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Carotid endarterectomy versus carotid stenting for asymptomatic carotid stenosis: Evaluating the overlapping meta-analyses of randomized controlled trials

Open AccessPublished:December 13, 2022DOI:https://doi.org/10.1016/j.ejro.2022.100460

      Abstract

      Background

      Asymptomatic carotid stenosis is associated with increased risk of ischemic stroke. The management of asymptomatic carotid stenosis ranges from open surgical approaches, minimally invasive endovascular interventions, and medical therapeutics. However, the research synthesis comparing these interventions, as shown by the scattered and overlapping published meta-analysis, has been inconsistent and non-comprehensive.

      Methods

      Using previously-employed methods, we searched for and compared published meta-analyses comparing carotid endarterectomy and carotid stenting. A comprehensive search was conducted for all relevant studies published until November 13th, 2021, using the following databases: PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, OVID, and Google Scholar.

      Results

      Five meta-analysis studies were included in this review. In summary, clinical findings were: carotid endarterectomy reduced the rate of ischemic stroke and stroke-related mortality, but led to a higher rate of intraoperative cranial nerve injury. There was no significant difference between carotid endarterectomy and carotid stenting in ipsilateral stroke and myocardial infarction events.

      Conclusions

      The clinical findings favor the carotid endarterectomy over the carotid stenting in terms of stroke incidence (overall and minor events) and stroke-related mortality rates. However, the carotid stenting was superior to the carotid endarterectomy in the events of cranial nerve injury during the intervention.

      Keywords

      1. Introduction

      Asymptomatic carotid stenosis is among the significant causes of ischemic stroke. The management of asymptomatic carotid stenosis ranges from open surgical approaches, minimally invasive endovascular interventions, and medical therapeutics [
      • Yuan G.
      • Zhou S.
      • Wu W.
      • Zhang Y.
      • Lei J.
      • Huang B.
      Carotid artery stenting versus carotid endarterectomy for treatment of asymptomatic carotid artery stenosis.
      ]. Over the past two decades, it has been proven that surgical intervention is superior to medical therapeutics to prevent disease progression and induce ipsilateral ischemic stroke [
      • Carreira M.
      • Duarte-Gamas L.
      • Rocha-Neves J.
      • Andrade J.P.
      • Fernando-Teixeira J.
      Management of the carotid artery stenosis in asymptomatic patients.
      ]. With the advances in the neurosurgical field within the last decade, various surgical interventions have emerged, including minimal invasive intervention to access and stent carotid stenosis. However, to date, the literature evidence regarding the interventional strategies for asymptomatic carotid stenosis is controversial and discordant.
      To date, several meta-analyses have analyzed the safety and efficacy of carotid endarterectomy compared to carotid stenting for asymptomatic carotid stenosis [
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      ,
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      ,
      • Dharmakidari S.
      • Bhattacharya P.
      • Chaturvedi S.
      Carotid artery stenosis: medical therapy, surgery, and stenting.
      ,
      • Houck D.A.
      • Kraeutler M.J.
      • Schuette H.B.
      • McCarty E.C.
      • Bravman J.T.
      Early versus delayed motion after rotator cuff repair: a systematic review of overlapping meta-analyses.
      ,
      • Wright J.G.
      • Swiontkowski M.F.
      • Heckman J.D.
      Introducing levels of evidence to the journal.
      ]. However, the reviews and meta-analyses on this topic—comparing carotid endarterectomy against carotid stenting—do not present consistent findings for these interventions and thus lead to discordant interpretations. Overlapping but non-confirmatory meta-analyses on the same research question are common and may lead to conflicting results. Hence, it is challenging to draw conclusions from the existing literature until the meta-analyses comparing these interventions are harmonized.
      This systematic review aims to evaluate all published meta-analyses comparing carotid endarterectomy and carotid stenting for asymptomatic carotid stenosis and highlight the gaps in the current evidence.

      2. Materials and methods

      This study was designed in line with prior published studies using the same approach to aggregate and compare meta-analytical findings [
      • Campbell K.A.
      • Saltzman B.M.
      • Mascarenhas R.
      • Khair M.M.
      • Verma N.N.
      • Bach Jr., B.R.
      • Cole B.J.
      Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? a systematic review of overlapping meta-analyses.
      ,
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ,
      • Moresoli P.
      • Habib B.
      • Reynier P.
      • Secrest M.H.
      • Eisenberg M.J.
      • Filion K.B.
      Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: a systematic review and meta-analysis.
      ].

      2.1 Literature search

      A comprehensive search was conducted for all relevant studies published before November 13th, 2021, using the following databases: PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, OVID, and Google Scholar using The relevant keywords included "Carotid Endarterectomy AND Carotid Stenosis", "Carotid Endarterectomy AND Asymptomatic Carotid Stenosis", "Carotid Stenting AND Carotid Stenosis", "Carotid Stenting AND Carotid Stenosis", "Carotid Stenting AND Asymptomatic Carotid Stenosis", "Carotid Endarterectomy AND Carotid Stenting AND Carotid Stenosis", "Carotid Endarterectomy AND Carotid Stenting AND Asymptomatic Carotid Stenosis". We filtered the search results to include only meta-analyses. Screening of the search results was conducted by two authors independently. Titles and abstracts were first screened, followed by full texts. Disagreements between authors were resolved by group discussion and through the help of a third author. Study metadata and abstracts were uploaded to the AutoLit platform (Nested Knowledge, St. Paul, MN) for screening and extraction.

      2.2 Eligibility criteria

      We included meta-analyses of randomized controlled trials (RCTs) comparing Carotid Endarterectomy and Carotid Stenting for Asymptomatic Carotid Stenosis. Non-RCT meta-analyses, systematic reviews without meta-analyses, review articles, editorials, case reports, and case series were excluded.

      2.3 Data extraction

      Data extraction was conducted by two authors independently for the following data: author, year/month of publication, study design, number of included RCTs in each meta-analysis, number of patients in both the Carotid Endarterectomy and Carotid Stenting groups, percent heterogeneity, and the results of the studies. The following outcomes were compared among different studies; overall stroke rate, ipsilateral stroke, major stroke, minor stroke, myocardial infarction, mortality, cranial nerve injury, overall complications.

      2.4 Quality assessment

      We used the Assessment of Multiple Systematic Review (AMSTAR) [
      • Hurley E.T.
      • Maye A.B.
      • Mullett H.
      Arthroscopic rotator cuff repair: a systematic review of overlapping meta-analyses.
      ] and Oxford Levels of Evidence [
      • Shea B.J.
      • Grimshaw J.M.
      • Wells G.A.
      • Boers M.
      • Andersson N.
      • Hamel C.
      • Porter A.C.
      • Tugwell P.
      • Moher D.
      • Bouter L.M.
      Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews.
      ] to evaluate the methodological quality of the studies. AMSTAR is widely used to assess the quality of systematic reviews and meta-analyses with good reliability [
      • Hurley E.T.
      • Maye A.B.
      • Mullett H.
      Arthroscopic rotator cuff repair: a systematic review of overlapping meta-analyses.
      ]. Two authors conducted the quality assessment criteria; a third author resolved any conflicts.

      3. Results

      3.1 Literature search

      The PRISMA flowchart for the study selection process is shown in Fig. 1. Database search retrieved overall number of 1020 searching results. After applying the filter of meta-analysis inclusion only, 975 articles were excluded. 45 articles were eligible to the next phase of screening, of which we excluded 30 due to the fact that these studies reported symptomatic cases only. 15 articles were sought for final (full-text) screening, ten out of them were excluded because they were non-RCT meta-analysis. Overall number of five studies were included in this systematic review. The flowchart illustrated the selection criteria for the included studies in this systematic review, and also mentioned the exclusion reasons.

      3.2 Baseline characteristics

      The characteristics of the included studies are highlighted in Table 1. We highlighted details about the published journal name, number of included patients within each intervention and date of publication. Last database search for the included meta-analyses ranged between April 2016 and July 2017. The number of included RCTs in each meta-analysis ranged between five to up nine studies.
      Table 1Characteristics of the Included Studies.
      AuthorPublication DateJournalNumber of Included StudiesLast Literature Search DateNumber of Carotid Endarterectomy patientsNumber of Carotid Stenting Patients
      Galyfos G et al.
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      May 2019Cardiovascular Revascularization Medicine7July 201741474827
      Yuan G et al.
      • Dharmakidari S.
      • Bhattacharya P.
      • Chaturvedi S.
      Carotid artery stenosis: medical therapy, surgery, and stenting.
      May 2018International Heart Journal5March 201618332581
      Cui L et al.
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      May 2018European Journal of Vascular and Endovascular Surgery6May 201715852316
      Kakkos SK et al.
      • Houck D.A.
      • Kraeutler M.J.
      • Schuette H.B.
      • McCarty E.C.
      • Bravman J.T.
      Early versus delayed motion after rotator cuff repair: a systematic review of overlapping meta-analyses.
      August 2017Journal of Vascular Surgery9March 201714792230
      Moresoli P et al.
      • Hurley E.T.
      • Maye A.B.
      • Mullett H.
      Arthroscopic rotator cuff repair: a systematic review of overlapping meta-analyses.
      August 2017Stroke5April 201611381881
      The included studies were published between August 2017 and May 2019. A total of 16 RCTs were published between 2001 and 2016 (Table 2).
      Table 2Included Primary Studies.
      AuthorGalyfos G et al.
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      Yuan G et al.
      • Yuan G.
      • Zhou S.
      • Wu W.
      • Zhang Y.
      • Lei J.
      • Huang B.
      Carotid artery stenting versus carotid endarterectomy for treatment of asymptomatic carotid artery stenosis.
      Cui L et al.
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      Kakkos SK et al.
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      Moresoli P et al.
      • Moresoli P.
      • Habib B.
      • Reynier P.
      • Secrest M.H.
      • Eisenberg M.J.
      • Filion K.B.
      Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: a systematic review and meta-analysis.
      Year20192018201820172017
      CREST 2010
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      YesNoYesYesYes
      Brooks et al. 2004
      • Carreira M.
      • Duarte-Gamas L.
      • Rocha-Neves J.
      • Andrade J.P.
      • Fernando-Teixeira J.
      Management of the carotid artery stenosis in asymptomatic patients.
      ,
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      YesYesYesNoYes
      SAPPHIRE 2004 [14,28]YesNoNoYesYes
      CAVATAS 2001
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ,
      • Wright J.G.
      • Swiontkowski M.F.
      • Heckman J.D.
      Introducing levels of evidence to the journal.
      YesNoNoYesNo
      SPACE-2 2016
      • Shea B.J.
      • Grimshaw J.M.
      • Wells G.A.
      • Boers M.
      • Andersson N.
      • Hamel C.
      • Porter A.C.
      • Tugwell P.
      • Moher D.
      • Bouter L.M.
      Development of AMSTAR: a measurement tool to assess the methodological quality of systematic reviews.
      YesNoNoYesNo
      ACT-1 2016 [24]YesNoYesYesYes
      Kuliha 2015 [19]YesNoNoYesYes
      Rosenfield 2016 et al. [25]NoYesNoNoNo
      Brott 2010 et al.
      • Yuan G.
      • Zhou S.
      • Wu W.
      • Zhang Y.
      • Lei J.
      • Huang B.
      Carotid artery stenting versus carotid endarterectomy for treatment of asymptomatic carotid artery stenosis.
      NoYesNoNoNo
      Liu 2009 et al. [21]NoYesNoNoNo
      Yadav 2004 et al. [29]NoYesNoNoNo
      Brooks 2014 et al.
      • Campbell K.A.
      • Saltzman B.M.
      • Mascarenhas R.
      • Khair M.M.
      • Verma N.N.
      • Bach Jr., B.R.
      • Cole B.J.
      Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? a systematic review of overlapping meta-analyses.
      NoNoYesNoNo
      Kougias 2015 et al. [18]NoNoYesNoNo
      Mannheim 2016 et al. [22]NoNoYesYesNo
      Kentucky 2004 (non-published data)NoNoNoYesNo
      Li 2014 et al. [20]NoNoNoYesNo

      3.3 Assessment of heterogeneity

      The Q-statistics and I2 values were used to quantify heterogeneity (Table 3). Four studies used sensitivity analysis and only one study Kakkos et al. [
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ] neglected to conduct sensitivity analysis. Galyfos G et al. [
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      ] used funnel plot and Habbord-Egger test. Yuan G et al. [
      • Yuan G.
      • Zhou S.
      • Wu W.
      • Zhang Y.
      • Lei J.
      • Huang B.
      Carotid artery stenting versus carotid endarterectomy for treatment of asymptomatic carotid artery stenosis.
      ] used the leave-one-out approach. Cui L et al. [
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      ] used manual exclusion of studies as the only method for limiting heterogeneity. Moresoli P et al. [
      • Moresoli P.
      • Habib B.
      • Reynier P.
      • Secrest M.H.
      • Eisenberg M.J.
      • Filion K.B.
      Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: a systematic review and meta-analysis.
      ] used the fixed-effects model with applying the inverse-variance weighting.
      Table 3Heterogeneity or Subgroup Analysis for the Variables in Meta-analyses.
      ItemsGalyfos G et al.
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      Yuan G et al.
      • Yuan G.
      • Zhou S.
      • Wu W.
      • Zhang Y.
      • Lei J.
      • Huang B.
      Carotid artery stenting versus carotid endarterectomy for treatment of asymptomatic carotid artery stenosis.
      Cui L et al.
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      Kakkos SK et al.
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      Moresoli P et al.
      • Moresoli P.
      • Habib B.
      • Reynier P.
      • Secrest M.H.
      • Eisenberg M.J.
      • Filion K.B.
      Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: a systematic review and meta-analysis.
      YearMay 2019May 2018May 2018August 2017August 2017
      Overall Stroke RateYesYesNoYesYes
      Ipsilateral StrokeYesN/ANoYesYes
      Major StrokeN/AN/ANoYesYes
      Minor StrokeN/AN/ANoYesYes
      Myocardial InfarctionYesYesNoYesYes
      MortalityYesYesNoYesYes
      Cranial Nerve InjuryN/AN/AN/AYesYes
      Overall ComplicationsYesN/AN/AN/AYes

      3.4 Jadad decision algorithm results

      There was heterogeneity among studies regarding the included rials, selection criteria, and methodology. This led to discordant results across the meta-analyses. The results of each meta-analysis are shown in Fig. 2.
      Fig. 2
      Fig. 2Results of the Included Meta-analyses. Numbers within each cell reflect the number of pooled primary studies in each analysis.

      3.5 Research question and primary trials

      All the included studies investigated the same research question: Carotid Endarterectomy versus Carotid Stenting for Asymptomatic Carotid Stenosis. However, the meta-analyses did not have the same primary trials, meaning the underlying set of data differed across meta-analyses. The included primary trials of each meta-analysis are listed in Table 2.

      3.6 Selection criteria and methodology

      The included meta-analyses did not have the same selection criteria. Galyfos G et al. [
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      ] included RCTs up to July 2017 with no lower limit for searching of results. The authors excluded trials with less than 50 total patients, trials reporting symptomatic patients, trials with unequal distribution of medical therapy, and trials published in a language other than English. Yuan G et al. [
      • Yuan G.
      • Zhou S.
      • Wu W.
      • Zhang Y.
      • Lei J.
      • Huang B.
      Carotid artery stenting versus carotid endarterectomy for treatment of asymptomatic carotid artery stenosis.
      ] included RCTs up to March 2016 with no lower limit for searching of results. The authors excluded non-RCT trials, but they did not set language restrictions to their exclusion criteria. The study by Cui L et al. [
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      ] included RCTs from 1994 up to May 2017. The authors excluded non-RCT trials and non-English trials without indicating another criterion. The study by Kakkos et al. [
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ] included RCTs up to March 2017 with no lower limit for searching of results. The authors excluded non-English RCTs. However, the authors requested unpublished data to be included in their study from investigators of unpublished trials. Moresoli P et al. [
      • Moresoli P.
      • Habib B.
      • Reynier P.
      • Secrest M.H.
      • Eisenberg M.J.
      • Filion K.B.
      Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: a systematic review and meta-analysis.
      ] included all RCTs without lower limit in the date up to April 2016 and limited their results to English and French Language only. In addition to that, they did not include non-published materials in their analysis. Each study's language restriction and methodological details are listed in Supplementary Table 1.
      Studies that reported fewer outcomes than expected were deemed of lower quality. According to this criteria, Kakkos et al. [
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ] study had the highest-quality evidence among the present meta-analyses (Fig. 3).

      3.7 Quality assessment

      According to Oxford Levels of Evidence, all the primary studies were RCTs and considered level II evidence (Table 4). Only one study by Kakkos et al. [
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ] used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) for quality assessment. A MeaSurement Tool to Assess Systematic Reviews (AMSTAR) results are presented in Table 5. The lowest AMSTAR score (Moderate) was given for Galyfos G et al. [
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      ] and Moresoli P et al. [
      • Moresoli P.
      • Habib B.
      • Reynier P.
      • Secrest M.H.
      • Eisenberg M.J.
      • Filion K.B.
      Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: a systematic review and meta-analysis.
      ], while the highest AMSTAR score (High) was given for the other three studies [
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      ,
      • Dharmakidari S.
      • Bhattacharya P.
      • Chaturvedi S.
      Carotid artery stenosis: medical therapy, surgery, and stenting.
      ,
      • Wright J.G.
      • Swiontkowski M.F.
      • Heckman J.D.
      Introducing levels of evidence to the journal.
      ].
      Table 4Methodological Information about the Included Studies.
      AuthorsPublication YearIncluded Studies DesignEvidence Level of Included StudiesSoftwareCochrane Handbook Guidelines useGRADE useSensitivity analysisPRISMA use
      Galyfos G et al.
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      2019RCTLevel IIStatsDirectNoNoYesYes
      Yuan G et al.
      • Yuan G.
      • Zhou S.
      • Wu W.
      • Zhang Y.
      • Lei J.
      • Huang B.
      Carotid artery stenting versus carotid endarterectomy for treatment of asymptomatic carotid artery stenosis.
      2018RCTLevel IIComprehensive Meta-AnalysisYesNoYesYes
      Cui L et al.
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      2018RCTLevel IIRYesNoNoYes
      Kakkos SK et al.
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      2017RCTLevel IIRevManYesYesNoYes
      Moresoli P et al.
      • Moresoli P.
      • Habib B.
      • Reynier P.
      • Secrest M.H.
      • Eisenberg M.J.
      • Filion K.B.
      Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: a systematic review and meta-analysis.
      2017RCTLevel IIRYesNoNoYes
      Table 5AMSTAR Assessment for the Included Studies. Moderate= More than one non-critical weakness (the meta-analysis has more than one weakness but no critical flaws), High= No or one non-critical weakness (the meta-analysis provides am accurate and comprehensive presentation of the results).
      ItemsGalyfos G et al. (2019)
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      Yuan G et al. (2018)
      • Yuan G.
      • Zhou S.
      • Wu W.
      • Zhang Y.
      • Lei J.
      • Huang B.
      Carotid artery stenting versus carotid endarterectomy for treatment of asymptomatic carotid artery stenosis.
      Cui L et al. (2018)
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      Kakkos SK et al. (2017)
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      Moresoli P et al. (2017)
      • Moresoli P.
      • Habib B.
      • Reynier P.
      • Secrest M.H.
      • Eisenberg M.J.
      • Filion K.B.
      Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: a systematic review and meta-analysis.
      Total, N (%)
      Was an a priori design provided?YesYesYesYesYes5, (100)
      Was there duplicate study selection and data extraction?YesYesYesYesYes5, (100)
      Was a comprehensive literature search performed?YesYesNoNoNo2, (40)
      Was the status of publication (i.e. grey literature) used as an inclusion criterion?YesYesYesYesYes5, (100)
      Was a list of studies (included and excluded) provided?YesNoYesYesNo3, (60)
      Were the characteristics of the included studies provided?YesYesYesYesYes5, (100)
      Was the scientific quality of the included studies assessed and documented?NoYesYesYesYes4, (80)
      Was the scientific quality of the included studies used appropriately in formulating conclusions?NoYesYesYesYes4, (80)
      Were the methods used to combine the findings of studies appropriate?YesYesYesYesYes5, (100)
      Was the likelihood of publication bias assessed?YesYesYesYesYes5, (100)
      Was the conflict of interest stated?YesYesYesYesYes5, (100)
      Overall Methodological Quality (L= Low, M= Moderate, H= High)MHHHM

      4. Discussion

      To the best of our knowledge, this is the first systematic review of the overlapping meta-analyses investigating Carotid Endarterectomy versus Carotid Stenting for Asymptomatic Carotid Stenosis. According to the Jadad decision algorithm, the study by Kakkos et al. [
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ] represents the highest quality meta-analysis comparing Carotid Endarterectomy versus Carotid Stenting for Asymptomatic Carotid Stenosis. Moreover, the identified discordant findings across studies show the need for higher-quality and better-coordinated meta-analyses. Although the findings of Kakkos et al. are the highest quality, they may require further assessment since the authors did not include 8 + studies found by other searches. Furthermore, the underlying studies support endarterectomy on major clinical outcomes other than risk of cranial nerve injury.
      Kakkos et al. [
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ] concluded that Carotid Endarterectomy is superior to Carotid Stenting in most clinical outcomes, including overall stroke rate, significant stroke incidence, minor stroke incidence, and mortality risk. However, the risk of cranial nerve injury was favoring the carotid stenting group over the carotid endarterectomy. Meanwhile, there were no significant differences between both interventions regarding the risk of developing ipsilateral stroke and the risk of myocardial infarction. Major stroke was defined as a stroke-inducing disability or morality, while minor stroke was defined as non-disabling (Fig. 2).
      We found conflicting results among different meta-analyses in the literature. The study by Galyfos et al. [
      • Galyfos G.
      • Sachsamanis G.
      • Anastasiadou C.
      • Sachmpazidis I.
      • Kikiras K.
      • Kastrisios G.
      • Giannakakis S.
      • Papapetrou A.
      • Papacharalampous G.
      • Maltezos C.
      Carotid endarterectomy versus carotid stenting or best medical treatment in asymptomatic patients with significant carotid stenosis: a meta-analysis.
      ] demonstrated that the overall stroke rate favored the carotid endarterectomy group, while the risk of developing ipsilateral stroke, myocardial infarction, mortality rate, and the overall complications was similar between carotid endarterectomy and carotid stenting. Yuan G et al. [
      • Yuan G.
      • Zhou S.
      • Wu W.
      • Zhang Y.
      • Lei J.
      • Huang B.
      Carotid artery stenting versus carotid endarterectomy for treatment of asymptomatic carotid artery stenosis.
      ] reported only three outcomes; the overall stroke rate and the mortality rate were similar between both groups, while the risk of myocardial infarction favored the carotid stenting group. The study by Cui L et al. [
      • Cui L.
      • Han Y.
      • Zhang S.
      • Liu X.
      • Zhang J.
      Safety of stenting and endarterectomy for asymptomatic carotid artery stenosis: a meta-analysis of randomised controlled trials.
      ] favored carotid endarterectomy regarding the overall stroke rate and minor stroke incidence. However, the risk of developing ipsilateral stroke, significant stroke incidence, myocardial infarction, and mortality rate were all comparable between carotid endarterectomy and carotid stenting. The study by Moresoli P et al. [
      • Moresoli P.
      • Habib B.
      • Reynier P.
      • Secrest M.H.
      • Eisenberg M.J.
      • Filion K.B.
      Carotid stenting versus endarterectomy for asymptomatic carotid artery stenosis: a systematic review and meta-analysis.
      ] did not favor an intervention regarding all clinical outcomes, except the risk of cranial nerve injury. It favored the carotid stenting over the carotid endarterectomy. The potential reasons for these discordant results are different eligibility criteria by authors and different databases for the search strategy. Some studies did not perform a comprehensive search in all available scientific databases. Furthermore, the different timeframe of the conducted searches is a possible contributing reason.
      There are several reasons why the study by Kakkos et al. [
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ] was found to have the highest quality of evidence. At first, this meta-analysis included nine studies, making it the most extensive meta-analysis in the current literature. Second, the authors followed the Cochrane Handbook for Systematic Reviews of Interventions to conduct their study. Nevertheless, Kakkos et al. [
      • Kakkos S.K.
      • Kakisis I.
      • Tsolakis I.A.
      • Geroulakos G.
      Endarterectomy achieves lower stroke and death rates compared with stenting in patients with asymptomatic carotid stenosis.
      ] acknowledged several limitations influencing their results. First, the GRADE assessment method for stroke and myocardial infarction outcomes showed insufficient and moderate evidence levels. Second, the number of myocardial infarction events was low to provide significant evidence. Third, the results suggested that the carotid endarterectomy is superior to the carotid stenting.
      The strengths of this study include the focus on reviewing the highest evidence quality and determination of the best results based on specific decision algorithms. According to Oxford Levels of Evidence, our study was limited to level I evidence. However, our results are limited by the quality of the included meta-analyses and their inherent limitations.

      5. Conclusions

      The clinical findings favor the carotid endarterectomy over the carotid stenting in terms of stroke incidence (overall and minor events) and stroke-related mortality rates. There was no significant difference between carotid endarterectomy and carotid stenting in ipsilateral stroke and myocardial infarction events. However, the carotid stenting was superior to the carotid endarterectomy in the events of cranial nerve injury during the intervention. Further meta-analytical studies investigating the safety and efficacy of carotid endarterectomy versus carotid stenting should draw from the findings of Kakkos et al. but ensure that a comprehensive search is undertaken of all subsequent evidence to continue updating the research synthesis on this clinical question.

      Ethical statement

      This work was completely free from involving human subjects.

      Funding

      None.

      CRediT authorship contribution statement

      KMK works for and holds equity in Nested Knowledge, Inc., works for Conway Medical LLC, and holds equity in Superior Medical Experts, Inc. DK has the following conflicts: Ownership in Nested Knowledge, Inc., Superior Medical Experts, Inc., Conway Medical LLC; Research support from: Microvention, Balt USA, Medtronic.

      Acknowledgments

      We acknowledge the Nested Knowledge developers, including Karl Holub, Stephen Mead, Jeff Johnson, and Darian Lehmann-Plantenberg, who made this study possible by creating the AutoLit and Synthesis platforms for systematic review.

      Appendix A. Supplementary material

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