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Editor's Choice – Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis

  • Stephen Ball
    Correspondence
    Corresponding author. Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, M13 9PL, UK.
    Affiliations
    Department of Vascular and Endovascular Surgery, The Royal Oldham Hospital, Pennine Acute Hospitals NHS Trust, Manchester, UK

    Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, UK
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  • Alexandra Ball
    Affiliations
    Department of Vascular and Endovascular Surgery, The Royal Oldham Hospital, Pennine Acute Hospitals NHS Trust, Manchester, UK
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  • George A. Antoniou
    Affiliations
    Department of Vascular and Endovascular Surgery, The Royal Oldham Hospital, Pennine Acute Hospitals NHS Trust, Manchester, UK

    Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, UK
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Open ArchivePublished:February 18, 2020DOI:https://doi.org/10.1016/j.ejvs.2020.01.022

      Objective

      This study investigates the prognostic significance of pre-operative symptom status and type of symptom in outcomes after carotid endarterectomy (CEA).

      Methods

      This review was conducted and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) to identify studies reporting peri-operative outcomes of CEA in symptomatic and asymptomatic patients. The last search was conducted in August 2019 and a methodological assessment was performed using the Newcastle Ottawa Scale. A meta-analysis of outcome data using the odds ratio (OR) as the summary statistic was conducted, and the precision of the effect was reported as 95% confidence interval (CI). Fixed effect or random effects models were used to calculate the pooled estimates.

      Results

      Eighteen studies reporting a total of 91 895 patients were included in the meta-analysis. Asymptomatic patients had a lower peri-operative risk of stroke (OR 0.5, 95% CI 0.45–0.54; p < .001) and death (OR 0.66, 95% CI 0.57–0.77; p < .001) than symptomatic patients, but the risk of myocardial infarction was not significantly different (OR 0.98, 95% CI 0.84–1.15; p = .82). Those suffering a pre-procedural stroke had an increased peri-operative risk of stroke and death vs. patients suffering a pre-procedural transient ischaemic attack or amaurosis fugax.

      Conclusion

      Patients undergoing CEA after a stroke have worse peri-operative outcomes in terms of stroke and death. Further research needs to be performed to ascertain the value of this finding in risk stratification systems and to investigate potential aetiological associations between pre-operative symptom status and peri-operative risk following a CEA.

      Keywords

      This paper demonstrates that patients undergoing carotid endarterectomy following a stroke have a higher peri-operative risk of stroke and death than asymptomatic patients or patients presenting with transient ischaemic attack or amaurosis fugax. This finding adds to the risk stratification evidence base in patients undergoing surgical treatment for carotid disease.

      Introduction

      Current European Society for Vascular Surgery (ESVS) guidelines recommend carotid endarterectomy (CEA) for symptomatic severe carotid stenosis.
      • Naylor A.R.
      • Ricco J.B.
      • de Borst G.J.
      • Debus S.
      • de Haro J.
      • Halliday A.
      • et al.
      Management of atherosclerotic carotid and vertebral artery disease: 2017 Clinical Practice Guidelines of the ESVS.
      To confer maximum benefit, CEA should be performed as soon as possible following symptoms of cerebral ischaemia, and certainly within two weeks. Patients with 70%–99% stenosis have an absolute risk reduction of 23% when CEA is performed within two weeks.
      • Moore W.S.
      • Boren C.
      • Malone J.M.
      • Roon A.J.
      • Eisenberg R.
      • Goldstone J.
      • et al.
      Natural history of nonstenotic, asymptomatic ulcerative lesions of the carotid artery.
      • Warlow C.
      MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis.
      • Warlow C.
      • Farrell B.
      • Fraser A.
      • Sandercock P.
      • Slattery J.
      Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
      • North American Symptomatic Carotid Endarterectomy Trial Collaborators
      • Barnett H.J.M.
      • Taylor D.W.
      • Haynes R.B.
      • Sackett D.L.
      • Peerless S.J.
      • et al.
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      For patients with asymptomatic disease, the ESVS recommends that CEA should be considered in the “average surgical risk” patient with a 60%–99% stenosis in the presence of one or more imaging features of increased risk, provided their peri-operative mortality and stroke rate is <3% and they have a greater than five year life expectancy. Specifically, in asymptomatic patients with >70% carotid stenosis, the annual risk of ipsilateral stroke is around 1%–2%.
      • Halliday A.
      Prevention of disabling and fatal strokes by successful carotid endarterectomy in patients without recent neurological symptoms.
      ,
      • Moneta G.L.
      • Taylor D.C.
      • Nicholls S.C.
      • Bergelin R.O.
      • Zierler R.E.
      • Kazmers A.
      • et al.
      Operative versus nonoperative management of asymptomatic high-grade internal carotid artery stenosis: improved results with endarterectomy.
      Therefore, in these patients, the benefit of intervention with CEA is minimal: in simple terms, around 32 CEAs would need to be undertaken to prevent one stroke over a five year period.
      • Moore W.S.
      • Boren C.
      • Malone J.M.
      • Roon A.J.
      • Eisenberg R.
      • Goldstone J.
      • et al.
      Natural history of nonstenotic, asymptomatic ulcerative lesions of the carotid artery.
      The operative mortality rate for CEA in symptomatic patients is <1%. The peri-operative risk of stroke is reported to be around 2%–3%.
      • Silver F.L.
      • Mackey A.
      • Clark W.M.
      • Brooks W.
      • Timaran C.H.
      • Chiu D.
      • et al.
      Safety of stenting and endarterectomy by symptomatic status in the carotid revascularization endarterectomy versus stenting trial (CREST).
      Much of the data concerning outcomes post CEA quote a 30 day end point of stroke/death. The first major trials, the European Carotid Surgery Trial (ECST)
      • Warlow C.
      MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis.
      and the North American Symptomatic Carotid Endarterectomy Trial (NASCET),
      • North American Symptomatic Carotid Endarterectomy Trial Collaborators
      • Barnett H.J.M.
      • Taylor D.W.
      • Haynes R.B.
      • Sackett D.L.
      • Peerless S.J.
      • et al.
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      reported a 30 day stroke risk of 6%–8%, but more recent trials, such as the International Carotid Stenting Study (ICSS)
      • Ederle J.
      • Dobson J.
      • Featherstone R.L.
      • Bonati L.H.
      • van der Worp H.B.
      • de Borst G.J.
      • et al.
      International Carotid Stenting Study Investigators
      Carotid artery stenting compared with endarterectomy in patients with symptomatic carotid stenosis (International Carotid Stenting Study): an interim analysis of a randomised controlled trial.
      and Carotid Revascularisation Endarterectomy vs. Stenting Trial (CREST),
      • Silver F.L.
      • Mackey A.
      • Clark W.M.
      • Brooks W.
      • Timaran C.H.
      • Chiu D.
      • et al.
      Safety of stenting and endarterectomy by symptomatic status in the carotid revascularization endarterectomy versus stenting trial (CREST).
      have shown a decrease in the stroke risk to 3%–5%. The risk of peri-operative myocardial infarction (MI) is quoted as 0.5%–1%; however, very few trials included MI as a 30 day end point. In the CREST, it was reported as 2.3%. In addition to stroke/death/MI, there is also the risk of cranial nerve injury (5%–9%) and wound complications (3%).
      With regard to asymptomatic patients, their 30 day outcomes are significantly better with the risk of stroke being 1%–2%, death 0.5%–1%, and MI 1%.
      • Warlow C.
      • Farrell B.
      • Fraser A.
      • Sandercock P.
      • Slattery J.
      Randomised trial of endarterectomy for recently symptomatic carotid stenosis: final results of the MRC European Carotid Surgery Trial (ECST).
      ,
      • North American Symptomatic Carotid Endarterectomy Trial Collaborators
      • Barnett H.J.M.
      • Taylor D.W.
      • Haynes R.B.
      • Sackett D.L.
      • Peerless S.J.
      • et al.
      Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis.
      While it is accepted that asymptomatic patients have better peri-operative outcomes following CEA, there is no meta-analysis reported comparing peri-operative outcomes following CEA in symptomatic and asymptomatic patients. Also, with regard to symptomatic patients, they are all classed as having the same risk, regardless of their qualifying symptom. Up to now, there is no single risk prediction model that is widely used that determines each individual's specific risk after CEA vs. best medical therapy incorporating their qualifying symptom.
      The aim of this study was to investigate the prognostic significance of symptom status in peri-operative outcomes following CEA. This was performed by conducting a systematic review and meta-analysis of studies that compared peri-operative outcomes after CEA between symptomatic and asymptomatic patients with subgroup analysis comparing the type of symptom.

      Methods

      The objectives of the systematic review, criteria for study inclusion, and methods of analysis were pre-specified in a protocol. This review was conducted and reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.
      • Liberati A.
      • Altman D.G.
      • Tetzlaff J.
      • Mulrow C.
      • Gøtzsche P.C.
      • Ioannidis J.P.A.
      • et al.
      The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration.

      Eligibility criteria

      All studies reporting on the 30 day outcomes from CEA in both symptomatic and asymptomatic patients were included. Reviews were excluded.
      The authors attempted to identify all observational studies specifically investigating and comparing the outcomes of CEA in these two well defined groups of patients. Studies explicitly reporting that they included patients who underwent combined CEA and coronary artery bypass grafting were excluded.

      Literature search methods

      A comprehensive and systematic search of the literature according to the PRISMA guidelines was undertaken for relevant studies. The following electronic bibliographic sources were searched: MEDLINE (1950 – present), Embase (1980 – present), CINAHL, and the Cochrane Controlled Register of Trials (CENTRAL). The last search was run in August 2019. Reference lists from retrieved reports were scrutinised for additional potentially eligible articles. Only English language articles were considered. Medical subject headings and other keywords used to identify relevant articles were “carotid endarterectomy” and “symptomatic” and “asymptomatic” and “peri-operative outcomes”.

      Data collection and analysis

      Eligibility for study inclusion was conducted by the lead author (S.B.) and data were inputted onto an Excel spreadsheet (Microsoft, Redmond, WA, USA) and checked by a second author (A.B.). The plan was to analyse pre-specified outcome measures. The number of patients within each group and the number of patients who developed an adverse post-operative event were extracted. Outcome end points were stroke, transient ischaemic attack (TIA), death of any cause, and MI occurring during the hospital stay or within 30 days of treatment. All strokes affecting either hemisphere (fatal or non-fatal, contralateral or ipsilateral, resulting from haemorrhage or infarction) were included.
      The information entered detailed: (i) study characteristics, including publication date, recruitment period, total number of patients, and number of CEAs performed; (ii) carotid disease related characteristics, including symptom status; and (iii) outcome parameters, mainly 30 day stroke, death, TIA and MI rates.
      The Newcastle Ottawa Scale was used to ascertain the validity of eligible studies.
      • Wells G.
      • Shea B.
      • O'Connell D.
      • Peterson J.
      The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.

      Statistical analysis

      A meta-analysis of outcome data was conducted using the odds ratio (OR) as the summary statistic, and the precision of the effect was reported as 95% confidence interval (CI). The unit of analysis was the individual patient. A fixed effect model was used to calculate the pooled effect estimate and 95% CI, unless there was statistical evidence of heterogeneity (p < .05 and I2 > 75%), in which case a random effects model was applied. A forest plot was created for each treatment effect.
      Between study heterogeneity was examined with the Cochrane's Q (chi square) test. Inconsistency was quantified by calculating I2 and interpreting it using the following guide: 0%–40% might not be important; 30%–60% may represent moderate heterogeneity; 50%–90% may represent substantial heterogeneity; and 75%–100% may represent considerable heterogeneity.
      • Higgins J.
      • Green S.
      Cochrane handbook for systematic reviews of interventions version 5.1.0.
      For each study, the effect by the inverse of its standard error was plotted. Publication bias was assessed both visually evaluating the symmetry of the funnel plot, and mathematically using the Egger's regression intercept if 10 or more studies reported data on the specific outcomes.
      Subgroup analysis was conducted for type of presenting symptom, termed index event (stroke, TIA, and amaurosis fugax). Furthermore, meta-regression models were formed to investigate changes in outcome differences over the years with the year of publication being used as the moderator.
      The following statistical software were used for data analysis: (i) Review Manager (RevMan) version 5.3 (The Cochrane Collaboration, 2014); and (ii) Comprehensive Meta-Analysis (Biostat, Englewood, NJ, USA).

      Results

      Literature search results and description of studies

      A total of 1175 records were identified via electronic and other resources. Another three articles were identified during the second level manual search of the reference lists of the full text articles. The full texts of 22 articles were examined in detail. Four studies were excluded, leaving a total of 18 studies included in the analysis. The literature search strategy is provided in Fig. 1.
      • Easton J.D.
      • Sherman D.G.
      Stroke and mortality rate in carotid endarterectomy: 228 consecutive operations.
      • Fode N.C.
      • Sundt T.M.
      • Robertson J.T.
      • Peerless S.J.
      • Shields C.B.
      Multicenter retrospective review of results and complications of carotid endarterectomy in 1981.
      • Healy D.A.
      • Clowes A.W.
      • Zierler R.E.
      • Nicholls S.C.
      • Bergelin R.O.
      • Primozich J.F.
      • et al.
      Immediate and long-term results of carotid endarterectomy.
      • Burns R.J.
      • Willoughby J.O.
      South Australian carotid endarterectomy study.
      • Goldstein L.B.
      • McCrory D.C.
      • Landsman P.B.
      • Samsa G.P.
      • Ancukiewicz M.
      • Oddone E.Z.
      • et al.
      Multicenter review of preoperative risk factors for carotid endarterectomy in patients with ipsilateral symptoms.
      • Hertzer N.R.
      • O'Hara P.J.
      • Mascha E.J.
      • Krajewski L.P.
      • Sullivan T.M.
      • Beven E.G.
      Early outcome assessment for 2228 consecutive carotid endarterectomy procedures: the Cleveland Clinic experience from 1989 to 1995.
      • 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.
      • Coppi G.
      • Moratto R.
      • Ragazzi G.
      • Nicolosi E.
      • Silingardi R.
      • Franciosi G.B.
      • et al.
      Comparing outcomes of carotid endarterectomy with international benchmarks: audit from an Italian vascular surgery department.
      • Flanigan D.P.
      • Flanigan M.E.
      • Dorne A.L.
      • Harward T.R.S.
      • Razavi M.K.
      • Ballard J.L.
      Long-term results of 442 consecutive, standardized carotid endarterectomy procedures in standard-risk and high-risk patients.
      • Feasby T.E.
      • Kennedy J.
      • Quan H.
      • Girard L.
      • Ghali W.A.
      Real-world replication of randomized controlled trial results for carotid endarterectomy.
      • Halm E.A.
      • Tuhrim S.
      • Wang J.J.
      • Rockman C.
      • Riles T.S.
      • Chassin M.R.
      Risk factors for perioperative death and stroke after carotid endarterectomy: results of the New York carotid artery surgery study.
      • Sidawy A.N.
      • Zwolak R.M.
      • White R.A.
      • Siami F.S.
      • Schermerhorn M.L.
      • Sicard G.A.
      Risk-adjusted 30-day outcomes of carotid stenting and endarterectomy: results from the SVS Vascular Registry.
      • Brott T.G.
      • Hobson R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      • Bekelis K.
      • Bakhoum S.F.
      • Desai A.
      • Mackenzie T.A.
      • Goodney P.
      • Labropoulos N.
      A risk factor-based predictive model of outcomes in carotid endarterectomy: the national surgical quality improvement program 2005-2010.
      • 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.
      • 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.
      • Brothers T.E.
      • Ricotta J.J.
      • Gillespie D.L.
      • Geraghty P.J.
      • Kenwood C.T.
      • Siami F.S.
      • et al.
      Contemporary results of carotid endarterectomy in “normal-risk” patients from the society for vascular surgery vascular registry presented at the forty-first annual symposium of the society for clinical vascular surgery, Miami, fla, March 12–16, 2013.
      • Pothof A.B.
      • Zwanenburg E.S.
      • Deery S.E.
      • O'Donnell T.F.X.
      • de Borst G.J.
      • Schermerhorn M.L.
      An update on the incidence of perioperative outcomes after carotid endarterectomy, stratified by type of preprocedural neurologic symptom.
      Figure 1
      Figure 1Literature search strategy to identify studies reporting on peri-operative outcomes following carotid endarterectomy for both symptomatic and asymptomatic patients.
      The total meta-analysis population comprised 91 895 patients (92 128 CEAs) of whom 40 486 were classed as symptomatic. Table 1 details the study characteristics. The validity of the studies was considered good based on the majority of studies achieving a rating of seven, based on the Newcastle–Ottawa Scale.
      Table 1Characteristics of the 18 individual studies included in the meta-analysis for prognostic role of pre-operative symptom status in carotid endarterectomy (CEA)
      First authorYearRecruitment periodNOSTypeNo. of patientsNo. CEAsAsymptomaticSymptomaticStrokeTIAAF
      Easton
      • Easton J.D.
      • Sherman D.G.
      Stroke and mortality rate in carotid endarterectomy: 228 consecutive operations.
      19771970–767Cohort228228561408357NR
      Fode
      • Fode N.C.
      • Sundt T.M.
      • Robertson J.T.
      • Peerless S.J.
      • Shields C.B.
      Multicenter retrospective review of results and complications of carotid endarterectomy in 1981.
      198619817Cohort3129312990822214771283461
      Healy
      • Healy D.A.
      • Clowes A.W.
      • Zierler R.E.
      • Nicholls S.C.
      • Bergelin R.O.
      • Primozich J.F.
      • et al.
      Immediate and long-term results of carotid endarterectomy.
      19891980–877Cohort200200771233687NR
      Burns
      • Burns R.J.
      • Willoughby J.O.
      South Australian carotid endarterectomy study.
      1991NR7Cohort2342341041304288NR
      Goldstein
      • Goldstein L.B.
      • McCrory D.C.
      • Landsman P.B.
      • Samsa G.P.
      • Ancukiewicz M.
      • Oddone E.Z.
      • et al.
      Multicenter review of preoperative risk factors for carotid endarterectomy in patients with ipsilateral symptoms.
      19941987–906Cohort11601160463697188509NR
      Hertzer
      • Hertzer N.R.
      • O'Hara P.J.
      • Mascha E.J.
      • Krajewski L.P.
      • Sullivan T.M.
      • Beven E.G.
      Early outcome assessment for 2228 consecutive carotid endarterectomy procedures: the Cleveland Clinic experience from 1989 to 1995.
      19971989–95Registry204622281401827261NRNR
      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.
      20031994–977Registry6038603818464192NRNRNR
      Coppi
      • Coppi G.
      • Moratto R.
      • Ragazzi G.
      • Nicolosi E.
      • Silingardi R.
      • Franciosi G.B.
      • et al.
      Comparing outcomes of carotid endarterectomy with international benchmarks: audit from an Italian vascular surgery department.
      2005NR6Cohort488488343145NRNRNR
      Flanigan
      • Flanigan D.P.
      • Flanigan M.E.
      • Dorne A.L.
      • Harward T.R.S.
      • Razavi M.K.
      • Ballard J.L.
      Long-term results of 442 consecutive, standardized carotid endarterectomy procedures in standard-risk and high-risk patients.
      2007April 1999–June 20058Cohort391442272170NRNRNR
      Feasby
      • Feasby T.E.
      • Kennedy J.
      • Quan H.
      • Girard L.
      • Ghali W.A.
      Real-world replication of randomized controlled trial results for carotid endarterectomy.
      20072000–016Cohort3283328312522031NRNRNR
      Halm
      • Halm E.A.
      • Tuhrim S.
      • Wang J.J.
      • Rockman C.
      • Riles T.S.
      • Chassin M.R.
      Risk factors for perioperative death and stroke after carotid endarterectomy: results of the New York carotid artery surgery study.
      2009January 2008–June 20098Cohort93089308665326558771778NR
      Sidawy
      • Sidawy A.N.
      • Zwolak R.M.
      • White R.A.
      • Siami F.S.
      • Schermerhorn M.L.
      • Sicard G.A.
      Risk-adjusted 30-day outcomes of carotid stenting and endarterectomy: results from the SVS Vascular Registry.
      20092005–077Registry32591368862506NRNRNR
      Brott
      • Brott T.G.
      • Hobson R.W.
      • Howard G.
      • Roubin G.S.
      • Clark W.M.
      • Brooks W.
      • et al.
      Stenting versus endarterectomy for treatment of carotid-artery stenosis.
      20102000–087RCTNR1240584656NRNRNR
      Bekelis
      • Bekelis K.
      • Bakhoum S.F.
      • Desai A.
      • Mackenzie T.A.
      • Goodney P.
      • Labropoulos N.
      A risk factor-based predictive model of outcomes in carotid endarterectomy: the national surgical quality improvement program 2005-2010.
      20132005–108Cohort35 69835 69820 01515 683NRNRNR
      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.
      20132006–107Cohort61061044816272819
      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.
      20142004–117Registry5758575839491809611878320
      Brothers
      • Brothers T.E.
      • Ricotta J.J.
      • Gillespie D.L.
      • Geraghty P.J.
      • Kenwood C.T.
      • Siami F.S.
      • et al.
      Contemporary results of carotid endarterectomy in “normal-risk” patients from the society for vascular surgery vascular registry presented at the forty-first annual symposium of the society for clinical vascular surgery, Miami, fla, March 12–16, 2013.
      20152005–117Registry3977397725211456NRNRNR
      Pothof
      • Pothof A.B.
      • Zwanenburg E.S.
      • Deery S.E.
      • O'Donnell T.F.X.
      • de Borst G.J.
      • Schermerhorn M.L.
      An update on the incidence of perioperative outcomes after carotid endarterectomy, stratified by type of preprocedural neurologic symptom.
      20182011–157Cohort16 73916 73997846955310426351216
      NOS = Newcastle Ottawa Scale; TIA = transient ischaemic attack; AF = amaurosis fugax; NR = not recorded; RCT = randomised controlled trial.

      Synthesis of results and outcome

      Symptomatic vs. asymptomatic

      The forest and scatter plots for the outcome parameters are presented in Figure 2, Figure 3, respectively.
      Figure 2
      Figure 2Forest plots of peri-operative outcomes (odds ratios, OR) for (A) stroke, (B) death, (C) transient ischaemic attack (TIA), and (D) myocardial infarction (MI) following carotid endarterectomy in patients with symptomatic vs. asymptomatic carotid disease. The solid squares denote the odds ratios (ORs), the horizontal lines represent the 95% confidence intervals (CIs), and the diamonds denote the pooled ORs. Symptomatic patients have a significantly higher rate of peri-operative stroke, death, and TIA compared with asymptomatic patients. M−H = Mantel–Haenszel.
      Figure 3
      Figure 3Scatter plots of log odds ratio for (A) stroke and (B) death following carotid endarterectomy in patients with symptomatic and asymptomatic carotid disease, with the year of publication as the moderator. The plots show the observed outcomes (odds ratios) of the individual studies against the quantitative predictor (year of publication). The difference in peri-operative stroke and death between symptomatic and asymptomatic patients has decreased over the years (p = .021 and p = .002, respectively).

      Stroke

      All 18 studies reported peri-operative or 30 day outcomes for stroke. The crude stroke rate was 3.3% in the symptomatic group and 1.5% in the asymptomatic group (OR 0.5, 95% CI 0.45–0.54; p < .001). Moderate heterogeneity amongst the studies was identified (I2 = 55%). The likelihood of publication bias was low (p = .46). The difference in peri-operative stroke between symptomatic and asymptomatic patients has decreased over the years (p = .021).

      Death

      Sixteen studies reported peri-operative or 30 day outcomes for death. The crude death rate was 1.2% in the symptomatic group and 0.7% in the asymptomatic group (OR 0.66, 95% CI 0.57–0.77; p < .001). Moderate heterogeneity among the studies was identified (I2 = 40%). The likelihood of publication bias was low (p = .24). The difference in peri-operative death between symptomatic and asymptomatic patients has decreased over the years (p = .002).

      TIA

      Four studies reported peri-operative or 30 day outcomes for TIA. The crude TIA rate was 0.9% in the symptomatic group and 0.4% in the asymptomatic group (OR 0.41, 95% CI 0.21–0.80; p = .01). No significant heterogeneity among the studies was identified (I2 = 30%).

      MI

      Nine studies reported peri-operative or 30 day outcomes for MI. The crude MI rate was 0.9% in both the symptomatic asymptomatic groups (OR 0.98, 95% CI 0.84–1.15; p = .82). Moderate heterogeneity among the studies was identified (I2 = 56%).

      Subgroup analysis

      Table 2 details the outcomes for the various subgroup comparisons. When comparing patients whose index event was stroke to asymptomatic patients, they had an increased risk of peri-operative stroke (OR 0.36, 95% CI 0.31–0.42; p < .001) and death (OR 0.45, 95% CI 0.34–0.59; p < .001).
      Table 2Outcome following subgroup analysis dependent on pre-operative symptom prior to carotid endarterectomy
      ComparisonOutcomeNo. of studiesOR (95% CI)p valueModelHeterogeneity
      Asymptomatic vs. strokeStroke100.36 (0.31–0.42)<.001FEI2=18%, p=.28
      Death90.45 (0.34–0.59)<.001FEI2=0%, p=.85
      TIA21.82 (0.21–15.46).58FEI2=0%, p=.86
      MI41.26 (0.90–1.78).18FEI2=0%, p=.46
      Asymptomatic vs. TIAStroke90.54 (0.46–0.64)<.001FEI2=20%, p=.27
      Death80.91 (0.66–1.25).56FEI2=0%, p=.49
      TIA20.84 (0.18–3.78).82FEI2=0%, p=.32
      MI40.88 (0.65–1.17).37FEI2=48%, p=.12
      Asymptomatic vs. AFStroke41.12 (0.77–1.63).55FEI2=19%, p=.29
      Death41.84 (0.99–3.42).06FEI2=54%, p=.09
      TIA10.28 (0.01–5.32).40NANA
      MI31.43 (0.82–2.49).21FEI2=27%, p=.25
      Stroke vs. TIAStroke91.43 (1.20–1.71)<.001FEI2=0%, p=.72
      Death81.87 (1.35–2.61)<.001FEI2=0%, p=.85
      TIA20.33 (0.02–6.57).47NANA
      MI40.73 (0.49–1.09).13FEI2=0%, p=.72
      Stroke vs. AFStroke42.80 (1.92–4.09)<.001FEI2=0%, p=.85
      Death43.72 (1.95–7.12)<.001FEI2=0%, p = .39
      TIA1NANANANA
      MI31.05 (0.56–1.97).88FEI2=0%, p=.80
      TIA vs. AFStroke41.94 (1.33–2.83).001FEI2=0%, p=.97
      Death42.11 (1.08–4.11).03FEI2=0%, p=.66
      TIA1NANANANA
      MI31.51 (0.82–2.77).19FEI2=0%, p=.91
      OR = odds ratio; CI = confidence interval; FE = fixed effect; TIA = transient ischaemic attack; AF = amaurosis fugax; MI = myocardial infarction; NA = not applicable.
      Patients whose index event was stroke had an increased risk of peri-operative stroke and death vs. those whose index event was TIA (OR 1.43, 95% CI 1.2–1.71 [p < .001]; OR 1.87, 95% CI 1.35–2.61 [p < .001], respectively). Patients whose index event was stroke had an increased risk of peri-operative stroke and death compared with those whose index event was amaurosis fugax (OR 2.8, 95% CI 1.92–4.09 [p < .001]; OR 3.72, 95% CI 1.95–7.12 [p < .001], respectively).
      Patients whose index event was TIA had an increased risk of peri-operative stroke compared with asymptomatic patients (OR 0.54, 95% CI 0.46–0.64; p < .001). Patients whose index event was TIA had an increased risk of peri-operative stroke and death compared with those whose index event was amaurosis fugax (OR 1.94, 95% CI 1.33–2.83 [p < .001]; OR 2.11, 95% CI 1.08–4.11 [p = .03], respectively).

      Discussion

      The beneficial effects of CEA on stroke prevention in patients with symptomatic carotid stenosis have been well documented. It has been reported that symptomatic patients have higher 30 day rates of stroke and death than asymptomatic patients. Within the symptomatic group of patients, those suffering a pre-operative stroke are thought to be at higher risk of post-operative complications,
      • 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.
      ,
      • Halm E.A.
      • Tuhrim S.
      • Wang J.J.
      • Rockman C.
      • Riles T.S.
      • Chassin M.R.
      Risk factors for perioperative death and stroke after carotid endarterectomy: results of the New York carotid artery surgery study.
      ,
      • Bekelis K.
      • Bakhoum S.F.
      • Desai A.
      • Mackenzie T.A.
      • Goodney P.
      • Labropoulos N.
      A risk factor-based predictive model of outcomes in carotid endarterectomy: the national surgical quality improvement program 2005-2010.
      ,
      • 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.
      ,
      • Pothof A.B.
      • Zwanenburg E.S.
      • Deery S.E.
      • O'Donnell T.F.X.
      • de Borst G.J.
      • Schermerhorn M.L.
      An update on the incidence of perioperative outcomes after carotid endarterectomy, stratified by type of preprocedural neurologic symptom.
      with some believing this is related to plaque morphology, in that those with more severe pre-operative symptoms have a more vulnerable plaque.
      • Howard D.P.J.
      • Van Lammeren G.W.
      • Redgrave J.N.
      • Moll F.L.
      • De Vries J.P.P.M.
      • De Kleijn D.P.V.
      • et al.
      Histological features of carotid plaque in patients with ocular ischemia versus cerebral events.
      ,
      • Howard D.P.J.
      • Van Lammeren G.W.
      • Rothwell P.M.
      • Redgrave J.N.
      • Moll F.L.
      • De Vries J.P.P.M.
      • et al.
      Symptomatic carotid atherosclerotic disease: correlations between plaque composition and ipsilateral stroke risk.
      This meta-analysis confirms previous findings that symptomatic patients have a significantly higher rate of peri-operative stroke, death and TIA compared with asymptomatic patients. However, the incidence of MI was not significantly different between the two groups. Subgroup analysis revealed that within the symptomatic group, those presenting with a worse pre-procedural symptom had significantly worse outcomes with regard to 30 day stroke and death rates. Those presenting with a stroke had significantly higher 30 day stroke and death rates compared with those presenting with TIA or amaurosis fugax.
      The results presented here are in line with those reported in CREST,
      • Silver F.L.
      • Mackey A.
      • Clark W.M.
      • Brooks W.
      • Timaran C.H.
      • Chiu D.
      • et al.
      Safety of stenting and endarterectomy by symptomatic status in the carotid revascularization endarterectomy versus stenting trial (CREST).
      which reports 30 day stroke rates of 3.2% and 1.4% in symptomatic and asymptomatic patients, respectively. While slightly higher, these figures are also consistent with those reported by the Society for Vascular Surgery registry.
      • Sidawy A.N.
      • Zwolak R.M.
      • White R.A.
      • Siami F.S.
      • Schermerhorn M.L.
      • Sicard G.A.
      Risk-adjusted 30-day outcomes of carotid stenting and endarterectomy: results from the SVS Vascular Registry.
      Halm et al.
      • Halm E.A.
      • Tuhrim S.
      • Wang J.J.
      • Rockman C.
      • Riles T.S.
      • Chassin M.R.
      Risk factors for perioperative death and stroke after carotid endarterectomy: results of the New York carotid artery surgery study.
      reported 30 day stroke rates of 2.4% and 1.3% in symptomatic and asymptomatic patients, respectively. The largest paper in the present review reported on data from the United States National Surgical Quality Improvement Program.
      • Bekelis K.
      • Bakhoum S.F.
      • Desai A.
      • Mackenzie T.A.
      • Goodney P.
      • Labropoulos N.
      A risk factor-based predictive model of outcomes in carotid endarterectomy: the national surgical quality improvement program 2005-2010.
      Some 35 698 patients were included, with 15 683 being symptomatic. Bekelis et al.
      • Bekelis K.
      • Bakhoum S.F.
      • Desai A.
      • Mackenzie T.A.
      • Goodney P.
      • Labropoulos N.
      A risk factor-based predictive model of outcomes in carotid endarterectomy: the national surgical quality improvement program 2005-2010.
      reported 30 day stroke rates of 2.3% and 1.1% for symptomatic and asymptomatic patients, respectively (OR 0.47, 95% CI 0.37–0.55). The 30 day death rate was 1.04% and 0.52% for symptomatic and asymptomatic patients, respectively (OR 0.5, 95% CI 0.39–0.64).
      This meta-analysis confirms earlier findings that symptomatic patients have worse peri-operative outcomes in terms of stroke and death but not for MI. More interestingly, it confirms that those patients presenting with worse neurology have worse outcomes.
      While these findings should be taken into consideration when consenting patients who have suffered a pre-procedural stroke, the findings alone are not sufficient to alter current clinical practice. Further work needs to be conducted focusing on why these patients have an increased risk of stroke.
      Before looking specifically at why patients with symptomatic carotid disease have an increased peri-operative risk of stroke and whether there is any way of identifying high risk patients, the aetiology of the peri-operative stroke needs to be determined. Are they haemorrhagic or infarcts, and, if the latter, do they occur in the middle cerebral artery (MCA) territory? If they do occur in the distribution of the MCA, then it is fair to assume that these could be thrombo-embolic events from the ruptured plaque. However, this needs to be addressed through both histological and neuro-imaging studies. Are endarterectomised plaques from patients who have suffered a pre-procedural stroke more advanced and unstable, as assessed histologically, than to those with pre-procedural TIA or amaurosis fugax?
      • Howard D.P.J.
      • Van Lammeren G.W.
      • Redgrave J.N.
      • Moll F.L.
      • De Vries J.P.P.M.
      • De Kleijn D.P.V.
      • et al.
      Histological features of carotid plaque in patients with ocular ischemia versus cerebral events.
      ,
      • Howard D.P.J.
      • Van Lammeren G.W.
      • Rothwell P.M.
      • Redgrave J.N.
      • Moll F.L.
      • De Vries J.P.P.M.
      • et al.
      Symptomatic carotid atherosclerotic disease: correlations between plaque composition and ipsilateral stroke risk.
      It may be more pertinent to look at the thrombus load, specifically on the surface of the ruptured plaque. This is sometimes difficult to quantify accurately, as the majority of this thrombus can be removed intra-operatively. Neuro-imaging would be best to achieve this, and, if proven, would almost certainly have implications regarding the peri-operative management in relation to antiplatelet therapy or heparin use.
      Whether peri-operative stroke can be attributed to hypoperfusion also needs to be addressed by ascertaining whether the use of shunts has any bearing and if the presence/absence of contralateral disease has any effect. With regard to the index event, the degree of cerebral ischaemia caused depends not only on the size of the emboli, but also on the extent and timing of subsequent reperfusion, the extent and distribution of collaterals, and autoregulatory capacity. Does clamping of the internal carotid artery and variations in blood pressure during CEA worsen the existing ischaemic insult in patients with poor cerebral autoregulation/collateralisation? Could this be potentiated if CEA is performed too early after the index event, before the cerebral circulation has had time to adapt?
      When in the peri-operative period strokes are more likely to occur also needs to be studied, as does the timing of the CEA. Studies exploring the risks of performing very urgent CEA, that is, within 48 h, have provided conflicting results. Some have reported no increased risks,
      • Sharpe R.
      • Sayers R.D.
      • London N.J.M.
      • Bown M.J.
      • McCarthy M.J.
      • Nasim A.
      • et al.
      Procedural risk following carotid endarterectomy in the hyperacute period after onset of symptoms.
      • Rantner B.
      • Schmidauer C.
      • Knoflach M.
      • Fraedrich G.
      Very urgent carotid endarterectomy does not increase the procedural risk.
      • Tsantilas P.
      • Kühnl A.
      • Kallmayer M.
      • Pelisek J.
      • Poppert H.
      • Schmid S.
      • et al.
      A short time interval between the neurologic index event and carotid endarterectomy is not a risk factor for carotid surgery.
      while others have reported increased risks.
      • Strömberg S.
      • Gelin J.
      • Österberg T.
      • Bergström G.M.L.
      • Karlström L.
      • Österberg K.
      Very urgent carotid endarterectomy confers increased procedural risk.
      • Nordanstig A.
      • Rosengren L.
      • Strömberg S.
      • Österberg K.
      • Karlsson L.
      • Bergström G.
      • et al.
      Editor's Choice – very urgent carotid endarterectomy is associated with an increased procedural risk: the carotid alarm study.
      • Milgrom D.
      • Hajibandeh S.
      • 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.
      A review by De Rango et al.
      • De Rango P.
      • Brown M.M.
      • Chaturvedi S.
      • Howard V.J.
      • Jovin T.
      • Mazya M.V.
      • et al.
      Summary of evidence on early carotid intervention for recently symptomatic stenosis based on meta-analysis of current risks.
      in 2015 concluded that there was insufficient evidence regarding early CEA and further randomised trials needed to be conducted to confer optimal timing. This should also specifically look at pre-procedural symptoms.
      Finally, the impact of comorbidities and medications, specifically antiplatelet agents, needs to be considered. Is it simply that these patients have more advanced atherosclerotic disease and hence generally higher risks of thrombo-embolic events? Does the choice and dose of antiplatelet agent have any impact on stroke risk? Are those who suffer a stroke while on an antiplatelet agent at more risk of further events? If the above can be addressed in future research, then there is potential to develop a scoring system to identify the more at risk patients. It may be possible to incorporate these data into risk prediction models that are currently used. However, this risk needs to be balanced against the patient's risk of stroke with medical management alone. If it is proven that stroke patients are at a slightly higher risk of peri-operative stroke, then provided this risk remains significantly lower than that risk with medical therapy alone, then CEA should still be offered. In light of improved medical care and greater public awareness/involvement with their own health care, the data regarding medical management of symptomatic carotid disease ought to be updated.
      The results of the present meta-analysis need to be interpreted in the context of limitations. Most studies included in the quantitative synthesis were observational cohort studies, some of a retrospective design, with a few being registries applying retrospective analysis of administrative datasets. Furthermore, the external validity of the results and transfer into contemporary practice is limited by the fact that the studies were published over a wide period spanning 1977 to 2018, reflecting varying clinical practices and peri-operative management over the years. An attempt was made to investigate potential heterogeneity resulting from evolving medical, anaesthetic, and surgical practices by performing a meta-regression analysis, which found an attenuation of differences in peri-operative outcomes of stroke and death between symptomatic and asymptomatic cases over the years. The studies were conducted in different countries, mostly across the Western world, reflecting different clinical settings, which introduces conceptual heterogeneity across the populations included in meta-analysis. Potential confounders, such as timing of surgery and demographics including age and sex, were not accounted for in the analysis. Lastly, even though a rigorous search strategy was applied to identify relevant reports, some studies may have escaped consideration.

      Conclusion

      Patients who undergo CEA after a stroke are at increased risk of peri-operative stroke and death, and this should be addressed when consenting such patients. This study highlights that further research needs to be conducted to ascertain the reasons for this increased risk so that preventative measures, if possible, can be put in place or indeed whether this risk remains acceptable vs. best medical therapy.

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      Linked Article

      • Should We Be (Even More) Restrictive in Selecting Patients for Carotid Endarterectomy?
        European Journal of Vascular and Endovascular SurgeryVol. 59Issue 4
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          The selection of patients for carotid endarterectomy (CEA) is one of the vascular surgeon's most delicate tasks. Although one knows that some patients will suffer a disabling stroke or die in the attempt to prevent these events, it is equally devastating when it happens. Thus, the solid evidence of the 1990s on the benefit of the procedure in patients with a significant symptomatic stenosis was welcomed.1,2 Even more welcomed were (and are) those studies further increasing the subgroups of patients who benefit the most, leading to well established evidence based guidelines.
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