Recent concepts in the management of extracranial carotid stenosis: Carotid endarterectomy versus carotid artery stenting
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.82741
Source of Support: None, Conflict of Interest: None
Carotid stenosis is seen in 10% of patients with ischemic stroke, and carotid endarterectomy (CEA) and carotid artery stenting (CAS) are the two invasive treatments options available. Pooled analysis of the three largest randomized trials of CEA involving more than 3000 symptomatic patients estimated 30-day stroke and death rate at 7.1% after CEA. Some subgroups among the symptomatic patients appeared to have more benefit from CEA. These include patients aged 75 years or more, patients with ulcerated plaques, and patients with recent transient ischemic attacks within 2 weeks of randomization. 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. The recent trials comparing CEA with CAS has not established its superiority over CEA. The carotid revascularization endarterectomy versus stenting (CREST) study showed that CAS is still associated with a higher periprocedural risk of stroke or death than CEA. In patients over 70 years of age, CEA is clearly superior to CAS. The increased risk of nonfatal myocardial infarction in the CREST group subjected to CEA clearly suggests that patients being considered for CEA or CAS require a careful preliminary cardiac evaluation. CAS can be justified for patients whose medical comorbidities or cervical anatomy make them questionable candidates for CEA. The benefit of revascularization by either method versus modern aggressive medical therapy has not been established for patients with asymptomatic carotid stenosis.
Keywords: Carotid stenosis, carotid stenting, carotid endarterectomy, myocardial infarction, stroke
Carotid stenosis is seen in 10% of patients with ischemic stroke and carotid endarterectomy (CEA) and carotid stenting (CAS) are the two invasive treatments options available. This article reviews the present status of the two procedures in the treatment of carotid stenosis.
During the 1980s, four major randomized clinical trials (RCTs), North American Symptomatic Carotid Endarterectomy Trial (NASCET), , the European Carotid Surgery Trial (ECST), ,, the Asymptomatic Carotid Atherosclerosis Study (ACAS),  and the Asymptomatic Carotid Surgery Trial (ACST), , were done in order to determine the benefit of CEA in symptomatic and asymptomatic carotid stenosis (ACS). Despite the different methods of estimation of stenosis used in these trials, the conclusions were reasonably consistent.
In the NASCET trial, surgical treatment was more beneficial than medical management alone; the cumulative risk of any ipsilateral stroke at 2 years was 26% in the medical group and 9% in the surgical group, an absolute risk reduction of 17%. The benefit of endarterectomy was still apparent at 8 years of follow-up. , In the moderate stenosis category (50-69%), surgery was more beneficial than medical therapy; in this subgroup at 5 years, the rate of any ipsilateral stroke was 15.7% in those treated surgically and 22.2% in those treated medically. In patients with less than 50% stenosis, the 5-year stroke rate was not significantly lower with endarterectomy than with medical therapy. , In the ECST trial, in patients with a stenosis of greater than 80% (60% by the NASCET criteria for calculating angiographic stenosis), the frequency of major stroke or death at 3 years was 26.5% in the control group and 14.9% in the surgery group, an absolute difference of 11.6%.  A US Veterans Affairs trial of CEA, the Veterans Affairs Cooperative Study (VACS), was stopped after 189 patients with symptomatic stenosis had been randomly allocated to surgery plus medication therapy versus medical management alone.  The rate of death, stroke or transient ischemic attack (TIA) was 7.7% in patients assigned to surgical treatment as compared with 19.4% in those managed without surgery.
Pooled analysis of the three largest randomized trials (VACS, NASCET, and ECST) involving more than 3000 symptomatic patients found a 30-day stroke and death rate of 7.1% after CEA.  When the combined outcome of fatal or disabling ipsilateral ischemic stroke, perioperative stroke, or death was considered, the benefit of surgery was evident only in patients with 80-99% stenosis. Surgery offered little or no long-term benefit to patients with near occlusion of a carotid artery, in whom the risk of stroke was lower among medically treated patients than in those with lesser degrees of severe stenosis, perhaps as a result of collateral blood flow. , Some symptomatic subgroups appeared to derive more benefit from CEA and these include patients aged 75 years or more, patients with ulcerated plaques, and patients with recent TIAs within 2 weeks of randomization. 
The first major trial of CEA in asymptomatic patients was conducted in 10 US Veterans Affairs medical centers to test the hypothesis that surgery in combination with aspirin and risk factor modification would result in fewer TIAs, strokes, and deaths than medical management alone.  The 30-day mortality rate was 1.9% in patients assigned to surgery, and the incidence of stroke was 2.4%, and combined rate was 4.3%. By 5 years, the differences in outcomes reached statistical significance, with a 10% overall rate of adverse events in the surgical group compared with 20% in the group given medical therapy alone. 
In the ACAS trial, 1662 patients with ACS (greater than 60%) were randomized to receive either medical therapy alone or medical plus surgical therapy.  After a median follow-up of 2.7 years, the aggregate 5-year risk of ipsilateral stroke, any perioperative stroke, or death was estimated to be 5.1% in the surgical group and 11.0% in the medical group, a relative risk (RR) reduction of 53%.  However, for surgery to be beneficial, the rate of perioperative death and other serious complications had to be less than 3%, and the expected patient survival had to be at least 5 years. The benefit of CEA in this study was predominantly in men, with lesser benefit in women and in diabetic patients. Furthermore, even though endarterectomy was beneficial in this asymptomatic cohort, the overall benefit in terms of stroke risk reduction was small compared with that in NASCET and ECST, in patients with symptomatic disease.  The ACST randomized 3120 asymptomatic patients with hemodynamically significant carotid artery stenosis to immediate CEA versus delayed surgery on the basis of the onset of symptoms. , The 30-day risk of stroke or death in either group, including the perioperative period, was 3.1%. Five year rates, including perioperative events, were 6.4% for the early-surgery group versus 11.7% for the group initially managed medically. It is important to emphasize that selection of asymptomatic patients for carotid revascularization should include careful consideration of life expectancy, age, sex, and comorbidities. The benefit of surgery may now be less than anticipated on the basis of earlier randomized trials, and the cited 3% complication rate should be interpreted in the context of interim advances in medical therapy. 
Medical therapy has changed dramatically over the last two decades, and the annual rates of stroke in medically treated patients with ACS have fallen from 2.5 to 1%.  Current estimates suggest that only 5% of patients with ACS stand to benefit from CEA in the era of modern medical therapy with antiplatelets, statins, and angiotensin-converting enzyme inhibitors. Further selection of patients can be enhanced by using advanced imaging of plaque morphology and content and assessment of cerebral vasomotor reactivity and reserve by Transcranial Doppler (TCD).  Two recent studies suggest that the use of TCD to detect embolic signals might be particularly useful in stratifying patients with ACS who would benefit from surgery., In the asymptomatic carotid smboli study (ACES), only 16% of patients with ACS had embolic signals on baseline transcranial Doppler, and only 13% of them had ipsilateral strokes during a 2-year follow-up period.  Although these results are promising, further larger-scale studies are needed before emboli monitoring can be recommended for clinical decision making. 
The risk factors for complications during surgery are patients with contralateral laryngeal nerve palsy, radiation therapy to the neck, previous CEA with recurrent stenosis, lesions high in the cervical internal carotid artery or below the clavicle in the common carotid artery, severe tandem lesions, age greater than 80 years, severe pulmonary disease, congestive heart failure (New York Heart Association class 3 or 4) or known severe left ventricular dysfunction, open heart surgery needed within 6 weeks, myocardial infarction (MI) within the past 4 weeks, unstable angina and contralateral carotid occlusion. ,
Complication rates associated with CEA have improved steadily over the past two decades. The 30-day stroke and mortality rates of 2.3% among asymptomatic patients in ACAS (1994) and 5.0% for symptomatic patients in the first part of the NASCET (1999) are often cited as benchmarks against which other forms of interventional therapy are compared. More recent reports, however, suggest considerably lower risks than reported in those early trials. Surgical training and case volume are important determinants of clinical outcomes with CEA. A population-based study of 14,095 CEA procedures in the state of Virginia between 1997 and 2001 reported cumulative stroke and mortality rates of 1.0% and 0.5%, respectively, and a progressive decline in these rates each year.  For 23,237 CEA procedures performed in Maryland between 1994 and 2003, the cumulative stroke rate was 0.73%. The stroke rate was 2.12% in 1994, 1.47% in 1995, and from 0.29 to 0.65% between 1996 and 2003, with a more pronounced reduction in perioperative stroke among symptomatic patients than among asymptomatic patients.  Similar findings were seen in other countries as well. ,,
In the late 1970s, CAS was described in isolated case reports. This was followed by larger case series and independent trials. ,,
Carotid and vertebral artery transluminal angioplasty study
This was the first randomized trial which compared the risks and benefits of angioplasty, with or without stenting of carotid and vertebral artery stenosis, with those of conventional surgery. , Patients had to have carotid artery stenosis (symptomatic or asymptomatic) that was suitable for either CEA or endovascular treatment. A total of 504 patients were enrolled and most patients in this group underwent angioplasty alone, but 26% also received stents because of suboptimal vessel dilatation or at the discretion of the intervening physician. The primary end point was any disabling stroke or death. , Secondary end points were any ipsilateral stroke lasting longer than 7 days and the combination of death or disabling ipsilateral stroke. There was no significant difference between endovascular treatment and surgery in any of these end points at 3 years. The restenosis rate was higher in the endovascular therapy group (14%) than in the surgery group (4%; P < 0.001). On the other hand, the surgery group had a higher rate of minor complications, including cranial nerve palsies and neck hematomas. ,
Carotid revascularization with endarterectomy or stenting systems
This study compared the outcomes of standard CEA versus CAS using distal embolic protection devices (EPDs).  All the patients in this study had at least 50% symptomatic stenosis or 75% ACS. At 30 days, 7 (2.4%) of 254 patients in the endarterectomy group had strokes and 1 of the 7 patients with stroke died, so the combined rate of stroke or death (the primary end point) was 2.4%. In the stenting group, 3 (2.1%) of 143 patients had strokes and no patients died. Overall, there was no significant difference in the composite of death, stroke, or MI: 3% for CEA and 2% for CAS patients. ,
The stenting and angioplasty with protection in patients at high risk for endarterectomy trial
In the stenting and angioplasty with protection in patients at high risk for endarterectomy (SAPPHIRE) trial, patients had to have either symptomatic carotid disease with 50% stenosis or greater or ACS of 80% or greater, determined by ultrasonography. Further, all patients had to have at least one comorbid condition that increased their perioperative risk.  Patients were randomized to undergo CAS with EPD or CEA.  The primary end points of this study were the cumulative incidence of major cardiovascular events at 1 year; death, stroke, or myocardial infarction within 30 days of intervention; and ipsilateral stroke between 31 days and 1 year. Secondary outcomes measured were the rates of target-vessel recanalization at 1 year, cranial nerve palsy, and surgical site complications. This represented a departure from the traditional composite end point of stroke and/or death, especially since it included asymptomatic elevations in cardiac isoenzyme and troponin levels that had not been measured in most previous studies of CEA. The stenting group had fewer adverse cardiac events (mainly non-Q wave myocardial infarction) than the surgery group. At 1 year, the rate of major ipsilateral stroke was 3.3% in the endarterectomy group versus 0% in the stenting group (the difference was not significant), and the cardiovascular event rates continued to be higher in the endarterectomy group.  At 3 years of follow-up, the results were similar. The trial concludes that in patients with severe carotid artery stenosis and increased surgical risk, there is no significant difference in long-term outcomes between patients who underwent CAS with an EPD and those who underwent CEA. 
The stent-protected angioplasty versus carotid endarterectomy (SPACE) trial
A total of 1200 patients with symptomatic carotid artery stenosis confirmed by ultrasonography were randomly assigned within 180 days of a TIA or moderate stroke to undergo CAS (n = 605) or CEA (n = 595).  The primary end point was ipsilateral ischemic stroke or death, 30 days after the procedure. The rate of the primary end point was 6.84% with stenting and 6.34% with CEA. The study failed to prove the noninferiority of CAS compared with CEA for the periprocedural complication rate. ,
The endarterectomy versus stenting in patients with symptomatic severe carotid stenosis (EVA-3S) study
EVA-3S was designed to study whether stenting was non-inferior to CEA in patients with symptomatic carotid stenosis of at least 60%.  The primary end point was to be the incidence of stroke or death within 30 days after treatment. However, the trial was stopped early after the inclusion of 527 patients for reasons of safety and futility. The 30-day incidence of any stroke or death was higher in the stenting group (9.6% vs. 3.9%). The 30-day incidence of disabling stroke or death was also higher in the stenting group (3.4% vs. 1.5%). At 6 months, the incidence of any stroke or death was 6.1% after CEA and 11.7% after stenting (P = 0.02). There was a trend toward more major local complications after stenting and systemic complications after endarterectomy. ,
International carotid stenting study
International Carotid Stenting Study (ICSS) trial had reported the results of the interim analysis of 1713 symptomatic patients.  The 30-day risk of stroke, death, or MI was significantly higher after stenting than after CEA (7.4% vs. 4.0%; RR 1.8; 95% CI 1.2-2.8; P = 0.003). The 120-day risk for stroke, death, or MI was still higher in the stenting cohort (8.5% vs. 5.2%; P = 0.006).  Furthermore, in a subset of 231 patients who underwent diffusion-weighted magnetic resonance imaging (MRI) both before and after carotid intervention, new ischemic brain lesions were documented far more frequently in the stenting group than in the CEA group (50% vs. 17%; adjusted odds ratio 5.2; 95% CI 2.8-9.8; P < 0.0001). 
Meta-analyses of carotid endarterectomy and carotid stenting trials
A meta-analysis of five randomized trials comparing CAS with CEA disclosed no difference in stroke or death rates at 30 days (8.1% vs. 6.3%), in MI, stroke, or death rates at 30 days (8.1% vs. 7.8%), or in stroke or death rates at 1 year (13.5% vs. 13.3%).  Another analysis of six trials involving 1177 patients found no difference between CAS and CEA in 30-day or 1-year rates of stroke and death. The studies included both symptomatic and asymptomatic patients across a range of surgical risk, as well as stenting with and without EPDs. The authors noted that CAS was associated with a lower rate of MI (RR 0.3; 95% CI 0.1-0.8; P < 0.02) and procedural morbidity such as cranial nerve injury (RR 0.05; 95% CI 0.01-0.3; P < 0.001).  In another meta-analysis of 11 trials that included 4796 patients, the risk of periprocedural mortality or stroke was lower with CEA than with CAS (OR 0.67; 95% CI 0.47-0.95; P < 0.025). 
Age is an important factor that could help in deciding about CEA or CAS. Among patients who were below 70 years, the 30-day incidence of stroke or death was comparable for CAS and CEA (5.1% and 4.5%, respectively). In patients who were 70 years of age or older, however, the risk of stroke or death for CAS was over twice that for CEA (10% vs. 4.4%; RR 2.4; 95% CI 1.6-3.5; P = 0.0078). Others also have found that CAS has a higher serious complication rate in older patients, probably because of the potential for catheter-directed devices to provoke cerebral emboli in the presence of the arterial tortuosity and calcification that often occur in the elderly. ,,
The carotid revascularization endarterectomy versus stenting trial
The carotid revascularization endarterectomy versus stenting trial (CREST) is a randomized multicenter trial comparing CAS to CEA in both symptomatic and asymptomatic patients., The primary end point was the occurrence of stroke, death, or MI during the periprocedural period and ipsilateral stroke up to 4 years. CREST is unique among the reported randomized trials comparing CAS and CEA in conventional risk patients because it included both symptomatic patients with >50% carotid stenosis and asymptomatic patients with >60% stenosis. A total of 2502 patients were included. There was no significant difference in the rates of the primary end point between CAS and CEA (7.2% vs. 6.8%; hazard ratio 1.11; 95% CI 0.81-1.51; P < 0.51). An interaction with age and treatment was detected (P < 0.02). Outcomes were slightly better after CAS for patients aged <70 years and better after CEA for patients aged >70 years. The periprocedural end point did not differ for CAS and CEA, but there were differences in the components, CAS versus CEA (stroke 4.1% vs. 2.3%, P < 0.012; and myocardial infarction 1.1% vs. 2.3%, P < 0.032). In CREST, CAS and CEA had similar short- and longer-term outcomes. During the periprocedural period, there was higher risk of stroke with CAS and higher risk of MI with CEA. 
Post crest scenario
CREST results are generally consistent with prior studies, which showed that CAS is still associated with a higher periprocedural risk of stroke or death than CEA, a difference maintained up to 4 years.  In patients over 70 years of age, CEA is clearly superior to CAS. More contemporary comparative data are needed on the medical management of ACS before either CAS or CEA can be recommended in these patients. There is a danger that CREST will be interpreted as sanctioning the continuation of the already widespread treatment of ACS with CAS, which is not warranted by the available data. There are at least three trials of intervention versus best medical management of ACS in progress. More data are needed regarding the durability and long-term outcomes of CAS. 
CEA should remain the procedure of choice for stroke prevention in patients with severe, symptomatic carotid stenosis [Table 1]. CAS may be a good alternative in those symptomatic patients who have major medical comorbidities precluding CEA, in those who have a restenosis after previous CEA, and in those with stenosis related to prior neck radiation [Table 2]. The increased risk of nonfatal MI in the CREST group subjected to CEA and the same risk in the SAPPHIRE trial clearly suggest that patients being considered for CEA or CAS require a careful preliminary cardiac evaluation. CAS generally seems to be most appropriate in the setting of ongoing trials until it has been shown conclusively to be at least as safe and durable as CEA. In the meantime, exceptions favoring CAS can be justified for patients whose medical comorbidities or cervical anatomy make them questionable candidates for CEA. The benefit of revascularization by either method versus modern aggressive medical therapy has not been established for patients with ACS.
[Table 1], [Table 2]