Management Of Asymptomatic Carotid Stenosis
Technology AssessmentManagement of AsymptomaticCarotid StenosisTechnologyAssessment ProgramPrepared for:Agency for HealthcareResearch and Quality540 Gaither RoadRockville, Maryland 20850Final ReportAugust 27, 2012
Management of Asymptomatic Carotid StenosisTechnology Assessment ReportProject ID: CRDT0510August 27, 2012Tufts Evidence-based Practice CenterGowri Raman, MD, MSGeorgios D. Kitsios, MD, PhDDenish Moorthy, MBBS, MSNira Hadar, MSIssa J. Dahabreh, MD, MSThomas F. O’Donnell, MDDavid E. Thaler, MD, PhD, FAHAEdward Feldmann, MDJoseph Lau, MDii
This report is based on research conducted by the Tufts Evidence-based PracticeCenter under contract to the Agency for Healthcare Research and Quality(AHRQ), Rockville, MD (Contract No. 290 2007 10055 1). The findings andconclusions in this document are those of the author(s) who are responsible for itscontents; the findings and conclusions do not necessarily represent the views ofAHRQ. No statement in this article should be construed as an official position ofthe Agency for Healthcare Research and Quality or of the U.S. Department ofHealth and Human Services.The information in this report is intended to help health care decision-makers;patients and clinicians, health system leaders, and policymakers, make wellinformed decisions and thereby improve the quality of health care services. Thisreport is not intended to be a substitute for the application of clinical judgment.Decisions concerning the provision of clinical care should consider this report inthe same way as any medical reference and in conjunction with all other pertinentinformation, i.e., in the context of available resources and circumstancespresented by individual patients.This report may be used, in whole or in part, as the basis for development ofclinical practice guidelines and other quality enhancement tools, or as a basis forreimbursement and coverage policies. AHRQ or U.S. Department of Health andHuman Services endorsement of such derivative products may not be stated orimplied.Disclosure: None of the investigators has any affiliations or financial involvementrelated to the material presented in this report.AcknowledgementsThe authors of this report thank other members of the Tufts Evidence-based PracticeCenter (EPC), Ethan Balk MD MPH and Thomas A Trikalinos MD PhD, for helpfulsuggestions on a draft version of this report. We thank Jenny Lamont, MS, for editing adraft and final version of this report.iii
Table of ContentsAbbreviations and Acronyms . viExecutive Summary . ES-1Introduction .1Background . 1Key Questions .5Methods .6Search Strategy . 6Study Selection . 6Data Extraction . 9Quality Assessment . 9Applicability . 10Data Analysis . 10Grading the Strength of Evidence . 11Results . 13Key Question 1 (Long-term outcomes) . 13Key Question 2 (Subgroups and treatment effect) . 50Key Question 3 (Outcomes occurring within 30 days) . 56Discussion. 70Summary of findings . 70Conclusions . 74Future research . 75References . 76Appendix A. Search Strategy . A-1Appendix B. Carotid stenosis data extraction form . B-1Appendix C. Study Flow Diagram. C-1Appendix D. Forest plot of medical therapy alone studies . D-1Appendix E. Baseline characteristics and results of included studies . E-1Appendix F. List of included studies . F-1List of TablesTable 1. Summary characteristics of studies of medical therapy that reported ipsilateral stroke . 13Table 2. Meta-analyses of incidence rates of events for all medical therapy studies . 17Table 3. Meta-regression analysis for the effect of the explanatory variable “recruitment closureyear” on the incidence rate of events . 19Table 4. Subgroup meta-analyses for the incidence rates of ipsilateral cerebrovascular outcomesfor older studies and recent studies . 20Table 5. Subgroup meta-analyses for the incidence rates of cerebrovascular events and death . 21Table 6. Summary characteristics of studies comparing CEA versus medical therapy . 23Table 7. Summary characteristics of studies comparing CAS versus CEA . 37Table 8. Summary incidence rates of ipsilateral stroke by treatment groups. 49iv
List of FiguresFigure 1. Forest plot of the incidence rates of ipsilateral stroke in medical therapy alone . 18Figure 2. Meta-regression of the log-event rates by recruitment closure year for the four majorischemic cerebrovascular outcomes . 20Figure 3. Meta-analysis of ipsilateral stroke in studies of CEA versus medical therapy. 30Figure 4. Meta-analysis of any stroke in studies of CEA versus medical therapy . 31Figure 5. Meta-analysis of any stroke or death in studies of CEA versus medical therapy . 32Figure 6. Meta-analysis of any death in studies of CEA versus medical therapy . 32Figure 7. Meta-analysis of fatal stroke in studies of CEA versus medical therapy . 33Figure 8. Meta-analysis of CVD deaths in studies of CEA versus medical therapy . 33Figure 9. Meta-analysis of composite endpoint of within 30-day stroke or death and subsequentipsilateral stroke in studies of CEA versus medical therapy . 34Figure 10. Forest plot of ipsilateral stroke in RCTs of CAS versus CEA. 47Figure 11. Forest plot of any periprocedural stroke, MI or death or postprocedural ipsilateralstroke in RCTs of CAS versus CEA . 47Figure 12. Forest plot of any periprocedural stroke or death or postprocedural ipsilateral stroke inRCTs of CAS versus CEA . 48Figure 13. Forest plot of ipsilateral stroke, and any stroke by subgroups* comparing CEA andmedical therapy with medical therapy alone . 52Figure 14. Meta-analysis of stroke and death during 30-day period in RCTs of CEA versusmedical therapy . 59Figure 15. Meta-analysis of stroke, MI, and death during 30-day period in RCTs CEA versusmedical therapy . 59Figure 16. Forest plot of any periprocedural stroke in RCTs of CAS versus CEA . 64Figure 17. Meta-analysis of any periprocedural stroke in nonrandomized comparative studies ofCAS versus CEA. 64Figure 18. Meta-analysis of any periprocedural stroke in nonrandomized comparative studies(administrative datasets) of CAS versus CEA . 65Figure 19. Meta-analysis of periprocedural death in nonrandomized comparative studies(administrative datasets) of CAS versus CEA . 66Figure 20. Forest plot of periprocedural MI in RCTs of CAS versus CEA . 66Figure 21. Meta-analysis of periprocedural MI in nonrandomized comparative studies of CASversus CEA . 67Figure 22. Meta-analysis of any periprocedural stroke or death in nonrandomized comparativestudies of CAS versus CEA . 68Figure 23. Meta-analysis of cranial nerve palsy in RCTs of CAS versus CEA . 69v
Abbreviations and RCTRRSAPPHIRESVS-VRTIAVAAsymptomatic Carotid Atherosclerosis StudyAngiotensin-converting enzyme inhibitorAmerican College of RadiologyAsymptomatic Carotid Surgery TrialAmerican Heart AssociationAmerican Stroke AssociationCoronary artery diseaseCarotid Revascularization Using Endarterectomy or StentingSystemsCarotid angioplasty and stentingCarotid Artery Stenosis with Asymptomatic Narrowing:Operation versus AspirinCarotid endarterectomyConfidence intervalCarotid Revascularization Endarterectomy Versus StentingTrialComputed tomography angiographyCardiovascular diseaseDigital subtraction angiographyDoppler ultrasoundEuropean Carotid Surgery TrialHazard ratioInternal carotid arteryIntersocietal Commission for the Accreditation of VascularLaboratoriesMyocardial infarctionMagnetic resonance angiographyNorth American Symptomatic Carotid Endarterectomy TrialOcular pneumoplethysmographyRandomized controlled trialRelative riskStenting and Angioplasty with Protection in Patients at HighRisk for EndarterectomySociety for Vascular Surgery–Vascular RegistryTransient ischemic attackVeterans Affairsvi
Executive SummaryBackgroundCarotid artery stenosis is an important cause of ischemic stroke and is increasingly prevalentfrom the fifth decade of life onward. Since carotid artery atherosclerosis can largely progresssilently and unpredictably, the first manifestation can be a debilitating or fatal stroke.Asymptomatic carotid artery stenosis affects approximately 7 percent of women and over 12percent of men, older than 70 years of age. Therapeutic options include carotid endarterectomy(CEA) and medical therapy, carotid angioplasty and stenting (CAS) and medical therapy, ormedical therapy alone. However, the optimal therapeutic management strategy for patients withasymptomatic carotid stenosis is unclear. The Centers for Medicare and Medicaid Services(CMS) is interested in a systematic review of the literature on these three treatment strategies forpatients with asymptomatic carotid stenosis. The Coverage and Analysis Group at the CMSrequested this report from the Technology Assessment Program (TAP) at the Agency forHealthcare Research and Quality (AHRQ). AHRQ assigned this report to the Tufts Evidencebased Practice Center (Tufts EPC) (Contract number HSSA 290 2007 10055 I).MethodsThe present technology assessment provides a systematic review of the literature of treatmentstrategies for patients with asymptomatic carotid artery stenosis. The following key questionswere formulated in consultation with CMS and AHRQ.1. In asymptomatic patients with carotid artery stenosis, what is the evidence on long-termclinical outcomes (at least 12 months of followup) including stroke, death, myocardialinfarction, and other cardiovascular events the following interventions?a. Medical therapy aloneb. CEA and medical therapy versus medical therapy alonec. CAS and medical therapy versus medical therapy aloned. CAS and medical therapy versus CEA and medical therapy2. Among comparative studies (CEA and medical therapy versus medical therapy alone, CASand medical therapy versus medical therapy alone, CAS and medical therapy versus CEAand medical therapy), what is the impact of the following patient, intervention, and studycharacteristics on treatment effect? Demographic and other baseline features including the assessment the applicability ofstudies to patients 65 years with asymptomatic carotid artery stenosis, subgroup ofpatients 80 years, and sex Clinical and anatomic features of carotid artery stenosis Average or high risk for CEA due to comorbid diseases Types of stents used and use of embolic protection devices Concurrent and postoperative treatments Length of followup Methodological quality of studies3. Among comparative studies (CEA and medical therapy versus medical therapy alone; CASand medical therapy versus medical therapy alone; CAS and medical therapy versus CEAES-1
and medical therapy), what is the evidence on adverse events and complications during theperiprocedural period?Search strategyA comprehensive search of the scientific literature was conducted in MEDLINE and theCochrane Central Register of Controlled Trials for English-language studies of adult humansubjects from inception through May 2012. In addition, bibliographies of systematic reviews andselected narrative reviews were searched to identify additional citations. We also searched theFood and Drug Administration (FDA) Web site, and we contacted corresponding authors ofeligible studies for unpublished data on outcomes of interest.Study eligibility criteriaPopulationEligible studies included those of adults ( 18 years) with asymptomatic carotid arterystenosis. Eligible stenoses included atherosclerotic narrowing of the lumen of the carotidbifurcation or the extracranial part of the internal carotid artery between 50 to 99 percent. Weaccepted the definition of “asymptomatic” patients used in each study. We included studies withmixed cohorts of patients (symptomatic and asymptomatic carotid artery stenosis), provided thatthe results were stratified according to symptom status.Intervention and comparatorWe included studies of medical therapy alone, CEA and medical therapy compared withmedical therapy alone, CAS and medical therapy compared with medical therapy alone, andCAS and medical therapy compared with CEA and medical therapy.OutcomesFor Key Questions 1 and 2, we included studies that reported only major clinical outcomes:stroke, death, myocardial infarction (MI), and other cardiovascular events. For Key Question 3,we included studies that reported safety outcomes related to a procedure or therapy (referred toas complications) or clinical outcomes, including stroke, death, or MI (referred to as adverseevents) occurring within 30 days of the procedures or within 30 days of followup in the medicaltherapy group.Study designsFor Key Question 1a evaluating long-term clinical outcomes of medical therapy alone, weincluded prospective cohort studies and the medical therapy arm of eligible randomizedcontrolled trials (RCTs) or prospective nonrandomized comparative studies.Sample size and duration of followupFor Key Question 1a, studies with at least 30 patients with a minimum average followup of12 months were included. For all other key questions comparing treatment strategies, weincluded at least 30 patients per intervention group and any duration of followup.Data analysisFor studies of medical therapy alone where numerical data of events and average followupperson-time were available, we calculated the incidence rate of events and its 95 percent exactES-2
Poisson confidence interval (95 percent CI). Summary estimates of incidence rates wereconstructed by fitting a generalized linear random effects meta-analysis model and wereexpressed as percent per year (instead of number of events per 100 person-years). We performedmeta-regression analyses with the last year of recruitment in each study to evaluate changes inthe rates of events over time. We conducted further exploratory subgroup and meta-regressionanalyses based on a prespecified set of clinically relevant explanatory variables and only for theoutcomes with at least five studies.For comparative studies, we conducted meta-analysis using a random effects model andreported the results as summary relative risk (RR). RCTs and nonrandomized comparativestudies were analyzed separately. When we identified discrepancies between published andunpublished data for a study, or extreme clinical heterogeneity between studies (i.e, inclusion ofdifferent patient groups), we refrained from conducting a meta-analysis but presented estimatesof each study in forest plots. In RCTs comparing treatments, we also estimated summaryincidence rates of ipsilateral stroke for each of the treatment arms.Study quality and applicabilityWe used a three-level (A or low risk of bias, B or moderate risk of bias, and C or high risk ofbias) system per the AHRQ methods guide to denote the methodological quality (risk of bias) ofeach study. Quality-A studies have the least bias and results are considered valid. Quality-Bstudies are susceptible to some bias, but it is not sufficient to invalidate the results. Quality-Cstudies have significant biases that may invalidate the study results.Study applicability was described using study specific characteristics such as age groups of 65 years and 80 years, sex, other baseline clinical features including comorbid medicaldiseases, center characteristics, medical therapy at baseline, and clinical or anatomic features ofcarotid artery stenosis ( 70 percent or 80 percent stenosis).Strength of evidenceFor each key question, grading of the strength of evidence provides an overall summary ofrisk of bias in individual studies, directness and precision of the evidence, and the consistencyacross studies. We used a four-category grading system per the AHRQ methods guide to gradethe strength of evidence. For Key Question 1a, evaluating effectiveness of medical therapy alone,the strength of evidence was graded on the basis of individual studies (prospective cohort studiesand trials with the medical therapy arms) rated quality-A or -B. For all other key questionscomparing treatment strategies, the strength of evidence was graded on the basis of individualRCTs rated quality-A or -B. The quality-C studies were excluded from the strength-of-evidenceassessment but are described in detail in full text of the report.Grades were assigned according to our level of confidence that the evidence reflects the trueeffect for the interventions of interest and were defined as follows: High strength of evidence indicates that there is a high level of assurance that the findingsof the literature are valid with respect to the relevant comparison and no importantscientific disagreement exists across studies. Further research is very unlikely to changeour confidence in the estimate of effect. Moderate strength of evidence indicates that there is a moderate level of assurance thatthe findings of the literature are valid with respect to the relevant comparison and littledisagreement exists across studies. Further research may change our confidence in theestimates of effect and may change the estimate.ES-3
Low strength of evidence indicates that there is a low level of assurance that the findingsof the literature are valid with respect to the relevant comparison. Underlying studies mayreport conflicting results. Further research is likely to change our confidence in theestimate of effect and may change the estimate for this outcome. Insufficient strength of evidence indicates that evidence is either unavailable or does notpermit estimation of an effect owing to a lack of data or sparse data. In general, whenonly one study has been published, the evidence was considered insufficient, unless thestudy was particularly large, robust, and of good quality.These ratings provide a shorthand description of the strength of evidence supporting themajor questions we addressed. However, they by necessity may oversimplify the many complexissues involved in the appraisal of a body of evidence. It is important to remember that theindividual studies evaluated in formulating the composite rating differed in their design,reporting, and quality. The strengths and weaknesses of the individual reports, as described indetail in the text and tables, should also be taken into consideration.ResultsThe literature search identified 60 eligible studies in 68 articles. In general, the definition of“asymptomatic” patients used in each study was heterogeneous. These included any of thefollowing at enrollment: those without symptoms, those with symptoms present for 6 monthsbefore their enrollment in the study but recently (within 6 months) asymptomatic, or those withsymptoms in a vascular territory other than ipsilateral carotid (e.g., vertebrobasilar territory). Alleligible studies are described in detail in full-text of the report. Only studies that contributed tograding the strength of evidence are described in the executive summary.Key Question 1Medical therapy alone (Key Question 1a)There is moderate strength of evidence among 20 quality-A and -B studies that medicaltherapy alone can reduce the incidence rate of ipsilateral stroke over time in patients withasymptomatic carotid stenosis.In 20 quality-A and -B studies of (any) medical therapy alone, the summary incidence rate ofipsilateral stroke was 1.59 (95% CI 1.21, 2.09) percent per year of followup. The summaryincidence rate estimate of 13 studies reporting the combined outcome of ipsilateral stroke ortransient ischemic attack (TIA) was 4.56 (95% CI 3.79, 5.47) percent per year of followup.The summary incidence rate for any stroke in 12 studies was 3.18 (95% CI 2.32, 4.35) and forany stroke or TIA in five studies was 5.71 (95% CI 3.30, 9.90) percent per year of followup.The summary incidence rate of all-cause death across 11 studies was 4.38 (95% CI 3.00, 6.41)percent per year of followup.In subgroup analyses, use of statins by 25 percent (vs. 25 percent) of the study populationand use of antiplatelet therapy by 50 percent (vs. 50 percent) of the study population wasassociated with significantly decreased rates of ipsilateral stroke.Changes in outcome incidence over time across studiesMeta-regression analyses showed that the incidence rates of ipsilateral stroke wassignificantly decreased in studies with a recruitment closure year between 2000 and 2010 (recentstudies) as compared with older studies (1.13 versus 2.38 percent per year, P for interaction ES-4
0.0008). The summary incidence rate of ipsilateral stroke or TIA, any territory stroke, and deathwas also significantly decreased in recent studies as compared with older studies.CEA and medical therapy versus medical therapy alone (Key Question 1b)There is moderate strength of evidence (that is not applicable to contemporary medicaltreatment) among three quality-A RCTs (the Veterans Affairs Cooperative Study [VA], theAsymptomatic Carotid Atherosclerosis Study (ACAS), and the Asymptomatic CarotidAtherosclerosis Trial [ACST]) that CEA and medical therapy can reduce the risk of ipsilateralstroke as compared with medical therapy alone, which was demonstrated by all three trials. Theresults from these trials are not applicable to contemporary clinical practice, as they do notcompare CEA with current best medical therapy. Patients with asymptomatic carotid stenosis didnot receive at randomization what is considered current best medical therapy, including the useof statins and targets for the treatment of blood pressure and diabetes. The meta-analyses of theseRCTs showed no difference between the two treatment groups for the risk of any death, fatalstroke, or CVD death.Ipsilateral stroke (including any stroke or death within 30 days)All three RCTs contributed to the analysis of ipsilateral stroke (defined as any stroke or deathwithin 30 days or subsequent ipsilateral stroke). In a meta-analysis, the CEA had a 31 percentsignificantly decreased risk of ipsilateral stroke (including perioperative stroke or death)compared with the medical therapy (summary RR 0.69, 95% CI 0.55, 0.87) withoutstatistical heterogeneity (I2 0.0%, P 0.90).Any stroke (including any death within 30 days)All three RCTs reported the outcome of any stroke, defined as events of perioperative strokeor death or subsequent nonperioperative any territory stroke. In a meta-analysis, the CEA had a32 percent significantly decreased risk of any stroke (including perioperative stroke or death) ascompared with the medical therapy group (summary RR 0.68, 95% CI 0.56, 0.82) withoutstatistical heterogeneity (I² 17.7%, P 0.30).Any stroke or deathAll three RCTs reported that the CEA had a nonsignificantly decreased risk for the combinedendpoint of any stroke or death compared with the medical therapy. A meta-analysis showed nosignificant difference between the two groups (summary RR 0.94, 95% CI 0.85, 1.03)without statistical heterogeneity (I² 19%, P 0.29).DeathA meta-analysis of the three RCTs showed no significant difference in death between the twointervention groups (summary RR 1.05, 95% CI 0.97, 1.14) and no statistical heterogeneity(I² 0.0%, P 0.60). When the meta-analysis was restricted to fatal stroke, the CEA had anonsignificantly decreased risk by 21 percent as compared with the medical therapy (summaryRR 0.79, 95% CI 0.57, 1.08) and no statistical heterogeneity (I² 0.0%, P 0.61).CVD outcomesA meta-analysis of three RCTs on cardiovascular deaths showed no significant differencebetween the two groups (summary RR 1.01, 95% CI 0.82, 1.25) with statisticallynonsignificant heterogeneity (I² 37.6%, P 0.20).ES-5
CAS and medical therapy versus medical therapy alone (Key Question 1c)The strength of evidence was graded as insufficient because of a lack of RCTs.CAS and medical therapy versus CEA and medical therapy (Key Question 1d)No statistically significant difference in the risk of ipsilateral stroke or the risk of thecomposite endpoint of ipsilateral stroke was found between CAS and CEA in two RCTs (onequality-A and one quality-B). The strength of evidence is graded as insufficient because in thesetrials, the included population had extreme clinical heterogeneity (i.e., one study representing apopulation of low-to-average risk and the other representing a high-risk population). Therefore,these studies were not combined in meta-analyses. Furthermore, there was selective reporting ofoutcomes of interest.The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) and theStenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy(SAPPHIRE) trial enrolled both symptomatic and asymptomatic patients who were assigned totreatments on the basis of stratified randomization according to symptom status. Thus, thetreatment assignment was randomized among the subgroup of patients with asymptomaticcarotid stenosis. However, among this subgroup, neither trial was powered to detect differencesin the primary outcome (composite endpoint). Therefore, the failure to find statisticallysignificant differences does not rule out the possibility that real differences exist betweeninterventions. CREST was conducted as an equivalence trial but was analyzed as a noninferioritytrial in the FDA submission and as a superiority trial in the published paper. The SAPPHIREtrial used group sequential design and was analyzed as a noninferiority trial in the publishedpapers. In this trial (SAPPHIRE), there were differences in reporting between the publishedpaper and unpublished data on the FDA Web site. One additional quality-B RCT
CAD Coronary artery disease CaRESS Carotid Revascularization Using Endarterectomy or Stenting Systems CAS Carotid angioplasty and stenting CASANOVA Carotid Artery Stenosis with Asymptomatic Narrowing: Operation versus Aspirin CEA Carotid endarterectomy CI Confidence interval CREST Carotid Revascularization Endarterectomy Versus Stenting
Jan 01, 1994 · screening of asymptomatic persons for CAS using physical exam or carotid ultrasound.3 This recommendation was based on new evidence at the time, including the Asymptomatic Carotid Artery Study (ACAS), a RCT involving 1662 subjects with asymptomatic stenosis greater than 60%. Results of ACAS suggested that the overall benefit of treatment with .
in asymptomatic carotid stenosis Acknowledge current equipoise between intensive medical management and carotid revascularization for high-grade asymptomatic carotid occlusive disease Discuss emerging concepts in pre-hospital and remote stroke care . Xact Stent. Emboshield Nav. 6.
Lee W. General principles of carotid Doppler ultrasonography. Ultrasonography. 2014 Jan;33(1):11-17. Whal Lee 12 Ultrasonography 33(1), January 2014 e-ultrasonography.org Carotid Artery Anatomy and Tips for Differentiating the Internal Carotid Arteries from the External Carotid Arteries The right carotid artery arises from the right brachiocephalic artery. Ultrasonography can show the most .
group, with Xact Carotid stent (Abbott Vascular, Santa Clara, California), Nexstent Carotid stent, Carotid Wallstent (Boston Scientific, Natick, Massachusetts) being classified as closed-cell stent and Precise carotid stent, Protégé carotid stent (Cordis, Warren, New Jersey), Acculink carotid stent (Acculink system,
Abbott Vascular XACT Carotid Stent System P040038 Sep 2005 Boston Scientific Corp. Carotid Wallstent Monorail Endoprosthesis P050019 Oct 2008 Boston Scientific Corp. Endotex Nexstent Carotid Stent and Delivery System and Endotex Carotid Stent and Monorail Delivery System P050025 Oct 2006 Medtronic Vascular
carotid stenosis, and surveillance after carotid surgery should be patient specific. . Stent Xact 10/8 x 40 6 mm Dia Balloon IVUS Assessment Case Study. After 7 mm Balloon Carotid Duplex @ 1 day. Figure 3 IVUS Monitored CAS - Deployed Stent Anatomy Circular Angio Guided 2/90 (2.2%) 129 44 cm/s
Asymptomatic Carotid (ACT)-1 Trial Randomized trial of asymptomatic patients 79 years of age who were not high surgical risk. CEA or carotid stenting with embolic protection (Nav6) using closed cell stent (Xact). Enrolled 2005-2013. Rosenfield et al, NEJM 2016 374:1011-1120
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