European Stroke Organisation Guideline On Endarterectomy and Stenting For Carotid Artery Stenosis, 2021

Guideline
European Stroke Journal

European Stroke Organisation guideline 2021, Vol. 6(2) I–XLVII
! European Stroke Organisation
on endarterectomy and stenting for 2021

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carotid artery stenosis DOI: 10.1177/23969873211012121
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Leo H Bonati1, Stavros Kakkos2*, Joachim Berkefeld3*,

Gert J de Borst4, Richard Bulbulia5, Alison Halliday5,
Isabelle van Herzeele6 , Igor Koncar7, Dominick JH McCabe8,
Avtar Lal9, Jean-Baptiste Ricco10, Peter Ringleb11,
Martin Taylor-Rowan12 and Hans-Henning Eckstein13
Abstract
Atherosclerotic stenosis of the internal carotid artery is an important cause of stroke. The aim of this guideline is to
analyse the evidence pertaining to medical, surgical and endovascular treatment of patients with carotid stenosis. These
guidelines were developed based on the ESO standard operating procedure and followed the Grading of
Recommendations, Assessment, Development, and Evaluation (GRADE) approach. The working group identified rele-
vant questions, performed systematic reviews and meta-analyses of the literature, assessed the quality of the available
evidence, and wrote recommendations. Based on moderate quality evidence, we recommend carotid endarterectomy
(CEA) in patients with 60–99% asymptomatic carotid stenosis considered to be at increased risk of stroke on best
medical treatment (BMT) alone. We also recommend CEA for patients with 70–99% symptomatic stenosis, and we
suggest CEA for patients with 50–69% symptomatic stenosis. Based on high quality evidence, we recommend
CEA should be performed early, ideally within two weeks of the last retinal or cerebral ischaemic event in patients
with 50–99% symptomatic stenosis. Based on low quality evidence, carotid artery stenting (CAS) may be considered in
patients < 70 years old with symptomatic 50–99% carotid stenosis. Several randomised trials supporting these rec-
ommendations were started decades ago, and BMT, CEA and CAS have evolved since. The results of another large trial
comparing outcomes after CAS versus CEA in patients with asymptomatic stenosis are anticipated in the near future.
Further trials are needed to reassess the benefits of carotid revascularisation in combination with modern BMT in
subgroups of patients with carotid stenosis.
8
Department of Neurology and Stroke Service, The Adelaide and Meath
Hospital, Dublin, incorporating the National Children’s Hospital –
Tallaght University Hospital, Dublin, Ireland; Royal Free Campus, UCL
Queen Square Institute of Neurology, London, UK; Academic Unit of
Neurology, School of Medicine, Trinity College Dublin, Ireland
9
1 European Stroke Organisation, Basel, Switzerland
Department of Neurology, University Hospital Basel, Basel, Switzerland; 10
Department of Vascular Surgery and Department of Clinical Research,
Department of Clinical Research, University of Basel, Basel, Switzerland
2 University of Poitiers, Poitiers, France
Department of Vascular Surgery, University of Patras Medical School, 11
Department of Neurology, University Hospital Heidelberg, Heidelberg,
Patras, Greece
3 Germany
Institute of Neuroradiology, University Hospital of Frankfurt am Main, 12
Institute of Cardiovascular Science, University of Glasgow, Glasgow,
Frankfurt, Germany
4 UK
Department of Vascular Surgery, University Medical Center Utrecht, 13
Department for Vascular and Endovascular Surgery, University
Utrecht, the Netherlands
5 Hospital, Technical University of Munich (TUM), Munich, Germany
Medical Research Council Population Health Research Unit, Clinical Trial
Service Unit and Epidemiological Studies Unit, Nuffield Department of *These authors contributed equally to this guideline.
Population Health, University of Oxford, Oxford, UK
6
Department of Thoracic and Vascular Surgery, Ghent University Corresponding author:
Hospital, Ghent, Belgium Leo H Bonati, Department of Neurology, University Hospital,
7
Clinic for Vascular and Endovascular Surgery, Serbian Clinical Centre, Petersgraben 4, CH-4031 Basel, Switzerland.
Belgrade, Serbia Email: [email protected]
II European Stroke Journal 6(2)
Keywords
Carotid stenosis, endarterectomy, stenting, medical therapy, stroke, transient ischaemic attack
Date received: 1 March 2021; accepted: 5 April 2021
Introduction the ESO Guidelines Board and the ESO Executive

Committee, based on a review of the intellectual and
Atherosclerotic carotid artery disease is one of the
financial disclosures of the proposed members.
major causes of ischaemic stroke and transient ischae-
The guidelines were developed using GRADE meth-
mic attack (TIA), accounting for about 10–15% of
odology7 and the ESO Standard Operating Procedure.8
cases, depending on the method of aetiological classi-
In brief, we defined the patient population, the interven-
fication and the patient population studied.1
Atherosclerotic carotid stenosis mostly occurs at the tions and comparators, the outcomes of clinical interest
carotid bifurcation, involving the distal common and (PICOs), and the design of studies to be included. The
the proximal internal carotid artery.2 Other sites which outcomes were rated as critical, important or of limited
are predisposed to develop atherosclerotic stenosis are importance according to the GRADE criteria.7,8
the origin of the common carotid artery and the cav-
ernous segment of the intracranial carotid artery. The Population
prevalence of atherosclerotic carotid disease increases
with age and is higher in men than in women. In This guideline makes recommendations on treatment
Caucasian populations, 50% stenosis of the carotid of patients with symptomatic or asymptomatic athero-
artery was identified in 2.3% of men in the sixth sclerotic carotid stenosis. Carotid stenosis was defined
decade, in 6.0% in the seventh decade and in 7.5% of as symptomatic if it had caused ischaemic cerebrovas-
men aged 80 years; in women, the corresponding pre- cular events in the ipsilateral eye (transient monocular
valence figures were 2.0%, 3.6% and 5.0% in these age blindness or retinal infarction) or cerebral hemisphere
groups, respectively.3 (transient ischaemic attack (TIA) or stroke) in the pre-
This guideline provides recommendations on the use ceding six months. Asymptomatic carotid stenosis was
of carotid endarterectomy (CEA) and carotid artery defined as a stenosis which was not associated with any
stenting (CAS) in patients with symptomatic or asymp- ocular or cerebral ischaemic events in the ipsilateral
tomatic stenosis of the extracranial carotid bifurcation carotid territory within the preceding six months.
caused by atherosclerosis. We did not review the avail-
able evidence regarding management of proximal
common carotid artery or intracranial internal carotid Patient subgroups. PICO questions were additionally
artery stenosis, or non-atherosclerotic causes of steno- analysed for the following pre-specified patient sub-
sis, such as secondary to dissection, fibromuscular dys- groups when data were available:
plasia, arteritis etc. Furthermore, we did not include
aspects of diagnostic imaging, peri-procedural manage- 1. Age (</70 years)
ment, technical aspects of CEA and CAS, or medical 2. Sex
therapy. Guidance on these topics can be found in 3. Degree of stenosis, according to the method used in
other guidelines.4–6 the NASCET study9 or its non-invasive equivalent
(mild: <50%, moderate: 50–69%, severe: 70–99%,
near occlusion (defined as collapse of the distal
Methods lumen))
This guideline document was commissioned by the 4. Time since most recent ischaemic event (for symp-
European Stroke Organisation (ESO). A multi- tomatic carotid stenosis)
disciplinary Module Working Group (MWG) was 5. Type of most recent ischaemic event (for symptoma-
established, consisting of experts in the field from vas- tic carotid stenosis): stroke, transient ischaemic
cular neurology, vascular surgery and neuroradiology, attack, ocular ischaemia (including transient monoc-
who are represented as authors of this guideline docu- ular blindness or amaurosis fugax and retinal
ment. The composition of this group was approved by infarction).
Bonati et al. III
Interventions and comparators Formation of PICO questions

Interventions and comparators are CAS, CEA, and A series of PICO (Population, Intervention,
contemporary best medical therapy (as defined by the Comparator, Outcome) questions were developed and
study authors at the time of the study). The guideline subsequently approved by the ESO Guidelines board
does not address carotid revascularisation done as part and the ESO Executive Committee. The PICO questions
of acute stroke therapy, or carotid angioplasty without were based on the peri-procedural and post-procedural
insertion of a stent. outcomes, graded as critical or important for decision
making, as well as combinations of these outcomes. We
only compared peri-procedural outcomes on their own
Outcomes in trials of CAS versus CEA. This resulted in 4 PICO
We graded outcomes occurring in the peri-procedural questions for the comparison of CEA versus medical
period of carotid artery revascularisation, as well as therapy alone, 4 PICO questions for the comparison
outcomes occurring in the post-procedural period on of CAS versus medical therapy alone and 11 PICO ques-
a scale of 0–9 to classify them as either critical for deci- tions for the comparison of CAS versus CEA in separate
sion making (grade 7–9; Table 1); important, but not trials in patients with asymptomatic carotid stenosis and
critical for making a decision (grade 4–6; Table 1); or of in patients with symptomatic carotid stenosis. We also
limited importance for making a decision (grade 0–3). formulated one PICO question concerning the risk of
Critical and important outcomes were included in the restenosis after CAS or CEA which was addressed using
evidence profile. combined data from patients with symptomatic and
The peri-procedural period was defined as the asymptomatic carotid stenosis; these data are reported
period between randomisation in the trial and 30 days in the section on symptomatic carotid stenosis.
after treatment, or as the first 30 days after random- Subgroup analyses for these PICO questions were also
isation in patients who did not undergo revascularisa- performed in the aforementioned pre-specified patient
tion (unless different definitions were used in individual subgroups, where data were available.
trials in question). Peri-procedural outcomes were
included as a measure of treatment safety. Post-
procedural outcomes (i.e. outcomes occurring beyond Literature search, data extraction and synthesis
the peri-procedural period) were included as a measure Literature searches were restricted to reports of rando-
of treatment efficacy. mised controlled trials (RCTs). We identified three
Table 1. Outcomes.
Peri-procedural outcomes graded as -Death
critical for decision making -Any stroke (ischaemic or haemorrhagic), defined as an acute onset of focal neu-
rological dysfunction, with symptoms lasting for longer than 24 h or leading to
death within 24 h, of non-traumatic vascular aetiology. Retinal infarction with
visual loss lasting for longer than 24 h, was included within the definition of
stroke.
-Major stroke, defined as resulting in substantial impairment or disability (measured
by a modified Rankin scale10 score of >2, typically 30 days or more after the
event, if available), or death
Peri-procedural outcomes graded as -Myocardial infarction, according to the definitions used in the individual trials
important for decision making -Cranial nerve injury
Post-procedural outcomes graded as -Ipsilateral stroke, occurring in the territory of the anterior or middle cerebral
critical for decision making artery on the side of the randomised artery.
-Any stroke
-Major stroke, defined as resulting in substantial impairment or disability (measured
by a modified Rankin Scale score10 (mRS) of >2, if available), or death
Post-procedural outcomes graded as -Death

important for decision making -Severe residual or recurrent stenosis (70% according to the NASCET method of
grading stenosis9 or its non-invasive equivalent) or occlusion of the treated
artery.
IV European Stroke Journal 6(2)
systematic reviews of RCTs in the Cochrane Database The relevant PICO group was responsible for ana-
of Systematic Reviews, which were of relevance to this lysing the available data and formulating an
guideline, one comparing CEA with medical therapy evidence-based recommendation according to the
alone for asymptomatic carotid stenosis,11 one compar- GRADE evidence profiles and the ESO standard oper-
ing CEA with medical therapy alone for symptomatic ating procedure. Random-effect metanalyses were con-
carotid stenosis12 and one comparing CAS with CEA ducted and relative intervention effects were
for asymptomatic or symptomatic carotid stenosis.13 summarised as risk ratios (RR) and their 95% confi-
For the comparisons of CEA versus medical therapy, dence interval. The absolute measure of intervention
and CAS versus CEA, systematic searches of the effects was calculated as the difference between the
MEDLINE, EMBASE, and Cochrane databases baseline risk of an outcome (patients receiving control
(from the date of the last search in the Cochrane intervention) and the risk of outcome after the inter-
reviews to 10 August 2020) were conducted by two vention was applied (risk of an outcome in patients
ESO Guidelines methodologists (AL and MTR) using who received an intervention). Absolute effects are
the same search terms which were defined in the based on the relative magnitude of an effect with
Cochrane reviews. For the comparison of CAS versus respect to the baseline risk, which is similar to risk
best medical therapy, a de novo search of the literature differences. The fewer value represents any value
was performed using the MEDLINE, EMBASE and below 1 per 1000 and the more value represents any
Cochrane databases from their inception until 10 value more than 1 per 1000.
August 2020, using the search terms provided in the The wording and the rating of the strength of each
Online Appendix. To reduce the number of duplicate recommendation was passed by majority voting by all
references identified, we simultaneously searched for MWG members. An Expert Consensus Statement,
relevant data in patients with asymptomatic and symp- based on voting by all MWG members, was presented
tomatic carotid stenosis. where the PICO group considered that there was
For each of the three main comparisons, a group of insufficient evidence available to provide clear
MWG members (a ‘PICO group’) was formed to select evidence-based recommendations for situations in
the studies for inclusion and to evaluate the available which practical guidance was needed for everyday clin-
evidence. Within each PICO group, two MWG mem- ical practice. Importantly, these Expert Consensus
bers independently screened the titles and abstracts of Statements should not be regarded as evidence-based
publications identified from the searches (first level recommendations since they only reflect the opinion of
selection), and subsequently assessed the full text of the majority of the members of the MWG.
potentially relevant studies (second level selection). The Guideline document was subsequently reviewed
Data were extracted independently by AL and MTR by all MWG members and modified until a consensus
from studies which met criteria for second level selec- was reached. Finally, the guideline document was peer-
tion, separately for patients with asymptomatic and reviewed and approved by external reviewers and mem-
those with symptomatic carotid stenosis. At least one bers of the ESO Guidelines Board and ESO Executive
additional MWG member checked the extracted data Committee.
results for accuracy.
For some PICO questions (PICO 6.1 and 6.9), we
included outcomes in pre-defined patient subgroups
Results
derived from pooled analyses of individual patient Endarterectomy or medical therapy for
data (IPD) from the EVA-3S, SPACE, ICSS and
CREST trials which were performed by the Carotid
asymptomatic carotid stenosis
Stenosis Trialists’ Collaboration (CSTC). Description of studies. The Veterans Administration (VA)
The risks of selection, performance, detection, attri- asymptomatic carotid stenosis cooperative study rando-
tion and reporting bias in each randomised trial were mised 444 men with 50% asymptomatic carotid ste-
assessed using the Cochrane Collaboration’s tool.14 nosis on angiography to CEA (n ¼ 211) or medical
Heterogeneity across studies was assessed using therapy alone (n ¼ 233) between 1983 and 1987.16
Cochran’s Q (reported as a p value) and I2 statistics.15 Five percent of patients turned out to have <50% ste-
For each PICO question and each outcome, the quality nosis after centralised analysis of the angiograms.
of evidence was rated using the GRADEpro Guideline Patients had never experienced any prior ipsilateral
Development Tool (McMaster University, 2015; devel- cerebrovascular events and were followed up for a
oped by Evidence Prime, Inc.) as high, moderate, low mean of 47.9 months. The results were reported
or very low.8 in 1993.
Bonati et al. V
The Asymptomatic Carotid Atherosclerosis Study description of the SPACE-2 trial is provided in sec-
(ACAS) randomly allocated 1662 patients with tion ‘Stenting or medical therapy for asymptomatic
60% asymptomatic carotid artery stenosis to CEA carotid stenosis.
(n ¼ 825) or medical therapy alone (n ¼ 834) between The effects of treatment are presented with medical
1987 and 1993. Patients were defined as being ‘asymp- therapy alone as the reference group. A summary of
tomatic’ if they never had cerebrovascular symptoms in findings is provided in Table 2.
the distribution of the ‘study’ carotid artery or verte-
brobasilar territory. Patients with contralateral cere- PICO 1.1: In patients with asymptomatic carotid steno-
bral hemispheric symptoms within the previous sis, does endarterectomy compared with medical therapy
45 days were excluded. Outcomes after a median alone reduce the long-term risk of ipsilateral stroke,
follow-up period of 2.7 years were reported in 1995.17 including peri-procedural stroke in any territory or peri-
The definition of haemodynamically-significant carotid procedural death? There is moderate quality evidence
stenosis was based on meeting at least one of three pre- that endarterectomy reduces the long-term risk of ipsi-
specified criteria from an ocular pneumoplethysmo- lateral stroke, including peri-procedural stroke in any
graphic (OPG-Gee) examination, an ultrasound of territory or peri-procedural death compared with med-
carotid arteries and/or catheter angiography indicating ical therapy alone (RR: 0.73, 95% CI: 0.59–0.90; equiv-
a diameter stenosis of 60% (NASCET methodology). alent to 19 fewer events with CEA per 1000, from 28
Patients randomised to surgery on the basis of ultra- fewer to 7 fewer; Figure 1.1).
sound findings, or ultrasound combined with OPG-
Gee were also required to have a catheter angiogram PICO 1.2: In patients with asymptomatic carotid steno-
prior to CEA. If a post-randomisation angiogram sis, does endarterectomy compared with medical therapy
revealed that the contralateral carotid artery was alone reduce the long-term risk of stroke in any territory,
more severely stenosed, that artery then became the including peri-procedural death? There is also moderate
allocated ‘study artery’. quality evidence that endarterectomy reduces the long-
The Asymptomatic Carotid Surgery Trial (ACST-1)
term risk of stroke in any territory, including peri-
randomised 3120 patients with 60% asymptomatic
procedural death, compared with medical therapy
carotid stenosis on ultrasound to immediate CEA
alone (RR: 0.74, 0.59–0.92; 31 fewer events with CEA
(n ¼ 1560, median delay one month (IQR: 0.3–2.5)) or
per 1000 patients; from 48 fewer to 9 fewer; Figure 1.2).
initial medical therapy with the option of deferred CEA
Comparison of the data on the estimated number of
(n ¼ 1560) between 1993 and 2003.18,19 The first ACST-
ipsilateral strokes (PICO 1.1) and strokes in any terri-
1 report in 2004 provided data on outcomes during
tory (PICO 1.2) suggests that CEA might also prevent
follow-up for up to five years (mean 3.4 years) after
strokes occurring outside the territory supplied by the
randomisation.18 A subsequent report in 2010 included
outcomes over a median follow-up period of nine years operated carotid artery.
(IQR 6–11 years) after randomisation.19 Subgroup data regarding age, sex and severity of
The Aggressive Medical Treatment Evaluation for stenosis were derived from ACST-1 only. The effect
Asymptomatic Carotid Artery Stenosis (AMTEC) of CEA is significantly modified by age (interaction
study randomised 55 patients with 70–79% carotid ste- p ¼ 0.04): there is moderate evidence of a benefit of
nosis to receive CEA (n ¼ 31) or medical therapy alone CEA in patients younger than 75 years (RR: 0.62,
(n ¼ 24) between 2009 and 2013.20 Stenosis was graded 0.49–0.78; Figure 1.2.2), but no evidence of benefit
by ultrasound examinations, but had to be confirmed observed in patients 75 years old (RR: 1.03, 95%
by computed tomographic or magnetic resonance angi- CI: 0.68–1.55, low quality evidence). There is no evi-
ography (CTA/MRA) or catheter angiography. The dence of a modification of the effect of CEA according
trial was stopped prematurely by the independent to sex (Figure 1.2.1) or severity of stenosis (Figure
data and safety monitoring board because of a high 1.2.3).
rate of the primary endpoint in the medical arm after
a median follow-up period of 3.3 years (maximum, PICO 1.3: In patients with asymptomatic carotid steno-
5.0 years); results were reported in 2015. sis, does endarterectomy compared with medical therapy
Data from patients with 50–99% asymptomatic alone reduce the long-term risk of major stroke, including
carotid stenosis randomly assigned to CEA peri-procedural death? There is moderate quality evi-
(n ¼ 203) or medical therapy alone (n ¼ 113) between dence that endarterectomy reduces the long-term risk
2009 and 2013 in the three-arm Stent-protected of major stroke, including peri-procedural death com-
Angioplasty in Asymptomatic Carotid Artery Stenosis pared with medical therapy alone (RR: 0.77: 0.61–0.98;
vs. Endarterectomy (SPACE-2) trial were also 14 fewer events with CEA per 1000; from 24 fewer to 1
included in the present section.21,22 A detailed fewer; Figure 1.3).
Table 2. Summary of findings for endarterectomy versus medical therapy for asymptomatic carotid stenosis (PICO 1.1–1.4). VI
Certainty assessment @ of patients Effect
@ of Study Risk of Other Medical Relative Absolute

studies design bias Inconsistency Indirectness Imprecision considerations Endarterectomy therapy (95% CI) (95% CI) Certainty Importance
PICO 1.1: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death
5 Randomised Not serious Not serious Seriousa Not serious None 139/2830 190/2764 RR 0.73 19 fewer per 1000 ⨁⨁⨁ CRITICAL
trials (4.9%) (6.9%) (0.59–0.90) (from 28 fewer to 7 MODERATE
fewer)
PICO 1.2: Long-term risk of stroke in any territory, including peri-procedural death
fewer)
PICO 1.2.1a: Long-term risk of stroke in any territory, including peri-procedural death. Subgroup: Men
fewer)
PICO 1.2.1b: Long-term risk of stroke in any territory, including peri-procedural death. Subgroup: Women
fewer)
PICO 1.2.2a: Long-term risk of stroke in any territory, including peri-procedural death. Subgroup: Age <75 years
trials (8.0%) (12.9%) (0.49 to 0.78) (from 66 fewer to 28 MODERATE
fewer)
PICO 1.2.2b: Long-term risk of stroke in any territory, including peri-procedural death. Subgroup: Age <75 years
1 Randomised Not serious Not serious Seriousa Seriousb None 41/329 39/321 RR 1.03 4 more per 1000 ⨁⨁ CRITICAL
trials (12.5%) (12.1%) (0.68–1.55) (from 39 fewer to 67 LOW
more)
PICO 1.2.3a: Long-term risk of stroke in any territory, including peri-procedural death. Subgroup: <80% Stenosis
fewer)
PICO 1.2.3b: Long-term risk of stroke in any territory, including peri-procedural death. Subgroup: 80% Stenosis
fewer)
PICO 1.3: Long-term risk of major stroke, including peri-procedural death
fewer)
PICO 1.4: Long-term risk of death
4 Randomised Not serious Not serious Seriousa Seriousb None 699/2619 667/2531 RR 1.02 5 more per 1000 ⨁⨁ IMPORTANT
more)
CI: confidence interval; RR: risk ratio.

a
Endarterectomy and medical therapy have evolved since the trials contributing the evidence were performed.
European Stroke Journal 6(2)
b
Few events and wide confidence intervals.
Bonati et al. VII
Figure 1.1. Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death in end-
arterectomy versus medical therapy for asymptomatic carotid stenosis.
Figure 1.2. Long-term risk of stroke in any territory, including peri-procedural death in endarterectomy versus medical therapy for
asymptomatic carotid stenosis.
Figure 1.2.1. Long-term risk of stroke in any territory, including peri-procedural death in endarterectomy versus medical therapy
for asymptomatic carotid stenosis.
Subgroup: Sex.
Subgroup: Age.
VIII European Stroke Journal 6(2)
Subgroup: Severity of carotid stenosis.
Figure 1.3. Long-term risk of major stroke, including peri-procedural death in endarterectomy versus medical therapy for asymp-
tomatic carotid stenosis.
Figure 1.4. Long-term risk of death in endarterectomy versus medical therapy for asymptomatic carotid stenosis.
PICO 1.4: In patients with asymptomatic carotid steno- stroke and the risk of stroke in any territory in these
sis, does endarterectomy compared with medical therapy patients. Based on the results of a single trial, we found
alone reduce the long-term risk of death? There is no no evidence that the benefit of CEA varied significantly
difference in long-term risk of death between patients between men and women, or according to the severity
assigned to endarterectomy and those assigned to med- of the carotid stenosis. We did not find evidence of an
ical therapy alone (RR: 1.02, 95% CI: 0.88–1.20; 5 increase of the benefit of surgery with increasing degree
more events with CEA per 1000 patients, from 32 of asymptomatic carotid stenosis. However, a recent
fewer to 53 more; low quality evidence; Figure 1.4). population-based study and systematic review sug-
gested an increase in stroke risk with increasing degrees
Analysis of current evidence and evidence-based recommenda- of asymptomatic carotid stenosis amongst patients
tion. Data to assess the benefit of endarterectomy com- receiving contemporary medical therapy.23 Age influ-
pared with medical therapy alone in patients with enced the effect of surgery in ACST-1, with benefits
asymptomatic carotid stenosis were available from only observed in patients < 75 years of age. As the
five RCTs which included a total of 5791 patients effect of age on treatment was only reported in a sub-
with mainly 60% stenosis. We found moderate qual- group analysis of a single trial and taking into account
ity evidence that CEA reduces the risk of ipsilateral the fact that cardiovascular disease mortality is
Bonati et al. IX
decreasing and life expectancy is increasing in these intra-plaque haemorrhage on MRI34,35 and micro-
patients, we refrained from making recommendations emboli24 or reduced cerebrovascular reserve36 on
for CEA in patients with asymptomatic carotid stenosis trans-cranial Doppler. This concept is currently being
based on fixed age limits. investigated in the Endarterectomy Combined With
The two largest trials contributing data were per- Optimal Medical Therapy (OMT) vs OMT Alone in
formed two to three decades ago. Best medical man- Patients With Asymptomatic Severe Atherosclerotic
agement of patients with atherosclerotic disease has Carotid Artery Stenosis at Higher-than-average Risk
evolved since, with more widespread use of statins of Ipsilateral Stroke (ACTRIS) trial, which is including
and other lipid-lowering agents, and stricter control patients with asymptomatic carotid stenosis who have
of blood pressure. Annual risks of ipsilateral stroke imaging features believed to confer an increased risk of
in more recent observational studies of patients with stroke.
asymptomatic carotid stenosis range from 0.34 to
1.4%, which is lower than in the medical arms of the Expert consensus statement.
RCTs.24–26 However, surgical techniques and peri-
operative management have also improved since these
Expert consensus statement:
landmark trials were completed. For these reasons, we
downgraded the overall quality of evidence for 12/12 experts concluded that in selected patients 75 years of
indirectness. age or older with 60% asymptomatic carotid artery ste-
nosis and an expected survival of at least five years, who are
considered to be at an increased risk of stroke on best
Recommendation medical therapy alone, carotid endarterectomy is suggested
In patients with 60% asymptomatic carotid artery stenosis after careful consideration of the risks and benefits at a
considered to be at increased risk of stroke on best medical multi-disciplinary team meeting.
therapy alone, we recommend carotid endarterectomy.
Quality of evidence: Moderate 丣丣丣
Strength of recommendation: Strong for carotid endarter- Stenting or medical therapy for asymptomatic
ectomy ""
carotid stenosis
This recommendation is independent of sex and stenosis
Description of studies. The Stent-protected Angioplasty in
severity.
Asymptomatic Carotid Artery Stenosis vs.
Endarterectomy (SPACE-2) trial was a randomised
Additional information. The question of whether carotid multi-centre study in Germany, Austria and
revascularisation confers additional benefits over Switzerland which aimed to assess the safety and effi-
modern medical therapy is being investigated in ongo- cacy of CAS or CEA compared with best medical ther-
ing RCTs: the Second European Carotid Surgery Trial apy (BMT) alone in patients with asymptomatic 50%
(ECST-2) enrolled 429 patients with asymptomatic or common or internal carotid artery stenosis.22 Stenoses
low-to-intermediate risk symptomatic carotid stenosis; were considered asymptomatic if patients had not expe-
follow-up is ongoing.27 The Carotid Revascularization rienced ipsilateral amaurosis fugax, a TIA or stroke
and Medical Management for Asymptomatic Carotid within the preceding 180 days. SPACE-2 started in
Stenosis Trial (CREST-2) includes two parallel trials 2009 as a three-arm trial randomly assigning patients
of stenting vs. medical therapy and endarterectomy vs.
to CEAþBMT, CASþBMT, or BMT alone in a 3:3:1
medical therapy in patients with 70% asymptomatic
ratio, with a target sample size of 3550 patients. For
carotid stenosis.28
CAS, the use of protection devices was not mandatory.
There is debate about whether CEA should only be
The trial design was changed in 2013 to a two-arm trial
performed in patients with asymptomatic carotid ste-
nosis who are considered to be at ‘higher risk’ of stroke of CEAþBMT versus CASþBMT. Due to slow
on best medical treatment (BMT) alone. The guidelines recruitment, the trial was stopped prematurely in
published by the European Society for Vascular 2014 after 513 patients had been randomised to CEA
Surgery (ESVS) have proposed that surgery should be (n ¼ 203), CAS (n ¼ 197) or BMT (n ¼ 113). This sec-
considered in selected patients with 60–99% asymp- tion of the guidelines only includes outcomes of
tomatic carotid stenosis with one or more imaging or patients in the CAS and BMT groups. Results after
clinical characteristics that may be associated with an one year of follow-up were previously published. The
increased risk of late ipsilateral stroke.4 These charac- primary efficacy endpoint (the cumulative risk of any
teristics may include, among others, silent infarction on stroke or death from any cause within 30 days, plus any
neuroimaging,29 high degree23 and progression of ipsilateral ischaemic stroke within five years of follow-
stenosis,30,31 echolucent plaque on ultrasound,32,33 up) is yet to be reported.
X European Stroke Journal 6(2)
We excluded two smaller RCTs because these stud- risk of bias (due to the early termination), imprecision,
ies did not report outcomes by symptom status,37,38 or and indirectness (insufficient length of follow-up),
patients were treated with primary balloon angioplas- resulting in a very low quality of evidence.
ty.38 Therefore, the SPACE-2 data were the only data
which could be used to address the PICO questions in Recommendation
this section.
In patients with asymptomatic carotid stenosis, we recom-
The effects of treatment are presented with medical mend against carotid artery stenting as a routine alternative
therapy alone as the reference group. A summary of to best medical therapy alone.
findings is provided in Table 3. Quality of evidence: Very low 丣
Strength of recommendation: Weak against carotid stenting
PICO 2.1: In patients with asymptomatic carotid steno- #?
sis, does stenting compared with medical therapy alone
reduce the long-term risk of ipsilateral stroke, including
peri-procedural stroke in any territory or peri-procedural Recommendations regarding the choice between
death? There is very low quality of evidence from stenting and endarterectomy in patients with asymp-
SPACE-2 of a non-significant increase in the risk of tomatic carotid stenosis, in whom revascularisation is
ipsilateral stroke, including peri-procedural stroke in considered to be appropriate are provided in section
any territory or peri-procedural death with stenting “Stenting or endarterectomy for asymptomatic carotid
compared with medical therapy alone (RR: 3.44, 95% stenosis”.
CI: 0.42–28.23; equivalent to 22 more events with
Additional information. Carotid artery stenting versus best
CAS per 1000 patients, from 5 fewer to 241 more;
medical therapy alone are being compared in one of the
Figure 2.1).
two parallel study arms in the ongoing Carotid
Revascularization and Medical Management for
PICO 2.2: In patients with asymptomatic carotid steno-
Asymptomatic Carotid Stenosis Trial (CREST-2).28
sis, does stenting compared with medical therapy alone
reduce the long-term risk of stroke in any territory, Stenting or endarterectomy for asymptomatic
including peri-procedural death? There is also very low
quality evidence from SPACE-2 of a non-significantly
carotid stenosis
higher risk of stroke in any territory, including peri- Description of studies. A single-centre trial in Lexington,
procedural death with stenting compared with medical Kentucky, USA randomised 85 participants with
therapy (RR: 4.59, 0.58–36.22; 32 more events with CAS 80% asymptomatic carotid stenosis to receive either
per 1000 patients, from 4 fewer to 312 more; Figure 2.2). CAS without a cerebral protection device (CPD) or
CEA and reported results up to four years after ran-
PICO 2.3: In patients with asymptomatic carotid steno- domisation in 2004.39 A further report in 2014 com-
sis, does stenting compared with medical therapy alone bined long-term outcomes for up to 10 years in both
reduce the long-term risk of major stroke, including asymptomatic and symptomatic patients who were
peri-procedural death? Only one such composite event enrolled in another trial at the same institution, but
occurred in each of the stenting and medical therapy the authors did not present separate data according
groups in SPACE-2 (RR: 0.57, 0.04–9.08; low quality to symptom status.40 Therefore, we chose the 2004
evidence; Figure 2.3). report to extract outcome data from patients with
asymptomatic stenosis to address our PICO questions.
PICO 2.4: In patients with asymptomatic carotid steno- The Carotid Revascularization Endarterectomy
sis, does stenting compared with medical therapy alone versus Stenting Trial (CREST), a multicentre trial in
reduce the long-term risk of death? There is very low the USA and Canada, randomised 1321 patients with
quality of evidence that the long-term risk of death 50% symptomatic carotid stenosis and 1181 patients
did not differ between patients treated with stenting with 60% asymptomatic carotid stenosis to CAS or
and medical therapy in SPACE-2 (RR: 0.29, 0.05– CEA between 2000 and 2008.41–48 Interventionists with
1.54; Figure 2.4). an experience of < 30 CAS procedures were required to
complete a training programme. The use of a CPD was
Analysis of current evidence and evidence-based recommenda- mandatory during stenting. Initial results were pub-
tions. The evidence from this single, prematurely termi- lished in 2010; the final trial results were published in
nated RCT is very limited. The recruited study 2016 with follow-up data for up to 10 years after ran-
population is too small, and the available follow-up domisation (median of 7.4 years). Only data from
period is too short to reliably compare data between asymptomatic patients were extracted for our analyses
treatment groups. We downgraded the evidence for the to address these PICO questions.
Bonati et al.
Table 3. Summary of findings for stenting versus medical therapy for asymptomatic carotid stenosis (PICO 2.1–2.4).
@ of Study Risk of Other Medical Relative Absolute

studies design bias Inconsistency Indirectness Imprecision considerations Stenting therapy (95% CI) (95% CI) Certainty Importance
1 Randomised Seriousa Not serious Seriousb Very seriousc None 6/197 1/113 RR 3.44 22 more per ⨁ CRITICAL
trials (3.0%) (0.9%) (0.42–28.23) 1000 VERY LOW
(from 5 fewer to
241 more)
PICO 2.2: Long-term risk of stroke in any territory, including peri-procedural death
1 Randomised Seriousa Not serious Seriousb Very seriousc None 8/197 1/113 RR 4.59 32 more per ⨁ CRITICAL
trials (4.1%) (0.9%) (0.58–36.22) 1000 VERY LOW
(from 4 fewer to
312 more)
PICO 2.3: Long-term risk of major stroke, including peri-procedural death
1 Randomised Seriousa Not serious Seriousb Not seriousc None 1/197 1/113 RR 0.57 4 fewer per 1000 ⨁⨁ CRITICAL
more)
1 Randomised Seriousa Not serious Seriousb Very seriousc None 2/197 4/113 RR 0.29 25 fewer per ⨁ IMPORTANT
trials (1.0%) (3.5%) (0.05–1.54) 1000 VERY LOW
(from 34 fewer to
19 more)
a
Trial was stopped early.
b
Insufficient length of follow-up to assess long-term effects.
c
Very wide confidence intervals.
XI
XII European Stroke Journal 6(2)
Figure 2.1. Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death in stenting
versus medical therapy for asymptomatic carotid stenosis.
Figure 2.2. Long-term risk of stroke in any territory, including peri-procedural death in stenting versus medical therapy for
Figure 2.3. Long-term risk of major stroke, including peri-procedural death in stenting versus medical therapy for asymptomatic
carotid stenosis.
Figure 2.4. Long-term risk of death in stenting versus medical therapy for asymptomatic carotid stenosis.
A single-centre trial in Houston, Texas, USA rand- stenosis to undergo CAS (with the use of a CPD,
omised 60 patients with 80% asymptomatic carotid where possible) or CEA and reported results in
stenosis to receive CAS (with mandatory use of a 2014.50 The primary outcome was the occurrence of
CPD) or CEA. The primary outcome was ‘cognitive new ischaemic brain lesions on magnetic resonance
performance’ after treatment; this and other clinical imaging after treatment. Clinical outcome events up
outcome data for up to 6 months after randomisation to 30 days after treatment were also reported, and
were reported in 2014.49 No data were available for these were made available and categorised according
five patients who withdrew consent or were lost to to symptom status following correspondence with the
follow-up. investigators.
A single-centre trial conducted in Ostrava, Czech The Randomized Trial of Stent versus Surgery for
Republic, randomised 63 patients with asymptomatic Asymptomatic Carotid Stenosis (ACT-1) allocated
and 87 patients with symptomatic 70% carotid 1453 participants <80 years of age with 70%
Bonati et al. XIII
asymptomatic carotid stenosis in a 3:1 ratio to undergo 0.62–2.00; 3 more events with stenting per 1000
CAS (with mandatory use of a CPD) or CEA between patients, from 8 fewer to 22 more; Figure 3.2).
2005 and 2013.51 A prior experience of 25 procedures
was required from surgeons and interventionists. The PICO 3.3: In patients with asymptomatic carotid steno-
initially planned sample size was 1658 participants, but sis, do endarterectomy and stenting differ in the long-term
the study was stopped prematurely due to slow enrol- risk of stroke in any territory, including peri-procedural
ment. Results up to five years after randomisation were death? There is moderate quality evidence that stenting
previously published. is likely associated with an increased long-term risk of
A single-centre trial at Carmel Medical Center in stroke in any territory or peri-procedural death (RR:
Israel randomised 136 participants with 70% asymp- 1.22, 0.87–1.71; 13 more events with stenting per 1000
tomatic carotid stenosis to receive CAS (with manda- patients, from 8 fewer to 42 more; Figure 3.3).
tory use of a CPD) or CEA. Results up to five years
after randomisation were reported in 2017.52 Three PICO 3.4: In patients with asymptomatic carotid steno-
patients were lost to follow-up. sis, do endarterectomy and stenting differ in the long-term
Events occurring up to one year after treatment risk of major stroke, including peri-procedural death?
were also extracted from the CAS and CEA groups There is low quality evidence that endarterectomy
of the 3-arm SPACE-2 trial (described in section and stenting do not differ in the long-term risk of
‘Stenting or medical therapy for asymptomatic carot- major stroke or peri-procedural death (RR: 0.99,
id stenosis’).22 0.15–6.68; 0 fewer events with stenting per 1000
We did not include data from the multi-centre patients, from 20 fewer to 20 more; Figure 3.4).
Stenting and Angioplasty with Protection in Patients
at High Risk for Endarterectomy (SAPPHIRE) trial PICO 3.5: In patients with asymptomatic carotid steno-
sis, do endarterectomy and stenting differ in the long-term
conducted in the USA,53–55 from one Chinese multi-
risk of death? There is low quality evidence that endar-
centre trial,56 and two single-centre studies conducted
terectomy and stenting do not differ in the long-term
in Beijing, China.57,58 Reasons for exclusion of these
risk of death (RR: 0.82, 0.31–2.20; 5 fewer events with
randomised studies were the inclusion of patients
stenting per 1000 patients, from 18 fewer to 32 more;
with both asymptomatic and symptomatic carotid
Figure 3.5).
stenosis without reporting of separate outcome data
according to symptomatic status, inclusion of ‘high
PICO 3.6: In patients with asymptomatic carotid steno-
surgical risk’ patients only, or results in the English
sis, do endarterectomy and stenting differ in the risk of
language only being available as a conference peri-procedural stroke? There is moderate quality evi-
abstract. dence that stenting is likely associated with an
The effects of treatment are presented with endar- increased risk of peri-procedural stroke (RR: 1.70,
terectomy as the reference group. A summary of find- 0.99–2.93; 10 more events with stenting per 1000
ings is provided in Table 4. patients, from 0 fewer to 28 more; Figure 3.6).
PICO 3.1: In patients with asymptomatic carotid steno- PICO 3.7: In patients with asymptomatic carotid steno-
sis, do endarterectomy and stenting differ in the long-term sis, do endarterectomy and stenting differ in the risk of
risk of ipsilateral stroke, including peri-procedural stroke peri-procedural death? There is high quality evidence
in any territory or peri-procedural death? There is that endarterectomy and stenting do not differ in the
moderate quality evidence that stenting is likely asso- risk of peri-procedural death (RR: 0.33, 0.02–5.33; 1
ciated with an increased long-term risk of post- less event with stenting per 1000 patients, from 1 less
procedural ipsilateral stroke, peri-procedural stroke to 6 more; Figure 3.7). We did not downgrade the qual-
in any territory, or peri-procedural death (RR: 1.25, ity of evidence for imprecision because only a single
95% CI: 0.88–1.79; equivalent to 9 more events with event occurred in each treatment group.
CAS per 1000 patients, from 4 fewer to 28 more;
Figure 3.1). PICO 3.8: In patients with asymptomatic carotid steno-
sis, do endarterectomy and stenting differ in the risk of
PICO 3.2: In patients with asymptomatic carotid steno- peri-procedural stroke or death? There is moderate
sis, do endarterectomy and stenting differ in the long-term quality evidence that stenting is likely associated with
risk of post-procedural ipsilateral stroke? There is low an increased risk of peri-procedural stroke or death as
quality evidence that endarterectomy and stenting do compared to endarterectomy (RR: 1.62, 0.96–2.76; 9
not differ in preventing post-procedural ipsilateral more events per 1000 patients, from 1 less to 27
stroke, excluding peri-operative events (RR: 1.12, more; Figure 3.8).
Table 4. Summary of findings for stenting versus endarterectomy for asymptomatic carotid stenosis (PICO 3.1–3.11).
XIV
@ of Study Risk of Other Relative Absolute

studies design bias Inconsistency Indirectness Imprecision considerations Stenting Endarterectomy (95% CI) (95% CI) Certainty Importance
6 Randomised Not serious Not serious Not serious Seriousa None 86/2018 46/1292 RR 1.25 9 more per ⨁⨁⨁ CRITICAL
trials (4.3%) (3.6%) (0.88–1.79) 1000 MODERATE
(from 4 fewer to
28 more)
PICO 3.2. Long-term risk of post-procedural ipsilateral stroke
5 Randomised Not serious Not serious Not serious Very seriousb None 23/926 20/927 RR 1.12 3 more per ⨁⨁ CRITICAL
trials (2.5%) (2.2%) (0.62–2.00) 1000 LOW
(from 8 fewer to
22 more)
PICO 3.3. Long-term risk of stroke in any territory, including peri-procedural death
trials (7.3%) (5.9%) (0.87–1.71) 1000 MODERATE
(from 8 fewer to
42 more)
PICO 3.4. Long-term risk of major stroke, including peri-procedural death
3 Randomised Not serious Not serious Not serious Very seriousb None 2/267 2/273 RR 0.99 0 fewer per ⨁⨁ CRITICAL
trials (0.7%) (0.7%) (0.15–6.68) 1000 LOW
(from 20 fewer to
20 more)
4 Randomised Not serious Not serious Not serious Very seriousb None 7/332 9/340 RR 0.82 5 fewer per ⨁⨁ IMPORTANT
trials (2.1%) (2.6%) (0.31–2.20) 1000 LOW
(from 18 fewer to
32 more)
PICO 3.6: Risk of peri-procedural stroke
trials (2.5%) (1.4%) (0.99–2.93) 1000 MODERATE
(from 0 fewer to
28 more)
PICO 3.7: Risk of peri-procedural death
6 Randomised Not serious Not serious Not serious Not serious None 1/1462 1/730 RR 0.33 1 fewer per ⨁⨁⨁⨁ CRITICAL
trials (0.1%) (0.1%) (0.02–5.33) 1000 HIGH
(from 1 fewer to 6
more)
PICO 3.8: Risk of peri-procedural stroke or death
trials (2.6%) (1.5%) (0.96–2.76) 1000 MODERATE
(from 1 fewer to
27 more)
(continued)
Bonati et al.
Table 4. Continued.
@ of Study Risk of Other Relative Absolute

studies design bias Inconsistency Indirectness Imprecision considerations Stenting Endarterectomy (95% CI) (95% CI) Certainty Importance
PICO 3.9: Risk of peri-procedural major stroke or death

trials (0.5%) (0.3%) (0.39–6.07) 1000 MODERATE
(from 2 fewer to
15 more)
PICO 3.10: Risk of peri-procedural myocardial infarction
7 Randomised Not serious Not serious Seriousc Seriousa None 12/2041 16/1304 RR 0.53 6 fewer per ⨁⨁ IMPORTANT
trials (0.6%) (1.2%) (0.25–1.15) 1000 LOW
(from 9 fewer to 2
more)
PICO 3.11: Risk of peri-procedural cranial nerve injury
5 Randomised Not serious Not serious Not serious Not serious Very strong 2/1823 36/1092 RR 0.09 30 fewer per ⨁⨁⨁⨁ IMPORTANT
trials associationd (0.1%) (3.3%) (0.03–0.28) 1000 HIGH
(from 32 fewer to
24 fewer)

a
Few events, wide confidence intervals.
b
c
Definition of myocardial infarction differed across trials.
d
Very large effect.
XV
XVI European Stroke Journal 6(2)
versus endarterectomy for asymptomatic carotid stenosis.
Figure 3.2. Long-term risk of post-procedural ipsilateral stroke in stenting versus endarterectomy for asymptomatic carotid
stenosis.
Figure 3.3. Long-term risk of stroke in any territory, including peri-procedural death in stenting versus endarterectomy for
Figure 3.4. Long-term risk of major stroke, including peri-procedural death in stenting versus endarterectomy for asymptomatic
carotid stenosis.
Figure 3.5. Long-term risk of death in stenting versus endarterectomy for asymptomatic carotid stenosis.
Bonati et al. XVII
Figure 3.6. Risk of peri-procedural stroke in stenting versus endarterectomy for asymptomatic carotid stenosis.
Figure 3.7. Risk of peri-procedural death in stenting versus endarterectomy for asymptomatic carotid stenosis.
Figure 3.8. Risk of peri-procedural stroke or death in stenting versus endarterectomy for asymptomatic carotid stenosis.
Figure 3.9. Risk of peri-procedural major stroke or death in stenting versus endarterectomy for asymptomatic carotid stenosis.
PICO 3.9: In patients with asymptomatic stenting per 1000 patients, from 2 fewer to 15
carotid stenosis, do endarterectomy and stenting more; Figure 3.9).
differ in the risk of peri-procedural major stroke or
death? There is moderate quality evidence that PICO 3.10: In patients with asymptomatic carotid ste-
stenting is likely associated with a slight increase nosis, do endarterectomy and stenting differ in the risk of
of the risk of major peri-procedural stroke or peri-procedural myocardial infarction? There is low qual-
death (RR: 1.54, 0.39–6.07; 2 more events with ity evidence that stenting is likely associated with a
XVIII European Stroke Journal 6(2)
Figure 3.10. Risk of peri-procedural myocardial infarction in stenting versus endarterectomy for asymptomatic carotid stenosis.
Figure 3.11. Risk of peri-procedural cranial nerve injury in stenting versus endarterectomy for asymptomatic carotid stenosis.
lower risk of peri-procedural myocardial infarction as also precluded meaningful subgroup analyses. Overall,
compared to endarterectomy (RR: 0.53, 0.25–1.15; 6 we found no clear evidence of statistically significant
fewer events with stenting per 1000 patients, from 9 differences in outcomes between endarterectomy or
fewer to 2 more; Figure 3.10). We additionally down- stenting that were rated as critical for decision
graded the quality of evidence for indirectness because making when treating patients with asymptomatic
all extracted events originated from the CREST and carotid stenosis (low to moderate quality evidence).
ACT-1 trials, where screening with ECG and cardiac As the available evidence is not sufficient to recom-
enzymes of all patients was performed before and after mend stenting as an alternative to endarterectomy,
treatment; the definition of myocardial infarction carotid endarterectomy presently remains the treat-
included elevation of cardiac enzymes alone, or in com- ment of choice for patients with asymptomatic carotid
bination with ECG changes only (without clinical stenosis considered to require revascularisation.
symptoms).
Recommendation
PICO 3.11: In patients with asymptomatic carotid ste- In patients with asymptomatic carotid stenosis in whom
nosis, do endarterectomy and stenting differ in the risk of revascularisation is considered to be appropriate, we sug-
peri-procedural cranial nerve injury? There is high qual- gest endarterectomy as the current treatment of choice.
ity evidence that stenting is associated with a lower risk Quality of evidence: Moderate 丣丣丣
of peri-procedural cranial nerve injury than endarter- Strength of recommendation: Weak for carotid endarterec-
ectomy (RR: 0.09, 95% CI: 0.03–0.28; 30 fewer events tomy "?
per 1000 patients with stenting, from 32 fewer to 24
fewer; Figure 3.11). We upgraded the quality of evi- Additional information. The Asymptomatic Carotid
dence by two levels for strength of effect. Surgery Trial-2 (ACST-2) has recently completed
recruitment of 3.638 patients with asymptomatic carot-
Analysis of current evidence and evidence-based recommenda- id stenosis who were randomly assigned to CAS or
tion. Data comparing the short-term risks and long- CEA.59 First results are expected in late 2021 and will
term effects between stenting and endarterectomy for considerably increase the evidence base, which may
asymptomatic carotid stenosis were available from lead to updates to the above recommendation.
seven trials including a total of 3373 patients. Most
studies required patients to have 60% carotid steno- Expert consensus statements.
sis for inclusion. Duration of follow-up in the largest
trials was for five years or more. The risks of most
outcome events were low, which led us to downgrade
the level of evidence for imprecision. Low event rates 12/12 experts concluded that in patients with asymptomatic
Bonati et al. XIX
carotid stenosis in whom revascularisation is considered to The effects of treatment are presented with medical
be appropriate and who are less suitable for surgery, stent- therapy alone as the reference group. A summary of
ing may be suggested. We recommend careful consideration findings is provided in Table 5.
of the risks and benefits at a multi-disciplinary team meeting.
PICO 4.1: In patients with symptomatic carotid steno-
sis, does endarterectomy compared with medical therapy
alone reduce the long-term risk of ipsilateral stroke,
including peri-procedural stroke in any territory or peri-
12/12 experts concluded that the independently assessed procedural death? The reduction in the long-term risk
risk of in-hospital stroke or death following endarterectomy of ipsilateral stroke, including peri-procedural stroke
or stenting for asymptomatic carotid stenosis should be as in any territory or peri-procedural death, with end-
low as possible, ideally below 2%.6
arterectomy is strongly dependent on the degree of
the symptomatic stenosis and the time interval
Endarterectomy or medical therapy for symptomatic between the index neurological event and randomisa-
tion. There is very low quality evidence for a benefit
carotid stenosis
of CEA if data from all symptomatic patients,
Description of studies. There are three RCTs which ran- regardless of the severity of their stenosis, are
domly assigned patients with symptomatic carotid grouped and analysed together (RR: 0.83, 95% CI:
artery stenosis to CEA or medical therapy alone in a 0.61–1.14; equivalent to 26 fewer events with CEA
1:1 ratio. The North American Symptomatic Carotid per 1000 patients, from 59 fewer to 21 more;
Endarterectomy Trial (NASCET) separately reported Figure 4.1). The level of evidence was additionally
results in patients with severe (70–99%), moderate (50– downgraded for inconsistency due to statistical het-
69%) or mild (<50%) symptomatic carotid stenosis.9 erogeneity between trials. Stratifying results by degree
The first report in 1991 included outcomes in 659 of stenosis, there is high quality evidence of a mean-
patients with severe stenosis who had experienced a ingful benefit of CEA in patients with 70–99% ste-
hemispheric or retinal transient ischaemic attack nosis (RR: 0.37, 0.27–0.50; 169 fewer events per 1000
(TIA) or a non-disabling stroke within the 120 days patients, from 196 fewer to 134 fewer; Figure 4.1.4);
before enrolment.60 The second report in 1998 included low quality evidence of potential benefit in an overall
outcomes in 858 patients with moderate stenosis and population of patients with 50–69% stenosis (RR:
1368 patients with mild stenosis with a transient ischae- 0.82, 0.58–1.15; 29 fewer events per 1000 patients,
mic attack or non-disabling stroke within 180 days from 67 fewer to 24 more); and no evidence of ben-
before study entry.61 The 1998 report also provided efit amongst patients with <50% stenosis (RR: 1.09,
long-term follow-up data for up to eight years in 0.64–1.85) or near-occlusion (RR: 1.03, 0.57–1.84;
patients with severe stenosis included in the first report. very low grade evidence each). The interaction
The MRC European Carotid Surgery Trial (ECST) between degree of stenosis and the effect of CEA
reported results in 778 patients with severe (70–99%) was significant (p < 0.0001).
and 374 patients with very mild (0–29%) symptomatic The benefit of CEA in patients with 50% stenosis
carotid stenosis in 1991,62,63 the results in 1599 patients was most pronounced amongst patients randomised
with mild to moderate (30–69%) symptomatic carotid within two weeks of the index neurological event
stenosis in 1996, and the final results with follow-up for (RR: 0.41, 0.30–0.58, 174 fewer events per 1000
up to eight years in all 3024 patients with symptomatic patients, from 206 fewer to 124 fewer, high quality evi-
carotid stenosis in 1998.64 Eligible patients had a non- dence; Figure 4.1.3), but benefit was still present up to
disabling ischaemic stroke, TIA or retinal infarction 12 weeks (p ¼ 0.001 for interaction with time).
attributable to the carotid stenosis in the preceding An individual patient data meta-analysis of all three
six months. In the publication from which data for trials showed that the degree of stenosis and time since
the current guideline were extracted, degrees of stenosis the last event modified the effect of CEA in an additive
had been re-measured according to the method used in manner. There was a significant 14.8% (95% CI: 6.2–
the NASCET trial.12 23.4%) absolute reduction in the five-year risk of ipsi-
The Veterans Affairs Cooperative Studies Program lateral carotid territory ischaemic stroke or any stroke
(VACSP) symptomatic carotid stenosis trial included or death within 30 days of CEA in patients with mod-
189 patients with >50% symptomatic carotid stenosis erate (50–69%) stenosis who were randomised within
and followed them up for a maximum of 33 months.65 14 days of their index ischaemic event (data not includ-
Eligible patients had an ischaemic stroke, TIA or tran- ed in SoF table or figure).66
sient monocular blindness in the preceding 120 days. There is no evidence that the benefit of CEA dif-
Results were reported in 1991. fers with age (Figure 4.1.1). Although the reduction
XX
Table 5. Summary of findings for endarterectomy versus medical therapy for symptomatic carotid stenosis (PICO 4.1–4.4).
@ of Study Risk Other Medical Relative Absolute

studies design of bias Inconsistency Indirectness Imprecision considerations Endarterectomy therapy (95% CI) (95% CI) Certainty Importance
PICO 4.1: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death (30-99% stenosis)
3 Randomised Not serious Seriousa Seriousb Seriousc None 394/3336 415/2754 RR 0.83 26 fewer per ⨁ CRITICAL
trials (11.8%) (15.1%) (0.61–1.14) 1000 VERY LOW
(from 59 fewer to
21 more)
PICO 4.1.1a: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death (50-99% stenosis): Age < 65 years
2 Randomised Not serious Not serious Seriousb Not serious None 86/731 93/550 RR 0.70 51 fewer per ⨁⨁⨁ CRITICAL
trials (11.8%) (16.9%) (0.53–0.92) 1000 MODERATE
(from 79 fewer to
14 fewer)
PICO 4.1.1b: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death (50-99% stenosis): Age 65 years
trials (12.0%) (21.8%) (0.44–0.73) 1000 MODERATE
(from 122 fewer
to 59 fewer)
PICO 4.1.2a. Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death (50-99% stenosis): Men
trials (11.1%) (21.1%) (0.44–0.67) 1000 MODERATE
(from 118 fewer
to 70 fewer)
PICO 4.1.2.b.: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death (50-99% stenosis): Women
2 Randomised Not serious Not serious Seriousb Seriousc None 63/461 60/371 RR 0.85 24 fewer per ⨁⨁ CRITICAL
trials (13.7%) (16.2%) (0.58–1.23) 1000 LOW
(from 68 fewer to
37 more)
PICO 4.1.3a: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death (50-99% stenosis): <2 weeks since most recent
ischaemic event
2 Randomised Not serious Not serious Seriousb Not serious Strong associationd 40/325 88/299 RR 0.41 174 fewer per ⨁⨁⨁⨁ CRITICAL
trials (12.3%) (29.4%) (0.30–0.58) 1000 HIGH
(from 206 fewer
to 124 fewer)
PICO 4.1.3b: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death (50-99% stenosis): 2–4 weeks since most recent
ischaemic event
trials (11.6%) (20.5%) (0.35–0.98) 1000 MODERATE
(from 133 fewer
to 4 fewer)
(continued)
Table 5. Continued.

Bonati et al.
PICO 4.1.3c: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death (50-99% stenosis): 4–12 weeks since most recent
ischaemic event
trials (11.3%) (16.3%) (0.51–0.95) 1000 MODERATE
(from 80 fewer to
8 fewer)
PICO 4.1.3d: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death (50-99% stenosis): >12 weeks since most recent
ischaemic event
2 Randomised Not serious Not serious Seriousb Very seriousd None 41/321 31/232 RR 1.01 1 more per ⨁ CRITICAL
trials (12.8%) (13.4%) (0.66–1.57) 1000 VERY LOW
(from 45 fewer to
76 more)
PICO 4.1.4a: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Near occlusion
trials (15.3%) (14.9%) (0.57–1.84) 1000 VERY LOW
(from 64 fewer to
125 more)
PICO 4.1.4b: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Severe (70–99%) stenosis
trials (9.7%) (26.8%) (0.27–0.50) 1000 HIGH
(from 196 fewer
to 134 fewer)
PICO 4.1.4c: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Moderate (50–69%) stenosis
trials (12.5%) (15.9%) (0.58–1.15) 1000 LOW
(from 67 fewer to
24 more)
PICO 4.1.4d: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Mild (<50%) stenosis
2 Randomised Not serious Seriousa Seriousb Seriousc None 212/1762 164/1413 RR 1.09 10 more per ⨁ CRITICAL
trials (12.0%) (11.6%) (0.64–1.85) 1000 VERY LOW
(from 42 fewer to
99 more)
PICO 4.2: Long-term risk of stroke in any territory, including peri-procedural death (30-99% stenosis)
trials (17.6%) (21.2%) (0.77–0.94) 1000 MODERATE
(from 49 fewer to
13 fewer)
PICO 4.2.1a: Long-term risk of stroke in any territory, including peri-procedural death: Near-occlusion
2 Randomised Not serious Not serious Seriousb Very seriousd None 32/157 25/114 RR 1.00 0 fewer per ⨁ CRITICAL
trials (20.4%) (21.9%) (0.46–2.21) 1000 VERY LOW
(continued)
XXI
XXII
Table 5. Continued.

(from 118 fewer

to 265 more)
PICO 4.2.1b: Long-term risk of stroke in any territory, including peri-procedural death: Severe (70–99%) stenosis
2 Randomised Not serious Seriousa Seriousa Not serious Strong associationd 84/518 143/436 RR 0.48 171 fewer per ⨁⨁⨁ CRITICAL
trials (16.2%) (32.8%) (0.29–0.81) 1000 MODERATE
(from 233 fewer
to 62 fewer)
PICO 4.2.1c: Long-term risk of stroke in any territory, including peri-procedural death: Moderate (50–69%) stenosis
trials (17.8%) (23.8%) (0.63–0.94) 1000 MODERATE
(from 88 fewer to
14 fewer)
PICO 4.2.1d: Long-term risk of stroke in any territory, including peri-procedural death: Mild (<50%) stenosis
2 Randomised Not serious Not serious Seriousb Seriousc None 318/1762 244/1413 RR 1.09 16 more per ⨁⨁ CRITICAL
trials (18.0%) (17.3%) (0.89–1.34) 1000 LOW
(from 19 fewer to
59 more)
PICO 4.3: Long-term risk of major stroke, including peri-procedural death (30-99% stenosis)
trials (4.5%) (5.5%) (0.51–1.22) 1000 LOW
(from 27 fewer to
12 more)
PICO 4.3.1a: Long-term risk of major stroke, including peri-procedural death: Near-occlusion
trials (7.6%) (6.1%) (0.35–5.08) 1000 VERY LOW
(from 40 fewer to
251 more)
PICO 4.3.1b: Long-term risk of major stroke, including peri-procedural death: Severe (70–99%) stenosis
trials (4.2%) (12.2%) (0.22–0.57) 1000 HIGH
(from 95 fewer to
52 fewer)
PICO 4.3.1c: Long-term risk of major stroke, including peri-procedural death: Moderate (50–69%) stenosis
trials (4.3%) (5.6%) (0.41–1.27) 1000 LOW
(from 33 fewer to
15 more)
(continued)
Bonati et al. XXIII
in the combined outcome was not statistically signif-
IMPORTANT
icant in women (Figure 4.1.2), this was likely due to
Importance
CRITICAL
the low number of women included in the trials
(n ¼ 832).

Certainty
⨁⨁
⨁⨁
LOW
LOW
alone reduce the long-term risk of stroke in any territory,
including peri-procedural death? Amongst patients with
(from 31 fewer to
(from 6 fewer to
all degrees of stenosis combined, there is moderate

0 fewer per
8 more per
31 more)
40 more)
quality of evidence that CEA reduced the long-term
Absolute
(95% CI)
1000
1000
risk of stroke in any territory, including peri-

procedural death, compared with medical therapy
alone (RR: 0.85, 95% CI: 0.77–0.94; 32 fewer events
(0.82–1.87)
(0.85–1.19)
per 1000 patients, from 49 fewer to 13 fewer;

(95% CI)
RR 1.24
RR 1.00
Relative
Figure 4.2). The evidence for a beneficial effect of

Effect
CEA was of moderate quality in patients with 70–

99% stenosis (RR: 0.48, 95% CI: 0.29–0.81; 171
576/2758
50/1413
fewer events per 1000 patients, from 233 fewer to 62

Medical
(20.9%)
therapy
(3.5%)
fewer; Figure 4.2.1) and in patients with 50–59% ste-

nosis (RR: 0.77, 95% CI: 0.63–0.94; 55 fewer events
Endarterectomy
per 1000 patients, from 88 fewer to 14 fewer).

@ of patients
Comparing the number of events prevented between

738/3335
79/1762
PICO 4.1 and PICO 4.2 within each stenosis category,

(22.1%)
PICO 4.3.1d: Long-term risk of major stroke, including peri-procedural death: Mild (<50%) stenosis
(4.5%)
it can be inferred that CEA mainly prevents ipsilateral

Endarterectomy and medical therapy have evolved since the trials contributing the evidence were performed.
stroke.
considerations

alone reduce the long-term risk of major stroke, including
Other
None
None
peri-procedural death? Amongst patients with all

degrees of stenosis combined, endarterectomy did not
Imprecision
significantly reduce the long-term risk of major stroke,

Seriousc
Seriousc
including peri-procedural death (RR: 0.79, 95% CI:

0.51–1.22; 12 fewer events per 1000 patients, from 27
fewer to 12 more; low quality evidence; Figure 4.3).
Indirectness
However, once again, the benefit of CEA varies

Seriousb
Seriousb
according to the degree of stenosis. In patients with

PICO 4.4: Long-term risk of death (30-99% stenosis)
70–99% stenosis, there is high quality evidence of ben-

efit (RR: 0.35, 95% CI: 0.22–0.57; 79 fewer events per
Inconsistency
1000 patients, from 95 fewer to 52 fewer; Figure 4.3.1).

Randomised Not serious Not serious
Randomised Not serious Not serious
Conversely, there was low quality evidence of potential

benefit in patients with 50–69% stenosis (RR: 0.73,
95% CI: 0.41–1.27; 15 fewer events per 1000 patients,
from 33 fewer to 15 more), low quality evidence of

Significant heterogeneity, I2 > 70%.
harm in patients with <50% stenosis (RR: 1.24, 95%

of bias
CI: 0.82–1.87), and very low quality evidence of harm

Risk
in patients with near occlusion (RR: 1.33, 95% CI:

Table 5. Continued.
0.35–5.08).
Certainty assessment
trials
trials
design
Study

Large effect.

studies
alone reduce the long-term risk of death?

@ of
Endarterectomy does not reduce the long-term risk of

2
d
b
c
a
XXIV European Stroke Journal 6(2)
Figure 4.1. Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death in end-
arterectomy versus medical therapy for 30–99% symptomatic carotid stenosis.
Figure 4.1.1. Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death in
endarterectomy versus medical therapy for 50–99% symptomatic carotid stenosis.
Subgroup: Age.
Subgroup: Sex.
death compared with medical therapy alone (RR: 1.00, stenosis was available from three trials, which includ-
95% CI: 0.85–1.19; 0 fewer events per 1000 patients, ed 6098 patients. Symptomatic carotid stenosis was
from 31 fewer to 40 more; low quality of evidence; defined by the occurrence of ischaemic ocular or
Figure 4.4). cerebral events attributable to the stenosis within
four to six months before enrolment, depending on
Analysis of current evidence and evidence-based recommenda- the trial and the severity of stenosis. The evidence
tion. Evidence of the effect of CEA compared with provided relates to the time when these trials were
medical therapy alone for symptomatic carotid performed three decades ago. Medical treatment of
Bonati et al. XXV
Subgroup: Time since last ischaemic event.
endarterectomy versus medical therapy for symptomatic carotid stenosis.
Subgroup: Severity of stenosis.
XXVI European Stroke Journal 6(2)
Figure 4.2. Long-term risk of stroke in any territory, including peri-procedural death in endarterectomy versus medical therapy for
30–99% symptomatic carotid stenosis.
for symptomatic carotid stenosis.
Figure 4.3. Long-term risk of major stroke, including peri-procedural death in endarterectomy versus medical therapy for 30–99%
symptomatic carotid stenosis.
patients with atherosclerotic carotid stenosis has techniques and perioperative management have also
improved, with widespread use of statins, the avail- improved since these trials were completed. We there-
ability of better antiplatelet treatment regimens and fore downgraded the overall quality of evidence for
stricter control of blood pressure. However, surgical indirectness.
Bonati et al. XXVII
Figure 4.3.1. Long-term risk of major stroke, including peri-procedural death in endarterectomy versus medical therapy for
Subgroup: Severity of Stenosis.
Figure 4.4. Long-term risk of death in endarterectomy versus medical therapy for 30–99% symptomatic carotid stenosis.
The benefits of CEA in patients with symptomatic occlusion in the early endarterectomy trials depended
carotid stenosis strongly depends on the degree of ste- on intra-arterial angiography, and there are no widely-
nosis. Amongst patients with severe (70–99%) stenosis, accepted standardised criteria for near-occlusion on
there is high quality evidence that CEA prevents ipsi- ultrasound or non-invasive angiography.67 We there-
lateral stroke, moderate quality evidence that it pre- fore could not make any clear recommendations on
vents stroke in any territory, and high quality the treatment of carotid near-occlusion in this guide-
evidence that it prevents major stroke, taking into line. The benefit of CEA also strongly depends on the
account the combined risks of peri-operative stroke timing of treatment, with the greatest reduction in
or death. In patients with moderate (50–69%) carotid stroke risk achieved if surgery is performed <14 days
stenosis, there is low quality evidence that CEA pre- of the index event. We found no evidence that the ben-
vents ipsilateral stroke and major stroke, and moderate efit of CEA varies substantially between men and
quality evidence for prevention of stroke in any terri- women or between older and younger patients.
tory, again taking into account the peri-operative The optimal management of patients with distal
stroke or death risk, if patients are operated upon tandem stenosis is uncertain. In NASCET, patients
within 14 days of their presenting cerebrovascular who had 85–99% extracranial ICA stenosis and any
event. There is no evidence that CEA prevents stroke degree of co-existing, ipsilateral intracranial athero-
in patients with mild (<50%) stenosis or near-occlusion sclerotic disease (IAD) had an increased risk of ipsi-
of the carotid artery. However, the definition of near- lateral stroke over three years if they were treated
XXVIII European Stroke Journal 6(2)
with best medical therapy alone compared with those symptomatic carotid stenosis that fulfilled our inclu-
without IAD (45.7% vs. 25.3%, relative risk 1.8, sion criteria. We excluded two small RCTs because
95% CI: 1.1–3.2).68 However, the three-year risk of these studies did not report outcomes according to
ipsilateral stroke in surgically-treated patients with symptom status,37,38 or patients were treated with pri-
85–99% extracranial ICA stenosis was similar in mary balloon angioplasty.38
those with and those without IAD (8.6% vs. 10%,
relative risk 0.9; 95% CI: 0.2–3.0). Therefore, IAD Stenting or endarterectomy for symptomatic
should not deter one from proceeding to CEA in carotid stenosis
suitable patients, whilst acknowledging that only a
Description of studies. A single-centre trial in Lexington,
very small number of patients with severe stenosis
Kentucky, USA randomised 104 patients with 70%
were included in this subgroup analysis of the
symptomatic carotid stenosis to receive either CAS
NASCET data.
without a cerebral protection device (CPD) or CEA
and reported results up to two years after randomisa-
Recommendations:
tion in 2001.69
In patients with severe (70–99%) symptomatic carotid The French multi-centre Endarterectomy versus
artery stenosis, we recommend carotid endarterectomy. Angioplasty in Patients with Symptomatic Severe
Quality of evidence: High 丣丣丣丣 Carotid Stenosis (EVA-3S) trial randomised 527
Strength of recommendation: Strong for carotid endarter-
patients with 60% symptomatic carotid stenosis to
ectomy ""
undergo CAS or CEA between 2000 and 2005.70–75
In patients with moderate (50–69%) symptomatic carotid Interventionists were required to have performed at
artery stenosis, we suggest carotid endarterectomy. least 12 CAS procedures, or at least 35 stenting pro-
Quality of evidence: Low 丣丣 cedures in the supra-aortic trunks, of which at least 5
Strength of recommendation: Weak for carotid endarterec- involved the carotid artery. The use of CPDs during
tomy "
stenting was made mandatory after an interim analy-
In patients with mild (<50%) symptomatic carotid artery sis raised safety concerns amongst patients treated
stenosis, we recommend against carotid endarterectomy. without CPDs. The trial was stopped early for
Quality of evidence: Very low 丣 safety and futility reasons. Initial results were pub-
Strength of recommendation: Strong against carotid endar- lished in 2006, and final results with available data
terectomy ##
over a median follow-up period of 7.1 years were
In patients with 50–99% symptomatic carotid stenosis in reported in 2014.
whom surgery is considered appropriate, we recommend The multi-centre Stent-supported Percutaneous
early endarterectomy, ideally within two weeks of the first Angioplasty of the Carotid artery versus
neurological event. Endarterectomy (SPACE) trial randomised 1214
Quality of evidence: High 丣丣丣丣 patients with 50% symptomatic carotid stenosis
Strength of recommendation: Strong for carotid endarter-
between CAS and CEA in Germany, Austria, and
ectomy ""
Switzerland between 2001 and 2006.76–78
These recommendations are independent of sex and age. Interventionists had to show proof of at least 25 suc-
cessful, consecutive percutaneous transluminal angio-
Additional information. The Second European Carotid plasty or stent procedures in the carotid artery. The
Surgery Trial (ECST-2) is comparing optimised med- use of a CPD was not mandatory. The trial was
ical therapy (OMT) alone versus OMT and carotid stopped early for reasons of futility and lack of fund-
revascularisation in patients with symptomatic carotid ing. Initial results were published in 2006 and final
stenosis estimated to be at low or intermediate risk of results up to two years after randomisation were pub-
stroke using ‘clinical risk modelling’, and in patients lished in 2008.
with asymptomatic carotid stenosis. ECST-2 discontin- A single-centre trial in Regensburg, Germany, rand-
ued recruitment after inclusion of 429 patients in its omised 87 patients with 70% symptomatic carotid
pilot phase and results are awaited (www.ecst2.com, stenosis to undergo CAS without a CPD or CEA
last accessed 2 February 2021). between 1999 and 2002.79 Recruitment was stopped
when the multi-centre SPACE trial, which had a simi-
lar study design, was commenced. Results over a
Stenting or medical therapy for symptomatic
median follow-up period of >5 years were published
carotid stenosis in 2008.
Description of studies. We identified no RCTs comparing The multi-centre International Carotid Stenting
stenting versus medical therapy alone in patients with Study (ICSS) randomised 1713 patients with 50%
Bonati et al. XXIX
symptomatic carotid stenosis to receive either CAS or provided moderate quality evidence that CEA was
CEA in Europe, Australia, New Zealand, and Canada superior to CAS in patients aged 65–74 years (hazard
between 2001 and 2008.80–83 Eligible patients had ratio (HR): 1.67, 95% CI: 1.23–2.27) and 75 years
symptoms attributable to their carotid stenosis within (HR: 1.85, 95% CI: 1.35–2.53), and low quality evi-
12 months before randomisation; however, only 4% dence that there was no difference in outcomes between
had symptoms which occurred more than 6 months stenting and endarterectomy amongst patients
before randomisation. Interventionists were required <65 years old (HR: 0.83, 95% CI: 0.56–1.21), with a
to have carried out at least 50 stenting procedures, at significant interaction between age and treatment effect
least 10 of which were in the carotid artery. Use of (p ¼ 0.003; data not shown in figure). There was no
CPDs was recommended but not mandatory. Initial evidence of an interaction with sex or severity of
results were published in 2011 and final results with stenosis.
data over a median follow-up period of 4.2 years were
reported in 2015. PICO 6.2: In patients with symptomatic carotid steno-
The single-centre Basel Carotid Artery Stenting sis, do endarterectomy and stenting differ in the long-term
Study (BACASS) randomised 20 patients with 50% risk of post-procedural ipsilateral stroke? There is mod-
symptomatic carotid stenosis to CAS with routine use erate quality of evidence that stenting and endarterec-
of a CPD or CEA between 1998 and 2002.84 tomy do not differ in their ability to prevent long-
Recruitment was stopped when the centre started term post-procedural ipsilateral stroke (RR: 1.06,
recruiting patients in ICSS. Results including follow- 95% CI: 0.74–1.51; equivalent to 1 more event with
up data over a median of four years after randomisa- stenting per 1000 patients, from 6 fewer to 12 more;
tion were published in 2008. Figure 6.2).
We also extracted relevant outcomes in symptom-
atic patients from the Ostrava and CREST trials, PICO 6.3: In patients with symptomatic carotid steno-
which are described in results section ‘Stenting or sis, do endarterectomy and stenting differ in the long-term
endarterectomy for asymptomatic carotid stenosis’. risk of stroke in any territory, including peri-procedural
Furthermore, we included outcomes in pre-defined death? There is moderate quality of evidence that end-
patient subgroups derived from pooled analyses of arterectomy is superior to stenting in preventing the
individual patient data (IPD) from the EVA-3S, combined long-term outcome of stroke in any territory
SPACE, ICSS and CREST trials which were per- or peri-procedural death (RR: 1.34, 95% CI: 1.08–1.66;
formed by the Carotid Stenosis Trialists 35 more events with stenting per 1000 patients, from
Collaboration (CSTC).85–87 8 more to 68 more; Figure 6.3).
We excluded one industry-funded multi-centre
randomised trial because the results were only PICO 6.4: In patients with symptomatic carotid steno-
reported in a conference abstract,88 and also excluded sis, do endarterectomy and stenting differ in the long-term
one single-centre and one multicentre randomised trial risk of major stroke, including peri-procedural death?
in which the majority of patients in the endovascular There is low quality of evidence that endarterectomy
group were treated with primary balloon and stenting do not differ in the long-term risk of major
angioplasty.89,90 stroke or peri-procedural death (RR: 1.19, 95% CI:
The effects of treatment are presented with endar- 0.88–1.62; 12 more events with stenting per 1000
terectomy as the reference group. A summary of find- patients, from 8 fewer to 39 more; Figure 6.4).
ings is provided in Table 6.
PICO 6.1: In patients with symptomatic carotid stenosis, do endarterectomy and stenting differ in the long-term
sis, do endarterectomy and stenting differ in the long-term risk of death? There is low quality of evidence that end-
risk of ipsilateral stroke, including peri-procedural stroke arterectomy and stenting do not differ in the long-term
in any territory or peri-procedural death? There is mod- risk of death (RR: 1.09, 95% CI: 0.94–1.27; 13 more
erate quality of evidence that endarterectomy is supe- events with stenting per 1000 patients, from 9 fewer to
rior to stenting in preventing the combined outcome of 38 more; Figure 6.5).
post-procedural ipsilateral stroke, peri-procedural
stroke in any territory, or peri-procedural death (RR: PICO 6.6: In patients with asymptomatic or symptom-
1.43, 95% CI: 1.17–1.75; equivalent to 31 more events atic carotid stenosis, do endarterectomy and stenting
with stenting per 1000 patients, from 12 more to 54 differ in the long-term risk of severe restenosis? For
more; Figure 6.1). In a pooled IPD analysis from the the analysis of restenosis, we combined the data from
EVA-3S, SPACE, ICSS and CREST trials, the relative trials including patients with asymptomatic carotid ste-
risk of this outcome varied with age87: this analysis nosis, symptomatic stenosis, or both. There is very low
Table 6. Summary of findings for stenting or endarterectomy for symptomatic carotid stenosis (PICO 6.1–6.12).
XXX
@ of Study Risk Other Relative Absolute

studies design of bias Inconsistency Indirectness Imprecision considerations Stenting Endarterectomy (95% CI) (95% CI) Certainty Importance
7 Randomised Not serious Not serious Seriousa Not serious None 261/2499 177/2466 RR 1.43 31 more per ⨁⨁⨁ CRITICAL
trials (10.4%) (7.2%) (1.17–1.75) 1000 MODERATE
(from 12 more to
54 more)
PICO 6.1.1a: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Age < 65 years
4 IPD of rando- Not serious Not serious Seriousa Seriousb None HR 0.83 ⨁⨁ CRITICAL
mised trials (0.56–1.21) LOW
PICO 6.1.1b: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Age 65–74 years
4 IPD of rando- Not serious Not serious Seriousa Not serious None HR 1.67 ⨁⨁⨁ CRITICAL
mised trials (1.23–2.27) MODERATE
PICO 6.1.1c: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Age 75 years
PICO 6.1.2a: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Men
PICO 6.1.2b: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Women
PICO 6.1.3a: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Severe (70-99%) stenosis
PICO 6.1.3b: Long-term risk of ipsilateral stroke, including peri-procedural stroke in any territory or peri-procedural death: Moderate (50-69%) stenosis
PICO 6.2: Long-term risk of post-procedural ipsilateral stroke
trials (2.6%) (2.4%) (0.74–1.51) 1000 MODERATE
(from 6 fewer to
12 more)
PICO 6.3. Long-term risk of stroke in any territory, including peri-procedural death
trials (14.5%) (10.2%) (1.08–1.66) 1000 MODERATE
(from 8 more to
68 more)
(continued)
Table 6. Continued.

Bonati et al.
PICO 6.4. Long-term risk of major stroke, including peri-procedural death

3 Randomised Not serious Not serious Seriousa Seriousb None 84/1117 71/1125 RR 1.19 12 more per ⨁⨁ CRITICAL
trials (7.5%) (6.3%) (0.88–1.62) 1000 LOW
(from 8 fewer to
39 more)
PICO 6.5. Long-term risk of death
5 Randomised Not serious Not serious Seriousa Seriousb None 278/1778 251/1762 RR 1.09 13 more per ⨁⨁ IMPORTANT
trials (15.6%) (14.2%) (0.94–1.27) 1000 LOW
(from 9 fewer to
38 more)
PICO 6.6: Long-term risk of severe restenosis
9 Randomised Not serious Seriousc Seriousa Seriousb None 212/3077 166/3147 RR 1.37 20 more per ⨁ IMPORTANT
trials (6.9%) (5.3%) (0.89–2.10) 1000(from 6 VERY LOW
fewer to 58
more)
PICO 6.7: Risk of peri-procedural stroke
trials (6.7%) (4.1%) (1.24–2.17) 1000 MODERATE
(from 10 more to
48 more)
PICO 6.8: Risk of peri-procedural death
8 Randomised Not serious Not serious Seriousa Very seriousd None 22/2538 14/2514 RR 1.45 3 more per ⨁ CRITICAL
trials (0.9%) (0.6%) (0.73–2.87) 1000 VERY LOW
(from 2 fewer to
10 more)
PICO 6.9: Risk of peri-procedural stroke or death
trials (6.9%) (4.1%) (1.20–2.34) 1000 MODERATE
(from 8 more to
55 more)
PICO 6.9.1a: Risk of peri-procedural stroke or death: Age < 70 years
trials (4.5%) (4.1%) (0.75–1.60) 1000 LOW
(from 10 fewer to
24 more)
PICO 6.9.1b: Risk of peri-procedural stroke or death: Age 70 years
6 Randomised Not serious Not serious Seriousa Not serious Strong associatione 122/1195 58/1213 RR 2.10 53 more per ⨁⨁⨁⨁ CRITICAL
trials (10.2%) (4.8%) (1.55–2.84) 1000 HIGH
(from 26 more to
88 more)
(continued)
XXXI
Table 6. Continued.
XXXII

PICO 6.9.2a: Risk of peri-procedural stroke or death: Men

trials (7.1%) (4.1%) (1.09–2.85) 1000 MODERATE
(from 4 more to
76 more)
PICO 6.9.2b: Risk of peri-procedural stroke or death: Women
trials (7.6%) (5.0%) (0.94–2.23) 1000 LOW
(from 3 fewer to
62 more)
PICO 6.9.3a: Risk of peri-procedural stroke or death: Severe (70–99%) stenosis
3 IPD of rando- Not serious Not serious Seriousa Not serious None 132/1393 86/1381 RR 1.52 32 more per ⨁⨁⨁ CRITICAL
mised trials (9.5%) (6.2%) (1.17–1.98) 1000 MODERATE
(from 11 more to
61 more)
PICO 6.9.3b: Risk of peri-procedural stroke or death: Moderate (50–69%) stenosis
3 IPD of rando- Not serious Not serious Seriousa Seriousd None 21/332 13/327 RR 1.59 23 more per ⨁⨁ CRITICAL
mised trials (6.3%) (4.0%) (0.81–3.12) 1000 LOW
(from 8 fewer to
84 more)
PICO 6.9.4a: Risk of peri-procedural stroke or death: 7 days since most recent ischaemic event
4 IPD of rando- Not serious Not serious Seriousa Not serious Very strong associatione 24/287 3/226 RR 6.30 70 more per ⨁⨁⨁⨁ CRITICAL
mised trials (8.4%) (1.3%) (1.92–20.66) 1000 HIGH
(from 12 more to
261 more)
PICO 6.9.4b: Risk of peri-procedural stroke or death: > 7 days since most recent ischaemic event
4 IPD of rando- Not serious Not serious Serious a Not serious None 129/1798 65/1815 RR 2.00 36 more per ⨁⨁⨁ CRITICAL
(from 18 more to
60 more)
PICO 6.9.5a: Risk of peri-procedural stroke or death: Hemispheric stroke as most recent ischaemic event
(from 10 more to
80 more)
PICO 6.9.5b: Risk of peri-procedural stroke or death: TIA as most recent ischaemic event
(from 7 more to
87 more)
(continued)
Bonati et al.
Table 6. Continued.

PICO 6.9.5c: Risk of peri-procedural stroke or death: Retinal ischaemia as most recent ischaemic event
3 IPD of rando- Not serious Not serious Seriousa Very seriousd None 15/310 14/297 RR 1.03 1 more per ⨁ CRITICAL
mised trials (4.8%) (4.7%) (0.50–2.09) 1000 VERY LOW
(from 24 fewer to
51 more)
PICO 6.10: Risk of peri-procedural major stroke or death
7 Randomised Not serious Not serious Seriousa Seriousb None 81/2495 60/2470 RR 1.33 8 more per ⨁⨁
trials (3.2%) (2.4%) (0.96–1.85) 1000 LOW
(from 1 fewer to
21 more)
PICO 6.11: Risk of peri-procedural myocardial infarction
6 Randomised Not serious Not serious Seriousa Seriousb Strong associatione 11/1878 23/1874 RR 0.48 6 fewer per ⨁⨁⨁ IMPORTANT
trials (0.6%) (1.2%) (0.24–0.98) 1000 MODERATE
(from 9 fewer to 0
fewer)
PICO 6.12: Risk of peri-procedural cranial nerve injury
6 Randomised Not serious Not serious Seriousa Not serious Very strong associatione 7/1892 103/1877 RR 0.10 49 fewer per ⨁⨁⨁⨁ IMPORTANT
trials (0.4%) (5.5%) (0.05–0.20) 1000 HIGH
(from 52 fewer to
44 fewer)

a
Stenting and endarterectomy have evolved since the time of the contributing trials.
b
c
Significant heterogeneity, I2 > 60%.
d
e
Large effect.
XXXIII
XXXIV European Stroke Journal 6(2)
versus endarterectomy for symptomatic carotid stenosis.
Figure 6.2. Long-term risk of post-procedural ipsilateral stroke in stenting versus endarterectomy for symptomatic carotid stenosis.
Figure 6.3. Long-term risk of stroke in any territory, including peri-procedural death in stenting versus endarterectomy for
Figure 6.4. Long-term risk of major stroke, including peri-procedural death in stenting versus endarterectomy for symptomatic
carotid stenosis.
Figure 6.5. Long-term risk of death in stenting versus endarterectomy for symptomatic carotid stenosis.
Bonati et al. XXXV
quality evidence that endarterectomy and stenting do PICO 6.8: In patients with symptomatic carotid steno-
not differ in the long-term risk of severe restenosis sis, do endarterectomy and stenting differ in the risk of
(RR: 1.37, 95% CI: 0.89–2.10; Figure 6.6). We addi- peri-procedural death? There is very low quality of evi-
tionally downgraded the evidence for inconsistency, as dence that stenting and endarterectomy do not differ in
there was evidence of substantial heterogeneity between the risk of peri-procedural death (RR: 1.45, 95% CI:
trials (I2 ¼ 57%). 0.73–2.87; 3 more events per 1000 patients with stent-
ing, from 2 fewer to 10 more; Figure 6.8).
sis, do endarterectomy and stenting differ in the risk of PICO 6.9: In patients with symptomatic carotid steno-
peri-procedural stroke? There is moderate quality of sis, do endarterectomy and stenting differ in the risk of
evidence that stenting is associated with a higher risk peri-procedural stroke or death? There is moderate
of peri-procedural stroke than endarterectomy (RR: quality evidence that stenting is associated with a
1.64, 95% CI: 1.24–2.17; 26 more events with stenting higher risk of peri-procedural stroke or death than end-
per 1000 patients, from 10 more to 48 more; arterectomy overall (RR: 1.68, 95% CI: 1.20–2.34; 28
Figure 6.7). more events with stenting per 1000 patients, from
Figure 6.6. Long-term risk of severe restenosis in stenting versus endarterectomy for symptomatic or asymptomatic carotid
stenosis.
Figure 6.7. Risk of peri-procedural stroke in stenting versus endarterectomy for symptomatic carotid stenosis.
Figure 6.8. Risk of peri-procedural death in stenting versus endarterectomy for symptomatic carotid stenosis.
XXXVI European Stroke Journal 6(2)
8 more to 55 more; Figure 6.9). However, these results (Figure 6.9.3) or type of most recent ischaemic event
vary with age. Amongst patients 70 years, there is (hemispheric stroke, transient ischaemic attack or
high quality evidence that CAS is associated with a ocular ischaemia; Figure 6.9.5).85
higher risk of this composite outcome compared with Another pooled analysis of IPD from EVA-3S,
CEA (RR: 2.10, 95% CI: 1.55–2.84; 53 more events SPACE, ICSS and CREST provides high-quality
with stenting per 1000 patients, from 26 more to 88 evidence of an increased risk of peri-procedural
more; Figure 6.9.1). Amongst patients <70 years, stroke or death with CAS compared with CEA
there is low quality evidence that the risk of this com- amongst patients treated <7 days after their most
bined outcome does not differ between the two treat- recent ischaemic event (RR: 6.30, 95% CI: 1.92–
ment modalities (RR: 1.10, 95% CI: 0.75–1.60; 4 more 20.66; 70 more events with CAS per 1000 patients,
events with stenting per 1000 patients, from 10 fewer to from 12 more to 261 more; Figure 6.9.4), and moderate
24 more). The interaction between age and treatment quality evidence for this difference amongst patients
effect is significant (p ¼ 0.009). There is no evidence of treated >7 days after the event (RR: 2.00, 95% CI:
an interaction with sex (Figure 6.9.2). 1.50–2.68; 36 more events with stenting per 1000
A pooled analysis of IPD from EVA-3S, SPACE patients, from 18 more to 60 more).86 The unadjusted
and ICSS provides no evidence for a modification of p-value for the interaction between timing and treat-
the effect of CAS versus CEA on the risk of peri- ment effect was 0.07, the adjusted p-value in the orig-
procedural stroke or death by the severity of stenosis inal publication was 0.06.
Figure 6.9. Risk of peri-procedural stroke or death in stenting versus endarterectomy for symptomatic carotid stenosis.
Figure 6.9.1. Risk of peri-procedural stroke or death in stenting versus endarterectomy for symptomatic carotid stenosis.
Subgroup: Age.
Bonati et al. XXXVII
Subgroup: Sex.
Subgroup: Time since last ischaemic event.
PICO 6.10: In patients with symptomatic carotid ste- with an increased risk of peri-procedural major stroke
nosis, do endarterectomy and stenting differ in the risk of or death (RR: 1.33, 95% CI: 0.96–1.85; 8 more events
peri-procedural major stroke or death? There is low with stenting per 1000 patients, from 1 fewer to 21
quality of evidence that stenting is likely associated more; Figure 6.10).
XXXVIII European Stroke Journal 6(2)
Subgroup: Type of last ischaemic event.
Figure 6.10. Risk of peri-procedural major stroke or death in stenting versus endarterectomy for symptomatic carotid stenosis.
Figure 6.11. Risk of peri-procedural myocardial infarction in stenting versus endarterectomy for symptomatic carotid stenosis.
PICO 6.11: In patients with symptomatic carotid ste- ‘indirectness’ due to the definition of myocardial
nosis, do endarterectomy and stenting differ in the risk of infarction used in the CREST trial which contributed
peri-procedural myocardial infarction? There is moderate to two thirds of the cardiac outcome events included in
quality of evidence that stenting is associated with a the aggregate analysis (see results section ‘Stenting
lower risk of peri-procedural myocardial infarction or endarterectomy for asymptomatic carotid stenosis’).
than endarterectomy (RR: 0.48, 95% CI: 0.24–0.98; 6
fewer events with stenting per 1000 patients, from 9 PICO 6.12: In patients with symptomatic carotid ste-
fewer to 0 fewer; Figure 6.11). Even though the relative nosis, do endarterectomy and stenting differ in the risk of
effect was large, there were a limited number of clini- peri-procedural cranial nerve injury? There is strong evi-
cally relevant cardiac outcome events observed. dence that stenting is associated with a lower risk of
Furthermore, we had additional concerns about peri-procedural cranial nerve injury than
Bonati et al. XXXIX
Figure 6.12. Risk of peri-procedural cranial nerve injury in stenting versus endarterectomy for symptomatic carotid stenosis.
endarterectomy (RR: 0.10, 95% CI: 0.05–0.20; 49 fewer myocardial infarction and mostly transient cranial
events with stenting per 1000 patients, from 52 fewer to nerve palsy (important for decision making).
44 fewer; Figure 6.12). We upgraded the quality of the The risks of peri-procedural stroke or death differ
evidence by two levels for strength of effect. between patient subgroups: there is high quality evi-
dence that stenting is associated with a higher risk of
Analysis of current evidence and evidence-based recommenda- this outcome in patients 70 years, and low quality
tion. Evidence to compare short-term risks and long- evidence that the risk of this outcome is similar in
term effects of CAS versus CEA for the treatment of patients <70 years. The higher risk of peri-procedural
symptomatic carotid stenosis was derived from 7 RCTs stroke or death after carotid artery stenting compared
which included a total of 4893 patients. It is important with endarterectomy is also more evident amongst
to note that the available evidence for CAS relates to patients treated within seven days of their index cere-
percutaneous trans-femoral stenting only. There are no brovascular event. After the peri-procedural period,
available data from RCTs on the safety of trans- there is moderate grade evidence that stenting and end-
carotid stenting. As such, all recommendations includ- arterectomy do not differ in their ability to prevent
ed in this guideline refer to trans-femoral CAS. All stroke.
studies included patients with 50% stenosis.
Symptomatic carotid stenosis was defined by the occur-
Recommendations
rence of ischaemic ocular or cerebral events attribut-
able to the stenosis within six months prior to In patients with symptomatic carotid artery stenosis requir-
enrolment, except in ICSS where a very small minority ing revascularisation, we recommend endarterectomy as the
treatment of choice.
of patients were enrolled 6–12 months after symptom
Quality of evidence: Moderate 丣丣丣
onset. Amongst the four largest trials contributing to Strength of recommendation: Strong for carotid endarter-
the evidence, the median duration of follow-up was ectomy ""
four to seven years in three studies and two years in
one study. When recruitment in these trials started In patients with symptomatic carotid stenosis <70 years old
requiring revascularisation, we suggest that stenting may be
20 years ago, carotid artery stenting was still at a rela-
considered as an alternative to endarterectomy.
tively early stage of technical development, peri- Quality of evidence: Low 丣丣
procedural medication regimens were not standardised, Strength of recommendation: Weak for carotid stenting "?
and there was limited experience with the procedure. In
addition, only a minority of patients included in these
trials were treated within the recommended 14 days of Additional information. In light of technical developments
their index ischaemic event. We therefore downgraded in stent design and cerebral protection devices, and
the quality of evidence for indirectness. alternative (trans-brachial and trans-carotid) access
Overall, there is moderate quality evidence that end- routes which are now available, new trials of stenting
arterectomy is superior to stenting when one considers in selected patients with symptomatic carotid stenosis
peri-procedural and post-procedural outcomes that are warranted.
were rated as ‘critical’ for decision making. The differ-
ences between stenting and endarterectomy are mainly Expert consensus statements.
apparent in the peri-procedural period: stenting is asso-
ciated with a higher risk of peri-procedural stroke than 12/12 experts concluded that the suitability of a patient with
endarterectomy (critical for decision making), whereas symptomatic carotid stenosis for carotid endarterectomy
endarterectomy is associated with higher risks of versus stenting should also take into account the interval
XL European Stroke Journal 6(2)
since their last ischaemic cerebrovascular event, as well as All recommendations and expert consensus statements
anatomical and morphological features, including the athero- are summarised in Tables 7 and 8.
sclerotic burden of the aortic arch. Carotid revascularisation has been studied in rand-
11/12 experts concluded that the independently assessed omised clinical trials for more than three decades, pro-
risk of in-hospital stroke or death following endarterectomy viding a wealth of evidence. Observational case series
or stenting for symptomatic carotid stenosis should not and large-scale registries are important to advance
exceed 4%.6 treatments and provide contemporary data on risks
12/12 experts concluded that where possible, the indication in real-world settings, but ultimately, the choice
for carotid endarterectomy or carotid artery stenting between treatment options should be informed by evi-
should be discussed at a multi-disciplinary team meeting. dence from high quality RCTs, where such trials are
Consensus decisions can be made in between meetings, in available. We therefore based our recommendations in
order not to delay urgent revascularisations. this guideline document for the choice between medical
12/12 experts concluded that the establishment of validated therapy alone, CEA or CAS on the evidence derived
local, regional or national registries, including audit systems from randomised clinical trials only.
for carotid interventions to monitor complication rates in In some areas, particularly for stenting of asymp-
patients with asymptomatic and symptomatic carotid steno- tomatic carotid stenosis, the available evidence from
sis is recommended. clinical trials is still limited. However, additional data
from large trials in asymptomatic carotid stenosis
which are currently ongoing are expected in the near
Discussion future and should provide a stronger evidence base to
This evidence-based guideline was developed following guide management of these patients.
the GRADE process and provides recommendations CAS and CEA differ in treatment-associated risks,
for the treatment of symptomatic and asymptomatic such as myocardial infarction and stroke. To fully
carotid stenosis by endarterectomy (CEA) or stenting determine the overall clinical impact of these outcomes
(CAS) versus best medical therapy alone. in patients, additional measures such as quality of life
Table 7. Synoptic table of all recommendations.
Strength of
Recommendations Quality of evidence recommendation
In patients with 60% asymptomatic carotid artery stenosis Moderate 丣丣丣 Strong for carotid endar-
considered to be at increased risk of stroke on best medical terectomy ""
therapy alone, we recommend carotid endarterectomy.
In patients with asymptomatic carotid stenosis, recommend Very low 丣 Weak against carotid
against carotid artery stenting as a routine alternative to best stenting #?
medical therapy alone.
In patients with asymptomatic carotid stenosis in whom revascu- Moderate 丣丣丣 Weak for carotid endar-
larisation is considered to be appropriate, we suggest endarterectomy "
terectomy as the current treatment of choice.
In patients with severe (70–99%) symptomatic carotid artery Moderate 丣丣丣 Strong for carotid endar-
stenosis, we recommend carotid endarterectomy. terectomy ""
In patients with moderate (50–69%) symptomatic carotid artery Low 丣丣 Weak for carotid endar-
stenosis, we suggest carotid endarterectomy. terectomy "
In patients with mild (<50%) symptomatic carotid artery stenosis, Very low 丣 Strong against carotid
we recommend against carotid endarterectomy. endarterectomy ##
In patients with 50–99% symptomatic carotid stenosis in whom High 丣丣丣丣 Strong for carotid endar-
surgery is considered appropriate, we recommend early end- terectomy ""
arterectomy, ideally within two weeks of the last neurological
event.
In patients with symptomatic carotid artery stenosis requiring Moderate 丣丣丣 Strong for carotid endar-
revascularisation, we recommend endarterectomy as the terectomy ""
treatment of choice.
In patients with symptomatic carotid stenosis <70 years old Low 丣丣 Weak for carotid stenting
requiring revascularisation, we suggest that stenting may be "
considered as an alternative to endarterectomy.
Bonati et al. XLI
Table 8. Synoptic table of all expert consensus statements.
Expert consensus statements Based on voting by all MWG members Voting results
In selected patients 75 years of age or older with 60% asymptomatic carotid artery stenosis and an 12/12
expected survival of at least five years, who are considered to be at an increased risk of stroke on
best medical therapy alone, carotid endarterectomy is suggested after careful consideration of
the risks and benefits at a multi-disciplinary team meeting.
In patients with asymptomatic carotid stenosis in whom revascularisation is considered to be 12/12
appropriate and who are less suitable for surgery, stenting may be suggested. We recommend
careful consideration of the risks and benefits at a multi-disciplinary team meeting.
The independently assessed risk of in-hospital stroke or death following endarterectomy or stenting 12/12
for asymptomatic carotid stenosis should be as low as possible, ideally below 2%.
The suitability of a patient with symptomatic carotid stenosis for carotid endarterectomy versus 12/12
stenting should also take into account the interval since their last ischaemic cerebrovascular
event, as well as anatomical and morphological features, including the atherosclerotic burden of
the aortic arch.
The independently assessed risk of in-hospital stroke or death following endarterectomy or stenting 11/12
for symptomatic carotid stenosis should be as low as possible, ideally below 4%.
Where possible, the indication for carotid endarterectomy or carotid artery stenting should be 12/12
discussed at a multi-disciplinary team meeting. Consensus decisions can be made in between
meetings, in order not to delay urgent revascularisations.
12/12 experts concluded that the establishment of validated local, regional or national registries, 12/12
including audit systems for carotid interventions to monitor complication rates in patients with
asymptomatic and symptomatic carotid stenosis is recommended.
MWG: Module Working Group.
and level of dependency should be systematically asymptomatic and symptomatic stenosis, respectively.
assessed in future trials. In-hospital thresholds may be more easily applicable to
We also acknowledge the fact that many of the trials routine clinical practice because many patients will not
providing the evidence for these guidelines were per- be independently assessed by a neurologist or stroke
formed two to three decades ago. There have been physician 30 days after intervention. Moreover, out-
important advances in the medical management of comes following CEA and CAS should ideally be ana-
patients with atherosclerosis, and technical develop- lysed at a local, regional and national level.
ments have also improved the safety of CEA and With modern medical management aiming for lower
CAS since then. Because we had some concerns – espe- targets for lipid and blood pressure control, and more
cially in patients with asymptomatic carotid stenosis – effective antiplatelet regimens (especially in patients
that the applicability of the findings obtained in earlier with recent symptoms), the risk of stroke in asymptom-
trials may not apply to current clinical practice with atic and symptomatic carotid stenosis is expected to be
contemporary medical and interventional treatment, lower than in the medical arms of some prior published
we reduced the grade of some of the evidence for trials. Ongoing trials are investigating whether contem-
‘indirectness’. porary medical therapy may obviate the need for inva-
Any benefit of CEA or CAS is closely related to sive revascularisation in selected patient groups.
peri-procedural complication rates. Since the in- There have been a number of developments in the
hospital complication rates of CEA and CAS have field of carotid artery stenting since the first trials
improved in recent years, expert consensus statements which compared stenting with endarterectomy were
were prepared which suggested that the independently- completed, including the design of closed-cell and
assessed peri-operative stroke and death rates after mesh-design stents,92,93 newer approaches to cerebral
CEA or CAS should ideally be below 2% in patients protection (involving reversal or arrest of blood
with asymptomatic carotid stenosis and below 4% in flow),94–105 and alternative access routes which avoid
patients symptomatic carotid stenosis. In randomised the aortic arch (including trans-brachial and trans-
trials, about two thirds of these events occurred in the carotid access.106–110 In addition, quality assurance
first two days after treatment, when patients were typ- programmes for stenting have been introduced in
ically still in hospital.91 Therefore these proposed some countries.111 For patients with symptomatic ste-
acceptable in-hospital thresholds of 2% and 4% corre- nosis, the restriction to the evidence from past rando-
spond with the traditionally-recommended 30-day mised trials may underestimate the role of CAS in
thresholds of 3% and 6% for patients with experienced centres who are able to maintain low
XLII European Stroke Journal 6(2)
peri-procedural complication rates. Although stenting tid artery stenting’, involves passing a fine wire and
using more modern state-of-the-art techniques might tube through the skin and into the narrowed artery in
reduce the peri-procedural risk of stroke, this needs the neck. A metal tube (stent) is placed inside the carot-
to be tested in randomised trials of CAS versus CEA. id artery to open it up with a view to preventing it from
Until further evidence is available, in patients requiring narrowing again. In patients who have not experienced
carotid revascularisation, the current weight of evi- recent symptoms (such as stroke, TIA, or ocular (eye)
dence is in favour of recommending CEA over CAS symptoms) from their carotid stenosis (‘asymptomatic
in most patient subgroups. patients’), but who are still considered to be at risk of
stroke on medication alone, we recommend carotid
endarterectomy. In patients who have recently experi-
Plain language summary
enced these symptoms (‘symptomatic patients’), we rec-
Carotid stenosis refers to narrowing of a major blood ommend carotid endarterectomy if the stenosis is
vessel in the neck (the carotid artery) which carries severe, and suggest carotid endarterectomy may be
blood to the eye and brain and is caused by fatty and considered if the stenosis is moderate. If surgery is rec-
calcium deposits in the blood vessel wall (atherosclero- ommended, we advise that carotid endarterectomy
tic plaque). Carotid stenosis may cause a transient should be carried out as early as possible after the
ischaemic attack (TIA or ‘warning stroke’) or a patient’s initial symptoms, preferably within two
stroke. The narrowing can be removed by a surgical weeks. Carotid artery stenting can be considered as
procedure called ‘carotid endarterectomy’, during an option to carotid endarterectomy in patients with
which the surgeon opens the artery and removes the symptomatic carotid stenosis, especially in patients
carotid plaque. An alternative treatment, called ‘caro- younger than 70 years of age.
Name Conflicts of interest
Leo H Bonati Co-Principal Investigator of the ECST-2 and ACST-2 trial. Grants from the Swiss National Science
Foundation, the Swiss Heart Foundation, the University of Basel and AstraZeneca for research
related to carotid artery disease. Consultancy fees from AstraZeneca.
Joachim Berkefeld Unrelated grants for angiographic imaging research from Siemens.
Gert J de Borst Member of the writing committee of the ESVS guideline on the management of carotid athero-
sclerotic disease; EU Horizon 2020 grant for stratification of carotid disease; consultation fees
from BAYER; Steering Committee Member ECST-2, CSTC.
Richard Bulbulia Co-PI ACST-2, Co-Chair, ESC Position Paper on Carotid Disease
Hans-Henning Eckstein Steering Committee SPACE-1, Co-PI SPACE-2, CSTC, Co-Investigator ROADSTER 1 and
ROADSTER 2, Co-Investigator ACST-2, EU Horizon 2020 grant for stratification of carotid
disease
Alison Halliday PI for the ACST trials, Steering committee member for ECST-2, past TSC member ICSS. Chair-Elect
of ESC Council on Stroke, co-author on the ESVS Carotid Guidelines, Co-author ESC Guidelines
on Dyslipidaemias, CSTC
Isabelle van Herzeele Consulting and Research Grants from Silkroad Medical, Medtronic and Impact APV Europe.
Stavros Kakkos Member of the writing committee of the ESVS guideline on the management of carotid athero-
sclerotic disease.
Igor Koncar EU Horizon 2020 grant for stratification of carotid disease, Member of the writing committee of the
ESVS guideline on the management of carotid atherosclerotic disease
Dominick JH McCabe Prior grant funding from: The Meath Foundation; The Irish Institute of Clinical Neuroscience; The
Irish Heart Foundation Stroke Prevention Bursary programme; The Trinity College Dublin
Innovation Bursary; The Vascular Neurology Research Foundation, Ireland. Unrestricted edu-
cational grant funding from: Biogen Idec, Ireland; Verum Diagnostica, GmbH; Bayer HealthCare,
Ireland; and SINNOWA Medical Science & Technology Co., China for unrelated translational
research studies. Member of the writing committee for the ESVS guidelines for the management
of patients with atherosclerotic carotid and vertebral artery stenosis (2017 and 2022).
Jean-Baptiste Ricco Grant and consultation fees from BAYER, Member of the writing committee of the ESVS guideline
on the management of carotid atherosclerotic disease
Peter Ringleb Steering Committee Member SPACE-2, CSTC. Unrelated grant from Boehringer Ingelheim
(ECASS-4). Unrelated lecture fees from Boehringer Ingelheim, Bayer, Pfizer, Daiichi Sankyo.
Bonati et al. XLIII
Funding 4. Naylor AR, Ricco JB, de Borst GJ, et al. Editor’s choice
The author(s) disclosed receipt of the following financial sup- – management of atherosclerotic carotid and vertebral
port for the research, authorship, and/or publication of this artery disease: 2017 clinical practice guidelines of the
article: Funding for the development of these guidelines was European society for vascular surgery (ESVS). Eur J
provided by the European Stroke Organisation, Basel, Vasc Endovasc Surg 2018; 55: 3–81.
5. Aboyans V, Ricco JB, Bartelink MEL, et al.; ESC
Switzerland.
Scientific Document Group. 2017 ESC guidelines on
Informed consent the diagnosis and treatment of peripheral arterial dis-
eases, in collaboration with the European society for
Not applicable.
vascular surgery (ESVS): document covering athero-
Ethical approval sclerotic disease of extracranial carotid and vertebral,
mesenteric, renal, upper and lower extremity arteries.
Ethical approval was not necessary for the work described in
Endorsed by: the European stroke organization (ESO)
this paper. the task force for the diagnosis and treatment of
peripheral arterial diseases of the European society
Guarantor
of cardiology (ESC) and of the European society for
A specific guarantor does not exist. The Module Working vascular surgery (ESVS). Eur Heart J 2018; 39:
Group has jointly developed the manuscript. 763–816.
6. Eckstein HH, Kühnl A, Berkefeld J, et al. Diagnosis,
Contributorship treatment and follow-up in extracranial carotid stenosis.
All listed authors have contributed to the preparation and Dtsch Arztebl Int 2020; 117: 801–807.
writing of the manuscript, researched literature and conceived 7. Guyatt GH, Oxman AD, Schünemann HJ, et al.
the guideline, were involved in protocol development, GRADE guidelines: a new series of articles in the jour-
reviewed and edited the manuscript and approved the final nal of clinical epidemiology. J Clin Epidemiol 2011; 64:
version of the manuscript. LHB, SK and JB wrote the first 380–382.
draft of the manuscript. 8. Ntaios G, Bornstein NM, Caso V, et al.; European
Stroke Organisation. The European stroke organisation
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European Stroke Organisation Guideline On Endarterectomy and Stenting For Carotid Artery Stenosis, 2021

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Guideline

European Stroke Journal

on endarterectomy and stenting for 2021

Leo H Bonati1, Stavros Kakkos2*, Joachim Berkefeld3*,

Introduction the ESO Guidelines Board and the ESO Executive

Interventions and comparators Formation of PICO questions

Post-procedural outcomes graded as -Death

@ of Study Risk of Other Medical Relative Absolute

CI: confidence interval; RR: risk ratio.

Certainty assessment @ of patients Effect

@ of Study Risk of Other Medical Relative Absolute

Certainty assessment @ of patients Effect

@ of Study Risk of Other Relative Absolute

@ of Study Risk of Other Relative Absolute

PICO 3.9: Risk of peri-procedural major stroke or death

CI: confidence interval; RR: risk ratio.

@ of Study Risk Other Medical Relative Absolute

@ of Study Risk Other Medical Relative Absolute

@ of Study Risk Other Medical Relative Absolute

(from 118 fewer

in the combined outcome was not statistically signif-

PICO 4.2: In patients with symptomatic carotid steno-

all degrees of stenosis combined, there is moderate

risk of stroke in any territory, including peri-

per 1000 patients, from 49 fewer to 13 fewer;

Figure 4.2). The evidence for a beneficial effect of

CEA was of moderate quality in patients with 70–

fewer events per 1000 patients, from 233 fewer to 62

fewer; Figure 4.2.1) and in patients with 50–59% ste-

per 1000 patients, from 88 fewer to 14 fewer).

Comparing the number of events prevented between

PICO 4.1 and PICO 4.2 within each stenosis category,

it can be inferred that CEA mainly prevents ipsilateral

PICO 4.3: In patients with symptomatic carotid steno-

peri-procedural death? Amongst patients with all

significantly reduce the long-term risk of major stroke,

including peri-procedural death (RR: 0.79, 95% CI:

However, once again, the benefit of CEA varies

according to the degree of stenosis. In patients with

70–99% stenosis, there is high quality evidence of ben-

1000 patients, from 95 fewer to 52 fewer; Figure 4.3.1).

Randomised Not serious Not serious

Conversely, there was low quality evidence of potential

from 33 fewer to 15 more), low quality evidence of

harm in patients with <50% stenosis (RR: 1.24, 95%

CI: 0.82–1.87), and very low quality evidence of harm

in patients with near occlusion (RR: 1.33, 95% CI:

PICO 4.4: In patients with symptomatic carotid steno-

sis, does endarterectomy compared with medical therapy

alone reduce the long-term risk of death?

Endarterectomy does not reduce the long-term risk of

Certainty assessment @ of patients Effect

@ of Study Risk Other Relative Absolute

@ of Study Risk Other Relative Absolute

PICO 6.4. Long-term risk of major stroke, including peri-procedural death

@ of Study Risk Other Relative Absolute

PICO 6.9.2a: Risk of peri-procedural stroke or death: Men

@ of Study Risk Other Relative Absolute

CI: confidence interval; RR: risk ratio.

Leo H Bonati1, Stavros Kakkos2, Joachim Berkefeld3,