Conundrum: a problem that is difficult to deal with (1) is probably an accurate description of the present controversies and lack of consensus on the management of asymptomatic carotid artery disease.
The definition of asymptomatic carotid stenosis (ACS) adopted as criteria for inclusion on prospective natural history studies and controlled trials (RCT’s) encompasses the absence of ipsilateral appropriate ocular and/or hemispheric symptoms—transient ischemic attacks (TIA) and stroke—for at least a 6-month period preceding diagnosis; the presence of contralateral symptoms or ipsilateral appropriate symptoms before that 6-month interval are not considered (2).
Atherosclerosis is the most common cause of ACS. Its prevalence increases from the 5th decade, being higher in patients older than 70 years, more common in men than women. It is not only associated to increased risk of ischemic stroke in the appropriate carotid territory, but also to a higher incidence of acute coronary events and vascular death (3).
The mechanisms underlying the ocular and hemispheric symptoms are more dependent on distal embolization from atherothrombosis in the carotid bifurcation rather than flow restriction, which is generally compensated through collateral circulation and functional integrity of the circle of Willis, even in the presence of concomitant intracranial occlusive disease.
Asymptomatic carotid stenosis and risk of stroke and mortality
Stroke is a leading cause of death in western world and a significant cause of disability and loss of quality of life. In the USA around 600,000 first-ever strokes occur each year (4) and in Europe it accounts for 1.1 million deaths per year, being the second leading cause of death (5). More than 50% of the survivors remain with some form of dependency for their daily activities (6). Its financial impact is very significant making stroke prevention a major goal for health policies.
Approximately 35% of all ischemic strokes are associated to carotid bifurcation stenosis, 25% of being related to intracranial disease (lacunar infarcts) and 20% approximately from cardioembolic nature. It is estimated that in 11% (out of those 35% ischemic strokes associated with carotid stenosis) stroke is the first-ever neurological event associated to a stenosis >50% of the internal carotid artery (ICA) (7). These represent an important number of patients where those first-ever strokes could be prevented or reduced by early diagnosis of a significant carotid lesion and prompt intervention, medical and/or surgical.
Durable benefit of carotid endarterectomy (CEA) for ICA 70–99% stenosis with a 50% reduction on stroke-risk from 12% to 6% at 5-year follow-up and a 4.6% absolute risk reduction at 10 years when compared with state-of-the-art best medical treatment (BMT), was clearly demonstrated irrespective of higher mortality mainly due to cardiac causes (2,8,9).
These observations were the basis for recommendations and Guidelines for the treatment of ACS, which should include control of modifiable risk factors and life-style changes for all patients plus invasive CEA for selected 70–99% stenosis in patients with acceptable life expectancy and provided the interventional risk would be <3% (3,10-13). Based on CREST trial results carotid artery stenting (CAS) was endorsed by the AHA/ACC guidelines as an alternative to CEA for ACS (11) but not on more recent Guidelines (13).
Critical evaluation of ACST results demonstrated a 4.6% relative risk reduction offered by CEA + BMT vs. BMT alone, which means that a significant number of procedures 950/1,000 could be ultimately considered unnecessary. Or that only 5% of all CEA’s—1 for every 20 CEAs (or only about 50 for every 1,000 CEAs—would be clinically effective in reducing stroke risk, meaning that 95% of all invasive procedures performed were probably unnecessary and potentially harmful, as there is a low but definitive risk associated to CEA (6).
Several other observations fueled the controversy on management of ACS drawing attention to the importance of medical, nonsurgical, intervention, based on effective reduction of stroke and death risks achieved with medial therapy in stenosis >50–60% and also on the fact that the majority of patients in randomized trials were not having proper and full medical intervention (14). Long-term mortality rates are associated to risk factors for coronary artery disease often present in patients with ACS such as age >70 years, male sex, smoking, high circulating cholesterol levels not properly controlled, arterial hypertension, diabetes, chronic renal dysfunction, which could explain the higher incidence of vascular events and coronary death overcoming the risk of cerebral infarction and stroke and raising questions on appropriateness of carotid interventions, particularly in older patients (15-20). Second, the effect of contemporary BMT including treatment of modifiable risk factors, smoking restriction (reinforced by legislation in some countries), active reduction of LDL cholesterol tailored to the stratification of cardiovascular risk by generalized use of statins and other lowering-lipid drugs, use of aspirin plus appropriate treatment of arterial hypertension (21), which has contributed to significantly reduce stroke-risk associated with moderate to severe ACS thus indirectly suggesting that medical management would be sufficient in patients with 50–99% ACS (22-24).
Similar effect of BMT was reported on the reduction of myocardial infarct rates (24) and in patients with intracranial stenosis, BMT alone offering better protection against stroke incidence than intervention with stenting (25). These observations were also echoed in Guidelines recommending that BMT should be the preferred option also for patients with high surgical risk for CEA (13).
Reduction in carotid plaque size with aggressive lipid-lowering treatment was documented, but progression of disease with increase on plaque size was noted in some patients, suggesting a non-uniform response of all stenosis to the same medical treatment (26,27). Rather than a size reduction in the plaques, aggressive lipid-lowering treatment as statins has shown an anti-inflammatory effect in the plaques, also decreasing their thrombogenicity and propensity for rupture (28).
Criticism for the isolated policy of BMT for all patients with 70–99% stenosis resulted from the fact that studies confirming reduction of stroke risk with BMT have included patients with moderate non-surgical 50–70% stenosis with a lower stroke-risk and also from published reports of insufficient patient compliance with medical treatment (7,29).
Improvement on the selection of ACS that would benefit from invasive treatment, either CEA or CAS, became a priority with a two-fold aim: (I) to reduce the excessive number of carotid interventions being performed, restricting its indications to subgroups of patients with higher risk of neurological events (II) to minimize variability in worldwide practice, ranging from the USA where almost 90% of all CEA have been performed for asymptomatic disease, comparing to 15–20% only in the north European countries, 30% in Australia, 40% in Hungary and Switzerland and 70% in Italy (30,31).
Definition of BMT as previously mentioned is multifactorial: life-style modifications with healthy habits such as exercise, Mediterranean diet, active smoking cessation, plus control of associated disorders as diabetes, arterial hypertension and renal dysfunction, reduction of LDL-C levels by use of appropriate lipid-lowering treatments and anti-platelet therapy. These are essential tools for proper management of atherosclerosis, and they should be pursued in all patients with atherosclerotic arterial disease, whatever location on carotid, coronary, aorto-iliac and peripheral segments, ultimately preventing cardiovascular events (32). The active reduction of LDL-C levels to <70 mg/dL for the high-risk group and <55 mg/dL for those in the very high-risk group by statins and other lowering-lipid drugs should be pursued to achieve maximal benefit on the reduction of vascular events and also to achieve stabilization of the carotid stenosis (33-35).
Is there strong evidence that isolated BMT will be sufficient to prevent strokes in ACS?
The suggestion that BMT treatment would not be enough for all patients with ACS—one fits all—has been recently clearly discussed (36) where not only reduction on overall death and stroke risk should be compared with long-term benefit of CEA and not only to 30-day outcome of the carotid intervention, but the very concept of truly asymptomatic patient is challenged. Some patients may have suffered neurological symptoms when asleep and the presence of silent brain infarcts in the carotid territory.
Progression of baseline 50–69% asymptomatic carotid stenosis was reported in 29.1% and 24.7% of patients, it was associated with an annual stroke rate ranging from 2.1% to 7.7% during an average follow-up of 3.5 years compared to 0.4% annually in those with stable plaques (37). Data from the ACSRS, a natural history study involving 1,121 patients with 50–99% asymptomatic carotid stenosis under medical treatment, demonstrated plaque progression in 19,8% during a mean follow-up of 4.0 years (38) associated to an annual risk of stroke of 2.0%, but included only 32% of the total number of strokes occurring during the same period. For more severe stenosis 80–99%, progression had an annual stroke-risk of 3.1%, suggesting that baseline severity of stenosis and its progression were independent predictors of stroke-risk, but not sufficient to identify all patients who developed strokes. More recent data from ACST1 confirmed that a two-level progression increased significantly the risk of stroke (39) and for very severe stenosis >90% a higher rate of ipsilateral neurological events and death was recognized without beneficial effect from medical treatment (40).
Therefore, the quest for the identification of subgroups of patients with increased risk of neurological dysfunction—vulnerable patient—or the recognition of active plaques more prone to disruption and brain embolization—vulnerable plaque—became a major goal-holy grail. Detecting vulnerable patients and/or vulnerable plaques underlying asymptomatic carotid stenosis would culminate in appropriated beneficial invasive treatment as well as in the reduction of the excessive number of unnecessary carotid procedures.
Not all ACS are equal—what is the profile of the patient at risk?
The concept of vulnerable plaque was derived from autopsy studies providing evidence than two-thirds to three-fourths of fatal acute myocardial infarctions were associated to rupture of the plaque’s fibrous cap leading to local thrombosis with or without coronary occlusion and distal embolization of atherothrombotic material. These observations provided better understanding of the pathophysiology of acute coronary syndromes attributed to active inflammation leading to rupture of coronary plaques loaded with lipids, covered by thin fibrous cap prone to rupture exposing the subendothelial contents to blood components, platelet adhesion, local thrombosis plus distal embolization (41-46). Identification of ulceration and/or thin-capped atheromatous plaques covering areas of lipid deposits or hemorrhagic components became target for imaging arteries in atherosclerosis. Pathology observations of specimens of carotid endarterectomies in symptomatic patients confirmed similar process due to intense inflammation, plaque rupture and ulceration, thrombogenic calcified noduli near the lumen, extrusion of subendothelial components (47,48), or from the core containing lipids and/or blood derivates (49) located close to the lumen of the artery (Figure 1). Recognition of pathological markers of plaque activity were obtained from histological detailed studies of carotid specimens (50,51) providing guidance for a better understanding of the requirements for carotid plaque imaging with new available non-invasive technologies in order to identify potential markers of plaque vulnerability (Figure 2). During the last 20 years various studies and a remarkable bulk of information emerged for the assessment of patients with ACS aiming to identify those subgroups at a higher risk to develop neurological symptoms, including plaque-related features (52)—vulnerable plaques—and patient-related parameters- vulnerable patient.
Despite all these advances, the degree of stenosis is still the most relevant factor for the clinical decision as suggested by ACAS and ACST trials (2,8,9) considering that more severe stenotic lesions are associated with higher neurological risk (53,54). Carotid plaques with specific morphological features predisposing to local thrombosis and distal brain embolization would possibly respond differently to adequate medical treatment (BMT) and different neurological risk was based on clinical data and macroscopic and histologic observations from endarterectomy specimens. A stable carotid plaque, with low risk of complications would have homogenous structure, regular non-eroded thick fibrous cap overlying a hard-central core with scarce inflammatory activity. In contrast vulnerable plaques may have heterogenous structure, ulcerated surface, soft lipid-rich or hemorrhagic core covered by a thin fibrous cap rich in inflammatory cells, prone to rupture, leading to embolization of thrombus or debris causing neurologic events (Figure 3).
Intensive research aiming to identify this subgroup of vulnerable plaques related to increased risk (prone to rupture or erosion) was conducted using ultrasonography (50-56), magnetic resonance imaging (MRI) (57-60), computed tomography angiography (CTA) (61), isolated or combined with positron emission tomography (PET-CTA), optical coherence tomography and contrast-enhanced ultrasound (CEUS) to detect increased neo-vascularization (62-64).
Our group studied the significance of plaque structure using advanced high-definition ultrasound technology (HDU) and provided evidence that heterogenous and echolucent plaques with gray-median scale (GSM) <25 as previously suggested (65) plus the juxta-luminal location of echolucent areas in heterogenous lesions, with evidence of surface disruption and higher degrees of stenosis were common in specimens obtained from CEA in symptomatic patients (66-69) (Figure 4) and its biochemical composition suggested increased plaque biological activity (70-74). In another study we showed that plaque heretogeneity assessed by HDU with the statistical geometric feature reflected plaque inflammation and a vulnerable plaque phenotype (75,76). By assessing the relative importance of all these factors an objective measurement of plaque activity was derived—Activity Index (AI)—in order to identify asymptomatic lesions prone to develop symptoms (Figure 5). Using advanced image analysis (77-79), its diagnostic accuracy was improved providing higher accuracy (78-80) to identify those asymptomatic lesions that developed appropriate neurological symptoms during a 4-year follow-up period (Figure 6). Many approaches have also been attempted by several groups interested in ultrasound. We have also successfully designed novel radiofrequency algorithms based on the center frequency shifts, that detected vulnerable plaques in vivo (confirmed by histology) with an accuracy of 78% (81).
The Asymptomatic Carotid Stenosis and Risk of Stroke (ACSRS) trial, mentioned above, a comprehensive natural history study involving 1,121 patients with asymptomatic 50–99% stenosis combining clinical parameters and computer-assisted plaque analysis based on HDU, identified a high-risk group with an annual rate of stroke of 5.3% (37) and confirmed the value of our previous observation of the significance of the juxta-luminal echolucent (black) area (JLBA) (67,82,83).
Studies with Transcranial Doppler (TCD) with detection of HITS on the middle cerebral artery provided recognition of embolization activity from the carotid plaques which is associated to an increased risk of stroke (84,85). Also, intensive medical therapy achieving low LDL levels has been demonstrated to effectively reduce the number of HITS detected in the middle cerebral artery with TCD and 1-year risk of stroke in a group of asymptomatic patients with stenosis >60% (86,87). In those patients without TCD HITS the 1-year risk of stroke was 1.3%, lower than potential risk of intervention.
MRI, CT and PET (88,89) offered a more objective, reproducible and both qualitative and quantitative characterization of the plaque structure, its components, and also the identification of functional activity like inflammation and thrombosis thus contributing to detect the more vulnerable carotid lesions. However, its widespread use in a busy clinical setting is probably not optimal neither cost-effective.
Studies with contrast-enhanced ultrasound (CEUS) provided evidence of increased vascularization within the plaque structure in patients with appropriate neurological syndromes (88) but its advantage to identify vulnerable asymptomatic plaques in comparison with easier and less-expensive HDU studies was not tested in more extensive prospective studies.
The vulnerable-patient concept emerged and it also of high interest. A comprehensive profile of the high risk patient emerged from the ACSRS study: (I) presence of 80–99% stenosis (II) high systolic blood pressure (III) smoking history of >10 pack-years (IV) contralateral TIA’s or stroke (V) plaque echolucency (Gray Scale Median-GSM) (VI) plaque type and area (VII) plaque structural heterogeneity evidenced by Discrete White Areas (DWA) (VIII) juxta-luminal black area >8 mm2 (JLBA) and (IX) progression of stenosis (18,38,52,83) (see appropriate chapter). In other studies, various clinical and brain imaging parameters were shown to be associated to a higher stroke-risk in ACS patients too namely (I) presence of contralateral neurological symptoms, either TIA’s and/or stroke (90-92) (II) contralateral internal carotid occlusion (90,93) (III) multivessel occlusive disease associated with exhausted vasomotor cerebral autoregulation (94) (IV) presence of clinically silent brain infarctions in the ipsilateral brain hemisphere to carotid stenosis (95).
The presence of active atherosclerotic disease in other territories with evidence of systemic inflammation, a known factor for progression and rupture of atherosclerotic plaques, and presence of hypercoagulation status may be associated to an increased stroke-risk in patients with ACS, but no definitive evidence has been yet produced.
Decline in cognitive function as a result of the presence of ACS has been extensively discussed. Improvement on cognitive function recognized after CEA and CAS was noted, but further studies may be required before indicating CEA in asymptomatic patients with cognitive impairment (36).
In Table 1 established markers of both, plaque and patient vulnerability with established evidence of an increased neurological risk are represented.
For practical purposes in a busy clinical set-up is difficult to use all these tests to identify the subgroup of asymptomatic patients with higher stroke-risk potentially benefiting from an appropriate prophylactic carotid intervention.
Therefore, based on current evidence we suggest the following strategy to assess patients with asymptomatic carotid 70–99% stenosis:
- Clinical and neurological assessment to identify modifiable and controllable risk factors for atherosclerosis and previous history of contralateral neurological symptoms.
- CT or MR brain imaging to identify ipsilateral silent brain infarcts.
- HD-Ultrasound studies to assess severity of stenosis and associated plaque features such as ulceration, significant JLBA, plaque echolucency and heterogeneity.
Why and when to intervene? CEA or CAS?
Management of ACS patients has two main objectives. First, to treat atherosclerosis aiming to control its progression, minimize ischemic events and reduce cardiovascular mortality through appropriate medical treatment (BMT) as previously mentioned. Second, is to prevent ipsilateral stroke as the first-ever neurological event.
The mechanisms leading to stroke associated in ACS are (I) embolization of thrombotic material and/or plaque debris from the carotid lesion to the brain circulation, (II) reduction in brain perfusion usually in patients with severe occlusive disease and multi-vessel involvement and (III) progression to complete occlusion which has been associated to ipsilateral strokes as demonstrated in ACST (8,9).
Acute internal carotid occlusion can be associated to major strokes in one third of the patients, to minor deficit or transient symptoms in another third or to be completely asymptomatic. Nevertheless at least in two thirds of the patients it may cause a disabling event. Also, patients with chronic internal carotid artery occlusion are at increased risk of stroke during follow-up (96,97).
Identification of a subgroup of patients with ACS with increased risk of stroke is mandatory and requires comprehensive clinical assessment beyond severity of stenosis as previously stated.
Based on current evidence, the management of ACS should begin with established medical treatment (BMT) for all patients immediately upon diagnosis and should include:
- Lifestyle modification with appropriate diet and physical exercise;
- Cessation of smoking habits;
- Control of diabetes, hypertension and renal dysfunction;
- Anti-platelet therapy;
- Active management of dyslipidemia with lipid-lowering medication.
Statins should be started immediately to achieve lipid targets and LDL-C levels according to cardiovascular risk stratification and complementary use of other drugs like ezetimibe or PCSK9 receptor inhibitors—proprotein convertase subtilisin-kexin type 9, a hepatic protease that attaches and internalizes LDL receptors into lysosomes, hence promoting their destruction. By preventing LDL receptor destruction, LDL-C levels can be lowered 50%-60% above that achieved by statin therapy alone (98). It should be used in patients with persistent high LDL-C levels not responding to treatment.
Active monitoring of the efficacy of BMT should be pursued and include: (I) assessment of patient compliance to medication (II) control of LDL-C and triglyceride levels and (III) carotid stenosis evaluation with ultrasound to monitor progression of disease and stabilization of the carotid plaque characteristics.
Immediate carotid intervention should only be considered in the following subgroups as also suggested in the recent ESVS Guidelines:
- Severely stenotic lesions (>90%) with or without contralateral occlusion.
- Plaque features such as (I) heterogenous echolucent plaques, with juxta-luminal location of the echolucent region (II) thin-capped lesion with erosion with mobile flaps and ulceration assessed by HDU as mentioned in the previous section.
- Homogeneous and very echolucent plaques assessed by GSM <25, with erosion or ulceration.
- Multivessel extracranial severe occlusive disease including contralateral ICA occlusion.
- Silent brain infarctions in appropriate location suggesting embolization from the carotid lesion, particularly in the absence of other cardioembolic sources.
- Evidence of embolic episodes during TCD monitorization.
Structural changes in carotid plaques due to widespread use of statins has been objectively documented by increased echogenicity, thickening of the echogenic cap and reduction of hypoechoic areas within the plaque area on high-definition ultrasonography (HDU) and reduction on plaque volume (26), evidence of histological modifications with increased fibrous proliferation and reduction of core lipid deposits on carotid plaque specimens have been documented following CEA in recently symptomatic patients (99). Data from virtual histology analysis based on IVUS observations conducted in natural history studies (100) from coronary arteries did suggest a change of paradigm from morphological features of plaque vulnerability from thin-capped lesions with a lipid-necrotic core leading to ulceration and thromboembolic coronary events, which were only responsible for a small percentage of patients developing acute coronary events during a 3.4-year follow-up study (42,45,46,101,102), to hemodynamic factors (103) leading to plaque erosion and exposure to blood components such as fibrinogen, endogenous inhibitors of fibrinolysis and to pro-coagulant microparticles (104-106) have challenged the true relevance of the concept of vulnerable plaque (102,106).
As an illustration, in Figure 7 it is shown a recent case of a patient with a 70% right ICA stenosis followed conservatively for 15 years on BMT and adequate triglyceride and LDL-C levels with clear stabilization of the plaque, increasing GSM and thickening of the echogenic cap. This patient suffered a TIA event and high definition ultrasonography revealed sudden progression of the plaque with erosion and a mobile flap and was successfully treated by CEA.
Stenosis severity and its hemodynamic effect leading to lesion erosion gained relevance again, especially in patients with endothelial dysfunction and reduced regenerative potential within the atheromatous plaques (105,106) in diabetes and renal dysfunction, and also drawing new attention to procoagulant components, which can predispose to local thrombosis at the plaque surface and distal embolization (106).
Monitoring the evolution of 70–90% asymptomatic carotid stenosis under correctly controlled BMT and objective assessment of the impact of hematological factors that may signal systemic inflammation and increased pro-thrombotic activity in the blood will be interesting research areas for the near future.
Which carotid intervention? CEA or CAS?
The gold standard technique has been CEA and its contemporary results showed a significant reduction on the stroke and mortality rates to around 1% (107), which is substantially lower than historical series (108).
CAS was introduced as a less invasive technique, not associated to peripheral nerve palsy, but its early results were disappointing. Technical evolution from materials to technology, as well as the increasing experience of the operators, confirmed its feasibility with relatively low risk, especially in asymptomatic patients.
The IKAROS study (65) suggested a higher risk for neurological complications, stroke and TIA’s, in echolucent lesions with GSM <25 despite the use of brain protection devices.
Five modern RCT's were conducted to compare CAS with CEA (EVA-3S, SPACE, ICSS, CREST, ACT-1 (109-113). The first four of these trials included symptomatic patients and showed that CAS was consistently associated to a higher peri-procedural neurological risk when compared to CEA and in the ICSS trial there was clear evidence of a significantly higher peri-procedural new brain infarcts after CAS when compared to CEA (114) Meta-analysis and reviews of these studies confirmed the non-superiority of CAS over CEA (115,116).
Could data from symptomatic patients be extrapolated to the management of ACS?
Nearly half (47%) of the CREST patients were asymptomatic and the results were not different in both groups regarding the primary endpoints (stroke and acute myocardial infarction). Nevertheless, if only stroke is considered, the risk of CAS was 2.5% and CEA was 1.4% (not statistically significant). In CREST trial the overall risk for both techniques were similar, most of the peri-operative strokes were minor, without significant disability, and small, silent myocardial infarctions detected by troponin elevation were markers of cardiac risk and increased future mortality. However, treatment of carotid stenosis is geared to prevent stroke and myocardial infarction is not a stroke equivalent. If silent myocardial infarction are to be included, then silent brain infarctions should also be searched as they are also markers of reduced life-expectancy and loss of brain mass with the associated cognitive impairment.
The ACT 1 published in 2016 was designed for asymptomatic patients. Its primary endpoints, as well as the overall results, were similar to the asymptomatic group of CREST and the peri-operative stroke rates were 2.8% for CAS and 1.4% for CEA patients (not statistically significant).
Comparison of CAS and CEA in contemporary administrative registries provides information from the “real-world” even if corresponding to a lower level of evidence; the risk of CAS was reported to be prohibitively high, and far higher than the accepted threshold from the AHA (111) in 47% of the CAS registries and only in 5% of the CEA registries (117).
Long-term outcomes and durability of both techniques are similar, according to data providing from CREST (118), ACT-1 (113) and ICSS (111) (symptomatic patients) trials. CAS techniques performed by very experienced operators with large caseloads (119,120), the use of reversed-flow protection and transcarotid revascularization (TCAR) (121-123) might be safer but require further evaluations.
In summary, when compared to CEA, CAS seems to be associated to higher peri-procedural stroke but overcoming this hurdle, long-term durability is equivalent to endarterectomy. CEA continues as the gold standard for intervention in patients with ACS and high risk for stroke as stated in Guidelines (13).
In our experience CAS has been reserved for non-atherosclerotic lesions, proximal (supra-aortic) or distal ICA stenosis, as well as for post-irradiation disease or hostile necks and in a very limited subgroup of patients who may have experienced vocal cord paralysis from a previous contralateral carotid or neck surgery.
Further research is required to clarify the cellular and biochemical mechanisms responsible for plaque progression and regression, the healing potential of superficial erosions and ulcerations with medical treatment in severe stenosis and also the effect of variations on flow dynamics and shear-stress forces on sudden destabilization of carotid plaques in patients on long-term best medical treatment. Proper surveillance will be required for those patients with 70–90% ACS on long-term medical management and delayed carotid intervention.
Funding: IG has been supported by the Swedish Research Council, Strategic Research Area Exodiab, Dnr 2009-1039, the Swedish Heart and Lung Foundation, the Skåne University Hospital Funds and the Swedish Stroke National Association.
Provenance and Peer Review: This article was commissioned by the Guest Editor (Dr. Kosmas I. Paraskevas) for the series “Carotid Artery Stenosis and Stroke: Prevention and Treatment Part I” published in Annals of Translational Medicine. The article was sent for external peer review organized by the Guest Editor and the editorial office.
Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/atm-2020-cass-12). The series “Carotid Artery Stenosis and Stroke: Prevention and Treatment Part I” was commissioned by the editorial office without any funding or sponsorship. The authors have no other conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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