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Endarterectomy or carotid artery stenting: the quest continues

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  • 1. The American Journal of Surgery 195 (2008) 259 –269 Review Endarterectomy or carotid artery stenting: the quest continues Michiel G. van der Vaart, M.D.a, Robbert Meerwaldt, M.D., Ph.D.b, Michel M.P.J. Reijnen, M.D., Ph.D.c, René A. Tio, M.D., Ph.D.d, Clark J. Zeebregts, M.D., Ph.D.a,* a Department of Surgery, Division of Vascular Surgery, University Medical Center Groningen, 9700 RB Groningen, The Netherlands b Department of Surgery, Isala Clinics, Zwolle, The Netherlands c Department of Surgery, Alysis Zorggroep, Lokatie Rijnstate, Arnhem, The Netherlands d Department of Cardiology, University Medical Center Groningen, 9700 RB Groningen, The Netherlands Manuscript received May 24, 2007; revised manuscript July 3, 2007 Abstract Background: Carotid endarterectomy (CEA) is still considered the “gold-standard” of the treatment of patients with significant carotid stenosis and has proven its value during past decades. However, endo- vascular techniques have recently been evolving. Carotid artery stenting (CAS) is challenging CEA for the best treatment in patients with carotid stenosis. This review presents the development of CAS according to early reports, results of recent randomized trials, and future perspectives regarding CAS. Methods: A literature search using the PubMed and Cochrane databases identified articles focusing on the key issues of CEA and CAS. Results: Early nonrandomized reports of CAS showed variable results, and the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial led to United States Food and Drug Administration approval of CAS for the treatment of patients with symptomatic carotid stenosis. In contrast, recent trials, such as the Stent-Protected Angioplasty Versus Carotid Endarterectomy trial and the Endarterectomy Versus Stenting in Patients with Symptomatic Severe Carotid Stenosis trial, (re)fuelled the debate between CAS and CEA. In the Stent-Protected Angioplasty Versus Carotid Endarterectomy trial, the complication rate of ipsilateral stroke or death at 30 days was 6.8% for CAS versus 6.3% for CEA and showed that CAS failed the noninferiority test. Analysis of the Endarterectomy Versus Stenting in Patients With Symptomatic Severe Carotid Stenosis trial showed a significant higher risk for death or any stroke at 30 days for endovascular treatment (9.6%) compared with CEA (3.9%). Other aspects–such as evolving best medical treatment, timely intervention, interventionalists’ experience, and analysis of plaque compo- sition–may have important influences on the future treatment of patients with carotid artery stenosis. Conclusions: CAS performed with or without embolic-protection devices can be an effective treatment for patients with carotid artery stenosis. However, presently there is no evidence that CAS provides better results in the prevention of stroke compared with CEA. © 2008 Excerpta Medica Inc. All rights reserved. Keywords: Carotid endarterectomy; Embolic-protection device; Stenting; Stroke preventionStroke and stroke-related death are increasing causes of event, first-year survivor are €18,517 (USD $25,016)/concern in the western world. Currently, stroke is the third patient, and lifetime costs are €43.129 (USD $58,257)/most common cause of mortality [1,2]. A Swedish publica- patient. This in turn accounts for 3% to 4% of total healthtion showed for the first time a stroke incidence of 213/ care costs in several European countries [4]. The estimated100,000 persons annually [3]. This generates an enormous direct and indirect cost generated so far by stroke in 2007 infinancial burden to the western society, as shown by a the United States is USD $62.7 billion [2].German cost analysis [4]. Direct medical costs for a first- Extracranial cerebral atherosclerosis causes 8% to 29% of all ischemic strokes [5]. Thrombotic emboli arising from cardiac origin are another more frequent cause of ischemic * Corresponding author. Tel.: 011-31-503613382; fax: 1-31-503611745. strokes [6 – 8]. The aim of treatment for patients with carotid E-mail address: czeebregts@hotmail.com stenotic disease lies in decreasing the risk of disabling0002-9610/08/$ – see front matter © 2008 Excerpta Medica Inc. All rights reserved.doi:10.1016/j.amjsurg.2007.07.022
  • 2. 260 M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269stroke or stroke-related death as consequences of thrombo- this previously largely unfounded practice [13–15,32]. Theembolism. Different medical-treatment strategies evolved European Carotid Surgery Trial (ECST) and the Northfrom studies initially aimed at treating patients with cardio- American Symptomatic Carotid Endarterectomy Trialvascular disease. For a long time, treatment consisted of 2 (NASCET) are the 2 most-referred trials on the subject ofmain modalities: medication and/or open surgery (carotid the treatment of patients with symptomatic carotid stenosis.endarterectomy [CEA]) [9 –12]. For most patients with ca- Inclusion criteria consisted of patients who had had a tran-rotid stenosis, surgical endarterectomy, rather than medical sient ischemic attack or nondisabling stroke in the internaltreatment, became the treatment of choice for stroke pro- carotid flow tract 6 months before enrollment. Despitephylaxis, with proven efficacy. Symptomatic patients who differences in carotid stenosis analysis, both trials came tohave carotid stenoses between 50% and 99% and perioper- the same conclusions [15]. Findings in the NASCET dem-ative rates of stroke and/or death 6% are best treated by a onstrated a decreased 2-year stroke risk from 26% in thecombination of best medical treatment (BMT) and surgery medical group to 9% in the CEA group, yielding an absoluteaccording to guidelines of the American Heart Association risk reduction of 17% (for patients with 70% carotidand results of large randomized trials [12–16]. The Asymp- stenosis). Perioperative risk rates for stroke and/or deathtomatic Carotid Atherosclerosis Study (ACAS) concluded were 5.8% in the surgical arm. Patients in this study whothat also asymptomatic patients with a carotid artery steno- had undergone surgical correction of high-grade stenosissis 60% are good candidates for CEA, with a reduced gained a durable benefit lasting 8 years [33]. It was further5-year ipsilateral stroke risk. Especially for this category of found that the efficacy of CEA increased with increasingpatients, CEA should be performed with low morbidity and degree of stenosis, previous stroke presentation, and pres-mortality rates in order to achieve a considerable risk re- ence of ulceration. Furthermore, the presence of diabetes,duction warranting the risks of the operation [17]. The coronary heart disease, or hypertension increased stroke riskAmerican Heart Association therefore recommended that in the medically treated group but not in the CEA group.(grade A) CEA be performed in asymptomatic patients with The ECST showed a decrease in the 3-year risk of strokea carotid stenosis of 60% to 99% if perioperative risk rates and/or death from 26.5% in the medical group to 14.9% inare 3% and if the patient has a life expectancy 5 years the CEA group. Interestingly, the early (30-day) rates of[1,12]. Results from these studies are discussed in detail stroke and/or death were higher in women (10.6%), inlater in this review. Results, as shown by Mullenix et al patients with systolic blood pressure 180 mm Hg (12.3%),[18], show that CEA is a safe, effective, and durable treat- and in patients with peripheral vascular disease (12.3%).ment even when not performed in “high-volume” CEA From the results of the pooled data (6,092 patients), acenters [18]. significant 16% absolute risk reduction during 5 years Despite the proven efficacy of CEA, great interest has (numbers needed to treat 6.3) was shown for symptomaticbeen generated in carotid angioplasty and stenting (CAS) as patients with a stenosis 70% (without near occlusion). Aan alternative to surgical therapy. The assets of CAS seem 4.6% absolute risk benefit was shown for patients with aobvious in patients with hostile necks because of previous 50% to 69% stenosis (numbers needed to treat 22). Overallsurgery and/or radiotherapy [19]. Moreover, CAS is less operative risk of stroke and/or death within 30 days afterinvasive compared with CEA and has decreased risk for surgery was 7.1%. For patients with near occlusion, thecranial nerve damage as well as the ability to treat lesions absolute risk reduction was 5.6% during 2 years (P .19),that are beyond the reach of CEA [20]. During the last and 1.7% during 5 years (P .9). Others have debated thedecade, several trials and series have been published com- benefit of CEA in patients with near occlusion. For exam-paring CAS with CEA [21–29]. The aim of this article is to ple, Fox et al [34] showed no apparent benefit of CEA inreview the literature concerning the results of CAS and to patients with near occlusion. The absolute risk reduction inelucidate on its current status. In addition, future options are the near-occlusion group was 4.2% compared with 17.8% indiscussed. those with severe stenoses but without near occlusion [34]. With near occlusion, there is relative protection against emboli because arterial diameter is decreased, and this mayMethods in part explain the relatively low long-term stroke risk in A literature search using the PubMed and Cochrane these patients. Numerous posthoc analyses of subgroupsdatabases identified articles focusing on the key issues of from the NASCET and the ECST have been published, butCEA and CAS. Manual cross-referencing was also per- they are beyond the scope of this review article.formed, and relevant references from selected papers were Other studies, such as the Asymptomatic Carotid Ath-reviewed. erosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST), were designed to investigate whetherHistory patients with asymptomatic stenotic lesions were eligible The first successful extracranial CEA (ICEA) procedure for CEA [35,36]. In ACST, a total of 3,120 asymptomaticwas performed in 1953. However, it took almost 20 years patients with stenotic lesions 60%, as seen on duplexbefore the results for therapy of patients with (symptomatic) Doppler ultrasound, were included. The 5-years risk forinternal carotid artery (ICA) stenosis were reported [30,31]. stroke (minor and major) in surgical patients was 6.4%In the 1980s, CEA was the most-performed vascular pro- versus 11.8% for patients who deferred surgery. Conse-cedure. It was not until the last two decades of the 20th quently, a significant absolute risk reduction of 5.4% wascentury that results from large randomized controlled trials noted, although a subgroup analysis showed clear benefitsconsidering BMT versus surgery were published supporting only for patients 75 years old. Fifty percent of people
  • 3. M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269 261Table 1Early carotid stent series dataAuthor Year n Symptomatic Technical success Morbidity and mortality rate Stroke rate (%) stenosis (%) rate (%) (30-day; %)Roubin et al [50] 2001 528 52 98 7.4 5.8Theron [43] 1996 69 NS 100 3 NSBergeron et al [49] 1999 99 58 97 7.1 1Diethrich et al [46] 1996 110 38 99 7.3 6.5Waigand [126] 1998 50 28 100 2 4Yadav et al [29,47] 1997 107 64 100 7.9 8.4Vozzi [127] 1997 22 45 96 9 9Wholey et al [44,57] 1997 108 56 95 5.5 3.6Henry et al [51] 1998 163 65 99 5.2 3Teitelbaum et al [52] 1998 22 68 100 27.3 24 NS not specified.older in age died of unrelated causes 5 years of follow-up. suitable to treat patients with severe concomitant cardiacFurthermore, the efficacy of CEA in women compared with and/or pulmonary disease. Other advantages include easymen was also one-third less based on higher perioperative access in patients with hostile necks because of previousrisks in women. Overall operative risk of stroke and/or surgery and/or radiotherapy. In addition, patients whosedeath within 30 days after surgery was 3.1%. The ACAS stenoses extended onto the base of the skull were accessiblehad similar results: There was risk reduction of 5.9% in for treatment.surgical patients with a stenosis 60%. The 2.3% operative Risk of embolic stroke limited early enthusiasm. Initialrisk of stroke and/or death in this trial was low. Approxi- strategies focused on neurologic rescue by fibrinolyticmately 50% of the strokes in the CEA arm were related to agents or techniques to remove embolic debris. Later treat-the surgical procedure, whereas the others were related to ment shifted from rescue to protection. Most of the resultscontrast arteriography. The ASA and Carotid Endarterec- of carotid PTA proved promising, with rates of stroketomy randomised controlled trial published in 2003, which and/or death ranging between 0% and 7.9%, but most stud-compared periop erative complications with CEA depend- ies were rather small and nonrandomized (Table 1) [43,ing on different acetylsalicylic acid dosages, disclosed a 44,46,47,49 –52,126,127]. Inclusion and exclusion criteriaperioperative complication risk of 4.6% [37]. Notable, re- were diverse, and PTAs were randomly carried out with orsults from the ACAS trial show that 20 CEAs would be without stenting. PTA alone had its limitations because ofneeded to prevent 1 stroke in 5 years of follow-up. Two its decreased (long-term) durability, but the use of a stentanalyses performed afterwards showed that despite the high certainly did not rule out possible danger. Problems re-numbers needed to treat, CEA in asymptomatic patients is ported were direct recoil of the vessel wall after dilatation,cost-effective [38,39]. increased embolism caused by catheter manipulation (4 Guidelines for performing CEA were distilled by the times greater compared with CEA), severe bradycardia, andAmerican Heart Association from these data. In symptom- hypotension after balloon dilatation and dissection [21,atic patients, the risk of stroke and/or death resulting from 53,54]. Intermingled with these reports, changes in tech-treatment by CEA should be 6% and for asymptomatic nique, especially the introduction of embolic-protection de-patients should be 3% [40]. vices (EPDs), took place.Endovascular treatment for carotid stenosis CAS technique and embolic protection devicesEarly reports Presently, having the patient under local anesthesia is the As a result of the widespread use of angioplasty and preferred way of performing CAS because, in this way, thestenting in the treatment of patients who have arterial ste- patient’s neurologic condition can be monitored continu-nosis in the context of coronary artery disease, treatment of ously [55]. Access is gained by way of the common femoralpatients with peripheral stenotic arterial vascular disease artery to perform selective catheterization of the commonalso evolved. With the advancing techniques of percutane- carotid artery. Recognition of normal and variant anatomyous transluminal angioplasty (PTA), treatment of patients of the aortic arch and the cervicocerebral circulation iswith carotid stenosis also became feasible. The first balloon required for successful performance of angiography andangioplasty for carotid stenosis was performed in 1979, and CAS. Selective angiography of both carotid arteries is rec-reports in the 1980s included balloon occlusion to decrease ommended before CAS to evaluate carotid stenosis severity,embolic complications [41– 43]. Meanwhile, carotid artery morphology, carotid tortuosity, calcification, intracranialstenting has been presented in an increasing variety of circulation stenosis, collateral circulation, and malforma-publications as a viable alternative to CEA in the treatment tions. Because there is a risk of embolization caused byof patients with extracranial carotid stenosis [43–50]. Sev- manipulation during the procedure, EPDs are increasinglyeral arguments have been brought forward to advocate its being used [56]. No randomized trials have compared CASuse. The minimally invasive nature of the procedure made it with EDPS versus CAS without EPDs. However, the avail-
  • 4. 262 M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269ability of EPDs seems to decrease the risk of embolic Table 2complications as described by the carotid artery stent reg- Carotid artery stent registriesistries [57,58]. Importantly, many other studies have not Registry N (% symptomatic) Combined MI/stroke/death rate (%)been powered to show a benefit from EPD. 30 d 1y Three different approaches to achieve protection havebeen used: (1) distal balloon occlusion, (2) distal filter BEACH 480 (25.3) 5.8* (1.0/4.4/1.5) 9.1# (1.1/7.0/3.2)placement, and (3) proximal occlusion with flow reversal ARCHeR 581 (23.8) 8.3* (2.4/5.5/2.1) 9.6* (0/1.3/0)[56,59]. Although all distal EPDs are able to capture and CABERNET 454 3.8# 11.5#remove embolic debris, this does not eradicate embolic CAPTURE 3,500 (13.8) 5.7* (.9/4.8/1.8) NAcomplications. Inability to deliver or deploy the EPD, EPD- CREATE 543 (17.4) 6.2* (1.0/4.5/1.9) NA MAVerIC 498 5.3# NAinduced vessel injury, ischemia caused by occlusion, and SECuRITY 398 (21) 8.5# (.7/6.9/.9) NAincomplete embolic debris removal may all result in em- CaRESS 143 (31) 2.1* (0/2.1/0) 10 (1.7/5.5/6.3)bolic cerebral complications. Microporous filters are posi- CREST 749 (30.7) 4.4* (0/4.0/.8) NAtioned in the ICA distal to the target lesion. The filter is MO.MA 157 (19.7) 5.7* (0/5.1/.6) NAconstrained with a delivery sheath to pass the carotid ste- PRIAMUS 416 (63.5) 4.6* (0/4.1/.5) NAnosis. Once in position, the delivery sheath is withdrawn to ARCHeR Acculink for Revascularization of Carotids in High-Riskdeploy the filter. Filters offer the advantage of continued Patients; CABERNET Carotid Artery Revascularization Using Bostoncerebral perfusion. In contrast, the delivery system is rela- Sci EPI Filterwire EX/EZ and EndoTex NexStent; CAPTURE Carotidtive large, which may interfere with crossing the stenosis, Acculink/Accunet Postapproval Trial to Uncover Rare Events; CaRESSand the stiffness of the system may be a problem in tortuous Carotid Revascularization Using Endarterectomy or Stenting Systems;vessels, increasing the risk of embolization during place- CREATE Carotid Revascularization With ev3 Arterial Technologyment of the filter. Occlusion balloons offer the advantage of Evaluation; MI myocardial infarction; MAVerIC Endarteractomylower device-crossing profiles, but they still require cross- Versus Angioplasty in Patients With Severe Symptomatic Carotid Steno-ing the stenosis as well as interruption of cerebral perfusion. sis; MO.MA Multicenter Registry to Assess the Safety and Efficacy ofOnce protection has been secured, the stent is put into place the MO.MA Cerebral Protection Device During Carotid Stenting; NAunder angiographic control. Stents used are mostly self- not available; PRIAMUS Proximal Flow Blockage Cerebral Protection During Carotid Stenting; SECuRITY Registry Study to Evaluate theexpanding, but balloon-expandable stents can be used when NeuroShield Bare Wire Cerebral Protection System and X-Act Stent intreating the ostium of the common carotid artery [55]. After Patients at High Risk for Carotid Endarterectomy.the stent is put in place, postdilatation is applied, followed * Data available from publications in peer-reviewed journals.by control angiogram. A perfect anatomic end result at # Data from: www.strokecenter.org/trials or www.cms.hhs.gov/med.angiography is not pursued (most studies accept residualstenosis 30%) because aggressive balloon dilatation ap-pears to increase the risk of complications, and residual stroke, and/or death at 30 days. The primary end point ofstenosis is mostly related to calcification, which often does efficacy was the incidence of ipsilateral stroke betweennot resolve with repeated dilatations [60]. The entire pro- 30 days and 1 year. These registries did not include acedure is performed with antiplatelet therapy, which in most control group.patients is achieved with a combination of acetyl salicylic Technical success was achieved in most studies in 97%acid and clopidogrel. Clopidogrel is stopped 6 weeks after of all patients. The incidence in 30-day myocardial infarc-the procedure, but acetyl salicylic acid is continued indefi- tion, stroke, and/or death varied between 2.1% and 8.3%nitely thereafter. [61– 63,65– 67]. Unfortunately, most registries did not dif- ferentiate between symptomatic and asymptomatic patientsProspective multicenter registries when analyzing results. However, the BEACH trial did and Compared with the early CAS series previously de- showed a composite end point of 7.9% in symptomaticscribed (Table 1), prospective registries with predefined patients (mortality 0.1%, stroke 7.4%, and myocardial in-inclusion and exclusion criteria, independent neurologic as- farction 1.1%) and 5.0% in asymptomatic patients (mortal-sessment, and oversight committees were designed to fur- ity 1.6%, stroke 3.4%, and myocardial infarction 0.7%).ther assess safety and United States Food and Drug Admin- Importantly, other registries showed that independent pre-istration approval of CAS with EPDs in high-risk patients dictors of stroke or death at 30 days included symptomatic(Table 2). High-risk surgical patients were defined as (eg, carotid stenosis, duration of filter deployment, and baselinethe Boston Sci EPI: A Carotid Stenting Trial for High-Risk chronic renal failure. Most registries have not yet been peerSurgical Patients [BEACH] trial) those with a surgically reviewed, but they have been presented at internationalinaccessible lesion, previous head and/or neck radiation, meetings, so results are preliminary.spinal immobility, restenosis after CEA, laryngeal palsy,tracheostoma, contralateral carotid stenosis, age 75 years,severe comorbidity, planned coronary bypass, or history of Initial randomized controlled trials comparingmajor surgery [61– 64]. The most common high-risk sur- CAS with CEAgery categories observed were anatomic criteria or previous The Leicester study was the first prospective randomizedCEA. Most registries were conducted to acquire United States singe-center trial investigating CAS versus CEA in symp-Food and Drug Administration or Conformité Européene (CE; tomatic patients [21]. The trial enrolled symptomatic low-Europe) approval. The primary safety end point was risk patients with carotid stenoses 70%. However, theusually the combined rate of myocardial infarction, study was terminated after allocation of only 17 partici-
  • 5. M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269 263Table 3Randomized trials of CAS versus CEATrial n Patients Primary end point Results (%)Leicester 17 Low-risk symptomatic 30-d stroke and/or death CAS 70 CEA 0Wallstent 219 Low-risk symptomatic 1-y stroke and/or death CAS 10.4 CEA 4.4SAPPHIRE 334 High-risk (a)symptomatic 30-d MI, stroke, and/or death (1-y stroke or death) CAS 12.2 CEA 20.1Kentucky 1 104 Low-risk symptomatic 30-d stroke and/or death CAS 1.8 CEA 1.9Kentucky 2 84 Low-risk asymptomatic 30-d stroke and/or death CAS 0 CEA 0CAVATAS 504 Low-risk (a)symptomatic 30-d stroke and/or death (3-y stroke) CAS 10.0 CEA 9.9SPACE 1,183 Low-risk symptomatic 30-d stroke and/or death CAS 6.8 CEA 6.3EVA-3S 527 Low-risk symptomatic 30-d stroke and/or death (4-y stroke) CAS 9.6 CEA 3.9CREST 2,500 Low-risk (a)symptomatic 30-d MI, stroke, and/or death (4-y stroke) Active enrollmentICSS 1,500 Low-risk symptomatic 30-d MI, stroke, and/or death (3-y stroke) Active enrollmentACT 1,540 Low-risk asymptomatic 30-d MI, stroke, and/or death (1-y stroke) Active enrollmentACST 5,000 Any risk asymptomatic 30-d MI, stroke, and/or death (1-y stroke) Active enrollment ACT Asymptomatic Carotid Stenosis Versus Endareterectomy Trial; CAS carotid artery stenting; CAVATAS Carotid and Vertebral ArteryTransluminal Angioplasty Study; CEA carotid endarterectomy; ICSS International Carotid Stenting Study; MI myocardial infarction.pants. Interim analysis showed that 70% of all patients in The run-in phase analysis from the Carotid Revascular-the CAS arm had neurologic complications. In contrast, ization Versus Stent Trial (CREST) focused on patient ageCEA was performed uneventfully (Table 3). and periprocedural risk for patients receiving CAS. Four The Carotid and Vertebral Artery Transluminal Angio- patient-age categories were created: 60 years, 60 to 69plasty Study was an international multicenter randomized years, 70 to 79 years, and 80 years. Risk of stroke or deathtrial with 504 patients, but it lacked strict inclusion and increased with age, but this was seen mainly in octogenar-exclusion criteria [27]. Major outcomes within the first 30 ians (12.1%) [24]. Risk was not mediated by adjustment fordays of treatment, defined as any disabling stroke or death, symptomatic status, use of antiembolic devices, sex, orshowed no significant difference between CAS and CEA percentage of stenosis. Notably, patients 80 years were(10.0% vs 9.9%). Noteworthy, only 26% of patients treated not excluded from actual randomization within CREST.endovascularly received a stent. At 1-year ultrasound fol- Carotid artery stenosis is relatively frequent in older pa-low-up, severe restenoses (70% to 90%) occurred signifi- tients. Large population-based studies indicated that thecantly more in the endovascular-treated group (CAS 14% vs prevalence of carotid stenosis increases to 10% in personsCEA 4%). The incidence of recurrent ipsilateral stroke ap- 80 years old [69]. In a subgroup analysis of NASCET, thepeared to be higher in the first year in cases of stenoses benefits of CEA in patients 75 years with symptomaticoccurring after CAS compared with stenoses occurring after carotid stenosis was compared with the benefit seen inCEA. However, survival analysis at 3-year follow-up younger patients [70]. Among medically treated patients,showed no difference in the occurrence of ipsilateral stroke the highest risk of stroke at 2 years was in patients 75(14.2%) between both groups [27,68]. The investigators years (36.5%). The perioperative rate of stroke and/or deathconcluded that there was a similar major risk and effective- was not higher in patients 75 years (5.2%) compared withness with endovascular treatment of ICA stenosis compared patients 65 years (7.9%). The absolute risk reduction bywith CEA, but minor complications were avoided with CEA in patients 75 years was 28.9% (number needed toendovascular treatment. Notably, the wide 95% confidence treat 3% of patients). The ECST data also indicate thatintervals in this study for stroke rate make interpretation of increasing age is associated with greater benefit from CEAthe data even harder. Results were certainly not up to the in patients with symptomatic carotid stenosis [71]. Further-standard advocated by the American Heart Association. more, Miller et al [72] showed, in a prospective analysis of The Kentucky randomized trials comparing CAS with 300 CEAs performed in patients 80 years, that periop-CEA were published in 2001 and 2004. The first publication erative risk is increased, but outcomes remain within ac-focused on symptomatic patients; the latter focused on ceptable guidelines [72].asymptomatic patients. Both studies reported low compli- In the Stenting and Angioplasty With Protection in Pa-cation rates for either treatment and challenged the “gold tients at High Risk for Endarterectomy (SAPPHIRE) trial,standard” of CEA [22,23]. However, the small number of the hypothesis was that CAS was not inferior to CEA inpatients in each group makes the extraordinarily low risk high-risk patients [29]. Both surgeons and interventionalrate difficult to interpret. Afterward, interest shifted to those cardiologists had to meet certain procedural criteria to par-patients who might benefit most from CAS. ticipate. Surgeons were required to have performed an av-
  • 6. 264 M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269erage of 30 CEAs/y, with low corresponding major com- Recent publicationsplication (eg, death, stroke, and/or myocardial infarction) Recently, results of 2 independent randomized noninfe-rates of 1%. The interventionalists were required to have riority controlled trials, the Stent-Protected Angioplastyperformed an average of 64 interventions/y, with low cor- versus Carotid Endarterectomy (SPACE) trial and the End-responding complication (eg, stroke, TIA) rates of 2%. A arterectomy Versus Stenting in Patients with Symptomatictotal of 723 symptomatic (stenosis 50%) or asymptomatic Severe Carotid Stenosis (EVA-3S) trial, were published(stenosis 80%) patients–normally deemed high risk for (Table 3). The SPACE trial included 1,183 symptomaticsurgery because of concomitant morbidity, such as cardio- patients with a 70% stenosis of the ICA [25]. Patientspulmonary disease or previous surgery–were considered were randomly allocated to either CAS or CEA. The tech-suitable for entry to either the endovascular- or surgical- nique used by the interventional physician (ie, type of stent,treatment arms. Consensus agreement by a multidisciplin- whether or not to use a protection device) was not restrictedary team of neurologists, surgeons, and interventionalists by protocol. Primary outcome was ipsilateral stroke, withwas required for a patient’s enrollment into the randomized symptoms lasting 24 hours or death between randomisa- tion and 30 days after treatment. The complication rate at 30arm of study. EPDs were used in the endovascular-treated days was 6.8% for CAS versus 6.3% for CEA. The nonin-group. The primary end point was the cumulative incidence feriority test was not significant (P .09). In this study, theof major cardiovascular events at 30 days and at 1 year after investigators concluded that CEA remains the preferredintervention. The study was stopped prematurely because of treatment for patients with symptomatic ICA stenosis be-slow enrollment: Most patients initially included were fi- cause evidence is lacking for equivalent or superior endo-nally excluded because perioperative risk with CEA was vascular treatment.deemed too high (n 409). Finally, 317 patients were The EVA-3S trial included 527 symptomatic patientsrandomized to CEA or CAS. Among patients in the ran- with an ICA stenosis of 60% to 90% according to NASCETdomized study, a significantly higher number of patients in guidelines [26]. The primary end point was any stroke orthe stenting arm had undergone previous coronary artery death within 30 days after intervention. The systematic usebypass (CAS 43% vs CEA 31%, P 0.05) and also had of a CPD was instituted during the trial on instigation of thehigher history of cardiovascular disease (CAS 85% vs CEA safety committee. Analysis showed a significant higher risk74%, P .05). for death or any stroke at 30 days for endovascular treat- The 30-day myocardial infarction, stroke, and death rate ment (9.6%) compared with CEA (3.9%), with a relativewas 4.8% in the CAS arm versus 9.8% in the CEA arm, thus risk of 2.5% and an absolute risk of 5.7%. Although morefavoring endovascular treatment (P .09) [29]. Results at minor and systemic complications occurred after CEA, this1 year (eg, myocardial infarction, ipsilateral stroke, and/or did not reach significance, except for patients with cranialdeath) were also in favor of endovascular treatment: 12.2% nerve injury. Noteworthy, the trial was ended prematurelyversus 20.1% for patients treated by surgery (P .048). for safety reasons. Inclusion stopped after enrollment of 527The 3-year incidence of stroke was similar between both patients, although power analysis indicated that 872 patientsarms (7%). were needed to reach a statistical power of 80%. Because Importantly, differences in this trial between CAS and the study was ended prematurely, the inferiority questionCEA treatment at the composite 1-year end point were still remains. Nevertheless, the results of CAS in therelated to a greater association of CEA with myocardial EVA-3s study differed from those in the SAPPHIRE trial.infarction. Without the inclusion of myocardial infarction, Reasons are probably multifactorial and may have been theno statistical differences in rates of stroke and/or death inclusion of more symptomatic patients in the EVA-3sbetween both groups would have been noted (CAS 5.5% vs study, the use of a protection device and antiplatelet ther-CEA 8.4%, P .4). The majority of myocardial infarctions apy, the EVA-3s study patients not being at high risk ofwere non–Q-wave events identified by routine postproce- developing coronary artery disease, and varying levels ofdural laboratory studies. experience in performing CAS. Furthermore, a systematic review showed that the 30-day rate of death or stroke after The majority of patients in the SAPPHIRE trial were CAS was 5.8% among patients treated without EPD com-asymptomatic. In the CAS arm, only 30% of patients were pared with 1.8% among those treated with EPD [58]. Earlysymptomatic; in the CEA arm, only 28% were symptomatic. in the EVA-3S trial, EPDs were not used, and the incidenceThe primary end point did not differ in these symptomatic of stroke was 25%. The study was even briefly stoppedpatients. In asymptomatic patients there was a difference and later on restarted with the incorporation of routine useafter one year in favor for those treated with CAS. of cerebral-protection devices. Nevertheless, the incidence A Cochrane review published in 2005 showed only 5 of stroke remained higher compared with CEA. Furtherrandomized controlled trials comparing CAS with CEA evidence must be awaited from a meta-analysis, which has[28]. The combined primary outcomes, defined as any been planned from the combined results after completion ofstroke or death within 30 days of intervention, did not differ the SPACE and EVA-3S trials and the still-ongoing Inter-between treatment arms. The meta-analysis was limited by national Carotid Stenting Study [73].the premature ending of 3 trials because of inconsistent useof stents and EPDs and heterogeneity of groups with regardto symptomatic status and surgical risk. Because of these The High-Risk Patientlimitations, this review concluded that CEA remained the Some conclude that CAS may be an excellent procedure“gold standard” of treatment. for high-risk patients who are not fit for surgery. Is CEA per
  • 7. M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –269 265se harmful in high-risk patients? It seems that when patients vincingly proven that CEA significantly decreases the riskmeet NASCET or ACAS exclusion criteria, they are marked of subsequent stroke in patients with severe carotid stenosis.as “high-risk.” However, complication rates in these high- Currently, surgery remains the “golden standard” of treat-risk patients are not per se increased when performing CEA. ment, but CAS has progressed in recent years and chal-Mozes [74] and Mozes et al [75] analyzed their CEA results lenged CEA. Despite many trials, only a few methodolog-by stratifying according to SAPPHIRE criteria for high-risk ically correct randomized trials compared CAS with CEA,patients [74,75]. Such criteria included positive stress test, and they failed to establish consensus. Using predefinedage 80 years, contralateral carotid occlusion, and repeated margins of noninferiority, recent trials–such as the SPACECEA. There were no statistical differences in either stroke and EVA-3S trials–indicated that CAS is not as good asor death rate between low- and high-risk patients. The CEA. Proponents of CAS responded by focusing on theinvestigators showed that CEA can be performed in such “interventionists’ experience and CAS methods” in bothhigh-risk patients with acceptable standard complication trials. Consequently, many have been left questioning therates. Ballotta et al [76] and Nguyen et al [77] showed that future of CAS compared with CEA.high-risk patients are more common than previously It is important to realize that most randomized trialsthought. Their perioperative neurologic and cardiac out- comparing CEA with CAS did not succeed in achievingcomes are comparable with those reported in other pa- recruitment as determined before the study. The Leicester,tients [76,77]. The idea that operative risk is higher in WALLSTENT, SPACE, and EVA-3S trials specified thatpatients excluded from NASCET or ACAS has not been the total intended number of patients should be 3,772. How-not supported. Definite accepted criteria to identify high- ever, only a total of 1,989 patients (52%) were randomizedrisk patients have not yet been developed. A study from as a result of early trial completion because of excess in riskthe Cleveland Clinic attempted by retrospective analysis in the CAS arm. The expanded use of CAS outside orga-to identify a subgroup of patients who were at increased nized randomized clinical trials further threatens studies ofrisk for CEA. From a prospective database covering a alternatives to CEA.10-year period, 3,061 patients with histories of CEA were Failure to achieve a study or meta-analysis with adequateexamined. High-risk patients were identified on the basis size will not produce convincing evidence of the value ofof presence of coronary artery disease, congestive heart CAS in stroke prevention. An important reason thatfailure, severe chronic obstructive disease, or renal fail- NASCET, ECST, ACST, and ACAS influenced clinicalure. The composite risk for stroke, death, and myocardial practice and proved the importance of CEA is that theyinfarction was 7.4% in high-risk patients compared with included large numbers of patients. It is therefore important3.8% in others. Perhaps such patients would benefit from to limit the use of CAS to randomized trials to ensurealternatives to CEA. statistical power to produce a consensus in best evidence- The above-mentioned risk factors, (ie, degree of stenosis, based therapy in patients with severe carotid stenosis.neurologic symptoms, etc) do not sufficiently identify the The technical expertise required from interventionistsreal risk presented by the patient. In contrast, plaque mor- participating in trials comparing CAS with CEA may in partphology may identify patients at risk for stroke during explain the excessive risk of CAS procedures. The require-intervention [78 – 82]. The risk of rupture is strongly related ments stipulated for interventionists in the EVA-3S trialto plaque composition and degree of carotid stenosis were having performed 12 previous CAS or 35 previous[80,83,84]. Gray-scale measurements (GSM) of intima– supra-aortic stenting procedures, and interventionists whomedia thickness using ultrasound have been studied to an- had not met these requirements still were allowed to partic-alyze vulnerable plaques. GSM is an overall measure of ipate in the study when their CAS procedures were super-plaque echogenicity in which low-GSM plaques generate vised. Furthermore, CEA has evolved during the last 30more embolic particles [85]. The Imaging in Carotid An- years and has been widely used by experienced vasculargioplasty and Risk of Stroke study showed that the onset of surgeons. In contrast, CAS is still in development and mayneurologic deficits during and after intervention signifi- not so easily be generalized. It is important to realize thatcantly increased in patients with low GSM values [86]. A the EVA-3S trial demonstrated what happens if CAS islow GSM is not a contraindication to CAS but rather a widely implemented by showing the results achieved whenpredictor of increased stroke risk. Low GSM values are CAS is performed outside of the “top” CAS units. Again,further related to future coronary events, higher rate of this calls for exclusive performance of CAS procedures inrestenosis, positive brain computed axial tomography for controlled clinical trials using standards of practice andischemic lesions, and rapid plaque progression [87–91]. expert technical skills.Other modalities, such as high-resolution magnetic reso- Some have concluded that CAS may be an excellentnance imaging, have also been tested as measures of plaque procedure for high-risk patients who are not fit for surgery.composition [92–97]. These imaging techniques may be- However, both CAS and CEA are being compared with thecome important in the planning of future clinical trials and BMT of more than a decade ago. Notably, the cumulativeBMT modalities. complication risk in SAPPHIRE is striking: 17% after 3 years for both CAS and CEA. As pointed out by others, perhaps such high-risk patients are better off without stent-Comments ing or endarterectomy [77]. Medical treatment has evolved The longevity of CEA predominantly has been deter- with modern angiotensin-converting enzymes inhibitors,mined by comparison among large-scale randomized trials. other antihypertensive drugs, statin medications, and newerRandomized trials comparing CEA with BMT have con- antiplatelet therapies [98 –102]. In the NASCET trial, only
  • 8. 266 M.G. van der Vaart et al. / The American Journal of Surgery 195 (2008) 259 –26950% of patients with increased lipid levels received lipid- provides better stroke prevention compared with CEA.lowering medication. A recent meta-analysis analyzing the Therefore, CEA still remains the “gold standard” of treat-relationship between statins and the risk of stroke showed a ment. Furthermore, evolving BMT, timely intervention, andrelative stroke reduction rate 21% [103]. The anti-inflam- analysis of plaque composition may have an important in-matory effects of statins seem as important as their lipid- fluence on the future treatment of patients with carotidlowering effects [104,105]. For antithrombotic therapy, artery stenosis.most patients in the NASCET and ACAS trials were takingaspirin only. In a large study, clopidogrel was comparedwith aspirin, and clopidogrel conferred an 8.7% risk reduc- References [1] Moore WS, Barnett HJ, Beebe HG, et al. 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