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Carotid Artery Stenting UpdateMehmet Cilingiroglu, Konstantinos Marmagkiolis, Mark H WholeyFuture Cardiol. 2013;9(2):193-197.

Abstract and IntroductionAbstract

Stroke is the third leading cause of death and the most common cause of long-term disability in the USA.Approximately 25% of strokes are due to carotid artery disease. The mechanisms of stroke include thromboticocclusion, thrombus embolism, atheroembolism and dissection or subintimal hematoma. Today,endarterectomy is the standard of care for management of significant carotid artery disease. The SAPPHIREtrial has proved the noninferiority of carotid artery stenting versus carotid endarterectomy in 'high-risk' patients,which led to the US FDA approval of carotid stent for high-risk patients. The CREST trial is the largestrandomized trial comparing stenting versus endarterectomy and showed no significant difference in death,

stroke or myocardial infarction. Over the last 15 years, the accumulation of experience, the improvement ofstent platforms and embolic protection devices, and the strong demand from patients for a less invasivealternative to carotid endarterectomy has made carotid artery stenting an equally efficient and safe procedurefor the prevention of stroke.

Carotid Artery Disease & Stroke

Stroke is the third leading cause of death and accounts for one in every 18 deaths in the USA. [1] With more than4.4 million stroke survivors today, stroke is the most common cause of long-term disability. Approximately 25%of strokes are due to carotid artery disease, of which approximately a third have stenosis warrantingrevascularization.[2]

Multiple mechanisms have been proposed to explain the increased stroke incidence in patients with carotidartery disease. Thrombotic occlusion of the carotid artery from plaque rupture, thrombus embolism in theintracranial circulation, atheroembolism, dissection or subintimal hematoma, and decreased cerebral perfusionthrough a stenotic carotid lesion have all been proposed as possible contributing factors.[3]

The annual stroke event rate for asymptomatic patients with significant carotid artery stenosis with optimalmedical therapy is estimated to be as low as 0.51.0%.[4] The prospective, randomized and multicenter ACAStrial demonstrated that carotid endarterectomy may reduce the 5-year risk of ipsilateral stroke by 53% inasymptomatic patients with carotid artery stenosis of >60%.[2] However, since that trial, newer medical therapyoptions have evolved with more potent statins and antiplatelet agents, among other treatments. Thus, itremains unclear whether, today, carotid artery stenting (CAS) or carotid endarterectomy (CEA) provideadditional benefits in patients on optimal medical therapy.

In symptomatic patients with previous stroke or transient ischemic attack, and severe carotid stenosis of >70%,the incidence of fatal or nonfatal ipsilateral stroke at 18 months is approximately 24% on medical therapy. Theprospective, randomized and multicenter NASCET study showed a reduction from 24 to 7% of all fatal ornonfatal ipsilateral strokes at 18 months with endarterectomy.[5]

Today, endarterectomy is the most frequently performed surgical procedure to prevent stroke and, in 2009,approximately 93,000 endarterectomy procedures were performed in the USA. [1]

Carotid Artery Disease Imaging Today

There are currently several limitations in the assessment of carotid artery disease by imaging. Carotid duplexultrasound is an excellent method for the initial evaluation of the extracranial carotid artery disease, but vesseltortuosity or calcification can affect its accuracy. Furthermore, it does not provide information about the archtype or the intracranial vasculature. Arch anatomy becomes extremely important when CAS is a
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revascularization option. It is needed to define the feasibility or ease of a CAS intervention because archatheroma, calcification or unusual arch types may increase the complexity and risks of a percutaneousintervention. The intracranial circulation anatomy is also an important consideration since up to 20% ofdiabetics have distal carotid siphon disease, which may contribute to symptoms even if the carotid bifurcationlesion is treated.

Computed tomography angiography requires high-flow contrast injections and it may not be well tolerated in

patients with impaired renal function, while additional radiation becomes another concern when follow-up isneeded.

Magnetic resonance angiography (MRA) is a safer imaging modality, but it is affected by patient motion and itmay frequently overestimate carotid lesions. Gadolinium- or contrast-enhanced MRA provides an overview,imaging from the arch origins to the circle of Willis, and time-of-flight MRA, which is susceptible to step artifactin the cervical carotid, cannot reliably inform the operator of the arch origins. Contrast-enhanced MRA is theimaging modality with the least heterogeneity of all noninvasive methods (e.g., computed tomographyangiography, time-of-flight MRA and duplex) and has the highest sensitivity and specificity.[6]

Selective carotid angiography is currently the gold standard for the assessment of carotid artery stenosis,although it is rarely performed in current practice. One of the limitations of invasive angiography is theinadequate description of the atherosclerotic plaque, while it is clearly associated with a 12% incidence ofstroke risk itself. Angioscopy, virtual histology, intravascular ultrasound, optical coherence tomography,

thermography and Raman spectroscopy have been used to characterize the carotid atherosclerotic plaque, butthe clinical importance of those findings remain to be described, as well as their potential risk of inducingiatrogenic stroke.

CAS/CEA Trials & Registries

The first large randomized study to demonstrate the feasibility and safety of percutaneous carotid interventionswas the CAVATAS study in 2001.[7] Despite the absence of embolic protection devices and the use of stents inonly 26% of the patients in the 'endovascular' arm, CAVATAS showed similar major risks and effectivenessbetween surgical and endovascular interventions in 3 years.

The SAPPHIRE trial was designed to prove the noninferiority of CAS versus CEA in high-risk patients forcarotid surgery who had symptomatic or asymptomatic carotid artery disease. [8] The cumulative incidence ofmajor cardiovascular events in 1 year, which included periprocedural events within the first 30 days (e.g.,death, stroke or myocardial infarction [MI]) showed a significant reduction of the primary composite end pointfor CAS compared with CEA (12.2 vs 20.1%). This 334 patient trial was criticized due to the high number ofpatients with carotid restenosis (20% in each group), who are known to do poorly with repeat CEA, the additionof MI in the primary end points, which was not used in the previously published CEA trials, and the selection ofa very 'sick' patient group with high morbidity and mortality rates.

Meta-analyses have shown that CEA is superior to CAS, especially regarding short-term outcomes, but thedifferences for intermediate-term outcomes are not significant.[912] It is important to recognize the heterogeneityof the studies included in those papers without the uniform use of stents or embolic protection devices.Furthermore, over the last decade, the carotid artery percutaneous techniques have undergone a tremendousevolution, with accumulation of experience and optimization of devices; therefore, studies performed byinexperienced operators in low-volume centers with older endovascular devices may not reflect the true valueof CAS today. This explains the diversity of results in different studies, which has been outlined in all meta-analyses.[912]

The CREST trial constitutes the largest randomized trial comparing CAS versus CEA for the treatment ofcarotid artery stenosis and for the prevention of stroke. A total of 2522 'standard-risk' patients with significantsymptomatic and asymptomatic carotid artery disease were randomized to CAS versus CEA. [13] CRESTshowed no significant difference in the 4-year primary end point rates between CAS and carotid CEA (7.2 vs6.8%). The periprocedural incidence of the primary end points was similar between CAS and CEA (5.2 vs4.5%), but there has been a lot of discussion and debate regarding the rates of the individual end points (death:0.7 vs 0.3%, p = 0.18; stroke: 4.1 vs 2.3%; p = 0.01; MI: 1.1 vs 2.3%; p = 0.03). The postprocedural incidenceof ipsilateral stroke was low in both CAS and CEA groups (2.0 vs 2.4%; p = 0.85). CREST also demonstratedthe feasibility of low periprocedural rates of stroke and death with CAS in symptomatic patients (6.0%) andasymptomatic patients (2.3%). Younger patients had slightly better outcomes with CAS, while older patients


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and females had slightly better outcomes with CEA. CREST is the first trial to show worse outcomes forfemales undergoing CAS in contrast to all the other trials (i.e., SPACE, ICCS and EVA3, among others). MIrates were clearly higher in patients undergoing CEA. Additionally, CREST investigated the rate of nonprimaryend point complications in both procedures that showed significantly decreased access site complications (1.1vs 3.7%) and cranial nerve injury (0 vs 5.3%) in CAS patients compared with CEA.

The most interesting message from CREST is the feasibility and safety of CAS in 'standard-risk' patients.

Furthermore, it needs to be mentioned that there was an important difference in 4-year outcome within CRESTfor patients suffering a procedural minor stroke and those sustaining a procedural MI. Patients sustaining MI,regardless of type, were statistically more likely to be dead at 4 years compared with those that did not.Patients suffering procedural minor stroke (more common among the CAS group) were at no more risk ofmortality than those who had an uncomplicated procedure.

European and Australian registries demonstrate a significant variation in clinical decision for carotidrevascularization. In a 48,185 patient European and Australian registry, CEA for the treatment of symptomaticcarotid artery disease varied from 31% in Italy to 100% in Denmark (average: 60.1%), while the overall strokeand death rate varied from 0.9% in Italy to 3.8% in Norway (average: 2.3%).[14] These differences probablyreflect variations in screening for carotid artery disease and different levels of approach for asymptomaticcarotid artery disease. CAS represented only 0.1% of the revascularization strategies in Denmark and less than7% in most participating countries, except Italy (17.4%) and Australia (11.7%).[14] However, CAS outcomesappear excellent with a 30-day stroke or death rate of 1.36%.[15]

Recent registries from 20,613 patients in New York and Florida from 2007 to 2009 who underwent CEA or CASshowed that CAS may be associated with increased mortality and stroke rates compared with CEA, especiallyin women.[16] It must be kept in mind that selection bias is an important parameter in the USA because untilJanuary 2012, the US FDA approval and the Center for Medicare and Medicaid Services reimbursementapplied only to high-risk patients (after the SAPHIRE trial). Therefore, almost all CAS procedures in thoseregistries are 'high-risk', while CEA is performed in healthier patients. Furthermore, ascertainment bias shouldbe considered as the majority of CAS procedures are performed either in postmarketing surveillance registriesor investigational device exemption trials in which the FDA mandates an independent neurological review. Anindependent neurological review of outcomes is associated with higher 30-day stroke and death rates.

CAS Today

Although rates of CEA have remained stable over the last decade, the use of CAS progressed dramatically

following the results of large randomized trials. CAS rates nearly doubled in 2005 after the publication of theSAPPHIRE trial and decreased by 22% after the publication of EVA-3S and SPACE in 2007.[17] A significantincrease is anticipated after the publication of CREST.

In Europe, the rates of CAS have increased from 1.1% in 2005 to 3.5% in 2010 with dramatic country-to-country variations ranging from 0 to 15% in the USA, from less than 3% in 1998 to 13% in 2008, while in

Australia, the rates have dropped from 14.4% in 2005 to 11.7% in 2010.[14]

In 2011, five international guideline committees (the American College of Cardiology/American HeartAssociation, the Society for Vascular Surgery, the European Society of Cardiology, the Australasian and theUK National Institute of Health and Clinical Excellence) published their recommendations for the managementof symptomatic and asymptomatic carotid artery disease. Major differences exist mainly regardingasymptomatic carotid artery disease from "no evidence to support CAS as a treatment for asymptomatic carotidstenosis" by the Australasian and NICE guidelines to "CAS may be considered as an alternative to CEA inhigh-volume centers" by the European Society of Cardiology guidelines. With regard to symptomatic carotid

artery disease, most committees agree that CAS should at least be considered as an alternative option inselected patient populations.[18]

The significant increase of CAS in the last year following the release of the CREST trial results has led to thepublication of the article 'Why the United States Center for Medicare and Medicaid Services should not extendreimbursement indications for carotid artery angioplasty/stenting' in four different peer-reviewed journals.[19] It isprobably the first time that an international team of specialists has made a public recommendation to Medicareagainst the extent of reimbursement to another specialty for a specific procedure.


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More than US$300 million have been spent in carotid trials from which $100 million were spent in CREST.There is already experience with 45,000 patients, 33 US registries, 13 randomized CAS clinical trials and 58years of experience with CEA and 15 years of experience with CAS. At experienced centers, both CEA andCAS appear to have low perioperative complications and excellent longer-term results. [13]

Conclusion

Despite the accumulation of experience in CAS over the last 15 years, the improvement of stent platforms andembolic protection devices, and the strong demand from the population for a less invasive alternative to CEA,the debate continues whether CAS is an equally efficient and safe procedure for the prevention of stroke. CASseems to be a relatively safe procedure for the prevention of stroke in selected patient populations, but for themajority, CEA remains as the treatment of choice.

The CREST trial suggested that both CAS and CEA are safe and effective choices for patients. They shouldnot be considered mutually exclusive but alternative and complimentary therapeutic methods. Thoughtfulpatient selection should direct them to the safest and most efficient option.

The development of centers of excellence, registries and the inclusion of carotid intervention training in thecurrent interventional or surgery training programs worldwide are needed to optimize the existing technicalskills and address further procedural improvements.

Current technology and research focuses on the accurate description of the carotid plaque and theidentification of high-risk patients for future events.

Over the last 20 years, coronary artery disease mortality has been declining steadily while the stroke mortalityrates have declined at a much slower rate. CAS represents an evolving and promising technology for thetreatment of carotid artery disease and the prevention of stroke. Effective collaboration between interventionalcardiologists, radiologists, vascular surgeons, neurointerventionalists and neurologists is needed for the battleagainst the stroke epidemic.

Future Perspective

CAS rates have increased slowly but steadily over the last years, mainly due to the uncertainty regarding thesafety and long-term outcomes of the procedure. After the publication of CREST, a dramatic increase ofcenters performing CAS is anticipated. Although it is unlikely that a larger randomized carotid arteryrevascularization trial may be published in the near future due to financial issues, it is certain that experience in

CAS will evolve, interventional techniques will improve, the industry will develop safer, more user-friendly andmore effective devices, and medical literature, noninvasive and invasive imaging will focus on the identificationof vulnerable plaques that will predict stroke in asymptomatic or symptomatic patients.

SidebarExecutive Summary

Stroke is the third leading cause of death and the most common cause of long-term disability in theUSA.

Approximately 25% of strokes are due to carotid artery disease.

Carotid duplex ultrasound, computed tomography angiography and magnetic resonance angiographyhave important limitations in the assessment of carotid artery disease.

The SAPPHIRE trial has proved the noninferiority of carotid artery stenting (CAS) versus carotidendarterectomy in high-risk patients with carotid artery disease. The CREST trial is the largestrandomized trial comparing CAS versus carotid endarterectomy and showed no significant differencesin death, stroke or myocardial infraction.

There are important variations in the CAS rates and national guidelines in different countries.

CAS rates have increased slowly but steadily over the last 10 years, but a dramatic increase isanticipated after the publication of the CREST trial.


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References

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2. Endarterectomy for asymptomatic carotid artery stenosis. Executive Committee for the AsymptomaticCarotid Atherosclerosis Study. JAMA273,14211428 (1995).

3. Brott TG, Halperin JL, Abbara S et al. 2011ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS guideline on themanagement of patients with extracranial carotid and vertebral artery disease: executive summary. Areport of the American College of Cardiology Foundation/American Heart Association Task Force onPractice Guidelines, and the American Stroke Association, American Association of NeuroscienceNurses, American Association of Neurological Surgeons, American College of Radiology, AmericanSociety of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imagingand Prevention, Society for Cardiovascular Angiography and Interventions, Society of InterventionalRadiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society forVascular Surgery. Circulation124,489532 (2011).

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* The NASCET trial: the first randomized trial to prove the noninferiority of carotid artery stentingcompared with carotid endarterectomy in high-risk patients.

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10. Bonati LH, Lyrer P, Ederle J, Featherstone R, Brown MM. Percutaneous transluminal balloonangioplasty and stenting for carotid artery stenosis. Cochrane Database Syst. Rev.9,CD000515(2012).

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randomised controlled clinical trials. BMJ340,c467 (2010).

12. Liu ZJ, Fu WG, Guo ZY, Shen LG, Shi ZY, Li JH. Updated systematic review and meta-analysis ofrandomized clinical trials comparing carotid artery stenting and carotid endarterectomy in the treatmentof carotid stenosis.Ann. Vasc. Surg.26,576590 (2012).

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** The CREST trial: the largest randomized trial to date comparing carotid artery stenting with carotidendarterectomy.

14. Vikatmaa P, Mitchell D, Jensen LP et al. Variation in clinical practice in carotid surgery in ninecountries 20052010. Lessons from VASCUNET and recommendations for the future of nationalclinical audit. Eur. J. Vasc. Endovasc. Surg.44,1117 (2012).

15. Stabile E, Garg P, Cremonesi A et al. European Registry of Carotid Artery Stenting: results from aprospective registry of eight high volume EUROPEAN institutions. Catheter Cardiovasc. Interv.80,329334 (2012).

16. Vouyouka AG, Egorova NN, Sosunov EA et al. Analysis of Florida and New York state hospitaldischarges suggests that carotid stenting in symptomatic women is associated with significant increasein mortality and perioperative morbidity compared with carotid endarterectomy. J. Vasc. Surg.56,334342 (2012).

17. Dumont TM, Rughani AI. National trends in carotid artery revascularization surgery. J.Neurosurg.116,12511257 (2012).

18. Paraskevas KI, Mikhailidis DP, Veith FJ. Comparison of the five 2011 guidelines for the treatment ofcarotid stenosis. J. Vasc. Surg.55,15041508 (2012).

* Comprehensive comparison of the most recent guidelines from the major societies internationally(the American College of Cardiology/American Heart Association, the Society for Vascular Surgery,the European Society of Cardiology, the Australasian and the UK National Institute of Health andClinical Excellence) for the treatment of carotid artery disease.

19. Abbott AL, Adelman MA, Alexandrov AV et al. Why the United States Center for Medicare andMedicaid Services (CMS) should not extend reimbursement indications for carotid arteryangioplasty/stenting. Eur. J. Vasc. Endovasc. Surg.43,247251 (2012).

Papers of special note have been highlighted as:

* of interest

** of considerable interest

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financialinterest in or financial conflict with the subject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents receivedor pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Future Cardiol. 2013;9(2):193-197. 2013 Future Medicine Ltd.

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