Diagnosis, Treatment and Follow-up in Extracranial Carotid Stenosis

Abstract

Background

Around 15% of cerebral ischemias are caused by lesions of the extracranial carotid artery. The goal of this guideline is to provide evidence- and consensus-based recommendations for the management of patients with extracranial carotid stenoses throughout Germany and Austria.

Methods

A systematic literature search (1990–2019) and methodical assessment of existing guidelines and systematic reviews; consensus-based answers to 37 key questions with evidence-based recommendations.

Results

The prevalence of extracranial carotid artery stenoses is around 4% overall, higher from the age of 65 years. The most important examination modality is duplex sonography. Randomized trials have shown that carotid endarterectomy (CEA) significantly reduces the 5-year risk of stroke in patients with 60–99 % asymptomatic stenoses (absolute risk reduction [ARR] 4.1% over 5 years, number needed to treat [NNT] 24) or 50–99% symptomatic stenoses (50–69%: ARR 4.6 % over 5 years, NNT 22; 70–99%: 15.9 % over 5 years, NNT 6). With the aid of intensive conservative treatment, the carotid artery-associated risk of stroke can be reduced to as little as 1% per year. Critical determination of indications and strict quality criteria are therefore necessary for CEA and carotid artery stenting (CAS). Systematic reviews of controlled trials comparing CEA and CAS show that the procedural risk of stroke is higher for CAS (asymptomatic: 2.6% versus 1.3%; symptomatic: 6.2% versus 3.8%). There are no differences in the long term. CEA is recommended as standard procedure for high-grade asymptomatic and moderate to high-grade symptomatic carotid artery stenoses; CAS may be considered as an alternative. For both procedures, the periprocedural combined rate of stroke or death should not exceed 2% for asymptomatic stenoses or 4% for symptomatic stenoses.

Conclusion

Future studies should evaluate even better selection criteria for optimal individualized treatment, whether conservative, surgical, or endovascular.

In around 15% of cases, cerebral ischemia is caused by lesions of the extracranial segment of the carotid artery; for this reason, optimal treatment of carotid stenoses is crucial (1). The interdisciplinary guideline presented here evaluates and compiles the findings of the existing comparative studies on conservative and invasive options for treatment of extracranial carotid artery stenoses. The goal of this new guideline is to ensure evidence-based care of patients with extracranial carotid stenoses throughout Germany and Austria.

The first multidisciplinary, evidence- and consensus-based, joint German/Austrian guideline for the management of extracranial carotid stenoses was published in 2012 (2). The present article summarizes the central recommendations of the updated clinical practice guideline, the long and short versions of which were published on the website of the Association of the Scientific Medical Societies in Germany (AWMF) in March 2020 (3).

Methods

Involvement of stakeholders and principles

Twenty-one medical societies and organizations were involved in the revision of the guideline (etable 1). In a process documented in the guideline report, all members of the guideline group provided written notification of any potential conflicts of interest. The guideline is multidisciplinary and based on evidence and consensus (an S3 classification in the German grading of guidelines). Each society/organization was entitled to cast one vote on every decision. All recommendations were agreed at a consensus conference or by means of a structured DELPHI process.

eTable 1. Participating professional societies and interest groups.

Society/organization	Officer 2019 (revised guideline)
German Vascular Society	Prof. H.-H. Eckstein, Munich
German Society of Neurology	Prof. P. Ringleb, Heidelberg Prof. D. Sander, Tutzing
German Society for Neurorehabilitation	No delegate nominated, active decision not to participate
German Stroke Society	Prof. P. Ringleb, Heidelberg Prof. Dr. D.G. Nabavi, Berlin
German Society for Ultrasound in Medicine	Prof. M. Köhrmann, Essen Prof. P. Ringleb, Heidelberg
German Society for Neuroradiology	Prof. J. Berkefeld, Frankfurt Prof. A. Dörfler, Erlangen
German Radiological Society	Prof. W. Gross-Fengels, Harburg
German Society of Interventional Radiology and Minimally Invasive Therapy	Prof. P. Huppert, Darmstadt
German Society of Angiology/Vascular Medicine	Dr. H. Lawall, Langensteinbach Dr. R. Langhoff, Berlin
German Cardiac Society	Prof. H. Mudra, Munich Prof. T. Zeller, Bad Krozingen
German Diabetes Society	Prof. O. Schnell, Munich PD Dr. K. Rittig, Frankfurt (Oder)
German Society of Gerontology and Geriatrics	Dr. C. Ploenes, Düsseldorf Dr. H. Görtz, Lingen
Austrian Union of Vascular Medicine	Prof. G. Fraedrich, Innsbruck Prof. B. Rantner, Munich
German Society for Thoracic and Cardiovascular Surgery	Prof. M. Czerny, Freiburg
German Society of Neurosurgery	Prof. K. Schwerdtfeger, Homburg
German Society of Surgery	Prof. M. Storck, Karlsruhe Prof. M. Steinbauer, Regensburg
German Society of Anaesthesiology and Intensive Care Medicine	Dr. R. Litz, Augsburg Prof. K. Engelhard, Mainz
German College of General Practitioners and Family Physicians	No delegate nominated, active decision not to participate
German Society for the Prevention and Rehabilitation of Cardiovascular Disease	No delegate nominated, no reply to invitation
Association of the Scientific Medical Societies in Germany	Prof. I. Kopp, Marburg
German Vascular League	Dr. S. Schulte, Cologne
German Association for Physiotherapy	A. Fründ, Bad Oeynhausen
German Association of Occupational Therapists	A. Hörstgen, KarslbadC. Lüdeking, Minden
German Nurses Association	R. Schamberger, Regensburg J. Hanl, Friedrichshafen
German Patient Support Group	No delegate nominated, no reply to invitation
Bavarian Association of Stroke Victims Munich	No delegate nominated, no reply to invitation
German Stroke Relief Group	Prof. Dr. D.G. Nabavi, Berlin Prof. Dr. R. Stingele, Berlin

Literature review and assessment of recommendations/evidence

The systematic literature search carried out for the purpose of updating the original guideline was restricted to guidelines (published from 2014 onward, eTable 2), systematic reviews, and meta-analyses (both from 2011 onward). Other types of studies, e.g., randomized controlled trials (RCT), cohort studies, and case–control studies, were also included if they contained data relevant to decision making or if neither guidelines nor systematic reviews with high-quality methods were available to answer one of the key questions.

eTable 2. National and international guidelines relevant to the management of extracranial carotid stenoses, 2014–2019.

Year	Scientific societies	Topic of guideline
2014	American Heart Association/ American Stroke Association	Prevention of stroke in patients with stroke and transient ischemic attack (e1)
2014	American Heart Association/ American Stroke Association	Primary prevention of stroke (e2)
2014	American Heart Association/ American Stroke Association	Prevention of stroke in women (e3)
2014	Canada	Best practice for stroke care (e4)
2014	Institute for Clinical Systems Improvement	Diagnosis and management of type 2 diabetes mellitus in adults (e5)
2014	European Society of Cardiology (ESC) and European Society of Anaesthesiology	Non-cardiac surgery: cardiovascular assessment and management (e6)
2015	German Society of Neurology	Acute treatment of ischemic stroke (supplement) – recanalization treatment (e7)
2015	German Society of Neurology and German Stroke Society	Secondary prophylaxis of ischemic stroke and transient ischemic attack, part 1 (e8)
2016	ESC and European Atherosclerosis Society	Management of dyslipidemias (e9)
2016	Royal College of Physicians	Stroke (e10)
2018	European Society for Vascular Surgery (ESVS) in collaboration with ESC	Management of carotid artery disease
2018	ESC in collaboration with ESVS	Diagnosis and treatment of peripheral arterial diseases
2017	Italian Stroke Organization	CEA and CAS (14)
2017	The Stroke Foundation, Australia	Clinical stroke management (e11)
2018	American Heart Association/ American Stroke Association	Early management of patients with acute ischemic stroke (e12)
2018	Society for Vascular Surgery	Follow-up after vascular surgery (e13)
2018	ESC and European Society for Hypertension	Management of arterial hypertension (e14)
2019	European Stroke Organization and European Society for Minimally Invasive Neurological Therapy	Mechanical thrombectomy in acute ischemic stroke (e15)

The systematic literature search was carried out in the databases Medline, Embase, and the Cochrane Database of Systematic Reviews; The search for national and international guidelines was conducted in the database of the Guidelines International Network. The total number of primary records was 5566, including 18 guidelines and 75 systematic reviews and meta-analyses.

The records identified were assessed partly by members of the steering group, partly by an external organization (KSR; Kleijnen Systematic Reviews Ltd., York, UK) (efigure).The key questions were each answered on the basis of the best evidence available from the publications, in the following descending order: guidelines, systematic reviews, meta-analyses, single RCT, other studies (cohort studies, case–control studies).

eFigure.

Flow chart of literature search

DAEB, Database of Deutsches Ärzteblatt; GIN, Guidelines International Network; GMS, German Medical Science Database; IQWIG, Institute for Quality and Efficiency in Health Care; KCE, Belgian Health Care Knowledge Centre; LWW, database of Lippincott Williams & Wilkins; MA, systematic review with meta-analysis; NGC, National Guideline Clearinghouse; NHS Economic, National Health Service Economic Evaluation Database; NICE, National Institute for Health and Care Excellence; RCT, randomized ccontrolled trial; SIGN, Scottish Intercollegiate Guidelines Network; SR, systematic review; TRIP, Turning Research Into Practice

The structured consensus finding followed the rules of the AWMF. Recommendations were classified by means of arrows and using the system conventional in German guidelines (etable 3):

eTable 3. Classification of level of evidence (LoE) and recommendation strength.

Study quality	LoE	Recommendation	Description	Symbol
Systematic review (meta-analysis) or high-quality randomized controlled trials (RCT) or cohort studies	1 (high)	Should	Strongly recommended	↑↑
RCT or cohort studies of limited quality	2–3 (moderate)	Should be considered	Recommended	↑
RCT or cohort studies of poor quality, all other study designs	4–5 (weak)	May be considered	Open recommendation	↔
Expert opinion	None	Expert consensus	–	EC

• ↑↑ corresponds to “strongly recommended”.

• ↑ corresponds to “ recommended” or “should be considered”.

• ↔ corresponds to “open recommendation” or “may be considered”.

• EC corresponds to “expert consensus”

Recommendations against the use of a given intervention are classified into two categories: “definitely not recommended” and “not recommended”. The level of evidence was determined in most cases by the evidence quality and was decided according to the stipulations of the Oxford Centre for Evidence-Based Medicine 2009. If insufficient information was available, expert consensus (EC) recommendations were reached by interdisciplinary discussion.

Results

Epidemiology

The population-level prevalence of ≥ 50% carotid stenosis, mostly caused by atherosclerosis, is around 4%. Carotid stenosis is associated with current smoking, increasing age, male sex, and the presence of vascular disease (4). Around 15% of cases of cerebral ischemia are caused by lesions of the extracranial segment of the carotid artery (1). Owing to the optimization of conservative treatment, the risk of a carotid-related ipsilateral cerebral infarction in a patient with a > 50% asymptomatic stenosis is around 1% per year (5). If carotid-associated symptoms occur, however, the risk of stroke rises to 11–25% within the first 14 days (6).

Symptoms and diagnosis

The typical symptoms of extracranial carotid artery stenosis are retinal ischemia (e.g., amaurosis fugax), unilateral paresis or dysesthesia, and speech disorders (aphasia) within the preceding 6 months. Dizziness as well as vertigo and memory disorders are atypical. A stenosis can also be classified as symptomatic if cerebral imaging demonstrates clinically silent ischemia (etable 4).

eTable 4. Important recommendations for the diagnosis of carotid stenoses.

Definition of asymptomatic and symptomatic carotid stenosis	Strength*1	LoE*2
Unchanged: A stenosis is classified as asymptomatic when no stenosis-associated symptoms have occurred during the previous 6 months.	EC
Modified: When a carotid stenosis has caused an ipsilateral cerebral infarction, ipsilateral transient ischemic attack, or ipsilateral retinal ischemia during the previous 6 months, it is classified as symptomatic.	EC
Diagnosis and follow-up of extracranial carotid stenosis	Strength*1	LoE*2
Modified: Whenever carotid stenosis is suspected, color-coded DUS should be performed by an experienced examiner.	↑↑	1
Unchanged: If there is any doubt about grading of the carotid stenosis, or if DUS is complicated by additive intrathoracic or intracranial vascular processes or by hemodynamically relevant contralateral vascular alterations, additional CTA or MRA is recommended.	EC
What diagnostic measures are necessary before the planned operation or intervention?	Strength*1	LoE*2
Unchanged: All patients with carotid stenoses should undergo clinical neurological examination.	EC
New: If CEA is considered, every DUS should be confirmed by means of CTA or MRA, or by repeated DUS performed by another qualified examiner.	↑	1
New: If CAS is considered, every DUS should be supplemented by CTA or MRA to obtain additional information about the aortic arch, the stenosis morphology, and the extracranial and intracranial circulation.	↑↑	1
Unchanged: Planned revascularization of the carotid artery should be preceded, in symptomatic patients, by imaging of the brain parenchyma. Such imaging can also yield important additional information in asymptomatic patients.	EC
Is screening (of high-risk groups) useful?	Strength*1	LoE*2
Unchanged: Routine screening for carotid stenosis should not be performed.	↓↓	1
Modified: In the presence of vascular risk factors and/or existing atherosclerotic disease in other territories, DUS of the carotid artery may be helpful. This examination should be limited to patients in whom therapeutic consequences can be anticipated.	EC
New: The sonographic detection of atherosclerotic carotid plaques may affect the cardiovascular risk estimation.	EC

*¹ Recommendation strength: ↑↑/↓↓, strongly recommended/definitely not recommended;

↑/↓, recommended/not recommended ↔, open recommendation

*² Level of evidence (LoE) 1–5 according to the Oxford Centre for Evidence-Based Medicine 2009

(see guideline report for this clinical practice guideline)

CAS, Carotid stenting; CEA, carotid endarterectomy; CTA, computed tomographic angiography; DUS, duplex sonography; EC, expert consensus; MRA, magnetic resonance tomography

The principal instrument-based examination is color-coded duplex sonography (DUS) (↑↑) together with determination of the extent of distal stenosis using the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method (EC) (7). If there is any doubt about grading, contrast-enhanced magnetic resonance angiography (MRA) and computed tomography angiography (CTA) can be carried out (EC). Symptomatic patients should undergo cerebral parenchyma imaging prior to carotid endarterectomy (CEA) or carotid artery stenting (CAS), and additional information may also be gained by this means in asymptomatic patients (EC). Vascular risk factors and conditions resulting from atherosclerosis (coronary heart disease [CHD], peripheral arterial occlusive disease) should be documented in all patients (EC).

Routine screening for carotid stenosis is definitely not recommended (↓↓). In the presence of vascular risk factors, however, screening may be useful in cases where the diagnosis of extracranial carotid stenosis would have therapeutic consequences (EC). Patients with known carotid stenosis should be followed up at 6- to 12-month intervals (EC).

Treatment

Conservative treatment of asymptomatic and symptomatic carotid stenosis

The management of patients with atherosclerotic carotid stenosis should comprise both consistent risk factor modification, including alterations of lifestyle (quitting smoking, healthy, balanced wholefood nutrition, exercise; ↑↑), and, if arterial hypertension and/or diabetes mellitus are present, treatment according to the guidelines (EC) (table 1). The recommended medication is 100 mg aspirin daily in asymptomatic stenoses (↑) and 100 mg aspirin or 75 mg clopidogrel in symptomatic stenoses (↑↑). Statins should be taken for long-term cardiovascular prevention (EC). As advised in current guidelines, LDL cholesterol should be lowered to < 70 mg%, or to < 50 mg% in high-risk atherosclerosis patients (8).

Table 1. Important recommendations for asymptomatic carotid stenosis.

New recommendations added to revised guideline	Strength*1	LoE*2
All patients with asymptomatic carotid stenosis should be recommended to eat a balanced mixed whole-food diet and physical activity. Smoking must be ceased..*3	↑↑	2a
All patients with a ≥ 50% asymptomatic atherosclerotic carotid stenosis should take 100 mg aspirin/day, providing that the risk of bleeding is low.	↑	2a
In patients with diabetes mellitus and/or arterial hypertension, the diabetes and/or hypertension should be treated according to current guidelines.*3	EC
All patients with a ≥ 50% asymptomatic atherosclerotic carotid stenosis should take a statin for long-term prevention of cardiovascular events (stroke, myocardial infarction, etc.). LDL cholesterol should be lowered, in a risk-adapted manner according to the current guidelines.*3	EC
In the presence of a 60–99% asymptomatic carotid stenosis, CEA should be considered, provided there is no increased surgical risk and one or more clinical or imaging findings are available that are associated with an increased risk of carotid-related in follow-up	↑	1
In the presence of a 60–99% asymptomatic carotid stenosis, CAS may be considered, provided there is no increased treatment-associated risk and one or more clinical or imaging findings are available that are presumably associated with an increased risk of carotid-related stroke in follow-up	↔	2a
The periprocedural stroke/death rate should be as low as possible for CEA or CAS of an asymptomatic stenosis. The in-hospital stroke/death rate should be monitored by expert neurologists and should not exceed 2%.	↑↑	2a

*¹ Recommendation strength: ↑/↓↓, strongly recommended/definitely not recommended;

↑/↓, recommended/not recommended ↔, open recommendation

*² Level of evidence (LoE) 1–5 according to the Oxford Centre for Evidence-Based Medicine 2009 (see guideline report for this clinical practice guideline)

*³ Equally valid for patients with asymptomatic and symptomatic carotid stenosis

CAS, Carotid stenting; CEA, carotid endarterectomy; EC, expert consensus

Invasive treatment: carotid endarterectomy or carotid stenting

Whether invasive treatment is indicated for a carotid artery stenosis should be decided by an interdisciplinary team including experienced neurologists (EC). The procedural complication rate should be monitored neurologically (EC). There was strong consensus for all recommendations after detailed assessment of the literature (8– 11). Important recommendations regarding treatment technique and follow-up examinations can be found in Table 2 and eTable 5.

Table 2. Important recommendations for treatment technique with CEA and CAS.

CEA	Strength*1	LoE*2
Modified: The selection of the surgical technique (eversion CEA, conventional CEA with patchplasty) should depend on the operating surgeon’s personal experience.	↑↑	1a
Unchanged: Since there is no distinct difference between the 30-day results after local/regional anesthesia or general anesthesia, either can be used. In choosing between the two, the patient’s preference and the individual experience and competency of the anesthesiological/vascular surgery team should be taken into account.	↑↑	1
New: The anesthesiological/vascular surgery team should offer the option of local/regional anesthesia, because clamping ischemia can be detected earlier in awake patients.	↑	2c
CAS	Strength*1	LoE*2
Unchanged: CAS should be preceded by dual platelet inhibition with aspirin (100 mg) and clopidogrel (75 mg).	↑	3
New: Treatment with clopidogrel should be initiated at least 3 days before the intervention at 75 mg/day or on the day before the intervention at 300 mg/day.	EC
Unchanged: The dual platelet inhibition should continue for at least 1 month.	EC

*¹ Recommendation strength: ↑↑/↓↓, strongly recommended/definitely not recommended;

↑/↓, recommended/not recommended ↔, open recommendation

*² Level of evidence (LoE) 1–5 according to the Oxford Centre for Evidence-Based Medicine 2009 (see guideline report for this clinical practice guideline)

CAS, carotid stenting; CEA, carotid endarterectomy; EC, expert consensus

eTable 5. Important recommendations for follow-up examinations after CEA or CAS.

	Strength*1	LoE*2
New: If early DUS follow-up shows a good result, DUS should be repeated after 6 months to rule out early recurrence of stenosis.	EC
New: DUS should be performed routinely at 12-month intervals after CEA and CAS, provided the findings could have therapeutic consequences.	EC
New: In patients thought to be at an elevated risk of recurrent stenosis during follow-up (women, diabetes mellitus, dyslipidemia, nicotine abuse) DUS should be repeated at 6-month intervals after CEA and after CAS. As soon as two successive examinations show the same findings, the interval can be increased to 12 months.	EC

*¹ Recommendation strength: ↑↑/↓↓, strongly recommended/definitely not recommended;

↑/↓, recommended/not recommended ↔, open recommendation

*² Level of evidence (LoE) 1–5 according to the Oxford Centre for Evidence-Based Medicine 2009

(see guideline report for this clinical practice guideline)

CAS, Carotid stenting; CEA, carotid endarterectomy; DUS, duplex sonography; EC, expert consensus

Indications for revascularization of asymptomatic carotid stenoses

RCT carried out in the 1990s showed that CEA in > 60% asymptomatic carotid artery stenoses had a preventive effect against stroke (12, 13). Owing to the major improvements in the pharmaceutical prevention of atherosclerosis since then, the consensus conference now recommends prophylactic CEA of 60 to 99% stenoses only in patients in whom the surgical risk is not elevated (Table 2, eTable 4). Moreover, there should be one or more clinical or imaging findings that are associated with an elevated risk of carotid artery-related stroke during follow-up (NEW, ↑). For instance, men have a much greater risk of stroke in the longer term than women, who do not benefit from revascularization measures until 10 years after treatment. Further important findings are contralateral transient ischemic attack or stroke, silent infarction on cerebral imaging, marked progression in extent of stenosis, predominantly echolucent plaques on sonography, intraplaque hemorrhage on MRI, a large plaque area (>80 mm²), spontaneous microembolisms on transcranial Doppler sonography (TCD), and limited cerebrovascular reserve capacity (table 3). In this situation, CAS may be considered (NEW, ↔). The pharmaceutical treatment accompanying CEA comprises administration of aspirin (↑↑) and of statins (NEW, ↑↑).

Table 3. The influence of clinical and morphological variables on the risk of stroke in the presence of an asymptomatic 60–99% carotid stenosis (modified from 8, 9).

Clinical variables	ARR/RR [95% CI], p-value
Men < 75 years (12)	ARR in 5 years: 6.5% [3.6; 9.4]
Contralateral TIA/stroke (29)	RR 3.0 [1.9; 4.73]
Morphological variables	OR/HR/ARR/RR [95% CI], p-value
Silent infarction on CCT (30)	HR 3.0 [1.46; 6.29]
Extent of stenosis 50–69% vs. 70–99%, meta-analysis (5)	1.6% vs. 2.4%/year (absolute risk)
Progression of 50–99% carotid stenosis by at least 10% (29)	RR 1.92 [1.14; 3.25]
Progression of 50–99% carotid stenosis /year* (31)	Progression by 1 category*, IRR 1.65 (1.1–2.45)Progression by 2 categories*, IRR 4.73 (2.23–9.63)
Echolucent plaques vs. echogenic plaques on DUS (32)	RR 2.61 [1.47; 4.63]
Intraplaque hemorrhage on MRI (33)	HR 3.66 [2.70; 4.95]
Plaque area (< 40 mm2 vs. > 80 mm2) on CTA (9, 34)	HR 5.81 [2.67; 12.67]
Spontaneous microembolization (TCD) (35)	OR 6.63 [2.85; 15.44]
Spontaneous microembolization PLUS echo-poor plaques on DUS (36)	OR 10.6 [2.98; 37.8]
Limited cerebrovascular reserve capacity (TCD) (37)	OR 6.14 [1.27; 29.5]

* Categories of stenosis: 50–69%, 70–89%, 90–99%, 100%

ARR, Absolute risk reduction; CCT, cranial computed tomography; CI, confidence interval; CTA, computed tomography angiography; DUS, duplex sonography; HR, hazard ratio; IRR, incidence rate ratio (relative comparison of incidence); MRI, magnetic resonance tomography; OR, odds ratio; RR, relative risk; TCD, transcranial Doppler sonography; TIA, transient ischemic attack

In a systematic review (five RCT) (14) comparing CAS and CEA in asymptomatic stenoses, the periprocedural stroke rate was 1.3% after CEA versus 2.6% after CAS (OR 0.53, 95% confidence interval [0.29; 0.96]). The reason for this significant difference was a lower rate of minor strokes after CEA (1%) than after CAS (2.2%) (OR 0.50 [0.25; 1.00]). The risks of death, severe stroke, and myocardial infarction did not differ significantly.

The SPACE-2 study (Stent Protected Angioplasty versus Carotid Endarterectomy) is the only three-arm RCT comparing CEA and CAS with optimized pharmaceutical therapy alone (best medical treatment, BMT). The trial was halted before completion because not enough patients could be recruited. Among the 513 patients analyzed, the 30-day combined rate of stroke and death was 2.5% for both CEA and CAS. At 12 months, almost identical results were found for the endpoint “periprocedural stroke or death PLUS any ipsilateral ischemic stroke” (CEA 2.5%, CAS 3.0%, BMT 0.9%; p = 0.530). Recurrent stenosis was somewhat more likely after CAS than after CEA (5.6% versus 2.0%; p = 0.068) (15).

Indications for revascularization of symptomatic carotid stenoses

A Cochrane Review published in 2017 (16) evaluated the individual patient data of three large RCT comparing CEA with BMT alone. CEA had no significant effect on the 5-year risk of ipsilateral stroke in 30–49% stenoses, but was advantageous in 50–69% stenoses (RR 0.84 [0.60; 1.18]) and significantly superior in 70–99% stenoses (RR 0.47 [0.25; 0.88]) (table 4).

Table 4. Important recommendations for symptomatic carotid stenosis.

Symptomatic carotid stenosis	Strength*1	LoE*2
Modified: CEA should be perfogmed in patients with a 70–99% stenosis after retinal ischemia, TIA, or non-disabling stroke.	↑↑	1a
Modified: CEA should also be performed in patients with a symptomatic 50–69% stenosis when no increased surgical risk is present. Male patients with a recent history of hemispheric symptoms (retinal ischemia, TIA, cerebral infarction mRS <3) will profit the most.	↑	2a
Modified: CAS may be considered in symptomatic patients with a 50–99% carotid stenosis and normal surgical risk.	↔	2a
Modified: The complication rates of CEA and CAS for symptomatic carotid stenoses should be monitored by neurologists. The documented combined rate of periprocedural stroke and death during the hospital stay should not exceed 4% for all (early) elective CEA or CAS procedures.	EC
Unchanged: CEA should be performed as soon as possible (within 3–14 days) after the index event.	↑↑	2
Unchanged: CAS should be considered as an alternative to CEA in symptomatic patients with a high surgical risk.	↑	2

*¹ Recommendation strength: ↑↑/↓↓, strongly recommended/definitely not recommended;

↑/↓, recommended/not recommended ↔, open recommendation

*² Level of evidence (LoE) 1–5 according to the Oxford Centre for Evidence-Based Medicine 2009 (see guideline report for this clinical practice guideline)

CAS, Carotid stenting; CEA, carotid endarterectomy; EC, expert consensus; TIA, transient ischemic attack

In a systematic review comparing CEA and CAS in symptomatic stenoses (nine RCT, 6984 patients) (17), the 30-day risk of stroke was 6.2% after CAS against 3.8% after CEA (RR 1.62 [1.31; 2.00]). The difference was still present at 48 months (RR 1.37 [1.11; 1.70]). There was no significant difference between the two procedures for the endpoints death and severe stroke. The 30-day risk of myocardial infarction was 1% after CAS and 2.2% after CEA (RR 0.44 [0.26; 0.75]), while cerebral nerve lesions within 30 days were observed significantly less often after CAS than after CEA (0.4% versus 7.1 %; RR 0.09 [0.04; 0.22]).

The timing of revascularization of symptomatic carotid stenoses

CEA should be performed within 3–14 days after the neurological index event in order to prevent early recurrence of stroke (↑↑). In a systematic review on the safety of CEA and CAS within the first two weeks, the 30-day combined risk of stroke or death was 3.8% for CEA and 6.8% after CAS (18).

The long-term results of carotid stenting and carotid endarterectomy

An analysis by the Carotid Stenosis Trialist Collaboration (four RCTs on CEA versus CAS in symptomatic stenoses, n = 4775 patients) showed that the combined risk of stroke or death within 120 days was 5.5% for CEA and 8.7% for CAS. In follow-up periods ranging from 2 to 7 years, the rates of new ipsilateral stroke were 3.1% and 3.2% for CEA and CAS, respectively. The numbers of events per year, not including periprocedural complications, were almost identical (CEA 0,6%, CAS 0.64%) (19).

Routinely collected data from Germany

The quality assurance measures mandated by German law enable evaluation of the outcome quality of CEA and CAS under routine conditions. Analysis of all elective procedures (CEA, 2009–2014: n = 142 074; CAS, 2012–2014: n = 13 086) showed that the combined risk of periprocedural stroke or death was 1.4% for asymptomatic and 2.5% for symptomatic carotid artery stenoses with CEA versus 1.7% and 3.7%, respectively, with CAS. The following variables were associated with higher risk: increasing age, physical status classification according to the American Socitey of Anesthesiology (ASA), symptomatic versus asymptomatic stenosis, 50–69% stenosis, and contralateral carotid artery occlusion (only for CEA) (20).

The time that elapsed between neurological index event and surgery had no influence on the in-hospital periprocedural combined rate of stroke or death for CEA, but for CAS the risk was elevated in the first 1 to 2 weeks (21, 22).

Clinical and morphological variables affecting the procedural risk

In the currently valid guideline of the European Society of Cardiology (ESC) and the European Society of Anaesthesiology (ESA), CEA is classified as an operation involving low to moderate risk (asymptomatic/symptomatic stenosis) (23). Because severe comorbidities (particularly severe coronary heart disease or severe heart failure) increase the procedural risk of CEA, staged diagnostic work-up of CHD as advised in the guideline is recommended in order to minimize the perioperative and long-term risk of myocardial infarction (↑↑). In the presence of a severe neurological deficit, CEA is associated with significantly higher rates of stroke and death (RR 2.50 [1.3; 4.8]) (24).

When determining whether CEA is indicated, one should also take account of anatomic morphological variables, which are associated with increased surgical risk (↑; eTable 2). CAS should therefore be considered as an alternative to CEA in symptomatic patients with high surgical risk (↑).

Discussion of the indication for CAS should include careful weighing up of the benefits and risks and take account of the potentially increased risks in patients over 70 years of age and in those who have recently had cerebral or ocular ischemia. CEA may therefore be considered as an alternative to CAS in these patients (↑). Furthermore, anatomic and plaque morphology factors should be heeded (etable 6).

eTable 6. Important recommendations for assessment of the periprocedural treatment risk with CEA and CAS.

Recommendations for CEA	Strength*1	LoE*2
New: When determining whether CEA is indicated, and to estimate the preventive value of surgery, it should be considered that the following comorbidities may negatively influence the treatment-associated risk and the ‧prognosis of CEA: – Coronary heart disease (CHD) – Heart failure (ejection fraction < 30%, pathologic stress test) – arterial hypertension (especially elevated diastolic blood pressure) – diabetes mellitus (especially if treated with insulin) – respiratory failure (especially copd) – severe kidney failure – known peripheral arterial occlusive disease – nicotine abuse (current or past)	↑↑	2a
Modified: When determining whether CEA is indicated and explaining the procedure to the patient, one should take into account that the perioperative risk of stroke and death is higher for symptomatic than for asymptomatic carotid stenoses.	↑↑	2a
Unchanged: When determining whether CEA is indicated, one should take into account that the perioperative risk of stroke and death is not higher for early elective CEA (within 2 weeks after the index event) than after delayed CEA (> 2 weeks).	↑↑	2a
Unchanged: When determining whether CEA is indicated, one should take into account that perioperative mortality in both men and women increases with advancing age, but the perioperative stroke rate does not.	↑↑	2a
New: In the presence of clinical signs of CHD, elective CEA should be preceded by a guideline-conform staged diagnostic work-up, including non-invasive and invasive techniques, to minimize the perioperative and long-term risk of myocardial infarction.	↑↑	2a
New: In the absence of clinical signs of CHD, non-invasive tests may be considered to minimize the perioperative and long-term risk of myocardial infarction.	↔	2b
New: When evaluating the risks and benefits of CEA, functional parameters (activities of daily living, functional autonomy, progressive deterioration of general health) should be considered.	↑	2a
New: When determining whether CEA is indicated, one should take into account that the following anatomic morphological variables are associated with higher procedural risk: – Tracheostomy – Contralateral paresis of the recurrent laryngeal nerve – High carotid bifurcation (C2 or above) – Contralateral carotid occlusion – Moderate (50 to 69%) stenoses (versus 70 to 99% stenoses) – Insufficient intracranial collateral blood supply	↑	2b
Recommendations for CAS	Strength*1	LoE*2
Unchanged: When determining whether CAS is indicated, one should consider whether the patient’s age and comorbidities may increase the risk of extracerebral complications or limit the prophylactic benefit of the intervention.	EC
New: When determining whether CAS is indicated and explaining the procedure to the patient, one should take into account that the peri-interventional risk of stroke and death is higher for symptomatic than for asymptomatic carotid stenoses.	↑↑	2
New: Before deciding to perform CAS, one should carefully weigh up the benefits and risks. The risks may be greater in patients over 70 years of age and after recent cerebral or ocular ischemia. It may be advisable to consider CEA as an alternative.	↑	2a
New: When determining whether CAS is indicated, anatomic and plaque morphology factors should be taken into account. Particularly the following variables are associated with higher procedural risk: – Pronounced aortic elongation (especially type III aortic arch) – Stenosis of the left carotid artery – Angulation of the carotid bifurcation – Calcification of the aortic arch – Pronounced (especially circumferential) plaque calcification – Long-segment stenosis (> 10 mm) – Free-floating thrombus	↑	2b

*¹ Recommendation strength: ↑↑/↓↓, strongly recommended/definitely not recommended;

↑/↓, recommended/not recommended ↔, open recommendation

*² Level of evidence (LoE) 1–5 according to the Oxford Centre for Evidence-Based Medicine 2009

(see guideline report for this clinical practice guideline)

CAS, Carotid stenting; CEA, carotid endarterectomy; CHD, coronary heart disease; COPD, chronic occlusive pulmonary disease; EC, expert consensus

Acceptable rates of periprocedural stroke or death

The combined periprocedural rate of stroke or death after CEA or CAS for (a)symptomatic stenosis should be as low as possible and should be monitored neurologically. Recent studies and data from the quality assurance register of the German Carotid Registry show that most hospitals achieve low complication rates. After exhaustive discussion, the consensus conference therefore strongly recommended lowering of the maximally acceptable upper limit for complications from 3% to 2% for asymptomatic carotid stenoses (NEW, ↑↑). For symptomatic carotid stenoses, the limit was lowered from 6% to 4% (NEW, EC).

Healthcare structures and professional qualifications

Because around 30% of complications (stroke, myocardial infarction, delayed bleeding) occur later than the day of treatment, CEA and CAS should always be performed as inpatient procedures (EC). Without exception, CEA should be carried out by qualified vascular surgeons in hospitals with at least 20 such operations each year (↑↑) (25– 28). CAS should be conducted by qualified physicians with documented experience of angiographic diagnosis and treatment of brain-supplying arteries (EC). Elective CAS interventions should be conducted exclusively in hospitals with an annual caseload of > 10 such procedures (↑↑) (26, 27). Moreover, there should be “24-h availability” of diagnostic measures (sonography, computer tomography, magnetic resonance imaging, angiography), monitoring, and endovascular and surgical intervention (etable 7).

eTable 7. Recommendations for healthcare structures.

Recommendations	Strength*1	LoE*2
Unchanged: Surgical and endovascular treatment of an extracranial carotid stenosis should not be performed as an outpatient procedure, because neurological symptoms or delayed bleeding may occur until up to more than 24 h later.	EC
Recommendations for CEA
Unchanged: CEA should always be performed by specialized vascular surgeons because the postoperative results are then better.	↑↑	2a
The following structural stipulations should be met for CEA: – Availability of intraoperative (including intracerebral) angiography and/or duplex sonography Modified: 24-h availability of a specialist in vascular surgery – 24-h availability of duplex sonography, computed tomography, or MRI – 24-h availability of a neurologist/vascular medicine specialist experienced in the treatment of cerebral ischemia – 24-h availability of an endovascular intervention service – Potential for monitoring (intermediate care, intensive care unit, stroke unit) New: 24-h availability of treatment for a complication-related intracranial mass	EC
New: Because the perioperative stroke/death rate is lower in hospitals with high annual caseloads, CEA should be performed exclusively in hospitals with caseloads of > 20 CEA/year.	↑↑	2a
Recommendations for CAS
Modified: CAS should be conducted by a clinically and technically qualified physician with extensive experience of recanalization procedures in brain-supplying arteries. A precondition for leading an elective CAS procedure is performance of at least 10 interventional treatments for carotid stenosis under supervision.	EC
The following structural stipulations should be met for CAS: – 24-h availability of a neurointerventional service that can perform selective intracranial angiography (selective microcatheter navigation) and, if needed, endovascular therapy (local thrombolysis, mechanical recanalization) – 24-h availability of duplex sonography, computed tomography, or MRI – 24-h availability of a neurologist/vascular medicine specialist experienced in the treatment of cerebral ischemia – Potential for monitoring (intermediate care, intensive care unit, stroke unit) New: 24-h availability of treatment for a complication-related intracranial mass New: 24-h availability of a specialist in vascular surgery	EC
Modified: Because the perioperative stroke/death rate is lower in hospitals with high annual caseloads, elective CAS should be performed exclusively in hospitals with caseloads of > 10 elective CAS/year.	↑↑	2a

**¹ Recommendation strength: ↑↑/↓↓, strongly recommended/definitely not recommended;

↑/↓, recommended/not recommended ↔, open recommendation

*² Level of evidence (LoE) 1–5 according to the Oxford Centre for Evidence-Based Medicine 2009

(see guideline report for this clinical practice guideline)

CAS, Carotid stenting; CEA, carotid endarterectomy; EC, expert consensus; MRI, magnetic resonance imaging

Discussion

Almost all of the recommendations contained in this revision of the clinical practice guideline on the diagnosis and treatment of extracranial carotid stenosis were adopted with strong consensus (≥ 95 %). The updated guideline therefore represents a broadly accepted basis for the treatment of extracranial carotid stenosis.

With the publication of numerous RCT, systematic reviews, and meta-analyses, discussion of the role of CAS has become less controversial and more objective. The literature data show a higher periprocedural rate of stroke after CAS and higher rates of myocardial ischemia and—predominantly transient—cerebral nerve lesions after CEA. The fact that the CAS complication rate depends on patient age and the interval between symptom onset and treatment indicates that advanced atherosclerosis and plaque instability are risk factors for CAS. Following intervention, there are no significant differences between CEA and CAS with regard to secondary prevention.

The primary data on which the analyses are based were largely generated no later than 2010. Decreased CAS case numbers and complementary indications for CEA hamper comparison of the two methods.

In contrast to the original version of the guideline, this revision defines subgroups of patients in whom the presence of specific clinical or imaging findings means that they are at greater risk of carotid artery-associated stroke at a later date. The corresponding recommendations aim at achieving rational, evidence-based determination of the indication for revascularization of high-grade asymptomatic stenoses in each individual case.

Further longitudinal studies of the risk of stroke in patients with asymptomatic carotid artery stenoses are needed to further refine appreciation of the roles of BMT, clinical variables, and modern methods of plaque imaging.

In contrast to the original version, the updated clinical practice guideline consented on lowering the acceptable upper limit for the combined rate of stroke and death to 2% for asymptomatic stenoses and 4% for symptomatic stenoses. While the previously recommended thresholds of 3% and 6% relate to 30-day results, the revised guideline considers only those complications that occur before discharge from hospital. Moreover, registry studies and reviews show that the early outcomes of CEA and CAS have improved in recent years (20).

Furthermore the guideline group has formulated clear recommendations on healthcare structures and on the qualifications of the treating physicians. In particular, CEA and CAS should be carried out only as inpatient procedures and only in hospitals with annual caseloads of 20 CEA or 10 CAS.

This revision of the clinical practice guideline recommends CEA as standard procedure for high-grade asymptomatic and for intermediate and high-grade symptomatic carotid stenoses. CAS may be considered as an alternative to CEA, provided the center concerned exhibits quality criteria analogous to those for CEA, with maximal complication rates of 2% for asymptomatic stenoses and 4% for symptomatic stenoses. The next revision of this guideline is scheduled for 2025.