Cervical Carotid Artery Stenosis: Latest Update on Diagnosis and Management

Cervical Carotid Artery Stenosis: Latest Update on Diagnosis and Management Peter Kan, MD, MPH, Maxim Mokin, MD, PhD, Travis M. Dumont, MD, Kenneth V. Snyder, MD, PhD, Adnan H. Siddiqui, MD, PhD, Elad I. Levy, MD, FACS, FAHA, and L. Nelson Hopkins, MD Abstract: Carotid atherosclerotic disease is implicated in 15% to 30% of all ischemic strokes. Carotid endarterectomy has been the standard treatment for carotid artery atherosclerosis, but carotid angioplasty and stenting have emerged as a less-invasive treatment alternative. In this article, we review the recent literature on the epidemiology, pathophysiology, investigations, and treatment for atherosclerotic carotid artery disease, focusing on the role of carotid endarterectomy and carotid angioplasty and stenting in the treatment of symptomatic and asymptomatic carotid lesions. (Curr Probl Cardiol 2012;37:127-169.) Drs Kan, Mokin, and Dumont have no conflicts of interest to disclose. Dr Hopkins receives grant/research support from Toshiba; is a consultant for Abbott, Boston Scientific, Cordis, Micrus, W.L. Gore; receives financial interest from AccessClosure, Augmenix, Boston Scientific, Claret Medical, Inc, Micrus, Valor Medical; sits as board/trustee/officer position for AccessClosure, Claret Medical, Inc; is on the speakers’ bureau for Abbott Vascular; and receives honoraria from Bard, Boston Scientific, Cordis, Memorial Healthcare System, Complete Conference Management, SCAI, and Cleveland Clinic. Dr Levy receives research grant support (principal investigator: Stent-Assisted Recanalization in acute Ischemic Stroke, SARIS), other research support (devices), and honoraria from Boston Scientific, research support from Codman and Shurtleff, ev3/Covidien Vascular Therapies; holds ownership interests in Intratech Medical, Ltd and Mynx/Access Closure; is consultant for Codman and Shurtleff, ev3/Covidien Vascular Therapies, TheraSyn Sensors, Inc; and receives fees for carotid stent training from Abbott Vascular and ev3/Covidien Vascular Therapies. He receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr Siddiqui has received research grants from the National Institutes of Health (coinvestigator: NINDS 1R01NS064592-01A1, hemodynamic induction of pathologic remodeling leading to intracranial aneurysms), University at Buffalo; has financial interests in Hotspur, Intratech Medical, StimSox, Valor Medical; is consultant for Codman and Shurtleff, Concentric Medical, ev3/Covidien Vascular Therapies, GuidePoint Global Consulting, and Penumbra; serves on the speakers’ bureau for Codman and Shurtleff, Genentech; serves on the advisory board for Codman and Shurtleff; and receives honoraria from American Association of Neurological Surgeons’ courses, Emergency Medicine Conference, Genentech, Neocure Group; and also from Abbott Vascular and Codman and Shurtleff for training in carotid stenting and endovascular stenting for aneurysm. He receives no consulting salary arrangements. All consulting is per project and/or per hour. Dr Snyder receives honoraria and an institutional grant from Toshiba. Note: Boston Scientific’s neurovascular business has been acquired by Stryker. Curr Probl Cardiol 2012;37:127-169. 0146-2806/$ – see front matter doi:10.1016/j.cpcardiol.2011.11.001

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Prevalence of Carotid Artery Stenosis he prevalence of carotid artery stenosis varies with age, gender, and symptomatic status. Each year, about 795,000 Americans suffer from a stroke, of which 80% are ischemic.1 Symptomatic carotid stenosis is implicated in 15% to 30% of all ischemic strokes.2,3 The reported prevalence of asymptomatic carotid artery stenosis of 50% or greater in patients less than 70 years of age is 4.8% for men and 2.2% for women.4 For patients 70 years or older, the prevalence rapidly increases to 12.5% and 6.9%, respectively. In patients 80 years or older, the respective prevalence of severe asymptomatic carotid stenosis (defined as ⱖ70%) is 3.1% for men and 0.9% for women.4

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David R. Holmes: Stroke is the most feared complication of cardiovascular disease as it is associated with major morbidity as well as mortality. It is the third leading cause of death and disability and accounts for approximately $80 billion in health care costs.

Pathophysiology of Carotid Artery Stenosis and Potential for Targeted Therapy Atherosclerosis is a dualistic process whereby deposition of both soft and hard material occurs within an artery. Atherosclerotic disease of the carotid artery has long been associated with typical concomitants of vascular disease, including hypercholesterolemia, hypertension, diabetes mellitus, obesity, and cigarette smoking.5,6 Its presence represents a potential source for stroke, and its treatment involves medical therapies to treat the aforementioned concomitant diseases. More recently the role of systemic and local inflammation has been recognized as an important concomitant of atherosclerosis and thus a potential therapeutic target.7-11 Typical macroscopic plaque characteristics, such as ulceration and hemorrhage, may all be explained by a common pathway of inflammation. Pathologic findings suggest inflammation plays a role in the development of atheromatous plaques and their transformation into symptomatic lesions.12 Carotid plaques removed from symptomatic patients frequently display signs of inflammation, including expression of inflammation mediators within the plaque.9,11,13,14 In addition, systemic markers of inflammation, such as elevated C-reactive protein, have been associated with an increased risk of carotid atherosclerosis progression and stroke.15 Microscopic evidence of inflammation within carotid atherosclerotic plaque may include expression of molecular inflammation 128

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mediators within plaque material, macrophage infiltration of plaque, evidence of hypoxia, and neovascularization. This is particularly true in echolucent (or primary atheromatous) plaques rather than echogenic (primarily sclerotic) plaques.11 Such lesions are more likely to become symptomatic,16 possibly because of increased susceptibility to inflammatory changes, including neovascularization, hypoxia, necrosis, and thinning of the overlying fibrous cap.12 Subsequent inflammatory changes within an atheroma, such as necrosis and infiltration with macrophages, are strongly associated with cap rupture and time elapsed since ischemic events.14 The precise mechanism of why such inflammatory processes occur at the carotid bifurcation remains unclear. However, it is likely that the development of carotid atherosclerosis is multifaceted. As the association between inflammation and atherosclerosis becomes more evident, medical therapies targeted to halt or reverse inflammatory changes to carotid plaques are likely to emerge. Aspirin, statins, and other medicines with anti-inflammatory properties that are already a part of the routine medical management of carotid artery stenosis may mitigate this effect.17 David R. Holmes: The role of inflammation in cardiovascular disease, including cerebrovascular disease, has received increased attention. The pleotrophic effect of statins is important in this regard. Although this concept of the pathophysiologic significance of inflammation is the subject of intense interest, efforts to identify a specific etiologic agent, for example, a specific virus, have failed.

Pathology and Correlation with Neurologic Symptoms Degree of stenosis has been a mainstay in the design of randomized carotid trials to date. Although relevant as a harbinger of stroke,18-20 degree of stenosis represents only 1 measure of carotid plaque characterization. Probably as important as the degree of stenosis is the rate of progression of stenosis. For example, 1 study showed that an increase from 50% to 69% to 90% to 99% in 1 year or less is associated with a fourfold increased risk of ipsilateral stroke.21 In addition to degree of stenosis and rate of progression, potential markers of higher stroke risk in patients with carotid artery plaques include abnormal morphologic characteristics, such as ulceration, hemorrhage, and detection of cerebral microemboli or silent infarction. These characteristics suggest a less stable atheromatous plaque that is more likely to embolize debris. Not all Curr Probl Cardiol, April 2012

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carotid plaques are alike, and identifying patients at greatest risk for ipsilateral ischemic events remains an important undertaking.21

David R. Holmes: The underlying mechanisms of instability in carotid plaques, including plaque ulceration, hemorrhage, and embolization, bear similarities to many of those characteristics seen in acute coronary syndromes. What is different, however, may be the finding that carotid stenosis severity is associated with increasingly worse acute outcomes, whereas in coronary circulation those lesions that result in subsequent acute myocardial infarction are often only moderate and less than 50%.

Plaque ulceration is among the most studied macroscopic irregularities noted in carotid artery stenosis. Several studies have displayed a correlation between plaque irregularities and increased stroke risk.22-24 The reported prevalence of plaque ulceration on pathologic examination is highly variable in both asymptomatic (14%-82%) and symptomatic (36%-79%) patients but is consistently reported with greater frequency in symptomatic patients.23-26 Plaque ulceration has been correlated with microemboli detectable by transcranial Doppler ultrasonography,27 and its presence represents an increased risk for future stroke in symptomatic or asymptomatic patients. Subgroup analysis from the North American Symptomatic Carotid Endarterectomy Trial (NASCET) found a correlation between ulcerated plaque and 2-year stroke risk.22 The effect of plaque ulceration was seen in all degrees of stenosis, but ulceration was associated with increased relative risk (RR) of stroke in more stenotic vessels (from 1.24 in patients with 75% stenosis to 3.43 in patients with 95% stenosis). Intraplaque hemorrhage is most frequently seen in the context of plaque ulceration28 and represents another relevant marker for increased stroke incidence. Microembolic activity, a risk factor for stroke,29 has been found in the setting of plaque hematoma.30,31 Like ulceration, on pathologic examination, intraplaque hemorrhage is seen more frequently in symptomatic patients (72%-94%) than asymptomatic patients (38%-71%).32,33 The natural history of carotid plaques is somewhat unclear, although the natural history of atherosclerotic disease is toward progression. In a longitudinal study of patients randomized to medical treatment as part of the Asymptomatic Carotid Surgery Trial (ACST), several patients progressed to occlusion (with or without symptoms), whereas a minority of patients had diminished stenosis on follow-up imaging studies.21 Recent advancements in imaging studies may help identify plaques with con130

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cerning features, such as inflammation, hemorrhage, and ulceration, in addition to degree of stenosis, to predict impending ischemic events.

Diagnostic Investigations Carotid Ultrasonography Carotid ultrasonography is an excellent initial screening tool for the evaluation of patients with suspected carotid artery disease. Its main advantage is its widespread availability and its noninvasive approach. Color-flow analysis is used to visualize vessel lumen grossly and to identify the presence and direction of blood flow. Traditionally, red shows blood flow toward the probe and blue indicates flow away from the probe. Spectral Doppler analysis of waveforms is used for evaluation of arterial blood hemodynamic at specific areas of the vessel under investigation, providing indirect measurement of degree of stenosis. Carotid ultrasonography also allows plaque composition analysis, which provides important information in assessing the risk of future stroke. Heterogeneous plaques with hypoechoic lesions were shown to be an independent risk factor for ipsilateral stroke.34 In 2003, a multidisciplinary panel of experts from the Society of Radiologists in Ultrasound reviewed studies from multiple laboratories to develop recommendations for diagnosis and stratification of internal carotid artery (ICA) stenosis, which resulted in the publication of a consensus statement.35 The consensus of the panel was that peak systolic velocities of 125-230 cm/s correlated with 50% to 69% of ICA stenosis, and ICA stenosis of ⱖ70% was diagnosed when peak systolic velocities were greater than 230 cm/s. Later, the consensus criteria for classifying carotid stenosis by ultrasound were validated and their initial accuracy was confirmed.36 Metaanalysis of the relationship between the degree of ICA by carotid ultrasound and digital subtraction angiography (DSA) also demonstrated excellent sensitivity and specificity of the ultrasound technique when diagnosing stenosis of 50% and above.37 However, carotid ultrasound is determined to be less accurate when measuring ICA stenosis below 50%. As a result, the Society of Radiologists in Ultrasound does not recommend subcategories for minor degree of stenosis. Certain special situations exist in which peak systolic velocities may not reflect accurately the severity of carotid artery stenosis. For example, when the stenosis exceeds 90%, Doppler velocities often decrease and may be extremely low. This is sometimes referred to as pseudonormalization. Tandem lesions occur when 2 or more areas of stenosis are found along the course of the ICA. Tandem lesions can also present with falsely Curr Probl Cardiol, April 2012

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diminished or normal range peak systolic velocities at the location of the more proximal stenosis. This phenomenon is a result of diminished peak systolic velocities between the 2 lesions. Discordance between the degree of stenosis by gray-scale analysis and Doppler velocity measurements can help in identifying these lesions, and further evaluation with computed tomography (CT) or magnetic resonance (MR) angiography is recommended.38 Another scenario in which the measurements are altered falsely is the presence of severe contralateral ICA stenosis or occlusion. Such a lesion will increase artificially the ipsilateral peak systolic velocities, and data from other imaging modalities should be considered when interpreting the degree of stenosis.39 Finally, gender differences between blood flow velocities through the ICA also exist, and women in general have higher carotid velocities than men.40 The main limitation of ultrasonography is that the technique is highly operator-dependent. The measurements of blood flow velocities depend greatly on the degree of ultrasound beam angle, and both systolic and diastolic peak velocities increase with a greater angle.41 Failure to use a fixed insonation angle during diagnostic evaluation with carotid Doppler testing can result in errors. Therefore, special attention is advised when performing measurements of tortuous vessels. Suboptimal patient positioning, which is frequently encountered in patients who are intubated or have a high carotid bifurcation, can also limit significantly the diagnostic value of carotid ultrasound. Despite these limitations, ultrasonography remains a widely used screening test for the evaluation of carotid artery disease because of its low cost and noninvasive nature. The use of standardized technical parameters and methods when performing carotid ultrasound has improved the reliability of results. As a general rule, when the results of carotid Doppler are unusual (such as unexpectedly low or high velocities, atypical waveforms, or suboptimal visualization), additional noninvasive imaging modalities or DSA should be performed to establish an accurate diagnosis.

Intravascular Ultrasound (IVUS) Successful application of intravascular sonography in the management of coronary atherosclerosis has led to its use in the evaluation and treatment of carotid artery disease. In interventional cardiology, IVUS has been demonstrated to detect reliably early atherosclerotic disease and monitor further progression and regression of atherosclerotic lesions.42 When used for evaluation of the carotid arteries, IVUS helps to diagnose accurately intimal thickening, concentric plaque, and the presence of 132

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plaque ulceration and calcification, in addition to the degree of stenosis.43,44 Color-flow IVUS provides color-coded information regarding intraluminal blood flow to differentiate better atherosclerotic plaque lesions from the vessel lumen.45 When applied immediately after stenting and angioplasty, IVUS provides detailed information about stent apposition and in-stent thrombus, helping to establish whether further treatment is required. In a series of 107 carotid angioplasty and stenting (CAS) procedures, Clark et al.46 reported that after a satisfactory result was demonstrated by angiography, subsequent IVUS findings resulted in additional treatment in 9% of patients: 4 patients required poststent angioplasty, 3 patients required additional stents to achieve complete plaque coverage, and 3 patients were found to have stent malapposition. Previous studies in which IVUS was applied show low complication risk, even when used before plaque dilatation.46,47 Nevertheless, the risk of vessel injury and difficulty in advancing the ultrasound probe in patients with tortuous vessels or through areas of high-grade stenosis limit the use of IVUS for routine assessment of carotid stenosis. At our institution, it is reserved for clinical situations when noninvasive imaging or DSA alone fails to establish an accurate evaluation of carotid stenosis and for poststenting assessment (Fig 1). In interventional cardiology, IVUS has already demonstrated its cost-effectiveness during percutaneous coronary interventions.48 David R. Holmes: The use of IVUS for routine assessment of carotid stenosis at the time of treatment may in part be related to a lack of familiarity with the device by some of the subspecialists involved in these procedures. It also may be related to the absence of a large body of information on the advantages of procedural guidance in the carotids as compared to the coronary arterial tree.

CT Angiography CT angiography offers several advantages when evaluating for carotid artery disease, including noninvasive imaging and high spatial resolution. This imaging modality has now become a standard test when evaluating patients with symptoms of stroke at many institutions. The introduction of multidetector CT technology allows acquisition of multiple image slices simultaneously, which greatly improves the speed of imaging without loss of resolution.49 Metaanalysis of the diagnostic accuracy of CT angiography compared with DSA confirmed that CT angiography is accurate in detecting severe carotid stenosis and especially for detection of complete Curr Probl Cardiol, April 2012

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Fig 1. IVUS after CAS shows good wall apposition and no in-stent thrombus.

occlusion, where its sensitivity and specificity reach 97% and 99%.50 In clinical practice, CT angiography is often performed following carotid ultrasound imaging that shows positive results for carotid artery disease. In a recent study assessing the cost-effectiveness of various noninvasive imaging modalities, Tholen et al.51 demonstrated that immediate CT angiography is indicated for patients with a high-risk profile for stroke or with a high prior probability of carotid artery stenosis or who can undergo surgery within 2 weeks after the initial symptoms of transient ischemic attack (TIA) or minor stroke. In addition to providing accurate measurements of luminal narrowing, CT angiography reliably assesses the characteristics of carotid artery atherosclerotic plaques. Although histologic plaque composition is better evaluated with MR angiography technique, CT angiography shows excellent sensitivity for detection of carotid plaque calcifications (Fig 2). Nevertheless, it should be noted that in the presence of extensive dense calcifications, beam-hardening artifact can obscure visualization of the carotid artery lumen and provide inaccurate estimation of the degree of stenosis. CT angiography is also capable of detecting large lipid-rich 134

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Fig 2. CT angiography of the ICA, coronal view (left) and 3D reconstruction (right), in a patient with suspected bilateral carotid artery stenosis shows extensive plaque calcifications at both carotid bifurcations and severe stenosis at both ICA origins.

necrotic core lesions and plaque hemorrhages; however, its diagnostic accuracy in detecting smaller lesions is less reliable.52 Because CT angiography is associated with radiation use, the imaging protocol setting should be closely observed to limit radiation exposure. CT angiography involves administration of intravenous contrast material, which has the potential for contrast-induced renal failure, especially in patients with preexisting renal disease. Baseline renal function tests, including glomerular filtration rate, help to determine whether the administration of nephroprotective agents, such as bicarbonate and acetylcysteine, is necessary to minimize the risk of renal injury.

David R. Holmes: The authors comment on the potential strategies to minimize the risk of renal injury. The efficacy of these approaches to minimize this, however, has been found to be disappointing when evaluated in rigorous large-scale randomized trials.

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Fig 3. Asymmetrical CT perfusion maps in a patient with high-grade left ICA stenosis before carotid artery stenting demonstrate increased CBV (top middle), TTP (top right), and MTT (bottom middle) in the left hemisphere, indicating maximized autoregulatory hemodynamic mechanisms to preserve brain perfusion. Such changes suggest that this patient is at higher risk to develop hyperperfusion syndrome.

CT Perfusion A combination of CT angiography with CT perfusion enables analysis of hemodynamic parameters associated with carotid artery disease. Whole-brain CT perfusion imaging with 320-detector-row CT scanners allows examination of the entire brain, providing valuable information about regions of the brain that are at risk for ischemia and status of the collateral circulation. Modern CT perfusion parameters include cerebral blood volume (CBV), cerebral blood flow (CBF), time-to-peak (TTP), and mean transient time (MTT). Symmetrical perfusion maps between the 2 hemispheres indicate normal cerebral circulation, whereas asymmetry in the vascular territory corresponding to the affected ICA may serve as a measure of perfusion disturbance (Fig 3). Changes in MTT and CBV can be observed in patients with ICA stenosis above 50%.53 These changes are thought to represent autoregulatory vasodilation—a compensatory mechanism that is intended to preserve cerebral oxygenation when collateral circulation alone is not adequate to maintain physiological parameters of cerebral blood perfu136

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sion. Thus, the typical perfusion pattern in severe carotid artery stenosis is an increase in MTT with maintenance of CBV. The application of an acetazolamide challenge can improve further the diagnostic value of CT perfusion when assessing cerebral hemodynamics by enhancing the asymmetry of CBF and CBV maps.54 This approach may help identify patients with ICA stenosis who are at higher risk for stroke. Acetazolamide is a carbonic anhydrase inhibitor that produces cerebral vasodilation. Normal response to acetazolamide administration is an increase in CBF and CBV, as seen in the normal hemisphere. In the affected hemisphere where autoregulatory mechanisms have already been maximized, acetazolamide challenge will not cause increased vasodilation; as a result, CBV and CBF will remain unchanged or even decrease because of vascular steal from the unaffected area. Incorporating perfusion analysis in the evaluation of patients undergoing ICA stenting also demonstrates the dynamic nature of brain perfusion following the repair of stenosis. In a study of patients with severe carotid stenosis where CT perfusion was used 5 days before and 1 week after ICA stenting, preoperative evaluation showed decreased CBF and increased MTT values in the cerebral areas supplied by the stenotic ICA.55 Following endovascular treatment with stenting, significant normalization of these perfusion parameters was observed.

MR Angiography MR angiography is based on the principle of signal variations between dynamic tissue (blood flowing through arteries and veins) vs surrounding stationary soft tissue. Time-of-flight MR angiography is performed without contrast medium and can be used safely in patients with impaired kidney function. This technique requires significant time for processing and is subject to significant motion artifacts, often necessitating the use of complementary imaging testing. For example, the combination of MR angiography with carotid ultrasound increases sensitivity and specificity of both tests in the diagnosis of carotid stenosis.56 Contrast-enhanced MR angiography with gadolinium reduces imaging time and enhances diagnostic accuracy when evaluating large-diameter vessels. Contrast-enhanced blood flow produces a stronger signal intensity, thus avoiding misinterpretation of the turbulent blood flow that is commonly found at the carotid bifurcation in areas of stenosis. Nevertheless, even contrast-enhanced MR angiography has been reported to overestimate the degree of carotid artery stenosis when compared with DSA.57 A metaanalysis on MR angiography for evaluation of carotid artery stenosis showed especially poor accuracy of this imaging method in diagnosing a moderate Curr Probl Cardiol, April 2012

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Fig 4. T1 sequence axial view of high-resolution MR image (left) demonstrates a hemorrhagic plaque of the right ICA (hyperintense crescent-shaped lesion indicated by the arrow). 3D reconstruction of MR angiogram (right) shows precise location of the hemorrhagic plaque at the bifurcation of the right common carotid artery.

degree of ICA stenosis. MR angiography showed better specificity in diagnosing high-grade stenosis or complete ICA occlusion.58 Variations in imaging postprocessing methods and magnet strength can affect image resolution and accuracy of stenosis measurement significantly.59 MR imaging-incompatible implanted devices, such as pacemakers in patients with cardiac disease, also limit its use in this subgroup of patients.

High-Resolution MR Imaging The main advantage of high-resolution MR technology in the noninvasive evaluation of carotid artery disease is its excellent characterization of atherosclerotic plaque composition. A dedicated surface coil, 3-Tesla magnet strength, and multiple sequences that suppress arterial blood signal are recent advancements that have resulted in superior carotid artery wall and plaque characterization by high-resolution MR imaging. Several studies have validated the diagnostic accuracy of high-resolution MR imaging in detecting plaque components and active inflammatory processes. Certain morphologic features of atherosclerotic plaques (known as vulnerable or high-risk plaques) carry a high risk for future stroke, and screening for the presence of such plaques is critical when formulating a treatment plan (Fig 4). In a study of patients with asymptomatic stenosis exceeding 50%, arteries with ruptured or thin fibrous caps and increased ratio of lipid-rich to necrotic core are associated with the develop138

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ment of subsequent stroke or TIA.60 Early or recent intraplaque hemorrhage is another marker for increased future stroke risk.61 Contrast-enhanced high-resolution MR imaging provides more distinct signal detection of the arterial vessel wall by improving contrast-to-noise ratio. Gadolinium is most commonly used, but its main disadvantage is nonspecific absorption by multiple tissues. Tissue-specific contrast agents provide an advantage over gadolinium contrast by detecting diseasespecific processes. For instance, ultrasmall superparamagnetic particles of iron oxide are absorbed by actively inflamed plaques with a high concentration of macrophages and can aid in differentiating between lowand high-risk plaques.62 The use of tissue-specific agents at this time is mostly investigational and lacks generally accepted protocols. The approach of monitoring the effect of lipid-lowering therapy by direct measurement of plaque progression and regression using imaging techniques such as MR imaging was first applied in cardiology. The same concept has been applied successfully to monitor the effect of statin treatment in atherosclerotic carotid artery disease. High-resolution MR imaging confirmed that aggressive lipid-lowering therapy causes a reduction in plaque inflammation and an increase in arterial luminal area.63,64 Continuation of statin treatment beyond 12 months resulted in further regression of atherosclerotic lesion, indicating a benefit of long-term treatment. David R. Holmes: The application of high-resolution MR for monitoring the effects of statin treatment is tremendously exciting. Given the fact that the carotid arterial tree can be imaged relatively readily compared with the coronary arterial tree makes this approach much more readily available.

Digital Subtraction Angiography Despite recent advances in noninvasive imaging technologies, including CT and MR angiography, conventional DSA still remains the gold standard in evaluating patients with suspected carotid artery disease. It allows clinicians to obtain the multiple high-quality views of the carotid artery that are essential for accurate measurements of the stenotic lesion and understanding precise anatomy of the vasculature proximal and distal to the plaque, especially when noninvasive diagnostic modalities provide conflicting results (Fig 5). The information obtained with diagnostic DSA is extremely important when determining if the patient should be treated with CAS or carotid endarterectomy (CEA), as well as when choosing the type of protection devices and stents for CAS. Compared with noninvasive modalities, DSA also has the added ability to assess collateral flow. Curr Probl Cardiol, April 2012

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Fig 5. Conventional digital subtraction angiogram (lateral view, left common carotid artery injection) confirms the presence of 67% stenosis at the left ICA origin.

DSA-related neurologic complications, namely, nondisabling and disabling stroke, are often cited by critics of this imaging modality. However, recent studies show that when performed by skilled physicians, the risk of periprocedural stroke is less than 1%.65-67 The endovascular surgical neuroradiology discipline has been established by the Accreditation Council for Graduate Medical Education to ensure that diagnostic and interventional extra- and intracranial endovascular procedures are performed by highly skilled and trained physicians.68

Medical Management of Carotid Artery Disease In general, medical management of patients with extracranial carotid artery disease follows the same principles as for other forms of general 140

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atherosclerosis. It includes lifestyle modifications, close monitoring and treatment of comorbid conditions, and lipid-lowering and antithrombotic therapy. The 2011 guidelines on the management of extracranial carotid artery disease list control of hyperlipidemia with statin agents in patients with carotid artery atherosclerosis under Class I recommendations.69 Lowdensity lipoprotein (LDL) cholesterol has a strong positive relationship with carotid atherosclerosis.70 The guidelines recommend the target goal of LDL concentration of lower than 100 mg/dL.69 A more aggressive regimen is advised for patients with a history of previous stroke or TIA, with the goal of LDL concentration near or below 70 mg/dL. In a systematic review of studies that evaluated the effect of statins on plaque morphology, a beneficial effect of statin therapy was observed.71 The studies included in this review varied in dose and duration of statin treatment, as well as diagnostic modalities used to monitor progression of plaque morphology. Despite the differences in study designs, a wide range of positive outcomes was observed, from slower progression of plaque to regression as early as 1 month of treatment. Maintaining LDL concentration lower than 100 mg/dL was the strongest predictor of positive response to treatment. The Stroke Prevention with Aggressive Reductions in Cholesterol Levels (SPARCL) was a prospective randomized trial that showed the beneficial effect of atorvastatin in patients with recent stroke or TIA in reducing the risk of subsequent stroke.72 Secondary analysis of a subgroup of SPARCL population patients with carotid artery stenosis revealed that aggressive lipid-lowering treatment was associated with a 33% reduction in the risk of stroke (hazard ratio 0.67; 95% confidence interval 0.47; 0.94; P ⫽ 0.02).73 Multiple randomized trials have compared aspirin, clopidogrel, or a combination of dipyridamole and aspirin only to show a modest difference in stroke prevention. In clinical practice, the choice of an antiplatelet agent in patients with carotid artery disease depends on the patient’s cardiovascular risk factor profile and the presence of comorbid conditions that might preclude the use of certain agents. The randomized Clopidogrel vs Aspirin in Patients at Risk of Ischemic Events study showed only a marginal benefit in reduction of the combined risk of stroke, myocardial infarction (MI), or vascular death from long-term treatment with clopidogrel, 75 mg daily, vs aspirin (325 mg daily) in patients with atherosclerotic vascular disease.74 Patients with a history of previous vascular events or diabetes benefited the most from clopidogrel therapy. Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance was a large study that enrolled more than Curr Probl Cardiol, April 2012

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15,000 patients and demonstrated no benefit for combined use of aspirin and clopidogrel vs aspirin alone in the prevention of stroke or death from cardiovascular causes.75 Similar nonsignificant results were observed when a combination of aspirin and clopidogrel treatment vs clopidogrel alone were compared in the management of atherothrombosis with clopidogrel in high-risk patients study with recent TIAs or ischemic stroke trial.76 It is important to point out that the dual antiplatelet therapy was associated with a higher risk of life-threatening or major bleeding complications. Therefore, in patients who are not undergoing revascularization with stenting, dual antiplatelet therapy with aspirin and clopidogrel is not routinely recommended.77

David R. Holmes: Dual antiplatelet therapy has been found to be associated with increased bleeding. Whether this is from the thienopyridine or aspirin itself is not completely clear. That has important implications with regards to the use of proton pump inhibitors; a major confounding issue is the fact that there may be also an indication for anticoagulant therapy in these patients. For example, patients with atrial fibrillation in whom stroke prevention rests on warfarin or 1 of the new agents is a very problematic group if they undergo drug-eluting stents because then they are faced with triple therapy.

In patients who are undergoing CAS, a dual antiplatelet regimen with aspirin and clopidogrel is recommended for at least 30 days following the procedure, followed by lifelong aspirin therapy. This is done to minimize the risk of in-stent thrombosis while stent endothelialization is taking place, as platelets play a central role in neointimal proliferation. A significant benefit of dual antiplatelet therapy on reducing adverse neurological outcomes and thrombosis rate without an additional increase in bleeding complications was clearly demonstrated by comparison with aspirin alone.78,79 Pathology results of stented coronary vessel segments show that complete reendothelialization is a slow process and can first be observed only 12 weeks after stenting.80 These findings advocate continuation of dual antiplatelet therapy following stenting for longer periods, but further studies are needed to define the optimal duration of such postprocedural treatment. Presently, several diagnostic tests measuring aspirin and clopidogrel resistance exist. Clopidogrel resistance seems to be more commonly encountered in patients undergoing stenting procedures: some studies indicate it can be encountered in up to one-half of the patients who receive clopidogrel.81,82 In patients with allergic reactions or who are nonresponders to clopidogrel, ticlopidine or prasugrel can be used as an alternative 142

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antiplatelet agent. Close monitoring of hematologic tests is advised when initiating treatment with ticlopidine, because of the risk of life-threatening agranulocytosis and thrombotic thrombocytopenic purpura. Prasugrel is contraindicated in patients with a history of TIA or stroke. David R. Holmes: Although ticlopidine has been used in this setting, with the availability of newer agents, its use is uncommon.

Finally, optimal medical management of hypertension, diabetes mellitus, and other cardiovascular risk factors (such as smoking, obesity, metabolic syndrome, and hyperhomocysteinemia) should also be closely followed.69 Poor serum glucose control in diabetic patients and hypertension are well-known risk factors for stroke and serve as independent risk factors for the development of carotid artery atherosclerosis.

Surgical Management and Stenting for Symptomatic Carotid Stenosis Carotid Endarterectomy The first reported case of CEA for stroke prevention was published in 1954.83 The first trials of CEA published in 1970 and 1984 displayed unfavorable complication rates compared to medical treatment.84,85 The technique was practiced and improved on, despite the negative results of these trials. Two pivotal randomized controlled trials (RCT) reported in the 1990s, the NASCET and the European Carotid Surgical Trial (ECST), have since established the effectiveness of CEA in reducing the risk of ischemic stroke in patients with symptomatic carotid artery disease.

North American Symptomatic Carotid Endarterectomy Trial (NASCET) The NASCET was initiated in the mid-1980s to compare the efficacy of CEA to the best medical therapy at the time (aspirin) in patients with symptomatic carotid artery disease.86 This study randomized 659 patients to medical or surgical treatment between February 1988 and January 1991. In NASCET, symptomatic patients were defined as patients who presented with a TIA (hemispheric or retinal), reversible ischemic neurologic deficits, or a minor stroke within the previous 120 days. The degree of stenosis was defined as 1 minus the residual lumen at the most narrowed portion of the vessel compared with the lumen diameter in the normal ICA distal to the lesion. In symptomatic patients with 70% to 99% Curr Probl Cardiol, April 2012

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ICA stenosis, the NASCET investigators reported a 2-year ipsilateral stroke risk of 26% in the medical group and 9% in the surgical group. This translates to an absolute risk reduction of 17%, an RR reduction of 65%, and only 6 patients needing treatment to avoid 1 stroke (number to treat). Other statistically significant benefits for CEA at 2 years included a lower risk of any stroke or death (15.8% vs 32.3%), a lower risk of major or fatal ipsilateral stroke (2.5% vs 13.1%), and a lower risk of major stroke or death (8.0% vs 19.1%). However, the benefits of CEA only apply to centers with a perioperative risk of stroke and death of less than 6%.86 The time in which the benefit of surgery emerges is only 3 months, and the benefit of surgery persists for at least 8 years.87 Other complications reported for the surgical group in NASCET include cranial nerve injury (8%), wound infection (3%), MI (1%), and other cardiovascular complications, such as arrhythmia and congestive heart failure (3%). For symptomatic patients with 50% to 69% stenosis, NASCET showed that the benefit of CEA over medical therapy is only moderate: the ipsilateral stroke risk over 5 years was 22.2% in the medical group, compared with 15.7% in the CEA group.88 This translates to an absolute risk reduction of only 6.5% (1.3%/year). Moreover, the benefit for CEA in this moderate-stenosis group is only significant in men and not in women, and there is no benefit for patients with amaurosis fugax. For symptomatic patients with less than 50% stenosis, NASCET found no significant difference in the 5-year risk of ipsilateral stroke between the CEA and medical groups.

European Carotid Surgery Trial (ECST) Similar to NASCET, ECST was a multicenter, prospective, RCT comparing CEA to aspirin in the treatment of patients with symptomatic carotid disease.89,90 This study randomized 3024 patients to medical or surgical treatment between October 1981 and March 1994. Symptomatic patients were defined as patients with TIA, retinal infarcts, or minor stroke within the previous 180 days. The percentage of stenosis was defined as 1 minus the lumen diameter at the most narrowed portion of the vessel compared with the estimated original diameter at the same site. In symptomatic patients with a 70% to 99% stenosis, ECST reported a significant reduction in the risk of stroke or death in patients treated with CEA compared with aspirin alone (21.9% in the medical group vs 12.3% in the CEA group). The 3-year risk of any ipsilateral ischemic stroke was also lower in the CEA group (2.8% vs 16.8%). The surgical risk of stroke and death in the 30-day perioperative period was 7.5%. Subsequently, ECST also reported the risk reduction in patients with 80% to 99% 144

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stenosis: 14.9% in the CEA group vs 26.5% in the medical group for any major stroke or death at 3 years. Similar to NASCET, ECST also found men to derive more benefit from CEA than women. The benefit of CEA was noted by the end of the first year, reached a maximum at 3 years, but still persisted for at least 10 years. Symptomatic patients with mild (⬍30%) stenosis did not benefit from surgery.

Veterans Affairs Cooperative Study on Symptomatic Stenosis The Veterans Affairs Cooperative Study on Symptomatic Stenosis was another multicenter, prospective, RCT comparing CEA to best medical therapy in the treatment of symptomatic carotid stenosis.91 Between July 1988 and February 1991, 189 men with symptomatic ICA stenosis of greater than 50% were randomized. At 12 months, there was a significant reduction in stroke or crescendo TIAs in patients treated with CEA and best medical therapy (7.7%) compared with patients treated with best medical therapy only (19.4%), an absolute risk reduction of 11.7% (P ⫽ 0.011). The benefit of surgery was even greater in patients with stenosis greater than 70% (absolute risk reduction, 17.7%; P ⫽ 0.004).

Pooled Analysis A pooled analysis of data from the NASCET, ECST, and Veterans Affairs trial 309 shared the same findings with NASCET regarding the benefit of CEA for symptomatic patients with more than 70% stenosis or with 50% to 69% stenosis.92 The analysis showed no benefit of CEA for patients with near-occlusion or for patients with 30% to 49% stenosis (harmful for ⬍30% stenosis). It also showed that gender and timing of CEA affects the degree of benefit from surgery. In the 70% to 99% patient group, there was proven benefit for men even if CEA was performed beyond 12 weeks from the symptomatic event, whereas for there to be a benefit in women, CEA had to be performed within 2 weeks. In general, the benefit for CEA in men with 70% to 99% stenosis was greatest if performed within 2 weeks. In the 50% to 69% group, there was proven benefit of CEA only for men but not for women and for men only if CEA was performed within 2 weeks. David R. Holmes: The impact of gender on outcome is of great importance. The specific reason for the differential effect in women is unclear—whether that is a result of differences in vessel size or differences in hematologic factors or other reasons is unclear.

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High-Risk Patients for CEA Despite the efficacy of CEA in the treatment of symptomatic carotid artery disease, high-risk factors for CEA are well established. Severe medical or surgical comorbidities, contralateral severe stenosis or occlusion,93 intraluminal thrombus, and evolving/unstable symptoms all increase the surgical risk for CEA. In these patients, CAS should be considered as an alternative treatment because none of the above high-risk features for surgery is considered high risk for CAS.

Carotid Angioplasty and Stenting Percutaneous transluminal carotid angioplasty was first described in the 1960s. Carotid angioplasty without stenting, however, has a high risk of embolism risk and recurrent stenosis. On the strength of the Carotid and Vertebral Artery Transluminal Angioplasty Study94 and other reports,95,96 the importance of stenting rather than primary angioplasty to limit the incidence of plaque rupture, arterial dissection, and acute carotid occlusion was realized. Introduced in the 1990s, CAS reduces the risk of embolization and carotid artery recoil. Multiple studies since suggest that CAS and CEA have similar long-term outcomes for patients with symptomatic carotid artery disease. The results of the pivotal CAS trials and registries are reviewed and discussed below.

Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) SAPPHIRE was a North American RCT aimed to demonstrate “noninferiority” of CAS compared with CEA.97 It was the first RCT in which the use of distal embolic protection was mandatory (Angioguard or Angioguard XP device; Cordis Warren, NJ). The study population consisted of 334 high-risk surgical patients with more than 70% being symptomatic (defined as ⱖ50% stenosis). The 30-day combined periprocedural adverse event rates (MI/stroke/death) were 4.8% for CAS patients and 9.8% for CEA patients (P ⫽ 0.09). At 1 year, the combined major adverse event rates (stroke/death/MI) were 12.2% for the CAS group and 20.1% for CEA group (P ⫽ 0.048 for noninferiority analysis and 0.053 for superiority analysis). At 1 year, CAS was superior to CEA with respect to MI (2.5% CAS vs 8.1% CEA, P ⫽ 0.03) and major ipsilateral stroke (0% CAS vs 3.5% CEA, P ⫽ 0.02). An analysis of the trial outcome that excludes MI still confers noninferiority of stenting. Partly, on the basis of these data, the US Food and Drug Administration (FDA) approved the use 146

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of stenting with distal protection for high-risk patients, and the Centers for Medicare and Medicaid Services provides reimbursement for symptomatic stenosis of 50% or greater. At 3 years, the combined major adverse event rates in SAPPHIRE were not significantly different between the 2 groups (24.6% of CAS vs 30.3% for CEA).98 These data strongly suggested noninferiority of CAS for high-risk, largely symptomatic patients. For symptomatic patients only, the incidence of the combined major adverse events at 1 year was 16.8% among the CAS group, compared with 16.5% of the CEA group (P ⫽ 0.95).97

Endarterectomy vs Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) EVA-3S was a French multicenter RCT again designed to show noninferiority of CAS compared with CEA.99 The study population consisted of 527 symptomatic patients with carotid stenosis of greater than 60% using the NASCET criteria.86 High-risk patients with significant medical comorbidities were excluded.99 The incidence of stroke or death at 30 days was 3.9% after CEA vs 9.6% after stenting (P ⫽ 0.01), and the results persisted at 6 months (6.1% and 11.7%, respectively; P ⫽ 0.02). The 30-day rate of disabling stroke or death was 3.4% in the CAS group compared with 1.5% in the CEA group. The study was terminated prematurely for safety reasons after completion of the above interim analysis. There were 2 major criticisms of the study. First, cerebral protection was initially not required until the safety committee instituted a protocol change because of a 25% 30-day rate of stroke or death in patients treated without embolic protection devices, compared with 7.9% in those treated with embolic protection devices (RR of 0.38 with the device). Second, there was a great disparity in experience between surgeons and interventionists. Surgeons were required to have completed 25 CEAs in the year before enrollment, but interventionists were certified after performing as few as 5 carotid stent procedures altogether (5 carotid stents among at least 35 stent procedures of supraaortic vessels or 12 carotid stents in total). Interventionists were also allowed to enroll patients in the trial while they were receiving their CAS training (two-thirds of the sites were still under tutelage at the beginning of the trial). Moreover, interventionists were allowed to use any new devices after experience with only 2 cases. Subgroup analysis based on CAS physician experience demonstrated a 12.3% stroke and death rate among endovascular physicians tutored in CAS during the trial, compared with 7.1% among those tutored Curr Probl Cardiol, April 2012

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in CAS during their endovascular training. Regardless, the overall 30-day rate of stroke or death of 9.6% associated with CAS in EVA-3S is higher than for contemporary trials or registries. Interestingly, the risk of stroke or death in the trial was higher in patients with high angulation (ICA– common carotid artery angulation ⬎60 degrees) (RR of 4.96 with high angulation), suggesting vessel tortuosity as a high-risk feature for CAS.

Stent-Protected Angioplasty vs Carotid Endarterectomy in Symptomatic Patients (SPACE) SPACE was another European multicenter RCT aimed to establish noninferiority of CAS compared with CEA in symptomatic patients with carotid stenosis (ⱖ50% by NASCET criteria86 or ⱖ70% by ECST criteria89,90).100 High-risk patients with significant medical comorbidities were again excluded. A total of 1183 patients were randomized. The 30-day rate of death or ipsilateral ischemic stroke was 6.84% with CAS and 6.34% with CEA (P ⫽ 0.09 with noninferiority analysis). The steering committee decided to terminate the study because of both futility and financial constraints because it was revealed that 2500 patients would be needed to power the study adequately to achieve the trial endpoints. Similar to EVA-3S, the main criticism of the SPACE study was the lack of distal embolic protection (it was used in only 27% of patients). However, unlike in EVA-3S, the rates of ipsilateral stroke or ipsilateral stroke or death within 30 days were not statistically different between the groups treated without and with distal embolic protection (6.2% vs 8.3%, respectively). Interestingly, the choice of stent did affect the periprocedural complication rate, which was lower in the closed-cell stent group than in the open-cell group (5.6% vs 11%, respectively), suggesting that a closed-cell stent provides better protection against thromboembolic events in the postoperative period owing to its fine porosity. In addition, younger patients (age ⬍68 years) showed a strong tendency toward a better outcome after CAS, whereas patients 68 years or older tended to have more favorable outcomes with CEA.

International Carotid Stenting Study (ICSS) ICSS is a multicenter, international, RCT in symptomatic patients with carotid stenosis of ⬎50% by NASCET criteria.86,101 A total of 1713 adults were randomized. The primary endpoint was the rate of fatal or disabling stroke at 3 years. An interim safety analysis at 120 days showed the primary endpoint had occurred in 4.0% of CAS patients vs 3.2% of CEA patients (P ⫽ 0.34). However, the risk of death, stroke, and MI was 148

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greater in the CAS group (8.5% vs 5.2% in the CEA group, P ⫽ 0.006). The risk of any stroke, any stroke or death, and all-cause death were also significantly higher with stenting (7.7%/8.5%/2.3% in the CAS group vs 4.1%/4.7%/0.8% in the CEA group). Interestingly, the investigators tried to correlate these clinical results with radiographic findings on MR imaging periprocedurally. In a subgroup analysis with 231 patients, they found more new ischemic brain lesions on diffusion-weighted MR imaging in patients who underwent stenting than in patients who underwent CEA (50 vs 17%). However, an embolic protection device use was not mandated (one-third of procedures were performed without 1). As in EVA-3S, the other main criticism of ICSS is the large disparity between the experience required of the surgeons and interventionists. In ICSS, the surgeons were required to have performed more than 50 CEAs with more than 10 per year, whereas the interventionists were only required to have performed more than 50 stent procedures (anywhere) and 10 CAS cases (overall).

Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) CREST is a North American, multicenter, RCT that compared the efficacy of CEA with CAS performed with embolic protection in standard-risk patients.102 It is the most recent and the largest CAS trial to date. Similar to SAPPHIRE,97 the patient population (2502 patients) consisted of both symptomatic patients (⬎50% stenosis) and asymptomatic patients (⬎70% stenosis).102 The proportion of patients with asymptomatic and symptomatic disease was 47 and 53%, respectively. The primary endpoints were periprocedural (30 day) rates of stroke, MI, or death, and postprocedural rate of ipsilateral stroke (30 day to 4 years). A credentialing phase for interventionists was included that required previous carotid stenting experience and monitoring of the performance of up to 20 procedures. The credentialing and training of the interventionists participating in CREST have been the most rigorous reported to date for any randomized trial evaluating endovascular treatments. On the basis of experience, training, and lead-in results from 1500 patients, the CREST International Management Committee selected 224 interventionists (among 427 applicants) to participate in the randomized phase of the trial. In CREST, surgeons were required to have performed more than 12 procedures per year with complication rates of less than 3% for asymptomatic patients and less than 5% for symptomatic patients. For periprocedural outcomes, CREST reported a stroke, MI, or death rate of 5.2% with stenting and 4.5% with surgery (P ⫽ 0.38). However, Curr Probl Cardiol, April 2012

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the risk of periprocedural stroke was 4.1% with CAS and 2.3% with CEA (P ⫽ 0.01), but the risk of periprocedural MI was higher with CEA: 2.3% vs 1.1% with CAS (P ⫽ 0.03). The combined rate of periprocedural MI, stroke, or death and ipsilateral stroke at 4 years was similar: 7.2% with CAS and 6.8% with CEA (P ⫽ 0.51). At 4 years, the ipsilateral postprocedural stroke rate was 2.0% with CAS vs 2.4% with CEA, P ⫽ 0.85. Interestingly, the risk of stroke or death was significantly higher for CAS in symptomatic patients compared with CEA (6.0% vs 3.2%) but not for asymptomatic patients (2.5% vs 1.4%). This could in part explain the results of the previous CAS trials in which the populations comprised symptomatic patients. Similar to SPACE, patients 70 years of age or older had a slightly better outcome with CEA and patients younger than 70 years had a slightly better outcome with CAS. Age is likely a surrogate for a difficult and diseased aortic arch, which is a high-risk feature for CAS. Nevertheless, the periprocedural outcomes for CREST are the best reported to date for both CEA and CAS. These results likely reflect the strict operator credentialing process and the accumulation of endovascular expertise. As mentioned, the risk of periprocedural stroke was found to be higher with CAS, and the risk of periprocedural MI was higher with CEA. In CREST, periprocedural strokes translated into a significant impact on the patients’ quality-of-life based on Short Form-36 (SF-36) scores, and the impact was found to be much worse than that of periprocedural MI.102,103 At 1 year, the effect on physical health from a periprocedural stroke was ⫺15.8 points on the physical component of SF-36, whereas the effect of periprocedural MI was only ⫺3.0. The study investigators found that even minor periprocedural strokes had a significant effect on mental health at 1 year, which measured ⫺3.4 on the mental component of the SF-36 survey.102 On the basis of these quality-of-life analyses among survivors at 1 year, the investigators concluded that stroke had a greater adverse effect on health than MI. Nevertheless, this view is controversial and frequently challenged because several studies have shown an association between MI and biomarkers for myocardial injury and future mortality in a variety of vascular and nonvascular procedures.104-107 David R. Holmes: The CREST trial is the most recent and most optimally conducted trial. Several points are considered by the authors, including (1) the noninferiority of the primary endpoint, (2) the difference in events between carotid arterial stenting and carotid endarterectomy with increased periprocedural stroke with the former and increased periprocedural myocardial infarction with the latter. Another important aspect of the differences in the trials was the difference in cranial nerve injury, which for some patients is very disturbing.

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Significance of Periprocedural MI in Carotid Intervention To address the impact of periprocedural MI on mortality of patients undergoing carotid intervention, the CREST investigators performed a post-hoc analysis to explore the prognostic significance of MI among patients undergoing either CAS or CEA.108 In CREST, an electrocardiogram and cardiac biomarker (a mixture of troponin-I or -T, creatinine kinase, and creatinine kinase-MB fraction) measurement were obtained routinely before and after the carotid revascularization procedure. MI was defined as biomarker elevation plus either chest pain or electrocardiogram evidence of ischemia. An additional category of biomarker elevation-only without symptoms or electrocardiogram changes was prespecified. Crude and risk-adjusted mortality rates were obtained and compared for patients with and without MI or biomarker elevation-only. Among 2502 patients, 14 MIs occurred in the CAS group and 28 MIs occurred in the CEA group. An additional 8 CAS and 12 CEA patients had biomarker elevation-only. Compared with patients without biomarker elevation-only or MI, mortality was higher over 4 years for those with MI (hazard ratio ⫽ 3.40, P ⬍ 0.001) or biomarker elevation-only (hazard ratio ⫽ 3.57, P ⫽ 0.005). After adjustment for baseline risk factors, the mortality of patients with perioperative MI or biomarker elevation-only remained significantly higher (hazard ratios of 3.67, P ⫽ 0.001 and 2.87, P ⫽ 0.023, respectively). In other words, patients with MI or biomarker elevationonly were 3 to 4 times more likely to die during the follow-up period than those with no evidence of MI (clinical or subclinical), even after adjustment for important baseline characteristics (including age, diabetes, and history of cardiovascular disease). By contrast, unlike MI and biomarker-only elevation, per-protocol analysis of CREST showed a lack of association between minor strokes and long-term mortality (P ⫽ 0.34).109 Compared with minor stroke, MI was associated with a 5.2 times higher risk of long-term mortality (P ⫽ 0.02). Thus, a patient who suffered a postprocedural MI has a 4-year survival rate of only 75%, compared with a 95% 4-year survival rate after a minor stroke. Clearly, on the basis of the above analyses of MIassociated mortality, the impact of MI after carotid intervention needs to be given strong consideration.

David R. Holmes: The periprocedural myocardial infarction discussion is excellent and should not be ignored.

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Carotid Registries Endovascular technologies evolved at a rate exceeding the development and completion of clinical trials, leading to the design of many prospective CAS registries to test new stents and embolic protection devices. The results of several such registries have been published. Enrollment into such registries was based on the limitations of the NASCET86 and Asymptomatic Carotid Atherosclerosis Study (ACAS)110 enrollment criteria and both symptomatic and asymptomatic patients were included. Patients enrolled in CAS registries met “high-risk” criteria that would have eliminated their inclusion in NASCET or ACAS. This includes both anatomic and physiological criteria. Physiological high-risk criteria include coexistent medical comorbid conditions, especially acute cardiac disease. Anatomic high-risk criteria include previous neck dissection or irradiation, along with high anatomic lesions that limit surgical accessibility. Such registries report the effectiveness of CAS in these high-risk settings, typically with a new stent or embolic protection device or both. For all such registries, the principal outcome is major adverse coronary and cerebral events (MACCE) within 30 days of the procedure. The incidence of MACCE is compared with the guidelines published in 1998 by the American Heart Association, with recommended perioperative morbidity of less than 6% for symptomatic and less than 3% for asymptomatic disease.111 The first CAS registry (SECuRITY) tested the Xact self-expanding stent and Emboshield distal protection device (Abbott Vascular, Abbott Park, IL). This study enrolled 305 symptomatic and asymptomatic patients. The final results and details of the study population were never published, but the 30-day MACCE data were presented at the annual meeting of Transcatheter Cardiovascular Therapeutics in 2003.112 A 30-day MACCE rate of 7.2% was sufficient for FDA approval of the devices in 2004. Four CAS registries were underway when the results of SECuRITY were presented. Acculink for Revascularization of Carotids in High-Risk patients (ARCHER),113 Boston Scientific EPI: A Carotid Stenting Trial for High-Risk Surgical Patients (BEACH),114 Medtronic AVE Selfexpanding CaRotid Stent System with distal protection In the treatment of Carotid stenosis (MAVErIC),115 and Carotid Artery Revascularization using the Boston Scientific FilterWire EX/EZ (CABERNET)116 were testing the Acculink/Accunet (Abbott), Wallstent/FilterWire (Boston Scientific, Natick, MA), Exponent/Guardwire (Medtronic Minneapolis, MN), and NexStent/FilterWire (Boston Scientific), respectively. The ARCHER trial enrolled 581 patients between May 2000 and September 152

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2003 (including 138 symptomatic and 443 asymptomatic patients), with 30-day MACCE rates of 7.2%, 13%, and 6.8% for all, symptomatic, and asymptomatic patients, respectively.113 The BEACH trial enrolled 480 patients between February 2002 and December 2003, including 112 symptomatic and 368 asymptomatic patients; the 30-day MACCE rates were 5.4% for all patients, 7.7% for symptomatic patients, and 4.7% for asymptomatic patients.114 The MAVErIC trial enrolled 498 patients between June 2001 and October 2004 (including 214 symptomatic and 284 asymptomatic patients), with 30-day MACCE rates of 5.4% for all patients, 8.4% for symptomatic patients, and 3.7% for asymptomatic patients.115 Last, the CABERNET trial enrolled 454 patients between February 2002 and March 2004 (including 99 symptomatic and 355 asymptomatic patients), with 30-day MACCE rates of 4.0%, 6.4%, and 3.3% for all, symptomatic, and asymptomatic patients, respectively.116 Another registry, Carotid Revascularization with ev3 Arterial Technology Evolution,117 enrolled 419 patients between April and October of 2004. Testing the Protégé stent and Spider antiembolic device (ev3), complication rates were higher than those for similarly sized carotid registry trials. The 30-day MACCE rates for all, symptomatic, and asymptomatic patients were 6.2%, 16.4%, and 4.0%, respectively. The next 3 published registries were larger than their predecessors, featuring enrollment of more than 1000 patients each. Each trial was designed to assess outcomes of stenting with embolic protection after FDA device approval. The Carotid Artery Stenting with Emboli protection Surveillance–Post Marketing Study118 represented the postmarket analysis of the Precise stent and Angioguard embolic protection devices employed as part of the SAPPHIRE97 clinical trial. Enrollment was 1493 patients between August 2003 and October 2005, including 325 symptomatic and 1168 asymptomatic patients, with 30-day MACCE rates of 4.8%, 6.2%, and 4.7% for all, symptomatic, and asymptomatic patients, respectively.118 The Carotid Acculink/Accunet Post Approval Trial to Uncover Unanticipated or Rare Events registry119 represented a postmarket analysis of the devices used in the ARCHER registry. Enrollment was 3500 patients between October 2004 and March 2006, including 483 symptomatic and 3017 asymptomatic patients, with 30-day MACCE rates of 6.3%, 12%, and 5.4%, respectively. The Emboshield and Xact post Approval Carotid stent Trial (EXACT)120 had an enrollment of 2145 patients (including 213 symptomatic and 1931 asymptomatic patients), with 30-day MACCE rates of 4.1%, 7.0%, and 3.7%, respectively. The Embolic Protection with Reverse Flow (EMPiRE)121 and ProximAl PRotection with the MO.MA Device DUring CaRotid Stenting Curr Probl Cardiol, April 2012

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(ARMOUR)32 trials tested similar devices that provide embolic protection by reversal of flow through the ICA. An inherent advantage of this method is a limitation of the amount of devices crossing the carotid lesion in comparison with distal protection systems. The EMPiRE trial enrolled 245 patients with carotid stenosis, including 78 symptomatic and 167 asymptomatic, between August 2006 and September 2008. Each patient had CAS with an FDA-approved stent of the surgeon’s choice and proximal protection with the Gore flow reversal device (W.L. Gore and Associates, Flagstaff, AZ).121 The overall 30-day rate of MACCE was 3.7%, with a 3.8% incidence in symptomatic and a 3.6% incidence in asymptomatic patients. The ARMOUR trial enrolled 225 patients with carotid stenosis (34 symptomatic, 191 asymptomatic) between September 2007 and February 2009.32 Each patient underwent CAS with an FDA-approved stent of the surgeon’s choice and proximal protection with the MO.MA device (Invatec S.p.a., Roncadelle, Italy). The overall rate of 30-day MACCE was 2.7%, with no events in symptomatic patients, and a 3.7% rate in asymptomatic patients. Notable in the EMPiRE and ARMOUR trials is a relatively low incidence of 30-day MACCE in symptomatic patients compared with other registries to date using distal protection devices. On the basis of these results, both the Gore and the MO.MA devices received FDA approval as proximal protection devices for CAS. David R. Holmes: The importance of proximal protection cannot be emphasized enough because it may alleviate the issue of periprocedural stroke that is occasionally seen with distal protection devices. This stroke may be the result of distal embolization even with the distal protection device in place or may be the result of trauma crossing the lesion initially.

The Evaluating the Use of the FiberNet EPS in Carotid Artery Stenting (EPIC) trial122 enrolled 237 patients with carotid stenosis (47 symptomatic and 190 asymptomatic) between March 2007 and May 2008. This trial tested a distal protection device unlike the fixed wire filters (Accunet [Abbott Vascular], FilterWire [Boston Scientific], and AngioGuard [Cordis]) or over-the-wire filters (Emboshield, Spider) tested in previous studies. The FiberNet filter (Lumen Biomedical, Maple Grove, MN) was designed to limit plaque disruption and increase surface area for collection of embolized materials. Its use in the EPIC trial resulted in the lowest incidence of 30-day MACCE compared with previous trials of distal protection devices, with an overall incidence of 3.0%, with 4.2% in symptomatic and 2.7% in asymptomatic patients. 154

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Comparison of Embolic Protection Devices In 2009, Garg et al.123 published a metaanalysis comparing outcomes in protected and unprotected CAS. On the basis of the 134 articles published between 1995 and 2007 that were included in their final analysis, the authors found significant benefit for using protection devices during CAS in both symptomatic patients (RR 0.67; 95% confidence interval 0.520.56) and asymptomatic patients (RR 0.61; 95% confidence interval 0.41-0.90). The overall risk of stroke was estimated to be reduced by 38%. Studies using distal ICA occlusion balloons, filters, and proximal occlusion devices were included in this metaanalysis. Interestingly, the authors also found that protection devices started to show significant benefit in preventing embolic events beginning in 2004, indicating that more recently developed devices are superior to earlier models. The most recent guidelines on the management of patients with extracranial carotid artery disease recommend the use of embolic protection devices during CAS to reduce the risk of periprocedural stroke.69

High-Risk Patients for CAS We are just beginning to understand the high-risk factor for CAS (unlike for CEA). We now know that several anatomic, patient, and lesion characteristics increase the risk of CAS: these include difficult aortic arch (Type 2 or 3 arch, bovine arch), diseased aortic arch, occluded or diseased external carotid artery, significant carotid tortuosity, absence of a distal landing zone, concentric calcification, hemorrhagic plaque, carotid origin disease, and severe peripheral vascular disease with difficult access. In patients with 1 or more of these characteristics, CEA should be considered as an alternative treatment, especially when none of the above high-risk factors for CAS is considered high risk for CEA.

Cerebral Hyperperfusion Syndrome Cerebral hyperperfusion syndrome is a rare complication associated with ICA revascularization, described following both CEA and stenting.124 Severity of ICA stenosis is an independent factor for development of hyperperfusion syndrome. This syndrome usually occurs within the first few days following intervention and is believed to be secondary to impaired autoregulation mechanisms. However, delayed presentations several weeks after surgery have also been described. Clinical presentation can be variable and includes headaches, seizures, and focal neurological deficits. The extreme manifestation of cerebral hyperperfusion syndrome is intracerebral hemorrhage, which is associated with high mortality rates. Close monitoring of blood pressure parameters following Curr Probl Cardiol, April 2012

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Fig 6. Because of a change in neurologic status 12 hours after left carotid artery stenting (case from Fig 5), a follow-up noncontrast CT scan was obtained and reveals a focal hemorrhage in the posterior limb of the internal capsule, because of hyperperfusion syndrome.

revascularization procedures is of critical importance to prevent development of hemorrhage. Several studies have assessed the role of CT perfusion in predicting development of cerebral hyperperfusion syndrome (Figs 3 and 6). At present, there is no agreement on which perfusion sequence can identify most reliably patients who are at higher risk for cerebral hyperperfusion syndrome. Data suggest that MTT or TTP and CBV can serve as potential diagnostic tools when screening for patients who are at higher risk (patients with increased MTT or TTP and CBV) to develop this complication.125,126

Management of Asymptomatic Carotid Stenosis The best evidence concerning the treatment of asymptomatic carotid stenosis comprised 2 trials, the ACAS110 and the ACST.127 To date, only 156

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1 small trial (consisting of 85 patients) has compared endarterectomy directly with stenting for patients with asymptomatic disease, with similar results between the 2 treatments.128 The SAPPHIRE trial97 and CREST102,129 included symptomatic and asymptomatic patients. Both trials suggested that CAS was comparable to endarterectomy for perioperative morbidity. Trials underway may offer a new perspective on the treatment of asymptomatic carotid disease. SPACE-2 is a large randomized trial that is currently randomizing patients to endarterectomy, stenting, or best medical management.130

The Case for Carotid Endarterectomy vs Best Medical Management The ACAS randomized 1662 patients with asymptomatic carotid stenosis to CEA plus best medical treatment or best medical treatment alone.110 Three patients were lost to follow-up after randomization to endarterectomy; the remaining 1559 patients were included in the analysis. Inclusion criteria included carotid stenosis of at least 60% measured by DSA or Doppler ultrasonography. Entry criteria included age between 40 and 79 years and no previous cerebrovascular infarction in the study vessel. Patients were enrolled between 1987 and 1993. Best medical treatment during enrollment consisted of antiplatelet therapy with 325 mg of aspirin and antihypertensive treatment. The primary endpoint was cerebral infarction occurring in the region of the study artery or any stroke or death, measured as 5-year aggregate risk as a percentage. With respect to the primary endpoint, the trial was favorable to CEA, with a 5-year risk of stroke or death of 5.1% for patients undergoing surgery compared with 11.0% for patients randomized to medical treatment. There were 146 patients who crossed over from 1 treatment arm to the other for a variety of reasons. More than two-thirds of these patients were randomized to endarterectomy. In total, 12% of patients randomized to endarterectomy did not undergo surgery, and 5% of patients randomized to medical management underwent ipsilateral endarterectomy. An astreated analysis showed no significant change in the primary outcome, with a 5-year risk of stroke or death of 5.1% for patients undergoing surgery compared with 11.5% for patients treated with medical management. The ACST randomized 3120 patients with asymptomatic carotid stenosis to CEA plus best medical management or best medical management alone.127 Carotid stenosis for all patients was measured at 60% or greater by Doppler ultrasonography. Entry criteria included no previous cerebrovascular infarction ipsilateral to the study vessel. Surgical intervention Curr Probl Cardiol, April 2012

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was to be performed as soon as possible after randomization, with specifics of anesthesia and shunting to be determined by the operating surgeons. Patients were enrolled between 1993 and 2003, during which time medical management included antiplatelet therapy, antihypertensive treatment, and lipid-lowering therapy. The primary endpoint comprised perioperative morbidity and nonperioperative stroke. Perioperative morbidity included stroke, MI, and death and was measured at 3.5% for all patients undergoing surgery, including crossover patients. The primary endpoint was reported as 5-year stroke (including contralateral stroke) or death risk. With respect to the primary endpoint, the trial was favorable toward stroke-preventing CEA, as patients randomized to surgery had a 6.4% 5-year risk of stroke or death compared with 11.7% for patients randomized to medical treatment. There was significant crossover in both groups, with 9% of patients randomized to surgery having never undergone endarterectomy, and 18% of patients randomized to medical surgery undergoing ipsilateral endarterectomy by the fifth year of follow-up. Medical treatment with antiplatelet and antihypertensive therapies was consistent with approximately 90% of patients in the study receiving antiplatelet therapy and approximately 81% receiving hypertensive therapy. However, the use of lipid-lowering therapy was noted to increase throughout the trial from 17% of those randomized in the earliest years of the study to an estimated 70% of all surviving patients at completion of the study.

Comparison of Carotid Angioplasty and Stenting vs Carotid Endarterectomy To date, no large randomized trial has compared directly the safety of CAS to endarterectomy in asymptomatic patients. Two trials, SAPPHIRE and CREST, have randomized both symptomatic and asymptomatic patients. The best evidence comparing stenting and endarterectomy in such patients can be elicited from subgroup analysis of these trials. The SAPPHIRE trial97 randomized 334 patients before early termination. Of these, 238 patients had asymptomatic disease. The primary endpoint was incidence of stroke, MI, or death within 30 days of intervention. The incidence of the primary endpoint was nearly double for patients undergoing endarterectomy (10.2%) compared to patients undergoing stenting (5.4%), although the result was not statistically significant (P ⫽ 0.20). In CREST, 1180 of 2502 patients randomized had asymptomatic carotid stenosis.102,129 There was no statistically significant difference in the primary outcome between asymptomatic patients randomized to endar158

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terectomy (3.6%) or stenting (3.5%). The periprocedural morbidity was similar to that reported for patients undergoing endarterectomy in the ACST trial (3.5%). The Asymptomatic Carotid stenosis, stenting vs endarterectomy Trial (ACT-1)112 aims to test definitively the equivalence of CAS to endarterectomy in asymptomatic patients with severe carotid stenosis. This trial is planned to enroll 1600 patients with a target study completion date of 2017. Patients with severe carotid stenosis are randomized at a 3:1 ratio to either CAS or CEA. Stenting procedures (XACT; Abbott) are performed with mandatory distal protection (NAV 6; Abbott). The primary outcome is an occurrence of major adverse events within the 30 days following intervention. The target date for data collection of this measure is August 2012. The 5-year incidence of ipsilateral stroke or death will be compared on study completion.

Improvements in Medical Management and a Definitive Three-Arm Trial Improvements of medical management with antihyperlipidemic and antihypertensive agents unavailable during the design of ACAS and ACST have brought into question whether carotid artery revascularization procedures are indicated for asymptomatic patients.130-132 The reported annual risk of ipsilateral stroke in patients with asymptomatic carotid stenosis of 60% or greater has decreased since the publication of ACAS (11.0% over 5 years, or approximately 2.2% yearly) to roughly 1% per year in a study of 200 patients undergoing evaluation with ultrasonic embolic detection published in 2005.133 Of interest, 9.1% of patients randomized to the medical arm of ACST had an ipsilateral ischemic stroke.21 The yearly stroke risk was approximately 1.7%. Recent prospective studies of patients with 50% or more carotid stenosis have shown very low incidence of ipsilateral stroke, with rates between 0.34%134 and 0.8%.135 Thus, with a diminished annual risk of stroke in the asymptomatic patient, the results of ACAS and ACST seem dated, the results for asymptomatic patients in SAPPHIRE and CREST seem irrelevant, and those for ACT-1 seem potentially irrelevant. The best evidence concerning the treatment of asymptomatic carotid stenosis may be on the horizon with an ongoing trial. SPACE-2 has a targeted completion date of 2015.130 This trial is planned to enroll 3640 patients with asymptomatic carotid artery stenosis to 1 of 3 arms. Patients with carotid stenosis of 70% or more by Doppler ultrasonography are eligible. All patients will be treated with best medical management (antiplatelet and antihyperlipiCurr Probl Cardiol, April 2012

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demic) and individual risk-factor modification. Patients will be randomized at a rate of 3:3:1 to endarterectomy, stenting, or medical management without intervention. Endarterectomy and stenting interventionists must have performed at least 40 procedures in the previous 24 months, with 20 procedures completed within the first SPACE trial with a complication rate of 6% or less. The primary endpoint is the 5-year risk of ipsilateral stroke or death. In addition, 30-day postoperative risk of stroke, death, and MI will be compared between patients undergoing endarterectomy or stenting.

Conclusions CEA and CAS are 2 complementary procedures for the treatment of atherosclerotic carotid disease. Much has been learned about them from RCTs and clinical experience. Given the lack of embolic protection device use and operator inexperience that characterize most European trials, CREST represents the largest, most rigorous and complete examination of CAS vs CEA to date, including both symptomatic and asymptomatic standard-risk patients. The results of CREST establish both CAS and CEA as very safe and effective choices for patients and their physicians. Ultimately, patient preference will have to be considered in the decision-making process, and outcomes can be optimized by choosing the right procedure for the right patient. David R. Holmes: Given the very large burden of mortality and morbidity associated with stroke, there has been intense interest in carotid arterial stenosis. This field continues to evolve with new insights into the pathophysiology of the disease and refinements in diagnostic and therapeutic regimens. This current article features an in-depth discussion about the changing field of treatments with new approaches, such as proximal embolic protection during carotid arterial stenting. After an in-depth discussion of the different options, medical, surgical, and interventional, the authors rightly conclude that ultimately patient preference will have to be considered in the decisionmaking process, and outcomes can be optimized by choosing the right procedure for the right patient. Acknowledgments: The authors thank Paul H. Dressel, BFA, for preparation of the illustrations and Debra J. Zimmer, AAS, CMA, for editorial assistance.

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