Asymptomatic carotid disease in patients with CAD in light of emerging stent and balloon technologies: is conservative treatment still appropriate?

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1 Asymptomatic carotid disease in patients with CAD in light of emerging stent and balloon technologies: is conservative treatment still appropriate? Salim Harris 1 1 Department of Neurology, Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia. Correspondence mail: Department of Neurology, Faculty of Medicine Universitas Indonesia. Jl. Salemba Raya no. 6 Jakarta 10430, Indonesia. salim.haris@ui.ac.id Abstract It has been known that coronary artery disease is strongly related to cerebrovascular events, such as carotid stenosis, due to atherosclerosis. A study in Japan concluded that the severity of coronary artery disease is strongly related to carotid stenosis. Therefore, carotid stenosis screening should be advised to all patients with CAD. This results in the emerging diagnosis of asymptomatic carotid disease. However, the management of asymptomatic carotid disease is still uncertain. While surgery (endarterectomy or stenting) was presumed to provide a better outcome, several risks should take into account. In this review, we aim to provide the justification of risk and favorable outcome between surgical treatment and medication treatment. Keywords: Asymptomatic carotid disease, coronary artery disease, medication, surgical. Introduction Recently, atherosclerosis has become a common pathology found all over the world. This has been a major cause for coronary artery disease. Unfortunately, atherosclerosis also a cause of carotid artery disease. As a consequences, coronary artery disease (CAD) and carotid disease is strongly related to each other. 1 3 A study in Japan reported high incidence of carotid disease in patients who underwent coronary artery bypass graft (CABG) due to severe CAD. 4,5 Another study showed that carotid stenosis observed by echography and angiography are strongly related to the severity of CAD. Echographic carotid stenosis was found in 36%

2 patients with 3-vessel CAD, 21.4% in patients with 2-vessel CAD, 14.5% in patients with 1- vessel CAD, and 7% in patients with 0-vessel CAD. Meanwhile, angiographic carotid stenosis found in 19.4% patients with 3-vessel CAD, 7.5% in patients with 2-vessel CAD, 3.4% in patients with 1-vessel CAD, and 2.1% in patients with 0-vessel CAD. 6 Wanamaker et al. did a carotid ultrasonography in 673 patients who underwent CABG to found probable risk factors of carotid artery stenosis (CAS). Significant stenosis defined as >50% stenosis while severe stenosis defined as >70% stenosis. This study identifies that age (>68.6), female gender, hypertension, prior stroke, dialysis, peripheral vascular disease (PVD) and left main disease are independent risk factors for significant carotid stenosis (>50%). 7 This results are similar to other study which showed that PVD, end stage kidney disease, advanced age and prior stroke are co-morbidities associated with CAS Moreover, history of stroke, PVD, and left main disease are strong predictors for severe stenosis (>70%). 7 More severe carotid artery stenosis leads to increased cerebrovascular events, such as stroke. Some specific features of carotid atherosclerosis were known as important factors, such as ulcerated/irregular plaques, intra-plaque hemorrhages, lipid-rich plaque, thin or ruptured fibrous cap plaque, and necrotic lipid core. Therefore, it is important to early recognize and appropriately treat CAS. 11 Asymptomatic carotid disease Asymptomatic carotid disease defined as hemodynamically significant stenosis resulting in decrease of pressure or flow of blood vessel, or both. 1 The diagnosis of asymptomatic carotid disease requires a duplex ultrasonography (US) or magnetic resonance (MR) angiography. Duplex ultrasonography which is less expensive and non-invasive does not directly measure the diameter of stenotic lesion, instead it measures blood flow velocity as indicator for severity. Therefore, it is less accurate in differentiating high-grade stenosis from a total occlusion. Indication for duplex US in asymptomatic carotid stenosis are as follows: Carotid bruit (Class IIa, level C) 2. Symptomatic peripheral arterial disease (Class IIb, level C) 3. Coronary artery disease (Class IIb, level C) 4. Atherosclerotic aortic aneurysm (Class IIb, level C) 5. Absence of clinical evidence of atherosclerosis but 2 risk factors including (Class IIb, level C)

3 a. Hypertension b. Hyperlipidemia c. Tobacco smoking d. First-degree relative with atherosclerosis diagnosed at < 60 years old e. Family history of ischemic stroke 6. Elective or urgent CABG MR angiography used to define the severity of stenosis, by a method in north American symptomatic carotid endarterectomy trial (NASCET) or European carotid surgery trial (ECST); although it sometimes overestimates the degree of stenosis, leading to a false positive result. 12 Fig 1. NASCET and ESCT study in measuring severity of the stenosis 12 Recently, the American heart association recommends carotid endarterectomy in patients with carotid artery stenosis as follows.

4 Table 1. AHA recommendations for carotid endarterectomy in carotid artery stenosis. 12 Stenosis (%) Recommendations Level of recommendations Symptomatic stenosis High grade ( 70%) Moderate ( 50 and <70%) CEA by a surgeon with perioperative mortality rate <6% CEA, depending on patientspecific factors such as age, sex, comorbidities and severity of symptoms Class I Level of evidence A Class I Level of evidence A Mild (<50%) No indications for CEA Class I Level of evidence A Asymptomatic stenosis High grade ( 60%) CEA: Carotid endarterectomy. Data taken from [82]. CEA when performed by a surgeon with a perioperative mortality rate of <3% Class I Level of evidence A However, despite the recommendations, there is still no consensus whether asymptomatic carotid stenosis patients should be revascularized. 13 It is still uncertain whether surgery beneficial to reduce stroke or death risk in patients with asymptomatic carotid stenosis. On the other hand, stroke risk was significantly decreased (<1%/year) in asymptomatic carotid patients who received medical treatment. 14 So, what is the justification for surgery in patients with asymptomatic carotid stenosis in terms of reducing death and stroke risk? Optimal medication treatment (OMT) Considering the unestablished reduced risk and monetary value of surgery, the treatment of asymptomatic carotid stenosis is now focused in medical treatment. Some trials provide a better outcome in the use of statin therapy, strict blood pressure control, and effective antiplatelet regimes. An ACST (asymptomatic carotid surgery trial) showed similar risk reduction in patients received medical treatment and endarterectomy 15. Moreover, stroke risk was lower in patients taking lipid-lowering drugs. Another randomized trial showed that statins lower stroke risk by a third and halve the numbers requiring revascularization in patients with cerebrovascular disease 16,17. Nowadays, medical treatment is considered a standard treatment for asymptomatic carotid stenosis; thus, reducing the need of stenting and endarterectomy. 13 It is recommended to maintain blood pressure <140/90 mmhg, but there is no specific target due to limited trial of carotid stenosis. In addition, aspirin, diet, exercise, glucose-lowering

5 drugs for diabetes mellitus patients were recommended for prevention of events. Lifestyle modification such as smoking cessation and reduction of body weight may also beneficial to reduce carotid disease risk. 13 Surgical treatment CREST study assess the efficacy of stenting and endarterectomy for carotid artery stenosis. The study includes symptomatic stenosis with ³ 50% stenosis on angiography, or ³ 70% on ultrasonography, or ³ 70% on CTA/MRA if ultrasonography was 50-69% and asymptomatic stenosis with ³ 60% stenosis on angiography, or ³ on ultrasonography, or ³ 80% on CTA/MRA if ultrasonography was 50-59%. The study showed that periprocedural events such as myocardial infarction, stroke, and death was higher in those receiving carotid artery stenosis (CAS) compared to carotid endarterectomy (CEA). Moreover, stroke and death in 4-year follow up also higher in CAS group compared to CEA. 18 End Point Table 2. Periprocedural events between CEA and CAS group 18 CAS (N = 1262) CEA (N = 1240) no. of patients (% ±SE) Periprocedural Period Absolute Treatment Effect of CAS vs. CEA (95% CI) percentage points Hazard Ratio for CAS vs. CEA (95% CI) P Value Death 9 (0.7±0.2) 4 (0.3±0.2) 0.4 ( 0.2 to 1.0) 2.25 (0.69 to 7.30) 0.18 Stroke Any 52 (4.1±0.6) 29 (2.3±0.4) 1.8 (0.4 to 3.2) 1.79 (1.14 to 2.82) 0.01 Major ipsilateral 11 (0.9±0.3) 4 (0.3±0.2) 0.5 ( 0.1 to 1.2) 2.67 (0.85 to 8.40) 0.09 Major nonipsilateral 0 4 (0.3±0.2) NA NA NA Minor ipsilateral 37 (2.9±0.5) 17 (1.4±0.3) 1.6 (0.4 to 2.7) 2.16 (1.22 to 3.83) Minor nonipsilateral 4 (0.3±0.2) 4 (0.3±0.2) 0.0 ( 0.4 to 0.4) 1.02 (0.25 to 4.07) 0.98 Myocardial infarction 14 (1.1±0.3) 28 (2.3±0.4) 1.1 ( 2.2 to 0.1) 0.50 (0.26 to 0.94) 0.03 Any periprocedural stroke or postprocedural ipsilateral stroke 52 (4.1±0.6) 29 (2.3±0.4) 1.8 (0.4 to 3.2) 1.79 (1.14 to 2.82) 0.01 Major stroke 11 (0.9±0.3) 8 (0.6±0.2) 0.2 ( 0.5 to 0.9) 1.35 (0.54 to 3.36) 0.52 Minor stroke 41 (3.2±0.5) 21 (1.7±0.4) 1.6 (0.3 to 2.8) 1.95 (1.15 to 3.30) 0.01 Any periprocedural stroke or death or postprocedural ipsilateral stroke Primary end point (any periprocedural stroke, myocardial infarction, or death or postprocedural ipsilateral stroke) 55 (4.4±0.6) 29 (2.3±0.4) 2.0 (0.6 to 3.4) 1.90 (1.21 to 2.98) (5.2±0.6) 56 (4.5±0.6) 0.7 ( 1.0 to 2.4) 1.18 (0.82 to 1.68) 0.38

6 Table 3. Events at 4-year follow up 18 and patients may have had an ipsilateral stroke known to cause more arterial term followed for age). by a nonipsilateral embolism The analyses stroke). of in age older were planned age due of Research to Integrity vascular of the tortuosity Department of Health and 16 at 1 year, as assessed with the use of the SF undergoing carotid endarterectomy) were excluded 0.54 or before more than any analyses 1.49 with were performed, result- per limit of the normal physical range or and higher mental according health scales. end point These of models less than to the center s laboratory, were adjusted in addition for symptomatic either stenting status, as sex, compared age, ing with in a endarterectomy, cohort of 2502 patients approximating an absolute Dyslipidemia difference of 1.2 was percent- more common among pa- for all analyses. chest pain or symptoms and consistent baseline health with ischemia status. or ECG evidence of ischemia, including new STsegment depression or elevation of more Results than point between the two those treatment in the groups. stenting Inten- group (85.8% vs. 82.9%, age points per year in tients the rate in of the the endarterectomy primary group than among 1 mm in two or more contiguous leads according tion-to-treat survival analysis P = 0.048), was both used, groups and Kaplan Meier survival curves risk factors, were plotted. and more Two than in- 80% of patients had had high rates of vascular to the core laboratory. Study 17 Population and Treatments From December 2000 through terim July 2008, analyses a total were severe performed stenosis with (Table the use 1). Baseline of characteristics Statistical Analyses of 2522 patients were randomly O Brien Fleming assigned to one boundaries, are reported 18 the according first after to approximately After randomiza- one fifth Tables of the patients 2 and 3 had in the been Supplementary re- Appendix. symptomatic status in Analyses were aimed at of testing the two for treatments superiority. (Fig. The 1). null hypothesis was that tion, the among two study the 1271 treatments patients cruited, randomly and assigned the second The after median approximately time from half randomization to the are equivalent; the alternative to undergo hypothesis carotid-artery was that stenting, the patients 36 (2.8%) had withdrew A sample consent, size 73 of (5.7%) 2500 pa- underwent tion techniques carotid end- 19 were and used 7 days to assess for carotid bias from endarterectomy. Stenting been procedure recruited. was Multiple-imputa- 6 days for carotid-artery stenting the treatments differ. tients was selected to arterectomy, provide a statistical and 33 (2.6%) power were differential lost to rates followup; among ratio the for 1251 the primary patients assigned the two groups. to carotid of patients assigned to the stenting group, and of withdrawal was performed from with the study embolic in protection in 96.1% of 90% to detect a hazard Downloaded from nejm.org at University of Notre Dame Aus on April 24, For personal use only. No other uses without permission. Figure 2. Primary end-point hazard ratio between CEA and CAS. Primary end-point: composite of stroke, myocardial infarction, or death from any cause during the periprocedural period or ipsilateral stroke within 4 years after randomization. 18 Furthermore, Wallaert et al. assess factors associated with 5-year survival after carotid The new england Stenting journal vs. Endarterectomy of medicine for Carotid-Artery Stenosis Table 2. Primary End Point, Components of the Primary End Point, and Other Events, According to Treatment Group.* End Point n engl j med 363;1 nejm.org n engl july j med 1, ;1 nejm.org july 1, Yr Periprocedural Study Period Period (Including Periprocedural Period) Absolute Treatment Absolute Hazard Treatment Ratio for Effect of CAS vs. CEA Effect of CAS CAS vs. vs. CEA CEA Hazard Ratio for CAS vs. CEA CAS CAS (N (N = 1262) = 1262) CEA (N = 1240) CEA (N = 1240) (95% CI) (95% CI) (95% CI) P Value (95% CI) P Value no. of patients no. of patients (% ±SE) (% ±SE) percentage points percentage points Death 9 (0.7±0.2) 94 (11.3±1.2) 4 (0.3±0.2) 83 (12.6±1.5) 0.4 ( 0.2 to 1.0) 1.3 ( (0.69 to 2.5) to 7.30) (0.83 to 1.51) 0.45 Stroke Any (4.1±0.6) (10.2±1.1) 29 (2.3±0.4) 75 (7.9±1.0) 1.8 (0.4 to 3.2) 2.3 ( (1.14 to 5.2) to 2.82) (1.04 to 1.89) 0.03 Major ipsilateral 11 (0.9±0.3) 16 (1.4±0.3) 4 (0.3±0.2) 6 (0.5±0.2) ( 0.1 to 1.2) 0.8 ( to ( ) to 8.40) (1.00 to 6.54) 0.05 Major nonipsilateral 0 6 (0.9±0.4) 4 (0.3±0.2) 8 (0.8±0.3) NA 0.1 ( 0.9 to 1.1) NA 0.73 NA (0.25 to 2.11) 0.56 Minor ipsilateral 37 (2.9±0.5) 52 (4.5±0.6) 17 (1.4±0.3) 36 (3.5±0.6) 1.6 (0.4 to 2.7) 1.0 ( (1.22 to 2.7) to 3.83) (0.94 to 2.19) 0.10 Minor nonipsilateral 4 (0.3±0.2) 33 (4.0±0.8) 4 (0.3±0.2) 29 (3.8±0.9) 0.0 ( 0.4 to 0.4) 0.2 ( (0.25 to 2.4) to 4.07) (0.67 to 1.82) 0.69 Myocardial infarction 14 (1.1±0.3) 28 (2.3±0.4) 1.1 ( 2.2 to 0.1) 0.50 (0.26 to 0.94) 0.03 Any periprocedural stroke or postprocedural ipsilateral stroke 52 (4.1±0.6) 72 (6.2±0.7) 29 (2.3±0.4) 50 (4.7±0.7) 1.8 (0.4 to 3.2) 1.5 ( (1.14 to 3.4) to 2.82) (1.00 to 2.06) Major stroke 11 (0.9±0.3) 16 (1.4±0.3) 8 (0.6±0.2) 10 (0.8±0.3) 0.2 ( 0.5 to 0.9) 0.6 ( (0.54 to 1.4) to 3.36) (0.70 to 3.42) 0.28 Minor stroke 41 (3.2±0.5) 56 (4.8±0.6) 21 (1.7±0.4) 40 (3.8±0.6) 1.6 (0.3 to 2.8) 1.0 ( (1.15 to 2.7) to 3.30) (0.93 to 2.09) 0.11 Any periprocedural stroke or death or postprocedural ipsilateral stroke Primary end point (any periprocedural stroke, myocardial infarction, or death or postprocedural ipsilateral stroke) 55 (4.4±0.6) 75 (6.4±0.7) 29 (2.3±0.4) 50 (4.7±0.7) 2.0 (0.6 to 3.4) 1.7 ( (1.21 to 3.7) to 2.98) (1.05 to 2.15) (5.2±0.6) 85 (7.2±0.8) 56 (4.5±0.6) 76 (6.8±0.8) 0.7 ( 1.0 to 2.4) 0.4 ( (0.82 to 2.6) to 1.68) (0.81 to 1.51) 0.51 * The periprocedural period was defined, according to the study protocol, as the 30-day period after the procedure (for all patients who underwent the assigned procedure within 30 days after Secondary randomization) aims or included the 36-day estimating period after randomization the modification of the treatment effect by symptomatic (1.0%) underwent carotid-artery stenting, and 47 endarterectomy, (for all patients who 64 did (5.1%) not undergo the assigned procedure within 30 days after randomization). Because the periprocedural period was relatively short, which minimized withdrew consent, 13 the need for censoring, event proportions and the absolute differences in event proportions were calculated as the percentage of patients This with events. study For the also 4-year concludes study period, proportions status, that reflecting risk sex, and of the age, stroke, absolute which efficacy were myocardial assessed of carotid-artery through infarct, stenting (3.8%) (CAS) or were over death that lost of to carotid within follow-up. end- 4-year follow arterectomy (CEA) were based on Kaplan Meier inclusion survival of estimates the interaction at the end of terms the 4 years. in the Hazard propor- ratios for Quality-control the periprocedural period and site-monitoring activities were based on data for all patients, censored at the end of the periprocedural period. All hazard ratios were adjusted for age, symptomatic up is higher in CAS group tional-hazards than CEA models group; (as a single and indicator is increasing vari- resulted with in the age. detection 18 status, and sex. P values were calculated on the basis of the significance of the hazard ratio (per study protocol). For death, stroke, and Stenting of irregular data has from been one myocardial infarction end points, patients may able have for had sex more and than symptomatic one event (e.g., status fatal stroke and a was linear counted center. as both The a death principal and a stroke, investigator and the Office Because of the small number of events, a univariate proportional-hazards model was used to estimate the hazard ratio for death during the before data analysis began but were not described and Human Services were notified and subsequently determined that some data were fabricat- periprocedural period, calcification. 19 the P value for minor nonipsilateral stroke during the periprocedural period, and the P value for major nonipsilateral stroke during the 4-year study period. in the study protocol. Longitudinal random-effect Absolute treatment effect, hazard ratio, and P growth-curve value for major models nonipsilateral 20 were stroke used were to not evaluate available the (NA) ed. because All data of the from small this number center of (which had enrolled events, resulting in unreliable estimates. effect of periprocedural events on health status 9 patients undergoing carotid-artery stenting and The New England Journal of Medicine The New England Journal of Medicine Downloaded from nejm.org at University of Notre Dame Aus on April 24, For personal use only. No other uses without permission. Copyright 2010 Massachusetts Medical Copyright Society. All 2010 rights Massachusetts reserved. Medical Society. All rights reserved. endarterectomy in patients with asymptomatic carotid stenosis. The study found out some major risk factors of death in 5-years such as age ³ 80, insulin dependent diabetes, dialysis, Figure 2. Primary End Point, According to Treatment Group. The primary end point was a composite of stroke, myocardial infarction, or death from any cause during the periprocedural period or ipsilateral

7 and ³ 80% contralateral ICA stenosis. Minor risk factors include age years, non-insulin dependent diabetes, smoking, COPD, chronic heart failure, egfr <60, not receiving statin and 50-80% or occluded contralateral ICA. 20 Figure 3. Factors attributed to 5-years survival after CEA in asymptomatic carotid stenosis. 20 However, SAPPHIRE trial showed that CAS is superior for asymptomatic carotid stenosis in patients with high surgical risk, in terms of major adverse events in 1080 days (all cause death, stroke, myocardial infarction). High surgical risk includes: 1. Significant cardiac disease (congestive heart failure, abnormal stress test, or need for open-heart surgery) 2. Severe pulmonary disease 3. Contralateral carotid occlusion 4. Contralateral laryngeal-nerve palsy 5. Recurrent stenosis after CEA 6. Previous radical neck surgery or radiotherapy 7. Age >80 years Moreover, higher risk of cerebrovascular events in patients underwent CAS were related to some features as follows.

8 Table 4. Risk stratification and identification for patients underwent CAS 21 Medical Comorbidity Anatomic Criteria Procedural Factor Elderly (>75/80 yrs) Type III aortic arch Inexperienced operator/center Symptom status Vessel tortuosity Embolic protection device not used Bleeding Heavy calcification Lack of femoral access risk/hypercoagulable state Severe aortic stenosis Lesion related thrombus Time delay to perform procedure from onset of symptoms Chronic kidney disease Echolucent plaque Decreased cerebral reserve Aortic arch atheroma Despite the risk that follows stenting or endarterectomy, some cases still apply where surgery remains preferable, such as the presence of microembolic signal in TCD, intraplaque hemorrhage on MRI, impaired cerebral vasoreactivity and rapid stenosis progression, which increases the risk of ipsilateral stroke by 3-fold corresponding to an absolute risk of ipsilateral stroke >3% per year. 13 In addition, periprocedural complication were relatively low with CES and CEA if done by experienced interventionists and surgeons who had verifiable good outcomes (CREST verified). 18 Surgery and OMT vs OMT alone An ongoing ACTRIS trial is conducted to stratify the risk of stroke and procedural stroke or death in patients receiving endarterectomy combined with OMT and OMT alone; in hope to further understand the need of surgical intervention in patients with carotid stenosis. 13 Figure 4. ACTRIS trial design. 13

9 Conclusions It is recommended for all patients with a known history of coronary artery disease to undergo carotid artery stenosis screening although asymptomatic. US Doppler can be used to detect atherosclerosis while MR angiography can assess the severity of the stenosis. Optimal medication treatment (OMT) should be the primary treatment of carotid stenosis. Surgery (endarterectomy or stenting) should be limited to highly selected patients and done by verified interventionists and surgeons in consideration of medical comorbidity, anatomical features, and procedural factors. Further study is still conducted to assess the benefit of endarterectomy combined with OMT and OMT alone. References 1. Craven TE, Ryu JE, Espeland M a, et al. Craven T E, Ryu J E, Espeland M A, et al. Evaluation of the associations between carotid artery atherosclerosis and coronary artery stenosis. A case-control study.[j]. Circulation, 1990, 82(4): Circulation. 1990;82: doi: /01.cir Hertzer NR, Young JR, Beven EG, et al. Coronary Angiography in 506 Patients With Extracranial Cerebrovascular Disease. Arch Intern Med. 1985;145(5): doi: /archinte O Leary DH, Polak JF, Kronmal RA, et al. Distribution and correlates of sonographically detected carotid artery disease in the Cardiovascular Health Study. The CHS Collaborative Research Group. Stroke. 1992;23(12): doi: /01.str Uekita K, Funayama N, Nishiura T, et al. [Prevalence of cervical and cerebral atherosclerosis and silent brain infarction in patients with multivessel coronary artery disease]. J Cardiol. 2001;38: Fukuda I, Osaka M, Nakata H, Sakamoto H. Clinical outcome for coronary artery bypass grafting in patients with severe carotid occlusive disease. J Cardiol. 2001;38(6): %5Cnhttp://sfx.hul.harvard.edu/sfx_local?sid=EMBASE&issn= &id=d oi:&atitle=clinical+outcome+for+coronary+artery+bypass+grafting+in+patients+with +severe+carotid+occlusi. 6. Tanimoto S, Ikari Y, Tanabe K, et al. Prevalence of carotid artery stenosis in patients

10 with coronary artery disease in Japanese population. Stroke. 2005;36(10): doi: /01.str e 7. Wanamaker KM, Moraca RJ, Nitzberg D, Magovern GJJ. Contemporary incidence and risk factors for carotid artery disease in patients referred for coronary artery bypass surgery. J Cardiothorac Surg. 2012;7:78. doi: / D Agostino RS, Svensson LG, Neumann DJ, Balkhy HH, Williamson WA, Shahian DM. Screening carotid ultrasonography and risk factors for stroke in coronary artery surgery patients. Ann Thorac Surg. 1996;62(6): Fukuda I, Gomi S, Watanabe K, Seita J. Carotid and aortic screening for coronary artery bypass grafting. Ann Thorac Surg. 2000;70(6): doi: /s (00) Drohomirecka A, Koltowski L, Kwinecki P, Wronecki K, Cichon R. Risk factors for carotid artery disease in patients scheduled for coronary artery bypass grafting. Kardiol Pol. 2010;68: isi: Mokin M, Dumont TM, Kass-Hout T, Levy EI. Carotid and vertebral artery disease. Prim Care. 2013;40(1): doi: /j.pop Brott TG, Halperin JL, Abbara S, et al ASA/ACCF/AHA/AANN/AANS/ACR/ASNR/CNS/SAIP/SCAI/SIR/SNIS/SVM/SVS Guideline on the Management of Patients With Extracranial Carotid and Vertebral Artery Disease: Executive Summary: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American Stroke Association, American Association of Neuroscience Nurses, American Association of Neurological Surgeons, American College of Radiology, American Society of Neuroradiology, Congress of Neurological Surgeons, Society of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of NeuroInterventional Surgery, Society for Vascular Medicine, and Society for Vascular Surgery. Stroke. 2011;42(8):e420-e463. doi: /str.0b013e d Calvet D, Amar L, Rossi GP, et al. Case of Asymptomatic Carotid Artery Stenosis in a Hypertensive Patient. Hypertension. 2017;69(6): doi: /hypertensionaha Abbott AL. Medical (nonsurgical) intervention alone is now best for prevention of stroke associated with asymptomatic severe carotid stenosis: Results of a systematic

11 review and analysis. Stroke. 2009;40(10). doi: /strokeaha Halliday A, Harrison M, Hayter E, et al. 10-year stroke prevention after successful carotid endarterectomy for asymptomatic stenosis (ACST-1): A multicentre randomised trial. Lancet. 2010;376(9746): doi: /s (10)61197-x 16. Sillesen H. Design and baseline characteristics of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Study. Cerebrovasc Dis. 2003;16(4): doi: / Protection H, Collaborative S. Heart Prevention Study Collaborative Group: MRC/BHF Heart Protection Study of antioxidant vitamin supplementation in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002;360(9326): doi: /s (02) Brott TG, Howard G, Roubin GS, et al. Long-Term Results of Stenting versus Endarterectomy for Carotid-Artery Stenosis. N Engl J Med. 2016;374(11): doi: /nejmoa Chiam PTL, Roubin GS, Iyer SS, et al. Carotid artery stenting in elderly patients: Importance of case selection. Catheter Cardiovasc Interv. 2008;72(3): doi: /ccd Wallaert JB, Cronenwett JL, Bertges DJ, et al. Optimal selection of asymptomatic patients for carotid endarterectomy based on predicted 5-year survival. J Vasc Surg. 2013;58(1): doi: /j.jvs White CJ. Carotid artery stenting. J Am Coll Cardiol. 2014;64(7): doi: /j.jacc