Clinical Practice Guideline
Diagnosis, Treatment and Follow-up in Extracranial Carotid Stenosis
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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).
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.
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.
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).
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):
- ↑↑ 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.
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).
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).
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).
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, 9, 10, 11). Important recommendations regarding treatment technique and follow-up examinations can be found in Table 2 and eTable 5.
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, ↑↑).
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).
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).
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, 26, 27, 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).
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.
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript received on 5 May 2020, revised version accepted on
22 June 2020
Clinical practice guidelines in Deutsches Ärzteblatt International, as in numerous other specialist journals, are not subject to a peer review procedure, since S3 guidelines represent texts that have already been evaluated, discussed, and broadly agreed upon multiple times by experts (peers).
Translated from the original German by David Roseveare
Prof. Dr. med. Hans-Henning Eckstein
Klinik und Poliklinik für Vaskuläre und Endovaskuläre Chirurgie
Klinikum rechts der Isar der Technischen Universität München
Ismaninger Str. 22, 81675 München, Germany
Cite this as:
Eckstein HH, Kühnl A, Berkefeld J, Lawall H, Storck M, Sander D:
Clinical practice guideline: Diagnosis, treatment and follow-up in extracranial carotid stenosis. Dtsch Arztebl Int 2020; 117: 801–7. DOI: 10.3238/arztebl.2020.0801
For eReferences please refer to:
Member of the Steering Group, Institute for Neuroradiology, University Hospital Frankfurt: Prof. Dr. med. Joachim Berkefeld
Member of the Steering Group, Ettlingen: Dr. med. Holger Lawall
Member of the Steering Group, Department of Vascular and Thoracic Surgery, Karlsruhe Municipal Hospital: Prof. Dr. med. Martin Storck
Member of the Steering Group, Department of Neurology and Stroke Unit, Benedictus Hospital Tutzing: Prof. Dr. med. Dirk Sander
German Vascular Society (DGG): Prof. Dr. med. Hans-Henning Eckstein
German Society of Neuroradiology (DGNR): Prof. Dr. med. Joachim Berkefeld
German Society for Angiology/Vascular Medicine (DGA): Dr. med. Holger Lawall
German Society of Surgery (DGCH): Prof. Dr. med. Martin Storck
German Society of Neurology (DGN): Prof. Dr. med. Dirk Sander
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