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Risk assessment for carotid artery stenting Expert Rev. Cardiovasc. Ther. 12(5), 565–572 (2014)
Beau M Hawkins*1, Mazen S Abu-Fadel1 and Kenneth Rosenfield2 1 Department of Internal Medicine, Cardiovascular Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 2 Vascular Medicine Section, Cardiology Division, Massachusetts General Hospital, Boston, MA, USA *Author for correspondence: Tel.: +1 405 271 4742 Fax: +1 405 271 2619 [email protected]
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Carotid artery stenting (CAS) is an effective and increasingly utilized therapy for carotid stenosis. Despite its safety, CAS does have procedural risks, which necessitates meticulous technique and careful patient selection for this procedure. A number of patient and anatomical characteristics have been shown to increase CAS risk, and recently, prediction models have been constructed to gauge individual patient risk objectively and comprehensively. This review discusses CAS risk assessment and offers a practical approach to the management of patients with carotid stenosis for which CAS is a viable treatment option. KEYWORDS: carotid artery stenting • carotid endarterectomy • carotid stenosis • prognosis • risk prediction • stroke
Landmark trials published two decades ago established that carotid endarterectomy (CEA) reduces stroke risk compared with medical therapy [1,2]. More recently, randomized trials comparing carotid artery stenting (CAS) to CEA have demonstrated similar composite outcomes in patients with symptomatic and asymptomatic carotid stenosis [3,4]. Current guidelines recommend CAS in symptomatic patients with >50% angiographic stenosis. In asymptomatic patients, the potential benefits are less clear, particularly since stroke risk reduction, the primary aim of carotid revascularization, has been recently improved with medical therapy for cardiovascular disease [5,6]. Interestingly, while CAS and CEA had similar composite cardiovascular outcomes in large randomized trials, the individual risks with each revascularization modality were different. CAS was shown to have a slightly higher minor stroke rate relative to CEA, while cranial nerve palsy and myocardial infarction (MI) rates were significantly higher with CEA [3]. In light of such data, the benefits of CAS are likely to be most robust in individuals in whom periprocedural stroke risk is the lowest, and this highlights the importance of comprehensively gaging stroke risk in patients eligible for CAS. A number of factors have been shown to increase CAS risk including both patient characteristics and anatomic features. Moreover, risk prediction models have been recently published that can assist with accurate quantification of individual CAS risk. Our aims here are to: identify the characteristics that are 10.1586/14779072.2014.901886
consistently considered important in influencing CAS risk, discuss the relevant literature that supports these assertions and review the tools that are available to estimate risk for patients considering CAS. This knowledge is vitally important since these factors may influence treatment decisions and impact shared decision making between clinicians and patients. Traditional risk factors Patient characteristics Age
Increasing age is a robust predictor of clinical events following CAS [7]. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) randomized 2502 patients with carotid stenosis to CEA or CAS. The primary end point was a composite of 30-day death, MI, stroke or ipsilateral stroke at 4 years. Overall, 597 patients over the age of 70 were treated with CAS, and a prespecified analysis demonstrated that age was significantly associated with adverse outcomes in patients receiving CAS. Despite CREST showing similar outcomes between CAS and CEA, CEA appeared to be associated with less risk in patients over the age of 70 years [3]. Observational studies have reported similar findings. Chaturvedi et al. recently reported the outcomes of 1166 octogenarians (22.2% of entire cohort) receiving CAS within the Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events Trial [8]. The 30-day stroke/death was 4.5% in
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Box 1. Features associated with increased carotid revascularization risk [5]. Characteristic • NYHA III or IV heart failure • Left ventricular ejection fraction 75–80 conferred a nearly twofold risk (RR: 1.88; 95% CI: 1.58–2.23) of stroke [10]. A more recently published meta-analysis also confirmed that this heightened stroke risk when CAS is performed in the elderly, but interestingly, mortality risk was not significantly different between young and elderly cohorts [11]. The converse was true for CEA, where stroke risk was found to be comparable between young and old patients, but mortality risk was clearly higher in the elderly. While the precise mechanisms linking adverse outcomes with increasing age remain incompletely defined, a number of explanations are plausible. Comorbidities, including those associated with atherosclerosis, increase with advancing age. Elderly individuals possess less cerebrovascular reserve and even minor events may become clinically apparent. Age may also be a marker of other entities associated with adverse CAS risk such as vessel tortuosity and hostile aortic arches. Symptomatic status
Symptomatic patients are felt to have carotid lesions that are metabolically active, vulnerable to disruption and more prone to initiating thromboembolic events that lead to clinically evident cerebrovascular events [12]. Evidence supporting this assumption rests on several grounds. Symptomatic carotids more often have pathological evidence of ulceration and thrombus. Local and systemic markers of inflammation are increased in patients with symptomatic disease. Advanced imaging modalities have identified correlations between ischemic cerebrovascular events and features of vulnerable plaques including fibrous cap rupture, large lipid cores and neovascularization. Thus, a symptomatic carotid lesion is inherently more prone to 566
causing stroke, and further mechanical disruption with angioplasty likely heightens this risk further. Individuals with carotid stenosis are classified as symptomatic if they have had either symptoms of stroke or a transient ischemic attack (TIA) within the prior 6 months. The symptoms or event must be related to the existing carotid disease – for example, having had a cardioembolic stroke 2 months prior would not necessary be sufficient to categorize an individual with a 50% carotid lesion as symptomatic from a ‘carotid perspective’. Just as age had been consistently linked to worse outcomes, symptomatic status is another feature associated with adverse events following CAS. A prespecified analysis of CREST based on symptomatic status was recently reported [13]. In this analysis, 1321 and 1181 patients were classified as symptomatic and asymptomatic, respectively. Periprocedural stroke or death rates in patients receiving CAS were more than twofold higher in symptomatic compared with asymptomatic patients (6.0 vs 2.5%) [13]. Other randomized trials have demonstrated similar findings. In the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study, a 1200 patient randomized study designed to demonstrate noninferiority of CAS to CEA in patients with symptomatic carotid stenosis; the 30-day rate of death or ipsilateral stroke was 6.8%. Similarly, the International Carotid Stenting Study (ICSS) trial, which examined exclusively symptomatic patients, reported an 8.5% rate of death, stroke or MI in patients treated with CAS at 120 days [14]. These higher event rates persist during longer term follow-up – 16.8% of symptomatic patients treated with CAS in the Stenting and Angioplasty with Protection in Patients at HIgh Risk for Endarterectomy (SAPPHIRE) trial reached the primary end point (defined as 30-day death, stroke, MI or ipsilateral stroke) between days 31 and 1 year [4]. In a large meta-analysis involving more than 19,000 patients, symptomatic status was associated with a nearly twofold increased risk of stroke or death (odds ratio: 1.86; 95% CI: 1.61–2.14) [10]. Additional patient characteristics
Current guidelines for the management of carotid stenosis suggest that several additional patient characteristics increase revascularization risk (BOX 1) [5]. They are ‘shared’ features felt to be associated with risk for both CAS and CEA, but definitive proof in published literature is generally lacking. These characteristics relate to impairment in cardiac and pulmonary function. Since fluid shifts and hemodynamic disturbances (e.g., hypotension) do occur during CAS, it is intuitive that patients with severe cardiopulmonary disease may be at higher risk during these procedures. MI occurred in 1.1% of patients during the periprocedural period in CREST [3], highlighting the potential for adverse cardiovascular events. Anatomic characteristics General considerations
In addition to appropriate patient selection, the successful and safe performance of CAS require careful traversing of the aortic Expert Rev. Cardiovasc. Ther. 12(5), (2014)
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arch, delicate carotid engagement and meticulous technique in device delivery to the lesion of interest. A significant proportion of ischemic events following CAS involve the contralateral, nonintervention hemisphere, highlighting the importance of catheter manipulation in the aortic arch as a source of embolic potential [15]. Likewise, periprocedural stroke following CAS occurs in patients with severe contralateral disease and occlusion, implying that factors beyond arch embolization are important as well [16]. Aortic arch characteristics
Aortic arches are classified into one of three types (I, II and III) based on the origins of the great vessels (innominate, left common carotid and left subclavian arteries) in relation to the outer and inner curvatures of the aortic arch (FIGURE 1). A type I arch is the simplest, where all three vessels takeoff in a plane parallel to the outer curvature of the arch. The type III arch is very angulated and generally involves the innominate originating below the inner arch curvature. The type III arch is the most difficult to traverse with catheters, particularly when attempting to access the right common carotid through the innominate artery. Special catheters are often required to engage the innominate, and delivery of sheaths and devices to the right internal carotid often requires increased force, catheter manipulation and procedural times. For all of these reasons, complication rates are expected to be higher. Faggioli et al. examined the impact of arch type and presence of arch anomalies (e.g., aberrant takeoff of arch vessels) on outcomes following CAS. While arch anomalies were not found to be predictive of adverse outcomes, increasing arch type was shown to be associated with neurological complications (odds ratio: 2.01; p = 0.03) [17]. More recently, Bijuklic et al. analyzed 728 CAS patients who underwent MRI pre- and post-CAS. They found that a type III arch significantly increased the risk of ischemic cerebral lesions, though most lesions were not associated with clinical events [18]. In addition to arch configuration, increased arch atheroma burden and proximal common carotid tortuosity have also been shown to increase CAS risk [19,20]. Plaque characteristics
A number of lesion characteristics have been reported to increase CAS risk. Some of these features include presence of thrombus, plaque ulceration, stenosis severity and calcification. In contrast to patient characteristics, such as age and symptomatic status, these variables are much more subjective and prone to reporting bias, and many trials have excluded patients with these characteristics from participation (e.g., thrombus). Thus, consistent quantitative data defining the risk of CAS performed in these settings are lacking. The rationale supporting thrombus as an adverse predictor is primarily found on hypothetical grounds supported by small case series. The presence of intraluminal thrombus is generally uncommon and was identified in 3 mm in diameter, while significant tortuosity was defined as two or more 90˚ bends within 5 cm of the lesion involving the takeoff of the internal carotid from the common carotid (FIGURE 2). The authors purported that the combination of these two anatomic features impairs device tracking, lesion dilatation and interferes with optimal stent deployment and expansion. There is general 567
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Figure 2. Severe internal carotid tortuosity. The dashed arrow highlights a critical internal carotid artery narrowing. The distal internal carotid artery is very tortuous (solid arrow), which could make distal embolic protection delivery difficult.
agreement that these features increase the difficulty of performing an efficient, straightforward procedure and therefore likely to increase CAS risk. However, excellent outcomes have been reported with CAS for calcified lesions in more recent times. Tsutsumi et al. reported outcomes in 43 patients receiving CAS in densely calcified lesions. Procedural success was 100%, and there was no death or stroke in any patient at 30 days [25]. Moreover, recently reported large registries have not identified calcification to be an important predictor of adverse events [26,27]. This disparity may relate to improved operator experience, better equipment design or better patient selection for CAS. Understanding that arch, great vessel and lesion characteristics influence case complexity and procedural outcomes, MacDonald et al. sought to develop an anatomic scoring system to predict the degree of difficulty present for novice operators when performing CAS [28]. Through a process of polling and consensus opinion known as the Delphi methodology, the authors were able to identify six variables associated with increasing procedural difficulty: type III arch, arch atheroma, bovine arch, lesion stenosis severity (pinhole stenosis), angulated distal internal carotid artery (ICA) and diseased common carotid or external carotid problem. On the basis of these six features, the authors were able to assign each anatomic subtype 568
(e.g., type III arch, pinhole stenosis, angulated distal ICA) into a category of lesser, moderate or particularly severe difficulty. While this system is practical and simple to use, the primary limitation is that it relies on anatomic information that can only be reliably gained by performing invasive angiography – preprocedural assessment is not possible. While identification of plaque characteristics such as calcification and thrombus may be informative for the interventionalist at the time of angiography, it is theoretically more important to identify unfavorable anatomic features noninvasively such that invasive procedures can be avoided when feasible. All angiographic procedures carry risks of bleeding, and diagnostic cerebral angiography is associated with a small albeit real risk of stroke and other neurological complications [29]. Multiple scoring systems have been developed using duplex ultrasonography to characterize carotid plaque and correlate it with pathological findings, the concept being that higher risk plaque (e.g., ulceration, hemorrhage) can be identified noninvasively, which may affect and alter treatment strategies. One such method, the Gray-Weale system, stratifies plaque on the basis of duplex into one of the five types on the basis of echogenicity, ranging from highly echolucent to severely calcified [30]. Another method, the Belesky method, categorizes plaque into categories (e.g., organized thrombus, hemorrhage/ lipid, fibrotic/calcified) on the basis of acoustic densities [31]. Such scoring systems are attractive due to their simplicity and reproducibility, but unfortunately, neither has been shown to be predictive of CAS outcomes. Reiter et al. applied the Gray-Weale and Beletsky systems to 698 patients receiving CAS. At 30 days, TIA or stroke occurred in 41 patients (5.9%). Neither scoring system could be accurately correlated to outcomes in this population after adjusting for baseline patient and lesion characteristics [32]. Embolic protection
The use of embolic protection is recommended for all CAS procedures and in fact is a requirement for reimbursement in the USA. Traditional distal embolic protection utilizes a filterbased device that is placed distal to the lesion in the internal carotid artery, dilation and stenting are then performed and the filter is removed to conclude the procedure. Compared with unprotected CAS, CAS utilizing distal embolic protection has been shown to reduce embolization to the brain and is associated with reduced ischemic cerebrovascular events [33,34]. In recent years, proximal embolic protection devices have been developed to further protect the intracranial circulation during CAS (FIGURE 3). Distal embolic protection requires lesion crossing to deploy the device in the distal ICA, a process that can result in plaque embolization particularly with very critical stenosis. ICA tortuosity can also impede distal embolic device delivery, spasm and dissection of the ICA can occur [35], and particulate debris smaller than the filter pores may not be trapped by these devices. In contrast, proximal protection devices function on the principal of flow cessation through the ICA during intervention. Theoretically, embolic debris does Expert Rev. Cardiovasc. Ther. 12(5), (2014)
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not have the opportunity to traverse the ICA and enter the intracranial circulation. Moreover, proximal devices do not require lesion crossing for deployment. Randomized trials have consistently demonstrated that cerebral embolization, as detected with magnetic resonance imaging, is reduced with proximal protection compared with distal protection [36,37]. Though this reduction in embolic brain loading has yet to be associated with a reduction in clinical events, most operators would agree that the ability to use proximal protection for a given case may lessen procedural risk. Situations in which the use of proximal embolic protection may not be feasible include severe ipsilateral external carotid artery disease as the device is most commonly deployed across the external carotid (FIGURE 2), concurrent common carotid disease, severe contralateral disease and severe lower extremity peripheral artery disease since these devices are bulkier and require larger arteriotomies (e.g., 9F). Operator experience & volume considerations
CAS is technically demanding, requires efficiency and is performed relatively infrequently compared with other endovascular procedures. As such, operator experience has been shown to be an important predictor of patient outcomes. Nallamothu et al. performed an analysis of 24,701 procedures performed by 2339 operators in the USA [38]. Compared with operators performing >12 procedures per year, 30-day mortality was significantly higher for operators performing 12
>10.0
Figure 4. Clinical use of the CAS score for estimation of in-hospital stroke or death following carotid stenting. Point assignments for each of the six variables are summated to generate a CAS score (step 1). The corresponding estimated risk for the calculated CAS score is identified (step 2). † Impending major surgery is any cardiac, vascular or other major surgery planned within 8 weeks. Symptomatic target lesion refers to symptoms within 6 months of procedure. CAS: Carotid artery stenting; CEA: Carotid endarterectomy. Reproduced with permission from Elsevier.
carotid artery revascularization and endarterectomy (CARE) registry. This registry includes symptomatic and asymptomatic patients, as well as those that are average and high surgical risk. The modeled outcome in this analysis was in-hospital stroke or death, which occurred in 2.4% of procedures. Six variables were retained in the final prediction model including: age, symptomatic status, absence of prior CEA, atrial fibrillation, impending major surgery and prior stroke. The NCDR CAS risk score is a simple, bedside tool that can be used to gage individual patient risk (FIGURE 4). In addition to being applicable to most patients considered for CAS, it utilizes clinical variables only, so the risk quantification can be accurately performed prior to angiographic procedures. Touze et al. recently published a ‘clinical rule’ that can be used to identify symptomatic patients who are at low risk for CAS [41]. This rule was derived from a systematic review of published literature and validated in three published randomized trials of CAS versus CEA in symptomatic patients. The rule consists of four variables: sex, contralateral occlusion, age and restenosis. In essence, ‘sex, contralateral occlusion, age and restenosis negative’ patients (women under 75 years with 570
contralateral occlusion or restenosis) are at low risk for CAS and can be considered for this revascularization modality. The primary limitation of this rule is that it is applicable only to symptomatic patients. Expert commentary
The increased utilization of CAS in place of CEA [42] coupled with a heightened emphasis of public outcomes reporting that will necessitate carotid interventionalists exercise meticulous judgment in selecting patients for CAS. Symptomatic status and age are the two most clearly established risk factors for CAS. Additionally, anatomic characteristics such as arch type and vessel tortuosity are also associated with increased risk as these entities pose technical challenges relating to catheter manipulation. Novel risk scores are now available that can be used preprocedurally to gage and quantify patient-specific risk. These tools represent a significant advancement, as clinicians now have the opportunity to provide an accurate risk estimate to patients, rather than merely categorizing patients as average or high risk. Five-year view
The following advances shall hopefully transpire over the ensuing years. The use of noninvasive imaging modalities to identify ‘at-risk’ carotid plaques [12], and the incorporation of this imaging data into treatment algorithms will be important in further refining patient risk. Moreover, such information may also be important in informing CAS strategy (e.g., using proximal vs distal protection). Demonstration of efficacy of novel carotid stenting strategies, such as those using direct carotid access [43], may allow for the avoidance of hostile anatomy that is encountered through the traditional femoral approach. Importantly, the use of risk prediction tools may be important in identifying subsets of patients most at risk for CAS, such that alternative treatment strategies (e.g., medical therapy) may be offered instead. In this regard, improved patient selection for CAS will likely become apparent, and perhaps a continued decline in stroke rates following CAS may be realized. Financial & competing interests disclosure
M Abu-Fadel has received Speakers’ Bureau from Abbott Vascular. K Rosenfield has received research grants from Abbott Vascular, Bard Peripheral Vascular, Medtronic/Invatec and Atrium; receiving consulting/ advisory board fees from Abbott Vascular, Boston Scientific Corp, Complete Expert Rev. Cardiovasc. Ther. 12(5), (2014)
CAS risk assessment
Conference Management, Harvard Clinical Research Institute, Contego, Micell and Becker Ventures; having equity in Lumen Biomedical, Medical Stimulation Corp, Angioguard (Cordis) and Micell; and serving on the board of directors for VIVA Physicians (501C3). The authors have no
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other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues
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• Increasing age and symptomatic status are the two best established risk factors for adverse events following carotid artery stenting (CAS). • A number of anatomical features including arch type, vessel tortuosity and calcification increase procedural complexity and have been shown to increase risk. • Risk scores are available to accurately quantify patient-specific risk for CAS. • The use of noninvasive imaging to identify plaque characteristics associated with stroke is an emerging area, and in the future, such techniques may have a role in predicting outcomes following CAS.
the American Academy of Neurology and Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2011; 57(8):1002-44
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Expert Rev. Cardiovasc. Ther. 12(5), (2014)
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Risk assessment for carotid artery stenting Expert Rev. Cardiovasc. Ther. 12(5), 565–572 (2014)
Beau M Hawkins*1, Mazen S Abu-Fadel1 and Kenneth Rosenfield2 1 Department of Internal Medicine, Cardiovascular Section, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA 2 Vascular Medicine Section, Cardiology Division, Massachusetts General Hospital, Boston, MA, USA *Author for correspondence: Tel.: +1 405 271 4742 Fax: +1 405 271 2619 [email protected]
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Carotid artery stenting (CAS) is an effective and increasingly utilized therapy for carotid stenosis. Despite its safety, CAS does have procedural risks, which necessitates meticulous technique and careful patient selection for this procedure. A number of patient and anatomical characteristics have been shown to increase CAS risk, and recently, prediction models have been constructed to gauge individual patient risk objectively and comprehensively. This review discusses CAS risk assessment and offers a practical approach to the management of patients with carotid stenosis for which CAS is a viable treatment option. KEYWORDS: carotid artery stenting • carotid endarterectomy • carotid stenosis • prognosis • risk prediction • stroke
Landmark trials published two decades ago established that carotid endarterectomy (CEA) reduces stroke risk compared with medical therapy [1,2]. More recently, randomized trials comparing carotid artery stenting (CAS) to CEA have demonstrated similar composite outcomes in patients with symptomatic and asymptomatic carotid stenosis [3,4]. Current guidelines recommend CAS in symptomatic patients with >50% angiographic stenosis. In asymptomatic patients, the potential benefits are less clear, particularly since stroke risk reduction, the primary aim of carotid revascularization, has been recently improved with medical therapy for cardiovascular disease [5,6]. Interestingly, while CAS and CEA had similar composite cardiovascular outcomes in large randomized trials, the individual risks with each revascularization modality were different. CAS was shown to have a slightly higher minor stroke rate relative to CEA, while cranial nerve palsy and myocardial infarction (MI) rates were significantly higher with CEA [3]. In light of such data, the benefits of CAS are likely to be most robust in individuals in whom periprocedural stroke risk is the lowest, and this highlights the importance of comprehensively gaging stroke risk in patients eligible for CAS. A number of factors have been shown to increase CAS risk including both patient characteristics and anatomic features. Moreover, risk prediction models have been recently published that can assist with accurate quantification of individual CAS risk. Our aims here are to: identify the characteristics that are 10.1586/14779072.2014.901886
consistently considered important in influencing CAS risk, discuss the relevant literature that supports these assertions and review the tools that are available to estimate risk for patients considering CAS. This knowledge is vitally important since these factors may influence treatment decisions and impact shared decision making between clinicians and patients. Traditional risk factors Patient characteristics Age
Increasing age is a robust predictor of clinical events following CAS [7]. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) randomized 2502 patients with carotid stenosis to CEA or CAS. The primary end point was a composite of 30-day death, MI, stroke or ipsilateral stroke at 4 years. Overall, 597 patients over the age of 70 were treated with CAS, and a prespecified analysis demonstrated that age was significantly associated with adverse outcomes in patients receiving CAS. Despite CREST showing similar outcomes between CAS and CEA, CEA appeared to be associated with less risk in patients over the age of 70 years [3]. Observational studies have reported similar findings. Chaturvedi et al. recently reported the outcomes of 1166 octogenarians (22.2% of entire cohort) receiving CAS within the Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events Trial [8]. The 30-day stroke/death was 4.5% in
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Box 1. Features associated with increased carotid revascularization risk [5]. Characteristic • NYHA III or IV heart failure • Left ventricular ejection fraction 75–80 conferred a nearly twofold risk (RR: 1.88; 95% CI: 1.58–2.23) of stroke [10]. A more recently published meta-analysis also confirmed that this heightened stroke risk when CAS is performed in the elderly, but interestingly, mortality risk was not significantly different between young and elderly cohorts [11]. The converse was true for CEA, where stroke risk was found to be comparable between young and old patients, but mortality risk was clearly higher in the elderly. While the precise mechanisms linking adverse outcomes with increasing age remain incompletely defined, a number of explanations are plausible. Comorbidities, including those associated with atherosclerosis, increase with advancing age. Elderly individuals possess less cerebrovascular reserve and even minor events may become clinically apparent. Age may also be a marker of other entities associated with adverse CAS risk such as vessel tortuosity and hostile aortic arches. Symptomatic status
Symptomatic patients are felt to have carotid lesions that are metabolically active, vulnerable to disruption and more prone to initiating thromboembolic events that lead to clinically evident cerebrovascular events [12]. Evidence supporting this assumption rests on several grounds. Symptomatic carotids more often have pathological evidence of ulceration and thrombus. Local and systemic markers of inflammation are increased in patients with symptomatic disease. Advanced imaging modalities have identified correlations between ischemic cerebrovascular events and features of vulnerable plaques including fibrous cap rupture, large lipid cores and neovascularization. Thus, a symptomatic carotid lesion is inherently more prone to 566
causing stroke, and further mechanical disruption with angioplasty likely heightens this risk further. Individuals with carotid stenosis are classified as symptomatic if they have had either symptoms of stroke or a transient ischemic attack (TIA) within the prior 6 months. The symptoms or event must be related to the existing carotid disease – for example, having had a cardioembolic stroke 2 months prior would not necessary be sufficient to categorize an individual with a 50% carotid lesion as symptomatic from a ‘carotid perspective’. Just as age had been consistently linked to worse outcomes, symptomatic status is another feature associated with adverse events following CAS. A prespecified analysis of CREST based on symptomatic status was recently reported [13]. In this analysis, 1321 and 1181 patients were classified as symptomatic and asymptomatic, respectively. Periprocedural stroke or death rates in patients receiving CAS were more than twofold higher in symptomatic compared with asymptomatic patients (6.0 vs 2.5%) [13]. Other randomized trials have demonstrated similar findings. In the Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE) study, a 1200 patient randomized study designed to demonstrate noninferiority of CAS to CEA in patients with symptomatic carotid stenosis; the 30-day rate of death or ipsilateral stroke was 6.8%. Similarly, the International Carotid Stenting Study (ICSS) trial, which examined exclusively symptomatic patients, reported an 8.5% rate of death, stroke or MI in patients treated with CAS at 120 days [14]. These higher event rates persist during longer term follow-up – 16.8% of symptomatic patients treated with CAS in the Stenting and Angioplasty with Protection in Patients at HIgh Risk for Endarterectomy (SAPPHIRE) trial reached the primary end point (defined as 30-day death, stroke, MI or ipsilateral stroke) between days 31 and 1 year [4]. In a large meta-analysis involving more than 19,000 patients, symptomatic status was associated with a nearly twofold increased risk of stroke or death (odds ratio: 1.86; 95% CI: 1.61–2.14) [10]. Additional patient characteristics
Current guidelines for the management of carotid stenosis suggest that several additional patient characteristics increase revascularization risk (BOX 1) [5]. They are ‘shared’ features felt to be associated with risk for both CAS and CEA, but definitive proof in published literature is generally lacking. These characteristics relate to impairment in cardiac and pulmonary function. Since fluid shifts and hemodynamic disturbances (e.g., hypotension) do occur during CAS, it is intuitive that patients with severe cardiopulmonary disease may be at higher risk during these procedures. MI occurred in 1.1% of patients during the periprocedural period in CREST [3], highlighting the potential for adverse cardiovascular events. Anatomic characteristics General considerations
In addition to appropriate patient selection, the successful and safe performance of CAS require careful traversing of the aortic Expert Rev. Cardiovasc. Ther. 12(5), (2014)
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arch, delicate carotid engagement and meticulous technique in device delivery to the lesion of interest. A significant proportion of ischemic events following CAS involve the contralateral, nonintervention hemisphere, highlighting the importance of catheter manipulation in the aortic arch as a source of embolic potential [15]. Likewise, periprocedural stroke following CAS occurs in patients with severe contralateral disease and occlusion, implying that factors beyond arch embolization are important as well [16]. Aortic arch characteristics
Aortic arches are classified into one of three types (I, II and III) based on the origins of the great vessels (innominate, left common carotid and left subclavian arteries) in relation to the outer and inner curvatures of the aortic arch (FIGURE 1). A type I arch is the simplest, where all three vessels takeoff in a plane parallel to the outer curvature of the arch. The type III arch is very angulated and generally involves the innominate originating below the inner arch curvature. The type III arch is the most difficult to traverse with catheters, particularly when attempting to access the right common carotid through the innominate artery. Special catheters are often required to engage the innominate, and delivery of sheaths and devices to the right internal carotid often requires increased force, catheter manipulation and procedural times. For all of these reasons, complication rates are expected to be higher. Faggioli et al. examined the impact of arch type and presence of arch anomalies (e.g., aberrant takeoff of arch vessels) on outcomes following CAS. While arch anomalies were not found to be predictive of adverse outcomes, increasing arch type was shown to be associated with neurological complications (odds ratio: 2.01; p = 0.03) [17]. More recently, Bijuklic et al. analyzed 728 CAS patients who underwent MRI pre- and post-CAS. They found that a type III arch significantly increased the risk of ischemic cerebral lesions, though most lesions were not associated with clinical events [18]. In addition to arch configuration, increased arch atheroma burden and proximal common carotid tortuosity have also been shown to increase CAS risk [19,20]. Plaque characteristics
A number of lesion characteristics have been reported to increase CAS risk. Some of these features include presence of thrombus, plaque ulceration, stenosis severity and calcification. In contrast to patient characteristics, such as age and symptomatic status, these variables are much more subjective and prone to reporting bias, and many trials have excluded patients with these characteristics from participation (e.g., thrombus). Thus, consistent quantitative data defining the risk of CAS performed in these settings are lacking. The rationale supporting thrombus as an adverse predictor is primarily found on hypothetical grounds supported by small case series. The presence of intraluminal thrombus is generally uncommon and was identified in 3 mm in diameter, while significant tortuosity was defined as two or more 90˚ bends within 5 cm of the lesion involving the takeoff of the internal carotid from the common carotid (FIGURE 2). The authors purported that the combination of these two anatomic features impairs device tracking, lesion dilatation and interferes with optimal stent deployment and expansion. There is general 567
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Figure 2. Severe internal carotid tortuosity. The dashed arrow highlights a critical internal carotid artery narrowing. The distal internal carotid artery is very tortuous (solid arrow), which could make distal embolic protection delivery difficult.
agreement that these features increase the difficulty of performing an efficient, straightforward procedure and therefore likely to increase CAS risk. However, excellent outcomes have been reported with CAS for calcified lesions in more recent times. Tsutsumi et al. reported outcomes in 43 patients receiving CAS in densely calcified lesions. Procedural success was 100%, and there was no death or stroke in any patient at 30 days [25]. Moreover, recently reported large registries have not identified calcification to be an important predictor of adverse events [26,27]. This disparity may relate to improved operator experience, better equipment design or better patient selection for CAS. Understanding that arch, great vessel and lesion characteristics influence case complexity and procedural outcomes, MacDonald et al. sought to develop an anatomic scoring system to predict the degree of difficulty present for novice operators when performing CAS [28]. Through a process of polling and consensus opinion known as the Delphi methodology, the authors were able to identify six variables associated with increasing procedural difficulty: type III arch, arch atheroma, bovine arch, lesion stenosis severity (pinhole stenosis), angulated distal internal carotid artery (ICA) and diseased common carotid or external carotid problem. On the basis of these six features, the authors were able to assign each anatomic subtype 568
(e.g., type III arch, pinhole stenosis, angulated distal ICA) into a category of lesser, moderate or particularly severe difficulty. While this system is practical and simple to use, the primary limitation is that it relies on anatomic information that can only be reliably gained by performing invasive angiography – preprocedural assessment is not possible. While identification of plaque characteristics such as calcification and thrombus may be informative for the interventionalist at the time of angiography, it is theoretically more important to identify unfavorable anatomic features noninvasively such that invasive procedures can be avoided when feasible. All angiographic procedures carry risks of bleeding, and diagnostic cerebral angiography is associated with a small albeit real risk of stroke and other neurological complications [29]. Multiple scoring systems have been developed using duplex ultrasonography to characterize carotid plaque and correlate it with pathological findings, the concept being that higher risk plaque (e.g., ulceration, hemorrhage) can be identified noninvasively, which may affect and alter treatment strategies. One such method, the Gray-Weale system, stratifies plaque on the basis of duplex into one of the five types on the basis of echogenicity, ranging from highly echolucent to severely calcified [30]. Another method, the Belesky method, categorizes plaque into categories (e.g., organized thrombus, hemorrhage/ lipid, fibrotic/calcified) on the basis of acoustic densities [31]. Such scoring systems are attractive due to their simplicity and reproducibility, but unfortunately, neither has been shown to be predictive of CAS outcomes. Reiter et al. applied the Gray-Weale and Beletsky systems to 698 patients receiving CAS. At 30 days, TIA or stroke occurred in 41 patients (5.9%). Neither scoring system could be accurately correlated to outcomes in this population after adjusting for baseline patient and lesion characteristics [32]. Embolic protection
The use of embolic protection is recommended for all CAS procedures and in fact is a requirement for reimbursement in the USA. Traditional distal embolic protection utilizes a filterbased device that is placed distal to the lesion in the internal carotid artery, dilation and stenting are then performed and the filter is removed to conclude the procedure. Compared with unprotected CAS, CAS utilizing distal embolic protection has been shown to reduce embolization to the brain and is associated with reduced ischemic cerebrovascular events [33,34]. In recent years, proximal embolic protection devices have been developed to further protect the intracranial circulation during CAS (FIGURE 3). Distal embolic protection requires lesion crossing to deploy the device in the distal ICA, a process that can result in plaque embolization particularly with very critical stenosis. ICA tortuosity can also impede distal embolic device delivery, spasm and dissection of the ICA can occur [35], and particulate debris smaller than the filter pores may not be trapped by these devices. In contrast, proximal protection devices function on the principal of flow cessation through the ICA during intervention. Theoretically, embolic debris does Expert Rev. Cardiovasc. Ther. 12(5), (2014)
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not have the opportunity to traverse the ICA and enter the intracranial circulation. Moreover, proximal devices do not require lesion crossing for deployment. Randomized trials have consistently demonstrated that cerebral embolization, as detected with magnetic resonance imaging, is reduced with proximal protection compared with distal protection [36,37]. Though this reduction in embolic brain loading has yet to be associated with a reduction in clinical events, most operators would agree that the ability to use proximal protection for a given case may lessen procedural risk. Situations in which the use of proximal embolic protection may not be feasible include severe ipsilateral external carotid artery disease as the device is most commonly deployed across the external carotid (FIGURE 2), concurrent common carotid disease, severe contralateral disease and severe lower extremity peripheral artery disease since these devices are bulkier and require larger arteriotomies (e.g., 9F). Operator experience & volume considerations
CAS is technically demanding, requires efficiency and is performed relatively infrequently compared with other endovascular procedures. As such, operator experience has been shown to be an important predictor of patient outcomes. Nallamothu et al. performed an analysis of 24,701 procedures performed by 2339 operators in the USA [38]. Compared with operators performing >12 procedures per year, 30-day mortality was significantly higher for operators performing 12
>10.0
Figure 4. Clinical use of the CAS score for estimation of in-hospital stroke or death following carotid stenting. Point assignments for each of the six variables are summated to generate a CAS score (step 1). The corresponding estimated risk for the calculated CAS score is identified (step 2). † Impending major surgery is any cardiac, vascular or other major surgery planned within 8 weeks. Symptomatic target lesion refers to symptoms within 6 months of procedure. CAS: Carotid artery stenting; CEA: Carotid endarterectomy. Reproduced with permission from Elsevier.
carotid artery revascularization and endarterectomy (CARE) registry. This registry includes symptomatic and asymptomatic patients, as well as those that are average and high surgical risk. The modeled outcome in this analysis was in-hospital stroke or death, which occurred in 2.4% of procedures. Six variables were retained in the final prediction model including: age, symptomatic status, absence of prior CEA, atrial fibrillation, impending major surgery and prior stroke. The NCDR CAS risk score is a simple, bedside tool that can be used to gage individual patient risk (FIGURE 4). In addition to being applicable to most patients considered for CAS, it utilizes clinical variables only, so the risk quantification can be accurately performed prior to angiographic procedures. Touze et al. recently published a ‘clinical rule’ that can be used to identify symptomatic patients who are at low risk for CAS [41]. This rule was derived from a systematic review of published literature and validated in three published randomized trials of CAS versus CEA in symptomatic patients. The rule consists of four variables: sex, contralateral occlusion, age and restenosis. In essence, ‘sex, contralateral occlusion, age and restenosis negative’ patients (women under 75 years with 570
contralateral occlusion or restenosis) are at low risk for CAS and can be considered for this revascularization modality. The primary limitation of this rule is that it is applicable only to symptomatic patients. Expert commentary
The increased utilization of CAS in place of CEA [42] coupled with a heightened emphasis of public outcomes reporting that will necessitate carotid interventionalists exercise meticulous judgment in selecting patients for CAS. Symptomatic status and age are the two most clearly established risk factors for CAS. Additionally, anatomic characteristics such as arch type and vessel tortuosity are also associated with increased risk as these entities pose technical challenges relating to catheter manipulation. Novel risk scores are now available that can be used preprocedurally to gage and quantify patient-specific risk. These tools represent a significant advancement, as clinicians now have the opportunity to provide an accurate risk estimate to patients, rather than merely categorizing patients as average or high risk. Five-year view
The following advances shall hopefully transpire over the ensuing years. The use of noninvasive imaging modalities to identify ‘at-risk’ carotid plaques [12], and the incorporation of this imaging data into treatment algorithms will be important in further refining patient risk. Moreover, such information may also be important in informing CAS strategy (e.g., using proximal vs distal protection). Demonstration of efficacy of novel carotid stenting strategies, such as those using direct carotid access [43], may allow for the avoidance of hostile anatomy that is encountered through the traditional femoral approach. Importantly, the use of risk prediction tools may be important in identifying subsets of patients most at risk for CAS, such that alternative treatment strategies (e.g., medical therapy) may be offered instead. In this regard, improved patient selection for CAS will likely become apparent, and perhaps a continued decline in stroke rates following CAS may be realized. Financial & competing interests disclosure
M Abu-Fadel has received Speakers’ Bureau from Abbott Vascular. K Rosenfield has received research grants from Abbott Vascular, Bard Peripheral Vascular, Medtronic/Invatec and Atrium; receiving consulting/ advisory board fees from Abbott Vascular, Boston Scientific Corp, Complete Expert Rev. Cardiovasc. Ther. 12(5), (2014)
CAS risk assessment
Conference Management, Harvard Clinical Research Institute, Contego, Micell and Becker Ventures; having equity in Lumen Biomedical, Medical Stimulation Corp, Angioguard (Cordis) and Micell; and serving on the board of directors for VIVA Physicians (501C3). The authors have no
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other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key issues
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• Increasing age and symptomatic status are the two best established risk factors for adverse events following carotid artery stenting (CAS). • A number of anatomical features including arch type, vessel tortuosity and calcification increase procedural complexity and have been shown to increase risk. • Risk scores are available to accurately quantify patient-specific risk for CAS. • The use of noninvasive imaging to identify plaque characteristics associated with stroke is an emerging area, and in the future, such techniques may have a role in predicting outcomes following CAS.
the American Academy of Neurology and Society of Cardiovascular Computed Tomography. J Am Coll Cardiol 2011; 57(8):1002-44
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Expert Rev. Cardiovasc. Ther. 12(5), (2014)
