ORIGINAL CONTRIBUTION. Carotid Artery Stenting vs Carotid Endarterectomy

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1 ONLINE FIRST ORIGINAL CONTRIBUTION Carotid Artery Stenting vs Carotid Endarterectomy Meta-analysis and Diversity-Adjusted Trial Sequential Analysis of Randomized Trials Sripal Bangalore, MD, MHA; Sunil Kumar, MD; Jørn Wetterslev, MD, PhD; Anthony A. Bavry, MD, MPH; Christian Gluud, MD, DMSci; Donald E. Cutlip, MD; Deepak L. Bhatt, MD, MPH Background: The role of carotid artery stenting (CAS) when compared with carotid endarterectomy (CEA) is controversial, with recent trials showing an increased risk of harm with CAS. Objective: To evaluate the periprocedural and intermediate to long-term benefits and harms of CAS compared with CEA. Data Sources and Study Selection: PubMed, EMBASE, and Cochrane Central Register of Controlled Trials searches for randomized clinical trials until June of CAS compared with CEA for carotid artery disease. Periprocedural ( -day) outcomes (death, myocardial infarction [MI], or stroke; death or any stroke; any stroke; and MI) and intermediate to long-term outcomes (outcomes as in the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy [SAPPHIRE] trial: composite of periprocedural death, MI, or stroke plus ipsilateral stroke or death thereafter; periprocedural death or stroke plus ipsilateral stroke thereafter; death or any stroke; and any stroke) were evaluated. Data Extraction: Two of us independently extracted data in duplicate. Baseline characteristics, inclusion and exclusion criteria, use of an embolic protection device, US vs non-us study, and the earlier-mentioned outcomes of interest were extracted from each trial. Data Synthesis: We identified randomized clinical trials randomizing participants. Carotid artery stenting was associated with an increased risk of periprocedural outcomes of death, MI, or stroke (odds ratio=.; 9% confidence interval, -.9), % and % increases in death or stroke and any stroke, respectively, but with % and % reductions in the risk of MI and cranial nerve injury, respectively, when compared with CEA. The trial sequential monitoring was crossed by the cumulative z curve, suggesting firm evidence for at least a % relative risk increase of periprocedural death or stroke and any stroke and at least a % reduction in MI with CAS compared with CEA. Similarly, CAS was associated with 9%, %, %, and % increases in the intermediate to long-term outcomes of SAPPHIRE-like outcome, periprocedural death or stroke and ipsilateral stroke thereafter, death or any stroke, and any stroke, respectively. The trial sequential monitoring was crossed by the cumulative z curve, suggesting firm evidence for at least a % relative risk increase of any stroke. Conclusions: In this largest and most comprehensive meta-analysis to date using outcomes that are standard in contemporary studies, CAS was associated with an increased risk of both periprocedural and intermediate to long-term outcomes, but with a reduction in periprocedural MI and cranial nerve injury. Strategies are urgently needed to identify who are best served by CAS vs CEA. Arch Neurol. ;():-. Published online October,. doi:./archneurol.. Author Affiliations are listed at the end of this article. CME available online at and questions on page CAROTID ARTERY STENTING (CAS) has emerged as an alternative to carotid endarterectomy (CEA) for the treatment of carotid artery occlusive disease and is endorsed by the American Heart Association/ American Stroke Association guidelines as a reasonable strategy when performed by operators with established periprocedural morbidity and mortality of % to % (class IIa). The European Society of Vascular Surgery recommends CAS instead of CEA in participants at high risk for cardiovascular disease if it is conducted in high-volume centers with documented low perioperative stroke and death rates. For editorial comment See also page However, the safety and efficacy of CAS are controversial. The most recent Cochrane review (9) on this topic found that CAS conferred significant reduc-

2 tions not only in cranial nerve injury but also in myocardial infarction (MI) (periprocedural); however, CAS was associated with a significant increase in -day death or stroke, which was no longer significant in a randomeffects model. In the recently concluded International Carotid Stenting Study (ICSS), CEA was superior to CAS at days following the procedure. These studies mainly evaluated periprocedural outcomes where the data are controversial. There are limited data on the intermediate to long-term outcomes of these revascularization strategies. Moreover, the results of the Carotid Revascularization Endarterectomy vs Stenting Trial showed equivalent long-term risks of the procedures. The objective of our analysis was to evaluate the periprocedural ( -day) and intermediate to long-term outcomes of CAS vs CEA in participants with carotid artery disease. METHODS ELIGIBILITY CRITERIA We conducted PubMed, EMBASE, and Cochrane Central Register of Controlled Trials searches using the terms carotid artery disease, endarterectomy, and carotid artery stenting in humans until June. We checked the reference lists of review articles, meta-analyses, and original studies identified by the electronic searches to find other eligible trials. There was no language restriction for the search. Authors of publications were contacted when results were unclear or when relevant data were not reported. Eligible trials had to fulfill the following criteria to be included in this analysis: () randomized clinical trials (RCTs) of participants with or without symptomatic carotid artery stenosis comparing CAS with CEA, with or without an embolic protection device (EPD); and () reporting -day or longerterm outcomes. SELECTION AND QUALITY ASSESSMENT Two of us (S.B. and S.K.) independently assessed trial eligibility and trial bias risk and extracted data. Disagreements were resolved by consensus. The bias risks of trials were assessed using the components recommended by the Cochrane Collaboration : sequence generation of allocation; allocation concealment; blinding of participants, personnel, and outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias. Of note, the studies did not differ for the quality components of incomplete outcome data, selective outcome reporting, or other sources of bias. For the component of blinding, given the nature of the trials (surgery vs less invasive procedure, done under different settings), none of the trials had blinding of participants or personnel. Thus, only blinding of outcome assessors was considered. Trials with high or unclear risk for bias for any of the first components were considered to have high risk of bias. Otherwise, they were considered to have low risk of bias. DATA EXTRACTION AND SYNTHESIS Periprocedural (-day) outcomes included death, MI, or stroke; death or stroke; any stroke; and MI. The intermediate to long-term outcomes were those as in the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial ; composite of periprocedural death, MI, or stroke plus ipsilateral stroke or death thereafter; periprocedural death or stroke plus ipsilateral stroke thereafter; death or any stroke; and any stroke. Other outcomes evaluated were cranial nerve injury and carotid restenosis. Of note, all the outcomes stated earlier include periprocedural events along with the intermediate to longterm events. The outcomes were chosen based on the relevance to contemporary trials comparing CAS vs CEA. The composite of periprocedural death, MI, or stroke plus ipsilateral stroke or death after the periprocedural period ( days) captures events related to the stenting or CEA during the periprocedural period and avoids capturing contralateral strokes during the extended period of follow-up. STATISTICAL ANALYSIS Intention-to-treat meta-analysis was performed in line with recommendations from the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Metaanalyses Statement,,9 using standard software (Stata version 9. statistical software; StataCorp LP, College Station, Texas). Heterogeneity was assessed using the I statistic. I is the proportion of total variation observed between the trials attributable to differences between trials rather than sampling error (chance), with I % considered low and I % considered high. We used the Peto method for odds ratios (ORs)., The Peto OR is viewed as the most optimal approach when there are relatively few events in individual trials. Publication bias was estimated visually by funnel plots and using the Begg test and the weighted regression test of Egger. Primary analyses were performed after stratifying the studies based on the cohort enrolled (symptomatic vs asymptomatic with carotid artery disease). Three different analyses were performed: () evaluation of periprocedural events (-day events); () evaluation of intermediate to long-term events; and () evaluation of intermediate to long-term events but excluding periprocedural events. Subgroup analyses were performed comparing the following: trials with low risk of bias vs trials with high risk of bias; use of an EPD or not; US trials vs non-us trials (to examine for variability in practice patterns); and all trials vs trials after excluding the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) trial, in which most underwent balloon angioplasty alone, the ICSS trial (interim analysis), in which the follow-up was only months for the intermediate to long-term analysis, and the CAVATAS for the periprocedural analysis. We estimated the difference between the estimates of the subgroups according to tests for interaction. P. indicates that the effects of treatment differ between the tested subgroups. For the intermediate to long-term analyses, to account for varying length of follow-up of different studies, various subgroup analyses were performed: years or less, to years, and more than years of follow-up. We also performed a metaregression analysis adjusting for duration of follow-up. In addition, a metaregression analysis was performed to evaluate the effect of age on outcomes. We used residual maximum likelihood to estimate the additive (between-study) component of variance for the metaregression analysis. Bootstrap analyses were performed using a Monte Carlo permutation test for metaregression using random permutations. TRIAL SEQUENTIAL ANALYSIS In a single trial, interim analyses increase the risk of type I error. To avoid an increase of overall type I error, monitoring boundaries can be applied to decide whether a single randomized trial could be terminated early because of the P value being

3 RCTs of CAS or CEA Articles retrieved for detailed evaluation Articles chosen for final analyses Excluded: not direct comparison of CAS or CEA or evaluating outcomes Excluded: not evaluating outcomes of interest Figure. Study selection. RCTs indicates randomized clinical trials; CAS, carotid artery stenting; and CEA, carotid endarterectomy. sufficiently small. Because no reason exists for the standards for a meta-analysis to be less rigorous than those for a single trial, analogous trial sequential monitoring boundaries (TSMBs) can be applied to meta-analysis as trial sequential analysis (TSA)., Cumulative meta-analysis of trials is at risk for producing random errors because of few data and repetitive testing of accumulating data, and the information size requirement analogous to the sample size of a single optimally powered clinical trial may not be met., The underlying assumption for TSA is that significance testing is performed each time a new trial is published. The TSA depends on the quantification of the required information size. In this context, the smaller the required information size is, the more lenient the TSA is, thus the more lenient the criteria are for statistical significance., A required diversity (D ) adjusted information size was calculated, with D being the relative variance reduction when the meta-analysis model is changed from a random-effects model to a fixed-effect model. 9 D is the percentage that the between-trial variability constitutes of the sum of the between-trial variability and a sampling error estimate considering the required information size. D is different from the intuitively obvious adjusting factor based on the common quantification of heterogeneity, the inconsistency (I ), which may underestimate the required information size. 9 The TSA was performed with a desire to maintain an overall % risk of type I error, being the standard in most metaanalyses and systematic reviews, and we calculated the required information size (ie, the meta-analysis information size needed to detect or reject an intervention effect of a % [or %] relative risk increase [RRI] with a % risk of type II error and power of %)., RESULTS STUDY SELECTION We identified RCTs through electronic and hand searches, of which a total of RCTs,,,-9 fulfilled the inclusion criteria and were chosen for this analysis (Figure ). Eleven trials reported both periprocedural and long-term outcomes. The CAVATAS data were obtained from the updated analysis reported recently. CHARACTERISTICS OF THE TRIALS The baseline characteristics, inclusion criteria, exclusion criteria, and bias-risk assessment are summarized in Table and Table. The RCTs enrolled : (.%) were randomized to CAS and (9.%) were randomized to CEA; the were followed up for a weighted mean (SD) of. (.) years. Of the trials, most included participants with symptomatic carotid artery disease except the trial by Brooks et al, the SAPPHIRE trial where % of participants were asymptomatic, the Carotid Revascularization Endarterectomy vs Stenting Trial where % of participants were asymptomatic, and the Trial of Endarterectomy vs Stenting for the Treatment of Carotid Atherosclerotic Stenosis in China 9 that included both cohorts. For most of our analyses, the symptomatic and asymptomatic cohorts of the Carotid Revascularization Endarterectomy vs Stenting Trial and the SAPPHIRE trial (data on file at Harvard Clinical Research Institute) were analyzed separately. In trials, an EPD was used in most Table. Baseline Characteristics of Included Trials Study Patients, No. Age, Mean, y Men, % Follow-up, Mean, mo HTN, % DM, % CAD, % Alberts, 9 Yes NA NA NA BACASS, Yes Brooks et al, Yes NA... Brooks et al, No NA. CAVATAS,, Yes CREST, 9 Both a EVA-S,, 9. Yes 9. NA ICSS interim analysis, Yes 9 Naylor et al, 99 NA Yes NA NA NA NA NA SAPPHIRE,. Both a... SPACE, 9. Yes... Steinbauer et al,. Yes NA 9. TESCAS-C, 9 NA Both a NA NA NA NA NA Abbreviations: BACASS, Basal Carotid Artery Stenting Study; CAD, coronary artery disease; CAVATAS, Carotid and Vertebral Artery Transluminal Angioplasty Study; CREST, Carotid Revascularization Endarterectomy vs Stenting Trial; DM, diabetes mellitus; EVA-S, Endarterectomy vs Angioplasty in Patients With Severe Carotid Stenosis; HTN, hypertension; ICSS, International Carotid Stenting Study; NA, not available; SAPPHIRE, Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy; SPACE, Stent-Protected Angioplasty vs Carotid Endarterectomy study; TESCAS-C, Trial of Endarterectomy vs Stenting for the Treatment of Carotid Atherosclerotic Stenosis in China. a Study includes symptomatic and asymptomatic.

4 Table. Inclusion and Exclusion Criteria and Study Design Study Inclusion Criteria Exclusion Criteria Bias Risk a Alberts, high-grade internal carotid artery stenosis NA ±± No Yes BACASS, Brooks et al, Brooks et al, CAVATAS,, CREST, EVA-S,, ICSS interim analysis, Naylor et al, 99 SAPPHIRE, SPACE, Steinbauer et al, TESCAS-C, 9 high-grade internal carotid artery stenosis (%-99% on duplex ultrasonography as per CAVATAS criteria and on magnetic resonance angiography) Sustaining events confined to the carotid circulation within mo of evaluation; % of the ipsilateral carotid bifurcation as determined by the NASCET with digital subtraction angiography documented internal carotid artery stenosis of % bifurcation as determined by NASCET criteria Stenosis of the common carotid artery; carotid bifurcation; internal carotid artery needing treatment and suitable for both carotid endarterectomy and endovascular treatment adults with % carotid artery stenosis; asymptomatic with % carotid artery stenosis by angiography Aged y with a hemispheric or retinal transient ischemic attack or nondisabling stroke (or retinal infarct) within d before enrollment, and stenosis of %-99% in the symptomatic carotid artery as determined by the NASCET method Aged y with symptomatic carotid artery stenosis % by the NASCET criteria (or noninvasive equivalent) deemed to require treatment; symptoms attributable to the randomized artery needed to have occurred within mo before randomization Internal carotid artery occlusion; free-floating carotid thrombus; recurrent internal carotid artery stenosis; after neck irradiation; history of intracranial hemorrhage within mo prior to the intervention; intracranial mass lesions or vascular malformations; life expectancy y; allergy to contrast media National Institutes of Health Stroke Scale score ; cardiac arrhythmia; symptoms of vertebral-basilar insufficiency or intracranial occlusive disease shown by cerebral angiography ± No Any symptoms of cerebrovascular ischemia; cardiac arrhythmia ± No Unsuitable for surgery because of medical or surgical risk factors or disabling stroke with no useful recovery of function within the region supplied by the treatable artery; thrombus in the carotid artery; severe intracranial carotid artery stenosis beyond the skull base; stenosis unsuitable for endovascular treatment No NA Yes Modified Rankin score (disabling stroke); nonatherosclerotic carotid artery disease; severe tandem lesions; previous revascularization of the symptomatic stenosis; uncontrolled hypertension or diabetes; unstable angina; percutaneous or surgical intervention within d of study procedure Major stroke without useful recovery of function; previous carotid endarterectomy or stenting in the randomized artery; contraindications for either treatment; planned coronary artery bypass grafting or other major surgery carotid artery disease NA No Aged y with carotid artery stenosis of % of the luminal diameter in with symptoms or a stenosis of % in those without symptoms and at high surgical risk for complications from carotid endarterectomy ( of the following: clinically significant cardiac disease, CHF, abnormal stress test, or need for open heart surgery; severe pulmonary disease, contralateral carotid artery occlusion, contralateral laryngeal nerve palsy, previous radical neck surgery, or radiation therapy to the neck; aged y) stenosis of carotid bifurcation or internal carotid artery within past mo; modified Rankin scale score ; aged y; stenosis of carotid bifurcation or internal carotid artery of % according to criteria of European Carotid Surgery Trial or % according to criteria of NASCET Patients with symptomatic carotid artery stenosis of % as defined by NASCET criteria from digital subtraction angiography Ischemic stroke within previous h; presence of intraluminal thrombus; total occlusion of target vessel; vascular disease precluding use of catheter-based techniques; intracranial aneurysm 9 mm in diameter; need for more than stents; history of bleeding disorder; percutaneous or surgical intervention planned within next d; ostial lesion of common carotid artery or brachiocephalic artery Intracranial bleeding in past 9 d; uncontrolled arterial hypertension; known intracranial arteriovenous malformation or aneurysm; severe concomitant disease with poor prognosis (life expectancy y); occlusion of common carotid or internal carotid artery; stenosis due to external compression; stenosis due to dissection; recurrent stenosis after surgery or stenting; radiation-induced stenosis; stenosis due to fibromuscular dysplasia; floating thrombus; additional intracranial stenosis with higher grade Aged or y; contralateral symptomatic carotid stenosis %-99% and contralateral asymptomatic carotid stenosis 9%-99%; tandem stenoses ipsilateral; cerebral ischemia within the last wk; fresh territorial infarction in carotid artery downstream of vascular territory with evidence of brain barrier disruption on magnetic resonance imaging; intracranial tumor or arteriovenous malformation; preterminal renal insufficiency (creatinine concentration mg/dl); surrounded thrombus; dissection; pseudo-occlusion; fibromuscular dysplasia or recurrent stenosis after previous carotid artery surgery; following myocardial infarction without revascularization procedures within the past mo Either symptomatic or asymptomatic carotid artery disease NA ±± Yes ± Yes EPD Use Yes (%) Yes Yes (%) Abbreviations: BACASS, Basal Carotid Artery Stenting Study; CAVATAS, Carotid and Vertebral Artery Transluminal Angioplasty Study; CHF, congestive heart failure; CREST, Carotid Revascularization Endarterectomy vs Stenting Trial; EPD, embolic protection device; EVA-S, Endarterectomy vs Angioplasty in Patients With Severe Carotid Stenosis; ICSS, International Carotid Stenting Study; NA, not available; NASCET, North American Carotid Endarterectomy Trial; SAPPHIRE, Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy; SPACE, Stent-Protected Angioplasty vs Carotid Endarterectomy study; TESCAS-C, Trial of Endarterectomy vs Stenting for the Treatment of Carotid Atherosclerotic Stenosis in China;, low risk of bias;, high risk of bias; ±, unclear risk of bias. SI conversion factor: To convert creatinine to micromoles per liter, multiply by.. a Bias risk is based on only the first components: allocation sequence, allocation concealment, and assessor blinding, respectively. No

5 A Weighted % Alberts a / /. (-.).9 BACASS / /. (.-.). Brooks et al / /. (.-.). CAVATAS / /.9 (.-.). CREST (symptomatic) / /. (.-.). EVA-S / /. (.-.). ICSS b / /.9 (.-.). Naylor et al / /. (.-9.).9 SAPPHIRE (symptomatic) / /. (.-.). SPACE / /9.9 (.-.). Steinbauer et al / / (.-.). Subtotal: I = 9.9%, P =. /9 /9. (.-.).9 CREST (asymptomatic) /9 /.99 (.-.) 9. SAPPHIRE (asymptomatic) / /. (.9-.). Subtotal: I =.%, P =. / /9. (.-.). Both TESCAS-C a / /. (.-.). Subtotal: I = NC, P = NC / /. (.-.). Overall: I = 9.%, P =. Test for interaction; P =. / 9/. (-.9). B Weighted % Alberts / /. (-.). BACASS / /. (.-.). Brooks et al / /. (.-.). CAVATAS a / / (.-.).9 CREST (symptomatic) / /. (.-.).99 EVA-S / /. (.-.9).99 ICSS b / /. (.-.). Naylor et al / /. (.-9.). SAPPHIRE (symptomatic) / /. (.-.). SPACE / /9.9 (.-.). Steinbauer et al / /. (.-.). Subtotal: I =.%, P =. /9 /9. (.-.) 9. CREST (asymptomatic) /9 /. (.-.9). SAPPHIRE (asymptomatic) / /. (.-.). Subtotal: I =.%, P =. / /9. (.-.) 9. Both TESCAS-C / /. (.-.). Subtotal: I = NC, P = NC / /. (.-.). Overall: I =.%, P =. Test for interaction; P =. / /. (.-.). Figure. Outcomes comparing carotid artery stenting (CAS) vs carotid endarterectomy (CEA). A, Periprocedural death, myocardial infarction, or stroke. a Death or any stroke used; b number of events is per protocol analysis. B, Periprocedural death or any stroke. a Death or any stroke lasting longer than days used; b number of events is per protocol analysis. The size of the data marker indicates the weight of each trial; OR, odds ratio; CI, confidence interval; and NC, not calculated. The expansions of the trial names are included in Table. participants.,,,,9, In the Stent-Protected Angioplasty vs Carotid Endarterectomy trial, EPDs were used only in % of participants (considered with the no- EPD group for this analysis). QUALITY ASSESSMENTS Among the RCTs included in this analysis, were considered trials with low risk of bias as described in Methods,,,,, and the others were considered trials with unclear or high risk of bias (Table ). PERIPROCEDURAL OUTCOMES Carotid artery stenting was associated with a % increase in the risk of periprocedural death, MI, or stroke (Figure A) when compared with CEA (meta-analytic rate,.% [9% confidence interval {CI},.%-

6 A Weighted % BACASS / /. (.-.). CAVATAS a / /. (.-.). CREST (symptomatic) / /. (-.9).9 EVA-S / /. (.-.).9 ICSS b / /. (.-.). Naylor et al / /. (.-9.).9 SAPPHIRE (symptomatic) / /. (.-.). SPACE / /9. (.-.9).9 Steinbauer et al / /. (.-.). Brooks / / Subtotal: I =.%, P =. / /. (.-.9) 9. CREST (asymptomatic) /9 /. (.-.9). SAPPHIRE (asymptomatic) / /. (.-.). Subtotal: I =.%, P =. / /9. (.-.9). Overall: I =.%, P =. Test for interaction; P =. / /. (.-.). B Weighted % Brooks et al / /. (.-.). CAVATAS / /. (.-.). CREST (symptomatic) / /. (.-). EVA-S / /. (.-.9). ICSS / /. (.-.). SAPPHIRE (symptomatic) / /. (.-.). Steinbauer et al / /. (.-.9). BACASS / / SPACE / /9 Subtotal: I =.%, P =.9 / 9/. (.-.9).9 CREST (asymptomatic) /9 /. (.-.). SAPPHIRE (asymptomatic) / /. (.-.).9 Subtotal: I =.%, P =.9 / /9. (.-.99). Overall: I =.%, P =.9 Test for interaction; P =. / /. (.-.). Figure. Outcomes comparing carotid artery stenting (CAS) vs carotid endarterectomy (CEA). A, Any periprocedural stroke. a Any disabling stroke and nondisabling stroke lasting longer than days used; b number of events is per protocol analysis. B, Periprocedural myocardial infarction. The size of the data marker indicates the weight of each trial; OR, odds ratio; CI, confidence interval; and NC, not calculated. The expansions of the trial names are included in Table..%] vs.% [9% CI,.%-.9%], respectively), driven mainly by the analysis in the symptomatic cohort (P interaction =.). Carotid artery stenting as compared with CEA was associated with a % increase in the risk of periprocedural death or stroke (Figure B) (meta analytic rate,.% [9% CI,.9%-.%] vs.% [9% CI,.%-.%], respectively) and a % increase in the risk of any periprocedural stroke (Figure A) (meta analytic rate,.9% [9% CI,.%-.%] vs.9% [9% CI,.%-.%], respectively). However, CEA as compared with CAS was associated with a % increase in the risk of periprocedural MI (Figure B) (meta analytic rate,.% [9% CI,.%-.%] vs.% [9% CI,.%-.%], respectively). The results were similar for both symptomatic and asymptomatic cohorts regarding these outcomes (P interaction.). There was no or low to modest heterogeneity in the analyses and no evidence for publication bias. TSA FOR PERIPROCEDURAL OUTCOMES For the outcome of death, MI, or stroke, the required diversity (D =%) adjusted information size (a priori diversity-adjusted information size= 9) was calculated based on a control event proportion (in the CEA group) of 9.%, an RRI of %, of %, and of %. The cumulative z curve crossed the traditional but not the TSMB, suggesting a lack of firm evidence for an RRI of % in the CAS group compared with the CEA group (Figure A). However, the cumulative

7 ACumulative z Score CCumulative z Score BCumulative z Score monitoring monitoring APDIS = 9 APDIS = 9 monitoring monitoring APDIS = APDIS = monitoring 9 monitoring APDIS = 9 APDIS = 9 Figure. analysis of the effects of carotid artery stenting (CAS) vs carotid endarterectomy (CEA) on periprocedural death, myocardial infarction, or stroke (A), on periprocedural death or stroke (B), and on periprocedural stroke (C). RRI indicates relative risk increase; APDIS, a priori diversity-adjusted information size. z curve crossed both the traditional and the TSMB for the outcomes of death or stroke (Figure B) and any stroke (Figure C), demonstrating firm evidence for a in the CAS group compared with the CEA group. However, for the outcome of MI, both the traditional and the TSMB were crossed by the cumulative z curve, demonstrating firm evidence for a % relative risk reduction in the CAS group compared with the CEA group. Analyzing only trials with low risk of bias, excluding -event trials, and/or the CAVATAS trial did not make any noticeable differences for the analyses. INTERMEDIATE TO LONG-TERM OUTCOMES Carotid artery stenting as compared with CEA was associated with a 9% increase in the risk for the SAPPHIRE-like composite outcome (Figure A), a % increase in the risk for the composite of periprocedural stroke or death plus ipsilateral stroke thereafter (Figure B), a % increase in the risk for death or stroke (Figure A), and a % increase in the risk for any stroke (Figure B). The results were similar for both symptomatic and asymptomatic cohorts (P interaction.). There was no or low to modest heterogeneity in the analyses and no evidence for publication bias. TSA FOR INTERMEDIATE TO LONG-TERM OUTCOMES For the SAPPHIRE-like composite outcome (Figure A), the cumulative z curve crossed neither the traditional nor the TSMB but was very close to the futility boundaries, suggesting a lack of firm evidence for a in the CAS group compared with the CEA group. Similarly, the cumulative z curve crossed neither the traditional nor the TSMB for the outcome of periprocedural death or stroke plus ipsilateral stroke thereafter (Figure B). For the outcome of death or stroke, the cumulative z curve crossed the traditional but not the TSMB, suggesting

8 A Weighted % Alberts a / /. (.-.). BACASS / /. (.-.9). Brooks et al / /. (.-.). CAVATAS / /.9 (.-.). CREST (symptomatic) b / / (.-.). EVA-S / /. (.9-.).9 ICSS c / /.9 (.-.). SAPPHIRE (symptomatic) / /. (.-.). SPACE d / /9. (.-.). Steinbauer et al / / (.-.). Subtotal: I =.%, P =. /9 /. (-.). CREST (asymptomatic) b /9 /. (.-.9). SAPPHIRE (asymptomatic) / /. (.-.9). Subtotal: I =.%, P =. / /9.9 (.-.). Both TESCAS-C / /.9 (.-.).9 Subtotal: I = NC, P = NC / /.9 (.-.).9 Overall: I =.%, P =.9 Test for interaction; P =. 9/ /.9 (-.). B Weighted % Alberts a / /. (.-.). BACASS / /. (.-.).9 Brooks et al / /. (.-.).9 CAVATAS / /. (.-.). CREST (symptomatic) / /. (.9-.).9 EVA-S 9/ /. (.-.9). ICSS b / /.9 (.-.). SAPPHIRE (symptomatic) c / /. (.-.). SPACE / /9. (.-.). Steinbauer et al / /. (.-9.). Subtotal: I =.%, P =.9 /9 9/.9 (.-.). CREST (asymptomatic) /9 /. (.9-.).9 SAPPHIRE (asymptomatic) c / /. (.-.9). Subtotal: I =.%, P =. 9/ /9 (.-.). Both TESCAS-C / /. (.-.). Subtotal: I = NC, P = NC / /. (.-.). Overall: I = 9.%, P =. Test for interaction; P =. / 9/. (.-.). Figure. Intermediate to long-term outcomes comparing carotid artery stenting (CAS) vs carotid endarterectomy (CEA). A, Intermediate to long-term outcomes as in the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. a Procedure-related death, vascular death, and ipsilateral stroke used; b periprocedural death and myocardial infarction or any stroke and any ipsilateral stroke thereafter used; c any death, stroke, or periprocedural myocardial infarction used; d ipsilateral stroke, vascular death, or periprocedural myocardial infarction used. B, Intermediate to long-term periprocedural stroke or death and ipsilateral stroke thereafter. a Procedure-related death, vascular death, and ipsilateral stroke used; b any stroke or periprocedural death used; c SAPPHIRE-like outcome used. The size of the data marker indicates the weight of each trial; OR, odds ratio; CI, confidence interval; and NC, not calculated. The expansions of the trial names are included in Table. a lack of firm evidence for a in the CAS group compared with the CEA group (Figure C). For the outcome of any stroke, the TSMB was crossed by the cumulative z curve, suggesting firm evidence for at least a with CAS when compared with CEA (Figure D). OTHER OUTCOMES Carotid artery stenting as compared with CEA was associated with an % reduction in the risk of cranial nerve injury (all reported cranial nerve injuries were in the periprocedural period, and none occurred during longer fol- 9

9 A Weighted % Alberts / /. (.-.).9 BACASS / /. (.-.9). Brooks et al / /. (.-.).9 CAVATAS / /.9 (.-.). EVA-S / /. (.9-.). ICSS / /. (.-.) 9. SAPPHIRE (symptomatic) / /. (.-.). SPACE a / /9. (.-.) 9. Steinbauer et al / /. (.-.). Subtotal: I =.%, P =. /9 /.9 (-.) 9. SAPPHIRE (asymptomatic) / /. (.-.9). Subtotal: I = NC, P = NC / /. (.-.9). Overall: I =.%, P =. Test for interaction; P =. 9/99 /. (-.). B Weighted % Alberts / /. (.-.9) BACASS / /. (.-.). CAVATAS / /. (-.). CREST (symptomatic) / /.9 (.-.). EVA-S / 9/. (-.) 9. ICSS / /.9 (.-.) 9. SAPPHIRE (symptomatic) / /. (.-.). SPACE / /9. (.-.). Steinbauer et al / /. (.-9.). Brooks et al / / Subtotal: I =.%, P =. 9/9 /. (.-.). CREST (asymptomatic) /9 /. (.9-.).9 SAPPHIRE (asymptomatic) / /. (.-.). Subtotal: I =.%, P =.9 / /9. (.9-.). Overall: I =.%, P =. Test for interaction; P =. / /. (.-.). Figure. Intermediate to long-term outcomes comparing carotid artery stenting (CAS) vs carotid endarterectomy (CEA). A, Intermediate to long-term death or any stroke. a Vascular deaths or ipsilateral stroke used. B, Any intermediate to long-term stroke. The size of the data marker indicates the weight of each trial; OR, odds ratio; CI, confidence interval; and NC, not calculated. The expansions of the trial names are included in Table. low-up) (OR=.; 9% CI,.-.; I =.%) (metaanalytic rate,.% [9% CI,.%-.9%] vs.% [9% CI,.%-.%], respectively) but a % increase in the risk of intermediate to long-term carotid restenosis (OR=.; 9% CI,.9-.; I =.%). Analysis of outcomes excluding periprocedural events showed that the treatment strategies were comparable with similar event rates across the groups (Table ). However, the event rate for all of the outcomes outside the periprocedural period was low. SUBGROUP ANALYSES The results of the subgroup analyses are summarized in Table. Analysis stratified by bias risk (low vs high risk of bias), EPD use vs no use, US vs non-us trials, and excluding the CAVATAS and/or ICSS data made no noticeable difference from the main analyses (P interaction.). To account for varying length of follow-up, additional analyses stratified by duration of follow-up did not make any noticeable difference to the analyses. Similarly, in a metaregression analysis evaluating the effect of length of follow-up, there was a trend toward no increased risk in the CAS group with longer length of follow-up ( months) for the outcomes of SAPPHIRE-like outcome (P=.) (efigure ; available at and death or any stroke (P=.9) (efigure ) but not for the outcomes of periprocedural death or stroke plus ipsilateral stroke thereafter (P=.) (efigure ) or any stroke (P=.9) (efigure ), where the increased risk

10 CCumulative z Score ACumulative z Score DCumulative z Score BCumulative z Score monitoring monitoring APDIS = APDIS = monitoring monitoring APDIS = APDIS = monitoring monitoring APDIS = APDIS = monitoring monitoring APDIS = 9 APDIS = 9 Figure. analysis of the effects of carotid artery stenting (CAS) vs carotid endarterectomy (CEA) on intermediate to long-term outcomes as in the Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy trial (A), on intermediate to long-term periprocedural stroke or death and ipsilateral stroke thereafter (B), on intermediate to long-term death or stroke (C), and on any intermediate to long-term stroke (D). RRI indicates relative risk increase; APDIS, a priori diversity-adjusted information size. with CAS persisted with follow-up duration. The P values for the trend were derived from Monte Carlo permutation using random observations. There was no relationship between outcomes and mean age of participants for any of the outcome measures (data not shown). COMMENT The results of this analysis of currently available data using outcome measures considered standard for contemporary trials suggest that CAS is associated with significantly increased risk for both periprocedural and intermediate to long-term outcomes when compared with CEA (except for cranial nerve palsies and periprocedural MI). The TSMB was crossed by the cumulative z curve, suggesting firm evidence for at least a of periprocedural death or any stroke, any periprocedural stroke, and any intermediate to long-term stroke but at least a % reduction in MI with CAS compared with CEA. PERIPROCEDURAL OUTCOMES Previous studies and meta-analyses have evaluated the efficacy and safety of CAS compared with CEA on periprocedural outcomes ( -day events). The most recent Cochrane review (9) evaluated randomized trials that enrolled participants and found that CAS conferred significant reductions in cranial nerve injury and MI but that it was associated with a significant increase in -day death or stroke, which was no longer significant in a random-effects model. More recent randomized trials not included in the Cochrane review suggest that CEA might be superior to CAS for - day events. In the recently concluded ICSS comparing CEA with CAS in participants with recently symptomatic carotid stenosis eligible for either procedure, CEA was superior to CAS at days following the procedure, with nearly twice as many strokes associated with CAS when compared with CEA. Our updated analyses including the most recent trials showed an in-

11 Table. Intermediate to Long-Term Events Comparing Carotid Artery Stenting vs Carotid Endarterectomy and Excluding Periprocedural Events Outcome Overall I Death or any stroke.9 (.9-.) (.-.9).9 (.-.).. Death or ipsilateral stroke.99 (.-.) (.-.). (.-.).. Any stroke. (.-.). (.-.). (.-.)..9 Ipsilateral stroke.9 (.-.). (.-.9). (.-.).. Abbreviations: CI, confidence interval; OR, odds ratio. P Interaction Table. Sensitivity Analysis Comparing Carotid Artery Stenting vs Carotid Endarterectomy High-Bias- Risk Trials Low-Bias- Risk Trials EPD No EPD US Trials Non-US Trials Excluding CAVATAS/ICSS, a Outcome P Interaction P Interaction P Interaction Periprocedural Death and MI. (-.). (-.).. (-.). (.9-.).. (.-.). (.-.).. (.-.) or stroke Death or any. (-.). (.-.99)..9 (.-.). (.9-.).9. (.-.). (.-.).9. (.-.) stroke Any stroke. (.9-9.9). (.-.).. (.-.). (.-.)..9 (.-.). (.-.).9. (.-.9) MI. (.-.). (.-.)..9 (.-.). (.-.).. (.-.).9 (.-).. (.9-.) Long-term SAPPHIRE-like. (.-.). (-.).9. (-.). (.-.).. (.-.). (-.).. (.9-.9) outcome Periprocedural.9 (.-.). (.9-.).9. (.-.9). (.9-.).. (-.). (.-.).. (.-.) stroke or death and ipsilateral stroke thereafter Death and any. (.-.). (-.).. (-.) 9 (.-.9).. (.-.9). (-.).. (.9-.) stroke Any stroke. (.-.). (.-.).. (.-.9). (-.9).. (-.). (.-.).. (.-.) Abbreviations: CAVATAS, Carotid and Vertebral Artery Transluminal Angioplasty Study; CI, confidence interval; EPD, embolic protection device; ICSS, International Carotid Stenting Study; MI, myocardial infarction; OR, odds ratio; SAPPHIRE, Stenting and Angioplasty With Protection in Patients at High Risk for Endarterectomy. a In the CAVATAS trial, more than % of in the carotid artery stenting group had balloon angioplasty only (excluded for both periprocedural and long-term outcomes). In the ICSS trial, follow-up was for only months (interim analysis) (excluded only for long-term outcomes). creased risk of periprocedural outcomes except for cranial nerve injury and MI. INTERMEDIATE TO LONG-TERM OUTCOMES To our knowledge, this is the largest meta-analysis evaluating the intermediate to long-term outcomes of CAS vs CEA. Our study differs from the analysis by Meier et al in that we evaluated outcomes considered standard for evaluating intermediate to long-term outcomes with CAS, namely periprocedural death, MI, or stroke plus ipsilateral stroke or death thereafter and periprocedural death or stroke plus ipsilateral stroke thereafter. We included the results of the recently published or presented studies, ie, the Carotid Revascularization Endarterectomy vs Stenting Trial and the ICSS (interim analysis). The CAVATAS trial had a stroke definition more in line with other trials. Analysis was stratified based on the cohort enrolled (symptomatic vs asymptomatic), which is clinically more meaningful. Finally, a robust TSA was performed with monitoring boundaries. Our results suggest that the periprocedural increased risk of CAS continues to be seen in the intermediate to long-term periods as well. These results were observed regardless of whether EPDs were used. The efficacy of an EPD in preventing stroke is controversial. In the magnetic resonance imaging substudy of the ICSS, new ischemic lesions were times more common in the stenting group than in the endarterectomy group following treatment. Moreover, EPDs were not effective in preventing cerebral ischemia during stenting. It is not clear whether this is due to embolization during deployment of the EPD itself. Similarly, investigators have questioned whether the operator experience has resulted in different results for studies in the United States compared with non-us studies. However, this is controversial. In the Endarterectomy vs Angioplasty in Patients With Severe Carotid Stenosis trial, participants treated by experienced interventionalists (who had performed carotid stenting procedures) had a higher -day risk of stroke or death of.% compared with % in participants treated by those who had performed or fewer procedures and.% in participants treated by interventionalists who were being

12 proctored. Our subgroup analysis based on US trials vs non-us trials did not show any significant interaction for any of the outcomes assessed. For intermediate to longterm outcomes, analysis of follow-up duration showed a trend toward equal risk with longer-term follow-up ( months) for only a few outcome measures, suggesting that the strategies may be equivalent with longer followup. However, this was not observed for any stroke or death or for any stroke. Our analysis for outcomes excluding periprocedural outcomes suggests that the procedures have similar risks outside the periprocedural period. This is likely due to the low event rate beyond the periprocedural period. Continued emphasis on reducing the periprocedural outcomes (as has been done more recently) is therefore more appropriate. Our meta-analysis raises a number of important issues. Despite our findings, CAS is likely to be complementary to CEA (given the advantages of being less invasive, having a shorter recovery period, etc), especially in those who are poor surgical candidates or are at elevated risk for periprocedural MI. There is an urgent need to develop risk scores to select participants who have a low risk of periprocedural complications following CAS. Although randomized trials account for observed differences in baseline variables, unmeasured confounders may be missed. The question of the effect of relatively inexperienced operators performing stenting vs well-experienced surgeons performing CEA has not been resolved. Moreover, the outcome measures used need more consideration with inclusion of cranial nerve palsies in the composite outcomes and perhaps only including disabling stroke. From a patient perspective, cranial nerve palsy is likely similar to a minor stroke. However, the trials available to date did not report these composite outcomes consistently, and these should be evaluated in a meta-analysis of individual patient data. There is also a need for innovation to prevent embolization during carotid stenting procedures, perhaps with proximal EPDs. In addition, the effects of carotid artery anatomy (bifurcation vs nonbifurcation) and lesion characteristics (calcified vs noncalcified, ulcerated vs not, thrombotic vs not), which are important factors for selection of in the real world, on the outcomes of these techniques have not been consistently reported in these trials. The questions of operator experience, patient selection, and optimal EPD use can be resolved only by a randomized trial designed to address these issues. STUDY LIMITATIONS As in other meta-analyses, given the lack of data in each trial, we did not adjust our analyses for medications used during and following the procedure. Although detailed sensitivity analyses on many variables were undertaken, given heterogeneity in the study protocols, clinically relevant differences could have been missed and are best assessed in a meta-analysis of individual patient data. All of the trials did not report all of the outcomes. The subgroup analyses might suffer from multiple testing. The results of the sensitivity analyses are best described as secondary and hypothesis generating only. Of note, for the SAPPHIRE-like composite outcome, studies like the Stent- Protected Angioplasty vs Carotid Endarterectomy trial did not routinely measure periprocedural enzymes or electrocardiograms; hence, the periprocedural MI rate may be underestimated. CONCLUSIONS In this largest and most comprehensive meta-analysis of the available evidence from randomized trials to date, using outcomes considered the current standard for these trials, CAS was associated with a significant increase in the risk of short- and long-term outcomes compared with CEA. This was confirmed by a TSA in which the monitoring boundaries were crossed, suggesting an RRI of at least % with stenting. However, CAS was associated with a significant reduction of periprocedural MI or cranial nerve palsies. Thus, there is a need for identifying subsets of participants who are at low risk with CAS. Accepted for Publication: August,. Published Online: October,. doi:. /archneurol.. Author Affiliations: New York University School of Medicine, New York (Dr Bangalore); Harvard Clinical Research Institute (Drs Bangalore and Cutlip), Beth Israel Deaconess Medical Center (Dr Cutlip), Brigham and Women s Hospital (Dr Bhatt), Veterans Affairs Boston Healthcare System (Dr Bhatt), and Harvard Medical School (Dr Bhatt), Boston, Massachusetts; University of Nebraska Medical Center, Omaha (Dr Kumar); Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark (Drs Wetterslev and Gluud); and College of Medicine, University of Florida, Gainesville (Dr Bavry). Correspondence: Deepak L. Bhatt, MD, MPH, VA Boston Healthcare System, VFW Pkwy, Boston, MA (dlbhattmd@post.harvard.edu). Author Contributions: Dr Bangalore had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Bangalore. Acquisition of data: Bangalore, Kumar, and Cutlip. Analysis and interpretation of data: Bangalore, Kumar, Wetterslev, Bavry, Gluud, and Bhatt. Drafting of the manuscript: Bangalore, Kumar, and Bavry. Critical revision of the manuscript for important intellectual content: Bangalore, Wetterslev, Gluud, Cutlip, and Bhatt. Statistical analysis: Bangalore, Wetterslev, Bavry, Gluud, and Bhatt. Administrative, technical, and material support: Wetterslev. Study supervision: Bangalore, Wetterslev, and Bhatt. Financial Disclosure: Dr Bhatt has received research grants from AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Heartscape, Sanofi Aventis, and The Medicines Company. Online-Only Material: The efigures are available at http: // Additional Contributions: Peter Ringleb, MD, and Markus Steinbauer, MD, provided clarification of their data.

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