Advertisement

Editor's Choice – Timing of Carotid Intervention in Symptomatic Carotid Artery Stenosis: A Systematic Review and Meta-Analysis

Open AccessPublished:December 22, 2021DOI:https://doi.org/10.1016/j.ejvs.2021.08.021

      Objective

      This review aimed to analyse the timing of carotid endarterectomy (CEA) and carotid artery stenting (CAS) after the index event as well as 30 day outcomes at varying time periods within 14 days of symptom onset.

      Methods

      A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-analysis statement, comprising an online search of the Medline and Cochrane databases. Methodical quality assessment of the included studies was performed. Endpoints included procedural stroke and/or death stratified by delay from the index event and surgical technique (CEA/CAS).

      Results

      Seventy-one studies with 232 952 symptomatic patients were included. Overall, 34 retrospective analyses of prospective databases, nine prospective, three RCT, three case control, and 22 retrospective studies were included. Compared with CEA, CAS was associated with higher 30 day stroke (OR 0.70; 95% CI 0.58 – 0.85) and mortality rates (OR 0.41; 95% CI 0.31 – 0.53) when performed ≤ 2 days of symptom onset. Patients undergoing CEA/CAS were analysed in different time frames (≤ 2 vs. 3 – 14 and ≤ 7 vs. 8 – 14 days). Expedited CEA (vs. 3 – 14 days) presented a sampled 30 day stroke rate of 1.4%; 95% CI 0.9 – 1.8 vs. 1.8%; 95% CI 1.8 – 2.0, with no statistically significant difference. Expedited CAS (vs. 3 – 14 days) was associated with no difference in stroke rate but statistically significantly higher mortality rate (OR 2.76; 95% CI 1.39 – 5.50).

      Conclusion

      At present, CEA is safer than transfemoral CAS within 2/7 days of symptom onset. Also, considering absolute rates, expedited CEA complies with the accepted thresholds in international guidelines. The ideal timing for performing CAS (when indicated against CEA) is not yet defined. Additional granular data and standard reporting of timing of intervention will facilitate future monitoring.

      Keywords

      The evidence from this systematic review and meta-analysis suggests that (at present) carotid endarterectomy (CEA) is safer than carotid artery stenting (CAS) when performed within two or seven days of the index event. Also, considering absolute rates of 30 day stroke, mortality, and death/stroke, CEA performed within two days of the index event complies with the accepted thresholds in international guidelines. The findings of this analysis will guide clinical practice when deciding on the type of intervention in the symptomatic patient with severe carotid stenosis. The ideal timing for performing CAS (when indicated against CEA) is not yet defined.

      Introduction

      Carotid revascularisation improves long term stroke free survival in patients with recent ischaemic stroke or transient ischaemic attack (TIA). Recency of the index event has been recognised as a key determinant of the effectiveness of revascularisation, balancing the natural history risk of a second (more severe) event against the potential for a higher peri-procedural risk when carotid interventions are performed very early after the onset of symptoms.
      The optimal timing for carotid revascularisation, by either carotid endarterectomy (CEA) or carotid artery stenting (CAS), remains a matter for debate. The 2017 European Society for Vascular Surgery (ESVS) guidelines advise that CEA should be performed within 14 days of the index neurological event, as this was the highest risk time period for recurrent stroke.
      • Naylor A.R.
      • Ricco J.B.
      • de Borst G.J.
      • Debus S.
      • de Haro J.
      • Halliday A.
      Editor's Choice - Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      This is particularly true for neurologically stable patients presenting with TIA or minor stroke. However, it remains unclear as to the optimal timing of either CEA or CAS within this 14 day time period (i.e., Is it better for the carotid intervention to be performed < 2 days, < 7 days, or perhaps 8 – 14 days after symptom onset?).
      A recent systematic review reported that the risk of recurrent stroke can vary from 6% within 2 – 3 days of the index event, to 20% within 7 days, and up to 26% within 14 days of the index event.
      • Tsantilas P.
      • Kuhnl A.
      • Kallmayer M.
      • Knappich C.
      • Schmid S.
      • Kuetchou A.
      • et al.
      Stroke risk in the early period after carotid related symptoms: a systematic review.
      Conversely, a meta-analysis of published studies comparing expedited carotid interventions (2 days) vs. early (3 – 14 days) found a significantly higher risk of procedural stroke when CEA was performed within 2 days of the index event.
      • Milgrom D.
      • Hajibandeh S.
      • Antoniou S.A.
      • Torella F.
      • Antoniou G.A.
      Editor's Choice - Systematic Review and Meta-Analysis of Very Urgent Carotid Intervention for Symptomatic Carotid Disease.
      However, this systematic review did not include two large national CEA registries (> 70 000 CEAs), which confounds meaningful interpretation of their data. In the case of CAS, the available data on safety very early after the onset of symptoms appears limited.
      • Naylor A.R.
      Time is brain: an update.
      The lack of high quality evidence and consensus definitions for what constitutes “early” or “urgent” carotid interventions has contributed to conflicting results in the literature. Heterogeneity regarding patient symptoms, medical therapy, and varying surgical approaches have also led to polarised debates about the timing of CEA in patients who present with neurological symptoms.
      • den Hartog A.G.
      • Moll F.L.
      • van der Worp H.B.
      • Hoff R.G.
      • Kappelle L.J.
      • de Borst G.J.
      Delay to carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      The aims of the current systematic review and meta-analysis were to analyse temporal changes in the timing of carotid interventions after symptom onset and to determine 30 day outcomes following CEA and CAS when performed at varying time periods in the first 14 days after onset of symptoms, to define the optimal timing and carotid intervention (CEA vs. CAS) in recently symptomatic patients.

      Methods

      A systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) statement.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      The literature search was from January 1995 to January 2021. Using the Medline and Cochrane databases, the following query (((“Carotid Stenosis”[Mesh]) AND “Stents”[Mesh]) OR “Endarterectomy, Carotid”[Mesh]) AND (“Stroke”[Mesh] OR Symptomatic OR timing of intervention) was used for online search.
      Eligibility criteria included any publication regarding the revascularisation of symptomatic carotid artery stenosis by either CAS or CEA. Timing of intervention and impact of delay on procedural risks were documented. Only atherosclerotic stenotic carotid disease was considered, with exclusion of procedures performed for non-atherosclerotic pathologies.
      Exclusion criteria were (1) articles published in a language other than English; and (2) case reports and literature reviews.
      Endpoints included any stroke and/or death within 30 days of intervention stratified by delay of intervention after the index event and by intervention technique (CEA and CAS). An analysis of reporting of timing of CEA and CAS after the index event was also performed.
      Stroke was defined as a rapidly developing clinical syndrome of focal disturbance of cerebral function lasting more than 24 hours or leading to death with no apparent cause other than that of vascular origin. Stroke was considered procedural if the event occurred at any time between the revascularisation procedure (day 0) and day 30 after revascularisation.
      Stroke was classified as disabling if there was an increase in the modified Rankin score (mRS) to ≥ 3, attributable to the event 30 days after the procedure. Neurological symptomatic status was defined as a transient ischaemic attack or minor disabling ischaemic stroke in the previous six months attributable to the ipsilateral carotid artery territory.
      For the purpose of this meta-analysis, “expedited intervention” was used to define any intervention performed within two days of the index event. Index event was defined as the symptom that led the patient to seek medical advice as suggested in the ESVS guidelines.
      • Naylor A.R.
      • Ricco J.B.
      • de Borst G.J.
      • Debus S.
      • de Haro J.
      • Halliday A.
      Editor's Choice - Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      Two reviewers (AC and JP) screened the identified studies independently and were also responsible for data extraction (Fig. 1). Collected data included type of study, year of publication, number of patients and consecutiveness, adjudication of events by a clinical event committee (CEC), age, gender, and criteria for carotid revascularisation (presence and type of neurological symptoms and their timing). The definition of intervention delay regarding the index event was registered in different studies. Neurological events after the index event and before intervention were registered as well as procedural (30 day) events: stroke, myocardial infarction (MI), and death. Comparative data between early and delayed intervention were analysed, especially for interventions performed ≤ 2 days vs. between 3 and 14 days and for interventions performed ≤ 7 days vs. between 8 and 14 days of the index event.
      Figure 1
      Figure 1Preferred reporting items for Systematic Reviews and Meta-Analysis (PRISMA) flow diagram summarising literature screening process for studies of timing after index event and outcome after carotid endarterectomy (CEA) or carotid artery stenting (CAS).
      When duplicates were identified, the most recent study was included unless the earlier version reported more data on specific parameters included in the analysis.

      Quality assessment

      The methodology of the studies and risk of bias were systematically assessed by two independent reviewers (AC and JP) using the Methodological Index for Non-Randomized Studies (MINORS) score,
      • Slim K.
      • Nini E.
      • Forestier D.
      • Kwiatkowski F.
      • Panis Y.
      • Chipponi J.
      Methodological Index for Non-Randomized Studies (MINORS): development and validation of a new instrument.
      with a maximum score of 16 for non-comparative and 24 for comparative studies. A score ≤ 8 was considered poor quality, 9 – 14 moderate quality, and 15 – 16 good quality for non-comparative studies. Cut off points were ≤ 14, 15 – 22, and 23 – 24, respectively, for comparative studies.
      Authorship of the studies was unblinded during review. Discrepancies between the reviewers during the search, selection, and quality assessment were resolved by discussion. In case of persisting disagreement, a third reviewer was consulted.

      Statistical analysis

      The software Review Manager 5.4 (REVMAN) was used to analyse data. Odds ratios (OR) and 95% confidence intervals (CI) were used for dichotomous variables, and mean differences (MDs) with 95% CI for continuous data.
      Statistical heterogeneity, defined as a measure of the variability of outcomes between studies, was assessed by the Cochran’s Q test: the H2 test (Higgins and Thompson) was used to quantify the magnitude of heterogeneity. The parameter I2 retrieved from the H2 test was used with a cut off of 25% for low, 25% – 50% for intermediate, and above 50% for high heterogeneity. A fixed effects model was used when heterogeneity (I2) was less than 50% and a random effects model was used when heterogeneity (I2) was high.

      Results

      A total of 1 495 potentially relevant articles were identified initially. After reviewing title or abstract, 112 articles were retrieved and 71 judged eligible for inclusion (Fig. 1). Agreement between reviewers was reached for all articles and arbitration by the third reviewer was unnecessary.
      Overall, there were 24 retrospective analyses of prospective national databases, 10 retrospective analyses of prospective databases, nine prospective studies, three RCTs, and three case control studies. The remaining 22 studies were retrospective, single centre, or multicentre, analysis of patient data. The total number of symptomatic patients in the constituent studies was 232 952 (Table 1). Methodological quality is reported in Supplementary Table S1. A total of 18 non-comparative studies of moderate quality and 53 comparative studies (50 moderate, two poor quality, and one good quality) were included (Supplementary Table S1).
      Table 1Analysis of study characteristics and intervention delay for carotid endarterectomy (CEA) or carotid artery stenting (CAS) after index event
      Article (Year) JournalType of articleCEA/

      CAS
      PatientsSymptomaticDefinition delay (days)Timing of interventionMean delay ± SD – d
      Kashyap
      • Kashyap V.S.
      • Schneider P.A.
      • Foteh M.
      • Motaganahalli R.
      • Shah R.
      • Eckstein H.H.
      • et al.
      Early outcomes in the ROADSTER 2 study of transcarotid artery revascularization in patients with significant carotid artery disease.
      (2020) Stroke
      Prosp; MulticentreCAS632164 (26)NRNRNR
      Karpenko
      • Karpenko A.
      • Starodubtsev V.
      • Ignatenko P.
      • Dixon F.
      • Bugurov S.
      • Bochkov I.
      • et al.
      Comparative analysis of carotid artery stenting and carotid endarterectomy in clinical practice.
      (2020) J Stroke Cerebrovasc Dis
      Retrosp; Single centreCEA/CAS1 791

      CEA: 1215 (57); CAS: 917 (43)
      160 (8.9)NRNRNR
      Jankowitz
      • Jankowitz B.T.
      • Tonetti D.A.
      • Kenmuir C.
      • Rao R.
      • Ares W.J.
      • Zussman B.
      • et al.
      Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
      (2020) Neurosurgery
      Retrosp analysis of prosp data; Single centreCEA/CAS120

      CEA: 59 (49.2); CAS: 61 (59.8)
      120 (100)Urgent (0–2)0–2 d: 120 (100)CEA: 1.6 ± 0.8; CAS: 1.0 ± 0.7; p <.001
      Roussopoulo
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      (2019) Eur J Neurol
      Prosp; MulticentreCEA311311 (100)Urgent (0–2); Early (3–14)0–2 d: 63 (20.3);

      3–14 d: 248 (79.7)
      NR
      Howie
      • Howie B.A.
      • Witek A.M.
      • Hussain M.S.
      • Bain M.D.
      • Toth G.
      Carotid endarterectomy and carotid artery stenting in a predominantly symptomatic real-world patient population.
      (2019) World Neurosurg
      Retrosp; Single centreCEA/CAS314

      CEA: 204 (64.9); CAS: 110 (35.1)
      265 (84.5)NRNRNR
      Vang
      • Vang S.
      • Hans S.S.
      Carotid endarterectomy in patients with high plaque.
      (2019) Surgery
      Retrosp; Single centreCEA1233509 (41.3)NRNRNR
      Lee
      • Lee J.
      • You J.H.
      • Oh S.H.
      • Shin S.
      • Kim B.M.
      • Kim T.S.
      • et al.
      Outcomes of stenting versus endarterectomy for symptomatic extracranial carotid stenosis: a retrospective multicenter study in Korea.
      (2018) Ann Vasc Surg
      Retrosp; MulticentreCEA/CAS677

      CEA: 331 (48.9); CAS: 346 (51.1)
      677 (100)NRNRNR
      Huang
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      (2018) J Vasc Surg
      Retrosp; Single centreCEA238238 (100)Early (0–14); (0–2); (3–7); (8–14); Delayed (15–180)0–2 d: 11 (4.6);

      3–7 d: 23 (9.7);

      8–14 d: 23 (9.7);

      15–180 d: 181 (76.1)
      NR
      Rocco
      • Rocco A.
      • Sallustio F.
      • Toschi N.
      • Rizzato B.
      • Legramante J.
      • Ippoliti A.
      • et al.
      Carotid artery stent placement and carotid endarterectomy: a challenge for urgent treatment after stroke-early and 12-month outcomes in a comprehensive stroke center.
      (2018) J Vasc Interv Radiol
      Retrosp analysis of prosp data; Single centreCEA/CAS110

      CEA: 48 (43.6); CAS: 62 (56.4)
      110 (100)NRNRCEA: 1.7 ± 2.4; CAS: 2.8 ± 2.1
      Seguchi
      • Seguchi M.
      • Shibata M.
      • Sato Y.
      • Maekawa K.
      • Kitano Y.
      • Sano T.
      • et al.
      The safety of carotid artery stenting for patients in the acute poststroke phase.
      (2017) J Stroke CerebrovascDis
      Retrosp; Single centreCAS105105 (100)Early (0–2); Delayed (3–180)0–2 d: 40 (38.1); 3–180 d: 65 (61.9)NR
      Rantner
      • Rantner B.
      • Kollerits 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.
      (2017) Stroke

      EVA-3S, SPACE, ICSS, CREST
      Retrosp analysis of prosp data; MulticentreCEA vs. CAS4 1384 138 (100)Early (0–7); Delayed (8–180)0–7 d: 513 (12.4); 8–180 d: 3625 (87.6)
      CEA2 045 (49.4)2 045 (100)Early (0–7); Delayed (8–180)0–7 d: 226 (11); 8–180 d: 1819 (89)34.5 ± 15.6
      CAS2 093 (50.6)2 093 (100)Early (0–7); Delayed (8–180)0–7 d: 287 (14); 8–180 d: 1806 (86)31 ± 14.4
      Hobeanu
      • Hobeanu C.
      • Lavallée P.C.
      • Rothwell P.M.
      • Sissani L.
      • Albers G.W.
      • Bornstein N.M.
      • et al.
      Symptomatic patients remain at substantial risk of arterial disease complications before and after endarterectomy or stenting.
      (2017) Stroke
      Nested case control studyCEA/CAS vs. BMT561

      CEA/CAS: 187 (33.3)

      BMT: 374 (66.7)
      187 (100)NRNR12.8 ± 4.9
      Nordanstig
      • Nordanstig A.
      • Rosengren L.
      • Stromberg S.
      • Osterberg K.
      • Karlsson L.
      • Bergstrom G.
      • et al.
      Editor's Choice - Very Urgent Carotid Endarterectomy is Associated with an Increased Procedural Risk: The Carotid Alarm Study.
      (2017) Eur J Vasc Endovasc Surg
      Prosp; MulticentreCEA418418 (100)Early (0–2); Delayed (3–14)0–2 d: 46 (11); 3–14 d: 372 (89)Early: 1.3 ± 0.69

      Delayed: 6.7 ± 2.9
      Kazandjian
      • Kazandjian C.
      • Kretz B.
      • Lemogne B.
      • Aboa Eboulé C.
      • Béjot Y.
      • Steinmetz E.
      Influence of the type of cerebral infarct and timing of intervention in the early outcomes after carotid endarterectomy for symptomatic stenosis.
      (2016) J Vasc Surg
      Retrosp analysis of prosp data; Single centreCEA114114 (100)Early (0–14); Delayed (15–180)0–14 d: 32 (28); 15–180 d: 82 (72)22 ± 33
      Tsantilas
      • Tsantilas P.
      • Kühnl A.
      • Kallmayer M.
      • Pelisek J.
      • Poppert H.
      • Schmid S.
      • et al.
      Short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.
      (2016) J Vasc Surg
      Retrosp analysis of prosp data; Single centreCEA401401 (100)Early (0–14); (0–2); (3–7); (8–14); Delayed (15–180)0–2 d: 60 (15); 3–7 d: 110 (27.4); 8–14 d: 65 (16.2); 15–180 d: 166 (41.4)NR
      Charbonneau
      • Charbonneau P.
      • Bonaventure P.L.
      • Drudi L.M.
      • Beaudoin N.
      • Blair J.F.
      • Elkouri S.
      An institutional study of time delays for symptomatic carotid endarterectomy.
      (2016) J Vasc Surg
      Retrosp; Single centreCEA103103 (100)(0–14); (15–90); (91–180)0–14 d: 40 (38.8); 15–90 d: 37 (35.9); 91–180 d: 26 (25.2)36.5 ± 21.4
      Chisci
      • Chisci E.
      • Pigozzi C.
      • Troisi N.
      • Tramacere L.
      • Zaccara G.
      • Cincotta M.
      • et al.
      Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients.
      (2015) Ann Vasc Surg
      Retrosp; Single centreCEA322322 (100)Early (0–14); Delayed (15–30);0–14 d: 100 (31.1); 15–30 d: 222 (68.9)16.8 ± 9.2

      4.6 ± 3.1

      22.3 ± 4.6
      Kretz
      • Kretz B.
      • Kazandjian C.
      • Bejot Y.
      • Abello N.
      • Brenot R.
      • Giroud M.
      • et al.
      Delay between symptoms and surgery for carotid artery stenosis: modification of our practice.
      (2015) Ann Vasc Surg
      Retrosp analysis of prosp data; Single centreCEA417417 (100)Early (0–15); Deferred (16–45); Delayed (46–180)0–15 d: 158 (37.9); 16–45 d: 79 (18.9); 46–180 d: 180 (43.2)7.7 ± 3.8

      28.3 ± 8.6

      89.4 ± 36.7
      Charmoille
      • Charmoille E.
      • Brizzi V.
      • Lepidi S.
      • Sassoust G.
      • Roullet S.
      • Ducasse E.
      • et al.
      Thirty-day outcome of delayed versus early management of symptomatic carotid stenosis.
      (2014) Ann Vasc Surg
      Retrosp; Single centreCEA149149 (100)Early (0–14); Late (15–180)0–14 d: 62 (41.6); 15–180 d: 87 (58.4)NR
      Rantner
      • Rantner B.
      How safe are carotid endarterectomy and carotid artery stenting in the early period after carotid-related cerebral ischemia?.
      (2014) Eur J Vasc Endovasc Surg
      Retrosp; Single centreCEA761761 (100)Early (0–14); (0–2); (3–7); (8–14); Delayed (15–180)0–2 d: 206 (27.1); 3–7 d: 219 (28.8); 8–14 d: 136 (17.9); 15–180 d: 200 (26.3)NR
      Tsivgoulis
      • Tsivgoulis G.
      • Krogias C.
      • Georgiadis G.S.
      • Mikulik R.
      • Safouris A.
      • Meves S.H.
      • et al.
      Safety of early endarterectomy in patients with symptomatic carotid artery stenosis: an international multicenter study.
      (2014) Eur J Neurol
      Prosp; MulticentreCEA165165 (100)Ultra-Early (0–2); Early (3–14)0–2 d: 20 (12); 3–14 d: 145 (88)6 ± 1.7
      Mo
      • Mo D.
      • Wang B.
      • Ma N.
      • Gao F.
      • Miao Z.
      Comparative outcomes of carotid artery stenting for asymptomatic and symptomatic carotid artery stenosis: a single-center prospective study.
      (2014) J NeuroIntervent Surg
      Retrosp analysis of prosp data; Single centreCAS402169 (42.0)NRNRNR
      Shahidi
      • Shahidi S.
      • Owen-Falkenberg A.
      • Hjerpsted U.
      • Rai A.
      • Ellemann K.
      Urgent best medical therapy may obviate the need for urgent surgery in patients with symptomatic carotid stenosis.
      (2013) Stroke
      Prosp; Single centreCEA115115 (100)Early (0–14); Deferred (15–30); Delayed (31–180)NR36.3 ± 25.1
      Sharpe
      • Sharpe R.
      • Sayers R.D.
      • London N.J.
      • Bown M.J.
      • McCarthy M.J.
      • Nasim A.
      • et al.
      Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.
      (2013) Eur J Vasc Endovasc Surg
      Retrosp; Single centreCEA475475 (100)Early (0–14); Hyperacute (0–2); (3–7); (8–14); Delayed (15–180)0–2 d: 41 (8.6); 3–7 d: 167 (35.2); 8–14 d: 133 (28.0); 15–180 d: 134 (28.2)NR
      Faggioli
      • Faggioli G.
      • Pini R.
      • Mauro R.
      • Gargiulo M.
      • Freyrie A.
      • Stella A.
      Perioperative outcome of carotid endarterectomy according to type and timing of neurologic symptoms and computed tomography findings.
      (2013) Ann Vasc Surg
      Retrosp analysis of prosp data; Single centreCEA610162 (27)Early (0–14); Deferred (15–30); Delayed (31–180)0–14 d: 60 (37.0); 15–30 d: 18 (11.1); 31–180 d: 84 (51.9)NR
      Hartog
      • den Hartog A.G.
      • Moll F.L.
      • van der Worp H.B.
      • Hoff R.G.
      • Kappelle L.J.
      • de Borst G.J.
      Delay to carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      (2013) Eur J Vasc Endovasc Surg
      Retrosp; Single centreCEA555555 (100)Early (0–14); Delayed (15–180)0–14 d: 105 (18.9); 15–180 d: 450 (81.1)40.3 ± 15.9
      Tas
      • Taş M.H.
      • Simşek Z.
      • Colak A.
      • Koza Y.
      • Demir P.
      • Demir R.
      • et al.
      Comparison of carotid artery stenting and carotid endarterectomy in patients with symptomatic carotid artery stenosis: a single center study.
      (2013) Adv Ther
      Retrosp; Single centreCEA/CAS65

      CEA 32 (49.2); CAS 33 (50.8)
      65 (100)NRNRNR
      Annambhotla
      • Annambhotla S.
      • Park M.S.
      • Keldahl M.L.
      • Morasch M.D.
      • Rodriguez H.E.
      • Pearce W.H.
      • et al.
      Early versus delayed carotid endarterectomy in symptomatic patients.
      (2012) J Vasc Surg
      Retrosp; Single centreCEA312312 (100)Early (0–30); (0–7); (8–14); (15–21); (22–30); Delayed (31–180)0–7 d: 27 (8.7); 8–14 d: 17 (5.4); 15–21 d: 12 (3.8); 22–30 d: 12 (3.8); 31–180 d: 243 (77.9)NR
      Kessler
      • Kessler I.
      • Gory B.
      • Macian F.
      • Nakiri G.
      • Al-Khawaldeh M.
      • Riva R.
      • et al.
      Carotid artery stenting in patients with symptomatic carotid stenosis: a single-center series.
      (2012) J Neuroradiol
      Retrosp; Single centreCAS5555 (100)NRNRNR
      Kimiagar
      • Kimiagar I.
      • Gur A.Y.
      • Auriel E.
      • Peer A.
      • Sacagiu T.
      • Bass A.
      Long-term follow-up of patients after carotid stenting with or without distal protective device in a single tertiary medical center.
      (2012) Vasc Endovascular Surg
      Retrosp; Single centreCEA/CAS116116 (100)NRNRNR
      Lin
      • Lin R.
      • Mazighi M.
      • Yadav J.
      • Abou-Chebl A.
      The impact of timing on outcomes of carotid artery stenting in recently symptomatic patients.
      (2009) J NeuroIntervent Surg
      Retrosp; Single centreCAS224224 (100)Early (0–30); Ultra-Early (0–14); Delayed (31–180)0–30 d: 122 (54.5); 31–180 d: 102 (45.5)NR
      Gray
      • Gray W.A.
      • Chaturvedi S.
      • Verta P.
      Thirty-day outcomes for carotid artery stenting in 6320 patients from 2 prospective, multicenter, high-surgical-risk registries.
      (2009) Circ Cardiovasc Intervent

      EXACT

      CAPTURE-2
      Prosp; MulticentreCAS6320759 (12.0)NRNRNR
      Ballotta
      • Ballotta E.
      • Meneghetti G.
      • Da Giau G.
      • Manara R.
      • Saladini M.
      • Baracchini C.
      Carotid endarterectomy within 2 weeks of minor ischemic stroke: a prospective study.
      (2008) J Vasc Surg
      Retrosp; Single centreCEA102102 (100)Early (0–14)0–14 d: 102 (100)6.3 ± 3.2
      Setacci
      • Setacci C.
      • de Donato G.
      • Chisci E.
      • Setacci F.
      • Stella A.
      • Faggioli G.
      • et al.
      Deferred urgency carotid artery stenting in symptomatic patients: clinical lessons and biomarker patterns from a prospective registry.
      (2008) Eur J Vasc Endovasc Surg
      Prosp; MulticentreCAS5757 (100)Deferred for TIA (1–2); Deferred for Stroke (14–30)1–2 d (TIA): 24 (42); 14–30 (Stroke): 33 (58)NR
      Massop
      • Massop D.
      • Dave R.
      • Metzger C.
      • Bachinsky W.
      • Solis M.
      • Shah R.
      • et al.
      Stenting and angioplasty with protection in patients at high-risk for endarterectomy: SAPPHIRE Worldwide Registry first 2,001 patients.
      (2008) Catheter Cardiovasc Interv
      SAPPHIRE RegistryCEA/CAS2001555 (27.7)NRNRNR
      Steinbauer
      • 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.
      (2008) J Vasc Surg
      RCTCEA/CAS87

      CEA: 44 (50.6); CAS: 43 (49.4)
      87 (100)NRNRNR
      Topakian
      • Topakian R.
      • Strasak A.M.
      • Sonnberger M.
      • Haring H.P.
      • Nussbaumer K.
      • Trenkler J.
      • et al.
      Timing of stenting of symptomatic carotid stenosis is predictive of 30-day outcome.
      (2007) Eur J Neurol
      Retrosp; Single centreCAS7777 (100)Early (0–14)0–14 d: 23 (29.9); 15–180 d: 54 (70.1)NR
      Suzue
      • Suzue A.
      • Uno M.
      • Kitazato K.T.
      • Nishi K.
      • Yagi K.
      • Liu H.
      • et al.
      Comparison between early and late carotid endarterectomy for symptomatic carotid stenosis in relation to oxidized low-density lipoprotein and plaque vulnerability.
      (2007) J Vasc Surg
      Retrosp; Single centreCEA7272 (100)Early (0–30); Delayed (31–180)0–30 d: 15 (20.8); 31–180 d: 57 (79.2)NR
      Dellagrammaticas
      • Dellagrammaticas D.
      • Lewis S.
      • Colam B.
      • Rothwell P.M.
      • Warlow C.P.
      • Gough M.J.
      Carotid endarterectomy in the UK: acceptable risks but unacceptable delays.
      (2007) Clin Med

      GALA TRIAL
      RCTCEA1 001867 (86.6)NRNR86 ± 30.0
      Flanigan
      • Flanigan D.P.
      • Flanigan M.E.
      • Dorne A.L.
      • Harward T.R.
      • Razavi M.K.
      • Ballard J.L.
      Long-term results of 442 consecutive, standardized carotid endarterectomy procedures in standard-risk and high-risk patients.
      (2007) J Vasc Surg
      Retrosp analysis of prosp data; Single centreCEA442170 (38.5)NRNRNR
      Sbarigia
      • Sbarigia E.
      • Toni D.
      • Speziale F.
      • Acconcia M.C.
      • Fiorani P.
      Early carotid endarterectomy after ischemic stroke: the results of a prospective multicenter Italian study.
      (2006) Eur J Vasc Endovasc Surg
      Prosp; MulticentreCEA9696 (100)NRNR1.5 ± 2
      Imai
      • Imai K.
      • Mori T.
      • Izumoto H.
      • Watanabe M.
      • Majima K.
      Emergency carotid artery stent placement in patients with acute ischemic stroke.
      (2005) Am J Neuroradiol
      Retrosp; Single centreCAS1717 (100)NRNR2.3 ± 2.4
      Rantner
      • Rantner B.
      • Pavelka M.
      • Posch L.
      • Schmidauer C.
      • Fraedrich G.
      Carotid endarterectomy after ischemic stroke--is there a justification for delayed surgery?.
      (2005) Eur J Vasc Endovasc Surg
      Retrosp; Single centreCEA104104 (100)Acute (0–24 hours); Ultra-Early (0–6 hours); (0–27); (28–180)0 d: 7 (6.7); <28 d: 29 (27.9); ≥28 d: 62 (59.6)
      Ecker
      • Ecker R.D.
      • Brown Jr., R.D.
      • Nichols D.A.
      • McClelland R.L.
      • Reinalda M.S.
      • Piepgras D.G.
      • et al.
      Cost of treating high-risk symptomatic carotid artery stenosis: stent insertion and angioplasty compared with endarterectomy.
      (2004) J Neurosurg
      Case ControlCEA/CAS436

      CEA: 391 (89.7) CAS: 45 (10.3)
      436 (100)NRNRNR
      Kastrup
      • Kastrup A.
      • Skalej M.
      • Krapf H.
      • Nägele T.
      • Dichgans J.
      • Schulz J.B.
      Early outcome of carotid angioplasty and stenting versus carotid endarterectomy in a single academic center.
      (2003) Cerebrovasc Dis
      Case ControlCEA/CAS242

      CEA: 142 (58.7); CAS: 100 (41.3)
      155 (64.0)NRNRNR
      Welsh
      • Welsh S.
      • Mead G.
      • Chant H.
      • Picton A.
      • O'Neill P.A.
      • McCollum C.N.
      Early carotid surgery in acute stroke: a multicentre randomised pilot study.
      (2003) Cerebrovasc Dis
      Prosp; MulticentreCEA4040 (100)Early (0–1); Delayed (60–180)0–1 d: 19 (47.5); 60–180 d: 21 (52.5)NR
      ECST
      Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
      (1988) Lancet
      RCTCEA vs. BMT1 8071 807 (100)NRNRNR
      National Registry
       Kuhrij
      • Kuhrij L.S.
      • Meershoek A.J.A.
      • Karthaus E.G.
      • Vahl A.C.
      • Hamming J.F.
      • Nederkoorn P.J.
      • et al.
      Factors associated with hospital dependent delay to carotid endarterectomy in the Dutch Audit for Carotid Interventions.
      (2019) Eur J Vasc Endovasc Surg

      Dutch Audit for Carotid Intervention
      Retrosp analysis of prosp data; MulticentreCEA8 6208 620 (100)Early (0–14)0–14 d: 6645 (78)11 ± 1.7
       Faateh
      • Faateh M.
      • Dakour-Aridi H.
      • Kuo P.L.
      • Locham S.
      • Rizwan M.
      • Malas M.B.
      Risk of emergent carotid endarterectomy varies by type of presenting symptoms.
      (2018) J Vasc Surg

      National Quality Improvement
      Retrosp analysis of prosp data; MulticentreCEA9 2719 271 (100)Emergency: Performed within the same hospitalisation OR reported as emergency by the teamEmergency: 546 (5.9); Non-emergency: 8725 (94.1)NR
       Tsantilas
      • Tsantilas P.
      • Kuehnl A.
      • Kallmayer M.
      • Knappich C.
      • Schmid S.
      • Breitkreuz T.
      • et al.
      Risk of stroke or death is associated with the timing of carotid artery stenting for symptomatic carotid stenosis: a secondary data analysis of the German Statutory Quality Assurance Database.
      (2018) J Am Heart Assoc

      German Statutory Quality Assurance
      Retrosp analysis of prosp data; MulticentreCAS4 7174 717 (100)Early (0–14); (0–2); (3–7); (8–14); Delayed (15–180)0–2 d: 550 (11.6); 3–7 d: 1579 (33.4); 8–14 d: 1244 (26.3); 15–180 d: 1344 (28.4)NR
       Blay
      • Blay Jr., E.
      • Balogun Y.
      • Nooromid M.J.
      • Eskandari M.K.
      Early carotid endarterectomy after acute stroke yields excellent outcomes: an analysis of the procedure-targeted ACS-NSQIP.
      (2018) Ann Vasc Surg

      ACS-NSQIP
      Retrosp analysis of prosp data; MulticentreCEA3 4273 427 (100)Early (0–7); Delayed (8–180)0–7 d: 3247 (94.7); 8–180 d: 180 (5.3)NR
       Avgerinos
      • Avgerinos E.D.
      • Farber A.
      • Abou Ali A.N.
      • Rybin D.
      • Doros G.
      • Eslami M.H.
      Early carotid endarterectomy performed 2 to 5 days after the onset of neurologic symptoms leads to comparable results to carotid endarterectomy performed at later time points.
      (2017) J Vasc Surg

      VSGNE Database
      Retrosp analysis of prosp data; MulticentreCEA989989 (100)0 d: 96 (9.8); 1–2 d: 322 (32.6)

      3–5 d: 94 (9.1); 6–180 d: 477 (48.2)
      NR
       Venermo
      • Venermo M.
      • Wang G.
      • Sedrakyan A.
      • Mao J.
      • Eldrup N.
      • DeMartino R.
      • et al.
      Editor's Choice - Carotid Stenosis Treatment: Variation in International Practice Patterns.
      (2017) Eur J Vasc Endovasc Surg

      VQI/Vascunet
      Retrosp analysis of prosp data; MulticentreCEA/CAS58 607

      CEA: 52 434 (89.5);

      CAS: 6 173 (10.5)
      30 520 (52.1)NRNRNR
       Kjorstad
      • Kjorstad K.E.
      • Baksaas S.T.
      • Bundgaard D.
      • Halbakken E.
      • Hasselgard T.
      • Jonung T.
      • et al.
      Editor's Choice - The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events.
      (2017) Eur J Vasc Endovasc Surg

      National Norwegian Carotid Study
      Retrosp analysis of prosp data; MulticentreCEA368368 (100)Early (0–14)0–14 d: 227 (61.7); 15–180 d: 141 (36.8)12.75 ± 4.3
       Loftus
      • Loftus I.M.
      • Paraskevas K.I.
      • Johal A.
      • Waton S.
      • Heikkila K.
      • Naylor A.R.
      • et al.
      Editor's Choice - Delays to surgery and procedural risks following carotid endarterectomy in the UK National Vascular Registry.
      (2016) Eur J Vasc Endovasc Surg

      UK National Vascular Registry
      Retrosp analysis of prosp data; MulticentreCEA33 19423 235 (70.0)Early (0–14); (0–2); (3–7); (8–14); (15–21); Delayed (22–180)0–2 d: 780 (3.4); 3–7 d: 5126 (22.1); 8–14 d: 6292 (27.1); 15–21 d: 2765 (11.9); 22–180 d: 8272 (35.6)2009: 9.3 ± 4.9;

      2010: 7.0 ± 4.1;

      2011: 5.5 ± 2.90;

      2012: 5.0 ± 2.3;

      2013: 4.5 ± 2.3;

      2014: 5.75 ± 6.7
       Jonsson
      • Jonsson M.
      • Gillgren P.
      • Wanhainen A.
      • Acosta S.
      • Lindström D.
      Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
      (2015) Eur J Vasc Endovasc Surg

      Swedvasc Registry
      Retrosp analysis of prosp data; MulticentreCAS323323 (100)Early (0–14); (0–2); (3–7); (8–14); Delayed (15–180)0–2 d: 13 (4.0); 3–7 d: 85 (26.3); 8–14 d: 80 (24.8); 15–180 d: 145 (44.9)NR
       Geraghty
      • Geraghty P.J.
      • Brothers T.E.
      • Gillespie D.L.
      • Upchurch G.R.
      • Stoner M.C.
      • Siami F.S.
      • et al.
      Preoperative symptom type influences the 30-day perioperative outcomes of carotid endarterectomy and carotid stenting in the Society for Vascular Surgery Vascular Registry.
      (2014) J Vasc Surg

      SVS Vascular Registry
      Retrosp analysis of prosp data; MulticentreCEA/CAS8 640

      CEA: 5 758 (66.6); CAS: 2 882 (33.3)
      2 904 (33.6)Symptomatic: Neurologic events in the previous 12 monthsNRNR
       Villwock
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      (2014) J Stroke Cerebrovasc Dis

      Nationwide Inpatient Sample
      Retrosp analysis of prosp data; MulticentreCEA vs. CAS72 797

      CEA: 62 327 (85.6);

      CAS: 13 470 (18.4)
      72 797 (100)Ultra-Early (0–2); Early (3–14)0–2 d: 41008 (56.3); 3–14 d: 31789 (43.7)NR
       Witt
      • Witt A.H.
      • Johnsen S.P.
      • Jensen L.P.
      • Hansen A.K.
      • Hundborg H.H.
      • Andersen G.
      Reducing delay of carotid endarterectomy in acute ischemic stroke patients: a nationwide initiative.
      (2013) Stroke

      Danish Stroke Registry/Danish Vascular Registry
      Retrosp analysis of prosp data; MulticentreCEA813813 (100)Early (0–14)NRDecrease in the delay to CEA with time: 13% underwent CEA in two weeks in 2007, 33% in 2008, 37% in 2009, 47% in 2010 (OR 5.8, 95% CI 4.3–10.1)
       Schermerhorn
      • Schermerhorn M.L.
      • Fokkema M.
      • Goodney P.
      • Dillavou E.D.
      • Jim J.
      • Kenwood C.T.
      • et al.
      The impact of Centers for Medicare and Medicaid Services high-risk criteria on outcome after carotid endarterectomy and carotid artery stenting in the SVS Vascular Registry.
      (2013) J Vasc Surg

      CMS
      Retrosp analysis of prosp data; MulticentreCEA/CAS10 107

      CEA: 6 370 (63.0);

      CAS: 3 737 (37.0)
      3 916 (38.7)NRNRNR
       Nolan
      • Nolan B.W.
      • De Martino R.R.
      • Goodney P.P.
      • Schanzer A.
      • Stone D.H.
      • Butzel D.
      • et al.
      Comparison of carotid endarterectomy and stenting in real world practice using a regional quality improvement registry.
      (2012) J Vasc Surg

      VSGNE

      2003–2010
      Retrosp analysis of prosp data; MulticentreCEA/CAS8 079

      CEA: 7 649 (94.6);

      CAS: 430 (5.4)
      2 763 (34.2)NRNRNR
       Stromberg
      • Stromberg S.
      • Gelin J.
      • Osterberg T.
      • Bergstrom G.M.
      • Karlstrom L.
      • Osterberg K.
      • et al.
      Very urgent carotid endarterectomy confers increased procedural risk.
      (2012) Stroke

      Swedvasc Registry
      Retrosp analysis of prosp data; MulticentreCEA2 5962 596 (100)0–2 d: 148 (5.7); 3–7 d: 804 (31.0); 8–14 d: 677 (26.1); 15–180 d: 967 (37.2)NR
       Garg
      • Garg J.
      • Frankel D.A.
      • Dilley R.B.
      Carotid endarterectomy in academic versus community hospitals: the national surgical quality improvement program data.
      (2011) Ann Vasc Surg

      National Surgery Quality Improvement
      Retrosp analysis of prosp data; MulticentreCEA17 3888 103 (46.6)NRNRNR
       Palombo
      • Palombo D.
      • Lucertini G.
      • Mambrini S.
      • Spinella G.
      • Pane B.
      Carotid endarterectomy: results of the Italian Vascular Registry.
      (2009) J Cardiovasc Surg

      Italian Vascular Registry
      Retrosp analysis of prosp data; MulticentreCEA5 8091 894 (32.6)NRNRNR
       Halliday
      • Halliday A.W.
      • Lees T.
      • Kamugasha D.
      • Grant R.
      • Hoffman A.
      • Rothwell P.M.
      • et al.
      Waiting times for carotid endarterectomy in UK: observational study.
      (2009) BMJ

      UK Surgeons undertaking CEA
      Retrosp analysis of prosp data; MulticentreCEA5 5134 576 (83)Early (0–12); (0–2); (2–4); (5–12); Delayed (13–180);0–2 d: 944 (20.0); 3–4 d: 654 (14); 5–12 d: 1621 (34); 13–180 d: 1372 (30)45.3 ± 19.4
       Vogel
      • Vogel T.R.
      • Dombrovskiy V.Y.
      • Haser P.B.
      • Scheirer J.C.
      • Graham A.M.
      Outcomes of carotid artery stenting and endarterectomy in the United States.
      (2009) J Vasc Surg

      Nationwide Inpatient Sample (2005)
      Retrosp analysis of prosp data; MulticentreCEA/CAS80 498

      CEA: 73 929 (91.8);

      CAS 6 569 (8.2)
      2 237 (2.8)NRNRNR
       Gladstone
      • Gladstone D.J.
      • Oh J.
      • Fang J.
      • Lindsay P.
      • Tu J.V.
      • Silver F.L.
      • et al.
      Urgency of carotid endarterectomy for secondary stroke prevention: results from the Registry of the Canadian Stroke Network.
      (2009) Stroke

      Canadian Stroke Network
      Retrosp analysis of prosp data; MulticentreCEA105105 (100)Early (0–14); Deferred (15–30); Delayed (31–180)0–14 d: 38 (36.2); 15–30 d: 53 (50.5); 31–180 d: 26 (24.8)37.8 ± 20.5
       Goodney
      • Goodney P.P.
      • Likosky D.S.
      • Cronenwett J.L.
      Factors associated with stroke or death after carotid endarterectomy in Northern New England.
      (2008) J Vasc Surg

      VSGNE 2003–2007
      Retrosp analysis of prosp data; MulticentreeCEA3 0921 360 (44)Emergency (0–6 h); Urgent (0–24 h)0–1 d: 309 (10)NR
       McPhee
      • McPhee J.T.
      • Hill J.S.
      • Ciocca R.G.
      • Messina L.M.
      • Eslami M.H.
      Carotid endarterectomy was performed with lower stroke and death rates than carotid artery stenting in the United States in 2003 and 2004.
      (2007) J Vasc Surg

      Nationwide Inpatient Sample
      Retrosp analysis of prosp data; MulticentreCEA/CAS259 080

      CEA: 245 045 (94.6);

      CAS 14 035 (5.4)
      20 750 (8)NRNRNR
       Pell
      • Pell J.P.
      • Slack R.
      • Dennis M.
      • Welch G.
      Improvements in carotid endarterectomy in Scotland: results of a national prospective survey.
      (2004) Scott Med J

      National Prospective Survey Scotland
      Retrosp analysis of prosp data; MulticentreCEA877855 (97.5)Early (0–30); Deferred (31–60)0–30 d: 103 (27); 31–60 d: 222 (58)NR
       Tu
      • Tu J.V.
      • Wang H.
      • Bowyer B.
      • Green L.
      • Fang J.
      • Kucey D.
      Risk factors for death or stroke after carotid endarterectomy: observations from the Ontario Carotid Endarterectomy Registry.
      (2003) Stroke

      Ontario Carotid Endarterectomy Registry
      Retrosp analysis of prosp data; MulticentreCEA6 0384 192 (69.4)NRNRNR
      Data are presented as n (%) unless stated otherwise. NR = not reported; Retrosp = retrospective; Prosp = prospective.

      Definitions

      The definitions of “delay” and “index event” were heterogeneous (Table 1). Most studies defined “early intervention” when CEA or CAS were performed within 14 days of the index event, although some studies applied stricter or looser definitions (Table 1). Stratification of the timing of events within the first 14 days was described in some studies, for example as “acute/urgent/emergency/ultra-early interventions” (Table 1). One study was identified that defined the timing of intervention as the time from the qualifying event (defined as the most recent neurological event before intervention, rather than the index event).
      • Nordanstig A.
      • Rosengren L.
      • Stromberg S.
      • Osterberg K.
      • Karlsson L.
      • Bergstrom G.
      • et al.
      Editor's Choice - Very Urgent Carotid Endarterectomy is Associated with an Increased Procedural Risk: The Carotid Alarm Study.

      Symptomatic status and timing of intervention

      Considering all symptomatic patients (232 952), the time to intervention was reported for 148 653 patients (63.8%), of whom 44 410 (29.9%) underwent either CEA or CAS within the first 48 hours and 108 139 (72.7%) within the first 14 days after the index event.
      Thirty-five studies reported outcomes after CEA alone (73 242), while five studies reported outcomes after CAS alone (5 443). Five studies reported mixed outcomes, three of which compared CEA (64 430) with CAS (15 624) (Table 2).
      Table 2Analysis of patient characteristics including the type of neurological symptoms undergoing carotid endarterectomy (CEA) or carotid artery stenting (CAS) after index event
      Article (Year)CEA / CASTime periodsSymptomatic CEA / CASAgeMale sexType of eventNew events before intervention
      TIACrescendo TIA / stroke in evolutionAfxMinor / major stroke
      Jankowitz
      • Jankowitz B.T.
      • Tonetti D.A.
      • Kenmuir C.
      • Rao R.
      • Ares W.J.
      • Zussman B.
      • et al.
      Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
      (2020)
      CEA vs. CASAll (0–2 d)120 (100)
      CEA59 (49.2)68.4 ± 11.338 (64)NRNRNRNRNR
      CAS61 (50.8)71.5 ± 12.942 (71)NRNRNRNRNR
      Roussopoulo
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      (2019)
      CEAAll (0–14 d)311 (100)69 ± 11230 (74)128 (41)28 (9)183 (59)NR
      0–2 d63 (20.3)67 ± 1545 (71)31 (49)13 (21)32 (51)NR
      3–14 d248 (79.7)69 ± 10186 (75)99 (40)17 (7)124 (50)NR
      Huang
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      (2018)
      CEAAll (0–180 d)238 (100)72 ± 9.1158 (68)176 (74)71 (30)62 (26)NR
      Group 1 (0–14 d)57 (23.9)72 ± 1034 (60.7)48 (84)18 (32)9 (16)NR
      0–2 d11 (4.6)
      3–7 d23 (9.7)
      8–14 d23 (9.7)
      Group 2 (14–180 d)181 (76.1)72 ± 8.8124 (70)128 (71)53 (29)53 (29)NR
      Seguchi
      • Seguchi M.
      • Shibata M.
      • Sato Y.
      • Maekawa K.
      • Kitano Y.
      • Sano T.
      • et al.
      The safety of carotid artery stenting for patients in the acute poststroke phase.
      (2017)
      CASAll (0–180 d)105 (100)
      0–2 d40 (38.1)74.8 ± 2.537 (92.5)9 (22.5)25 (62.5)31 (77.5)NR
      3–180 d65 (61.9)77.0 ± 3.559 (90.8)NR0 (0)NRNRNR
      Rantner
      • Rantner B.
      • Kollerits 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.
      (2017)

      EVA-3S, SPACE, ICSS, CREST
      CEA vs. CASAll (0–180 d)4138 (100)
      CEA vs. CAS0–7 d513 (12.4)355 (8.6)258 (6.2)258 (6.2)67 (1.6)NR
      CEA226 (11)69.2 ± 8.9157 (3.8)112 (2.7)112 (2.7)30 (0.7)NR
      CAS287 (14)68.3 ± 9.0198 (4.9)146 (3.5)146 (3.5)37 (0.9)NR
      CEA vs. CAS8–180 d3625 (87.6)2536 (61.3)1277 (30.9)1277 (30.9)643 (15.5)NR
      CEA1819 (89)69.6 ± 9.41285 (31.1)649 (15.7)649 (15.7)317 (7.7)NR
      CAS1806 (86)69.6 ± 9.21251 (30.2)628 (15.2)628 (15.2)326 (7.9)NR
      Nordanstig
      • Nordanstig A.
      • Rosengren L.
      • Stromberg S.
      • Osterberg K.
      • Karlsson L.
      • Bergstrom G.
      • et al.
      Editor's Choice - Very Urgent Carotid Endarterectomy is Associated with an Increased Procedural Risk: The Carotid Alarm Study.
      (2017)
      CEA0–2 d
      Of the most recent neurological event before intervention.
      75 (18)73.0 ± 8.555 (73)28 (37)14 (19)18 (24)15 (20)NA
      3–14 d
      Of the most recent neurological event before intervention.
      343 (82)73.7 ± 8.5237 (69)106 (31)17 (5)12 (24)138 (40)NA
      Tsantilas
      • Tsantilas P.
      • Kühnl A.
      • Kallmayer M.
      • Pelisek J.
      • Poppert H.
      • Schmid S.
      • et al.
      Short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.
      (2016)
      CEAAll (0–180 d)401 (100)69.8 ± 3.7273 (68.1)174 (43.4)102 (25.4)125 (31.1)NR
      0–2 d60 (15)70.8 ± 10.144 (72)32 (53)13 (22)15 (3.7)NR
      3–7 d110 (27.4)70.8 ± 14.175 (68)46 (42)29 (26)35 (8.7)NR
      8–14 d65 (16.2)70.8 ± 18.841 (63.1)25 (39)9 (14)31 (7.7)NR
      14–180 d166 (41.4)68.5 ± 3.5113 (68.1)71 (43)51 (31)44 (10.9)NR
      Charbonneau
      • Charbonneau P.
      • Bonaventure P.L.
      • Drudi L.M.
      • Beaudoin N.
      • Blair J.F.
      • Elkouri S.
      An institutional study of time delays for symptomatic carotid endarterectomy.
      (2016)
      CEAAll (0–180 d)103 (100)68.5 ± 13.371 (68.9)42 (40.8)21 (20.4)40 (38.8)43 (42)
      0–14 d40 (38.8)26 (36.6)12 (28.6)5 (23.8)23 (57.5)NR
      15–90 d37 (35.9)26 (36.6)18 (42.9)7 (33.3)12 (30.0)NR
      91–180 d26 (25.2)19 (26.8)12 (28.6)9 (42.9)5 (12.5)NR
      Chisci
      • Chisci E.
      • Pigozzi C.
      • Troisi N.
      • Tramacere L.
      • Zaccara G.
      • Cincotta M.
      • et al.
      Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients.
      (2015)
      CEAAll (0–30 d)322 (100)73.2 ± 9235 (73)166 (51)43 (13)27 (9)129 (40)NR
      0–14 d100 (31.1)72.5 ± 9.175 (75)52 (52)17 (17)5 (5)43 (43)NR
      15–30 d222 (68.9)73.5 ± 8.9160 (72)114 (51)26 (12)22 (10)86 (39)NR
      p = .35p = .68
      Kretz
      • Kretz B.
      • Kazandjian C.
      • Bejot Y.
      • Abello N.
      • Brenot R.
      • Giroud M.
      • et al.
      Delay between symptoms and surgery for carotid artery stenosis: modification of our practice.
      (2015)
      CEAAll (0–180 d)417 (100)
      0–15158 (37.9)73.8 ± 10116 (73.4)58 (36.7)20 (12.7)56 (35.4)NR
      16–4579 (18.9)73.8 ± 1153 (67.1)33 (41.8)9 (11.4)24 (30.4)NR
      46–180180 (43.2)73.1 ± 9.6136 (75.6)55 (30.6)21 (11.7)77 (42.8)NR
      Jonsson
      • Jonsson M.
      • Gillgren P.
      • Wanhainen A.
      • Acosta S.
      • Lindström D.
      Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
      (2015)
      CASAll (0–180 d)323 (100)
      0–2 d13 (4.0)69 ± 6.410 (76.9)2 (15.4)0 (0)2 (15.4)9 (69.2)NR
      3–7 d85 (26.3)71 ± 8.758 (68.2)37 (43.5)0 (0)15 (17.6)33 (38.9)NR
      8–14 d80 (24.8)72 ± 9.360 (74.1)37 (46.3)1 (1.3)9 (11.134 (30)NR
      15–180 d145 (44.9)70 ± 8.798 (67.6)62 (42.8)0 (0)35 (24.1)38 (33.1)NR
      Charmoille
      • Charmoille E.
      • Brizzi V.
      • Lepidi S.
      • Sassoust G.
      • Roullet S.
      • Ducasse E.
      • et al.
      Thirty-day outcome of delayed versus early management of symptomatic carotid stenosis.
      (2014)
      CEAAll (0–180 d)149 (100)71.5119 (79.9)60 (40.3)19 (12.7)14 (9.4)75 (50.3)NR
      0–14 d62 (41.6)69.7 ± 10.968 (78.2)29 (46.8)11 (17.7)6 (9.7)27 (43.5)NR
      15–180 d87 (58.4)71.2 ± 13.351 (82.3)31 (35.6)8 (21.8)8 (9.2)48 (55.2)NR
      Rantner
      • Rantner B.
      • Schmidauer C.
      • Knoflach M.
      • Fraedrich G.
      Very urgent carotid endarterectomy does not increase the procedural risk.
      (2014)
      CEAAll (0–180 d)761 (100)70.1 ± 9.7559 (73.5)305 (40.1)162 (21.3)294 (38.6)NR
      0–2 d206 (27.1)70.1 ± 10.3152 (73.8)115 (55.8)37 (18)54 (26.2)NR
      3–7 d219 (28.8)70.9 ± 9.4159 (72.6)91 (41.6)51 (23.3)77 (35.2)NR
      8–14 d136 (17.9)71.0 ± 9.2102 (75.0)54 (39.7)33 (24.3)49 (36.0)NR
      15–180 d200 (26.3)68.5 ± 9.5146 (73.0)45 (22.5)41 (20.5)114 (57.0)NR
      Tsivgoulis
      • Tsivgoulis G.
      • Krogias C.
      • Georgiadis G.S.
      • Mikulik R.
      • Safouris A.
      • Meves S.H.
      • et al.
      Safety of early endarterectomy in patients with symptomatic carotid artery stenosis: an international multicenter study.
      (2014)
      CEAAll (0–14 d)165 (100)69 ± 10114 (69)50 (30)115 (70)NR
      0–2 d20 (12)70±1211 (55)7 (35)13 (65)NR
      3–14 d145 (88)68 ± 10154 (71)44 (30)101 (70)NR
      Shahidi
      • Shahidi S.
      • Owen-Falkenberg A.
      • Hjerpsted U.
      • Rai A.
      • Ellemann K.
      Urgent best medical therapy may obviate the need for urgent surgery in patients with symptomatic carotid stenosis.
      (2013)
      CEAAll115 (100)NRNR39 (34)11 (9)65 (56.5)NR
      Sharpe
      • Sharpe R.
      • Sayers R.D.
      • London N.J.
      • Bown M.J.
      • McCarthy M.J.
      • Nasim A.
      • et al.
      Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.
      (2013)
      CEAAll475 (100)NRNR72 (57)94 (20)109 (23)
      Faggioli
      • Faggioli G.
      • Pini R.
      • Mauro R.
      • Gargiulo M.
      • Freyrie A.
      • Stella A.
      Perioperative outcome of carotid endarterectomy according to type and timing of neurologic symptoms and computed tomography findings.
      (2013)
      CEAAll (0–180 d)162 (100)NRNR81 (50)9 (5.6)72 (44.4)NR
      0–1460 (37)NRNR36 (60)2 (3.3)22NR
      15–3018 (11.1)NRNR12 (66.7)2 (11.1)4NR
      31–18084 (51.9)NRNR33 (39.3)5 (5.9)46NR
      Annambhotla
      • Annambhotla S.
      • Park M.S.
      • Keldahl M.L.
      • Morasch M.D.
      • Rodriguez H.E.
      • Pearce W.H.
      • et al.
      Early versus delayed carotid endarterectomy in symptomatic patients.
      (2012)
      CEAAll (0–180 d)312 (100)NR200 (64.1)106 (34.0)205 (65.6)
      0–7 d27 (8.7)68.6 ± 9.816 (59.3)7 (25.9)20 (74.1)
      8–14 d17 (5.4)68.8 ± 14.79 (52.9)3 (17.6)14 (82.4)
      15–21 d12 (3.8)67.5 ± 14.38 (66.7)3 (25)9 (75)
      22–30 d12 (3.8)70.7 ± 9.38 (66.7)1 (8.3)11 (91.7)
      31–180 d243 (77.9)70.4 ± 9.7159 (65)92 (38)151 (62)
      Lin
      • Lin R.
      • Mazighi M.
      • Yadav J.
      • Abou-Chebl A.
      The impact of timing on outcomes of carotid artery stenting in recently symptomatic patients.
      (2009)
      CASAll (0–180 d)224 (100)
      0–30 d
      Early category was subclassified into ultra-early (0–14 d) with not significant difference compared with other categories.
      122 (54.5)72 ± 10.280 (65.6)77 (62.6)46 (37.4)
      31–180 d102 (45.5)69 ± 9.963 (61.8)72 (71.3)29 (28.7)
      p = .002p = .39
      Ballotta
      • Ballotta E.
      • Meneghetti G.
      • Da Giau G.
      • Manara R.
      • Saladini M.
      • Baracchini C.
      Carotid endarterectomy within 2 weeks of minor ischemic stroke: a prospective study.
      (2008)
      CEA0–14 d102 (100)NR65 (65.7)0 (0)0 (0)0 (0)102 (100)
      Only minor strokes were included.
      NR
      Setacci
      • Setacci C.
      • de Donato G.
      • Chisci E.
      • Setacci F.
      • Stella A.
      • Faggioli G.
      • et al.
      Deferred urgency carotid artery stenting in symptomatic patients: clinical lessons and biomarker patterns from a prospective registry.
      (2008)
      CASAll (0–30 d)57 (100)76.7 ± 8.037 (64.9)NR
      0–2 d24 (42)24 (100)0 (0)NR
      14–30 d33 (58)0 (0)33 (100)NR
      Suzue
      • Suzue A.
      • Uno M.
      • Kitazato K.T.
      • Nishi K.
      • Yagi K.
      • Liu H.
      • et al.
      Comparison between early and late carotid endarterectomy for symptomatic carotid stenosis in relation to oxidized low-density lipoprotein and plaque vulnerability.
      (2007)
      CEAAll (0–180 d)72 (100)NR
      0–30 d15 (20.8)65.4 ± 7.014 (93.3)7 (46.7)8 (14.0)NR
      31–180 d57 (79.2)69.2 ± 7.447 (76.9)27 (47.4)30 (52.6)NR
      Dellagrammaticas
      • Dellagrammaticas D.
      • Lewis S.
      • Colam B.
      • Rothwell P.M.
      • Warlow C.P.
      • Gough M.J.
      Carotid endarterectomy in the UK: acceptable risks but unacceptable delays.
      (2007) GALA Trial
      CEA867 (100)71.5 ± 3.5687 (69)303 (35)146 (17)231 (27)NR
      Flanigan
      • Flanigan D.P.
      • Flanigan M.E.
      • Dorne A.L.
      • Harward T.R.
      • Razavi M.K.
      • Ballard J.L.
      Long-term results of 442 consecutive, standardized carotid endarterectomy procedures in standard-risk and high-risk patients.
      (2007)
      CEA170 (38.5)NRNRNRNRNRNRNR
      Sbarigia
      • Sbarigia E.
      • Toni D.
      • Speziale F.
      • Acconcia M.C.
      • Fiorani P.
      Early carotid endarterectomy after ischemic stroke: the results of a prospective multicenter Italian study.
      (2006)
      CEA96 (100)69.4 ± 9.881 (84.3)NRNRNRNRNR
      Imai
      • Imai K.
      • Mori T.
      • Izumoto H.
      • Watanabe M.
      • Majima K.
      Emergency carotid artery stent placement in patients with acute ischemic stroke.
      (2005)
      CAS17 (100)69.913 (76.4)NRNRNRNRNR
      Rantner
      • Rantner B.
      • Pavelka M.
      • Posch L.
      • Schmidauer C.
      • Fraedrich G.
      Carotid endarterectomy after ischemic stroke--is there a justification for delayed surgery?.
      (2005)
      CEAAll (0–180 d)104 (100)69.4 ± 9.880 (87.1)NRNRNRNRNR
      0–6 hours7 (6.7)
      0–27 d29 (27.9)
      28–180 d62 (59.6)
      Welsh
      • Welsh S.
      • Mead G.
      • Chant H.
      • Picton A.
      • O'Neill P.A.
      • McCollum C.N.
      Early carotid surgery in acute stroke: a multicentre randomised pilot study.
      (2003)
      CEAAll (0–180 d)40 (100)
      0–1 d19 (47.5)65.8 ± 8.911 (57.9)NRNRNRNRNR
      60–180 d21 (52.5)68.3 ± 9.512 (57.1)NRNRNRNRNR
      ECST
      Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
      (1988)
      CEA vs. BMT1 807 (100)NRNRNRNRNRNRNR
      National audits
       Kuhrij
      • Kuhrij L.S.
      • Meershoek A.J.A.
      • Karthaus E.G.
      • Vahl A.C.
      • Hamming J.F.
      • Nederkoorn P.J.
      • et al.
      Factors associated with hospital dependent delay to carotid endarterectomy in the Dutch Audit for Carotid Interventions.
      (2019)

      Dutch Audit for Carotid Intervention
      CEAAll8 620 (100)72 ± 9.06010 (70)NRNRNRNRNR
      0–14 d6 645 (78)NRNRNRNRNRNRNR
       Faateh
      • Faateh M.
      • Dakour-Aridi H.
      • Kuo P.L.
      • Locham S.
      • Rizwan M.
      • Malas M.B.
      Risk of emergent carotid endarterectomy varies by type of presenting symptoms.
      (2018)

      National Quality Improvement
      CEAAll9 271 (100)NRNRNRNRNRNRNR
      eCEA546 (5.9)70.5 ± 11.2348 (63.7)206 (37.7)61 (11.2)279 (51.1)NR
      Non-eCEA8 725 (94.1)70.8 ± 9.95 390 (61.8)3 282 (37.6)1 507 (17.3)3 935 (45.1)NR
       Tsantilas
      • Tsantilas P.
      • Kuehnl A.
      • Kallmayer M.
      • Knappich C.
      • Schmid S.
      • Breitkreuz T.
      • et al.
      Risk of stroke or death is associated with the timing of carotid artery stenting for symptomatic carotid stenosis: a secondary data analysis of the German Statutory Quality Assurance Database.
      (2018)

      German Statutory Quality Assurance
      CASAll (0–180 d)4 717 (100)69.8 ± 9.83 201 (67.8)1 351 (28.6)797 (16.9)2 126 (45.1)NR
      0–2 d550 (11.6)69.1 ± 10.1386 (70.2)155 (28.2)65 (11.8)268 (48.7)NR
      3–7 d1 579 (33.4)69.6 ± 9.91070 (67.8)472 (29.9)212 (13.4)796 (50.4)
      8–14 d1 244 (26.3)70.1 ± 9.9835 (67.1)306 (24.6)234 (18.8)622 (50.0)NR
      15–180 d1 344 (28.4)69.9 ± 9.5910 (67.7)418 (31.1)286 (21.3)440 (32.7)NR
       Blay
      • Blay Jr., E.
      • Balogun Y.
      • Nooromid M.J.
      • Eskandari M.K.
      Early carotid endarterectomy after acute stroke yields excellent outcomes: an analysis of the procedure-targeted ACS-NSQIP.
      (2018)
      CEAAll (0–180 d)3 427 (100)NR2181 (63.6)NRNRNRNRNR
       ACS-NSQIP0–7d3 247 (94.7)NRNRNRNRNRNRNR
      8–180 d180 (5.3)NRNRNRNRNRNRNR
       Rocco
      • Rocco A.
      • Sallustio F.
      • Toschi N.
      • Rizzato B.
      • Legramante J.
      • Ippoliti A.
      • et al.
      Carotid artery stent placement and carotid endarterectomy: a challenge for urgent treatment after stroke-early and 12-month outcomes in a comprehensive stroke center.
      (2018)
      CEA / CAS110 (100)NR78 (70.9)10 (9.1)100 (90.9)NR
       Avgerinos
      • Avgerinos E.D.
      • Farber A.
      • Abou Ali A.N.
      • Rybin D.
      • Doros G.
      • Eslami M.H.
      Early carotid endarterectomy performed 2 to 5 days after the onset of neurologic symptoms leads to comparable results to carotid endarterectomy performed at later time points.
      (2017)

      VSGNE Database
      CEAAll (0–180 d)989 (100)69.6 ± 10.7653 (66)NRNRNRNRNR
      0 d477 (48.2)69.4 ± 10.5307 (64.4)NRNRNRNRNR
      1–2 d96 (9.8)70.1 ± 10.966 (68.8)NRNRNRNRNR
      3–5 d322 (32.6)69.9 ± 10.8210 (65.2)NRNRNRNRNR
      6–180 d94 (9.1)69.3 ± 11.470 (74.5)NRNRNRNRNR
       Kjorstad
      • Kjorstad K.E.
      • Baksaas S.T.
      • Bundgaard D.
      • Halbakken E.
      • Hasselgard T.
      • Jonung T.
      • et al.
      Editor's Choice - The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events.
      (2017)

      National Norwegian Carotid Study
      CEA368 (100)NRNR135 (36.7)64 (17.4)167 (45.4)12 (3.3%)
       Hobeanu
      • Hobeanu C.
      • Lavallée P.C.
      • Rothwell P.M.
      • Sissani L.
      • Albers G.W.
      • Bornstein N.M.
      • et al.
      Symptomatic patients remain at substantial risk of arterial disease complications before and after endarterectomy or stenting.
      (2017)
      CEA/CAS187 (100)71 ± 10142 (75.9)NRNRNRNRNR
       Loftus
      • Loftus I.M.
      • Paraskevas K.I.
      • Johal A.
      • Waton S.
      • Heikkila K.
      • Naylor A.R.
      • et al.
      Editor's Choice - Delays to surgery and procedural risks following carotid endarterectomy in the UK National Vascular Registry.
      (2016)

      UK National Vascular Registry
      CEA23 235 (70.0)72.8 ± 3.715 510 (66.8)11 029 (47.5)3 553 (15.3)8 229 (35.4)NR
       Villwock
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      (2014)

      NIS Registry
      CEA vs. CASAll (0–14 d)72 797 (100)NRNR
      0–2 d41 008 (56.3)NR22 601 (55.1)38 001 (52.2)3 007 (4.1)NRNR
      CEA31 899 (43.8)NR17 10529 936 (41.1)1 963 (2.7)NRNR
      CAS9 109 (12.5)NR5 4968065 (11.1)1 044 (1.4)NRNR
      3–14 d31 789 (43.7)NR25 146 (79.1)22 207 (30.5)12 582 (17.3)NRNR
      CEA30 428 (41.8)NR22 43619 729 (27.1)10 699 (14.7)NRNR
      CAS4 361 (6.0)NR2 7102 478 (3.4)1 883 (2.6)NRNR
       Stromberg
      • Stromberg S.
      • Gelin J.
      • Osterberg T.
      • Bergstrom G.M.
      • Karlstrom L.
      • Osterberg K.
      • et al.
      Very urgent carotid endarterectomy confers increased procedural risk.
      (2012)

      Swedvasc Registry
      CEAAll (0–180 d)2 596 (100)71.9 ± 8.21 731 (66.7)1 041 (40.1)54 (2.1)508 (19.6)993 (38.3)NR
      0–2 d148 (100)69.8 ± 8.6104 (70.3)70 (47.3)17 (11.5)23 (15.5)38 (25.7)NR
      3–7 d804 (100)72.6 ± 8.2526 (65.4)363 (45.1)19 (2.4)122 (15.2)300 (37.3)NR
      8–14 d677 (100)72.7 ± 8.2438 (64.7)279 (41.2)14 (2.1)107 (15.8)259 (38.3)NR
      15–180 d967 (100)71.0 ± 8.1663 (68.6)329 (34.0)4 (0.4)256 (26.5)411 (42.5)NR
       Garg
      • Garg J.
      • Frankel D.A.
      • Dilley R.B.
      Carotid endarterectomy in academic versus community hospitals: the national surgical quality improvement program data.
      (2011)

      National Surgery Quality Improvement
      CEA8 103 (46.6)NRNRNRNRNRNRNR
       Palombo
      • Palombo D.
      • Lucertini G.
      • Mambrini S.
      • Spinella G.
      • Pane B.
      Carotid endarterectomy: results of the Italian Vascular Registry.
      (2009)

      Italian Vascular Registry
      CEA1 894 (32.6)NRNRNRNRNRNRNR
       Halliday
      • Halliday A.W.
      • Lees T.
      • Kamugasha D.
      • Grant R.
      • Hoffman A.
      • Rothwell P.M.
      • et al.
      Waiting times for carotid endarterectomy in UK: observational study.
      (2009)

      UK Surgeons undertaking CEA
      CEAAll (0–180 d)4 576 (100)NRNR1 914 (41.8)916 (20.0)1 634 (35.7)NR
      0–2 d944 (20.6)NRNRNRNRNRNRNR
      3–4 d654 (14.3)NRNRNRNRNRNRNR
      5–12 d1 621 (35.4)NRNRNRNRNRNRNR
      13–180 d1 372 (30.0)NRNRNRNRNRNRNR
       Vogel
      • Vogel T.R.
      • Dombrovskiy V.Y.
      • Haser P.B.
      • Scheirer J.C.
      • Graham A.M.
      Outcomes of carotid artery stenting and endarterectomy in the United States.
      (2009)

      Nationwide Inpatient Sample (2005)
      CEA/CAS2 237 (100)NRNRNRNRNRNRNR
       Gladstone
      • Gladstone D.J.
      • Oh J.
      • Fang J.
      • Lindsay P.
      • Tu J.V.
      • Silver F.L.
      • et al.
      Urgency of carotid endarterectomy for secondary stroke prevention: results from the Registry of the Canadian Stroke Network.
      (2009)

      Canadian Stroke Network
      CEA105 (100)NRNRNRNRNRNRNR
       Goodney
      • Goodney P.P.
      • Likosky D.S.
      • Cronenwett J.L.
      Factors associated with stroke or death after carotid endarterectomy in Northern New England.
      (2008)

      VSGNE (2003–2007)
      CEAAll1 360 (100)NRNR680 (50)572 (42.1)340 (25)NR
      Emergency / Urgent309 (22.7)NRNRNRNRNRNR
       Pell
      • Pell J.P.
      • Slack R.
      • Dennis M.
      • Welch G.
      Improvements in carotid endarterectomy in Scotland: results of a national prospective survey.
      (2004)

      National Prospective Survey Scotland
      CEAAll (0–60 d)855 (100)NR510 (58.2)NRNRNRNRNR
      0–30 d103 (27)NRNRNRNRNRNRNR
      31–60 d222 (58)NRNRNRNRNRNRNR
       Tu
      • Tu J.V.
      • Wang H.
      • Bowyer B.
      • Green L.
      • Fang J.
      • Kucey D.
      Risk factors for death or stroke after carotid endarterectomy: observations from the Ontario Carotid Endarterectomy Registry.
      (2003)

      Ontario Carotid Endarterectomy Registry
      CEA4 192 (69.4)NRNRNRNRNRNRNR
      Data are presented as n (%) or mean ± standard deviation, unless stated otherwise. NA = not applicable; NR = not reported. p value is considered significant if ≤ .050.
      Of the most recent neurological event before intervention.
      Early category was subclassified into ultra-early (0–14 d) with not significant difference compared with other categories.
      Only minor strokes were included.
      Stratification of demographic data, type of neurological index event, and occurrence of new neurological symptoms, stratified by intervention delay are detailed in Table 2.
      Where reported, patients presenting with crescendo TIAs were more likely to undergo an early intervention.
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      ,
      • Seguchi M.
      • Shibata M.
      • Sato Y.
      • Maekawa K.
      • Kitano Y.
      • Sano T.
      • et al.
      The safety of carotid artery stenting for patients in the acute poststroke phase.
      The remaining presenting events (TIA, amaurosis fugax and stroke) were evenly distributed by intervention delay, with few exceptions (Table 2).

      Primary and secondary outcomes

      Peri-operative (30 day) outcomes along with data on hospitalisation duration (in days), stratified by intervention delay and by type of revascularisation (CEA vs. CAS) are detailed in Table 3. Almost all of the CAS procedures in the varying meta-analyses were performed via the transfemoral route. No published studies have evaluated outcomes for transcarotid artery revascularisation (TCAR) vs. CEA, with stratification for delays to treatment.
      • Coelho A.
      • Prassaparo T.
      • Mansilha A.
      • Kappelle J.
      • Naylor R.
      • de Borst G.J.
      Critical appraisal on the quality of reporting on safety and efficacy of transcarotid artery stenting with flow reversal.
      Table 3Analysis of post-procedural outcomes after carotid endarterectomy (CEA) or carotid artery stenting (CAS), stratified by delay after index event
      Study, yearCEA/CAS0–2 d3–7 d8–14 d15–30 d31–180 d
      30 day stroke – % (n)
       Jankowittz, 2020
      • Jankowitz B.T.
      • Tonetti D.A.
      • Kenmuir C.
      • Rao R.
      • Ares W.J.
      • Zussman B.
      • et al.
      Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
      CEA5.1 (3)
      CAS3.3 (2)
       Huang, 2018
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      CEA27 (3)0 (0)4.3 (1)0.6 (1)
       Tsantilas, 2018
      • Tsantilas P.
      • Kuehnl A.
      • Kallmayer M.
      • Knappich C.
      • Schmid S.
      • Breitkreuz T.
      • et al.
      Risk of stroke or death is associated with the timing of carotid artery stenting for symptomatic carotid stenosis: a secondary data analysis of the German Statutory Quality Assurance Database.
      German Statutory Quality
      CAS3.8 (21)3.5 (56)1.8 (22)2.2 (30)
       Sharpe, 2013
      • Sharpe R.
      • Sayers R.D.
      • London N.J.
      • Bown M.J.
      • McCarthy M.J.
      • Nasim A.
      • et al.
      Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.
      CEA2.4 (1)1.8 (3)0.8 (1)0.8 (1)
       Stromberg, 2012 Swedvasc
      • Stromberg S.
      • Gelin J.
      • Osterberg T.
      • Bergstrom G.M.
      • Karlstrom L.
      • Osterberg K.
      • et al.
      Very urgent carotid endarterectomy confers increased procedural risk.
      CEA10.8 (16)2.5 (20)3.4 (23)4.0 (39)
       Nordanstig, 2017
      • Nordanstig A.
      • Rosengren L.
      • Stromberg S.
      • Osterberg K.
      • Karlsson L.
      • Bergstrom G.
      • et al.
      Editor's Choice - Very Urgent Carotid Endarterectomy is Associated with an Increased Procedural Risk: The Carotid Alarm Study.
      CEA8.0 (6)3.0 (9)
       Avgerinos, 2017

      VSGNE
      • Avgerinos E.D.
      • Farber A.
      • Abou Ali A.N.
      • Rybin D.
      • Doros G.
      • Eslami M.H.
      Early carotid endarterectomy performed 2 to 5 days after the onset of neurologic symptoms leads to comparable results to carotid endarterectomy performed at later time points.
      CEA3.5 (20)2.4 (10)
       Tsantilas, 2016
      • Tsantilas P.
      • Kühnl A.
      • Kallmayer M.
      • Pelisek J.
      • Poppert H.
      • Schmid S.
      • et al.
      Short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.
      CEA0 (0)1.8 (2)1.5 (1)1.8 (3)
       Loftus, 2016 UK National Vascular Registry
      • Loftus I.M.
      • Paraskevas K.I.
      • Johal A.
      • Waton S.
      • Heikkila K.
      • Naylor A.R.
      • et al.
      Editor's Choice - Delays to surgery and procedural risks following carotid endarterectomy in the UK National Vascular Registry.
      CEA3.1 (24)2.0 (103)1.7 (107)1.8 (199)
       Jonsson, 2015
      • Jonsson M.
      • Gillgren P.
      • Wanhainen A.
      • Acosta S.
      • Lindström D.
      Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
      CAS0 (0)3.5 (3)6.3 (5)3.5 (5)
       Rantner, 2014
      • Rantner B.
      • Schmidauer C.
      • Knoflach M.
      • Fraedrich G.
      Very urgent carotid endarterectomy does not increase the procedural risk.
      CEA8 (3.9)4 (1.8)6 (4.4)5 (2.5)
       Villwock, 2014CEA1.1 (341)1.6 (496)
       NIS
      In hospital data
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      CAS1.7 (154)1.8 (77)
       Roussopoulou, 2019
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      CEA7.9 (5)4.4 (11)
       Seguchi, 2017
      • Seguchi M.
      • Shibata M.
      • Sato Y.
      • Maekawa K.
      • Kitano Y.
      • Sano T.
      • et al.
      The safety of carotid artery stenting for patients in the acute poststroke phase.
      CAS2.5 (1)6.2 (4)
       Setacci, 2007
      • Setacci C.
      • de Donato G.
      • Chisci E.
      • Setacci F.
      • Stella A.
      • Faggioli G.
      • et al.
      Deferred urgency carotid artery stenting in symptomatic patients: clinical lessons and biomarker patterns from a prospective registry.
      CEA0 (0)0 (0)
       Blay, 2018 ACS-NSQIP
      • Blay Jr., E.
      • Balogun Y.
      • Nooromid M.J.
      • Eskandari M.K.
      Early carotid endarterectomy after acute stroke yields excellent outcomes: an analysis of the procedure-targeted ACS-NSQIP.
      CEA2.7 (86)2.8 (5)
       Rantner, 2017
      • Rantner B.
      • Kollerits 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.
      CEA1.3 (3)3.4 (63)
      CAS8.0 (23)6.8 (122)
       Annambhotla, 2012
      • Annambhotla S.
      • Park M.S.
      • Keldahl M.L.
      • Morasch M.D.
      • Rodriguez H.E.
      • Pearce W.H.
      • et al.
      Early versus delayed carotid endarterectomy in symptomatic patients.
      CEA0 (0)0 (0)1.6 (4)
       Chisci, 2016
      • Chisci E.
      • Pigozzi C.
      • Troisi N.
      • Tramacere L.
      • Zaccara G.
      • Cincotta M.
      • et al.
      Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients.
      CEA3.0 (3)0.4 (1)
       Kretz, 2015
      • Kretz B.
      • Kazandjian C.
      • Bejot Y.
      • Abello N.
      • Brenot R.
      • Giroud M.
      • et al.
      Delay between symptoms and surgery for carotid artery stenosis: modification of our practice.
      CEA1.3 (2)1.5 (4)
       Charmoille, 2014
      • Charmoille E.
      • Brizzi V.
      • Lepidi S.
      • Sassoust G.
      • Roullet S.
      • Ducasse E.
      • et al.
      Thirty-day outcome of delayed versus early management of symptomatic carotid stenosis.
      CEA0 (0)3.5 (3)
       Faggioli, 2013
      • Faggioli G.
      • Pini R.
      • Mauro R.
      • Gargiulo M.
      • Freyrie A.
      • Stella A.
      Perioperative outcome of carotid endarterectomy according to type and timing of neurologic symptoms and computed tomography findings.
      CEA6.6 (4)2.9 (3)
       Ballotta, 2008
      • Ballotta E.
      • Meneghetti G.
      • Da Giau G.
      • Manara R.
      • Saladini M.
      • Baracchini C.
      Carotid endarterectomy within 2 weeks of minor ischemic stroke: a prospective study.
      CEA0 (0)
       Suzue, 2007
      • Suzue A.
      • Uno M.
      • Kitazato K.T.
      • Nishi K.
      • Yagi K.
      • Liu H.
      • et al.
      Comparison between early and late carotid endarterectomy for symptomatic carotid stenosis in relation to oxidized low-density lipoprotein and plaque vulnerability.
      CEA0 (0)0 (0)
      30 day myocardial infarction – % (n)
       Jankowittz, 2020
      • Jankowitz B.T.
      • Tonetti D.A.
      • Kenmuir C.
      • Rao R.
      • Ares W.J.
      • Zussman B.
      • et al.
      Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
      CEA3.4 (2)
      CAS4.9 (3)
       Huang, 2018
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      CEA0 (0)0 (0)0 (0)3.3 (6)
       Tsantilas, 2018 German Statutory Quality
      • Tsantilas P.
      • Kuehnl A.
      • Kallmayer M.
      • Knappich C.
      • Schmid S.
      • Breitkreuz T.
      • et al.
      Risk of stroke or death is associated with the timing of carotid artery stenting for symptomatic carotid stenosis: a secondary data analysis of the German Statutory Quality Assurance Database.
      CAS0.3 (1)0.1 (1)0 (0)0.1 (1)
       Jonsson, 2015
      • Jonsson M.
      • Gillgren P.
      • Wanhainen A.
      • Acosta S.
      • Lindström D.
      Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
      CAS0 (0)3.5 (3.0)2.5 (2)1.4 (2)
       Avgerinos, 2017

      VSGNE
      • Avgerinos E.D.
      • Farber A.
      • Abou Ali A.N.
      • Rybin D.
      • Doros G.
      • Eslami M.H.
      Early carotid endarterectomy performed 2 to 5 days after the onset of neurologic symptoms leads to comparable results to carotid endarterectomy performed at later time points.
      CEA1.4 (8)1.2 (5)
       Tsantilas, 2016
      • Tsantilas P.
      • Kühnl A.
      • Kallmayer M.
      • Pelisek J.
      • Poppert H.
      • Schmid S.
      • et al.
      Short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.
      CEA2.0 (1)1.0 (1)0 (0)1.0 (1)
       Roussopoulo, 2019
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      CEA0 (0)0.8 (2)
       Seguchi, 2017
      • Seguchi M.
      • Shibata M.
      • Sato Y.
      • Maekawa K.
      • Kitano Y.
      • Sano T.
      • et al.
      The safety of carotid artery stenting for patients in the acute poststroke phase.
      CAS0 (0)0 (0)0 (0)0 (0)0 (0)
       Setacci, 2007
      • Setacci C.
      • de Donato G.
      • Chisci E.
      • Setacci F.
      • Stella A.
      • Faggioli G.
      • et al.
      Deferred urgency carotid artery stenting in symptomatic patients: clinical lessons and biomarker patterns from a prospective registry.
      CEA0 (0)0 (0)0 (0)0 (0)0 (0)
       Annambhotla, 2012
      • Annambhotla S.
      • Park M.S.
      • Keldahl M.L.
      • Morasch M.D.
      • Rodriguez H.E.
      • Pearce W.H.
      • et al.
      Early versus delayed carotid endarterectomy in symptomatic patients.
      CEA0 (0)0 (0)0 (0)0 (0)0.8 (2)
       Chisci, 2016
      • Chisci E.
      • Pigozzi C.
      • Troisi N.
      • Tramacere L.
      • Zaccara G.
      • Cincotta M.
      • et al.
      Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients.
      CEA0 (0)0 (0)0 (0)1.8 (4)
       Charmoille, 2014
      • Charmoille E.
      • Brizzi V.
      • Lepidi S.
      • Sassoust G.
      • Roullet S.
      • Ducasse E.
      • et al.
      Thirty-day outcome of delayed versus early management of symptomatic carotid stenosis.
      CEA0 (0)0 (0)0 (0)3.5 (3)
       Faggioli, 2013
      • Faggioli G.
      • Pini R.
      • Mauro R.
      • Gargiulo M.
      • Freyrie A.
      • Stella A.
      Perioperative outcome of carotid endarterectomy according to type and timing of neurologic symptoms and computed tomography findings.
      CEA0 (0)0 (0)0 (0)0 (0)0 (0)
       Ballotta, 2008
      • Ballotta E.
      • Meneghetti G.
      • Da Giau G.
      • Manara R.
      • Saladini M.
      • Baracchini C.
      Carotid endarterectomy within 2 weeks of minor ischemic stroke: a prospective study.
      CEA0 (0)0 (0)0 (0)
       Blay, 2018 ACS-NSQIP
      • Blay Jr., E.
      • Balogun Y.
      • Nooromid M.J.
      • Eskandari M.K.
      Early carotid endarterectomy after acute stroke yields excellent outcomes: an analysis of the procedure-targeted ACS-NSQIP.
      CEA0.99 (32)0.56 (1)
       Kretz, 2015
      • Kretz B.
      • Kazandjian C.
      • Bejot Y.
      • Abello N.
      • Brenot R.
      • Giroud M.
      • et al.
      Delay between symptoms and surgery for carotid artery stenosis: modification of our practice.
      CEA0.6 (1)1.2 (3)
      30 day mortality – % (n)
       Jankowittz, 2020
      • Jankowitz B.T.
      • Tonetti D.A.
      • Kenmuir C.
      • Rao R.
      • Ares W.J.
      • Zussman B.
      • et al.
      Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
      CEA0 (0)
      CAS1.6 (1)
       Huang, 2018
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      CEA0 (0)0 (0)0 (0)0.6 (1)
       Tsantilas, 2018 German Statutory Quality
      • Tsantilas P.
      • Kuehnl A.
      • Kallmayer M.
      • Knappich C.
      • Schmid S.
      • Breitkreuz T.
      • et al.
      Risk of stroke or death is associated with the timing of carotid artery stenting for symptomatic carotid stenosis: a secondary data analysis of the German Statutory Quality Assurance Database.
      CAS2.2 (12)0.9 (14)0.6 (8)0.7 (10)
       Jonsson, 2015
      • Jonsson M.
      • Gillgren P.
      • Wanhainen A.
      • Acosta S.
      • Lindström D.
      Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
      CAS0 (0)0 (0)3.8 (3)0.7 (1)
       Sharpe, 2013
      • Sharpe R.
      • Sayers R.D.
      • London N.J.
      • Bown M.J.
      • McCarthy M.J.
      • Nasim A.
      • et al.
      Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.
      CEA0 (0)0 (0)0.8 (1)0 (0)
       Stromberg, 2012 Swedvasc
      • Stromberg S.
      • Gelin J.
      • Osterberg T.
      • Bergstrom G.M.
      • Karlstrom L.
      • Osterberg K.
      • et al.
      Very urgent carotid endarterectomy confers increased procedural risk.
      CEA2.0 (3)1.2 (10)1.5 (10)1.7 (16)
       Avgerinos, 2017 VSGNE
      • Avgerinos E.D.
      • Farber A.
      • Abou Ali A.N.
      • Rybin D.
      • Doros G.
      • Eslami M.H.
      Early carotid endarterectomy performed 2 to 5 days after the onset of neurologic symptoms leads to comparable results to carotid endarterectomy performed at later time points.
      CEA1.2 (7)1.4 (6)
       Tsantilas, 2016
      • Tsantilas P.
      • Kühnl A.
      • Kallmayer M.
      • Pelisek J.
      • Poppert H.
      • Schmid S.
      • et al.
      Short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.
      CEA3.0 (2)1.0 (1)0 (0)1.0 (1)
       Loftus, 2016
      • Loftus I.M.
      • Paraskevas K.I.
      • Johal A.
      • Waton S.
      • Heikkila K.
      • Naylor A.R.
      • et al.
      Editor's Choice - Delays to surgery and procedural risks following carotid endarterectomy in the UK National Vascular Registry.
      UK National Vascular Registry
      CEA1.0 (8)0.9 (46)0.7 (44)0.8 (88)
       Rantner, 2014
      • Rantner B.
      • Schmidauer C.
      • Knoflach M.
      • Fraedrich G.
      Very urgent carotid endarterectomy does not increase the procedural risk.
      CEA0.5 (1)0 (0)0.7 (1)0.5 (1)
       Villwock, 2014CEA0.4 (129)0.8 (258)
       NIS
      In hospital data
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      CAS2.1 (191)1.6 (69)
       Roussopoulo, 2019
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      CEA0 (0)0.4 (1)
       Nordanstig, 2017
      • Nordanstig A.
      • Rosengren L.
      • Stromberg S.
      • Osterberg K.
      • Karlsson L.
      • Bergstrom G.
      • et al.
      Editor's Choice - Very Urgent Carotid Endarterectomy is Associated with an Increased Procedural Risk: The Carotid Alarm Study.
      CEA0 (0)0.3 (1)0 (0)0 (0)
       Seguchi, 2017
      • Seguchi M.
      • Shibata M.
      • Sato Y.
      • Maekawa K.
      • Kitano Y.
      • Sano T.
      • et al.
      The safety of carotid artery stenting for patients in the acute poststroke phase.
      CAS0 (0)0 (0)0 (0)0 (0)0 (0)
       Annambhotla, 2012
      • Annambhotla S.
      • Park M.S.
      • Keldahl M.L.
      • Morasch M.D.
      • Rodriguez H.E.
      • Pearce W.H.
      • et al.
      Early versus delayed carotid endarterectomy in symptomatic patients.
      CEA0 (0)0 (0)0 (0)0 (0)0 (0)
       Chisci, 2016
      • Chisci E.
      • Pigozzi C.
      • Troisi N.
      • Tramacere L.
      • Zaccara G.
      • Cincotta M.
      • et al.
      Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients.
      CEA0 (0)0 (0)0 (0)0 (0)0 (0)
       Blay, 2018 ACS-NSQIP
      • Blay Jr., E.
      • Balogun Y.
      • Nooromid M.J.
      • Eskandari M.K.
      Early carotid endarterectomy after acute stroke yields excellent outcomes: an analysis of the procedure-targeted ACS-NSQIP.
      CEA1.2 (38)2.8 (5)
       Kretz, 2015
      • Kretz B.
      • Kazandjian C.
      • Bejot Y.
      • Abello N.
      • Brenot R.
      • Giroud M.
      • et al.
      Delay between symptoms and surgery for carotid artery stenosis: modification of our practice.
      CEA1.9 (3)1.5 (4)
       Charmoille, 2014
      • Charmoille E.
      • Brizzi V.
      • Lepidi S.
      • Sassoust G.
      • Roullet S.
      • Ducasse E.
      • et al.
      Thirty-day outcome of delayed versus early management of symptomatic carotid stenosis.
      CEA1.7 (1)1.2 (1)
       Faggioli, 2013
      • Faggioli G.
      • Pini R.
      • Mauro R.
      • Gargiulo M.
      • Freyrie A.
      • Stella A.
      Perioperative outcome of carotid endarterectomy according to type and timing of neurologic symptoms and computed tomography findings.
      CEA1.6 (1)0 (0)3.6 (3)
       Ballotta, 2008
      • Ballotta E.
      • Meneghetti G.
      • Da Giau G.
      • Manara R.
      • Saladini M.
      • Baracchini C.
      Carotid endarterectomy within 2 weeks of minor ischemic stroke: a prospective study.
      CEA0 (0)
      30 day death / stroke – % (n)
       Jankowittz, 2020
      • Jankowitz B.T.
      • Tonetti D.A.
      • Kenmuir C.
      • Rao R.
      • Ares W.J.
      • Zussman B.
      • et al.
      Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
      CEA5.1 (3)
      CAS4.9 (3)
       Roussopoulou, 2019
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      CEA7.9 (5)4.8 (12)
       Huang, 2018
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      CEA27 (3)0 (0)4.3 (1)1.1 (2)
       Nordanstig, 2017
      • Nordanstig A.
      • Rosengren L.
      • Stromberg S.
      • Osterberg K.
      • Karlsson L.
      • Bergstrom G.
      • et al.
      Editor's Choice - Very Urgent Carotid Endarterectomy is Associated with an Increased Procedural Risk: The Carotid Alarm Study.
      CEA8.0 (6)3.0 (9)
       Tsantilas, 2016
      • Tsantilas P.
      • Kühnl A.
      • Kallmayer M.
      • Pelisek J.
      • Poppert H.
      • Schmid S.
      • et al.
      Short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.
      CEA3.0 (2)3.0 (3)2.0 (1)2.0 (3)
       Loftus, 2016 UK National Vascular Registry
      • Loftus I.M.
      • Paraskevas K.I.
      • Johal A.
      • Waton S.
      • Heikkila K.
      • Naylor A.R.
      • et al.
      Editor's Choice - Delays to surgery and procedural risks following carotid endarterectomy in the UK National Vascular Registry.
      CEA29 (3.7)128 (2.5)132 (2.1)254 (2.3)
       Jonsson, 2015
      • Jonsson M.
      • Gillgren P.
      • Wanhainen A.
      • Acosta S.
      • Lindström D.
      Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
      CAS0 (0)4.7 (4)6.3 (6)4.1 (6)
       Rantner, 2014
      • Rantner B.
      • Schmidauer C.
      • Knoflach M.
      • Fraedrich G.
      Very urgent carotid endarterectomy does not increase the procedural risk.
      CEA4.4 (9)1.8 (4)5.1 (7)2.5 (5)
       Sharpe, 2013
      • Sharpe R.
      • Sayers R.D.
      • London N.J.
      • Bown M.J.
      • McCarthy M.J.
      • Nasim A.
      • et al.
      Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.
      CEA2.4 (1)1.8 (3)0.8 (1)0.8 (1)
       Stromberg, 2012CEA11.5 (17)3.6 (29)4.0 (27)5.4 (52)
       Swedvasc
      • Stromberg S.
      • Gelin J.
      • Osterberg T.
      • Bergstrom G.M.
      • Karlstrom L.
      • Osterberg K.
      • et al.
      Very urgent carotid endarterectomy confers increased procedural risk.
       Nordanstig, 2017
      • Nordanstig A.
      • Rosengren L.
      • Stromberg S.
      • Osterberg K.
      • Karlsson L.
      • Bergstrom G.
      • et al.
      Editor's Choice - Very Urgent Carotid Endarterectomy is Associated with an Increased Procedural Risk: The Carotid Alarm Study.
      CEA6 (8)10 (3)
       Seguchi, 2017
      • Seguchi M.
      • Shibata M.
      • Sato Y.
      • Maekawa K.
      • Kitano Y.
      • Sano T.
      • et al.
      The safety of carotid artery stenting for patients in the acute poststroke phase.
      CAS2.5 (1)6.2 (4)
       Rantner, 2017
      • Rantner B.
      • Kollerits 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.
      CEA1.3 (3)3.6 (65)
      CAS8.4 (24)7.1 (129)
       Chisci, 2016
      • Chisci E.
      • Pigozzi C.
      • Troisi N.
      • Tramacere L.
      • Zaccara G.
      • Cincotta M.
      • et al.
      Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients.
      CEA3.0 (3)0.4 (1)
      Mean 30 day death / stroke ± standard deviation
       Jankowittz, 2020
      • Jankowitz B.T.
      • Tonetti D.A.
      • Kenmuir C.
      • Rao R.
      • Ares W.J.
      • Zussman B.
      • et al.
      Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
      CEA5.6±3.2
      CAS5.3±4.1
      p=.66
       Huang, 2018
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      CEA4.7±7.23.3±1.72.0±1.51.8±1.5
       Tsantilas, 2018 German Statutory Quality
      • Tsantilas P.
      • Kuehnl A.
      • Kallmayer M.
      • Knappich C.
      • Schmid S.
      • Breitkreuz T.
      • et al.
      Risk of stroke or death is associated with the timing of carotid artery stenting for symptomatic carotid stenosis: a secondary data analysis of the German Statutory Quality Assurance Database.
      CAS3.5±1.23.3±0.92.5±0.6
       Villwock, 2014
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      NIS
      In hospital data
      CEA for Stroke3.5±1.27.3±1.5
      CAS for Stroke4.3±1.57.3±1.5
      CEA for TIA/AFX1.8±0.16.5±1.2
      CAS for TIA/AFX1.3±0.46.0±1.2
       Roussopoulo, 2019
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      CEA6.5±1.710.3±2.0
       Seguchi, 2017
      • Seguchi M.
      • Shibata M.
      • Sato Y.
      • Maekawa K.
      • Kitano Y.
      • Sano T.
      • et al.
      The safety of carotid artery stenting for patients in the acute poststroke phase.
      CAS22.5±6.321.5±4.6
       Chisci, 2016
      • Chisci E.
      • Pigozzi C.
      • Troisi N.
      • Tramacere L.
      • Zaccara G.
      • Cincotta M.
      • et al.
      Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients.
      CEA3.7±2.22.5±1.5
      TIA = transient ischaemic attack; AFX = amaurosis fugax
      In hospital data

      Carotid endarterectomy vs. carotid artery stenting

      Overall data

      Outcome data from eight CEA studies (88 129) and two CAS studies (3 551) are detailed in Table 4. In CEA patients, 30 day stroke was 1.4% (95% CI 0.9 – 1.8) when performed within 0 – 2 days, vs. 1.8% (95% CI. 1.5 – 2.0) when performed between three and 14 days. In CAS patients, 30 day stroke was 1.8% (95% CI 1.3 – 2.3) when performed within two days, vs. 2.2% (95% CI 0.3 – 4.2) between three and 14 days (Table 4). Across all intervention timings, there were higher rates of stroke after CAS (vs. CEA), while there were higher rates for MI after CEA (vs. CAS). Individual study data used to calculate the pooled rates are available in Supplementary Table S2 (Supplementary material).
      Table 4Pooled estimated prevalence in different sized samples on main outcomes, stratified by intervention timing and type of procedure
      CEACAS
      0–2 days – % (95% CI)3–14 days – % (95% CI)0–2 days – % (95% CI)3–14 days – % (95% CI)
      30 d stroke1.4 (0.9–1.8); SE 0.2
      Lower risk of stroke with CEA vs. CAS within two days of index event.
      ,
      In either category (CEA or CAS) stroke risk is lower within two days vs. 3–14 days of index event.
      1.8 (1.5–2.0); SE 0.1
      Lower risk of stroke with CEA vs. CAS within 3–14 days of index event.
      ,
      In either category (CEA or CAS) stroke risk is lower within two days vs. 3–14 days of index event.
      1.8 (1.3–2.3); SE 0.2
      Lower risk of stroke with CEA vs. CAS within two days of index event.
      ,
      In either category (CEA or CAS) stroke risk is lower within two days vs. 3–14 days of index event.
      2.2 (0.3–4.2); SE 0.5
      Lower risk of stroke with CEA vs. CAS within 3–14 days of index event.
      ,
      In either category (CEA or CAS) stroke risk is lower within two days vs. 3–14 days of index event.
      30 d MI1.5 (0.7–2.2); SE 0.20.9 (0.0–1.7); SE 0.20.6 (0.0–2.5); SE 0.60.2 (0.0–1.3); SE 0.3
      30 d mortality0.5 (0.4–0.6); SE 0.00.8 (0.8–0.9); SE 0.02.2 (1.8–2.6); SE 1.41.3 (0.3–2.2); SE 0.3
      30 d death/stroke4.9 (2.0–7.9); SE 1.22.5 (1.8–3.2); SE 0.23.5 (0.0–8.4)2.4 (0.7–6.1)
      CAS = carotid artery stenting; CEA = carotid endarterectomy; CI = confidence interval; MI = myocardial infarction; SE = standard error.
      Lower risk of stroke with CEA vs. CAS within two days of index event.
      Lower risk of stroke with CEA vs. CAS within 3–14 days of index event.
      In either category (CEA or CAS) stroke risk is lower within two days vs. 3–14 days of index event.

      Carotid endarterectomy vs. carotid artery stenting when performed ≤ 2 days after the index event

      Two moderate quality studies reported outcomes after CEA vs. CAS (75 917) when performed within two days of the index event, including one retrospective analysis of prospective single centre data (120) and one retrospective analysis of Nationwide Inpatient Sample (NIS) database (72 797).
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      ,
      • Jankowitz B.T.
      • Tonetti D.A.
      • Kenmuir C.
      • Rao R.
      • Ares W.J.
      • Zussman B.
      • et al.
      Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
      Compared with CEA, meta-analysed data revealed significantly higher risks for 30 day stroke when CAS was performed within ≤ 2 days (OR 0.70; 95% CI 0.58 – 0.85) as well as significantly higher rates of 30 day death (OR 0.41; 95% CI 0.31 – 0.53) (Fig. 2). One of the above mentioned registries (72 797) analysed patients with and without cerebral infarction separately and concluded that expedited revascularisation in patients with cerebral infarction on admission increased the risk of iatrogenic stroke and death; the increase in mortality was more dramatically seen in patients treated by CAS. No differences were found in stroke/death rates between CEA and CAS if patients presented without infarction.
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      Figure 2
      Figure 2Forest plot showing the odds ratio (OR) for (A) 30 day stroke and (B) 30 day mortality after carotid endarterectomy (CEA) vs. carotid artery stenting (CAS) within two days of index event. A Mantel-Haenszel (M-H) fixed effect model was used for meta-analysis. OR are shown with 95% confidence intervals (CI).

      Carotid endarterectomy vs. carotid artery stenting when performed 3 – 14 days after index event

      The same large national registry (72 797) cited in the previous section also reported comparative outcomes between CEA vs. CAS when performed 3 – 14 days after the index event (with or without cerebral infarction). There was no statistically significant difference in 30 day stroke after CAS (1.8%) vs. after CEA (1.6%; OR 1.1; 95% CI 0.9 – 1.4). However, 30 day mortality was statistically significantly higher after CAS (1.6%) vs. after CEA (0.8%; OR 1.9; 95% CI 1.4 – 2.5). Again, no differences were found in stroke/death rates between CEA and CAS if patients presented without infarction.
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.

      Outcomes after carotid endarterectomy

      ≤ 2 days vs. 3 – 14 days after index event

      A total of nine moderate quality manuscripts were included in this analysis, three of which were retrospective analyses of national registries, two prospective multicentre studies, and four retrospective studies. CEA performed 3 – 14 days after the index event was associated with a statistically significantly lower 30 day death/stroke risk (OR 2.05; 95% CI 1.56 – 2.68) compared with performing CEA within ≤ 2 days of index event. No statistically significant difference was attained regarding 30 day stroke, MI, and mortality (OR 1.87; 95% CI 0.99 – 3.51, OR 1.50; 95% CI 0.21 – 10.45, and OR 1.11; 95% CI 0.58 – 2.14, respectively) (Fig. 3).
      Figure 3
      Figure 3Forest plot showing the odds ratio (OR) for (A) 30 day stroke, (B) 30 day myocardial infarction (MI), (C) 30 day mortality, and (D) stroke/mortality after carotid endarterectomy (CEA) within ≤ 2 vs. 3 – 14 days of the index event. A Mantel-Haenszel (M-H) fixed effect model was used for meta-analysis. OR are shown with 95% confidence intervals (CI).
      Meta-analysis of 30 day stroke, mortality, and MI included the same core studies, while in the analysis of 30 day death/stroke, three studies were excluded as they did not report the composite outcome,
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      ,
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      ,
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      while one study was included that only reported combined stroke/death data, with worse outcomes reported in the expedited cohort (Fig. 3).
      • Sharpe R.
      • Sayers R.D.
      • London N.J.
      • Bown M.J.
      • McCarthy M.J.
      • Nasim A.
      • et al.
      Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.

      ≤ 7 days vs. 8 – 14 days after index event

      A total of five moderate quality manuscripts were included in this analysis, two of which were retrospective analyses of national registries and three retrospective studies. Meta-analyses (Fig. 4) revealed that CEA performed within 7 days of the index event was associated with a significantly lower risk of 30 day stroke compared with 8 – 14 days (OR 0.67; 95% CI 0.54 – 0.84). There was no difference regarding CEA performed within 7 days of the index event (vs. 8 – 14) in the outcomes 30 day mortality (OR 1.86; 95% CI 0.19 – 18.21), 30 day death/stroke (OR 0.79; 95% CI 0.47 – 1.34), or 30 day MI (OR 1.94; 95% CI 0.09 – 41.03) (Fig. 4).
      Figure 4
      Figure 4Forest plot showing the odds ratio (OR) for (A) 30 day stroke, (B) 30 day myocardial infarction (MI), (C) 30 day mortality, and (D) stroke/mortality after carotid endarterectomy (CEA) within ≤ 7 vs. 8 – 14 days of the index event. A Mantel-Haenszel (M-H) fixed effect model was used for meta-analysis. OR are shown with 95% confidence intervals (CI).

      Outcomes after carotid artery stenting

      ≤ 2 days vs. 3 – 14 days after index event

      This systematic review identified 17 578 patients who underwent CAS ≤ 14 days of symptom onset, including 9 833 (55.9%) who underwent CAS within ≤ 2 days of the index symptom. Two moderate quality national registries compared outcomes when CAS was performed within ≤ 2 days vs. 3 – 14 days of the index symptom.
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      ,
      • Jonsson M.
      • Gillgren P.
      • Wanhainen A.
      • Acosta S.
      • Lindström D.
      Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
      Compared with CAS interventions within 3 – 14 days, performing CAS ≤ 2 days was not associated with significant differences in 30 day stroke (OR 1.36; 95% CI 0.84 – 2.21) or 30 day MI (OR 2.23; 95% CI 0.34 – 14.41) However, performing CAS within ≤ 2 days of the index symptom was associated with significantly higher risks of 30 day death (OR 2.76; 95% CI 1.39 – 5.50) compared with CAS interventions within 3 – 14 days of the index event (Fig. 5). A single study (n = 323) reported the results of a comparative analysis of 30 day death/stroke and showed no significant difference when CAS was performed in either time period (OR 0.61; 95% CI 0.03 – 11.06).
      • Jonsson M.
      • Gillgren P.
      • Wanhainen A.
      • Acosta S.
      • Lindström D.
      Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
      Figure 5
      Figure 5Forest plot showing the odds ratio (OR) for (A) 30 day stroke, (B) 30 day myocardial infarction (MI), and (C) 30 day mortality after carotid artery stenting (CAS) within ≤ 2 vs. 3 – 14 days of the index event. A Mantel-Haenszel (M-H) fixed effect model was used for meta-analysis. OR are shown with 95% confidence intervals (CI).

      ≤ 7 days vs. 8 – 14 days after index event

      The same national registries that compared outcomes when CAS was performed ≤ 2 days vs. 3 – 14 days, also analysed outcomes ≤ 7 days vs. 8 – 14 days.
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      ,
      • Jonsson M.
      • Gillgren P.
      • Wanhainen A.
      • Acosta S.
      • Lindström D.
      Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
      Forest Plot analyses (Fig. 6) revealed that there was no significant difference in 30 day stroke, MI, or mortality when CAS was performed ≤ 7 days vs. 8 – 14 days after the index event (OR 1.18; 95% CI 0.29 – 4.83, OR 1.62; 95% CI 0.35 – 7.43, and OR 0.67; 95% CI 0.04 – 10.12, respectively).
      Figure 6
      Figure 6Forest plot showing the odds ratio (OR) for (A) 30 day stroke, (B) 30 day myocardial infarction (MI), and (C) 30 day mortality after carotid artery stenting (CAS) within ≤ 7 vs. 8 – 14 days of the index event. A Mantel-Haenszel (M-H) fixed effect model was used for meta-analysis. OR are shown with 95% confidence intervals (CI).

      Recurrent events while awaiting a carotid intervention

      Recurrent neurological events occurring after a decision to perform CEA but before it was performed were reported rarely. In one single centre study, 42% of patients who waited 0 – 180 days to undergo CEA suffered a recurrent TIA or stroke prior to CEA.
      • Charbonneau P.
      • Bonaventure P.L.
      • Drudi L.M.
      • Beaudoin N.
      • Blair J.F.
      • Elkouri S.
      An institutional study of time delays for symptomatic carotid endarterectomy.
      The National Norwegian Carotid Study reported that 3.3% suffered recurrent symptoms prior to undergoing CEA within 14 days of the index event (Table 2).
      • Kjorstad K.E.
      • Baksaas S.T.
      • Bundgaard D.
      • Halbakken E.
      • Hasselgard T.
      • Jonung T.
      • et al.
      Editor's Choice - The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events.

      Neurological outcome

      Surprisingly, few studies used the National Institutes of Health Stroke Scale (NIHSS) to quantify improvements in neurological disability after carotid interventions, stratified for the timing of carotid interventions (Table 3). A single centre study reported improved neurological outcomes for interventions performed within 14 days vs. 15 – 30 days of the index event (NIHSS range 0.9 ± 0.4 vs. 0.5 ± 0.2; p = .011).
      • Chisci E.
      • Pigozzi C.
      • Troisi N.
      • Tramacere L.
      • Zaccara G.
      • Cincotta M.
      • et al.
      Thirty-day neurologic improvement associated with early versus delayed carotid endarterectomy in symptomatic patients.
      Other studies report NIHSS range but with no discriminative data concerning carotid intervention delay from index event.
      • Jankowitz B.T.
      • Tonetti D.A.
      • Kenmuir C.
      • Rao R.
      • Ares W.J.
      • Zussman B.
      • et al.
      Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
      ,
      • Kjorstad K.E.
      • Baksaas S.T.
      • Bundgaard D.
      • Halbakken E.
      • Hasselgard T.
      • Jonung T.
      • et al.
      Editor's Choice - The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events.
      ,
      • Rocco A.
      • Sallustio F.
      • Toschi N.
      • Rizzato B.
      • Legramante J.
      • Ippoliti A.
      • et al.
      Carotid artery stent placement and carotid endarterectomy: a challenge for urgent treatment after stroke-early and 12-month outcomes in a comprehensive stroke center.

      Hospital stay

      Hospital stay analysis presented a trend towards prolonged stay in patients undergoing CEA between 3 – 14 days after the index event vs. ≤ 2 days, with a mean difference (MD) of −1.28 (95% CI −6.96 – 4.40) (Fig. 7).
      Figure 7
      Figure 7Forest plot showing the mean difference for hospital stay after carotid endarterectomy (CEA) within ≤ 2 vs. 3 – 14 days after the index event. Mean differences are shown with 95% confidence intervals (CI). SD = standard deviation; IV = inverse variance.
      Only one study
      • Seguchi M.
      • Shibata M.
      • Sato Y.
      • Maekawa K.
      • Kitano Y.
      • Sano T.
      • et al.
      The safety of carotid artery stenting for patients in the acute poststroke phase.
      reported length of hospital stay after CAS, with non-significant difference between intervention ≤ 2 vs. 3 – 14 days (MD −1.0; 95% CI −3.1 – 1.1).

      Discussion

      The ESVS guidelines advise that CEA (CAS) should be performed within 14 days of symptom onset.
      • Naylor A.R.
      • Ricco J.B.
      • de Borst G.J.
      • Debus S.
      • de Haro J.
      • Halliday A.
      Editor's Choice - Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      Evidence suggests that there has been a major drive towards performing interventions < 14 days (especially in Europe), where the median delay to CEA is now 11 days in the Netherlands,
      • Kuhrij L.S.
      • Meershoek A.J.A.
      • Karthaus E.G.
      • Vahl A.C.
      • Hamming J.F.
      • Nederkoorn P.J.
      • et al.
      Factors associated with hospital dependent delay to carotid endarterectomy in the Dutch Audit for Carotid Interventions.
      7 days in Sweden,
      • Kragsterman B.
      • Nordanstig A.
      • Lindstrom D.
      • Stromberg S.
      • Thuresson M.
      • Nordanstig J.
      Editor's Choice - Effect of more expedited carotid intervention on recurrent ischaemic event rate: a national audit.
      9 days in Germany,
      • Tsantilas P.
      • Kühnl A.
      • Kallmayer M.
      • Pelisek J.
      • Poppert H.
      • Schmid S.
      • et al.
      Short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.
      and 11 days in the UK.
      • Loftus I.M.
      • Paraskevas K.I.
      • Johal A.
      • Waton S.
      • Heikkila K.
      • Naylor A.R.
      • et al.
      Editor's Choice - Delays to surgery and procedural risks following carotid endarterectomy in the UK National Vascular Registry.
      A temporal trend towards a progressive decrease in delays from index event to undergoing CEA (or CAS) has been reported by several national registries.
      • Loftus I.M.
      • Paraskevas K.I.
      • Johal A.
      • Waton S.
      • Heikkila K.
      • Naylor A.R.
      • et al.
      Editor's Choice - Delays to surgery and procedural risks following carotid endarterectomy in the UK National Vascular Registry.
      • Witt A.H.
      • Johnsen S.P.
      • Jensen L.P.
      • Hansen A.K.
      • Hundborg H.H.
      • Andersen G.
      Reducing delay of carotid endarterectomy in acute ischemic stroke patients: a nationwide initiative.
      • Kretz B.
      • Kazandjian C.
      • Bejot Y.
      • Abello N.
      • Brenot R.
      • Giroud M.
      • et al.
      Delay between symptoms and surgery for carotid artery stenosis: modification of our practice.
      The proportion of Danish Stroke Registry patients
      • Charbonneau P.
      • Bonaventure P.L.
      • Drudi L.M.
      • Beaudoin N.
      • Blair J.F.
      • Elkouri S.
      An institutional study of time delays for symptomatic carotid endarterectomy.
      undergoing carotid interventions within two weeks of the index event increased from 13% in 2007 to 47% by 2010 (OR 5.8; 95% CI 4.3 – 10.1).
      • Witt A.H.
      • Johnsen S.P.
      • Jensen L.P.
      • Hansen A.K.
      • Hundborg H.H.
      • Andersen G.
      Reducing delay of carotid endarterectomy in acute ischemic stroke patients: a nationwide initiative.
      Similar findings were reported by the UK National Vascular Registry.
      • Loftus I.M.
      • Paraskevas K.I.
      • Johal A.
      • Waton S.
      • Heikkila K.
      • Naylor A.R.
      • et al.
      Editor's Choice - Delays to surgery and procedural risks following carotid endarterectomy in the UK National Vascular Registry.
      However, uncertainty persists regarding the ideal timing for either CEA or CAS within the 14 day time frame to balance the dichotomy between recurrent stroke prevention and minimising peri-operative risks.
      • Witt A.H.
      • Johnsen S.P.
      • Jensen L.P.
      • Hansen A.K.
      • Hundborg H.H.
      • Andersen G.
      Reducing delay of carotid endarterectomy in acute ischemic stroke patients: a nationwide initiative.
      The Swedish Vascular Registry (Swedvasc) were the first to highlight concerns about intervening within ≤ 48 hours of the index event, as they observed an 11.5% rate of 30 day death/stroke, compared with 3.6% (3 – 7 days), 4% (8 – 14 days), and 5.4% (> 14 days) for CEA. However, only a small proportion of Swedvasc patients were treated ≤ 48 hours (5.7%), which may have limited the generalisability of the Swedish registry data.
      • Stromberg S.
      • Gelin J.
      • Osterberg T.
      • Bergstrom G.M.
      • Karlstrom L.
      • Osterberg K.
      • et al.
      Very urgent carotid endarterectomy confers increased procedural risk.
      Other (much larger) national registries have not corroborated the Swedvasc findings. In the German CEA registry (56 000 CEAs), there was no difference in 30 day death/stroke between patients treated ≤ 48 hours by CEA (3%) vs. later time periods (2.5% between 3 – 7 days; 2.6% between 8 – 14 days; 2.3% for CEA thereafter).
      • Tsantilas P.
      • Kühnl A.
      • Kallmayer M.
      • Pelisek J.
      • Poppert H.
      • Schmid S.
      • et al.
      Short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.
      In the UK national registry involving 20 000 patients, conclusions were that the pathway from most recent symptom to surgery for patients with symptomatic carotid stenosis, could be shortened to maximise the benefit of intervention, without increased peri-operative risk in the period. However, they admitted a slight increase in peri-operative risk of stroke and death in the first 48 hours.
      • Loftus I.M.
      • Paraskevas K.I.
      • Johal A.
      • Waton S.
      • Heikkila K.
      • Naylor A.R.
      • et al.
      Editor's Choice - Delays to surgery and procedural risks following carotid endarterectomy in the UK National Vascular Registry.
      In this systematic review, 44 410 (29.9%) carotid interventions were undertaken within ≤ 2 days of the index event with no significant difference in 30 day stroke, mortality, and MI, while CEA performed 3 – 14 days after the index event was associated with a significantly lower risk of the composite outcome 30 day death/stroke. On the other hand, CEA within 7 days was associated with a significantly lower risk of stroke (vs. 8 – 14 days).
      These contradictory results may be explained by the differences in included studies in each analysis, as already shown. Compared with the analysis of the outcomes stroke and mortality, analysis of the composite outcome stroke/death did not include data from two national registries and one prospective multicentre study,
      • Roussopoulou A.
      • Tsivgoulis G.
      • Krogias C.
      • Lazaris A.
      • Moulakakis K.
      • Georgiadis G.S.
      • et al.
      Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
      ,
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      ,
      • Huang Y.
      • Gloviczki P.
      • Duncan A.A.
      • Kalra M.
      • Oderich G.S.
      • DeMartino R.R.
      • et al.
      Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
      while it included data from one retrospective single centre study that only reported combined stroke/death data.
      • Sharpe R.
      • Sayers R.D.
      • London N.J.
      • Bown M.J.
      • McCarthy M.J.
      • Nasim A.
      • et al.
      Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.
      Therefore, studies included in the analysis of 30 day stroke, death, and MI are of better study design compared with the studies in the 30 day death/stroke analysis, even though quality assessment is similar.
      There were inconsistent findings regarding timing and outcomes in CAS patients. In patients undergoing CAS ≤ 2 days of the index event (vs. 3 – 14), there was no apparent difference in 30 day stroke or MI but there was a statistically significantly higher risk of death. Conversely, there were no differences in 30 day outcomes between CAS performed ≤ 7 days (vs. 8 – 14). The pathophysiology of procedural stroke may differ with expedited (vs. delayed) interventions in line with acute changes in atherosclerotic plaque vulnerability, which have been associated with an increased risk of embolism and neurological events after CAS.
      • van Lammeren G.W.
      • Reichmann B.L.
      • Moll F.L.
      • Bots M.L.
      • de Kleijn D.P.
      • de Vries J.P.
      • et al.
      Atherosclerotic plaque vulnerability as an explanation for the increased risk of stroke in elderly undergoing carotid artery stenting.
      The systematic review also addressed the question of whether CEA or CAS was safer (or equivalent) when performed in the first 14 days after symptom onset. Compared with CEA, CAS was associated with significantly higher 30 day stroke and death rates when performed within ≤ 2 days of symptom onset. In an individual patient meta-analysis of data from the four largest RCTs comparing CEA with CAS (4 138 patients), CAS was associated with significantly higher risks of 30 day stroke, mortality, and death/stroke when performed within ≤ 7 days of the index event.
      • Villwock M.R.
      • Singla A.
      • Padalino D.J.
      • Deshaies E.M.
      Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
      These data suggest that, at the current time, CEA is probably safer than CAS both when performed ≤ 2 days and ≤ 7 days after symptom onset. However, virtually all of the CAS procedures in the current meta-analyses were performed via the transfemoral route. Registry data suggest that TCAR can be performed with 30 day outcomes similar to CEA in symptomatic patients.
      • Malas M.B.
      • Dakour-Aridi H.
      • Wang G.J.
      • Kashyap V.S.
      • Motaganahalli R.L.
      • Eldrup-Jorgensen J.
      • et al.
      Transcarotid artery revascularization versus transfemoral carotid artery stenting in the Society for Vascular Surgery Vascular Quality Initiative.
      Unfortunately, no studies have published outcome data for TCAR when used in the first 14 days after symptom onset,
      • Coelho A.
      • Prassaparo T.
      • Mansilha A.
      • Kappelle J.
      • Naylor R.
      • de Borst G.J.
      Critical appraisal on the quality of reporting on safety and efficacy of transcarotid artery stenting with flow reversal.
      and these data are keenly awaited.
      There are relatively few data published on the incidence of recurrent events prior to expedited interventions. A prospective cohort study concluded that the risk was about 12% with modern best medical therapy, but that half of all recurrent events occurred within two days of the index event.
      • Eriksson H.
      • Koskinen S.
      • Nuotio K.
      • Heikkila H.M.
      • Vikatmaa P.
      • Silvennoinen H.
      • et al.
      Predictive Factors for Pre-operative Recurrence of Cerebrovascular Symptoms in Symptomatic Carotid Stenosis.
      On the other hand, a recent meta-analysis revealed a cumulative 120 day risk of recurrent stroke of 1.97% (95% CI 0.75 – 3.17) in recent large RCTs, which was statistically significantly lower than in historical controls.
      • Fisch U.
      • von Felten S.
      • Wiencierz A.
      • Jansen O.
      • Howard G.
      • Hendrikse J.
      • et al.
      Editor's Choice - Risk of stroke before revascularisation in patients with symptomatic carotid stenosis: a pooled analysis of randomised controlled trials.
      Historically, vascular surgeons have not really considered the prevention of recurrent stroke in the time period between initiating investigation and initial management and undergoing CEA as being their primary responsibility. However, this attitude is likely to change as more symptomatic patients are started on dual antiplatelet therapy (DAPT) within 24 hours of symptom onset. The 2017 ESVS guidelines recommended that early treatment with DAPT “may be considered” to prevent recurrent events (prior to CEA) in patients with TIA or minor ischaemic stroke and an ipsilateral 50% – 99% stenosis awaiting CEA (Evidence IIb, Level C).
      • Naylor A.R.
      • Ricco J.B.
      • de Borst G.J.
      • Debus S.
      • de Haro J.
      • Halliday A.
      Editor's Choice - Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
      At the time, the ESVS Writing Group were unable to recommend routine DAPT in all symptomatic patients because there was no compelling evidence that this strategy conferred additional benefit over antiplatelet monotherapy.
      However, based on a meta-analysis of three recent RCTs (CHANCE, POINT, and FASTER) in which 10 447 patients were randomised within 24 hours of experiencing a minor ischaemic stroke (NIHSS ≤ 3) or “high risk TIA” (ABCD
      • Tsantilas P.
      • Kuhnl A.
      • Kallmayer M.
      • Knappich C.
      • Schmid S.
      • Kuetchou A.
      • et al.
      Stroke risk in the early period after carotid related symptoms: a systematic review.
      score ≥ 4) to aspirin monotherapy or short term aspirin and clopidogrel DAPT, there is now compelling evidence to support short term treatment with DAPT in these patient subgroups.
      • Prasad K.
      • Siemieniuk R.
      • Hao Q.
      • Guyatt G.
      • O'Donnell M.
      • Lytvyn L.
      • et al.
      Dual antiplatelet therapy with aspirin and clopidogrel for acute high risk transient ischaemic attack and minor ischaemic stroke: a clinical practice guideline.
      A recently published RCT also proved that in the subgroup of stroke patients with carotid artery stenosis, ticagrelor added to aspirin in the first 24 hours after the event, had greater absolute risk reduction of stroke or death at 30 days than stroke patients without carotid artery stenosis with a clinically meaningful benefit with a number needed to treat of 34 (95% CI 19 – 171).
      • Amarenco P.
      • Denison H.
      • Evans S.R.
      • Himmelmann A.
      • James S.
      • Knutsson M.
      • et al.
      Ticagrelor added to aspirin in acute nonsevere ischemic stroke or transient ischemic attack of atherosclerotic origin.
      Methodological quality assessment revealed that the included studies are moderate to low quality, with a single high quality study in this analysis. Only a small number of studies was eligible for quantitative analysis, hindering conclusions. Also, heterogeneity of quantitative synthesis is significant, as determined by the I2 test. Risk of bias is therefore significant. Probably one of the main biases was introduced in the election for CAS/CEA (selection bias), with fit patients treated by CEA while high risk patients were treated by CAS. Also, with the inclusion of mainly prospective cohort studies the risk of confounding is inherent.
      In conclusion, the predicted magnitude of procedural risks will ultimately determine whether CEA or CAS is safer in the early time period after onset of symptoms.
      • Kashyap V.S.
      • Schneider P.A.
      • Foteh M.
      • Motaganahalli R.
      • Shah R.
      • Eckstein H.H.
      • et al.
      Early outcomes in the ROADSTER 2 study of transcarotid artery revascularization in patients with significant carotid artery disease.
      The evidence from the current systematic review and meta-analysis suggests that (at present) CEA is still safer than transfemoral CAS when performed ≤ 2 days of the index event. Also, considering absolute rates, expedited CEA complies with the accepted thresholds in international guidelines. The ideal timing for performing CAS (when indicated against CEA) is not yet defined and it remains to be seen whether newer CAS technologies (such as TCAR) can provide outcomes similar to CEA when performed in the first 2 – 7 days after symptom onset. Additional granular data and standard reporting of timing of intervention will facilitate future clinical decisions.

      Conflict of interest

      None.

      Funding

      None.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

      References

        • Naylor A.R.
        • Ricco J.B.
        • de Borst G.J.
        • Debus S.
        • de Haro J.
        • Halliday A.
        Editor's Choice - Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS).
        Eur J Vasc Endovasc Surg. 2018; 55: 3-81
        • Tsantilas P.
        • Kuhnl A.
        • Kallmayer M.
        • Knappich C.
        • Schmid S.
        • Kuetchou A.
        • et al.
        Stroke risk in the early period after carotid related symptoms: a systematic review.
        J Cardiovasc Surg (Torino). 2015; 56: 845-852
        • Milgrom D.
        • Hajibandeh S.
        • Antoniou S.A.
        • Torella F.
        • Antoniou G.A.
        Editor's Choice - Systematic Review and Meta-Analysis of Very Urgent Carotid Intervention for Symptomatic Carotid Disease.
        Eur J Vasc Endovasc Surg. 2018; 56: 622-631
        • Naylor A.R.
        Time is brain: an update.
        Expert Rev Cardiovasc Ther. 2015; 13: 1111-1126
        • den Hartog A.G.
        • Moll F.L.
        • van der Worp H.B.
        • Hoff R.G.
        • Kappelle L.J.
        • de Borst G.J.
        Delay to carotid endarterectomy in patients with symptomatic carotid artery stenosis.
        Eur J Vasc Endovasc Surg. 2014; 47: 233-239
        • Moher D.
        • Liberati A.
        • Tetzlaff J.
        • Altman D.G.
        • PRISMA Group
        Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
        Int J Surg. 2010; 8: 336-341
        • Slim K.
        • Nini E.
        • Forestier D.
        • Kwiatkowski F.
        • Panis Y.
        • Chipponi J.
        Methodological Index for Non-Randomized Studies (MINORS): development and validation of a new instrument.
        ANZ J Surg. 2003; 73: 712-716
        • Nordanstig A.
        • Rosengren L.
        • Stromberg S.
        • Osterberg K.
        • Karlsson L.
        • Bergstrom G.
        • et al.
        Editor's Choice - Very Urgent Carotid Endarterectomy is Associated with an Increased Procedural Risk: The Carotid Alarm Study.
        Eur J Vasc Endovasc Surg. 2017; 54: 278-286
        • Roussopoulou A.
        • Tsivgoulis G.
        • Krogias C.
        • Lazaris A.
        • Moulakakis K.
        • Georgiadis G.S.
        • et al.
        Safety of urgent endarterectomy in acute non-disabling stroke patients with symptomatic carotid artery stenosis: an international multicenter study.
        Eur J Neurol. 2019; 26: 673-679
        • Seguchi M.
        • Shibata M.
        • Sato Y.
        • Maekawa K.
        • Kitano Y.
        • Sano T.
        • et al.
        The safety of carotid artery stenting for patients in the acute poststroke phase.
        J Stroke Cerebrovasc Dis. 2018; 27: 83-91
        • Coelho A.
        • Prassaparo T.
        • Mansilha A.
        • Kappelle J.
        • Naylor R.
        • de Borst G.J.
        Critical appraisal on the quality of reporting on safety and efficacy of transcarotid artery stenting with flow reversal.
        Stroke. 2020; 51: 2863-2871
        • Villwock M.R.
        • Singla A.
        • Padalino D.J.
        • Deshaies E.M.
        Stenting versus endarterectomy and the impact of ultra-early revascularization for emergent admissions of carotid artery stenosis.
        J Stroke Cerebrovasc Dis. 2014; 23: 2341-2349
        • Jankowitz B.T.
        • Tonetti D.A.
        • Kenmuir C.
        • Rao R.
        • Ares W.J.
        • Zussman B.
        • et al.
        Urgent treatment for symptomatic carotid stenosis: the Pittsburgh Revascularization and Treatment Emergently After Stroke (PIRATES) Protocol.
        Neurosurgery. 2020; 87: 811-815
        • Huang Y.
        • Gloviczki P.
        • Duncan A.A.
        • Kalra M.
        • Oderich G.S.
        • DeMartino R.R.
        • et al.
        Outcomes after early and delayed carotid endarterectomy in patients with symptomatic carotid artery stenosis.
        J Vasc Surg. 2018; 67: 1110-1119
        • Sharpe R.
        • Sayers R.D.
        • London N.J.
        • Bown M.J.
        • McCarthy M.J.
        • Nasim A.
        • et al.
        Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.
        Eur J Vasc Endovasc Surg. 2013; 46: 519-524
        • Jonsson M.
        • Gillgren P.
        • Wanhainen A.
        • Acosta S.
        • Lindström D.
        Peri-procedural risk with urgent carotid artery stenting: a population based Swedvasc Study.
        Eur J Vasc Endovasc Surg. 2015; 49: 506-512