference in patients undergoing carotid revascularisation.
      • Bonati L.H.
      • Gregson J.
      • Dobson J.
      • McCabe D.J.H.
      • Nederkorn P.J.
      • van der Worp H.B.
      • et al.
      Restenosis and risk of stroke after stenting or endarterectomy for symptomatic carotid stenosis in the International Carotid Stenting Study (ICSS): secondary analysis of a randomised trial.
      • Muller M.M.
      • Jongen L.M.
      • Altinbas A.
      • Blackham K.A.
      • Nederkoorn P.J.
      • Macdonald S.
      • et al.
      Silent intracranial haemorrhage in patients randomized to stenting or endarterectomy for symptomatic carotid stenosis.
      • Hobson R.W.
      • Howard V.J.
      • Brott T.G.
      • Howard G.
      • Roubin G.S.
      • Ferguson R.D.
      • et al.
      Organizing the carotid revascularization endarterectomy versus stenting trial (CREST): national Institutes of Health Care financing administration and industry funding.
      • Hobson R.W.
      • Howard V.J.
      • Roubin G.S.
      • Brott T.G.
      • Ferguson R.D.
      • Popma J.J.
      • et al.
      Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase.
      • Hobson R.W.
      • Howard V.J.
      • Roubin G.S.
      • Ferguson R.D.
      • Brott T.G.
      • Howard G.
      • et al.
      Credentialing of surgeons as interventionists for carotid artery stenting: experience from the lead-in phase of CREST.
      • Howard V.J.
      • Voeks J.H.
      • Lutsep H.L.
      • Mackey A.
      • Milot G.
      • Sam A.D.
      • et al.
      Does sex matter? Thirty-day stroke and death rates after carotid artery stenting in women versus men results from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) lead-in phase.
      • Lal B.K.
      • Brott T.G.
      The Carotid Revascularization Endarterectomy vs. Stenting Trial completes randomization: lessons learned and anticipated results.
      • Brott T.G.
      • Hobson 2nd, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      • Brott T.G.
      • Hobson II, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      • Hopkins L.N.
      • Roubin G.S.
      • Chakhtoura E.Y.
      • Gray W.A.
      • Ferguson R.D.
      • Katzen B.T.
      • et al.
      The Carotid Revascularization Endarterectomy versus Stenting Trial: credentialing of interventionalists and final results of the lead-in phase.
      • Mantese V.A.
      • Timaran C.H.
      • Chiu D.
      • Begg R.J.
      Brott TG, CREST Investigators
      The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) stenting versus carotid endarterectomy for carotid disease.
      • Perkins W.J.
      • Lanzino G.
      • Brott T.G.
      Carotid stenting vs endarterectomy: new results in perspective.
      • Sheffet A.J.
      • Roubin G.
      • Howard G.
      • Howard V.
      • Moore W.
      • Meschia J.F.
      • et al.
      Design of the carotid revascularization endarterectomy vs. Stenting trial (CREST).
      • Silver F.L.
      • Mackey A.
      • Clark W.M.
      • Brooks W.
      • Timaran C.H.
      • Chiu D.
      • et al.
      Safety of stenting and endarterectomy by symptomatic status in the carotid revascularization endarterectomy versus stenting trial (CREST).
      • Cohen D.J.
      • Stolker J.M.
      • Wang K.
      • Magnuson E.A.
      • Clark W.M.
      • Demaerschalk B.M.
      • et al.
      Health-related quality of life after carotid stenting versus carotid endarterectomy: results from CREST (Carotid Revascularization Endarterectomy versus Stenting Trial).
      • Voeks J.H.
      • Howard G.
      • Roubin G.S.
      • Malas M.
      • Cohen D.J.
      • Sternbergh W.C.
      • et al.
      Age and outcomes after carotid stenting and endarterectomy: the carotid revascularization endarterectomy versus stenting trial.
      • Blackshear J.L.
      • Cutlip D.E.
      • Roubin G.S.
      • Hill M.D.
      • Leimgruber P.P.
      • Begg R.J.
      • et al.
      Myocardial infarction after carotid stenting and endarterectomy: results from the carotid revascularization endarterectomy versus stenting trial.
      • Howard V.J.
      • Lutsep H.L.
      • Mackey A.
      • Demaerschalk B.M.
      • Sam A.D.
      • Gonzales N.R.
      • et al.
      Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Lal B.K.
      • Beach K.W.
      • Roubin G.S.
      • Lutsep H.L.
      • Moore W.S.
      • Malas M.B.
      • et al.
      Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial.
      • Longbottom M.E.
      • Roberts J.N.
      • Tom M.
      • Hughes S.E.
      • Howard V.J.
      • Sheffets A.J.
      • et al.
      Interventions to increase enrollment in a large multicenter phase 3 trial of carotid stenting vs. endarterectomy.
      • Hill M.D.
      • Brooks W.
      • Mackey A.
      • Clark W.M.
      • Meschia J.F.
      • Morrish W.F.
      • et al.
      Stroke after carotid stenting and endarterectomy in the carotid revascularization endarterectomy versus stenting trial (CREST).
      • Vilain K.R.
      • Magnusen E.A.
      • Li H.
      • Clark W.M.
      • Begg R.J.
      • Sam A.D.
      • et al.
      Costs and cost-effectiveness of carotid stenting versus endarterectomy for patients at standard surgical risk results from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Timaran C.H.
      • Mantese V.A.
      • Malas M.
      • Brown O.W.
      • Lal B.K.
      • Moore W.S.
      • et al.
      Differential outcomes of carotid stenting and endarterectomy performed exclusively by vascular surgeons in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Gonzales N.R.
      • Demaerschalk B.M.
      • Voeks J.H.
      • Tom M.
      • Howard G.
      • Sheffet A.J.
      • et al.
      Complication rates and center enrollment volume in the carotid revascularization endarterectomy versus stenting trial.
      ,
      • Howard G.
      • Voeks J.H.
      • Meschia J.F.
      • Howard V.J.
      • Brott T.G.
      Picking the good apples statistics versus good judgment in choosing stent operators for a multicenter clinical trial.
      • Meschia J.F.
      • Voeks J.H.
      • Leimgruber P.P.
      • Mantese V.A.
      • Timaran C.H.
      • Chiu D.
      • et al.
      Management of vascular risk factors in the carotid revascularization endarterectomy versus stenting trial (CREST).
      • Sheffet A.J.
      • Flaxman L.
      • Tom M.
      • Hughes S.E.
      • Longbottom M.E.
      • Howard V.J.
      • et al.
      Financial management of a large multisite randomized clinical trial.
      • Zierler R.E.
      • Beach K.W.
      • Bergelin R.O.
      • Lal B.K.
      • Moore W.S.
      • Roubin G.S.
      Agreement between site-reported and ultrasound core laboratory results for duplex ultrasound velocity measurements in the Carotid Revascularization Endarterectomy versus Stenting Trial.
      • Meschia J.F.
      • Hopkins L.N.
      • Altafullah I.A.
      • Wechsler L.R.
      • Stotts G.
      • Gonzales N.R.
      • et al.
      Time from symptoms to carotid endarterectomy or stenting and perioperative risk.
      • Howard G.
      • Hopkins L.N.
      • Moore W.S.
      • Katzen B.T.
      • Chakhtoura E.
      • Morrish W.F.
      • et al.
      Temporal changes in periprocedural events in the carotid revascularization endarterectomy versus stenting trial.
      • Hye R.J.
      • Mackey A.
      • Hill M.D.
      • Vocks J.H.
      • Cohen D.J.
      • Wang K.
      • et al.
      Incidence, outcomes, and effect on quality of life of cranial nerve injury in the Carotid Revascularization Endarterectomy versus Stenting Trial.
      • Malas M.
      • Glebova N.O.
      • Hughes S.E.
      • Voeks J.H.
      • Qazi U.
      • Moore W.S.
      • et al.
      Effect of patching on reducing restenosis in the carotid revascularization endarterectomy versus stenting trial.
      • Sheffet A.J.
      • Voeks J.H.
      • Mackey A.
      • Brooks W.
      • Clark W.M.
      • Hill M.D.
      • et al.
      Characteristics of participants consenting versus declining follow-up for up to 10 years in a randomized clinical trial.
      • Voeks J.H.
      • Howard G.
      • Roubin G.
      • Farb R.
      • Heck D.
      • Logan W.
      • et al.
      Mediators of the age effect in the carotid revascularization endarterectomy versus stenting trial (CREST).
      • Brott T.G.
      • Howard G.
      • Roubin G.S.
      • Meschia J.F.
      • Mackey A.
      • Brooks W.
      • et al.
      Long-term results of stenting versus endarterectomy for carotid-artery stenosis.
      • Brott T.G.
      • Howard G.
      • Roubin G.S.
      • Meschia J.F.
      • Mackey A.
      • Brooks W.
      • et al.
      Long-term results of stenting versus endarterectomy for carotid-artery stenosis.
      • Hye R.J.
      • Voeks J.H.
      • Malas M.B.
      • Tom M.
      • Longson S.
      • Blackshear J.L.
      • et al.
      Anesthetic type and risk of myocardial infarction after carotid endarterectomy in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Moore W.S.
      • Popma J.J.
      • Roubin G.S.
      • Voeks J.H.
      • Jones M.
      • Howard G.
      • et al.
      Carotid angiographic characteristics in the CREST trial were major contributors to periprocedural stroke and death differences between carotid artery stenting and carotid endarterectomy.
      • Lal B.K.
      • Meschia J.F.
      • Howard G.
      • Brott T.G.
      Carotid stenting versus carotid endarterectomy: what did the Carotid Revascularization Endarterectomy versus Stenting Trial show and where do we go from here?.
      • Sheffet A.J.
      • Howard G.
      • Sam A.D.
      • Jamil Z.
      • Weaver F.
      • Chiu D.
      • et al.
      Challenge and yield of enrolling racially and ethnically diverse patient populations in low event rate clinical trials.
      • Jones M.R.
      • Howard G.
      • Roubin G.S.
      • Blackshear J.L.
      • Cohen D.J.
      • Cutlip D.E.
      • et al.
      Periprocedural stroke and myocardial infarction as risks for long-term mortality in CREST.
      • Lal B.K.
      • Roubin G.S.
      • Jones M.
      • Clark W.
      • Mackey A.
      • Hill M.D.
      • et al.
      Influence of multiple stents on peri-procedural stroke after carotid artery stenting in the Carotid Revascularization Endarterectomy versus Stent Trial (CREST).
      • Moore W.S.
      • Voels J.H.
      • Roubin G.S.
      • Clark W.M.
      • Howard V.J.
      • Jones M.R.
      • et al.
      Duration of asymptomatic status and outcomes following carotid endarterectomy and carotid artery stenting in the Carotid Revascularization Endarterectomy versus Stent Trial.
      • Rosenfield K.
      • Matsumura J.S.
      • Chaturvedi S.
      • Riles T.
      • Ansel G.M.
      • Metzger D.C.
      • et al.
      Randomized trial of stent versus surgery for asymptomatic carotid stenosis.
      • Rosenfield K.
      • Masumura J.S.
      • Chaturvedi S.
      • Riles T.
      • Ansel G.M.
      • Metzger D.C.
      • et al.
      • Weinberg I.
      • Beckman J.A.
      • Matsumara J.S.
      • Rosenfield K.
      • Ansel G.
      • Chaturvedi S.
      • et al.
      Carotid stent fractures are not associated with adverse events. Results from the ACT-1 multicenter randomized trial (carotid angioplasty and stenting versus endarterectomy in asymptomatic subjects who are at standard risk for carotid endarterectomy with significant extracranial carotid stenotic disease).
      • Hoffman A.
      • Engelter S.
      • Taschner C.
      • Mendelowitch A.
      • Merlo A.
      • Radue E.-W.
      • et al.
      Carotid artery stenting versus carotid endarterectomy – a prospective randomised controlled single-centre trial with long-term follow-up (BACASS).
      • Kuliha M.
      • Roubeci M.
      • Prochazka V.
      • Jonszta T.
      • Hrba T.
      • Havelka J.
      • et al.
      Randomized clinical trial comparing neurological outcomes after carotid endarterectomy or stenting.
      • Mannheim D.
      • Karmeli R.
      A prospective randomized trial comparing endarterectomy to stenting in severe asymptomatic carotid stenosis.
      • Steinbauer M.G.
      • Pfister K.
      • Greindl M.
      • Schlachetzki F.
      • Borisch I.
      • Schuirer G.
      • et al.
      Alert for increased long-term follow-up after carotid artery stenting: results of a prospective, randomized, single-center trial of carotid artery stenting vs carotid endarterectomy.
      • Ling F.
      • Jiao L.Q.
      Preliminary report of trial of endarterectomy versus stenting for the treatment of carotid atherosclerotic stenosis in China (TESCAS-C).
      • Wang P.
      • Liang C.
      • Du J.
      • Li J.
      Effects of carotid endarterectomy and carotid artery stenting on high-risk carotid stenosis patients.
      • Liu C.W.
      • Liu B.
      • Ye W.
      • Wu W.W.
      • Li Y.J.
      Carotid endarterectomy versus carotid artery stenting: a prospective randomized trial.
      • Li F.M.
      • Zhong J.X.
      • Jiang X.
      • Wang Q.Z.
      • Guo Y.
      Therapeutic effect of carotid artery stenting versus endarterectomy for patients with high-risk carotid stenosis.
      Carotid Stenting Trialists Collaboration
      Short-term outcome after stenting versus endarterectomy for symptomatic carotid stenosis: a preplanned meta-analysis of individual patient data.
      • Bonati L.H.
      • Fraedrich G.
      Carotid Stenting Trialists Collaboration
      Age modifies the relative risk of stenting versus endarterectomy for symptomatic carotid stenosis: a pooled analysis of EVA-3S, SPACE and ICSS.
      • Rantner B.
      • Goebel G.
      • Bonati L.H.
      • Ringleb P.A.
      • Mas J.L.
      • Fraedrich G.
      The risk of carotid artery stenting compared with carotid endarterectomy is greatest in patients treated within 7 days of symptoms.
      • Touze E.
      • Trinquart L.
      • Felgueriras R.
      • Rerkasem K.
      • Bonati L.H.
      • Meliksetyan G.
      • et al.
      A clinical rule (sex, contralateral occlusion, age, and restenosis) to select patients for stenting versus carotid endarterectomy: systematic review of observational studies with validation in randomized trials.
      • Calvet D.
      • Mas J.-L.
      • Algra A.
      • Becquemin J.-P.
      • Bonati L.H.
      • Dobson J.
      • et al.
      Carotid stenting: is there an operator effect? A pooled analysis from the carotid stenting trialists' collaboration.
      • Howard G.
      • Roubin G.S.
      • Jansen J.
      • Halliday A.
      • Fraedrich G.
      • Eckstein H.-H.
      Association between age and risk of stroke or death from carotid endarterectomy and carotid stenting: a meta-analysis of pooled patient data from four randomised trials.
      • Calvet D.
      • Mas J.-L.
      Carotid Stenosis Trialists Collaboration
      Symptomatic carotid stenosis: is stenting as safe and effective as carotid endarterectomy?.
      • Rantner B.
      • Kollertis B.
      • Roubin G.S.
      • Ringleb P.A.
      • Jansen O.
      • Howard G.
      • et al.
      Early endarterectomy carries a lower procedural risk than early stenting in patients with symptomatic stenosis of the internal carotid artery results from 4 randomized controlled trials.
      • Volkers E.J.
      • Greving J.P.
      • Hendrickse J.
      • Algra A.
      • Kappelle L.J.
      • Becquemin J.-P.
      Body mass index and outcome after revascularization for symptomatic carotid artery stenosis.
      • Volkers E.J.
      • Algra A.
      • Kappelle J.
      • Jansen O.
      • Howard G.
      • Hendrikse J.
      • et al.
      Prediction models for clinical outcome after a carotid revascularisation procedure: an external validation study.
      Even for those interested in the management of carotid disease, it remains a daunting task to keep abreast of the literature. The aim was to provide an overview of clinically important primary/secondary analyses, from the 20 RCTs.

      Materials and methods

      A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      The PubMed/MEDLINE, Embase, and Cochrane databases were searched by two investigators (A.R.N, A.J.B.) from 1 January 1998 to 20 March 2019 to identify RCTs comparing early and late outcomes after CEA vs. CA/CAS. Data extraction was performed independently and results were compared between investigators. Any disagreement was resolved by consensus. Using medical subject heading terms (“carotid endarterectomy”, “carotid artery stenting”, and “randomised trials”), along with manual searching of references derived from constituent RCTs, previous meta-analyses and manual searches of journals, 620 reports were identified (Fig. 1). Abstracts were read to identify RCTs comparing CEA and CA/CAS. Of the 620 reports, 480 were excluded as they were not carotid RCTs and 14 were excluded (RCT methodology), leaving 126 publications for the systematic review.
      • Naylor A.R.
      • Bolia A.
      • Abbott R.J.
      • Pye I.
      • Smith J.L.
      • Lennard N.
      • et al.
      Randomised trial of carotid endarterectomy versus carotid angioplasty: a stopped trial.
      CAVATAS investigators
      Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.
      • McCabe D.J.H.
      • Pereira A.C.
      • Clifton A.
      • Bland M.
      • Brown M.M.
      CAVATAS investigators
      Restenosis after carotid angioplasty, stenting, or endarterectomy in the carotid and vertebral artery transluminal angioplasty study (CAVATAS).
      • Coward L.J.
      • McCabe D.J.
      • Ederle J.
      • Featherstone R.L.
      • Clifton A.
      • Brown M.M.
      CAVATAS Investigators
      Long-term outcome after angioplasty and stenting for symptomatic vertebral artery stenosis compared with medical treatment in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.
      • Bonati L.
      • Ederle J.
      • McCabe D.J.H.
      • Dobson J.
      • Featherstone L.
      • Gaines P.A.
      • et al.
      Long-term risk of carotid restenosis in patients randomly assigned to endovascular treatment or endarterectomy in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): long-term follow-up of a randomised trial.
      • Ederle J.
      • Bonati L.H.
      • Dobson J.
      • Featherstone R.L.
      • Gaines P.A.
      • Beard J.D.
      • et al.
      Endovascular treatment with angioplasty or stenting versus endarterectomy in patients with carotid artery stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): long-term follow-up of a randomised trial.
      • Bonati L.H.
      • Ederle J.
      • Dobson J.
      • Engelter S.
      • Featherstone R.L.
      • Gaines P.A.
      • et al.
      CAVATAS Investigators
      Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.
      • Alberts M.J.
      Results of a multicenter prospective randomized trial of carotid artery stenting vs carotid endarterectomy.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.C.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.L.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy for treatment of asymptomatic carotid stenosis: a randomised trial in a community hospital.
      • Brooks W.H.
      • Jones M.R.
      • Gisler P.
      • McClure R.R.
      • Coleman T.C.
      • Breathitt L.
      • et al.
      Carotid angioplasty with stenting versus endarterectomy: 10-year randomized trial in a community hospital.
      • Yadav J.S.
      • Wholey M.H.
      • Kuntz R.E.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • et al.
      Protected carotid-artery stenting versus endarterectomy in high-risk patients.
      • Gurm H.S.
      • Yadav J.S.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • Bajwa T.K.
      • et al.
      Long-term results of carotid stenting versus endarterectomy in high-risk patients.
      • Stolker J.M.
      • Mahoney E.M.
      • Safley D.M.
      • Pomposelli F.B.
      • Yadav J.S.
      • Cohen D.J.
      • et al.
      Health-related quality of life following carotid stenting versus endarterectomy: results from the SAPPHIRE (Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy) trial.
      • Mahoney E.M.
      • Greenberg D.
      • Lavelle T.A.
      • Natarajan A.
      • Berezin R.
      • Ishak K.J.
      • et al.
      Costs and cost-effectiveness of carotid stenting versus endarterectomy for patients at increased surgical risk: results from the SAPPHIRE trial.
      EVA-3S Investigators
      Carotid angioplasty and stenting with and without cerebral protection clinical alert from the endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis (EVA-3S) trial.
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      • Mas J.-L.
      • Trinquart L.
      • Leys D.
      • Albucher J.-F.
      • Rousseau H.
      • Viguier A.
      • et al.
      Endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis (EVA-3S) trial: results up to 4 years from a randomised, multicentre trial.
      • Arquizan C.
      • Trinquart L.
      • Touboul P.-J.
      • Long A.
      • Feasson S.
      • Terriat B.
      • et al.
      Restenosis is more frequent after carotid stenting than after endarterectomy: the EVA-3S study.
      • Naggara O.
      • Touze E.
      • Beyssen B.
      • Trinquart L.
      • Chatellier G.
      • Meder J.-F.
      • et al.
      Anatomical and technical factors associated with stroke or death during carotid angioplasty and stenting results from the endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis (EVA-3S) trial and systematic review.
      • Mas J.-L.
      • Arquizan C.
      • Calvet D.
      • Viguier A.
      • Albucher J.-F.
      • Piquet P.
      • et al.
      Long-term follow-up study of endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis trial.
      The SPACE Collaborative Group
      30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
      • Eckstein H.H.
      • Ringleb P.
      • Allenberg J.R.
      • Berger J.
      • Fraedrich G.
      • Hacke W.
      • et al.
      Results of the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study to treat symptomatic stenoses at 2 years: a multinational, prospective, randomised trial.
      • Fiehler J.
      • Jansen O.
      • Berger J.
      • Eckstein H.H.
      Differences in complication rates among the centre in the SPACE study.
      • Stingele R.
      • Berger J.
      • Alfk K.
      • Eckstein H.H.
      • Fraedrich G.
      • Allenberg J.
      • et al.
      Clinical and angiographic risk factors for stroke and death within 30 days after carotid endarterectomy and stent protected angioplasty: a sub-analysis of the SPACE study.
      • Jansen O.
      • Fiehler J.
      • Hartmann M.
      • Bruckmann H.
      Protection or non-protection in carotid stent angioplasty: the influence of interventional techniques on outcome data from the SPACE trial.
      • Demirel S.
      • Attigah N.
      • Bruijjnen H.
      • Ringleb P.
      • Eckstein H.H.
      • Fraedrich G.
      • et al.
      Multicenter experience on eversion versus conventional carotid endarterectomy in symptomatic carotid artery stenosis: observations from the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE-1) trial.
      • Eckstein H.H.
      • Reiff T.
      • Ringleb P.
      • Jansen O.
      • Mansmann U.
      • Hacke W.
      • et al.
      SPACE-2: a missed opportunity to compare carotid endarterectomy, carotid stenting, and best medical treatment in patients with asymptomatic carotid stenoses.
      • Reiff T.
      • Eckstein H.H.
      • Mansman U.
      • Jansen O.
      • Fraedrich G.
      • Mudra H.
      • et al.
      Angioplasty in asymptomatic carotid artery stenosis vs endarterectomy compared to best medical therapy: one year interim results of SPACE-2.
      International Carotid Stenting Study Investigators
      Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.
      • Bonati L.H.
      • Jongen L.M.
      • Haller S.
      • Flach H.Z.
      • Dobson J.
      • Nederkoorn P.J.
      • et al.
      New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a substudy of the International Carotid Stenting Study (ICSS).
      • Altinbas A.
      • van Zandvoort M.J.E.
      • van den Berg E.
      • Jongen L.M.
      • Algra A.
      • Moll F.L.
      • et al.
      Cognition after carotid endarterectomy or stenting: a randomized comparison.
      • Altinbas A.
      • Algra A.
      • Brown M.M.
      • Featherstone R.L.
      • Kappelle J.
      • de Borst G.J.
      • et al.
      Effects of carotid endarterectomy or stenting on blood pressure in the International Carotid Stenting Study (ICSS).
      • Altinbas A.
      • Algra A.
      • Brown M.M.
      • Featherstone R.L.
      • Kappelle L.J.
      • de Borst G.J.
      • et al.
      Effects of carotid endarterectomy or stenting on hemodynamic complications in the International Carotid Stenting Study: a randomized comparison.
      • Altinbas A.
      • van Zandvoort M.J.E.
      • van den Berg E.
      • Algra A.
      • de Borst G.J.
      • Hendrickse J.
      • et al.
      The effect of white matter lesions on cognition after carotid revascularization.
      • Ederle J.
      • Davagnanam I.
      • van der Worp H.B.
      • Venables G.S.
      • Lyrer P.A.
      • Featherstone R.L.
      • et al.
      Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial.
      • Gensicke H.
      • Zumbrunn T.
      • Jongen L.
      • Nederkoorn P.J.
      • MacDonald S.
      • Gaines P.A.
      • et al.
      Characteristics of ischemic brain lesions after stenting or endarterectomy for symptomatic carotid artery stenosis: results from the International Carotid Stenting Study–Magnetic Resonance Imaging Substudy.
      • Reichmann B.L.
      • Hellings W.E.
      • van der Worp H.B.
      • Nederkoorn P.J.
      • Algra A.
      • Brown M.M.
      • et al.
      Interprocedural comparison of changes in natural flow velocity patterns in the internal carotid artery following CAS or CEA.
      • Reichman B.L.
      • Hellings W.E.
      • van der Worp H.B.
      • Algra A.
      • Brown M.M.
      • Mali W.P.
      • et al.
      Flow velocities in the external carotid artery following carotid revascularization.
      • Rostamzadeh A.
      • Zumbrunn T.
      • Jongen L.
      • Nederkoorn P.J.
      • MacDonald S.
      • Lyrer P.A.
      • et al.
      Predictors of acute and persisting ischemic brain lesions in patients randomized to carotid stenting or endarterectomy.
      • Altinbas A.
      • Hendrickse J.
      • Algra A.
      • van Zandvoort M.J.E.
      • Brown M.M.
      • Bonati L.H.
      • et al.
      Ipsilateral foetal-type posterior cerebral artery is associated with cognitive decline after carotid revascularisation.
      • Altinbas A.
      • Algra A.
      • Bonati L.H.
      • Brown M.M.
      • Kappelle J.
      • de Borst G.J.
      • et al.
      Periprocedural hemodynamic depression is associated with a higher number of new ischemic brain lesions after stenting in the International Carotid Stenting Study-MRI Substudy.
      • Bost R.B.C.
      • Hendrickse J.
      • Algra A.
      • de Borst G.J.
      • Kappelle J.
      • Jongem L.M.
      • et al.
      Effects of carotid endarterectomy or stenting on arterial diameters in the circle of Willis.
      • Burow A.
      • Lyrer P.A.
      • Nederkoorn P.J.
      • Brown M.M.
      • Szatjel R.
      • Engelter S.T.
      • et al.
      Echographic risk index and cerebral ischemic brain lesions in patients randomized to stenting versus endarterectomy for symptomatic carotid artery stenosis.
      • Doig D.
      • Turner E.L.
      • Dobson J.
      • Featherstone R.L.
      • de Borst G.J.
      • Brown M.M.
      • et al.
      Incidence, impact and predictors for cranial nerve palsy and haematoma following carotid endarterectomy in the International Carotid Stenting Study.
      • Doig D.
      • Turner E.L.
      • Dbson J.
      • Featherstone R.L.
      • de Borst G.J.
      • Stansby G.
      Risk factors for stroke, myocardial infarction, or death following carotid endarterectomy: results from the International Carotid Stenting Study.
      • Huibers A.
      • Calvet D.
      • Kennedy F.
      • Czuriga-Kovacs K.R.
      • Featherstone R.L.
      • Moll F.L.
      • et al.
      Mechanism of procedural stroke following carotid endarterectomy or carotid artery stenting within the International Carotid Stenting Study (ICSS) randomised trial.
      • Gensicke H.
      • van der Worp H.B.
      • Nederkoorn P.J.
      • Macdonald S.
      • Gaines P.A.
      • van der Lugt A.
      • et al.
      Ischaemic brain lesions after carotid artery stenting increase future cerebrovascular risk.
      • Bonati L.H.
      • Dobson J.
      • Featherstone R.L.
      • Ederle J.
      • van der Worp H.B.
      • de Borst G.J.
      • et al.
      Long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomized trial.
      • Bonati L.H.
      • Dobson J.
      • Featherstone R.L.
      • Ederle J.
      • Bart van der Worp H.
      • de Borst G.J.
      • et al.
      Supplementary material: long-term outcomes after stenting versus endarterectomy for treatment of symptomatic carotid stenosis: the International Carotid Stenting Study (ICSS) randomised trial.
      • Doig D.
      • Hobson B.M.
      • Muller M.
      • Jager H.R.
      • Featherstone R.L.
      • Brown M.M.
      Carotid anatomy does not predict the risk of new ischaemic brain lesions on diffusion-weighted imaging after carotid artery stenting in the ICSS-MRI substudy.
      • Doig D.
      • Turner E.L.
      • Dobson J.
      • Featherstone R.L.
      • Lo R.T.
      • Gaines P.A.
      • et al.
      Prediction of stroke, myocardial infarction or death within 30-days of carotid artery stenting: results from the International Carotid Stenting Study.
      • Featherstone R.L.
      • Dobson J.
      • Ederle J.
      • Doig D.
      • Bonati L.H.
      • Morris S.
      • et al.
      Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): a randomised controlled trial with cost-effectiveness analysis.
      • Muller M.D.
      • Ahlhelm F.J.
      • von Hessling A.
      • Doig D.
      • Nederkoorn P.J.
      • MacDonald S.
      Vascular anatomy predicts the risk of cerebral ischemia in patients randomized to carotid stenting versus endarterectomy.
      • Huibers A.
      • Hendrickse J.
      • Brown M.M.
      • Pegge S.A.
      • Arnold M.
      • Moll F.L.
      • et al.
      Upper extremity blood pressure difference in patients undergoing carotid revascularisation.
      • Bonati L.H.
      • Gregson J.
      • Dobson J.
      • McCabe D.J.H.
      • Nederkorn P.J.
      • van der Worp H.B.
      • et al.
      Restenosis and risk of stroke after stenting or endarterectomy for symptomatic carotid stenosis in the International Carotid Stenting Study (ICSS): secondary analysis of a randomised trial.
      • Muller M.M.
      • Jongen L.M.
      • Altinbas A.
      • Blackham K.A.
      • Nederkoorn P.J.
      • Macdonald S.
      • et al.
      Silent intracranial haemorrhage in patients randomized to stenting or endarterectomy for symptomatic carotid stenosis.
      • Hobson R.W.
      • Howard V.J.
      • Brott T.G.
      • Howard G.
      • Roubin G.S.
      • Ferguson R.D.
      • et al.
      Organizing the carotid revascularization endarterectomy versus stenting trial (CREST): national Institutes of Health Care financing administration and industry funding.
      • Hobson R.W.
      • Howard V.J.
      • Roubin G.S.
      • Brott T.G.
      • Ferguson R.D.
      • Popma J.J.
      • et al.
      Carotid artery stenting is associated with increased complications in octogenarians: 30-day stroke and death rates in the CREST lead-in phase.
      • Hobson R.W.
      • Howard V.J.
      • Roubin G.S.
      • Ferguson R.D.
      • Brott T.G.
      • Howard G.
      • et al.
      Credentialing of surgeons as interventionists for carotid artery stenting: experience from the lead-in phase of CREST.
      • Howard V.J.
      • Voeks J.H.
      • Lutsep H.L.
      • Mackey A.
      • Milot G.
      • Sam A.D.
      • et al.
      Does sex matter? Thirty-day stroke and death rates after carotid artery stenting in women versus men results from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) lead-in phase.
      • Lal B.K.
      • Brott T.G.
      The Carotid Revascularization Endarterectomy vs. Stenting Trial completes randomization: lessons learned and anticipated results.
      • Brott T.G.
      • Hobson 2nd, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      • Brott T.G.
      • Hobson II, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      • Hopkins L.N.
      • Roubin G.S.
      • Chakhtoura E.Y.
      • Gray W.A.
      • Ferguson R.D.
      • Katzen B.T.
      • et al.
      The Carotid Revascularization Endarterectomy versus Stenting Trial: credentialing of interventionalists and final results of the lead-in phase.
      • Mantese V.A.
      • Timaran C.H.
      • Chiu D.
      • Begg R.J.
      Brott TG, CREST Investigators
      The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) stenting versus carotid endarterectomy for carotid disease.
      • Perkins W.J.
      • Lanzino G.
      • Brott T.G.
      Carotid stenting vs endarterectomy: new results in perspective.
      • Sheffet A.J.
      • Roubin G.
      • Howard G.
      • Howard V.
      • Moore W.
      • Meschia J.F.
      • et al.
      Design of the carotid revascularization endarterectomy vs. Stenting trial (CREST).
      • Silver F.L.
      • Mackey A.
      • Clark W.M.
      • Brooks W.
      • Timaran C.H.
      • Chiu D.
      • et al.
      Safety of stenting and endarterectomy by symptomatic status in the carotid revascularization endarterectomy versus stenting trial (CREST).
      • Cohen D.J.
      • Stolker J.M.
      • Wang K.
      • Magnuson E.A.
      • Clark W.M.
      • Demaerschalk B.M.
      • et al.
      Health-related quality of life after carotid stenting versus carotid endarterectomy: results from CREST (Carotid Revascularization Endarterectomy versus Stenting Trial).
      • Voeks J.H.
      • Howard G.
      • Roubin G.S.
      • Malas M.
      • Cohen D.J.
      • Sternbergh W.C.
      • et al.
      Age and outcomes after carotid stenting and endarterectomy: the carotid revascularization endarterectomy versus stenting trial.
      • Blackshear J.L.
      • Cutlip D.E.
      • Roubin G.S.
      • Hill M.D.
      • Leimgruber P.P.
      • Begg R.J.
      • et al.
      Myocardial infarction after carotid stenting and endarterectomy: results from the carotid revascularization endarterectomy versus stenting trial.
      • Howard V.J.
      • Lutsep H.L.
      • Mackey A.
      • Demaerschalk B.M.
      • Sam A.D.
      • Gonzales N.R.
      • et al.
      Influence of sex on outcomes of stenting versus endarterectomy: a subgroup analysis of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Lal B.K.
      • Beach K.W.
      • Roubin G.S.
      • Lutsep H.L.
      • Moore W.S.
      • Malas M.B.
      • et al.
      Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial.
      • Longbottom M.E.
      • Roberts J.N.
      • Tom M.
      • Hughes S.E.
      • Howard V.J.
      • Sheffets A.J.
      • et al.
      Interventions to increase enrollment in a large multicenter phase 3 trial of carotid stenting vs. endarterectomy.
      • Hill M.D.
      • Brooks W.
      • Mackey A.
      • Clark W.M.
      • Meschia J.F.
      • Morrish W.F.
      • et al.
      Stroke after carotid stenting and endarterectomy in the carotid revascularization endarterectomy versus stenting trial (CREST).
      • Vilain K.R.
      • Magnusen E.A.
      • Li H.
      • Clark W.M.
      • Begg R.J.
      • Sam A.D.
      • et al.
      Costs and cost-effectiveness of carotid stenting versus endarterectomy for patients at standard surgical risk results from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Timaran C.H.
      • Mantese V.A.
      • Malas M.
      • Brown O.W.
      • Lal B.K.
      • Moore W.S.
      • et al.
      Differential outcomes of carotid stenting and endarterectomy performed exclusively by vascular surgeons in the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Gonzales N.R.
      • Demaerschalk B.M.
      • Voeks J.H.
      • Tom M.
      • Howard G.
      • Sheffet A.J.
      • et al.
      Complication rates and center enrollment volume in the carotid revascularization endarterectomy versus stenting trial.
      • Howard G.
      • Voeks J.H.
      • Meschia J.F.
      • Howard V.J.
      • Brott T.G.
      Picking the good apples statistics versus good judgment in choosing stent operators for a multicenter clinical trial.
      • Meschia J.F.
      • Voeks J.H.
      • Leimgruber P.P.
      • Mantese V.A.
      • Timaran C.H.
      • Chiu D.
      • et al.
      Management of vascular risk factors in the carotid revascularization endarterectomy versus stenting trial (CREST).
      • Sheffet A.J.
      • Flaxman L.
      • Tom M.
      • Hughes S.E.
      • Longbottom M.E.
      • Howard V.J.
      • et al.
      Financial management of a large multisite randomized clinical trial.
      • Zierler R.E.
      • Beach K.W.
      • Bergelin R.O.
      • Lal B.K.
      • Moore W.S.
      • Roubin G.S.
      Agreement between site-reported and ultrasound core laboratory results for duplex ultrasound velocity measurements in the Carotid Revascularization Endarterectomy versus Stenting Trial.
      • Meschia J.F.
      • Hopkins L.N.
      • Altafullah I.A.
      • Wechsler L.R.
      • Stotts G.
      • Gonzales N.R.
      • et al.
      Time from symptoms to carotid endarterectomy or stenting and perioperative risk.
      Figure 1
      Figure 1Preferred Reporting Items for Systematic reviews and Meta-Analyses statement (PRISMA) flow diagram of randomised controlled trials comparing carotid artery stenting with carotid endarterectomy. CEA = carotid endarterectomy; CAS = carotid artery stenting; RCT = randomised controlled trial.
      The project comprised three sections. Firstly, 30 day risks, including death, stroke, death/stroke, disabling stroke, death/disabling stroke, myocardial infarction (MI), death/stroke/MI, and cranial nerve injury (CNI) were examined. These were meta-analysed for (i) CEA vs. CAS in all asymptomatic patients; (ii) CEA vs. CAS in all symptomatic patients; (iii) CEA vs. CAS in asymptomatic patients where RCTs recruited >500 patients (excluding CA); and (iv) CEA vs. CAS in symptomatic patients where RCTs recruited >500 patients (excluding CA). The second section provides an overview of clinically useful secondary analyses. Where possible, data from meta-analyses by the Carotid Stent Trialists Collaboration (CSTC) were used, rather than individual RCTs. Unless stated, most were pre-planned analyses. The third section reports meta-analyses for late stroke. Several RCTs recruited symptomatic and asymptomatic patients (Table S1, supplementary material), but did not always provide separate outcome data. Data from a meta-analysis by Kakkos et al. were used,
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      where the authors contacted the Principle Investigator (PI) of the RCT by Kuliha et al.
      • Mannheim D.
      • Karmeli R.
      A prospective randomized trial comparing endarterectomy to stenting in severe asymptomatic carotid stenosis.
      to provide information about missing data in asymptomatic patients (Stavros Kakkos, personal communication).
      The Jadad score was used to assess the quality of RCTs (Table S1).
      • Jadad A.R.
      • Moore R.A.
      • Carroll D.
      • Jenkinson C.
      • Reynolds D.J.
      • Gavaghan D.J.
      • et al.
      Assessing the quality of reports of randomized clinical trials: is blinding necessary?.
      To score a point, the RCT had to report withdrawals/dropouts in each study and their reasons. Additional points were given if the randomisation method was described and deemed appropriate, and if the method of blinding was described and considered appropriate. Points were deducted if the randomisation method was described, but deemed inappropriate, and where blinding was described, but considered inappropriate. The Jadad score ranges from 0 (lowest quality) to 5 (highest quality).
      Five and nine year data for late ipsilateral stroke, any stroke, and major stroke were taken from a 2019 CSTC meta-analysis of the four largest RCTs: the Endarterectomy Versus Angioplasty in patients with symptomatic severe carotid stenosis trial (EVA-3S), the Stent Protected percutaneous Angioplasty of the Carotid artery versus Endarterectomy trial (SPACE); the International Carotid Stenting Study (ICSS) and the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

      Statistical analyses

      Statistical analyses were carried out with the R package for Microsoft Windows (version 3.1). Random and fixed effect meta-analyses were performed using proportions of patients experiencing the outcome of interest. Odds ratios (OR) or hazard ratios (HR), with 95% confidence intervals (CIs) were calculated for each RCT. In RCTs where one arm reported no post-operative events, but another arm reported at least one event, a fixed factor of 0.5 was added to cells of the study results with zero events to calculate an appropriate OR and allow synthesis. This type of continuity correction is an established approach to incorporate zero event studies and 0.5 is the most common choice of correction factor.
      • Cheng J.
      • Pullenayegum E.
      • Marshall J.K.
      • Iorio A.
      • Thabane L.
      Impact of including or excluding both armed zero event studies on using standard meta-analysis methods for rare event outcome: a simulation study.
      Studies with zero outcome events in both limbs were excluded from the meta-analysis. ORs were combined using meta-analysis, involving fixed/random effects models, as appropriate. Interstudy heterogeneity was analysed using the I2 statistic, which describes the percentage total variation across studies because of heterogeneity and is a recognised method of quantifying heterogeneity in literature syntheses.
      • Cheng J.
      • Pullenayegum E.
      • Marshall J.K.
      • Iorio A.
      • Thabane L.
      Impact of including or excluding both armed zero event studies on using standard meta-analysis methods for rare event outcome: a simulation study.
      An I2 value ≥ 50% reflects significant heterogeneity due to real differences in study populations, protocols, and interventions. Based on the I2 statistic, a fixed effects model was used if I2 was <50% and a random effects model if I2 was >50%. A p value < .05 was considered statistically significant. Meta-analyses of proportions were used to calculate weighted proportions for the events of interest, using a fixed or random effects model based on the I2 statistic. Additional statistical analyses were undertaken, as necessary (A.S.), usually involving 2 × 2 contingency tables using a Fisher's exact test (FET), with a two tailed p value.

      Results

      Credentialing of transfemoral CAS practitioners

      In CREST, 427 practitioners applied to perform CAS;
      • Howard V.J.
      • Voeks J.H.
      • Lutsep H.L.
      • Mackey A.
      • Milot G.
      • Sam A.D.
      • et al.
      Does sex matter? Thirty-day stroke and death rates after carotid artery stenting in women versus men results from the Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) lead-in phase.
      238 (56%) entered the ‘lead in’ phase; 73 (17%) were exempted and allowed to randomise, while 116 (27%) were rejected (inexperience, event rates too high). CREST maintained strict oversight. After one outcome event, a centre was put “on watch”. After two, the centre was placed “on audit”. Upon completion of the “lead in” phase, 21 centres were “on watch”, while 14 were being “audited”. In EVA-3S, CAS practitioners had performed >12 CAS procedures and/or 35 stents in supra-aortic vessels.
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      SPACE required interventionists to have performed 25 CA/CAS procedures.
      The SPACE Collaborative Group
      30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
      ICSS required 50 stent procedures, including 10 CAS interventions.
      • Bonati L.H.
      • Jongen L.M.
      • Haller S.
      • Flach H.Z.
      • Dobson J.
      • Nederkoorn P.J.
      • et al.
      New ischaemic brain lesions on MRI after stenting or endarterectomy for symptomatic carotid stenosis: a substudy of the International Carotid Stenting Study (ICSS).
      The latter three RCTs allowed less experienced practitioners to be proctored by more experienced colleagues, until they reached competency.

      Risk factor control and antiplatelet therapy

      In CEA patients, there was no mention of antiplatelet strategies in four RCTs.
      • Alberts M.J.
      Results of a multicenter prospective randomized trial of carotid artery stenting vs carotid endarterectomy.
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      International Carotid Stenting Study Investigators
      Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.
      • Wang P.
      • Liang C.
      • Du J.
      • Li J.
      Effects of carotid endarterectomy and carotid artery stenting on high-risk carotid stenosis patients.
      Antiplatelet monotherapy was used in 11 RCTs,
      • Naylor A.R.
      • Bolia A.
      • Abbott R.J.
      • Pye I.
      • Smith J.L.
      • Lennard N.
      • et al.
      Randomised trial of carotid endarterectomy versus carotid angioplasty: a stopped trial.
      CAVATAS investigators
      Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.
      • Yadav J.S.
      • Wholey M.H.
      • Kuntz R.E.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • et al.
      Protected carotid-artery stenting versus endarterectomy in high-risk patients.
      The SPACE Collaborative Group
      30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
      • Eckstein H.H.
      • Reiff T.
      • Ringleb P.
      • Jansen O.
      • Mansmann U.
      • Hacke W.
      • et al.
      SPACE-2: a missed opportunity to compare carotid endarterectomy, carotid stenting, and best medical treatment in patients with asymptomatic carotid stenoses.
      • Brott T.G.
      • Hobson II, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      • Rosenfield K.
      • Masumura J.S.
      • Chaturvedi S.
      • Riles T.
      • Ansel G.M.
      • Metzger D.C.
      • et al.
      • Kuliha M.
      • Roubeci M.
      • Prochazka V.
      • Jonszta T.
      • Hrba T.
      • Havelka J.
      • et al.
      Randomized clinical trial comparing neurological outcomes after carotid endarterectomy or stenting.
      • Steinbauer M.G.
      • Pfister K.
      • Greindl M.
      • Schlachetzki F.
      • Borisch I.
      • Schuirer G.
      • et al.
      Alert for increased long-term follow-up after carotid artery stenting: results of a prospective, randomized, single-center trial of carotid artery stenting vs carotid endarterectomy.
      • Liu C.W.
      • Liu B.
      • Ye W.
      • Wu W.W.
      • Li Y.J.
      Carotid endarterectomy versus carotid artery stenting: a prospective randomized trial.
      Carotid Stenting Trialists Collaboration
      Short-term outcome after stenting versus endarterectomy for symptomatic carotid stenosis: a preplanned meta-analysis of individual patient data.
      while aspirin and clopidogrel was recommended in four.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.C.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.L.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy for treatment of asymptomatic carotid stenosis: a randomised trial in a community hospital.
      • Mannheim D.
      • Karmeli R.
      A prospective randomized trial comparing endarterectomy to stenting in severe asymptomatic carotid stenosis.
      • Ling F.
      • Jiao L.Q.
      Preliminary report of trial of endarterectomy versus stenting for the treatment of carotid atherosclerotic stenosis in China (TESCAS-C).
      In CAS patients, antiplatelet monotherapy was used in two RCTs,
      • Naylor A.R.
      • Bolia A.
      • Abbott R.J.
      • Pye I.
      • Smith J.L.
      • Lennard N.
      • et al.
      Randomised trial of carotid endarterectomy versus carotid angioplasty: a stopped trial.
      CAVATAS investigators
      Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.
      while dual antiplatelet therapy (DAPT) was used in the rest. DAPT duration varied from two to four weeks,
      • Yadav J.S.
      • Wholey M.H.
      • Kuntz R.E.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • et al.
      Protected carotid-artery stenting versus endarterectomy in high-risk patients.
      four weeks,
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      The SPACE Collaborative Group
      30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
      • Brott T.G.
      • Hobson II, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      • Rosenfield K.
      • Masumura J.S.
      • Chaturvedi S.
      • Riles T.
      • Ansel G.M.
      • Metzger D.C.
      • et al.
      • Kuliha M.
      • Roubeci M.
      • Prochazka V.
      • Jonszta T.
      • Hrba T.
      • Havelka J.
      • et al.
      Randomized clinical trial comparing neurological outcomes after carotid endarterectomy or stenting.
      • Ling F.
      • Jiao L.Q.
      Preliminary report of trial of endarterectomy versus stenting for the treatment of carotid atherosclerotic stenosis in China (TESCAS-C).
      six weeks,
      • Eckstein H.H.
      • Reiff T.
      • Ringleb P.
      • Jansen O.
      • Mansmann U.
      • Hacke W.
      • et al.
      SPACE-2: a missed opportunity to compare carotid endarterectomy, carotid stenting, and best medical treatment in patients with asymptomatic carotid stenoses.
      • Steinbauer M.G.
      • Pfister K.
      • Greindl M.
      • Schlachetzki F.
      • Borisch I.
      • Schuirer G.
      • et al.
      Alert for increased long-term follow-up after carotid artery stenting: results of a prospective, randomized, single-center trial of carotid artery stenting vs carotid endarterectomy.
      and 12 weeks.
      • Liu C.W.
      • Liu B.
      • Ye W.
      • Wu W.W.
      • Li Y.J.
      Carotid endarterectomy versus carotid artery stenting: a prospective randomized trial.
      In four RCTs, the duration of DAPT was not specified.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.C.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.L.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy for treatment of asymptomatic carotid stenosis: a randomised trial in a community hospital.
      International Carotid Stenting Study Investigators
      Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.
      • Mannheim D.
      • Karmeli R.
      A prospective randomized trial comparing endarterectomy to stenting in severe asymptomatic carotid stenosis.
      ICSS evaluated serial blood pressure (BP) changes in 766 CAS patients and 819 CEA patients.
      • Altinbas A.
      • Algra A.
      • Brown M.M.
      • Featherstone R.L.
      • Kappelle J.
      • de Borst G.J.
      • et al.
      Effects of carotid endarterectomy or stenting on blood pressure in the International Carotid Stenting Study (ICSS).
      Pre-operatively, there was no difference in BP between CEA and CAS patients. At discharge, both CAS and CEA were associated with BP decreases, which were greater after CAS. At one and 12 months, systolic/diastolic BP differences no longer persisted, but significantly fewer CAS patients took antihypertensive medications at 12 months compared with CEA patients.
      CREST evaluated how well risk factor control was being implemented,
      • Sheffet A.J.
      • Flaxman L.
      • Tom M.
      • Hughes S.E.
      • Longbottom M.E.
      • Howard V.J.
      • et al.
      Financial management of a large multisite randomized clinical trial.
      requiring four domains to be maintained: (i) low density lipoprotein cholesterol < 100 mg/dL (59% baseline, 74% after 48 months); (ii) systolic BP < 140 mmHg (52% baseline, 65% at 48 months); (iii) fasting blood glucose < 126 mg/dL (75% baseline, 81% at 48 months); and (iv) smoking cessation (74% baseline, 81% at 48 months). Only 17% achieved all four domain targets at baseline, increasing to 36% by 48 months.

      Peri-operative morbidity and mortality

      Peri-operative stroke/death

      Asymptomatic patients

      Fig. 2 details procedural risks in seven RCTs (n = 3467) comparing CEA with CAS (i.e., excluding CA). CAS patients incurred significantly higher rates of “any stroke” and “death/any stroke” compared with CEA patients. Regarding the other end points, there was no significant difference. In Fig. 3, 30 day data are detailed for 3034 patients in the three largest RCTs that randomised >500 patients. CAS was associated with significantly higher rates of “any stroke” compared with CEA
      Figure 2
      Figure 2Thirty day outcomes after carotid artery stenting (CAS) vs. carotid endarterectomy (CEA) in 3467 asymptomatic patients randomised within seven randomised controlled trials (RCTs).
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.L.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy for treatment of asymptomatic carotid stenosis: a randomised trial in a community hospital.
      ,
      • Yadav J.S.
      • Wholey M.H.
      • Kuntz R.E.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • et al.
      Protected carotid-artery stenting versus endarterectomy in high-risk patients.
      ,
      • Eckstein H.H.
      • Reiff T.
      • Ringleb P.
      • Jansen O.
      • Mansmann U.
      • Hacke W.
      • et al.
      SPACE-2: a missed opportunity to compare carotid endarterectomy, carotid stenting, and best medical treatment in patients with asymptomatic carotid stenoses.
      ,
      • Brott T.G.
      • Hobson II, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      ,
      • Rosenfield K.
      • Masumura J.S.
      • Chaturvedi S.
      • Riles T.
      • Ansel G.M.
      • Metzger D.C.
      • et al.
      ,
      • Mannheim D.
      • Karmeli R.
      A prospective randomized trial comparing endarterectomy to stenting in severe asymptomatic carotid stenosis.
      ,
      • Steinbauer M.G.
      • Pfister K.
      • Greindl M.
      • Schlachetzki F.
      • Borisch I.
      • Schuirer G.
      • et al.
      Alert for increased long-term follow-up after carotid artery stenting: results of a prospective, randomized, single-center trial of carotid artery stenting vs carotid endarterectomy.
      OR = odds ratio; CI = confidence interval; MI = myocardial infarction.
      Figure 3
      Figure 3Thirty day outcomes following carotid artery stenting (CAS) vs. carotid endarterectomy (CEA) in three randomised controlled trials (RCTs) that randomised > 500 asymptomatic patients.
      • Eckstein H.H.
      • Reiff T.
      • Ringleb P.
      • Jansen O.
      • Mansmann U.
      • Hacke W.
      • et al.
      SPACE-2: a missed opportunity to compare carotid endarterectomy, carotid stenting, and best medical treatment in patients with asymptomatic carotid stenoses.
      ,
      • Brott T.G.
      • Hobson II, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      ,
      • Rosenfield K.
      • Masumura J.S.
      • Chaturvedi S.
      • Riles T.
      • Ansel G.M.
      • Metzger D.C.
      • et al.
      OR = odds ratio; CI = confidence interval; MI = myocardial infarction.

      Symptomatic patients

      Fig. 4 details peri-operative risks in 10 RCTs (n = 5797) comparing CEA with CAS (i.e., excluding CA). CAS was associated with significantly higher rates of “any stroke”, “death/any stroke”, “death/disabling stroke”, and “death/stroke/MI”. In Fig. 5, outcome data are presented for 4754 patients in the largest four RCTs that randomised >500 patients. CAS was associated with significantly higher rates of “any stroke”, “death/stroke”, and “death/stroke/MI”.
      Figure 4
      Figure 430 day outcomes following carotid artery stenting (CAS) vs. carotid endarterectomy (CEA) in ten randomised controlled trials (RCTs) which included 5797 symptomatic patients.
      • Naylor A.R.
      • Bolia A.
      • Abbott R.J.
      • Pye I.
      • Smith J.L.
      • Lennard N.
      • et al.
      Randomised trial of carotid endarterectomy versus carotid angioplasty: a stopped trial.
      ,
      • Alberts M.J.
      Results of a multicenter prospective randomized trial of carotid artery stenting vs carotid endarterectomy.
      ,
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.C.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital.
      ,
      • Yadav J.S.
      • Wholey M.H.
      • Kuntz R.E.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • et al.
      Protected carotid-artery stenting versus endarterectomy in high-risk patients.
      ,
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      ,
      The SPACE Collaborative Group
      30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
      ,
      International Carotid Stenting Study Investigators
      Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.
      ,
      • Brott T.G.
      • Hobson II, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      ,
      • Mannheim D.
      • Karmeli R.
      A prospective randomized trial comparing endarterectomy to stenting in severe asymptomatic carotid stenosis.
      ,
      • Wang P.
      • Liang C.
      • Du J.
      • Li J.
      Effects of carotid endarterectomy and carotid artery stenting on high-risk carotid stenosis patients.
      OR = odds ratio; CI = confidence interval; MI = myocardial infarction.
      Figure 5
      Figure 5Thirty day outcomes following carotid endarterectomy (CEA) vs. carotid artery stenting (CAS) in four randomised controlled trials (RCTs) that randomised > 500 symptomatic patients.
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe carotid stenosis.
      ,
      The SPACE Collaborative Group
      30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
      ,
      International Carotid Stenting Study Investigators
      Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.
      ,
      • Brott T.G.
      • Hobson II, R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      OR = odds ratio; CI = confidence interval; MI = myocardial infarction.

      Aetiology of peri-operative stroke

      Seven RCTs published data on 309 patients who suffered a peri-operative stroke.
      CAVATAS investigators
      Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.
      • Naggara O.
      • Touze E.
      • Beyssen B.
      • Trinquart L.
      • Chatellier G.
      • Meder J.-F.
      • et al.
      Anatomical and technical factors associated with stroke or death during carotid angioplasty and stenting results from the endarterectomy versus angioplasty in patients with symptomatic severe carotid stenosis (EVA-3S) trial and systematic review.
      The SPACE Collaborative Group
      30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
      • Huibers A.
      • Calvet D.
      • Kennedy F.
      • Czuriga-Kovacs K.R.
      • Featherstone R.L.
      • Moll F.L.
      • et al.
      Mechanism of procedural stroke following carotid endarterectomy or carotid artery stenting within the International Carotid Stenting Study (ICSS) randomised trial.
      • Vilain K.R.
      • Magnusen E.A.
      • Li H.
      • Clark W.M.
      • Begg R.J.
      • Sam A.D.
      • et al.
      Costs and cost-effectiveness of carotid stenting versus endarterectomy for patients at standard surgical risk results from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Kuliha M.
      • Roubeci M.
      • Prochazka V.
      • Jonszta T.
      • Hrba T.
      • Havelka J.
      • et al.
      Randomized clinical trial comparing neurological outcomes after carotid endarterectomy or stenting.
      • Steinbauer M.G.
      • Pfister K.
      • Greindl M.
      • Schlachetzki F.
      • Borisch I.
      • Schuirer G.
      • et al.
      Alert for increased long-term follow-up after carotid artery stenting: results of a prospective, randomized, single-center trial of carotid artery stenting vs carotid endarterectomy.
      Overall, 86% of strokes after CEA were ischaemic, with intracerebral haemorrhage (ICH) accounting for 14%. After CAS, 94% of strokes were ischaemic, with 6% being due to ICH. Strokes after CEA were significantly more likely to be due to ICH (FET p = .036).
      CREST reported patterns of computed tomographic infarction after peri-operative stroke.
      • Vilain K.R.
      • Magnusen E.A.
      • Li H.
      • Clark W.M.
      • Begg R.J.
      • Sam A.D.
      • et al.
      Costs and cost-effectiveness of carotid stenting versus endarterectomy for patients at standard surgical risk results from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      The most common was “scattered embolic infarction” (38% of CAS strokes) vs. 38% after CEA. “Cortical infarction” occurred in 31% of CAS patients suffering a stroke and in 21% of CEA patients, while “subcortical infarction” was present in 17% of CAS patients and 31% of CEA patients. Bilateral or multiple territory infarctions were present in 14% of CAS related strokes vs. 0% after CEA.
      ICSS was unable to determine the likeliest cause of ischaemic stroke in 14/58 (24%) CAS patients and 5/27 (19%) CEA patients.
      • Huibers A.
      • Calvet D.
      • Kennedy F.
      • Czuriga-Kovacs K.R.
      • Featherstone R.L.
      • Moll F.L.
      • et al.
      Mechanism of procedural stroke following carotid endarterectomy or carotid artery stenting within the International Carotid Stenting Study (ICSS) randomised trial.
      Ipsilateral embolism was considered responsible for 10/58 (17%) post-CAS strokes vs. 4/27 (15%) after CEA. Haemodynamic stroke was attributed to 15/58 (26%) strokes after CAS vs. 5/27 (19%) after CEA. Post-operative thrombosis was responsible for 11/58 (19%) of strokes after CAS vs. 4/27 (15%) after CEA. Cardiac embolism caused 2/58 (3%) of strokes after CAS vs. 3/27 (11%) after CEA. Multiple aetiologies were attributed in 3/58 (5%) strokes after CAS vs. 0% after CEA.

      Vascular territory and timing of peri-operative stroke

      Eight RCTs reported the vascular territory in 330 strokes.
      CAVATAS investigators
      Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.
      • Yadav J.S.
      • Wholey M.H.
      • Kuntz R.E.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • et al.
      Protected carotid-artery stenting versus endarterectomy in high-risk patients.
      The SPACE Collaborative Group
      30 day results from the SPACE trial of stent-protected angioplasty versus carotid endarterectomy in symptomatic patients: a randomised non-inferiority trial.
      • Huibers A.
      • Calvet D.
      • Kennedy F.
      • Czuriga-Kovacs K.R.
      • Featherstone R.L.
      • Moll F.L.
      • et al.
      Mechanism of procedural stroke following carotid endarterectomy or carotid artery stenting within the International Carotid Stenting Study (ICSS) randomised trial.
      • Vilain K.R.
      • Magnusen E.A.
      • Li H.
      • Clark W.M.
      • Begg R.J.
      • Sam A.D.
      • et al.
      Costs and cost-effectiveness of carotid stenting versus endarterectomy for patients at standard surgical risk results from the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST).
      • Rosenfield K.
      • Masumura J.S.
      • Chaturvedi S.
      • Riles T.
      • Ansel G.M.
      • Metzger D.C.
      • et al.
      • Kuliha M.
      • Roubeci M.
      • Prochazka V.
      • Jonszta T.
      • Hrba T.
      • Havelka J.
      • et al.
      Randomized clinical trial comparing neurological outcomes after carotid endarterectomy or stenting.
      • Steinbauer M.G.
      • Pfister K.
      • Greindl M.
      • Schlachetzki F.
      • Borisch I.
      • Schuirer G.
      • et al.
      Alert for increased long-term follow-up after carotid artery stenting: results of a prospective, randomized, single-center trial of carotid artery stenting vs carotid endarterectomy.
      • Volkers E.J.
      • Algra A.
      • Kappelle L.J.
      • Becquemin J.-P.
      • de Borst G.J.
      • Brown M.M.
      • et al.
      Safety of carotid revascularization in patients with a history of coronary artery heart disease.
      After CEA, 93% were ipsilateral, with 7% contralateral or vertebrobasilar. After CAS, 91% were ipsilateral, with 9% contralateral/vertebrobasilar (FET p = .537). CSTC reported the timing of peri-operative stroke in 4797 patients.
      • Volkers E.J.
      • Algra A.
      • Kappelle L.J.
      • Becquemin J.-P.
      • de Borst G.J.
      • Brown M.M.
      • et al.
      Safety of carotid revascularization in patients with a history of coronary artery heart disease.
      The risk of “immediate” stroke (day of procedure) was 4.7% after CAS vs. 1.9% after CEA (OR 2.6, 95% CI 1.9–3.8). Delayed stroke (days 1–30) was 2.5% after CAS vs. 2% after CEA (OR 1.3, 95% CI 0.9–1.9).

      Temporal trends in peri-operative death/stroke/MI

      CREST hypothesised that increasing experience would reduce peri-operative complications after CAS.
      • Hye R.J.
      • Mackey A.
      • Hill M.D.
      • Vocks J.H.
      • Cohen D.J.
      • Wang K.
      • et al.
      Incidence, outcomes, and effect on quality of life of cranial nerve injury in the Carotid Revascularization Endarterectomy versus Stenting Trial.
      After adjusting for symptom status and patient characteristics, there was no significant decline in death/stroke/MI across three successive time periods (6%, 5.9%, and 5.6%, respectively) or in death/stroke (5.1%, 5.1%, and 4.7%, respectively). There was a non-significant decrease in death/stroke after CAS in asymptomatic patients (2.7%, 1.9%, and 1.7%, respectively).

      Factors associated with increased 30 day death/stroke

      Clinical predictors

      Age

      A CSTC meta-analysis (Table 1) on the effect of age on 30 day death/stroke in 4754 symptomatic patients
      • Calvet D.
      • Mas J.-L.
      Carotid Stenosis Trialists Collaboration
      Symptomatic carotid stenosis: is stenting as safe and effective as carotid endarterectomy?.
      observed that age had no effect on death/stroke after CEA, but there was an increase in death/stroke with increasing age after CAS. When compared with CEA (column 3, Table 1), a threshold of 70 years was statistically significant. Above 70 years, CAS incurred significantly higher rates of death/stroke.
      • Huibers A.
      • Hendrickse J.
      • Brown M.M.
      • Pegge S.A.
      • Arnold M.
      • Moll F.L.
      • et al.
      Upper extremity blood pressure difference in patients undergoing carotid revascularisation.
      Below 70 years, CAS had similar death/stroke rates to CEA.
      Table 1Effect of age on 30 day death/stroke in symptomatic patients randomised within EVA-3S, SPACE-1, ICSS, and CREST
      Based on individual patient meta-analysis by the Carotid Stent Trialists Collaboration. Table reproduced with permission from Naylor AR et al.136
      Age group, yCAS

      HR (95% CI)
      CEA

      HR (95% CI)
      CAS vs. CEA

      HR (95% CI)
      <601.0
      All HR age based calculations were compared against patients aged <60 years.
      1.0
      All HR age based calculations were compared against patients aged <60 years.
      0.62 (0.31–1.23)
      60–641.79 (0.89–3.60)1.01 (0.34–1.9)1.07 (0.56–2.01)
      65–692.16 (1.13–4.13)0.81 (0.43–1.52)1.61 (0.90–2.88)
      70–744.01 (2.19–7.32)1.20 (0.68–2.13)2.09 (1.32–2.32)
      75–793.94 (2.14–7.28)1.29 (0.74–2.25)1.91 (1.21–3.01)
      ≥804.15 (2.20–7.84)1.09 (0.57–2.10)2.43 (1.35–4.38)
      Age based hazard ratio (HR) calculation for carotid artery stenting (CAS) vs. carotid endarterectomy (CEA). If HR is < 1.0, CAS is associated with lower peri-operative death/stroke. If HR is > 1.0, CAS is associated with higher rates of peri-operative stroke/death. All HR age based calculations compared against age <60 years; CI = confidence interval.
      a Based on individual patient meta-analysis by the Carotid Stent Trialists Collaboration. Table reproduced with permission from Naylor AR et al.
      • Naylor A.R.
      • Ricco J.B.
      • de Borst G.J.
      • Debus S.
      • de Haro J.
      • Halliday A.
      • et al.
      Management of atherosclerotic carotid and vertebral artery disease: 2017 Clinical practice guidelines of the European Society for Vascular Surgery (ESVS).
      b All HR age based calculations were compared against patients aged <60 years.

      Sex

      In CREST, 30 day death/stroke/MI was significantly higher after CAS in women (6.8%) vs. 3.8% in women undergoing CEA (HR 1.84, 95% CI 1.02–3.37).
      • Lal B.K.
      • Beach K.W.
      • Roubin G.S.
      • Lutsep H.L.
      • Moore W.S.
      • Malas M.B.
      • et al.
      Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial.
      Female sex had no influence on MI after CEA/CAS, but stroke was significantly higher in women undergoing CAS (5.5%) vs. 2.2% after CEA (HR 2.63, 95% CI 1.23–5.65). Sex effects were most marked in symptomatic women, possibly because of smaller calibre arteries and higher baseline BP.
      • Lal B.K.
      • Beach K.W.
      • Roubin G.S.
      • Lutsep H.L.
      • Moore W.S.
      • Malas M.B.
      • et al.
      Restenosis after carotid artery stenting and endarterectomy: a secondary analysis of CREST, a randomised controlled trial.

      Baseline BP

      Increased diastolic BP was an independent risk factor for stroke after CEA but not after CAS.
      • Doig D.
      • Turner E.L.
      • Dbson J.
      • Featherstone R.L.
      • de Borst G.J.
      • Stansby G.
      Risk factors for stroke, myocardial infarction, or death following carotid endarterectomy: results from the International Carotid Stenting Study.
      • Doig D.
      • Turner E.L.
      • Dobson J.
      • Featherstone R.L.
      • Lo R.T.
      • Gaines P.A.
      • et al.
      Prediction of stroke, myocardial infarction or death within 30-days of carotid artery stenting: results from the International Carotid Stenting Study.
      The relative risk of stroke increased by a factor of 1.3 per 10 mmHg (95% CI 1.02–1.66).
      • Doig D.
      • Turner E.L.
      • Dobson J.
      • Featherstone R.L.
      • Lo R.T.
      • Gaines P.A.
      • et al.
      Prediction of stroke, myocardial infarction or death within 30-days of carotid artery stenting: results from the International Carotid Stenting Study.

      Side of lesion

      There were inconsistent data in the RCTs. SPACE reported that the side of the symptomatic lesion had no impact on 30 day death/stroke after CAS (left 6% vs. right 7.7% [p = .51]) or CEA (left 6.1% vs. right 4.9% [p = .58]).
      • Stingele R.
      • Berger J.
      • Alfk K.
      • Eckstein H.H.
      • Fraedrich G.
      • Allenberg J.
      • et al.
      Clinical and angiographic risk factors for stroke and death within 30 days after carotid endarterectomy and stent protected angioplasty: a sub-analysis of the SPACE study.
      ICSS reported no effect in CEA patients (left 4.4% vs. right 3.6% [p = .52]), while death/stroke was significantly higher after left sided CAS (left 9.4% vs. right 5.1% [p = .019]).
      • Doig D.
      • Turner E.L.
      • Dobson J.
      • Featherstone R.L.
      • Lo R.T.
      • Gaines P.A.
      • et al.
      Prediction of stroke, myocardial infarction or death within 30-days of carotid artery stenting: results from the International Carotid Stenting Study.

      Effect of body mass index

      In EVA-3S/SPACE, body mass index (BMI) did not influence death/stroke after CAS (BMI < 20 = 7%; BMI 20–25 = 9%; BMI 25–30 = 10%; BMI > 30 = 8% [ptrend = .39]) or CEA (BMI < 20 = 3%; BMI 20–25 = 7%; BMI 25–30 = 8%; BMI > 30 = 6% [ptrend = .77]).
      • Volkers E.J.
      • Algra A.
      • Kappelle J.
      • Jansen O.
      • Howard G.
      • Hendrikse J.
      • et al.
      Prediction models for clinical outcome after a carotid revascularisation procedure: an external validation study.

      Operating in the first 14 days after symptom onset

      A CSTC meta-analysis (n = 2839)
      • Touze E.
      • Trinquart L.
      • Felgueriras R.
      • Rerkasem K.
      • Bonati L.H.
      • Meliksetyan G.
      • et al.
      A clinical rule (sex, contralateral occlusion, age, and restenosis) to select patients for stenting versus carotid endarterectomy: systematic review of observational studies with validation in randomized trials.
      observed that 30 day death/stroke was significantly higher when CAS was performed less than seven days after symptom onset (9.4%) vs. 2.8% after CEA (OR 3.4, 95% CI 1.01–13.1; p = .03). Thirty day death/stroke remained significantly higher when CAS was performed 8–14 days after symptom onset (8.1%) vs. 3.4% after CEA (OR 2.42, 95% CI 1.0–5.7; p = .04).
      • Touze E.
      • Trinquart L.
      • Felgueriras R.
      • Rerkasem K.
      • Bonati L.H.
      • Meliksetyan G.
      • et al.
      A clinical rule (sex, contralateral occlusion, age, and restenosis) to select patients for stenting versus carotid endarterectomy: systematic review of observational studies with validation in randomized trials.
      A second meta-analysis (n = 138) included symptomatic CREST patients.
      • Volkers E.J.
      • Greving J.P.
      • Hendrickse J.
      • Algra A.
      • Kappelle L.J.
      • Becquemin J.-P.
      Body mass index and outcome after revascularization for symptomatic carotid artery stenosis.
      Thirty day death/stroke after CAS less than seven days after symptom onset was 8.4% vs. 1.3% after CEA (OR 6.51, 95% CI 2.0–21.21; p = .002). Thirty day fatal/disabling stroke was also significantly more common when CAS was performed less than seven days after symptom onset (3.1%) vs. 0.4% after CEA (OR 8.38, 95% CI 1.09–64.76; p = .04).

      Effect of pre-existing coronary heart disease death/stroke

      CSTC evaluated 30 day death/stroke in 4641 symptomatic patients stratified for the presence of coronary heart disease (CHD) and age.
      • Volkers E.J.
      • Algra A.
      • Kappelle L.J.
      • Becquemin J.-P.
      • de Borst G.J.
      • Brown M.M.
      • et al.
      Supplemental Data to: safety of Carotid Revascularization in Patients with a History of Coronary Artery Heart Disease.
      CHD was present in 1293 patients (28%). In patients with CHD, 30 day death/stroke was significantly higher after CAS compared with CEA in patients aged ≥75 years (HR 2.78, 95% CI 1.32–5.85) but not in patients aged 70–74 years (HR 1.09, 95% CI 0.45–2.65) or those aged < 70 years (HR 1.71, 95% CI 0.79–3.71). In patients with no history of CHD, 30 day death/stroke after CAS was significantly higher in patients aged 70–74 years (HR 3.62, 95% CI 1.80–7.29) and ≥75 years (HR 2.64, 95% CI 1.52–4.59); however, it was equal in patients aged < 70 years (HR 1.05, 95% CI 0.63–1.73). CSTC concluded that CEA should not be withheld in patients with CHD and that CAS was as safe as CEA in patients with CHD aged <75 years. In patients without CHD, CAS outcomes were only equivalent to CEA in patients aged <70 years.
      • Volkers E.J.
      • Algra A.
      • Kappelle L.J.
      • Becquemin J.-P.
      • de Borst G.J.
      • Brown M.M.
      • et al.
      Supplemental Data to: safety of Carotid Revascularization in Patients with a History of Coronary Artery Heart Disease.

      “Previously” asymptomatic vs. “totally” asymptomatic

      An unplanned CREST analysis reported that early and late CEA/CAS outcomes were unaffected when stratified for whether asymptomatic patients had never reported any clinical events in the past vs. patients who had reported symptoms more than six months in the past.
      • Rosenfield K.
      • Matsumura J.S.
      • Chaturvedi S.
      • Riles T.
      • Ansel G.M.
      • Metzger D.C.
      • et al.
      Randomized trial of stent versus surgery for asymptomatic carotid stenosis.

      Imaging predictors for peri-operative stroke

      Stenosis severity and bilateral severe disease

      In CAVATAS, ICSS, SPACE, and CREST, stenosis severity and/or the presence of contralateral occlusion/severe stenosis had no effect on death/stroke after CEA/CAS.
      • Bonati L.H.
      • Ederle J.
      • Dobson J.
      • Engelter S.
      • Featherstone R.L.
      • Gaines P.A.
      • et al.
      CAVATAS Investigators
      Length of carotid stenosis predicts peri-procedural stroke or death and restenosis in patients randomized to endovascular treatment or endarterectomy.
      • Stingele R.
      • Berger J.
      • Alfk K.
      • Eckstein H.H.
      • Fraedrich G.
      • Allenberg J.
      • et al.
      Clinical and angiographic risk factors for stroke and death within 30 days after carotid endarterectomy and stent protected angioplasty: a sub-analysis of the SPACE study.
      • Doig D.
      • Turner E.L.
      • Dbson J.
      • Featherstone R.L.
      • de Borst G.J.
      • Stansby G.
      Risk factors for stroke, myocardial infarction, or death following carotid endarterectomy: results from the International Carotid Stenting Study.
      • Doig D.
      • Turner E.L.
      • Dobson J.
      • Featherstone R.L.
      • Lo R.T.
      • Gaines P.A.
      • et al.
      Prediction of stroke, myocardial infarction or death within 30-days of carotid artery stenting: results from the International Carotid Stenting Study.
      • Lal B.K.
      • Meschia J.F.
      • Howard G.
      • Brott T.G.
      Carotid stenting versus carotid endarterectomy: what did the Carotid Revascularization Endarterectomy versus Stenting Trial show and where do we go from here?.

      Plaque features

      CREST analysed plaque features on pre-randomisation angiograms in 438 CEA and 1240 CAS patients. Sequential lesions and remote lesions extending beyond the bulb were associated with significantly higher death/stroke rates after CAS (5.8%) vs. 0.7% after CEA (OR 9.01, 95% CI 1.2–6.78).
      • Lal B.K.
      • Meschia J.F.
      • Howard G.
      • Brott T.G.
      Carotid stenting versus carotid endarterectomy: what did the Carotid Revascularization Endarterectomy versus Stenting Trial show and where do we go from here?.
      Plaque length > 13 mm was associated with a 6.1% death/stroke after CAS vs. 1.9% after CEA (OR 3.42, 95% CI 1.19–9.78).
      • Lal B.K.
      • Meschia J.F.
      • Howard G.
      • Brott T.G.
      Carotid stenting versus carotid endarterectomy: what did the Carotid Revascularization Endarterectomy versus Stenting Trial show and where do we go from here?.
      CREST undertook a separate analysis in 1123 CAS patients to see if increasing age was associated with plaque length. CREST concluded that plaque length accounted for only 8% of the increased risk in elderly CAS patients, suggesting other mechanisms were responsible for the age effect.
      • Brott T.G.
      • Howard G.
      • Roubin G.S.
      • Meschia J.F.
      • Mackey A.
      • Brooks W.
      • et al.
      Long-term results of stenting versus endarterectomy for carotid-artery stenosis.

      Pre-existing white matter lesions on magnetic resonance imaging

      ICSS scored pre-operative white matter lesions (WMLs) using the Age Related White Matter Changes (ARWMC) score. The median pre-operative score was 7.
      • Ederle J.
      • Davagnanam I.
      • van der Worp H.B.
      • Venables G.S.
      • Lyrer P.A.
      • Featherstone R.L.
      • et al.
      Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial.
      An ICSS subgroup (CAS = 536; CEA = 500) was stratified for whether the ARWMC score was <7 or ≥ 7. With CEA, there was no relationship between ARWMC score and peri-operative stroke. With CAS, peri-operative stroke was significantly increased with an ARWMC score ≥7 compared with when the score was <7 (HR 2.76, 95% CI 1.17–6.51).
      • Blackshear J.L.
      • Cutlip D.E.
      • Roubin G.S.
      • Hill M.D.
      • Leimgruber P.P.
      • Begg R.J.
      • et al.
      Myocardial infarction after carotid stenting and endarterectomy: results from the carotid revascularization endarterectomy versus stenting trial.
      Higher rates of disabling stroke were also observed in CAS patients whose ARWMC score was ≥7 (HR 3, 95% CI 1.1–8.36). When comparing CEA with CAS in patients with an ARWMC score ≥7, CAS was associated with significantly higher stroke rates (HR 2.98, 95% CI 1.29–6.93; p = .011). There was no difference in procedural stroke in either CEA or CAS patients with an ARWMC <7. ICSS concluded that CAS should be avoided in patients with extensive WMLs on pre-operative MRI.
      • Ederle J.
      • Davagnanam I.
      • van der Worp H.B.
      • Venables G.S.
      • Lyrer P.A.
      • Featherstone R.L.
      • et al.
      Effect of white-matter lesions on the risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the International Carotid Stenting Study (ICSS): a prespecified analysis of data from a randomised trial.

      CAS techniques and peri-operative stroke

      CSTC performed a meta-analysis on the influence of cerebral protection devices (CPD), stent design, pre-dilatation, post-dilatation, and DAPT on 30 day death/stroke in 1557 CAS patients in ICSS, EVA-3S, and SPACE.
      • Muller M.D.
      • von Felten S.
      • Algra A.
      • Becquemin J.-P.
      • Brown M.M.
      • Bulbulia R.
      • et al.
      Immediate and delayed procedural stroke or death in stenting versus endarterectomy for symptomatic carotid stenosis.
      Open cell stents were associated with significantly higher rates of death/stroke (10.3% in 595 patients) compared with closed cell stents (6% in 962 patients [RR 1.76, 95% CI 1.23–2.52; p = .002]). Filter CPDs were not associated with a significant reduction in death/stroke (8.0% in 950 patients) vs. 7.1% in 607 CAS procedures where no CPD was used (RR 1.1, 95% CI 0.71–1.70; p = .67). Pre-dilatation was not associated with increased death/stroke (7.4% in 760 patients) vs. 7.9% in 796 CAS procedures without pre-dilatation (RR 0.98, 95% CI 0.69–1.44; p = .919). Post-dilatation was associated with a 7.2% death/stroke rate in 1177 patients vs. 8.2% in 134 CAS patients without post-dilatation (RR 0.87, 95% CI 0.47–1.62; p = .67). CAS using DAPT did not confer a significant reduction in 30 day death/stroke (7.5% in 1357 patients) vs. 9.4% in 171 CAS patients on aspirin monotherapy (RR 0.84, 95% CI 0.5–1.4; p = .52).
      • Yadav J.S.
      • Wholey M.H.
      • Kuntz R.E.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • et al.
      Protected carotid-artery stenting versus endarterectomy in high-risk patients.

      Number of stents inserted

      CREST analysed 1531 “lead in” and 1121 trial patients undergoing CAS and showed that when one stent was deployed, the peri-operative stroke rate was 4% in 2545 patients vs. 15% where two or more stents were deployed (OR 2.9, 95% CI 1.49–5.64). Patients with two or more stents were significantly more likely to have ulcerated plaques (p = .006), be older (p = .01), and have longer lesion lengths (p = .02).
      • Moore W.S.
      • Voels J.H.
      • Roubin G.S.
      • Clark W.M.
      • Howard V.J.
      • Jones M.R.
      • et al.
      Duration of asymptomatic status and outcomes following carotid endarterectomy and carotid artery stenting in the Carotid Revascularization Endarterectomy versus Stent Trial.

      Volume: outcome relationship and specialty performing CAS

      In a CSTC meta-analysis of interventionist experience in 1546 symptomatic CAS patients,
      • Howard G.
      • Roubin G.S.
      • Jansen J.
      • Halliday A.
      • Fraedrich G.
      • Eckstein H.-H.
      Association between age and risk of stroke or death from carotid endarterectomy and carotid stenting: a meta-analysis of pooled patient data from four randomised trials.
      30 day death/stroke did not vary with lifetime operator experience (p = .8) or lifetime operator stenting experience (p = .7). Annual CAS volume did influence 30 day death/stroke, where three or fewer CAS procedures per year were associated with a 10.1% rate of death/stroke vs. 5.1% in interventionists performing more than six procedures per annum (OR 2.30, 95% CI 1.36–3.87). CREST found that the specialty of the interventionist did not influence procedural risks.
      • Perkins W.J.
      • Lanzino G.
      • Brott T.G.
      Carotid stenting vs endarterectomy: new results in perspective.
      • Gonzales N.R.
      • Demaerschalk B.M.
      • Voeks J.H.
      • Tom M.
      • Howard G.
      • Sheffet A.J.
      • et al.
      Complication rates and center enrollment volume in the carotid revascularization endarterectomy versus stenting trial.

      Predicting stroke/death after CEA/CAS

      CSTC tested 23 models for predicting 30 day death/stroke in 2184 CAS patients and 2261 CEA patients.
      • Wodarg F.
      • Turner E.L.
      • Dobson J.
      • Ringleb P.A.
      • Mali W.
      • Fraedrich G.
      • et al.
      Influence of stent design and use of cerebral protection devices on outcome of carotid artery stenting: a pooled analysis of individual patient data.
      None could reliably predict 30 day risks in symptomatic patients undergoing CEA or CAS.

      Non-stroke complications after CEA or CAS

      Peri-operative MI and type of anaesthesia used during CEA

      In CREST, the incidence of MI after CAS was 19/1123 (1.7%); 35/1038 (3.4%) with CEA under general anaesthesia; and 2/111 (1.8%) with CEA under locoregional anaesthesia.
      • Moore W.S.
      • Popma J.J.
      • Roubin G.S.
      • Voeks J.H.
      • Jones M.
      • Howard G.
      • et al.
      Carotid angiographic characteristics in the CREST trial were major contributors to periprocedural stroke and death differences between carotid artery stenting and carotid endarterectomy.

      Local complications

      Cranial nerve injury

      In a meta-analysis of 7535 patients in 13 RCTs,
      • Naylor A.R.
      • Bolia A.
      • Abbott R.J.
      • Pye I.
      • Smith J.L.
      • Lennard N.
      • et al.
      Randomised trial of carotid endarterectomy versus carotid angioplasty: a stopped trial.
      CAVATAS investigators
      Endovascular versus surgical treatment in patients with carotid stenosis in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS): a randomized trial.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.C.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy: randomized trial in a community hospital.
      • Brooks W.H.
      • McClure R.R.
      • Jones M.R.
      • Coleman T.L.
      • Breathitt L.
      Carotid angioplasty and stenting versus carotid endarterectomy for treatment of asymptomatic carotid stenosis: a randomised trial in a community hospital.
      • Yadav J.S.
      • Wholey M.H.
      • Kuntz R.E.
      • Fayad P.
      • Katzen B.T.
      • Mishkel G.J.
      • et al.
      Protected carotid-artery stenting versus endarterectomy in high-risk patients.
      • Mas J.-L.
      • Chatellier G.
      • Beyssen B.
      • Branchereau A.
      • Moulin T.
      • Becquemin J.-P.
      • et al.
      Endarterectomy versus stenting in patients with symptomatic severe