Eur J Vasc Endovasc Surg (xxxx) xxx, xxx

SYSTEMATIC REVIEW

Prognostic Role of Pre-Operative Symptom Status in Carotid

Endarterectomy: A Systematic Review and Meta-Analysis
a,b,*
Stephen Ball , Alexandra Ball a, George A. Antoniou a,b

a
Department of Vascular and Endovascular Surgery, The Royal Oldham Hospital, Pennine Acute Hospitals NHS Trust, Manchester, UK
b
Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, UK

WHAT THIS PAPER ADDS

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.

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 0.45e0.54; p < .001) and death (OR 0.66, 95%
CI 0.57e0.77; p < .001) than symptomatic patients, but the risk of myocardial infarction was not significantly
different (OR 0.98, 95% CI 0.84e1.15; p ¼ .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: Amaurosis fugax, Asymptomatic, Carotid endarterectomy, Peri-operative, Stroke, Transient ischaemic attack
Article history: Received 25 July 2019, Accepted 16 January 2020, Available online XXX
Ó 2020 European Society for Vascular Surgery. Published by Elsevier B.V. All rights reserved.

INTRODUCTION within two weeks. Patients with 70%e99% stenosis have an

Current European Society for Vascular Surgery (ESVS)
guidelines recommend carotid endarterectomy (CEA) for
symptomatic severe carotid stenosis.1 To confer maximum
benefit, CEA should be performed as soon as possible
following symptoms of cerebral ischaemia, and certainly
* Corresponding author. Division of Cardiovascular Sciences, School of
Medical Sciences, University of Manchester, Manchester, M13 9PL, UK.
E-mail address: steball@doctors.org.uk (Stephen Ball).
1078-5884/Ó 2020 European Society for Vascular Surgery. Published by
Elsevier B.V. All rights reserved.
https://doi.org/10.1016/j.ejvs.2020.01.022
absolute risk reduction of 23% when CEA is performed
within two weeks.2e5
For patients with asymptomatic disease, the ESVS rec-
ommends that CEA should be considered in the “average
surgical risk” patient with a 60%e99% 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%e
2%.6,7 Therefore, in these patients, the benefit of

Please cite this article as: Ball S et al., Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis,
European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2020.01.022
2 Stephen Ball et al.
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.2
The operative mortality rate for CEA in symptomatic
patients is <1%. The peri-operative risk of stroke is reported
to be around 2%e3%.8 Much of the data concerning out-
comes post CEA quote a 30 day end point of stroke/death.
The first major trials, the European Carotid Surgery Trial
(ECST)3 and the North American Symptomatic Carotid
Endarterectomy Trial (NASCET),5 reported a 30 day stroke
risk of 6%e8%, but more recent trials, such as the Inter-
national Carotid Stenting Study (ICSS)9 and Carotid Revas-
cularisation Endarterectomy vs. Stenting Trial (CREST),8
have shown a decrease in the stroke risk to 3%e5%. The
risk of peri-operative myocardial infarction (MI) is quoted as
0.5%e1%; 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%e9%) and wound complications (3%).
With regard to asymptomatic patients, their 30 day
outcomes are significantly better with the risk of stroke
being 1%e2%, death 0.5%e1%, and MI 1%.4,5 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 quali-
fying 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 sys-
tematic 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 Sys-
tematic reviews and Meta-Analyses (PRISMA) guidelines.10
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 out-
comes of CEA in these two well defined groups of patients.
Studies explicitly reporting that they included patients who
Please cite this article as: Ball S et al., Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis,
European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2020.01.022
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 e present), Embase
(1980 e 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 ar-
ticles 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 devel-
oped 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 characteris-
tics, 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.11
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 heteroge-
neity (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%e40% might not be important; 30%e60% may
Role of Symptom Status in Carotid Endarterectomy 3

represent moderate heterogeneity; 50%e90% may repre-
sent substantial heterogeneity; and 75%e100% may
represent considerable heterogeneity.12
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. 1.13e30
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
Identification
validity of the studies was considered good based on the
majority of studies achieving a rating of seven, based on the
NewcastleeOttawa Scale.
Synthesis of results and outcome
Symptomatic vs. asymptomatic. The forest and scatter
plots for the outcome parameters are presented in Figs 2
and 3, 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 0.45e0.54; p < .001). Moderate hetero-
geneity amongst the studies was identified (I2 ¼ 55%). The
likelihood of publication bias was low (p ¼ .46). The dif-
ference in peri-operative stroke between symptomatic and
asymptomatic patients has decreased over the years
(p ¼ .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 0.57e0.77; p < .001). Moderate hetero-
geneity among the studies was identified (I2 ¼ 40%). The
likelihood of publication bias was low (p ¼ .24). The dif-
ference in peri-operative death between symptomatic and
asymptomatic patients has decreased over the years
(p ¼ .002).
TIA. Four studies reported peri-operative or 30 day out-
comes for TIA. The crude TIA rate was 0.9% in the symp-
tomatic group and 0.4% in the asymptomatic group (OR

Records identified through Additional records identified

database searching through other sources
n = 1 173 n=2
Screening

Records screened Records excluded

n = 1 175 n = 1 156
Eligibility

Second level manual Full text articles assessed for Full text articles
search of reference lists eligibility excluded, with reasons
n=3 n = 22 n=4
Included

Studies included in quantative

synthesis (meta-analysis)
n = 18

Figure 1. Literature search strategy to identify studies reporting on peri-operative outcomes following
carotid endarterectomy for both symptomatic and asymptomatic patients.

Please cite this article as: Ball S et al., Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis,
European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2020.01.022
4 Stephen Ball et al.

Table 1. Characteristics of the individual studies included in the meta-analysis for prognostic role of pre-operative symptom status
in carotid endarterectomy (CEA)

First Year Recruitment NOS Type No. of No. CEAs Asymptomatic Symptomatic Stroke TIA AF
author period patients
Easton13 1977 1970e76 7 Cohort 228 228 56 140 83 57 NR
Fode14 1986 1981 7 Cohort 3129 3129 908 2221 477 1283 461
Healy15 1989 1980e87 7 Cohort 200 200 77 123 36 87 NR
Burns16 1991 NR 7 Cohort 234 234 104 130 42 88 NR
Goldstein17 1994 1987e90 6 Cohort 1160 1160 463 697 188 509 NR
Hertzer18 1997 1989e95 Registry 2046 2228 1401 827 261 NR NR
Tu19 2003 1994e97 7 Registry 6038 6038 1846 4192 NR NR NR
Coppi20 2005 NR 6 Cohort 488 488 343 145 NR NR NR
Flanigan21 2007 April 1999e 8 Cohort 391 442 272 170 NR NR NR
June 2005
Feasby22 2007 2000e01 6 Cohort 3283 3283 1252 2031 NR NR NR
Halm23 2009 January 2008e 8 Cohort 9308 9308 6653 2655 877 1778 NR
June 2009
Sidawy24 2009 2005e07 7 Registry 3259 1368 862 506 NR NR NR
Brott25 2010 2000e08 7 RCT NR 1240 584 656 NR NR NR
Bekelis26 2013 2005e10 8 Cohort 35 698 35 698 20 015 15 683 NR NR NR
Faggioli27 2013 2006e10 7 Cohort 610 610 448 162 72 81 9
Geraghty28 2014 2004e11 7 Registry 5758 5758 3949 1809 611 878 320
Brothers29 2015 2005e11 7 Registry 3977 3977 2521 1456 NR NR NR
Pothof30 2018 2011e15 7 Cohort 16 739 16 739 9784 6955 3104 2635 1216
NOS ¼ Newcastle Ottawa Scale; TIA ¼ transient ischaemic attack; AF ¼ amaurosis fugax; NR ¼ not recorded; RCT ¼ randomised controlled trial.

0.41, 95% CI 0.21e0.80; p ¼ .01). No significant heteroge-
neity among the studies was identified (I2 ¼ 30%).
MI. Nine studies reported peri-operative or 30 day out-
comes for MI. The crude MI rate was 0.9% in both the
symptomatic asymptomatic groups (OR 0.98, 95% CI 0.84e
1.15; p ¼ .82). Moderate heterogeneity among the studies
was identified (I2 ¼ 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 0.31e0.42;
p < .001) and death (OR 0.45, 95% CI 0.34e0.59; p < .001).
Patients whose index event was stroke had an increased
risk of peri-operative stroke and death vs. those whose in-
dex event was TIA (OR 1.43, 95% CI 1.2e1.71 [p < .001]; OR
1.87, 95% CI 1.35e2.61 [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 1.92e4.09
[p < .001]; OR 3.72, 95% CI 1.95e7.12 [p < .001],
respectively).
Patients whose index event was TIA had an increased risk
of peri-operative stroke compared with asymptomatic pa-
tients (OR 0.54, 95% CI 0.46e0.64; 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 1.33e
Please cite this article as: Ball S et al., Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis,
European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2020.01.022
2.83 [p < .001]; OR 2.11, 95% CI 1.08e4.11 [p ¼ .03],
respectively).
DISCUSSION
The beneficial effects of CEA on stroke prevention in pa-
tients with symptomatic carotid stenosis have been well
documented. It has been reported that symptomatic pa-
tients 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,19,23,26,28,30 with some believing this is
related to plaque morphology, in that those with more
severe pre-operative symptoms have a more vulnerable
plaque.31,32
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. Sub-
group 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,8 which reports 30 day stroke rates of 3.2% and
1.4% in symptomatic and asymptomatic patients, respec-
tively. While slightly higher, these figures are also consistent
with those reported by the Society for Vascular Surgery
Role of Symptom Status in Carotid Endarterectomy 5

A Asymptomatic Symptomatic Odds Ratio Odds Ratio

Study or Subgroup Events Total Events Total M-H, Fixed , 95% CI M-H, Fixed, 95% CI Weight
Easton 1977 5 56 19 140 0.62 [0.22, 1.76] 0.7%
Fode 1986 36 908 98 2221 0.89 [0.61, 1.32] 4.1%
Healy1989 1 77 3 123 0.53 [0.05, 5.15] 0.2%
Burns 1991 4 104 8 130 0.61 [0.18, 2.08] 0.5%
Goldstein 1994 10 463 40 697 0.36 [0.18, 0.73] 2.3%
Hertzer 1997 22 1401 26 827 0.49 [0.28, 0.87] 2.4%
Tu 2003 61 1846 213 4192 0.64 [0.48, 0.85] 9.5%
Coppi 2005 2 343 1 145 0.84 [0.08, 9.39] 0.1%
Flanigan 2007 1 272 1 170 0.62 [0.04, 10.04] 0.1%
Feasby 2007 26 1252 73 2031 0.57 [0.36, 0.90] 4.1%
Halm 2009 165 6653 140 2655 0.46 [0.36, 0.57] 14.7%
Sidawy 2009 11 862 12 506 0.53 [0.23, 1.21] 1.1%
Brott 2010 21 656 8 584 2.38 [1.05, 5.42] 0.6%
Bekelis 2013 220 20015 365 15683 0.47 [0.39, 0.55] 30.4%
Faggioli 2013 3 448 7 162 0.15 [0.04, 0.58] 0.8%
Geraghty 2014 64 3949 62 1809 0.46 [0.33, 0.66] 6.3%
Brothers 2015 20 2521 40 1456 0.28 [0.16, 0.49] 3.8%
Pothof 2018 125 9784 211 6955 0.41 [0.33, 0.52] 18.3%
Total (95% CI) 797 51610 1327 40486 0.50 [0.45, 0.54] 100.0%
Heterogeneity: Chi2 = 38.13, df = 17 (p = .002); I2 = 55%
Test for overall effect: Z = 14.94 (p < .00001) 0.01 0.1 1 10 100
Favours asymptomatic Favours symptomatic
B
Asymptomatic Symptomatic Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total M-H, Fixed , 95% CI M-H, Fixed, 95% CI Weight
Easton 1977 2 56 13 140 0.36 [0.08, 1.66] 1.7%
Fode 1986 23 908 41 2221 1.38 [0.82, 2.32] 5.5%
Healy1989 0 77 1 123 0.53 [0.02, 13.10] 0.3%
Burns 1991 1 104 2 130 0.62 [0.06, 6.95] 0.4%
Goldstein 1994 5 463 11 697 0.68 [0.23, 1.97] 2.1%
Hertzer 1997 13 1401 12 827 0.64 [0.29, 1.40] 3.6%
Tu 2003 30 1846 63 4192 1.08 [0.70, 1.68] 9.1%
Coppi 2005 0 343 0 145 Not estimable
Feasby 2007 10 1252 18 2031 0.90 [0.41, 1.96] 3.3%
Flanigan 2007 0 272 0 170 Not estimable
Sidawy 2009 6 862 4 506 0.88 [0.25, 3.13] 1.2%
Bekelis 2013 104 20015 163 15683 0.50 [0.39, 0.64] 43.4%
Faggioli 2013 3 448 0 162 2.55 [0.13, 49.70] 0.2%
Geraghty 2014 30 3949 18 1809 0.76 [0.42, 1.37] 5.9%
Brothers 2015 8 2521 6 1456 0.77 [0.27, 2.22] 1.8%
Pothof 2018 60 9784 78 6955 0.54 [0.39, 0.76] 21.6%
Total (95% CI) 295 44301 430 37247 0.66 [0.57, 0.77] 100.0%
Heterogeneity: Chi2 = 21.62, df = 13 (p = .06); I2 = 40%
Test for overall effect: Z = 5.41 (p < .00001) 0.01 0.1 1 10 100
Favours asymptomatic Favours symptomatic
C
Asymptomatic Symptomatic Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total M-H, Fixed , 95% CI M-H, Fixed, 95% CI Weight
Healy 1989 1 77 3 123 0.53 [0.05, 5.15] 8.9%
Sidawy 2009 4 862 7 506 0.33 [0.10, 1.14] 34.2%
Faggioli 2013 6 448 0 162 4.77 [0.27, 85.22] 2.8%
Brothers 2015 4 2521 11 1456 0.21 [0.07, 0.66] 54.2%
Total (95% CI) 15 3908 21 2247 0.41 [0.21, 0.80] 100.0%
Heterogeneity: Chi2 = 4.26, df = 3 (p = .23); I2 = 30%
Test for overall effect: Z = 2.59 (p = .010) 0.01 0.1 1 10 100
Favours asymptomatic Favours symptomatic
D
Asymptomatic Symptomatic Odds Ratio Odds Ratio
Study or Subgroup Events Total Events Total M-H, Fixed , 95% CI M-H, Fixed, 95% CI Weight
Goldstein 1994 11 463 22 463 0.49 [0.23, 1.02] 6.9%
Flanigan 2007 1 272 0 170 1.88 [0.08, 46.51] 0.2%
Feasby 2007 23 1252 18 2031 2.09 [1.12, 3.89] 4.3%
Sidawy 2009 5 862 3 506 0.98 [0.23, 4.11] 1.2%
Bekelis 2013 125 20015 122 15683 0.80 [0.62, 1.03] 43.8%
Faggioli 2013 2 448 4 162 0.18 [0.03, 0.98] 1.9%
Geraghty 2014 49 3949 22 1809 1.02 [0.62, 1.69] 9.6%
Brothers 2015 27 2521 14 1456 1.12 [0.58, 2.13] 5.7%
Pothof 2018 123 9784 71 6955 1.23 [0.92, 1.66] 26.4%
Total (95% CI) 366 39566 276 29235 0.98 [0.84, 1.15] 100.0%
Heterogeneity: Chi2 = 18.23, df = 8 (p = .02); I2 = 56%
Test for overall effect: Z = 0.23 (p = .82) 0.01 0.1 1 10 100
Favours asymptomatic Favours symptomatic

Figure 2. Forest plots of peri-operative outcomes 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.
MH ¼ ManteleHaenszel.

Please cite this article as: Ball S et al., Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis,
European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2020.01.022
6 Stephen Ball et al.

A
1.00
0.70
0.40

Log odds ratio

0.10
–0.20
–0.50
–0.80
–1.10
–1.40
–1.70
–2.00
1972 1977 1982 1987 1992 1997 2002 2007 2012 2017 2022
Year
B
1.00
0.70
0.40
Log odds ratio

0.10
–0.20
–0.50
–0.80
–1.10
–1.40
–1.70
–2.00
1972 1977 1982 1987 1992 1997 2002 2007 2012 2017 2022
Year

Figure 3. Scatter plots of log odds ratio for (A) stroke and (B) death following carotid endar-
terectomy 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 indi-
vidual 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 ¼ .021 and p ¼ .002, respectively).

registry.24 Halm et al.23 reported 30 day stroke rates of 2.4%
and 1.3% in symptomatic and asymptomatic patients,
respectively. The largest paper in the present review re-
ported on data from the United States National Surgical
Quality Improvement Program.26 Some 35 698 patients
were included, with 15 683 being symptomatic. Bekelis
et al.26 reported 30 day stroke rates of 2.3% and 1.1% for
symptomatic and asymptomatic patients, respectively (OR
0.47, 95% CI 0.37e0.55). The 30 day death rate was 1.04%
and 0.52% for symptomatic and asymptomatic patients,
respectively (OR 0.5, 95% CI 0.39e0.64).
This meta-analysis confirms earlier findings that symp-
tomatic patients have worse peri-operative outcomes in
terms of stroke and death but not for MI. More interest-
ingly, 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 symp-
tomatic 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 pa-
tients who have suffered a pre-procedural stroke more
advanced and unstable, as assessed histologically, than to
those with pre-procedural TIA or amaurosis fugax?31,32 It
may be more pertinent to look at the thrombus load, spe-
cifically 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-

Please cite this article as: Ball S et al., Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis,
European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2020.01.022
Role of Symptom Status in Carotid Endarterectomy 7

Table 2. Outcome following subgroup analysis dependent on pre-operative symptom prior to carotid endarterectomy

Comparison Outcome No. of studies OR (95% CI) p value Model Heterogeneity

Asymptomatic Stroke 10 0.36 (0.31e0.42) <.001 FE I2¼18%, p¼.28
vs. stroke
Death 9 0.45 (0.34e0.59) <.001 FE I2¼0%, p¼.85
TIA 2 1.82 (0.21 .58 FE I2¼0%, p¼.86
e15.46)
MI 4 1.26 (0.90e1.78) .18 FE I2¼0%, p¼.46
Asymptomatic Stroke 9 0.54 (0.46e0.64) <.001 FE I2¼20%, p¼.27
vs. TIA
Death 8 0.91 (0.66e1.25) .56 FE I2¼0%, p¼.49
TIA 2 0.84 (0.18e3.78) .82 FE I2¼0%, p¼.32
MI 4 0.88 (0.65e1.17) .37 FE I2¼48%, p¼.12
Asymptomatic Stroke 4 1.12 (0.77e1.63) .55 FE I2¼19%, p¼.29
vs. AF
Death 4 1.84 (0.99e3.42) .06 FE I2¼54%, p¼.09
TIA 1 0.28 (0.01e5.32) .40 NA NA
MI 3 1.43 (0.82e2.49) .21 FE I2¼27%, p¼.25
Stroke vs. TIA Stroke 9 1.43 (1.20e1.71) <.001 FE I2¼0%, p¼.72
Death 8 1.87 (1.35e2.61) <.001 FE I2¼0%, p¼.85
TIA 2 0.33 (0.02e6.57) .47 NA NA
MI 4 0.73 (0.49e1.09) .13 FE I2¼0%, p¼.72
Stroke vs. AF Stroke 4 2.80 (1.92e4.09) <.001 FE I2¼0%, p¼.85
Death 4 3.72 (1.95e7.12) <.001 FE I2¼0%, p ¼ .39
TIA 1 NA NA NA NA
MI 3 1.05 (0.56e1.97) .88 FE I2¼0%, p¼.80
TIA vs. AF Stroke 4 1.94 (1.33e2.83) .001 FE I2¼0%, p¼.97
Death 4 2.11 (1.08e4.11) .03 FE I2¼0%, p¼.66
TIA 1 NA NA NA NA
MI 3 1.51 (0.82e2.77) .19 FE I2¼0%, p¼.91
OR ¼ odds ratio; CI ¼ confidence interval; FE ¼ fixed effect; TIA ¼ transient ischaemic attack; MI ¼ myocardial infarction; NA ¼ not applicable.

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 ca-
rotid 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,33e35 while others
have reported increased risks.36e38 A review by De Rango
et al.39 in 2015 concluded that there was insufficient evi-
dence 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 athero-
sclerotic 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 aware-
ness/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

Please cite this article as: Ball S et al., Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis,
European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2020.01.022
8 Stephen Ball et al.
being registries applying retrospective analysis of adminis-
trative 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 con-
ceptual 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 high-
lights that further research needs to be conducted to
ascertain the reasons for this increased risk so that pre-
ventative measures, if possible, can be put in place or
indeed whether this risk remains acceptable vs. best med-
ical therapy.
REFERENCES
1 Naylor AR, Ricco JB, de Borst GJ, Debus S, de Haro J, Halliday A,
et al. Management of atherosclerotic carotid and vertebral artery
disease: 2017 Clinical Practice Guidelines of the ESVS. Eur J Vasc
Endovasc Surg 2018;55:3e81.
2 Moore WS, Boren C, Malone JM, Roon AJ, Eisenberg R,
Goldstone J, et al. Natural history of nonstenotic, asymptomatic
ulcerative lesions of the carotid artery. Arch Surg 1978;113:1352e
9.
3 Warlow C. MRC European Carotid Surgery Trial: interim results
for symptomatic patients with severe (70e99%) or with mild (0e
29%) carotid stenosis. Lancet 1991;337:1235e43.
4 Warlow C, Farrell B, Fraser A, Sandercock P, Slattery J. Rando-
mised trial of endarterectomy for recently symptomatic carotid
stenosis: final results of the MRC European Carotid Surgery Trial
(ECST). Lancet 1998;351:1379e87.
5 North American Symptomatic Carotid Endarterectomy Trial Col-
laborators, Barnett HJM, Taylor DW, Haynes RB, Sackett DL,
Peerless SJ, et al. Beneficial effect of carotid endarterectomy in
symptomatic patients with high-grade carotid stenosis. N Engl J
Med 1991;325:445e53.
6 Halliday A. Prevention of disabling and fatal strokes by successful
carotid endarterectomy in patients without recent neurological
symptoms. Lancet 2004;363:1491e502.
7 Moneta GL, Taylor DC, Nicholls SC, Bergelin RO, Zierler RE,
Kazmers A, et al. Operative versus nonoperative management of
asymptomatic high-grade internal carotid artery stenosis:
improved results with endarterectomy. Stroke 1987;18:1005e10.
8 Silver FL, Mackey A, Clark WM, Brooks W, Timaran CH, Chiu D,
et al. Safety of stenting and endarterectomy by symptomatic status
Please cite this article as: Ball S et al., Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis,
European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2020.01.022
in the carotid revascularization endarterectomy versus stenting
trial (CREST). Stroke 2011;42:675e80.
9 International Carotid Stenting Study Investigators, Ederle J,
Dobson J, Featherstone RL, Bonati LH, van der Worp HB, de
Borst GJ, et al. Carotid artery stenting compared with endarter-
ectomy in patients with symptomatic carotid stenosis (Interna-
tional Carotid Stenting Study): an interim analysis of a
randomised controlled trial. Lancet 2010;375:985e97.
10 Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC,
Ioannidis JPA, et al. The PRISMA statement for reporting sys-
tematic reviews and meta-analyses of studies that evaluate health
care interventions: explanation and elaboration. J Clin Epidemiol
2009;62:e1e34.
11 Wells G, Shea B, O’Connell D, Peterson J. The Newcastle-Ottawa
Scale (NOS) for assessing the quality of nonrandomised studies in
meta-analyses. Available at: http://www.ohri.ca/programs/
clinical_epidemiology/oxford.asp. [Accessed 16 January 2020].
12 Higgins J, Green S. Cochrane handbook for systematic reviews of
interventions version 5.1.0. Available at: https://training.cochrane.
org/handbook. [Accessed 16 January 2020].
13 Easton JD, Sherman DG. Stroke and mortality rate in carotid
endarterectomy: 228 consecutive operations. Stroke 1977;8:565e
8.
14 Fode NC, Sundt TM, Robertson JT, Peerless SJ, Shields CB.
Multicenter retrospective review of results and complications of
carotid endarterectomy in 1981. Stroke 1986;17:370e6.
15 Healy DA, Clowes AW, Zierler RE, Nicholls SC, Bergelin RO,
Primozich JF, et al. Immediate and long-term results of carotid
endarterectomy. Stroke 1989;20:1138e42.
16 Burns RJ, Willoughby JO. South Australian carotid endarterec-
tomy study. Med J Aust 1991;154:650e3.
17 Goldstein LB, McCrory DC, Landsman PB, Samsa GP,
Ancukiewicz M, Oddone EZ, et al. Multicenter review of preop-
erative risk factors for carotid endarterectomy in patients with
ipsilateral symptoms. Stroke 1994;25:1116e21.
18 Hertzer NR, O’Hara PJ, Mascha EJ, Krajewski LP, Sullivan TM,
Beven EG. Early outcome assessment for 2228 consecutive carotid
endarterectomy procedures: the Cleveland Clinic experience from
1989 to 1995. J Vasc Surg 1997;26:1e10.
19 Tu JV, 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. Stroke
2003;34:2568e73.
20 Coppi G, Moratto R, Ragazzi G, Nicolosi E, Silingardi R,
Franciosi GB, et al. Comparing outcomes of carotid endarterec-
tomy with international benchmarks: audit from an Italian
vascular surgery department. Ital Hear J 2005;6:917e21.
21 Flanigan DP, Flanigan ME, Dorne AL, Harward TRS, Razavi MK,
Ballard JL. Long-term results of 442 consecutive, standardized
carotid endarterectomy procedures in standard-risk and high-risk
patients. J Vasc Surg 2007;46:876e82.
22 Feasby TE, Kennedy J, Quan H, Girard L, Ghali WA. Real-world
replication of randomized controlled trial results for carotid
endarterectomy. Arch Neurol 2007;64:1496e500.
23 Halm EA, Tuhrim S, Wang JJ, Rockman C, Riles TS, Chassin MR.
Risk factors for perioperative death and stroke after carotid end-
arterectomy: results of the New York carotid artery surgery study.
Stroke 2009;40:221e9.
24 Sidawy AN, Zwolak RM, White RA, Siami FS, Schermerhorn ML,
Sicard GA. Risk-adjusted 30-day outcomes of carotid stenting and
endarterectomy: results from the SVS Vascular Registry. J Vasc
Surg 2009;49:71e9.
25 Brott TG, Hobson RW, Howard G, Roubin GS, Clark WM,
Brooks W, et al. Stenting versus endarterectomy for treatment of
carotid-artery stenosis. N Engl J Med 2010;363:11e23.
26 Bekelis K, Bakhoum SF, Desai A, Mackenzie TA, Goodney P,
Labropoulos N. A risk factor-based predictive model of outcomes
in carotid endarterectomy: the national surgical quality
improvement program 2005-2010. Stroke 2013;44:1085e90.
Role of Symptom Status in Carotid Endarterectomy
27 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 tomog-
raphy findings. Ann Vasc Surg 2013;27:874e82.
28 Geraghty PJ, Brothers TE, Gillespie DL, Upchurch GR, Stoner MC,
Siami FS, 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.
J Vasc Surg 2014;60:639e44.
29 Brothers TE, Ricotta JJ, Gillespie DL, Geraghty PJ, Kenwood CT,
Siami FS, 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 12e16,
2013. J Vasc Surg 2015;62:923e8.
30 Pothof AB, Zwanenburg ES, Deery SE, O’Donnell TFX, de Borst GJ,
Schermerhorn ML. An update on the incidence of perioperative
outcomes after carotid endarterectomy, stratified by type of pre-
procedural neurologic symptom. J Vasc Surg 2018;67:785e92.
31 Howard DPJ, Van Lammeren GW, Redgrave JN, Moll FL, De
Vries JPPM, De Kleijn DPV, et al. Histological features of carotid
plaque in patients with ocular ischemia versus cerebral events.
Stroke 2013;44:734e9.
32 Howard DPJ, Van Lammeren GW, Rothwell PM, Redgrave JN,
Moll FL, De Vries JPPM, et al. Symptomatic carotid atherosclerotic
disease: correlations between plaque composition and ipsilateral
stroke risk. Stroke 2015;46:182e9.
33 Sharpe R, Sayers RD, London NJM, Bown MJ, McCarthy MJ,
Nasim A, et al. Procedural risk following carotid endarterectomy
Please cite this article as: Ball S et al., Prognostic Role of Pre-Operative Symptom Status in Carotid Endarterectomy: A Systematic Review and Meta-Analysis,
European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2020.01.022
9
in the hyperacute period after onset of symptoms. Eur J Vasc
Endovasc Surg 2013;46:519e24.
34 Rantner B, Schmidauer C, Knoflach M, Fraedrich G. Very urgent
carotid endarterectomy does not increase the procedural risk. Eur
J Vasc Endovasc Surg 2015;49:129e36.
35 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.
J Vasc Surg 2017;65:12e20.
36 Strömberg S, Gelin J, Österberg T, Bergström GML, Karlström L,
Österberg K. Very urgent carotid endarterectomy confers
increased procedural risk. Stroke 2012;43:1331e5.
37 Nordanstig A, Rosengren L, Strömberg S, Österberg K, Karlsson L,
Bergström G, et al. Editor’s Choice e very urgent carotid endar-
terectomy is associated with an increased procedural risk: the
carotid alarm study. Eur J Vasc Endovasc Surg 2017;54:278e86.
38 Milgrom D, Hajibandeh S, Hajibandeh S, Antoniou SA, Torella F,
Antoniou GA. Editor’s Choice e systematic review and meta-
analysis of very urgent carotid intervention for symptomatic ca-
rotid disease. Eur J Vasc Endovasc Surg 2018;56:622e31.
39 De Rango P, Brown MM, Chaturvedi S, Howard VJ, Jovin T,
Mazya MV, et al. Summary of evidence on early carotid inter-
vention for recently symptomatic stenosis based on meta-analysis
of current risks. Stroke 2015;46:3423e36.