1 Extracranial Carotid DiseaseTodd W Gensler MD FACS Assistant Clinical Professor of Surgery Eastern Virginia Medical School Sentara Vascular Specialists Hampton Roads Virginia

2 Faculty Disclosure I have nothing to disclose

3 Educational Need/Practice GapGap = Difference between current practice and optimal practice relevant to the educational need Need = The issue/problem that underlies the practice gap

4 Objectives Describe indications for intervention Identify risk factors for open and endovascular approaches to treatment Discuss best medical therapy and its current role in management

5 Expected Outcome Critical appraisal of which patients should be chosen to undergo intervention for extracranial carotid disease Evaluation of appropriate modality of therapy for individual patient characteristics Institution of best medical therapy for all patients with extracranial carotid disease

6 Stroke Statistics About 795,000 Americans each year suffer a new or recurrent stroke. That means, on average, a stroke occurs every 40 seconds. Stroke kills more than 129,000 people a year. That's about 1 of every 18 deaths. It is the 5th leading cause of death. On average, every 4 minutes someone dies of stroke. Americans paid about $95 billion in 2015 for stroke-related medical costs and disability.

7 Carotid Disease & Stroke75% ischemic Most common source: extracranial carotid artery disease – 15-20% Embolic - plaque morphology; intraplaque hemorrhage and rupture Thrombotic – cardiac embolus, in-situ thrombosis of critical stenosis

8 DEBATES Which patients should undergo intervention? AsymptomaticIf intervention is indicated, what type of intervention should be performed? CEA Trans-femoral stenting TransCarotid Artery Revascularization (TCAR) What is best medical therapy and when is BMT a stand-alone “intervention”?

9 2012 Which Treatment Is Best for Asymptomatic Patients: Medical Management or Revascularization? CMS asked this question in January 2012 as part of a Medical Evidence Development and Coverage Advisory Committee (MEDCAC) public hearing A multidisciplinary panel heard presentations from physician-leaders with expertise in CEA, CAS, and medical stroke prevention The speakers provided a detailed summary of the evidence supporting available treatments and their own perspective on patient needs. The panel then questioned the designated speakers Members scored responses on a scale of 1 (low confidence) to 5 (high confidence

10 “How confident are you that there is adequate evidence to determine if persons who are asymptomatic with carotid atherosclerosis can be identified as being at high risk for stroke?” the mean score was 3 (range, 1 to 4) “For persons with asymptomatic carotid atherosclerosis who are not generally considered at high risk for stroke, how confident are you that there is adequate evidence to determine whether or not CAS or CEA or best medical therapy alone is the favored treatment strategy to decrease stroke or death?” the mean score was 2.89 (range, 1 to 5) “For persons with asymptomatic carotid atherosclerosis (≥ 60% by angiography or ≥ 70% by ultrasound) who are not generally considered at high risk for adverse events from CEA, how confident are you that there is adequate evidence to determine whether or not either CAS or CEA is the favored treatment strategy, as compared to best medical therapy alone, to decrease stroke or death?” the mean score was 2 (range, 1 to 5)

11 Event Rates in Patients With Carotid Artery Stenosis Managed Without Revascularization

12 A total of 1121 patients with asymptomatic carotid stenosis of 50% to 99% in relation to the bulb diameter (European Carotid Surgery Trial [ECST] method) underwent six monthly clinical assessments and carotid duplexes for up to 8 years (mean follow-up, 4 years). Progression or regression was considered present if there was a change of at least one grade higher or lower, respectively, persisting for at least two consecutive examinations Regression occurred in 43 (3.8%), no change in 856 (76.4%), and progression in 222 (19.8%) patients. For the entire cohort, the 8-year cumulative ipsilateral cerebral ischemic stroke rate was zero in patients with regression, 9% if the stenosis was unchanged, and 16% if there was progression (average annual stroke rates of 0%, 1.1%, and 2.0%, respectively) For patients with baseline stenosis 70% to 99%, in the absence of progression (n = 349), the 8-year cumulative ipsilateral cerebral ischemic stroke rate was 12%. In the presence of progression (n = 77), it was 21% (average annual stroke rates of 1.5% and 2.6%, respectively)

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14 Asymptomatic Disease—Consensus GuidelinesClass 1--Selection of asymptomatic patients for carotid revascularization should be guided by an assessment of comorbid conditions, life expectancy, and other individual factors and should include a thorough discussion of the risks and benefits of the procedure with an understanding of patient preferences. (Level C) Class IIa--It is reasonable to perform CEA in asymptomatic patients who have more than 70% stenosis of the internal carotid artery if the risk of perioperative stroke, MI, and death is low (Level A) Class IIb--Prophylactic CAS might be considered in highly selected patients with asymptomatic carotid stenosis (minimum 60% by angiography, 70% by validated Doppler ultrasound), but its effectiveness compared with medical therapy alone in this situation is not well established (Level B)

15 Symptomatic Disease Natural History of Ischemic StrokeHemorrhagic conversion – 4% asymptomatic, 0.6% symptomatic 26% little or no disability at 3 months 25% mild to moderate disability 27% severe disability 22% deceased at three months

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17 TIA/Non-disabling CVA within 120dSurgery compared with maximal medical tx Degree of stenosis based on duplex findings Study halted prematurely. Results published in 1991. 81% RRR in surgical group with stenoses >70% No benefit seen in stenoses <50%

18 Consensus Recommendations—Class 1Patients at average or low surgical risk who experience nondisabling ischemic stroke† or transient cerebral ischemic symptoms, including hemispheric events or amaurosis fugax, within 6 months (symptomatic patients) should undergo CEA if the diameter of the lumen of the ipsilateral internal carotid artery is reduced more than 70%‡ as documented by noninvasive imaging (Level of Evidence: A) or more than 50% as documented by catheter angiography (Level of Evidence: B) and the anticipated rate of perioperative stroke or mortality is less than 6%. CAS is indicated as an alternative to CEA for symptomatic patients at average or low risk of complications associated with endovascular intervention when the diameter of the lumen of the internal carotid artery is reduced by more than 70% as documented by noninvasive imaging or more than 50% as documented by catheter angiography and the anticipated rate of periprocedural stroke or mortality is less than 6%. (Level of Evidence: B)

19 Timing of Carotid InterventionHistorically done frequently and early ~ 1960s Increase M&M – ischemic infarct  hemorrhagic infarct 4-6 weeks interval of waiting Up to ~21% stroke risk in that period < 2 weeks mild to moderate neurologic deficit Less than 1/3 of MCA distribution with Ischemia No uncontrolled HTN Appropriately select patients

20 Consensus Recommendations—Class IIaWhen revascularization is indicated for patients with TIA or stroke and there are no contraindications to early revascularization, intervention within 2 weeks of the index event is reasonable rather than delaying surgery (Level of Evidence B)

21 Consensus Recommendations--Class IIIExcept in extraordinary circumstances, carotid revascularization by either CEA or CAS is not recommended when atherosclerosis narrows the lumen by less than 50%. (Level of Evidence: A) Carotid revascularization is not recommended for patients with chronic total occlusion of the targeted carotid artery. (Level of Evidence: C) Carotid revascularization is not recommended for patients with severe disability¶ caused by cerebral infarction that precludes preservation of useful function. (Level of Evidence: C)

22 Modality of Therapy Carotid Endarterectomy Trans-femoral Carotid StentTransCarotid Artery Revascularization

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24 Randomized Stent TrialsEVA-3S SPACE ICSS

25 Randomized Stent TrialsCREST ACT-1

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29 ICSS Prospective Randomized Trial comparing CEA w/ CAS in Sx Pts50 Academic Ctrs in Europe, Australia, New Zealand, and Canada 1° 120 days included Death, Stroke, or Procedural MI

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31 RCT Transfemoral Carotid Stenting

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33 1° Endpoints Peri-Procedural (≤30d) Post-Procedural (30d+)Stroke (either hemisphere) MI Death Post-Procedural (30d+) Ipsilateral Stroke

34 CREST R ANDOMIZATION

35 CREST OUTCOMES

36 PRIMARY ENDPT CEA CAS P VALUE DEATH, ST, MI 61 (4.9%) 75 (5.9%) 0.38 DEATH 4 (0.3%) 9 (0.7%) 0.18 STROKE 29 (2.3%) 52 (4.1%) 0.01 MI 61 (4.8%) 33 (2.6%) 0.005

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38 ? CREST DESIGN FLAW DEATH=STROKE=MISIMPLE ADDITION OF PRIMARY ENDPOINTS IMPLIES THAT DEATH=STROKE=MI ALL PRIMARY ENDPOINTS ARE IMPORTANT, BUT SHOULD BE WEIGHED ACCORDING TO SEVERITY

39 WHY WAS THERE A HIGHER MI RATE W/ CEA IN CREST?10y ago BMT did not include statins and Beta blockers pre-op CAS patients were on dual anti-platelet therapy (Plavix and ASA) but CEA patients were on ASA alone

40 WHY WAS THERE A HIGHER RATE OF STROKE WITH CAS?

41 WHY WAS THERE A HIGHER RATE OF STROKE WITH CAS?Long lesions > 12.85mm Sequential lesions Distal lesions Type 3 Aortic arch Atherosclerotic aortic arch Tortuosity of the ICA Circumferential calcification Ulcerative lesions

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44 SURVIVAL In CREST, survival among CEA and CAS patients was identical due to the surprising finding that stroke, even minor, compromised survival similar to MI

45 10 yr DATA

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49 ACT-1 Cumulative 5 yr stroke free survival1453 pts with asymptomatic, >70% carotid stenosis, not high risk CEA CAS with distal embolic protection Stenting was noninferior to endarterectomy with regard to the primary composite end point (stroke and death) S/D at 30 days 2.9% CAS and 1.7% CEA (p=.33) 30 days to 5 yrs, freedom from ipsilateral stroke 97.8% CAS and 97.3 CEA% (p=.51) Cumulative 5 yr stroke free survival 93.1% CAS and 94.7% CEA (p=.44)

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51 TCAR Sx pts ≥ 50% and Asx pts ≥ 70% with high risk criteria for CEA1° endpoint All stroke, death, 30 d 2° endpoints CN injury All stroke, death, MI, stroke/death Acute device, technical, and procedural success Access complications

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53 ROADSTER Pivotal Single arm trial – 141 patients 26% symptomaticOver 50% performed using MAC/local anesthetic 99% technical, and 96% procedural success rates Combined stroke/death rate of 2.8% (4 patients, 1 with minor stroke). Incidence of microemboli as seen on MRI equivalent to CEA (17 – 19%), and significantly less than transfemoral CAS (73%).

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58 Carotid revascularization for primary prevention of stroke (CREST-2) is two independent multicenter, randomized controlled trials of carotid revascularization and intensive medical management versus medical management alone in patients with asymptomatic high-grade carotid stenosis.

59 CREST-2 One trial will randomize patients in a 1:1 ratio to endarterectomy versus no endarterectomy and another will randomize patients in a 1:1 ratio to carotid stenting with embolic protection versus no stenting. Medical management will be uniform for all randomized treatment groups and will be centrally directed

60 CREST-2 Primary Outcome Measures:Stroke and death [ Time Frame: 4 years ] The primary outcome is the composite of stroke plus death within 44 days after randomization and ipsilateral stroke thereafter up to 4 years. Secondary Outcome Measures: Cognitive Function [ Time Frame: 4 years ] To assess if MEDICAL management differs from CAS, and differs from CEA, to maintain the level of cognitive function at the 4-year assessment. Major Stroke [ Time Frame: 4 years ] if there are treatment differences in the incidence of major stroke at 4-years among all arms of the study Effect modification [ Time Frame: 4 years ] Potential effect modification of the CAS or CEA versus MEDICAL differences, based on patient age, sex, severity of carotid stenosis, restenosis, risk factor level, and duration of asymptomatic period.

61 CREST-2 CREST-2 is enrolling 2,480 patients at 120 centers in the United States and Canada Patients must have at least 70 percent stenosis and be asymptomatic, defined as having no stroke or stroke-like symptoms ipsilateral to the stenosis within 180 days of randomization in the trial Modeling clinical practice, referring physicians will recommend appropriate revascularization — surgery or stenting — for each patient, based on clinical, radiologic and angiographic assessment, demographic information, and patient preference Patients in each group will then be randomized to receive medical management alone or medical management plus revascularization

62 CREST-2 In many cases the patient may be a candidate for either surgery or stenting, but just as patients in standard practice can't have both procedures, trial participants will select a procedure after informed consideration and discussion with the physician CREST-2 has a detailed protocol for medical management of all trial participants, targeting optimal lipid profiles, blood pressure, glycemic control, smoking cessation, ideal body mass index, nutritional and dietary recommendations, and physical activity and exercise

63 Is “asymptomatic” carotid disease really asymptomatic?Cross sectional studies associate asymptomatic carotid disease to current cognitive impairment: Chang et al; Neurosci Biobehav Rev 2013; 37(8): Review: 7/8 studies supported the association Suemoto et al; Atherosclerosis 2015; 243(2): Jackson et al; Arch Clin Neuropsychol 2016: 31(1): 1-7 Longitudinal studies associate carotid disease to future cognitive decline: Zhong et al; Atherosclerosis 2012; 224: Arntzen et al; Cerebrovasc Dis 2012; 33: Romero et al;Stroke 2009; 40: Johnston et al; Ann Intern Med 2004; 140:

64 Proposed mechanisms of impairmentMicroembolic events Hypoperfusion Carotid disease is a marker of small vessel disease

65 Cerebral Perfusion Principles

66 Impaired Autoregulation?Balestrini et al; Neurology 2013; 80: TCD breath holding index (BHI) severe unilateral asymptomatic pts Abnormal BHI Odds Ratio 14.6 for cognitive decline over 3 years Buratti et al; J Cereb Blood Flow Metab 2015 Oct TCD breath holding index in asymptomatic pts Abnormal BHI => 44% declined; Normal BHI => 9% declined over 1 year Avirame et al; J Cereb Blood Flow Metab 2015: 35: TCD and CO2 challenge and resting state fMRI Ipsilateral hemisphere vasomotor reactivity (VMR) was lower Reduced VMR correlated with reduced functional connectivity

67 Mechanism of Cognitive DeclineIf this was generalized small vessel ischemic disease we would expect more similar responses in each hemisphere independent of unilateral carotid disease; postulated exhausted autoregulation

68 What is the effect of revascularization?Lun et al; Cerebrovasc Dis 1999; 9(2)74-81 Systematic Review of Cognitive Changes from CEA 16/28 studies showed benefit; 12/28 no change Studies after 1984 tended to report no change No conclusion could be drawn Pettigrew et al; Neurology 2000; 55(1): 30-34 ACAS study CEA vs Best Medical therapy – 5 year MMSE (Mini-Mental State Exam) Mean age 67, MMSE scores in both groups, n=1,662 No group difference over the 5 years, slight overall decline

69 Who benefits the most? Ghogawala et al; J Stroke Cerebrovasc Dis 2013; 22 (7): Prospective MRI perfusion study before/after CEA Post-operative MCA flow improvement was the best predictor of cognitive improvement Huang et al; J Am Coll Cardiol 2013; 61:2503-9 Prospective CT perfusion study on patients undergoing CAS Baseline perfusion deficit predicted cognitive benefit Akioka et al; Q J Nucl Med Mol Imaging 2015 (Epub) SPECT study in 109 patients undergoing CEA or CAS Cerebral blood flow and reactivity to acetazolamide measured Group 1=nl flow/reactivity; Group 2=nl flow, low reactivity; Group 3 = low flow, low reactivity; all had similar white matter burden All groups improved, with disproportionate improvement in group 3

70 Cognitive Impairment and Asx Carotid DiseaseCarotid disease is associated with cognitive impairment by cross-sectional and longitudinal data The association is not explained by vascular risk factors or small vessel ischemic changes on MRI No clear superiority of CAS or CEA; efficacy data are mixed in terms of cognitive improvement vs decline Poor baseline perfusion and/or vasoreactivity may predict improvements with revascularization

71 Should memory evaluations routinely include carotid artery studies?Not yet…. Future studies should: Select revascularization candidates on the basis of cognitive impairment Executive domain, Mild Cognitive Impairment Include perfusion and/or reactivity measures to select potential candidates Randomize against best medical therapy