In asymptomatic patients, there are no guidelines to support routine screening for atherosclerotic carotid artery disease. In patients with carotid bruits discovered on routine examination, further diagnostic tests for identification of carotid disease are recommended if they are candidates for carotid revascularization [1]. In patients scheduled for coronary artery bypass graft surgery (CABG), screening for carotid stenosis is recommended in patients older than 65 years, those with left main coronary stenosis, known peripheral arterial disease, a history of smoking, a history of TIA or stroke, or in the presence of a carotid bruit [32]. Patients with transient retinal or hemispheric neurological deficits should be screened for extracranial carotid artery disease [1, 32].

Current management decisions for atherosclerotic carotid disease depend heavily on the severity of luminal stenosis. Therefore, accurate grading of stenosis severity is essential to good decision-making.

Three randomized trials compared carotid endarterectomy (CEA) plus aspirin with aspirin alone in asymptomatic patients. In the VACS trial, 444 men with asymptomatic stenosis of ≥50 % by angiography (NASCET criteria) were randomized to medical therapy plus CEA or medical therapy alone [48]. There was no difference in ipsilateral stroke (CEA 4.7 % vs. medical 9.4 %, P = NS) or combined end point of stroke and death (CEA 41.2 % vs. medical 44.2 % P = NS) at a mean follow-up of 4 years.

The ACAS trial randomized 1,662 patients with asymptomatic carotid stenosis of ≥60 % by angiography (NASCET criteria) to medical therapy plus CEA or medical therapy alone [19]. The estimated 5-year risk of ipsilateral stroke and any perioperative stroke or death was 11.0 % for the medical group and 5.1 % for the surgical group (relative risk reduction 53 %, 95 % CI, 22–72 %, P = 0.004). The risk of stroke and death for patients undergoing CEA was the highest during the first month after endarterectomy, whereas the risk for medical patients was evenly distributed throughout 5 years. Using ACAS eligibility requirements, 19 surgeries would be necessary to prevent one stroke over 5 years. Although not statistically significant, the benefit of CEA was greater in men when compared to women (reduction of 5-year event rate; men 66 %, 95 % CI, 36–82 % vs. women 17 %, 95 % CI, –96–65 %, P = 0.10). There was no relationship for risk of stroke and increasing percent stenosis in the medical treatment group. A post hoc analysis suggested that CEA in patients with contralateral occlusion provides no long-term benefit and may be harmful [49].

ACST evaluated 3,120 asymptomatic patients with ≥60 % carotid stenosis by ultrasound [23]. The risk of perioperative stroke or death was 3.1 % (95 % CI 2.3–4.1 %). The 5-year risk of perioperative death or total stroke was reduced from 11.8 to 6.4 % with CEA. The benefit of surgery was significant for both men and women and across varying degrees of stenosis (60–99 % stenosis). The 10-year risk of perioperative stroke or death was reduced from 17.9 to 13.4 % with CEA [50]. Half of this reduction was in disabling or fatal strokes.

Three large studies have been performed evaluating the benefit of CEA versus medical therapy in symptomatic patients with carotid artery disease. In these trials, medical therapy included smoking cessation, antiplatelet, antihypertensive, and lipid-lowering agents. However, similar to trials in patients with asymptomatic carotid stenosis, the end points of medical treatment were not specified, and the nature of the medical treatment varied with the time of patient enrollment and randomization [28, 29].

The VA 309 trial screened 5,000 men who presented within 4 months with a small stroke, TIA, or transient monocular blindness and randomized 189 to either CEA with best medical therapy or best medical therapy alone [51]. These patients had angiographically defined internal carotid stenosis >50 %. This trial was ended prematurely when early results from NASCET and ECST confirmed the significant benefit of CEA. At a mean follow-up of 1 year, there was a reduction in ipsilateral stroke or TIA from 19.4 % in the medical treatment arm to 7.7 % in the surgical arm (P = 0.011).

The NASCET trial investigators randomized 2,885 patients with a TIA or non-disabling stroke within 180 days of enrollment to CEA with medical therapy or medical therapy alone. Patients were originally stratified according to the degree of stenosis: <50, 50–69, and 70–99 %. After randomizing 659 patients with ≥70 % stenosis, that portion of the study was concluded. CEA demonstrated an absolute risk reduction of 17 % (26 % vs. 9 %, P < 0.001) in the rate of ipsilateral stroke at 2 years [6, 52]. Among patients with a 50–69 % stenosis, there was an absolute risk reduction of 6.5 % in the rate of ipsilateral stroke in those treated with CEA (22.7 % vs. 15.7 %, P = 0.04) after 5-year follow-up [28]. In patients with <50 % stenosis, there was no benefit for CEA compared to medical therapy. The 5-year rate of ipsilateral stroke was 18.7 % in those treated medically and 14.9 % in those treated with CEA (P = 0.16) [28]. For patients with stenosis >70 %, the perioperative risk of stroke or death was 5.8 %, whereas for those with stenosis 50–69 %, it was 6.7 %. The number needed to treat to prevent 1 stroke in a 2-year period was 8 for patients with stenosis >70 % and 20 for patients with stenosis 50–69 %.

The ESCT trial investigators randomized 3,024 patients with a TIA or non-disabling stroke within 180 days of enrollment to CEA with medical therapy or medical therapy alone [29]. In patients with ≥80 % stenosis by ESCT criteria (70 % stenosis by NASCET criteria), the rate of major stroke or death at 3 years was 26.5 % in the medical therapy group and 14.9 % in the CEA group, an absolute reduction of 11.6 % favoring surgery (P < 0.001). There was no benefit for patients who had near occlusion of the carotid artery. The perioperative risk of stroke or death was 7.0 %.

Based on the above data, CEA has been established as the preferred treatment to prevent stroke for average surgical risk symptomatic patients with ≥50 % carotid stenosis [28, 29] and average-risk asymptomatic patients with ≥60 % carotid stenosis [19, 23, 48] compared with medical therapy provided the perioperative risk of stroke and death do not exceed 3 % for asymptomatic patients and 6 % for symptomatic patients. Symptomatic patients should undergo CEA within 14 days of presenting event provided there are no contraindications for revascularization. Asymptomatic patients undergoing CEA should have a life expectancy of more than 5 years [44].

The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) was a multicenter, prospective RT that compared CAS with an embolic protection device (EPD) to CEA in patients at increased risk for surgery [53]. To be included, patients had to have symptomatic stenosis ≥50 % by angiography or asymptomatic stenosis ≥80 % by ultrasound with one or more high-risk features (Table 35.1) and be eligible for either CEA or CAS. Investigators in this trial had a median experience of 64 CAS procedures (range 20–700). Of 747 patients randomized, 334 were eligible for either CAS or CEA and entered the trial, and 413 patients were entered into a registry. Among 334 patients randomized, 167 underwent CEA and CAS, respectively. The primary end point of the trial was the cumulative incidence of death, stroke, or myocardial infarction within 30 days after the procedure or death or ipsilateral stroke between 31 days and 1 year. The 30-day death or stroke rate was 5.6 % for CEA and 4.8 % for CAS. Rates of 30-day MI were higher, although statistically nonsignificant, for CEA when compared to CAS (6.1 % CEA, 2.4 % CAS, P = 0.10). At 1 year, the primary composite end point was reached in 20.1 % of patients with CEA as compared to 12.2 % patients with CAS (P = 0.048 for non-inferiority). In addition, target vessel revascularization at 1 year (CEA 4.3 %, CAS 0.6 %, P = 0.04) and cranial nerve palsy rates (CEA 4.9 %, CAS 0 %, P = 0.03) favored stenting. On the basis of this data, in April 2004, an FDA panel advisory recommended approval of the devices used in this trial. Three-year follow-up of the SAPPHIRE trial continues to show no differences for the primary end point between CEA and CAS (CEA 30.3 %, CAS 24.6 %, P = 0.27) [54].

Following FDA approval of carotid stent systems for symptomatic high surgical risk patients with ≥70 % carotid stenosis, several post-market surveillance registries have been launched. An overview of RTs and registries for patients undergoing CAS is provided in Table 35.2 and Fig. 35.5.

The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) trial, published in 2001, was the first multicenter clinical trial which randomized 504 symptomatic patients at average risk for CEA in 22 centers to CEA (253 patients) or endovascular revascularization (251 patients) [55]. In patients with technically successful endovascular revascularization, stents were used in only 26 % (55/213). The 30-day outcome of death and stroke was equivalent for both CEA and CAS (10 %). CEA had a higher rate of cranial nerve palsy and hematoma as compared to CAS (cranial nerve palsy 9 % CEA vs. 0 % CAS, P < 0.0001; hematoma 7 % CEA vs. 1 % CAS, P < 0.0015). The 1-year death or stroke rate was comparable, 13.4 % CEA versus 14.3 % CAS, P = NS. The 1-year restenosis rate (>70–99 %) was 14 % for CAS as compared to 4 % for CEA (P < 0.001). At 3-year follow-up, no difference in the rate of death or stroke was noted (14.2 % CEA vs. 14.3 % CAS, P = NS) [56].

Several multicenter randomized trials (RTs) comparing CAS to CEA for average surgical risk patients with both symptomatic and asymptomatic carotid stenoses have been published, while others are ongoing (Table 35.2). The Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterectomy (SPACE) trial was designed to prove non-inferiority of CAS as compared to CEA in average surgical risk symptomatic patients with ≥50 % carotid stenosis by angiography [57]. It was a multinational, multicenter RT with the primary end point of ipsilateral stroke or death between randomization and 30-day follow-up. Initially, 1,200 patients were randomized between March 2001 and Feb 2006 (595 patients to CEA and 605 patients to CAS). Tutoring of inexperienced interventionalists enrolling study patients was permitted. Surgeons had to provide proof of 25 consecutive carotid endarterectomy procedures. At the time of an interim analysis, the primary end point occurred in 6.4 % of patients randomized to CEA and 6.8 % randomized to CAS (P = NS). The incidence of any stroke was 6.2 % in CEA and 7.5 % in CAS (P = NS). Importantly, EPDs were used in only 27 % of cases. Although no difference was seen between CAS and CEA, this analysis showed that 2,500 patients would be needed to prove non-inferiority of CAS. The SPACE steering committee acknowledged a lack of funds sufficient to enroll the requisite number of patients and suspended the trial.

The Endarterectomy Versus Angioplasty in patients with Symptomatic Severe carotid Stenosis (EVA-3S) trial was similar to the SPACE trial in that it was a RT designed to assess non-inferiority of CAS as compared to CEA in average-risk symptomatic patients with carotid stenosis [58]. The symptomatic carotid stenosis threshold was increased to >60 %. This was a multicenter trial conducted in France from 2000 to 2005. The primary end point was the incidence of 30-day death or any stroke. The trial was stopped after enrolling 527 of the intended 872 patients for reasons of safety and futility. Two hundred and sixty-two patients underwent CEA and 265 received CAS. The primary end point was lower in patients undergoing CEA as compared to CAS (3.8 % CEA vs. 9.4 % CAS, P = 0.01), and EVA-3S concluded that CAS was inferior to CEA for symptomatic patients with carotid stenosis >60 %. Critics of this study point to the fact that trial operators certified to perform CAS could have little (5 prior cases) or no experience (interventions performed with a tutor), and EPDs were used in a minority of the trial, after 5 out of 20 patients treated without EPD suffered a stroke. This resulted in protocol changes by the EVA-3S safety committee. At 4-year follow-up, excluding periprocedural complications, rates of death or any stroke were comparable between CEA and CAS (HR 1.39, 95% CI 0.96–2.00; P = 0.08) [58].

The International Carotid Stenting Study (ICSS) was another European RT that enrolled 1,713 (CAS = 855 or CEA = 858) symptomatic patients at average risk for CEA with carotid stenosis >50 % by angiography (NASCET criteria) [59]. Amazingly for a modern trial, the use of EPDs was optional. To qualify as an experienced center, a surgeon must have performed 50 CEA procedures and an interventionalist (physician or surgeon), 10 CAS procedures. However, if the center had no CAS experience, they could still enroll patients into the trial if they were tutored by a proctor.

The primary outcome of ICSS was the 3-year rate of any fatal or disabling stroke. The 3-month interim analysis demonstrated a similar result between the two groups (4.0 % for CAS and 3.2 % for CEA, P = 0.34). The 120-day rate of death, stroke, or MI was 8.5 % in the CAS group and 5.2 % in the CEA group (P = 0.006).

The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) is the largest randomized trial published comparing CAS with EPD to CEA [60]. There were 2,502 average surgical risk patients with symptomatic (1,321) and asymptomatic (1,181) carotid stenosis randomized to either CEA or CAS. The primary outcome of periprocedural stroke, death, or MI or follow-up ipsilateral stroke was not different between the two groups at 4 years (7.2 % for CAS and 6.8 % for CEA). The 30-day risk of all stroke was higher for CAS (4.1 % vs. 2.3 %, P = 0.01), whereas CEA was associated with a higher 30-day risk of MI (2.3 % vs. 1.1 %, P = 0.03). The rate of ipsilateral stroke over a mean follow-up of 2.5 years was similar between the two groups. CAS trended safer than CEA for patients ≤69 years of age, while CEA yielded better outcomes in those >70 years of age.

The Asymptomatic Carotid Stenosis Stenting versus Endarterectomy (ACT I) trial will further help evaluate risk of CAS versus CEA in asymptomatic patients at average risk for CEA. This trial is enrolling 1,540 patients with asymptomatic stenosis greater than 70 % at average risk for CEA and randomizing them, on a 3:1 basis, to CAS or CEA [35]. The aim is to demonstrate the non-inferiority of CAS using the Emboshield Embolic Protection System and Emboshield Pro Embolic Protection System with the Xact Carotid Stent System (Abbott Vascular Corporation, Abbott Park, Illinois) to CEA for the treatment of asymptomatic extracranial carotid atherosclerotic disease. The primary end point is death, stroke, or MI at 30 days and ipsilateral stroke between 31 and 365 days. Secondary end points include target lesion revascularization, device and procedural success, ipsilateral stroke at 5 years, and economic and quality of life indicators.

The American College of Cardiology Foundation/Society for Cardiovascular Angiography and Interventions/Society for Vascular Medicine and Biology/Society of Interventional Radiology/American Society of Interventional and Therapeutic Neuroradiology (ACCF/SCAI/SVMB/SIR/ASITN) published a clinical expert consensus document on carotid stenting in 2007 [1]. Per this consensus statement, CAS is recommended in patients with symptomatic stenosis greater than 50 % and asymptomatic stenosis greater than 80 % (NASCET criteria) who are at high risk for CEA.

For average surgical risk patients, the recently published American Heart Association stroke guidelines make CAS a level 1 indication for symptomatic patients with carotid stenosis >50 % by angiography at average risk for CEA. In patients at high-risk for CEA, CAS is indicated among patients with symptomatic stenosis >70 % provided perioperative risk morbidity and mortality rates are 4–6 %, respectively [44]. This document did not comment on revascularization for patients with asymptomatic carotid stenosis. The recently published guidelines on extracranial carotid and vertebral artery disease make CAS a class 1 indication for symptomatic patients with carotid stenosis >50 % by angiography (NASCET method) provided the anticipated rate of stroke or death is less than 6 %. For asymptomatic patients with carotid stenosis >60 % by angiography (NASCET method), CAS can be considered in highly selected patients [45]. A summary of recommendations for CAS by various professional societies is provided in Table 35.3.