Carotid Artery Stenting for Stroke Prevention Jacqueline Saw, MD

Transcription

1 Canadian Journal of Cardiology 30 (2014) 22e34 Review Jacqueline Saw, MD Division of Cardiology, Department of Medicine, Vancouver General Hospital, Vancouver, British Columbia, Canada See editorial by Almekhlafi et al., pages of this issue. ABSTRACT Stroke is a global epidemic with a significant economic burden to patients, families, and societies at large. In the industrialized world, stroke is the third most common cause of death, the second most common cause of dementia, and the most common reason for acquired disability in adulthood. Overall, 20%-30% of ischemic strokes are related to extracranial carotid artery stenosis. Revascularization with carotid endarterectomy (CEA) is the gold-standard treatment for patients with significant carotid stenosis. Carotid artery stenting (CAS) has become an accepted alternative to CEA over the past decade for patients at high surgical risk, and has progressively evolved into an elegant procedure over the past 3 decades, with dedicated equipment including proximal embolic occlusion devices that have minimized procedural strokes. Highesurgical-risk CAS registries have established this procedure as an alternative to CEA for high-risk patients. The RESUME L accident vasculaire cerebral (AVC) est une epidemie mondiale qui represente un fardeau economique important pour les patients, les familles et les societes dans leur ensemble. Dans le monde industrialise, l AVC est la troisième cause la plus frequente de decès, la deuxième cause la plus frequente de demence et la raison la plus frequente d incapacite acquise à l âge adulte. Dans l ensemble, 20 % à 30 % des AVC ischemiques sont lies à la stenose de la carotide extracrânienne. La revascularisation par l endarteriectomie carotidienne (EAC) est le traitement de reference chez les patients ayant une stenose carotidienne importante. L implantation d une endoprothèse carotidienne (IEC) est devenue une solution de rechange reconnue à l EAC au cours de la dernière decennie chez les patients exposes à un risque chirurgical eleve, et est progressivement devenue au cours des 3 dernières decennies une intervention de premier ordre, Stroke is a global epidemic with significant economic burden to patients, families, and societies at large. Stroke is the third leading cause of death in Canada 1 and the fourth leading cause of death in the United States. 2 Stroke is also the leading cause of death and disability in Canada, resulting in premature death and long-term disability. 1 The majority of strokes are ischemic in origin (w 80%), and the remainder (w 20%) are hemorrhagic. 3 Overall, w 20% of ischemic strokes are related to extracranial carotid artery stenosis. Carotid artery stenosis is quite common, with 2%-8% of the population having asymptomatic stenosis of > 50%, 4 with a higher prevalence among patients with heart disease (18.2%) or concomitant hypertension and heart disease (22.1%). 5 The prevalence is even higher among patients with acute strokes, with up to 60% having carotid stenosis on duplex ultrasonography. 6 The risk of stroke related to carotid stenosis is dependent on the severity of stenosis, the symptom status of the patient, and specific lesion characteristics. Symptomatic patients, defined as those who have had stroke or transient Received for publication June 14, Accepted September 11, Corresponding author: Dr Jacqueline Saw, 2775 Laurel Street, Level 9, Vancouver General Hospital, Vancouver, British Columbia V5Z1M9, Canada. Tel.: þ ; fax: þ jsaw@mail.ubc.ca See page 32 for disclosure information. ischemic attack within the previous 6 months, have a much higher stroke risk than do asymptomatic individuals. Revascularization with carotid endarterectomy (CEA) is the gold-standard treatment for patients with significant carotid stenosis. Over the past decade, carotid artery stenting (CAS) has become an accepted alternative to CEA for patients at high surgical risk, and more recently a large trial has shown similar outcomes for > 50% patients at standard risk. As such, the proportion of carotid revascularization performed as CAS has increased progressively over the past decade in the United States, from 2.8% in 1998 to 12.6% in The proportion of revascularization performed for symptom status differs in various regions. Of note, carotid revascularization was preferentially performed in asymptomatic patients in the United States in 91.8% of cases between 2005 and In contrast, data from Canada over the past decade suggest that the majority (w 60%) of CEA procedures were performed in symptomatic patients. This article reviews the background, advancements in equipment, and clinical trial data from CAS studies on stroke prevention. Carotid Endarterectomy The first CEA procedure was reported by Eastcott in 1954, 6 with subsequent gradual and eventual widespread uptake of this procedure by the early 1980s. Several landmark X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.

2 Jacqueline Saw 23 Carotid Revascularization Endarterectomy vs Stent Trial (CREST) has shown similar outcomes with CAS and CEA for patients at standard risk, although CAS is associated with higher minor stroke events and CEA is associated with higher myocardial infarction (MI) events. However, CAS is technically challenging and requires a meticulous approach, with a protracted learning curve that should involve experience with > 70 cases. Careful patient selection is instrumental in avoiding procedural complications, and the procedure should be avoided in patients with prohibitive anatomy. This article reviews the use of CAS for extracranial carotid artery stenosis, considering technical aspects, registry and clinical trial outcomes data, determinants of success, and contemporary guidelines. utilisant un equipement dedie pourvu de dispositifs d occlusion proximale contre l embolie qui ont minimise les AVC lies aux interventions. Les registres sur le risque chirurgical eleve lors d IEC ont etabli que cette intervention est une solution de rechange à l EAC chez les patients exposes à un risque eleve. L etude CREST (Carotid Revascularization Endarterectomy versus Stent Trial) a montre des resultats similaires avec l IEC et l EAC chez les patients exposes à un risque normal, bien que l IEC soit associee à un risque plus eleve d AVC mineur et que l EAC soit associee un risque plus eleve d infarctus du myocarde (IM). Cependant, l IEC represente un defi technique de taille et necessite une approche meticuleuse, de même qu une longue courbe d apprentissage qui devrait comporter une experience > 70 cas. La selection rigoureuse des patients est essentielle pour eviter les complications liees à l intervention, et l intervention devrait être evitee chez les patients ayant une anatomie plus complexe. Cet article passe en revue l utilisation de l IEC lors de stenose de la carotide extracrânienne, en tenant compte des aspects techniques, des donnees des registres et des resultats de l essai clinique, des determinants du succès et des lignes directrices actuelles. randomized trials in the 1990s established the efficacy of CEA compared with medical therapy in stroke reduction for patients with symptomatic carotid stenosis or high-grade asymptomatic carotid stenosis (Table 1) These trials helped established parameters for revascularization for both symptomatic and asymptomatic carotid stenosis, with current American Heart Association guidelines recommending CEA for symptomatic patients with 50%-99% stenosis and for asymptomatic patients with 60%-99% stenosis if periprocedural risk of stroke or death are < 6% and < 3%, respectively. 15 However, this procedure is invasive and may cause serious periprocedural complications (eg, death, stroke, myocardial infarction [MI], cranial nerve palsy, wound infection, or hemorrhage). Consequently, carotid angioplasty and stenting was pursued > 3 decades ago as a less invasive approach that avoids surgery-related complications. CAS Experience The first carotid angioplasty in humans was performed in 1980 by Kerber et al. 16 Early pioneering work led to the recognition of multiple challenges with percutaneous carotid intervention. Carotid atherosclerotic plaques may be more friable and prone to embolism and, unfortunately, the brain is not a forgiving end organ. In addition, early procedures were impeded by nondedicated equipment (guide catheters, balloons, and stents) that were cumbersome and lacked embolic protection, resulting in thromboembolism, vessel recoil, abrupt closure, dissection, and restenosis. Thus, early procedures had high complication rates and were initially reserved for palliative treatment of inoperable patients. The development of low-profile dedicated carotid catheters and balloons, the evolution of stent technology, and the subsequent development of emboli protection devices (EPDs) led to the breakthrough of this technique as a low-risk alternative to CEA. The initial experience with carotid stents in 1989 was based on the Palmaz-Schatz balloon-expandable stents, which unfortunately were not adequate to withstand external superficial forces in the neck. Such stents for CAS were limited by stent compression, restenosis, and fractures, and these were soon replaced by self-expanding stents, which have the intrinsic capability of rebounding to their original shape after external compression. The braided mesh WALLSTENT (Boston Scientific, Natick, MA) is made from cobalt alloy woven into a tube and can expand when the sheath is withdrawn during deployment. Subsequent self-expanding stents are nitinol based and can be segregated into 2 types of cell design: closed cell with small free-cell areas between the metallic struts and open cell with larger gaps. This was Table 1. Summary of key CEA trials for symptomatic and asymptomatic patients Trial name Year N* Stenosis (%) Symptom status Procedural death or stroke rate (%) Mean follow-up (y) Ipsilateral stroke: CEA vs medical treatment, % (P value) Death or stroke: CEA vs medical treatment, % (P value) VAST > 50 Symptomatic vs vs 19.4 (P ¼ 0.011) NASCET Symptomatic vs 26 (P < 0.001) 15.8 vs 32.3 (P < 0.001) NASCET Symptomatic vs 22.2 (P ¼ 0.045) 33.2 vs 43.3 (P ¼ 0.005) ECST > 80 Symptomatic vs 20.6 (P < 0.001) 14.9 vs 26.5 (P ¼ 0.001) VA Cooperative > 50 Asymptomatic vs 9.4 (P ¼ 0.056) 41.2 vs 44.2 (P > 0.05) ACAS Asymptomatic vs 11.0 (P ¼ 0.004) 25.6 vs 31.9 (P ¼ 0.08) ACST Asymptomatic vs 11.0 nonoperative stroke 6.4 vs 11.8 (P < ) ACAS, Asymptomatic Carotid Atherosclerosis Study; ACST, Asymptomatic Carotid Surgery Trial; CEA, carotid endarterectomy; ECST, European Carotid Surgery Trial; NASCET, North American Symptomatic Carotid Endarterectomy Trial; VA, Veterans Affairs; VAST, Veterans Affairs Symptomatic Trial. * Number of patients with stenosis severity in the overall trial.

3 24 Canadian Journal of Cardiology Volume followed by hybrid nitinol stents that have both closed and open cells, such as the Cristallo Ideale stent (Invatec, Rondelle, Italy), which has an open-cell design at the edges of the stent to increase conformability and deliverability and a closed-cell design in the middle portion of the stent to prevent plaque prolapse. In general, open-cell stents allow greater flexibility, deliverability, stent conformability, and wall apposition, whereas closed-cell stents have more surface wall coverage, which theoretically protects from plaque protrusion and embolization of atheroembolic debris; they also have greater radial force and strength. There have been conflicting reports from various nonrandomized retrospective studies evaluating the impact of cell design on neurologic complications and mortality. There was suggestion of benefit with closed-cell design with regard to lower plaque protrusion and subsequent embolization. It is likely that the actual cell size and surface area coverage is more important. Nevertheless, a small randomized study of 40 patients did not show reduction of microembolic signals (MESs) on transcranial Doppler or new cerebral lesions on diffusion-weighted magnetic resonance imaging (DW-MRI) with closed-cell stents. 17 Thus, there is no consensus as to the preferred selfexpanding stent for CAS. CAS carries a risk of periprocedural distal embolization of atherosclerotic fragments Thus, a variety of protection systems have been designed and are routinely used with CAS to reduce procedural embolism. Although there is some controversy regarding the absolute necessity of EPDs related to incomplete embolic protection efficacy and to the increase in procedural complexity and duration of procedure, 22 most interventionists performing CAS believe that the benefits (albeit incomplete embolic protection) outweigh the risks of EPDs. 23,24 There have been significant advances in EPDs since the first procedure described in 1990 by Theron et al., and they can be classified as distal (filter or balloon EPDs) or proximal EPDs (balloon EPDs). 25 Distal filter EPD There are numerous filter EPDs that are available for clinical use with CAS (Fig. 1): Angioguard XP (Cordis Corp, Miami Lakes, FL), NAV6 (Abbott Vascular/Abbot Laboratories, Abbott Park, IL), Accunet (Abbott Vascular), FilterWire EZ (Boston Scientific), Spider (ev3/covidien, Plymouth MA), Fibernet (Medtronic, Minneapolis MN), and Gore Embolic Filter (W.L. Gore & Associates, Flagstaff, AZ). Filter EPDs are low profile and typically can be advanced across a carotid stenosis without previous angioplasty. The advantages with filter EPDs are the ease of delivery and deployment and the ability to visualize the carotid artery during the procedure without interrupting antegrade intracranial flow. Limitations with these devices include the potential for distal embolization during initial lesion crossing, the inability to capture particles smaller than the pore size of the filter, the incomplete seal of the artery when not properly deployed (especially in a tortuous landing zone), and carotid artery spasm and dissection. Although there is no randomized comparison of different filter EPDs on clinical outcomes, ex vivo bench comparison and retrospective studies show key differences in these devices that may affect device selection. Loghmanpour et al. performed an elegant bench test of 6 contemporary filter EPDs in which 2 sizes of microspheres (143 and 200 mm) were injected into a curved tube containing the EPD. 26 They showed that the Gore Embolic Filter had the highest capture efficiency, whereas the Spider had the lowest. Conversely, the proportion of lost particles was highest with the Spider and lowest with the Gore Embolic Filter. In a recent retrospective comparison of 6 different filter EPDs, univariate analysis showed that devices having a concentric shape have greater capture efficiency, lower porosity, lower number of pores, and lower pore density and are associated with lower periprocedural complications. 26 However, multivariate analysis was inconclusive for these filter characteristics. Distal occlusion EPD There is only 1 currently available distal balloon EPD called the GuardWire system (Medtronic). The mechanism of action involves EPD balloon occlusion of the internal carotid artery distal to the stenosis to occlude antegrade blood flow before angioplasty and stenting. Subsequently, the carotid artery is aspirated to evacuate embolic debris before EPD balloon retrieval. The advantage of this EPD is the low-profile balloon-tipped wire that crosses the stenotic lesion more readily than does a filter EPD. However, there are many disadvantages with this approach, including occlusion of antegrade flow, which is not tolerated in w 5% of patients, limited lesion visualization because of occlusion, potential distal carotid dissection at the EPD balloon inflation site, and inadequate protection from atheroemboli through external carotid artery collaterals or through escape from incomplete aspiration. Since the availability of filter EPDs and proximal EPDs, this type of EPD is now seldom used. Proximal occlusion EPD The most recent advance in EPDs for CAS is the proximal occlusion EPD, which addresses some of the disadvantages of distal EPDs. The MO.MA Proximal Cerebral Protection Device (Medtronic) is based on the principle of balloon occlusion of the common carotid and external carotid arteries, which interrupts blood flow during wire crossing, angioplasty, and stenting. The GORE Flow Reversal System (W. L. Gore & Associates) uses the same principle but with the addition of flow reversal with a filtered arteriovenous shunt between the common carotid artery and femoral vein. With these systems, the entire CAS procedure is protected even before the wiring of the carotid stenosis, with more complete embolic protection. The disadvantages of these systems are larger arterial sheath access (at least 9 F), more cumbersome setup requiring both common carotid and external carotid balloon inflation, a longer procedure, and intolerance of carotid occlusion in 5%-10% of patients. However, the superiority in embolic protection with these EPDs far outweighs their disadvantages, as shown in their superior efficacy. More recently, a direct carotid access EPD was developed and is in early stages of clinical evaluation. The MICHI Neuroprotection System (Silk Road Medical, Sunnyvale, CA) requires an 8F transcervical sheath access, with an arteriovenous shunt established through femoral venous return. Although this direct carotid approach appears more invasive, it may circumvent procedural and embolic complications related to aortic arch atheroma, complex aortic arch access, common carotid atheroma, and vessel tortuosity.

4 Jacqueline Saw 25 Figure 1. Currently available filter emboli protection devices and their characteristics. Abbott Vascular s Accunet and Nav6 images courtesy of Abbott Vascular ª 2013 Abbott. All Rights Reserved. Gore Embolic Filter is reproduced with permission from Gore Medical. ANGIOGUARD XP Emboli Capture Guidewire System reproduced with permission of the Cordis Corporation. ª Cordis Corporation Fibernet Emboli Protection Device reproduced with permission from Medtronic. Spider is reproduced with permission from Covidien. SpiderFX is a trademark of a Covidien company. ª Covidien. All rights reserved. FilterWire EZ Embolic Protection System reproduced with permission of Boston Scientific Corporation. ª 2013 Boston Scientific Corporation or its affiliates. All rights reserved. Carotid Stenting Registry and Trial Outcomes Highesurgical-risk CAS registries Early voluntary registries in the 1990s reported data on CAS in a broad spectrum of patients with varying surgical risks and use of nonstandardized techniques and equipment. Subsequent industry-sponsored prospective multicentre registries focused primarily on safety and efficacy of CAS in patients at high surgical risk and were conducted as investigational exemption trials to obtain US Food and Drug Administration (FDA) or CE Mark approval for specific carotid stent and EPD platforms (Table 2) These registries had comparable predefined inclusion and exclusion criteria, independent neurologic assessment of patients, and oversight by safety and protocol-monitoring committees. Symptomatic (stenosis > 50%) and asymptomatic (stenosis > 80%) patients at high surgical risk (Table 3) were enrolled, and notably such patients were excluded in previous randomized CEA vs medical therapy trials. The primary safety end point generally included the composite of death, stroke, and MI at 30 days. The primary efficacy end point usually included 30-day safety events plus the incidence of ipsilateral stroke or death between 31 days and 1 year after CAS. Aspirin and clopidogrel therapy was standard after CAS. The periprocedural complications of death and stroke at 30 days have steadily diminished with newer registries over the past decade (Fig. 2), reflecting improvement in operator experience and equipment advancement (eg, proximal EPDs). The periprocedural stroke and death rates in these contemporary highesurgical-risk CAS registries are less than the recommended CEA event rate of < 6% for symptomatic patients and < 3% for asymptomatic patients.

5 26 Canadian Journal of Cardiology Volume Table 2. Summary of highesurgical-risk carotid artery stenting registry results Trial name Company/device Stent andepd Used N Symptomatic (%) 30-day D þ S þ MI (%) 30-day D þ S (%) 1-y outcome* (%) ARCHeR Guidant/Abbott AccuLink % pooled AccuNet ARCHeR 1 Guidant/Abbott AccuLink OTW 158 e No EPD ARCHeR 2 Guidant/Abbott AccuLink OTW 278 e AccuNet OTA ARCHeR 3 Guidant/Abbott AccuLink RX 145 e e AccuNet RX BEACH Boston Scientific WALLSTENT FilterWire EX/EZ CABERNET Boston Scientific NexStent FilterWire EX/EZ CREATE ev3 Protege Spider OTW CREATE ev3 Acculink 160 e 5.6 e e Spider RX Spider RX MAVErIC 1 þ 2 Medtronic Exponent e 11.8 GuardWi MAVErIC Int l Medtronic ExponentInterceptor Plus 51 e 5.9 e 11.8 MO.MA Invatec Any stentmo.ma e PASCAL Medtronic Exponent 115 e 8 e e Any CE Mark EPD PRIAMUS Invatec Any stent e MO.MA SECURITY Abbott Xact Emboshield EMPIRE GORE Any stent e e GORE Flow Reversal EPIC Lumen Any stent e e FiberNet PROTECT Abbott Xact (3 y) Emboshield ARMOUR Invatec Any stent MO.MA e ARCHeR, ACCULINK for Revascularization of Carotids in High-Risk Patients; ARMOUR, Proximal Protection With the Mo. Ma Device During Carotid Stenting; BEACH, Boston Scientific EPI-A Carotid Stenting Trial for High-Risk Surgical Patients; CABERNET, Carotid Artery Revascularization Using the Boston Scientific EPI FilterWire EX/EZ and the EndoTex NexStent CREATE, Cartoid Revascularization With ev3 Arterial Technology Evolution; D, death; EMPIRE, Embolic Protection With Reverse Flow; EPD, emboli protection device; EPIC, FiberNet Embolic Protection System in Carotid Artery Stenting Trial; MAVErIC, Medtronic AVE Self-Expanding Carotid Stent System With Distal Protection in the Treatment of Carotid Stenosis; MI, myocardial infarction; OTW, over-the-wire; PASCAL, Performance and Safety of the Medtronic AVE Self-Expandable Stent in Treatment of Carotid Artery Lesions; PRIAMUS, Proximal Flow Blockage Cerebral Protection During Carotid Stenting; PROTECT, Protected Carotid Artery Stenting in Patients at High Risk for Carotid Endarterectomy; RX, rapid exchange; S, stroke; SECURITY, Registry Study to Evaluate the Neuroshield Bare Wire Cerebral Protection System and X-Act Stent in Patients at High Risk for Carotid Endarterectomy. * 30-day death, stroke, and MI plus ipsilateral stroke days. Table 3. Standard highesurgical-risk criteria adapted from SAPPHIRE and high-risk registries Anatomic criteria Medical comorbidities Carotid lesion at C2 or higher Age 80 y Carotid lesion below the clavicle Congestive heart failure (NYHA class 3/4) Previous radical neck surgery or Angina pectoris (CCS class 3/4) irradiation Contralateral carotid artery occlusion Previous ipsilateral CEA Contralateral laryngeal nerve palsy Tracheostomy Left main coronary artery or 2-vessel coronary disease, or both Need for open heart surgery Left ventricular ejection fraction 30% Recent myocardial infarction (< 30 d) Severe chronic pulmonary disease Severe renal disease CCS, Canadian Cardiovascular Society; CEA, carotid endarterectomy; NYHA, New York Heart Association; SAPPHIRE, Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy. After the approval of several carotid stent and EPD platforms, the FDA mandated prospective registries to monitor device safety and efficacy outside of clinical trials. These large postmarketing registries reflect important real-world clinical practice and experience. Most of these studies are ongoing, and preliminary results have been presented or published (Table 4) In aggregate, > 27,000 patients at high surgical risk have been enrolled in these registries to date. These contemporary studies confirm that periprocedural death and stroke event rates can be achieved with CAS within the benchmarks recommended for CEA (< 3% for asymptomatic patients and < 6% for symptomatic patients), despite the enrollment of patients at high surgical risk. CAS vs CEA randomized trials for standard/low-risk patients The earliest randomized trials comparing CAS to CEA were fraught with limitationsdan outmoded carotid angioplasty approach, lack of consistent use of EPDs and self-expanding

6 Jacqueline Saw 27 Figure 2. Highesurgical-risk carotid artery stenting registries (30-day death and stroke rates) ARCHeR, ACCULINK for Revascularization of Carotids in High-Risk Patients; ARMOUR, Proximal Protection With the Mo. Ma Device During Carotid Stenting; BEACH, Boston Scientific EPI-A Carotid Stenting Trial for High-Risk Surgical Patients; CABERNET, Carotid Artery Revascularization Using the Boston Scientific EPI FilterWire EX/EZ and the EndoTex NexStent; CREATE, Cartoid Revascularization With ev3 Arterial Technology Evolution; EMPIRE, Embolic Protection With Reverse Flow; EPIC, FiberNet Embolic Protection System in Carotid Artery Stenting Trial; MAVErIC, Medtronic AVE Self-Expanding Carotid Stent System With Distal Protection in the Treatment of Carotid Stenosis; PROTECT, Protected Carotid Artery Stenting in Patients at High Risk for Carotid Endarterectomy; SAPPHIRE, Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy; SECURITY, Registry Study to Evaluate the Neuroshield Bare Wire Cerebral Protection System and X-Act Stent in Patients at High Risk for Carotid Endarterectomy. stents, and performance by inexperienced CAS operators. Thus, these early studies were of poor scientific quality and are not discussed here. Instead, modern randomized trials comparing contemporary CAS technique (most with routine EPDs) are discussed. Of note, many of these contemporary trials still do not fairly compare both procedures, because many trials allowed inexperienced operators to perform CAS and compared these outcomes to skilled surgeons with established low CEA complication rates and high procedural volume. Comparing procedural outcomes of interventionists and surgeons of divergent skill and experience does not fairly compare the different procedures. In addition, not all new trials mandated EPD use. Most of these randomized studies compared patients at standard/low surgical risk, with the exception of the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) study. Of note, the primary end points are not universal in these studies, with several including MI as a composite efficacy end point as opposed to a safety end point, which had raised criticisms in the neurology/vascular communities because CAS and CEA were not designed to reduce MI, and traditional CEA vs medical trials did not include MI in the efficacy end points. The counter argument is that MI is an important event after revascularization procedures that predicts cardiovascular outcome. Specifically, MI after CEA was associated with higher subsequent mortality. 45 SAPPHIRE. This was the first contemporary randomized study to compare CAS using EPDs vs CEA for symptomatic (stenosis > 50%) and asymptomatic (stenosis > 80%) patients who were at high risk for undergoing CEA (Table 4), 46 as dictated by anatomic risks and medical comorbidities. Both surgeons and interventionists participating in this trial must have established a periprocedural stroke and death rate of < 6%. The PRECISE stent and AngioGuard filter EPDs (Cordis) were used for CAS. The primary end point was a composite of death, stroke, and MI at 30 days plus death or ipsilateral stroke between 30 days and 1 year. This was a noninferiority trial and was terminated early in 2002 when an interim analysis showed the condition of noninferiority was met. Of the 307 patients randomized, 156 Table 4. Postmarketing carotid artery stenting registries 30-day event rates for patients at high surgical risk 30-day event rates CAPTURE 41 N ¼ 3500 CAPTURE-2 41 N ¼ 5297 CASES-PMS 42 N ¼ 1493 EXACT 43 N ¼ 2145 SAPPHIRE-WW 44 N ¼ 15,003 Manufacturer Abbott Abbott Cordis Abbott Cordis Carotid stent used AccuLink AccuLink PRECISE Xact PRECISE EPD used AccuNet AccuNet AngioGuard Emboshield AngioGuard Proportion symptomatic 14% 14.3% 21.8% 9.9% 30% Death, stroke and MI All patients 6.3% 3.5% 5.0% 4.1% 4.5% Symptomatic patients 12.0% 6.0% 6.2% e e Asymptomatic patients 5.4% 3.0% 4.7% e e Death and any stroke All patients 5.7% 3.3% e 4.1% 4.1% Symptomatic patients 10.6% 5.7%% e 7.0% 5.6% Asymptomatic patients 4.9% 2.8% e 3.7% 3.5% Death and disabling stroke All patients 2.9% e e 1.5% e Symptomatic patients e e e 2.8% e Asymptomatic patients e e e 1.4% e Death 1.8% e 1.0% 0.9% 1.2% Stroke 4.8% 2.7% 3.8% 3.6% 3.3% MI 0.9% e 0.8% 0.2% 0.6% CAPTURE, Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events; CASES-PMS, Carotid Artery Stenting With Emboli Protection Surveillance-Post-Marketing Study; EPD, emboli protection device; EXACT, Emboshield and Xact Post Approval Carotid Stent; MI, myocardial infarction; SAPPHIRE-WW, Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy Worldwide.

7 28 Canadian Journal of Cardiology Volume underwent CAS and 151 underwent CEA, and 29% were symptomatic. Technical success was 95.6% with CAS. The primary end point occurred in 12.2% of patients with CAS and 20.1% with CEA (P ¼ for noninferiority). In the superiority analysis, P ¼ for the intention-to-treat analysis, and for the per-treatment analysis. The 30- day rates of death, stroke, and MI were 4.4% for CAS and 9.9% for CEA (P ¼ 0.06). Moreover, 1-year target vessel revascularization (0.6% vs 4.3%; P ¼ 0.04) and cranial nerve palsy (0% vs 5.3%; P ¼ 0.003) were lower with CAS. Longterm follow-up to 3 years showed no difference in the prespecified composite end point (death, stroke, or MI within 30 days, or death or ipsilateral stroke between 31 days and 1080 days), 24.6% with CAS vs 26.9% with CEA. 47 This study established CAS as a valid alternative to CEA in high-risk patients, and led to FDA approval for this indication. Endarterectomy vs Angioplasty in Patients With Symptomatic Severe Carotid Stenosis (EVA-3S) study. This French study compared CAS to CEA in patients at low to normal surgical risk with symptomatic (previous transient ischemic attack or nondisabling stroke within 120 days) carotid stenosis 60%. 48 Originally designed to enroll 872 patients for noninferiority comparison, the study was stopped prematurely after accrual of 527 patients because of excess events in the CAS arm. EPD use initially was not mandated but became mandatory after preliminary analysis showed a trend to higher 30-day death or stroke rate without EPDs (adjusted odds ratio of 2.5). Credentialing requirements for interventionists were low, only 12 lifetime CAS procedures or 35 stent procedures in the supra-aortic trunk if at least 5 of these procedures were for the carotid artery. Those who did not meet credentialing requirements were still able to perform CAS and enroll patients as long as the procedures were proctored by eligible clinicians. Participating vascular surgeons must have performed at least 25 CEAs in the preceding year. The 30-day death or stroke rate was 3.9% with CEA and 9.6% with CAS (relative risk, 2.5; P ¼ 0.01). The 30-day disabling stroke or death rate was 1.5% with CEA and 3.4% with CAS (P ¼ 0.26). Stroke or death rate at 6 months was 6.1% with CEA and 11.7% with CAS (P ¼ 0.02). The 30-day death or stroke rate was 7.9% with EPDs (n ¼ 227) and 25% without EPDs (n ¼ 20) (P ¼ 0.03). Cranial nerve injury was more common after CEA (7.7% vs 1.1%; P < 0.001). This study was strongly criticized by the interventional community because interventionists with limited CAS experience were allowed to enroll. Interventionists could have done as little as 5 lifetime CAS procedures or be under tutelage during the trial. In fact, two thirds of sites initially had interventionists who were under tutelage, and this is an important limitation because there is a steep learning curve for CAS. 30,31 The overall stroke rate with CAS (9.2%) was much higher than that in contemporary CAS trials (3.6% in SAPPHIRE), in which the selection of interventionists was more rigourous. Lack of universal use of EPDs and inexperience with EPDs among their interventionists were also concerns. In the CAS procedures without EPD use, the 30- day death or stroke rate was > 3-fold that in procedures using EPDs. Furthermore, only 85% of patients were receiving dual-antiplatelet therapy after CAS. Stent-Supported Percutaneous Angioplasty of the Carotid Artery vs Endarterectomy (SPACE) study. This was a European randomized multicentre trial evaluating if CAS was noninferior to CEA for the treatment of symptomatic (neurologic or ocular events within 6 months) severe carotid stenosis (ultrasonography 70% or angiography 50% by North American Symptomatic Carotid Endarterectomy Trial criteria or 70% by European Carotid Surgery Trial criteria) in low-risk patients. 49 The primary end point was 30-day ipsilateral stroke or death rate. Vascular surgeons must have performed 25 consecutive successful CEA procedures. Interventionists requirement was 25 successful percutaneous angioplasties, although these did not have to be carotid procedures. Although any CE Markeapproved device was allowed, EPD use was not mandated and was deployed in only 27% of CAS procedures. The planned enrollment was 1900 patients, but the study was stopped prematurely after 1183 patients because of funding problems. The 30-day rate of death or ipsilateral stroke was 6.84% with CAS and 6.34% with CEA (absolute difference 0.51%; 90% confidence interval [CI], 1.89%-2.91%; P ¼ 0.09). The upper 90% CI of 2.91% was higher than the prespecified noninferiority threshold of 2.5%, and thus noninferiority was not met. P ¼ 0.09 can be interpreted as a 9% chance that CAS is not inferior to CEA. At 2-year follow-up, there was no difference in the primary end point plus ipsilateral stroke up to 2 years between groups (9.5% CAS vs 8.8% CEA; hazard ratio [HR], 1.1; P ¼ 0.62). 50 This study received a number of major criticisms, including being tremendously underpowered because it was stopped prematurely, with a conditional power of only 52%. The absolute difference of 0.51% between CAS and CEA with a 90% CI of 1.89%-2.91% crosses zero, suggesting that the difference is nonsignificant or uncertain. Moreover, the rationale for the assumption of a 5% event rate and a 2.5% noninferiority margin was not specified. Because the actual event rate was 6.6%, the predetermined noninferiority margin of 2.5% may have been too restrictive. The lack of mandated EPD use and its subsequent low use was also strongly criticized, because this may have contributed to the suboptimal CAS results. The technical experience of the interventionists was also heavily criticized because there was no need for any previous CAS experience. In addition, clinical and safety end points such as MI, cranial nerve palsy, and wound complications were not evaluated in this study. Carotid Revascularization Endarterectomy vs Stent Trial (CREST). This is the largest randomized trial comparing CAS to CEA; it was sponsored by the US National Institute of Neurological Disorders/National Institute of Health and Abbott Vascular. 51 The trial enrolled 2516 patients of low to standard risk from December 2000 to July This study was originally intended to enroll only symptomatic patients with carotid stenosis ( 50% on angiography or 70% by ultrasonography, computed tomography, or magnetic resonance angiography), but expanded in 2004 to include asymptomatic patients (stenosis 60% by angiography, 70% by ultrasonography, or 80% by computed tomography/magnetic resonance angiography) to improve enrollment and broaden the study population. The RX AccuLink stent and RX AccuNet EPD (Abbott Vascular) were used. The primary end point was the composite of death, stroke,

8 Jacqueline Saw 29 and MI at 30 days, plus ipsilateral stroke up to 4 years followup. All participating interventionists underwent a rigourous credentialing process, with a minimum experience of 30 lifetime CAS procedures (20 cases using the AccuLink/ AccuNet system), and had to enroll at least 3 patients in the lead-in phase. Ultimately, only w 50% of interventionists who applied to participate were selected for the randomized study. Patients were followed for a median of 2.5 years, and 47.2% were asymptomatic. Of patients who were randomized to CAS, 67.1% had balloon angioplasty before stenting, 96.1% had EPDs used, and 87.9% had dual-antiplatelet therapy for 4 weeks after CAS. The primary end point of stroke, MI, or all-cause death at 4 years was not different between groups: 7.2% with CAS and 6.8% with CEA (HR, 1.11; 95% CI, ; P ¼ 0.51). Mortality was not different between groups (0.7% CAS vs 0.3% CEA; P ¼ 0.18). Stroke rate was higher with CAS (4.1% CAS vs 2.3% CEA; P ¼ 0.01), but MI rate was lower with CAS (1.1% CAS vs 2.3% CEA; P ¼ 0.03). Of note, the difference in strokes was driven by minor ipsilateral strokes (2.9% CAS vs 1.4% CEA; P ¼ 0.009), with no difference in major strokes (0.9% CAS vs 0.6% CEA). The ipsilateral stroke rate during follow-up was similar: 2.0% with CAS and 2.4% with CEA (P ¼ 0.85). Nevertheless, both major and minor strokes were found to have significant impact on physical health at 1 year, whereas the impact with MI was less certain. Minor strokes also had significant impact on mental health at 1 year. Cranial nerve palsy was less frequent with CAS (0.3% vs 4.7% CEA; HR, 0.07; CI, ). There was a significant interaction between treatment assignment and age, with an increased stroke risk associated with CAS among patients > 70 years of age. Younger patients were found to have slightly fewer events after CAS, whereas older patients had fewer events after CEA. There was no statistical interaction between treatment assignment and symptomatic status for the primary end point. Overall, the CREST study showed that in standard-risk patients, CAS and CEA had similar rates of composite events at 4 years. However, patients undergoing CAS had slightly higher rates of minor stroke events, whereas patients undergoing CEA had slightly higher rates of MI. The lower event rates with CAS in this study when compared with previous randomized studies likely reflect the more rigourous selection of interventionists. Likewise, the CEA event rates were remarkably low, 3.2% for symptomatic patients and 1.4% for asymptomatic patients, also reflecting excellent surgical skills. Given the rigour of operator selection, whether the results of CREST may be replicated in the community remains to be seen. The higher stroke risk among older patients undergoing CAS is believed to result from higher anatomic risks (type III aortic arch, cervical artery tortuosity, arch vessel calcification, lesion calcification, and decreased cerebral reserve) and may be circumvented by careful case selection and attention to anatomic complexities of tortuosity and calcification. In fact, 2 large CAS series by Grant et al. (N ¼ 418) and Setacci et al. (N ¼ 144) of patients > 80 years of age undergoing CAS showed that low periprocedural rates can be achieved if performed by experienced operators in high-volume centres and combined with careful patient selection. 52,53 International Carotid Stenting Study (ICSS). This was a European multicentre trial that randomized 1711 low- or standard-risk patients with symptomatic carotid stenosis > 50% to either CAS or CEA. Surgeons were required to have performed at least 50 CEA procedures ( 10 cases per year), and interventionists were required to have performed a minimum of 50 stenting procedures, with at least 10 in the carotid artery. Centres not fulfilling these criteria could still join as supervised centres with procedures proctored. Noninvasive imaging of the carotid artery (including duplex ultrasonography) was acceptable for study entry, and catheter angiography was not required before randomization. Any CE markeapproved device was allowed, and EPD use was not mandatory but was recommended. The primary outcome was fatal or disabling stroke at 3 years. The interim safety analysis of the 120-day rate of death, stroke, or MI during the procedure was published in The rate of disabling stroke or death at 120 days was 4.0% with CAS and 3.2% with CEA (HR, 1.28; 95% CI, ). Three MIs during procedures were recorded in the CAS group (all fatal) compared with 4 in the CEA group (all nonfatal). EPDs were used in 72% of cases. Of the 828 patients in whom CAS was initiated as allocated, 64 (8%) had the procedure aborted before the insertion of a stent (38 procedures were aborted because of difficulty gaining access to the stenosis, 15 were aborted because of an occluded artery, and 7 patients had stenosis < 50%). These high failure rates raise doubts about the experience of the interventionists. As a consequence, the 120-day rate of death, stroke, or MI was 8.5% with CAS and 5.2% with CEA (HR, 1.69; P ¼ 0.006). The 3-year results are not yet available. The major criticism of this trial remains the low credentialing requirement and experience of interventionists. In a 231-patient DW-MRI substudy of ICSS, more patients in the CAS arm had 1 new lesion seen on DWI at a median of 1 day after the procedure (50% vs 17% for CEA; P < ). 55 However, in 2 study centres where detailed neuropsychological examinations were performed, there was no statistically significant difference on cognition between the 2 procedures, although there was a trend to worsening cognition with CAS. 56 In another study by Bijuklic et al., 57 new lesions seen on DWI after CAS were identified in 32.8% of 728 patients who underwent CAS with routine MRI follow-up, but these were not associated with major adverse cerebral and cardiovascular events. Proximal occlusion EPD studies The development of dedicated carotid proximal occlusion EPDs established another important milestone with CAS. These devices offer superior capture efficiency of embolic material during CAS because, theoretically, they provide protection throughout all phases of intervention and obstruct antegrade flow during the procedure. Montorsi et al. randomized 53 patients undergoing CAS to the MO.MA proximal EPD or FilterWire EZ distal EPD. 58 Transcranial Doppler (n ¼ 53) was performed to evaluate for MESs, and DW-MRI was performed (n ¼ 35) for new cerebral lesions. MO.MA significantly reduced MESs during lesion crossing, stent crossing (27% vs 100%; P < ), stent deployment (27% vs 100%; P < ), stent dilation (27% vs 96%; P < ), and total MES counts (P < 0.001). New cerebral lesions seen on DW-MRI occurred in

9 30 Canadian Journal of Cardiology Volume % of patients with FilterWire EPDs and 14% with MO.MA EPDs (P ¼ 0.14). Likewise, in the study Prevention of Cerebral Embolization by Proximal Balloon Occlusion Compared to Filter Protection During Carotid Artery Stenting (PROFI), 62 patients were randomized to the Emboshield filter EPD (Abbott Vascular) or the MO.MA proximal EPD. There was a significant reduction in the incidence of new cerebral ischemic lesions (45.2% vs 87.1%; P ¼ 0.001) with proximal EPDs on DW-MRI. Procedural duration was longer in the proximal EPD group compared with the filter group (30 8 minutes vs 22 7 minutes; P ¼ 0.003). Balloon intolerance was observed in 3 of 31 patients with proximal EPDs; nevertheless, these procedures still concluded under cerebral protection. Therefore, both these studies showed convincingly that proximal EPDs reduced new cerebral ischemic lesions with CAS when compared with filter EPDs. Several prospective multicentre single-arm registries with proximal EPDs have been done with the MO.MA and GORE Flow Reversal System. 31,35,39,59-61 The meta-analysis from Bersin et al. nicely summarized the results from these 6 independent registries involving 2397 patients who underwent CAS with either of the 2 proximal EPDs. 62 The primary end point of total stroke, MI, and death at 30 days was 2.25%. The individual incidence of stroke was 1.71%, that of MI was 0.02%, and that of death was 0.40%. Patients tolerated the proximal EPDs well, with device intolerance defined as either the need to interrupt the use of the proximal EPD or the use of an alternative method of protection (filter EPD), which was observed in only 0.63% and 0.35% of patients, respectively. Interestingly, symptomatic status was not an independent risk factor for stroke with proximal EPDs (unlike filter EPDs), which is likely explained by the high capture efficiency of embolic debris. Another novel system, the direct carotid MICHI Neuroprotection System has early limited but promising data. 63 In the Silk Road Medical Embolic Protection System First-in- Man (PROOF) study, 44 patients underwent CAS with this system. Procedural success was 100%, with no major stroke, MI, or death within 30 days. A subgroup of 31 patients had DW-MRI performed: 16% had evidence of new ischemic brain lesions but no clinical sequelae. Transient intolerance to reverse flow was reported in 9% of patients, but in all cases, intolerance was managed by minimizing the duration of reverse flow during the procedure. Overall, the advancement and clinical data on proximal EPDs are quite promising, with low periprocedural stroke rates. Although the duration of the procedure is longer and EPD deployment more technically challenging compared with filter EPDs, this is offset by the superiority of embolic protection and should be the preferred EPD of choice for experienced operators, especially in the treatment of symptomatic patients. Asymptomatic carotid artery stenosis Although patients with asymptomatic carotid stenosis are at increased risk of ipsilateral stroke, and randomized trials (Veterans Affairs Cooperative Study Group, 12 Asymptomatic Carotid Artery Stenosis study [ACAS] and Asymptomatic Carotid Surgery Trial [ACST]) (Table 1) have shown reduction in stroke events with CEA, these studies were performed before the availability of contemporary medical therapy. Randomized CAS trials included a mixture of symptomatic and asymptomatic patients, with no CAS trial specifically targeting asymptomatic patients and no randomized trial comparing CAS to medical therapy. Thus, revascularization for asymptomatic patients is currently considered controversial. In a recent meta-analysis by Raman et al. that evaluated 47 CAS and CEA studies, 64 the authors concluded that there was insufficient evidence comparing CAS to CEA in asymptomatic patients, with overall nonstatistical difference in ipsilateral stroke events (1 study showed a trend to higher stroke risk with CAS but another study showed a lower trend to stroke risk). Since medical therapy has significantly improved in the past 2 decades, modern comparative studies on revascularization vs medical therapy is pertinent, with the randomized CREST II and SPACE II trials under way. Importance of CAS Operator Experience The CAS procedure is technically challenging and requires meticulous technique to avoid procedural complications, along with good clinical judgement on case selection (Fig. 3). Operator experience is considered instrumental in procedural success and minimizing complications. Several studies have shown that operator experience may reduce CAS complications. In a single-centre retrospective analysis of the first 200 CAS procedures performed at Baylor College, procedural time and contrast volume decreased significantly with increasing experience. 65 The procedural time plateaued after about 100 cases had been performed. The actuarial plot also showed that the probability of complications decreased with increasing Figure 3. (A) Before carotid artery stenting. (B) After carotid artery stenting.

10 Jacqueline Saw 31 experience, with the plateau also around 100 cases. Likewise, the Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events (CAPTURE) 2 postmarketing registry demonstrated a striking inverse relationship between 30-day death or stroke rate and procedural volume. Using a regression model, the estimated minimum number of CAS procedures to achieve a death or stroke rate < 3% was 72 cases. In addition to volume, procedural specialty may also impact CAS outcomes. In the lead-in phase of CREST, vascular surgeons had a statistically higher rate of complications compared with interventional cardiologists and neuroradiologists, which was attributed to limited catheter-based experience among surgeons. 66 These volume thresholds are much higher than the credentialing requirement established by various societies recommending 25 supervised cases of CAS to become independent operators. 67 The author s personal experience is that a smaller volume may be adequate to learn the basic techniques of CAS, but a much larger volume is required to troubleshoot and manage challenging cases (severe tortuosity of aortic arch and carotid arteries) and to appreciate anatomy that should be avoided (eg, heavy calcification, thrombus, string sign, severe tortuosity) (Table 5). These studies underscore the importance of operator experience in performing CAS safely and probably explain in large part the suboptimal results of several randomized CAS vs CEA trials in which inexperienced interventionists were allowed to randomize patients (EVA-3S, SPACE, and ICSS). Guidelines for CAS Indications The American Heart Association guidelines for CAS were reported in 2011 soon after the publication of CREST results. 15 CAS is indicated as an alternative to CEA for symptomatic patients who are at average or low risk of complications with CAS and have > 70% carotid stenosis by noninvasive imaging or > 50% by catheter angiography (class I; level of evidence B, compared with level of evidence A for CEA for this indication). CAS may also be considered as an alternative to CEA in patients at high surgical risk with symptomatic stenosis > 70%, when medical conditions greatly increase the risk of surgery or when anatomic risks are present (eg, radiation-induced stenosis, restenosis after CEA) (class IIb; level of evidence B). CAS, as recommended earlier, is reasonable when performed by operators with established periprocedural morbidity and mortality rates of 4%-6% (class IIa; level of evidence B). Regarding asymptomatic carotid stenosis ( 60% by angiography or 70% by validated Doppler ultrasonography), prophylactic CAS may be considered in highly selected patients, but its effectiveness compared with medical therapy alone is not well established in this situation (class IIb; level of evidence B). The Canadian Best Practice Recommendations for Stroke Care was updated in September CAS may be considered for symptomatic patients with 50%-99% carotid stenosis who are not operative candidates for technical, anatomic, or medical reasons (level of evidence A), and interventionists should have expertise in carotid procedures and an expected risk of periprocedural morbidity and mortality rate < 5%. For asymptomatic patients with carotid stenosis of 60%-99%, CAS may be considered in patients Table 5. Anatomic contraindications to carotid artery stenting 1. Inability to safely achieve vascular access 2. Severe tortuosity of the aortic arch (type III arch) 3. Severe tortuosity of the common carotid artery or internal carotid artery 4. Intracranial aneurysm or arteriovenous malformation requiring therapy 5. Heavy concentric lesion calcification ( 3 mm in width) 6. Thrombotic lesion 7. Total occlusion of lesion 8. Long subtotal occlusion (string sign) 9. Friable aortic arch atheroma who are not operative candidates for technical, anatomic, or medical reasons provided that there is a < 3% risk of periprocedural morbidity and mortality. Contraindications for CAS Despite the improvement in equipment and operator skills and experience, there remain select patients in whom CAS is considered high risk and associated with higher complications. These high-risk features can be divided into medical factors, anatomic factors, and procedural factors. Medical factors include elderly age (> years), chronic renal insufficiency, decreased cerebral reserve (eg, dementia, previous strokes), inability to tolerate aspirin or clopidogrel therapy, or both, and life expectancy < 5 years. Anatomic contraindications are listed in Table 5. According to expert consensus, 1 of the highest predictors of adverse events with CAS is type III aortic arch (in which the great vessels arise from more than 2 reference carotid artery diameter inferior to the apex of the aortic arch). 69 Studies have shown a > 2.5-fold increased risk of periprocedural strokes and complications with type III aortic arch. 70,71 The presence of severe aortic arch atheroma (> 5-mm thickness or mobile debris) on transesophageal echocardiography also correlated with higher cerebral embolism, presumed caused by catheter manipulation in the arch. 72 Thus, it has been proposed that elderly patients with complex aortic arch morphologic characteristics may benefit from preprocedural transesophageal echocardiography to visualize the arch. Heavily calcified carotid stenosis theoretically may cause underexpansion of stents and potential risk of rupture with high-inflation pressures. However, there are conflicting reports about the relationship between stroke occurring during the procedure and lesion calcification. Procedural factors that increase CAS risk include lack of EPD use, inexperienced operators, nonfemoral access, and possibly use of open-cell stents. Cost-Effectiveness of CAS vs CEA There have been several cost-effectiveness analyses performed for CAS vs CEA, with several studies showing that CAS has a higher procedural cost because of higher equipment cost and is overall less cost-effective than CEA in the United States. 73 However, there are also studies that showed CAS to be cost-effective compared with CEA in patients at high surgical risk, even in the Canadian health system. 74,75 These discrepancies highlight differences in cost-effectiveness depending on patient selection, regional differences in equipment cost, and procedural complications and outcome.