Carotid endarterectomy (CEA) is the gold standard for

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1 Carotid Artery Stenting Versus Carotid Endarterectomy A Comprehensive Meta-Analysis of Short-Term and Long-Term Outcomes Konstantinos P. Economopoulos, MD; Theodoros N. Sergentanis, MS; Georgios Tsivgoulis, MD; Anargiros D. Mariolis, MD, PhD; Christodoulos Stefanadis, MD, PhD Background and Purpose The comparison between carotid endarterectomy and carotid artery stenting (CAS) remains a debated field, especially in the context of long-term outcomes. Methods Concerning the short-term (30-day) analysis, the numbers of outcomes per arm were abstracted, whereas outcomes per arm and hazard ratios were abstracted for long-term ( 1-year) results. Results Thirteen randomized trials (3723 carotid endarterectomy and 3754 CAS patients) were eligible. Regarding short-term outcomes, CAS was associated with elevated risk for stroke and death or stroke. CAS also exhibited a marginal trend toward higher death and death or disabling stroke rates. Carotid endarterectomy presented with higher rates of myocardial infarction and cranial nerve injury. Concerning long-term outcomes, CAS was associated with higher rates of stroke (pooled OR, 1.37; 95 CI, 1.13 to 1.65) and death or stroke (pooled OR, 1.25; 95 CI, 1.06 to 1.48). These findings were replicated at the level of pooled hazard ratios and marginally regarding secondary preventive efficacy. The difference in long-term stroke rates was particularly sizeable in patients 68 years, but little difference in rates was observed in those 68 years. No statistically significant heterogeneity became evident. Metaregression did not reveal any significant modifying effect mediated by symptomatic/asymptomatic status, distal protection, early termination of trials, area of study origin, or CAS learning curve. Conclusions This meta-analysis points to the significantly less frequent stroke events after carotid endarterectomy at the long-term context. The outcomes of carotid endarterectomy seem superior to CAS, but there may be subgroups, particularly younger patients, in whom the results seem equivalent. (Stroke. 2011;42: ) Key Words: carotid endarterectomy carotid stenosis meta-analysis stenting Carotid endarterectomy (CEA) is the gold standard for treating severe carotid artery stenosis; carotid artery stenting (CAS) represents a therapeutic option for patients in whom CEA is contraindicated. 1 This timely topic has drawn attention at the meta-analytic level; several publication-based meta-analyses have appeared in the literature. A recent meta-analysis by Meier et al has examined short-term (periprocedural, 30-day outcomes) and intermediate-term (long-term) discrepancies between CEA and CAS. 2 At the short-term, Meier et al 2 pointed to lower periprocedural risk of death or stroke for CEA mainly due to a borderline decrease in the risk of stroke but not death; on the other hand, CEA was accompanied by a higher risk of periprocedural myocardial infarction and cranial nerve injury. Importantly, no long-term differences were demonstrated in the meta-analysis by Meier et al 2 concerning the outcome of stroke or death. After the recent meta-analysis by Meier et al, 2 the appearance of the results by the Carotid Revascularization Endarterectomy versus Stent Trial (CREST) 3 has marked a turning point in the continuum of studies examining CEA versus CAS because the inclusion of 2502 patients has shed light on both short-term and long-term outcomes. In addition, the publication of long-term results by Carotid and Vertebral Artery Transluminal Angioplasty (CAVATAS) 4 and Stent-supported Percutaneous Angioplasty of the Carotid artery versus Endarterectomy (SPACE) 5 studies has created a new context concerning long-term effects. In view of the former considerations, this meta-analysis aims to provide a comprehensive approach to short-term and long-term comparison between CEA and CAS synthesizing all available data coming from published randomized studies. Methods Trial Identification This meta-analysis has adopted the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for Received October 17, 2010; accepted October 22, From the School of Medicine (K.P.E., T.N.S.), University of Athens, Athens, Greece; the Department of Neurology (G.T.), Democritus University of Thrace, School of Medicine, Alexandroupolis, Greece; the Comprehensive Stroke Center (G.T.), Department of Neurology, University of Alabama at Birmingham Hospital, Birmingham, AL; and the First Department of Cardiology (A.D.M., C.S.), School of Medicine, University of Athens, Hippokration Hospital, Athens, Greece. The online-only Data Supplement is available at Correspondence to Konstantinos P. Economopoulos, MD, Fellow Researcher, School of Medicine, University of Athens, 5 Menalou, Maroussi, Athens, Greece. economopoulos@sni.gr 2011 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 688 Stroke March 2011 Table. Pooled ORs and HRs (CAS vs CEA) for the Short-Term and Long-Term Outcomes* Short-Term Long-Term (Analysis on ORs) Long-Term (Analysis on HRs) Outcomes No. of Studies ORs (95 CI) P Derived From the Z Test Test for Heterogeneity Publication Bias No. of Studies ORs (95 CI) P Derived From the Z Test Test for Heterogeneity Publication Bias No. of Studies HRs (95 CI) P Derived From the Z Test Test for Heterogeneity Death ( ) ( ) ( ) Stroke ( ) ( ) ( ) Myocardial infarction ( ) Death or stroke Death or disabling stroke Death or stroke or myocardial infarction Cranial nerve injury ( ) ( ) ( ) ( ) NC ( ) NC ( )* ( ) *All pooled ORs were derived from fixed-effects models except for cells marked with a dagger (random-effects model). NC indicates not calculated ( 9 studies). systematic reviews and meta-analyses. 6 Details of the search strategy are provided in the Supplemental Methods (Methods I, available at Data Abstraction The following data were collected: journal name, year of publication, country, single center/multicenter status, early termination of the trial, source of funding, reporting of short-term (30-days) or longterm ( 1-year) data, definitions adopted, inclusion criteria, duration of follow-up, number of patients, proportion of patients being asymptomatic, having hypertension, diabetes, hyperlipidemia/dyslipidemia, cardiovascular disease, distal protection rate, type of stent, antiplatelet therapy, surgical technique, and the number of outcome events per arm. Short-term outcomes were the following: death, stroke, myocardial infarction, death or stroke, death or ipsilateral stroke, death or disabling stroke, death or stroke or myocardial infarction, and cranial nerve injury. Data (number of patients and, where available, hazard ratio [HR]) were abstracted for the following long-term outcomes: death, stroke, myocardial infarction, death or stroke, death or ipsilateral stroke, death or disabling stroke, death or stroke, or myocardial infarction. Statistical Analysis Statistical analysis comprised calculation of pooled ORs and HRs, evaluation of between-study heterogeneity and publication bias, metaregression, and sensitivity analysis. Details of statistical analysis are provided in the Supplemental Methods (Methods II). Results Among the 1206 articles in MEDLINE that were retrieved, the relevant conference abstracts, 13 randomized trials (whose results are presented in 20 abstracts/articles) were eligible 3 5,7 23 ; this corresponds to 3723 CEA and 3754 CAS patients. Characteristics of eligible trials are provided in Supplemental Table III. The definitions adopted and the outcomes examined are presented in Supplemental Tables IV and V. The number of events and patients is provided in Supplemental Table VI. Pooled ORs and HRs for all outcomes are provided in the Table. Concerning short-term outcomes, CAS was associated with elevated risk for stroke and death or stroke. CAS also exhibited a trend of borderline significance toward higher death and death or disabling stroke rates. On the other hand, CEA presented with higher rates of myocardial infarction and cranial nerve injury. Figure 1 depicts the relevant forest plots. Regarding long-term outcomes, CAS was associated with higher rates of stroke and death or stroke. These findings were replicated at the level of pooled HRs. No significant associations implicated death or the combined outcome of death or disabling stroke. Figure 2 depicts the respective forest plots. A post hoc analysis focusing especially on the postprocedural phase (ie, later than 30 days after the intervention) replicated the long-term result on the incidence of stroke (pooled OR, 1.27; 95 CI, 0.98 to 1.64, fixed effects) at a borderline level (P 0.067). Metaregression did not reveal any significant modifying associations; details are provided in Supplemental Table VII. Nevertheless, the more elaborate analysis adopting a cutoff level of 68 years 4,14 (or 70 years 5 ) revealed that the difference in long-term stroke events was particularly sizeable for patients 68 years (pooled HR, 1.71; 95 CI, 1.19 to 2.45; P 0.004, fixed effects), whereas no significant difference was noted for patients 68 years (Figure 3). The exploratory metaregression analysis did not reveal any significant modifying effect by cardiovascular disease, diabetes, hypertension, or hyperlipidemia/dyslipidemia (data not shown). Significant publication bias was demonstrated only regarding short-term death (P 0.03). The visual inspection of the funnel plot (Supplemental Figure VIII) revealed potentially unpublished small studies favoring CEA in terms of periprocedural mortality (asymmetry at the upper right quadrant). Given that the definition concerning the long-term outcome death or stroke in SPACE 5 and CREST 3 studies was limited to postprocedural ipsilateral strokes, a sensitivity analysis was performed excluding these 2 sizeable studies. Despite the lower statistical power, the result shifted to the

3 Economopoulos et al CAS vs CEA: Meta-Analysis of Long-Term Outcomes 689 A Odds ratio (95 CI) B Odds ratio (95 CI) LEICESTER (1998) (1.01, ) 0.96 (0.02, 49.43) 0.68 (0.11, 4.15) 0.30 (0.01, 8.33) 2.80 (1.28, 6.14) 1.21 (0.36, 4.04) 1.17 (0.74, 1.83) 0.85 (0.44, 1.64) 1.94 (1.27, 2.96) 1.79 (1.13, 2.85) LEICESTER (1998) WALLSTENT (2001) (1.01, ) 2.96 (1.02, 8.61) 0.60 (0.14, 2.60) 0.30 (0.01, 8.33) 2.63 (1.23, 5.58) 0.87 (0.31, 2.45) 1.13 (0.72, 1.76) 1.01 (0.56, 1.81) 1.88 (1.26, 2.81) 1.90 (1.21, 3.00) Overall (I squared = 24.1, p = 0.214) 1.53 (1.23, 1.91), p<0.001 Overall (I squared = 33.5, p = 0.122) 1.54 (1.25, 1.89), p< C Odds ratio (95 CI) D Odds ratio (95 CI) LEICESTER (1998) 1.09 (0.02, 59.40) 0.10 (0.01, 1.88) 0.13 (0.01, 2.59) (0.05, 5.69) (0.01, 8.40) (0.02, 55.27) (0.02, 55.27) (0.04, 5.46) (0.04, 0.47) (0.12, 1.25) (0.00, 0.98) (0.01, 2.77) 2.68 Steinbauer et al (2008) 0.33 (0.01, 8.41) (0.17, 3.37) 0.49 (0.25, 0.93) (0.00, 0.34) 0.02 (0.00, 0.15) 0.06 (0.02, 0.18) Overall (I squared = 0.0, p = 0.994) 0.48 (0.29, 0.78), p=0.003 Overall (I squared = 0.0, p = 0.599) 0.09 (0.05, 0.16), p< borderline level of significance (pooled OR, 1.22; 95 CI, 0.98 to 1.52; P 0.08). Discussion This meta-analysis points to the significantly less frequent stroke events after CEA at the long-term context; importantly, this has been confirmed both at the level of ORs and HRs, pointing to the validity of the underlying association. The sizeable difference at the level of stroke events has resulted in a similar significant result concerning the combined outcome death or stroke. Noticeably, the difference in the incidence of stroke was marginally replicated at the analysis focusing especially on the postprocedural phase (later than 30 days after the intervention), pointing to the secondary preventive efficacy of CEA. No long-term differences became evident regarding the isolated outcome of mortality. Concerning short-term outcomes, the present meta-analysis confirms and essentially expands at a formally statistically significant level the conclusions reached by Meier et al about stroke. 2 Specifically, the rate of periprocedural stroke and consequently the combined outcome death or stroke were in favor of CEA, whereas the numerically favorable for CEA OR concerning death was only of borderline significance. Consequently, an impressive analogy between short-term and long-term results emerged: CEA seemed to exhibit lower rates of stroke and death or stroke in both timeframes. Indeed, the majority of individual studies, despite their large sample size, seemed deprived of adequate power for the Figure 1. Forest plot of short-term ORs for (A) stroke, (B) death or stroke, (C) myocardial infarction, and (D) cranial nerve injury. documentation of such a long-term finding; the meta-analytic approach, however, was capable of reaching this composite conclusion. The present meta-analysis confirms the increased risk for periprocedural cranial nerve injuries and myocardial infarction after CEA. Rather expectedly, the outcome death or stroke or myocardial infarction pointed to a null association at the short-term analysis, because its constituents pointed to opposite directions. Noticeably, the larger newly published studies (CREST, CAVATAS, SPACE, Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis [EVA-3S]) 3 5,8,13,14,17,18 did not provide a cardiological follow-up capable of monitoring myocardial infarction as time progressed. A notion that has been extensively discussed is the existence and importance of a learning curve in CAS. It has been postulated that inherent difficulties of CAS placement may have created unfavorable events in CAS arms. 2,7,13,24,25 As reflected on the most recent trials, the complication rates of CAS seem to continuously decline; it is tempting to envisage a parallel trend concerning the hazards of CEA so that the ORs do not change very much along with publication year. Nevertheless, metaregression pointed to trials showing a benefit from CAS during the earlier publication years, although this trend did not reach formal significance. This meta-analysis extrapolated the short-term findings of the recent individual patient data meta-analysis by the Carotid Stenting Trialists Collaboration 26 on long-term stroke

4 690 Stroke March 2011 A Odds ratio (95 CI) B Odds ratio (95 CI) (0.01, 8.33) 1.96 (1.11, 3.48) 1.00 (0.47, 2.12) 1.10 (0.75, 1.60) WALLSTENT (2001) 3.73 (1.18, 11.84) 0.44 (0.03, 5.88) 1.41 (0.94, 2.11) 0.97 (0.59, 1.59) 1.11 (0.75, 1.63) Steinbauer et al (2008) (0.53, ) 0.40 Steinbauer et al (2008) 1.03 (0.41, 2.59) (1.02, 2.37) (0.82, 1.68) (1.04, 1.92) (1.04, 2.17) Overall (I squared = 0.0, p = 0.508) 1.37 (1.13, 1.65), p=0.001 Overall (I squared = 0.0, p = 0.554) 1.25 (1.05, 1.48), p= favors CAS favors CEA favors CAS favors CEA C D ratio (95 CI) ratio (95 CI) 1.39 (0.96, 2.01) (0.56, 1.32) (0.77, 1.57) (0.77, 1.60) (1.04, 1.89) (0.55, 2.12) 7.27 Overall (I squared = 3.3, p = 0.309) 1.27 (1.01, 1.59), p= (1.05, 2.15) Overall (I squared = 14.7, p = 0.321) 1.21 (1.01, 1.45), p= events. Our meta-analysis suggested that the difference in long-term stroke events was particularly sizeable in patients 68 years, whereas no significant difference was observed in those 68 years. This represents an important finding because, despite the superiority of CEA, there may be certain subgroups, for instance, younger patients, in whom the results seem equivalent. Nevertheless, longer follow-up from numerous studies would be desirable to establish the meaningfulness of age as a long-term effect modifier, because metaregression with mean age of patients did not yield a significant result. Null findings of the metaregression analyses, which are worth commenting on, pertain to distal protection, early Figure 2. Forest plot of long-term outcomes: (A) stroke (OR), (B) death or stroke (OR), (C) stroke (HR), and (D) death or stroke (HR). A ratio (95 CI) termination of trials, area of study origin, commercial sponsor, and symptomatic/asymptomatic status of patients. Asymptomatic patients may well exhibit distinct rates of events 2 ; however, discrepancies between CEA and CAS seem not to be modified by asymptomatic status. Accordingly, the null finding regarding distal protection is in line with the results of the International Carotid Stenting -MRI (ICSS-MRI) substudy, which concluded that protection devices did not seem effective in preventing cerebral ischemia during CAS. 27 Our analysis seems rather to portray early termination as a simple cause of low statistical power than as a factor creating systematic deviation from the nonterminated trials. Potentially meaningful risk factors for surgery (such as B ratio (95 CI) 1.06 (0.42, 2.64) (1.36, 7.79) (0.28, 1.04) (0.96, 3.39) (0.61, 1.82) (0.79, 2.20) Overall (I squared = 24.3, p = 0.267) 0.84 (0.57, 1.23), p=0.359 Overall (I squared = 35.7, p = 0.211) 1.71 (1.19, 2.45), p= Figure 3. Forest plots depicting HRs concerning long-term stroke for patients (A) 68 years old and (B) 68 years old.

5 Economopoulos et al CAS vs CEA: Meta-Analysis of Long-Term Outcomes 691 cardiovascular disease, diabetes, hypertension, hyperlipidemia/dyslipidemia) did not seem able to interfere with the generalizability of the results. Despite the clinically expected heterogeneity between existing studies in terms of adopted outcome definitions, expertise of specialists and centers, concomitant antiplatelet drug treatment, type of stent, and/or distal protection devices used in CAS, formal statistical tests did not point to substantial heterogeneity with the exception of the outcome death or stroke or myocardial infarction. This may imply that the aforementioned factors could not distort the underlying differences between CAS and CEA. The lack of publication bias also points to the validity of the present results. A sole exception of publication bias emerged, indicating potentially unpublished small studies, which might have favored CEA in terms of periprocedural mortality. Certain limitations of this meta-analysis should be acknowledged. Our approach was based on data abstracted from publications and not on individual patient data; thus, our results should be viewed as hypothesis-generating and not as definitive evidence. Moreover, the fact that each trial reported its own set of outcomes may have led to limited statistical power. Heterogeneity in definitions of outcomes may represent a potential limitation; however, the sensitivity analysis has not pointed to major differentiation of results. Moreover, the lack of universal reporting concerning the expertise and specialty of operators among trials may have interfered with the results of individual studies given that in the CREST lead-in phase, the periprocedural death or stroke or myocardial infarction rate ranged from 1.6 to 7.7 depending on the operator s specialty 28 ; however, the effect of this phenomenon should not be overestimated given that no substantial heterogeneity was detected. It should be also declared that some studies exhibited particularities; for instance, in CAVATAS, only a minority of 26 had been treated with stents and the remaining with percutaneous transluminal angioplasty. 21 As expected, this meta-analysis could not assess issues that have not been thoroughly examined by the individual studies; for instance, timing of endarterectomy after stroke may interfere with the risk for adverse events, 29 but only 4 studies provided relevant data. 7,8,14,22 Accordingly, this meta-analysis could not shed light into restenosis and its possible interference with long-term prognosis. Conclusions The present meta-analysis may improve the current understanding of the fine balance describing the CEA versus CAS comparison. On the one hand, an impressive analogy between short-term and long-term results emerged: CEA seemed to exhibit lower rates of stroke and death or stroke in both timeframes. On the other hand, the association between CEA and increased risk for periprocedural cranial nerve injuries as well as myocardial infarction was confirmed. In addition, the present analysis lends support to the recent mounting evidence indicating that CAS is associated with a substantially higher risk of short-term and long-term stroke in patients aged 70 years compared with CEA. CAS represents a therapeutic option that necessitates careful selection of patients. Taken as a whole, the outcomes of CEA seem superior to CAS, but there may be subgroups, particularly younger patients, in whom the results seem equivalent. None. Disclosures References 1. Mitka M. findings offer conflicting views on future role of carotid artery stenting. JAMA. 2010;303: Meier P, Knapp G, Tamhane U, Chaturvedi S, Gurm HS. Short term and intermediate term comparison of endarterectomy versus stenting for carotid artery stenosis: systematic review and meta-analysis of randomised controlled clinical trials. 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