I have the following potential conflicts of interest to report. honorarium: 1. St Jude Medical 2. Biotronik 3. Boston Scientific

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1 Stenting carotideo nel paziente sintomatico alla luce dei nuovi trials Savona, 11 Aprile 2015 Gioel GabrioSecco, MD, PhD Emodinamica e CardiologiaInterventistica Ospedale SantiAntonio e Biagio e Cesare Arrigo Alessandria

2 I have the following potential conflicts of interest to report Consulting, research grants, travel reimbursement, speaker Consulting, research grants, travel reimbursement, speaker honorarium: 1. St Jude Medical 2. Biotronik 3. Boston Scientific

3 10-15% percent of all ischemic strokes originate from a stenosis at the level of the internal carotid artery; In patients with carotid disease, the purpose of carotid revascularization is the prevention of (recurrent) stroke; For more than 50 years CEA has been considered the gold-standard treatment for severe asymptomatic and symptomatic carotid stenoses; CAS has emerged in the last 15 years as minimally invasive alternative to surgery However, its role remains highly controversial; The debates has been fueled by the multiples medical specialties involved and by the disappointing results of CAS in randomized comparisons with CEA; While some have interpreted those findings as clear-cut clinical evidence, other have suggested that most of the trials may have compared the two revascularization modalities in an unfair way.

4 Alternative: A thing you can chose to do out of two or more possibilities Is CAS an alternative to CEA in symptomatic patients? Technical Scientific aspects evidence

5 CEA CAS is an indisputable Alternative to CEA CAS

6 6 trials have randomized >300 patients to CAS vs. CEA: SAPPHIRE trial: high risk for surgery - symptomatic and asymptomatic; CAVATAS trial; SPACE trial; EVA-3S trial; standard risk for surgery only symptomatic patients ICSS trial; CREST: standard risk for surgery symptomatic and asymptomatic

7 performed in the late 1990s; randomized 504 symptomatic ptsat low to moderate risk for surgery to CEA or CAS; The incidence of death or stroke at 30 days was 10.0% in the endovascular group and 9.9% in the surgical group; The study was criticized by the interventional community for the low stenting rate (26%) and the lack of EPDs, unavailable at the time; At 8 years, no differencein ipsilateralstroke, ipsilateralstroke or transient ischemic attack, or any stroke between the two arms was observed.

8 Randomized 334 both asymptomatic (71%) and symptomatic (29%) ptsat a high risk for surgery to CAS with the systematic use of EPDs or CEA; The primary endpoint (a composite of death, stroke, or MI within 30 days after the intervention or death or ipsilateralstroke between 31 days and 1 year) showed a trend in favor of CAS(12.2% vs. 20.1% -p = 0.053); Patients who underwent CAS had significantly fewer myocardial infarctionsat 30 days (1.9% vs. 6.6%, p = 0.04); At 3 year follow-up, CAS and CEA were equally effectivein terms of stroke prevention.

9 Included 1,200 participants and was terminated because of slow enrollment and lack of funding; Found no difference in the incidence of ipsilateralstroke or death at 30 days between patients allocated to CAS or CEA, with an event rate of 6.8% and 6.3%, respectively; EPDs were used in a minority of CAS patients; At 2 years, the outcomes of the two groups were comparable

10 Included 527 patients, was stopped prematurely because of a significantly increased event rate among CAS patients(death or stroke 9.6% vs 3.9%); At 6 months, the incidence of any stroke or death was 11.7% in the CAS group and 6.1% in the CEA group (p = 0.02); This study was heavily criticized for the minimal requirements in terms of endovascular experience; In the endovascular arm, 39%of patients were treated by a physician in training; At 4 year follow-up, the death or stroke rate still favored CEA, driven by the 30 day events; However, beyond 30 days, no difference in adverse outcomes between CAS and CEA was observed

11 Randomized 1,713 symptomatic patients to CAS or CEA; The primary endpoint was the long-term rate of any fatal or disabling stroke; The authors reported first an interim safety analysis: the 120-day rate of stroke, death, or procedural MI occurred in 8.5% in CAS vs5.2% in CEA(p = 0.006); The incidence of disabling stroke or death at 120 days did not differ (4.0% vs3.2%); The use of EPD was not mandatory in this trial; The 5-year risk incidence of fatal or disabling stroke did not differ between CAS (6.4%) and CEA (6.5%); Beyond 30 days after treatment, there was no difference in the rates of ipsilateral stroke in the territory of the treated carotid artery (4.7% for CAS vs. 3.4% for CEA)

12 Randomized 2,502 symptomatic and asymptomatic pts to CAS with EPDs or CEA; The primary composite endpoint was stroke, MI, or death from any cause during the periprocedural period or ipsilateral stroke within 4 years after randomization; Over a median follow-up period of 2.5 years, there was no significant difference in the estimated 4 year rates of the primary endpoint between the CAS group and the CEA group (7.2% and 6.8%-p = 0.51); The 4 year rate of stroke or death was 6.4% with CAS and 4.7% with CEA (p = 0.03); Periproceduralrates of individual components of the endpoints differed between the CAS and CEA groups for stroke (4.1% vs. 2.3%, p = 0.01) and MI (1.1% vs. 2.3%, p = 0.03); After this period, the incidence of ipsilateralstroke with stenting and with endarterectomywas similarly low (2.0% and 2.4%-p = 0.85); Finally, in CREST, there was an association between periproceduralmi more common in the CEA arm and long-term mortality.

13 50% Trial Enrollment August 2006 First Lead-in patient Lead-in Phase completed N=1,564 Randomization Phase completed 1 year follow-up completed NIH Analysis

14 SPACE-2 study: -started in 2009 to compare state-of-the art medical prevention vscea and CAS in pts with severe asymptomatic carotid stenosis.: -SPACE-2A: CEA + best medical treatment vs. best medical treatment alone -SPACE 2B: CAS + best medical treatment vs. best medical treatment alone ACST-2 -is randomizing up to ptswith severe asymptomatic carotid stenosis to CEA or CAS. -30-day major event rates without splitting it for treatment modality for 691 patients showing an encouraging disabling stroke, fatal MI, and death rate of 1.0% ACT-I -randomized asymptomatic patients to CAS vs. CEA in a 3:1 ratio. The study has been prematurely halted after the enrollment of approximately 1600 pts

15 CREST-2 study is composed of two RCTs of carotid revascularization and best medical management versus medical management alone in patients with asymptomatic highgrade carotid stenosis. -One trial will randomize patients in a 1:1 ratio to CEA vs. no CEA -One trial will randomize patients in a 1:1 ratio to CAS vs. no CAS. no new randomized data will be gathered in the next years for the most important question: CAS vscea in symptomatic patients. For asymptomatic patients some, likely non-conclusive, information should be gathered e from the ACT-1 trial, while from the most important trial, namely ACST-2, likely no data will be available for several years to come. Finally, both SPACE-2 and CREST-2, if completed, will allow only indirect comparisons of CAS vs. CEA.

16 In the light of RCTs findings, is this the time to quit CAS? YES Time has come to stop inappropriate approach to CAS

17 Inexperience of the EVA-3S, SPACE, and ICSS investigators patients exposed to a two-fold increased risk - insufficient operator skills - inappropriate patient selection

18 The consistency of the results suggests the presence of a learning curve SmoutJ, Macdonald S, Weir G et al. Carotid artery stenting: relationship between experience and complication rate. International Journal of Stroke 2010.

19 Normal CCA No arch disease Diseased CCA Normal CCA Arch atheroma Diseased CCA Bovine Normal arch Bovine + Type III Type III Arch Diseased / not diseased Arch Normal / bovine / type III CCA Normal / diseased Distal ICA Normal / tortuous Lesion standard / pinhole Straightforward Difficult

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21 Combined A total of 24 studies with concurrently reported protected and unprotected data The relative risk (0.59) of total stroke was significantly lower (p < 0.05) for protected compared to unprotected CAS. Garg N, et al. J ENDOVASC THER 2009;16:

22 A Meta-analysis analysis of Proximal Occlusion Device Outcomes in Carotid Artery Stenting Robert M. Bersin, MD, MPH, FACC, FSCAI Medical Director, Endovascular Services Swedish Medical Center, Seattle, Washington R. Bersin et al, Catheterization and Cardiovascular Interventions, 2012

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24 When patient evaluation doesn t include pre- procedural information on aortic arch and supra-aortic aortic trunk anatomy. When CAS is performed without adequate cerebral protection. EVA 3S SPACE ICSS When CAS is performed with limited requirements for endovascular expertise.

25 No EPD Consistency + Inexperienced CAS Operators = Poor CAS Results ICSS, EVA-3S, SPACE EPD Mandatory + Credentialed CAS Operators = Positive CAS Results CREST and other RCTs/PCTs* * PCT: Prospective Controlled Trial

26 CAS alternative to CEA for stroke prevention CAS therapeutic option for all interventionalists Complex but applicable Absolutely not applicable

27 30d MANE rate vs enrollment start and duration

28 Protected carotid artery stenting, if performed in experienced centers with adequate techniques and by trained physicians, is a safe, effective and durable therapy, with low peri-operative complications and excellent long-term results. For the future, both CEA and protected CAS appear to be equally reliable therapeutic strategiesfor preventing stroke. Conclusion

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