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Carotid Artery Stent Placement for Atherosclerotic Disease: Rationale, Technique, and Current Status¹

¹ From the Division of Interventional Neurovascular Radiology, University of California–San Francisco Medical Center, Calif. Received May 18, 1999; revision requested July 16; revision received September 23; accepted October 12. Address correspondence to C.C.P., Interventional Neuroradiology Unit, Royal Perth Hospital, GPO Box X2213, Perth, Western Australia 6001, Australia (e-mail: constantine.phatouros@rph.health.wa.gov.au).

	ABSTRACT

TOP ABSTRACT INTRODUCTION RATIONALE FOR CAROTID... ENDOVASCULAR TREATMENT OF... REFERENCES

 
Carotid arterial endarterectomy is considered to be the standard for the treatment of atherosclerotic carotid arterial occlusive disease. This has been validated with results of several randomized controlled trials in which its effectiveness has been demonstrated over that of the best nonsurgical therapy. In the past several years, however, carotid angioplasty with stent placement has emerged as a potential alternative to carotid endarterectomy. This article represents a critical examination of the rationale for carotid revascularization; the history of endovascular techniques for the treatment of carotid atherosclerosis, beginning with balloon angioplasty and evolving to the use of stents; and the evidence supporting the effectiveness of the endovascular approach. A brief description of the current technical aspects of carotid artery stent placement is presented. The future status of the endovascular approach will be determined with randomized trials in which carotid artery stent placement is directly compared with endarterectomy, as well as by the potential for further innovation and improvement in endovascular devices, technique, and safety.

Index terms: Brain, infarction, 10.78, 172.721 • Carotid arteries, interventional procedures, 172.1267 • Carotid arteries, stenosis or obstruction, 172.721 • State of the Art • Stents and prostheses, 172.1267

	INTRODUCTION

TOP ABSTRACT INTRODUCTION RATIONALE FOR CAROTID... ENDOVASCULAR TREATMENT OF... REFERENCES

 
Cerebrovascular disease is the third leading cause of mortality in the United States (1,2). In the United States, approximately 600,000 people experience a stroke annually, costing an estimated $30 billion in treatment and lost productivity (3,4). Carotid arterial occlusive disease is responsible for up to 25% of these strokes (5). Findings of large population-based studies indicate the prevalence of carotid artery stenosis is approximately 0.5% in the 6th decade and increases to 10% in persons over 80 years of age. The vast majority of cases are asymptomatic (6–8). Surgical carotid endarterectomy is currently the accepted standard of treatment for revascularization of extracranial carotid occlusive disease (9). During the past 2 decades, endovascular techniques that began with carotid artery angioplasty have progressed to stent-supported angioplasty. These minimally invasive techniques are gaining wider acceptance, thus challenging the preeminent status of carotid endarterectomy.

	RATIONALE FOR CAROTID REVASCULARIZATION

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The first successful carotid endarterectomy procedure we know of was performed in 1953 by DeBakey for the treatment of an occluded cervical carotid artery (10). The following year, in the United Kingdom, Eastcott performed the first successful carotid endarterectomy we know of in which the circulation to the brain was intentionally interrupted to remove a stenotic plaque (11,12). During the next 3 decades, the number of surgical carotid endarterectomy procedures performed increased steadily until the mid 1980s, when a number of critical reports suggested unacceptable rates of perioperative stroke or death (13–18). It was also reported that 32% of endarterectomies performed in the United States in Medicare recipients were for inappropriate indications (19). Despite only anecdotal evidence of efficacy, approximately 1 million carotid endarterectomies were performed worldwide between 1974 and 1985 (20,21).

Following a temporary decline, rates of carotid endarterectomy in the United States and Canada are again increasing since the publication of favorable, well-constructed clinical studies beginning in 1991 with the North American Symptomatic Carotid Endarterectomy Trial (NASCET) (22,23). Carotid endarterectomy has since attained the mantle of "the standard" in revascularization for carotid occlusive disease. In 1996, approximately 130,000 carotid endarterectomies were performed in the United States, twice that in 1991 (24).

In the NASCET, conducted at 106 centers in the United States, Canada, Europe, and Australia, 2,885 patients with symptomatic carotid stenosis were stratified into two groups: 30%–69%-diameter stenosis (2,226 patients) (24) and 70%–99%-diameter stenosis (659 patients) (23). The NASCET demonstrated unequivocal benefit of surgery over medical management in symptomatic patients with a severe carotid stenosis of 70% or greater. In the NASCET, the degree of carotid stenosis was determined by the ratio between the luminal diameter at the point of greatest stenosis and that of the normal artery beyond the carotid bulb.

Endarterectomy reduced the 2-year risk of any ipsilateral stroke from 26% (annual event rate of 13%) in the medical group to 9% in the surgical group, thus yielding an absolute risk reduction of 17%. Therefore, for every 100 patients undergoing surgery, 17 nonfatal strokes or deaths were prevented over a 2-year period. However, this risk reduction was not equal for all patients. The benefit was twice as great in patients with a stenosis of 90%–99% than in those with a stenosis of 70%–79%.

The durability of this benefit at 8-year follow-up has recently been reported (24). The 8-year risk of an ipsilateral disabling stroke was 6.7%, that of any ipsilateral stroke was 15.2%, that of any stroke was 29.4%, and that of any stroke or death was 46.6%. Therefore, despite the durability of endarterectomy in preventing an ipsilateral disabling stroke, the risk of any stroke or death over the ensuing 8 years was nearly 50%.

The eligibility requirements for the NASCET were strictly defined. Patient exclusion criteria included a previous ipsilateral endarterectomy; an intracranial lesion that was more severe than the surgically accessible lesion; no angiographic depiction of both carotid arteries and their intracranial branches; or lung, liver, or renal failure. Temporary exclusion criteria included uncontrolled diabetes mellitus; hypertension; unstable angina pectoris; myocardial infarction within the previous 6 months; contralateral carotid endarterectomy within the previous 4 months; signs of progressive neurologic dysfunction; or a major surgical procedure within the previous 30 days. These patients could be included if the disorder responsible for their ineligibility resolved within 120 days of their qualifying cerebrovascular event.

In the NASCET, neurologic classification was performed 30 and 90 days after the procedure with strokes (any new focal neurologic deficit lasting >24 hours) categorized as disabling (modified Rankin score 3) or nondisabling. If sufficient functional recovery occurred within 90 days, the stroke could be reclassified from disabling to nondisabling (25). The authors reported a 5.8% incidence of perioperative stroke and death (0.6%) in the endarterectomy group. The inclusion of perioperative myocardial infarction (0.9%) increased the complication rate to 6.7% (23).

The NASCET results examining the benefit of carotid endarterectomy in patients with symptomatic moderate stenoses of 30%–69%, over a mean follow-up of 5 years, have now been reported. For patients with a stenosis of 50%–69%, the 5-year rate of any ipsilateral stroke was 15.7% in the surgical group versus 22.2% in the medical group, an absolute reduction in risk of any ipsilateral nonfatal or fatal stroke of 6.5% (1.3% per annum). However, among patients with 30%–49% stenosis, the 5-year rate of any ipsilateral stroke was 14.9% for patients who underwent surgery versus 18.7% for patients who were medically treated; an insignificant risk reduction. The perioperative rate of disabling stroke and death was 2% (24). It is interesting that a daily dosage of less than 650 mg of aspirin was associated with a significantly increased risk of perioperative stroke or death.

Recently, the surgical and medical complication rates for all patients (n = 1,415) undergoing carotid endarterectomy as part of the NASCET (30%–99% symptomatic stenosis) have been reported (26,27). The overall rate of perioperative stroke or death (1.1%) was 6.5%. Five baseline variables were predictive of a significantly increased surgical risk: hemispheric versus retinal transient ischemic attack as the qualifying event, left-sided procedure, contralateral carotid occlusion, ipsilateral ischemic lesion on computed tomographic (CT) scans, and irregular or ulcerated ipsilateral plaque.

The incidence of perioperative wound complications was 9.3%, and that of cranial nerve damage was 8.6% (26). Medical complications occurred in 8.1% of patients undergoing endarterectomy. All of these patients experienced a cardiovascular complication, and approximately one-fourth had attendant noncardiovascular medical complications. Cardiovascular complications included myocardial infarction (1.2%), congestive heart failure (1.2%), and hypotension (2.1%). Patients with a history of myocardial infarction, angina pectoris, or hypertension were at a significantly higher risk. Medical complications resulted in prolonged hospitalization in approximately 30% of cases (27).

The results of the European Carotid Surgery Trial (ECST), another large, multicenter, randomized controlled trial, were in accordance with the NASCET results after adjustment for the different methods used to calculate the angiographic degree of carotid stenosis (28–30). The ECST method of calculating angiographic stenosis, by using an approximation of the normal carotid bulb diameter as the denominator rather than the diameter of the distal cervical internal carotid artery used in the NASCET, resulted in overestimation of narrowing compared with the estimation in the NASCET.

The ECST enrolled 3,024 patients stratified into three groups: 0%–29%, 30%–69%, and 70%–99% carotid stenosis, with a mean follow-up of 6.1 years. The final ECST report demonstrated that endarterectomy reduced the Kaplan-Meier 3-year risk of major stroke or death in patients with a symptomatic stenosis of 80% or greater (60% as measured by the NASCET method) from 26.5% in the control group (an annual event rate of 8.8%) to 14.9% in the surgical group; an absolute risk reduction of 11.6% at 3 years. The rate of nonfatal stroke (symptoms lasting >7 days) or death (1.3%) from surgery was 7%. The ECST did not specify rates of nonstroke surgical complications, such as cranial nerve injury or cardiac events (30,31).

The Veterans Affairs Cooperative Symptomatic Carotid Stenosis Trial, or VACSP-309, a third randomized trial on endarterectomy in patients with symptomatic carotid stenosis, was prematurely terminated when the NASCET and ECST data were released (32). The VA-CSP-309 enrolled 189 male patients, with a mean follow-up of 11.9 months, demonstrating an absolute risk reduction of stroke or crescendo transient ischemic attacks of 11.7% in men with a 50% carotid stenosis or greater who underwent endarterectomy (17.7% for >70% stenosis). The authors reported a perioperative surgical stroke or death rate of 5.5%. Among the three perioperative deaths, none were due to ischemic stroke.

The only large, well-constructed, randomized controlled trial with findings published of which we are aware in which surgical endarterectomy was compared with medical therapy in patients with asymptomatic carotid stenosis is the Asymptomatic Carotid Atherosclerosis Study (ACAS), which enrolled 1,662 patients at 39 centers with a median follow-up of 2.7 years (33). As in the NASCET, the inclusion criteria were stringent. Patients were excluded from the ACAS because of previous cerebral infarction; previous endarterectomy with restenosis; previous extracranial-to-intracranial bypass; any disorder that could seriously complicate surgery or prevent continuing participation for 5 years; long-term anticoagulation therapy; or a surgically inaccessible lesion. Patients in the medical control group received 325 mg of aspirin per day. Some authors have suggested this does not represent optimum medical therapy (the recommended dose in the NASCET was 1,300 mg/d) since high-dose aspirin, ticlopidine, and aspirin combined with warfarin may be more effective (34).

The ACAS reported an actuarial estimated 5-year risk (mean follow-up was only 2.7 years) for ipsilateral stroke or any perioperative stroke or death in patients with a carotid stenosis of 60% or greater, of 5.1% for patients who underwent surgery versus 11% (annual event rate of 2.2%) for patients who were medically treated, yielding an absolute risk reduction of 5.9% (1.2% per annum). Therefore, over a 5-year period, approximately one stroke per year was prevented for every 85 patients undergoing endarterectomy. However, the absolute reduction in risk of disabling ipsilateral stroke was only 2.6%, which doubles the number of endarterectomies needed to prevent one ipsilateral disabling stoke compared with any ipsilateral stroke. This result was obtained with a very low 30-day perioperative stroke or death (0.1%) rate of 2.3%; 52% of these complications were attributable to strokes caused by diagnostic cerebral arteriography (arteriography stroke rate of 1.2%). Stratification of data revealed no significant reduction in risk of stroke or death for female patients undergoing endarterectomy. Furthermore, no correlation between benefit and degree of stenosis was demonstrated.

The Veterans Affairs Cooperative Study, or VA-CSP-167, a smaller multicenter trial in which 444 men with asymptomatic carotid stenosis of 50% or greater were enrolled, failed to demonstrate a statistically significant difference in the combined rate of stroke or death between the endarterectomy and medical groups at a mean follow-up of 47.9 months. The authors concluded that a modest effect could not be excluded because of the relatively small sample size. The 30-day perioperative rate of permanent stroke or death was 4.7%, which included a 0.4% rate of stroke from diagnostic cerebral angiography (35). Cardiac-related deaths were the most frequent perioperative cause of mortality.

The ECST also reported on the risk of stroke in the distribution of the asymptomatic carotid artery in 2,295 patients stratified into four categories of carotid stenosis: 0%–29% stenosis (n = 1,270); 30%–69% stenosis (n = 843); 70%–99% stenosis (n = 127); occlusion (n = 55). During a mean follow-up of 4.5 years, the 3-year Kaplan-Meier risks for ipsilateral stroke and fatal stroke were 2.1% and 0.3%, respectively. The 3-year risk of ipsilateral stroke for patients with an asymptomatic, severe (70%–99% stenosis) carotid stenosis was 5.7%. This was significantly less than the 17.1%, 3-year ipsilateral stroke risk for ECST patients with a symptomatic, severe, carotid stenosis treated medically and was not significantly greater than the 3.1%, 3-year risk of stroke ipsilateral to a severe, symptomatic, carotid stenosis after successful endarterectomy.

Given the modest benefit according to the results of the asymptomatic endarterectomy trials and the low annual event rates associated with asymptomatic carotid stenosis, the cost-effectiveness of performing surgical endarterectomy for asymptomatic carotid stenosis has been questioned (36). The results of a second, large, multicenter, randomized trial examining endarterectomy in patients with asymptomatic carotid stenosis, the Asymptomatic Carotid Surgery Trial, currently in progress (37), are awaited.

A systematic review of the risk of stroke or death due to endarterectomy for symptomatic carotid stenosis was performed by Rothwell et al (38). The authors analyzed 51 studies performed since 1980, including the NASCET, reporting an overall risk of stroke and/or death of 5.64%. The overall death rate was 1.62%; the risk of a fatal stroke (0.86%) slightly exceeded the risk of a nonstroke death (0.7%). The authors noted there was significant heterogeneity in the reported stroke and mortality rates between studies. Studies in which neurologic outcome assessment was by a neurologist reported higher risks of stroke and death.

Rothwell et al performed a similar systematic review comparing the risk of stroke and death due to carotid endarterectomy, performed by the same surgeons in the same institutions, for symptomatic versus asymptomatic stenosis (39). The authors analyzed 25 studies performed since 1980, reporting an overall risk of stroke and/or death in patients with asymptomatic lesions of 3.53%. This risk estimate was significantly lower than that in patients with symptomatic lesions and was consistent across virtually all studies.

Wennberg et al (40) assessed the perioperative mortality among 113,300 Medicare patients undergoing carotid endarterectomy during 1992 and 1993 in "trial hospitals" (those participating in NASCET and ACAS, n = 86) and "nontrial hospitals" (nonfederal institutions in which endarterectomy was performed, n = 2,613) (40). The perioperative mortality rate was 1.4% at trial hospitals compared with 2.5% at low-volume (six procedures or less per year) nontrial hospitals. Age was strongly correlated with perioperative mortality: Patients 85 years or older were three times more likely to die than those younger than 70 years. On the basis of these findings, the authors advised caution in translating the efficacy of carefully controlled studies of carotid endarterectomy to effectiveness in everyday practice.

In summary, results from these trials have demonstrated that endarterectomy confers a notable benefit over medical management in patients with symptomatic carotid stenosis of 70% or greater, with lesser, albeit significant, degrees of benefit in patients with symptomatic lesions of 50%–69% stenosis and asymptomatic lesions of 60% stenosis or greater. However, important caveats apply. Patient selection criteria should be strictly adhered to (41). A recent, prospective, citywide audit of 184 consecutive patients undergoing endarterectomy reported only 49% of these procedures were for appropriate indications (42). The surgeon should have a perioperative complication rate low enough to ensure the full (or any) benefit from the procedure. Some authors (43) have even suggested that surgical teams provide data on their rates of stroke or death within 30 days of surgery, adjusted for the severity of carotid disease and coexistent conditions, to referring physicians and patients. Finally, there is ongoing debate as to the cost-effectiveness of surgery for asymptomatic carotid stenosis, which, according to some authors, is not proved (36).

	ENDOVASCULAR TREATMENT OF CAROTID OCCLUSIVE DISEASE

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History
Percutaneous transluminal balloon angioplasty for carotid artery stenosis was reported on by Kerber et al (44) in 1980. In 1987, Theron et al (45) published findings on internal carotid angioplasty in 48 patients with de novo atherosclerosis or postsurgical restenosis. Technical success was achieved in 94% of cases, with a 4.1% rate of serious morbidity (45). In Kachel’s review of the literature through 1995 (46), 523 carotid angioplasty procedures had subsequently been reported. The overall technical success rate was 96.2%, with a 2.1% rate of morbidity, 6.3% rate of transient minor complications, and no deaths.

In one of the largest single institution series of which we are aware, Gil-Peralta et al (47) in 1996 performed 85 balloon angioplasties in 82 patients with symptomatic carotid stenoses of greater than 70% during a 4-year period. They reported a technical success rate of 92% (residual stenosis <50%), with a 30-day mortality rate of 0% and a major morbidity rate of 4.9%, which compares very favorably to the rates in the ECST and NASCET. The rate of recurrent stenosis (all of which was asymptomatic) was 6.7% at a mean follow-up of 18.7 months, with almost all cases occurring between the 3rd and 6th months. Rates of restenosis (<2 years) reported in other large angioplasty series are between 0% and 16% (46,48–51), and the rate reported in carotid endarterectomy series is approximately 10% in the 1st year (52–55).

Despite ostensibly favorable results, simple balloon angioplasty has a number of potential drawbacks, including vessel wall recoil, angiographically evident intimal dissection, and plaque dislodgment with particulate embolization. Angioplasty of atherosclerotic lesions has been reported to generate emboli composed of atheroma, cholesterol crystals, thrombus, and platelet aggregates (56–59). Embolization due to microparticles has been demonstrated both during and after carotid endarterectomy and has been shown to correlate with complex plaque morphology (60) and with clinical postoperative cerebral ischemia (61–64).

However, studies examining the frequency of emboli during carotid balloon angioplasty with use of transcranial Doppler ultrasonography (US) have failed to show a clear-cut correlation between embolism frequency and neurologic sequelae (57–59). Crawley et al (58), in an analysis of 14 patients undergoing carotid balloon angioplasty versus 14 patients undergoing endarterectomy with shunt placement, reported a mean of 202 embolic signals during carotid balloon angioplasty compared to 52 during carotid endarterectomy. However, during the recovery period of 20 minutes, the mean number of embolic signals was lower for balloon angioplasty than for endarterectomy (five vs 19, respectively). There was no correlation between the number of transcranial Doppler US–detected emboli and the periprocedural stroke rate.

The risk of cerebral damage is thought to depend on the size and composition of the embolic material, as well as on the extent and location of brain involvement. Because it is difficult to accurately distinguish between air and particulate emboli by using transcranial Doppler US (65), the lack of correlation between emboli and clinical sequelae has led to the suggestion that the majority of emboli detected during balloon angioplasty are either gaseous or small platelet aggregates less than 200 µm in diameter, all of which correlate with a more benign outcome (56–58). This underscores the importance of premedication with antiplatelet agents. A recent study examining the rate of cerebral microembolic signals in nine patients following transient ischemic attacks or minor strokes showed a rapid decline in seven patients, starting 30 minutes after an intravenous acetylsalicylic acid (antiplatelet) bolus injection (66).

Endovascular revascularization of carotid occlusive disease may result in cerebral hypoperfusion from luminal compromise because of catheters and guide wires that cross the stenotic lesion and/or during balloon inflation. This is of even greater relevance in the presence of contralateral carotid artery occlusion or stenosis. Eckert et al (67) monitored 22 patients undergoing carotid balloon angioplasty by using transcranial Doppler US, noting that a greater than 50% reduction of middle cerebral artery mean blood flow velocity compared with baseline values represented a critical threshold for the development of ischemic symptoms (transient ischemic attacks in five patients and minor stroke in one patient) in conscious patients, even with short (10–40-second) occlusion times. However, Crawley et al (58) reported hemodynamic ischemia time was significantly longer with endarterectomy than balloon angioplasty and was not predictive of adverse neurologic outcome.

It is recommended that balloon inflation and occlusion times be kept to less than 30 seconds to avoid potential cerebral ischemia. If there is attendant compromise of the contralateral carotid artery, establishing the adequacy of the cerebral collateral circulation becomes even more important, and the procedure should be performed with as little sedation as possible to facilitate neurologic monitoring. Tsurutani et al (68) described the successful use of a continuous-perfusion dilation catheter in a conscious patient with a contralateral carotid occlusion and poor collateral vessels who on two separate occasions lost consciousness and experienced convulsions when a conventional balloon angioplasty catheter was inflated for only 10 seconds.

Current Status
The impetus for carotid stent placement has arisen principally from findings of trials of stent-assisted balloon angioplasty versus simple balloon angioplasty in the coronary arteries, which have consistently demonstrated a persistent benefit in event-free survival at 1 year and a lower rate of repeat angioplasty (69–71). The purported advantages of stent placement over simple angioplasty include avoiding plaque dislodgment, intimal dissection, elastic vessel recoil, and late restenosis.

Since 1996, there have been at least 11 individual large carotid stent series with published findings, with a total number of patients of 929 (51,72–81) (Table 1). Comparative analysis of these articles is made difficult by inconsistencies in the sample populations, lesion characteristics, endovascular techniques, and outcome data. However, the overall reported rate of technical success is greater than 95%; procedure-related mortality rates (including cardiac deaths) are 0.6%– 4.5%; major stroke rates are 0%–4.5%; minor stroke rates are 0%–6.5%; and the 6-month restenosis rate is less than 5%. This is with exclusion of the studies by Teitelbaum et al (79) and Waigand et al (80), both of which represented very high-risk cohorts.

Vitek et al (84) recently presented their experience in treating 404 patients with carotid angioplasty and stent placement. They report a technical success rate of 98%; 30-day morbidity and mortality rate of 1.9%; major stroke rate of 0.7%; minor stroke rate of 5.8%; and a 5% rate of restenosis (>50% narrowing), 65% of which was due to collapse of balloon-expandable stents. The authors report a lower complication rate in the last 122 patients (with increased procedure-related clinical experience): a minor stroke rate of 2.5%, with no major strokes or deaths.

Wholey et al (85) published the results of a worldwide stent survey in which 3,047 endovascular cervical carotid artery stent procedures are reported on from 24 centers in North America, Europe, Asia, and South America. They report a 30-day procedure-related mortality rate of 0.98%; major stroke rate of 1.35%; minor stroke rate of 2.53%; and a restenosis rate at 6 and 12 months of 2.23% and 2.48%, respectively. Centers that performed fewer than 50 procedures had a 6.4% rate of major stroke and death, compared to 2.3% for centers that performed 50–100 procedures. The authors thus suggest a 50-case learning curve for carotid stent placement.

Yadav et al (76) reported that in their series of 107 patients who underwent elective carotid artery stent placement, 77% would have been excluded according to the NASCET criteria; they thus claimed that their cohort represents a high-risk group, the implication being that had such patients been included in NASCET, the surgical complication rate may have been higher. Indeed, a retrospective analysis by Sundt et al (82,86), in which 3,111 consecutive patients who underwent endarterectomy were stratified into six risk classes according to neurologic status, coexistent morbid conditions, and angiographic variables, revealed a very low major complication rate (permanent stroke, myocardial infarction, or death) for patients with class I or II disease, whereas patients with class IV disease had an 8.1% risk (with a 2.9% mortality rate) (Table 2). Factors correlating with increased surgical morbidity and mortality rates included unstable neurologic status; the presence of coexistent morbid conditions; age greater than 70 years; and contralateral internal carotid artery occlusion.

Estes et al (87) followed up until 1992 a random sample of 22,165 Medicare beneficiaries who underwent carotid endarterectomy between 1988 and 1990. They identified patients with acute myocardial infarction, congestive heart failure, diabetes mellitus, or age greater than 80 years as having diminished perioperative and long-term survival rates following carotid endarterectomy. However, according to Dorros (88), these high-risk patients were excluded from the NASCET not because the surgical outcomes may have been adversely influenced but primarily because attendant coexistent morbidities could have potentially contaminated the outcome data.

NASCET criteria were applied to the patient cohorts in five of these carotid stent placement series, demonstrating that 79% of these 574 patients would have failed eligibility because of coexistent morbidities (72,76–78,80). In spite of this, morbidity rates of 2.0%–7.9% and mortality rates of 0.6%–2.0% for these carotid stent placement articles compare favorably with those in the NASCET and the ECST. However, it should be noted that 41% (n = 233) of these patients had asymptomatic carotid stenosis for which lower endarterectomy morbidity and mortality rates would be expected.

Mathur et al (89) retrospectively analyzed the risk factors for stroke in 231 patients undergoing elective stent placement of the extracranial carotid arteries, 14% of which were NASCET eligible. The overall 30-day stroke rate was 6.9%; however, by stratifying for the NASCET-eligible group, the stroke rate decreased to 2.7%. Advanced age (>80 years) and long or multiple stenoses were found to be independent predictors of periprocedural strokes. However, contralateral carotid occlusion, prior carotid endarterectomy, and combined carotid and coronary procedures, all of which are associated with a higher incidence of complications in carotid endarterectomy, were not found to have an increased risk of adverse outcome in patients who have undergone stent placement (53,89–92).

Mericle et al (93) also reported on 23 patients with high-grade carotid stenosis and a contralateral carotid occlusion undergoing elective carotid stent placement. The 30-day perioperative stroke or death rate was 0%. This is in contrast with the perioperative stroke or death rate for contralateral occlusions in the NASCET, which was 14.3% (23). Increased age was also identified as a predictor of increased risk for carotid stent placement procedures by Chastain et al (94). The authors stratified 182 patients undergoing elective carotid artery stent placement into three age groups: older than 80 years, age of 75–79 years, and 74 years or younger. The overall rate of major stroke or death (0.5%) was 1.6%, with a 0.5% rate of myocardial infarction. Neurologic complications (mostly minor strokes) were significantly more frequent in patients older than 80 years than for those 74 years or younger; 25% versus 8.6%, respectively (94).

Carotid stent placement may therefore have advantages over carotid endarterectomy in specific clinical subgroups such as patients with (a) substantial coexistent morbidities, (b) contralateral carotid occlusion, (c) postendarterectomy restenosis, (d) radiation-induced stenosis, and (e) surgically inaccessible (high, low, or tandem) lesions. Yadav et al (95) reported on 22 patients who underwent angioplasty and stent placement for postendarterectomy carotid stenosis, with no major strokes and only one minor stroke (4.5%). Lanzino et al (96) also reported similar favorable results in 18 patients undergoing angioplasty and stent placement for recurrent carotid stenosis following endarterectomy, with no periprocedural strokes and one transient ischemic attack. Meyer et al (53) reported a perioperative morbidity or mortality rate of 10.8% in their series of 82 patients undergoing carotid endarterectomy for recurrent stenoses—five times the risk of a routine endarterectomy at the authors’ institution.

Radiation-induced carotid stenosis is also more difficult to treat surgically because of long lesion length, periarterial scarring with ill-defined planes of resection, and a higher rate of wound complications (97–99). A further advantage of stent placement over endarterectomy is an absent risk of cranial nerve damage. Ballotta et al (100), in a recent prospective review of 200 consecutive carotid endarterectomies, reported a 12.5% incidence of nonpermanent cranial nerve and cervical nerve injuries comprising hypoglossal (5.5%), recurrent laryngeal (4%), superior laryngeal (1%), marginal mandibular, and greater auricular (2%) palsies. The mean recovery time was 5.8 months. Two patients (8%) with recurrent laryngeal nerve palsies had prolonged recovery times of 31 and 37 months.

There are few published studies directly comparing carotid endarterectomy with carotid stent placement. Jordan et al (101) retrospectively compared 107 patients who underwent endarterectomy with 166 patients who underwent carotid stent placement and were prospectively followed up and reported a higher early minor stroke rate in the stent group (6.6% vs 0.6%) but a higher rate of major stroke or death in the surgical cohort (4.2% vs 2.8%).

We know of one article (102) on an early prospective, randomized study in 17 patients treated for symptomatic stenoses of greater than 70%. The authors reported no complications in 10 patients undergoing endarterectomy; however, five of seven patients who underwent stent placement had strokes, three of which were disabling at 30 days. This prompted early stoppage of the trial in favor of endarterectomy. However, the carotid stent procedures were performed by an interventionist who had performed only eight carotid angioplasties prior to the trial commencement. Furthermore, the trial methods do not specify the antiplatelet regimen used prior to carotid stent placement. It appears patients received only aspirin in relatively low doses. In addition, intraprocedural heparin administration was limited to a single intravenous bolus of 5,000 U before the first balloon inflation. These factors may at least partially explain these poor results.

Retrospective studies examining the cost of endarterectomy versus stent placement have indicated lower costs for their respective procedures (103–105).

Technique
The following protocol is based on that practiced at the University of California, San Francisco, Medical Center. However, it should be noted that variations in protocol and technique have been described by many experienced operators, producing excellent results. As such, the following descriptions represent a guide to technique while recognizing that substantial diversity currently exists and that both endovascular devices and procedure protocol are rapidly evolving.

A complete neurologic history and examination is requisite prior to any carotid stent procedure. Ideally, this should be performed and documented by both the interventionist and the cerebrovascular neurology team. A baseline brain CT scan or magnetic resonance (MR) image should be obtained to document preexistent infarction and to exclude nonvascular neurologic disease such as tumor that may mimic transient ischemic attacks. Baseline laboratory values, including hemoglobin and hematocrit levels; serum creatinine, blood urea nitrogen, and electrolytes levels; and prothrombin and activated partial thromboplastin times, as well as a preprocedural electrocardiogram and chest radiograph are obtained.

Patients fast from midnight before the procedure but are permitted to take any regular medications (particularly antihypertensive medicines) orally with a sip of water. Patients receiving long-term anticoagulation should discontinue warfarin 3 days prior to the procedure and are admitted the day before for intravenous heparin administration. Similarly, patients with preexistent renal disease are admitted on the prior day for intravenous hydration. Oral enteric-coated aspirin (325 mg/d) and clopidogrel (75 mg/d) are recommended at least 3 days before the procedure to reduce periprocedural platelet emboli. Experimental data suggest aspirin and clopidogrel have a synergistic effect on platelet antiaggregation, on antithrombotic activity, and in preventing myointimal proliferation (restenosis) (106,107).

The procedure is usually performed with the patient under conscious sedation by using local anesthesia of the femoral artery region. The pedal pulses are examined (with Doppler US if not palpable) and are marked for later reference. A urinary catheter is inserted, and external cardiac pacing leads are attached to the patient prior to sterile draping. A sheath is inserted into the common femoral artery, and a baseline activated clotting time is obtained. The groin sheath size is dependent on the stent used and the sheath length: The current self-expanding Wallstent (Schneider, Minneapolis, Minn) requires the minimal use of a 9–10-F guiding catheter (Brite Tip; Cordis Endovascular, Miami Lakes, Fla) or a 90-cm length 7–8-F sheath (Arrow Interventional, Reading, Pa). Newer devices with smaller-diameter stent-delivery catheters and balloons may require only a 6–7-F sheath.

Preliminary diagnostic angiography of both carotid arteries in a minimum of two planes that includes the intracranial circulation should be performed. Selective catheterization of the common carotid arteries in persons younger than 40 years can usually be accomplished by using small-diameter (5- or 5.5-F) catheters with simple shapes (a short angled tip), such as a 5-F UCSF II catheter (Cordis Endovascular) or 5.5-F Norman catheter (Cook, Bloomington, Ind) in combination with soft-tipped guide wires such as a 0.035-inch Bentson guide wire (Cook) with a long, floppy (and shapeable) tip that is relatively atraumatic.

In older patients, vessel elongation, tortuosity, and dilatation may necessitate the use of larger-diameter and hence stiffer catheters such as a Berenstein catheter (USCI, Billerica, Mass), which has a 7-F shaft that tapers to a 5-F tip, in combination with stiffer guide wires such as a hydrophilic, coated, 0.035-inch Terumo glide wire (Medi-tech, Watertown, Mass). Alternatively, a reverse-curve catheter such as a Simmons type may be used. The Simmons catheter may be preferred for the evaluation of carotid bifurcation disease because only a short length of leading guide wire is required, thus reducing the likelihood of guide wire impingement against atherosclerotic plaque.

Standard angiographic projections for demonstrating the carotid bifurcation are anteroposterior, lateral, and an ipsilateral anterior oblique (30°–45°) projection. The internal carotid artery invariably arises posterior to the external carotid artery, and, in most cases, laterally; thus, an ipsilateral anterior oblique or lateral view is usually optimal for displaying the bifurcation. However, pinhole or weblike high-grade stenoses may be underestimated unless multiple oblique projections are obtained (108). A contrast material injection rate of 5–8 mL/sec, for a total volume of 5–8 mL, can be used for the carotid bifurcation, and a rate of 6–8 mL/sec, for a total volume of 7–10 mL, can be used for the intracranial circulation.

A filming rate of three to five images per second for 4–5 seconds followed by one image per second for 7–8 seconds is usually employed (109). In the case of presumed internal carotid artery occlusion, prolonged filming is necessary, as otherwise delayed, faint, anterograde opacification of the cervical internal carotid artery may be missed ("string sign" of critical internal carotid artery stenosis) (110). Standard anteroposterior and lateral intracranial views should be obtained in all cases to establish the adequacy of the intracranial collateral circulation via the external carotid and anterior communicating arteries and also to document any intracranial stenotic lesions. Many experienced operators also advocate routine vertebral angiography to assess collateral flow via the posterior communicating arteries and document any extracranial or intracranial vertebrobasilar stenoses. Certainly, in cases of contralateral carotid occlusion, bilateral severe stenosis, or deficient anterior collateral pathways, evaluation of the adequacy of collateral flow via the posterior circulation becomes even more important.

After acquisition of the appropriate diagnostic images, the patient receives an intravenous loading dose of heparin (70–100 U per kilogram of body weight) large enough for a target therapeutic activated clotting time of 2–2.5 times the baseline or 250–300 seconds. This is followed by a continuous intravenous heparin infusion (15–20 U/kg/h) or hourly boluses of half the initial dose. The prophylactic or "bailout" role of glycoprotein IIb/IIIa inhibitors such as abciximab, which have been shown to decrease mortality and morbidity in a number of coronary stent studies and also potentially improve long-term patency rates, remains undefined in carotid artery stent placement (111–113). These agents may have a potential role in the uncommon event of acute stent thrombosis, since platelet aggregation (white thrombus) represents the primary mechanism (114).

Self-expanding stents such as the Wallstent are currently the most frequently used type for internal carotid artery origin disease; hence, primarily this technique will be described. In general, a 300-cm exchange guide wire (Storq; Cordis Endovascular) is placed into the ipsilateral external carotid artery, and the guiding catheter is advanced over this into the distal common carotid artery by using a coaxial system: a 90-cm, 9-F guide catheter primed with an inner, 110-cm, 7-F Berenstein diagnostic catheter (USCI). In younger patients (<50 years) and those with nontortuous great vessels, primary selection of the common carotid artery with the coaxial guiding catheter system or long sheath may be attempted. The guiding catheter is then connected to a continuous pressurized saline and heparin flush (1 U of heparin per milliliter of normal saline at 100 mL/h) via a large-bore Tuohy-Borst type–rotating hemostatic valve (Big Easy; Microvena, White Bear Lake, Minn). Prior to guide-catheter positioning, 1 inch of topical 2% nitroglycerin paste (nitropaste) may be applied to reduce the likelihood of mechanically induced arterial vasospasm (115).

If the minimum internal carotid artery diameter is 2.5 mm or less, it is initially traversed under digital road map guidance with a 2.3-F microcatheter (Rapid Transit; Cordis Endovascular) and a 0.014-inch guide wire (Transend; Scimed, Maple Grove, Minn) to reduce the risk of embolism. The microcatheter tip is positioned within the petro cavernous segment of the internal carotid artery, and the Transend guide wire is exchanged for a 300-cm, 0.014-inch exchange-length guide wire (Balance; Advanced Cardiovascular Systems, Santa Clara, Calif). Alternatively, the lesion can be initially crossed by using the 0.014-inch exchange guide wire alone.

Carotid stenoses of lesser severity may be initially traversed under road map guidance by using an 0.018-inch or 0.035-inch guide wire; however, these larger-diameter and hence stiffer guide wires have an increased risk of plaque dislodgment and should not generally be advanced beyond the cervical segment of the internal carotid artery because of the risk of intimal dissection or vessel spasm.

The decision to predilate the lesion by using balloon angioplasty depends on the type and size of stent being used, the narrowest luminal diameter, and the morphologic configuration of the stenotic segment. Many operators perform routine predilation to approximately 4.0 mm diameter. However, others suggest that the risk of embolism is highest during this part of the procedure and that if atraumatic crossing of the lesion with the stent-delivery catheter is possible without predilation, it may be attempted. However, if any resistance to advancement is encountered, then the stent-delivery-catheter is removed and predilation is performed. Certainly, if the smallest luminal diameter is 2.5 mm or less, then predilation to approximately 3.5–4.0-mm diameter is recommended (Titan; Cordis Endovascular).

Ideally, a single, brief (<30-second) balloon inflation is performed. Prior to balloon inflation, 0.5 mg of atropine or 0.1–0.2 mg of glycopyrrolate is administered intravenously to prevent reflex bradycardia or asystole, which may occur in 5%–10% of patients. A road map image is obtained, and the stent-delivery catheter is advanced over the immobilized guide wire. The interventionist should also note the bony landmarks that delineate the desired stent position, as patient movement may degrade the road map image. Advancement of the stent-delivery catheter can also straighten and distort the internal carotid artery, rendering such landmarks inaccurate.

The stent is carefully advanced across the lesion and, when satisfactorily positioned, is deployed by immobilizing the delivery catheter and retracting the outer sleeve for a self-expanding stent or inflating the balloon to deploy the balloon-expandable stent. Following stent deployment, the delivery catheter or balloon may be gently rotated to aid in stent separation and then may be carefully withdrawn while ensuring the stent remains stationary.

Postdeployment angioplasty by using a high-pressure (12–20-atm), semi-compliant balloon (Jupiter; Cordis Endovascular) may then be performed to closely appose the stent and intima and, moreover, to expand regions of residual stent narrowing. This may require the use of varying-diameter balloons, particularly if the stent extends into the common carotid artery. Obvious gaps between the stent circumference and endoluminal surface should be avoided, since this potentially increases the risk of acute or delayed thromboembolism (116). The balloon should be inflated for no longer than 30 seconds at 12–20 atm at a time, with a sufficient pause between inflations to allow restoration of cerebral perfusion. In general, postdeployment stent balloon angioplasty is performed from distal to proximal. Residual ulceration external to the stent is usually of no clinical importance (Fig 1).

View larger version (70K): [in this window] [in a new window] [Download PPT slide]   Figure 1a. Lateral angiographic views of the right carotid artery in a 70-year-old man who 10 years previously underwent bilateral carotid endarterectomies complicated by a left hemispheric perioperative stroke. A recurrent right carotid arterial stenosis was demonstrated at US after right-sided amaurosis fugax. (a) A 60% stenosis of the right internal carotid artery at the bifurcation (arrow) with ulceration (arrowheads) is shown. (b) The stenosis was successfully treated by using an 8-mm-diameter 40-mm-long Wallstent positioned across the carotid bifurcation. Note the small area of residual ulceration (arrow) external to the stent, which is of no importance.

View larger version (47K): [in this window] [in a new window] [Download PPT slide]   Figure 1b. Lateral angiographic views of the right carotid artery in a 70-year-old man who 10 years previously underwent bilateral carotid endarterectomies complicated by a left hemispheric perioperative stroke. A recurrent right carotid arterial stenosis was demonstrated at US after right-sided amaurosis fugax. (a) A 60% stenosis of the right internal carotid artery at the bifurcation (arrow) with ulceration (arrowheads) is shown. (b) The stenosis was successfully treated by using an 8-mm-diameter 40-mm-long Wallstent positioned across the carotid bifurcation. Note the small area of residual ulceration (arrow) external to the stent, which is of no importance.

Anteroposterior and lateral cerebral angiograms should be obtained after stent placement in all cases to exclude any embolic branch occlusion and to document new patterns of flow. The patient is carefully examined neurologically. Neurologic deficits may be due to intracranial embolism, hemorrhage, or reperfusion injury (117). The phenomenon of reperfusion hemorrhage following surgical endarterectomy is well described. Ouriel et al (118), in a review of 1,471 patients undergoing surgical endarterectomy, reported a 0.75% incidence of intracerebral hemorrhage. Hemorrhage occurred at a median of 3 days postoperatively and accounted for 35% of the total perioperative neurologic events. Death of massive hemorrhage and herniation occurred in 36% of cases. Factors correlating with an increased hemorrhage risk were hypertension, high-grade ipsilateral stenosis, high-grade contralateral stenosis or occlusion, and younger age. Schoser et al (117) reported on two patients with reperfusion hemorrhage—one intraparenchymal hemorrhage and one subarachnoid hemorrhage following balloon angioplasty for carotid and vertebral artery stenoses.

Prior to stent deployment, the mean arterial blood pressure should be maintained at or above baseline. However, following successful revascularization, lowering the mean arterial pressure to 10%–20% below baseline may be desirable to prevent cerebral reperfusion injury (Fig 2). Intravenous diltiazem may be used after a procedure to control elevated blood pressure (5 mg/kg/min loading dose followed by a continuous intravenous infusion of 5–15 µg/kg/min), particularly when the hypertension is associated with headache or neurologic sequelae, as the diltiazem has minimal cerebral vasodilatory effects (119). Alternatively, postprocedural prolonged bradycardia and/or hypotension may occur as a result of carotid sinus dysfunction, necessitating the use of intravenous vasopressors or ionotropic agents (120).

View larger version (78K): [in this window] [in a new window] [Download PPT slide]   Figure 2a. Lateral angiographic views of the left carotid artery in an 80-year-old man who underwent carotid Doppler US (not shown) prior to coronary bypass surgery, which suggested a high-grade stenosis of the cervical left internal carotid artery beyond the carotid bulb. (a) A critical left internal carotid arterial stenosis with ulceration (arrow) was confirmed at angiography. (b) The stenosis was successfully treated with a 7-mm-diameter 20-mm-long Wallstent placed within the internal carotid artery. The patient developed right-sided hemiparesis and expressive dysphasia immediately after revascularization. There was no angiographic evidence of an embolic branch occlusion. The patient made a full clinical recovery over the next few days. The presumed mechanism, based on postoperative CT findings (not shown) demonstrating cerebral edema of the left hemispheric convexity, was reperfusion injury. Diffusion-weighted MR imaging, transcranial Doppler US, and single photon emission CT scanning may be useful if a reperfusion injury is suspected.

View larger version (86K): [in this window] [in a new window] [Download PPT slide]   Figure 2b. Lateral angiographic views of the left carotid artery in an 80-year-old man who underwent carotid Doppler US (not shown) prior to coronary bypass surgery, which suggested a high-grade stenosis of the cervical left internal carotid artery beyond the carotid bulb. (a) A critical left internal carotid arterial stenosis with ulceration (arrow) was confirmed at angiography. (b) The stenosis was successfully treated with a 7-mm-diameter 20-mm-long Wallstent placed within the internal carotid artery. The patient developed right-sided hemiparesis and expressive dysphasia immediately after revascularization. There was no angiographic evidence of an embolic branch occlusion. The patient made a full clinical recovery over the next few days. The presumed mechanism, based on postoperative CT findings (not shown) demonstrating cerebral edema of the left hemispheric convexity, was reperfusion injury. Diffusion-weighted MR imaging, transcranial Doppler US, and single photon emission CT scanning may be useful if a reperfusion injury is suspected.

Postprocedural hematocrit values are obtained, since the likelihood of a retroperitoneal hematoma is increased with the use of large-diameter sheaths in conjunction with high levels of anticoagulation. The patient is usually monitored in the intensive care unit for 12–24 hours after treatment. Administration of clopidogrel (75 mg/d) is continued for 4–6 weeks, and administration of enteric-coated aspirin (325 mg/d) is continued indefinitely. The patient is advised to avoid vigorous neck manipulation or deep massage. A follow-up US examination of the neck is performed at 6 months to document continued patency, since restenosis usually occurs within the first 6 months after treatment.

In terms of stent sizing, the stent margins should optimally extend 1 cm beyond the proximal and distal margins of the stenotic plaque. This may necessitate crossing the external carotid artery origin, which does not usually result in clinically important sequelae (Fig 3). Prominent carotid artery curves or kinks should also be taken into account when determining the appropriate stent length. It is not desirable to position the stent margins within an acute bend or kink in the carotid artery as this risks luminal obstruction by the stent. This is less of a problem (although not eliminated) with more "conformable" self-expanding nitinol stents (SMART Stent; Cordis Endovascular). Another potential problem that may be encountered is relocation of carotid artery redundancies or kinks adjacent to the stent margins. In our experience, these "nouveau" kinks have not usually been flow limiting and thus have not required further intervention.

View larger version (97K): [in this window] [in a new window] [Download PPT slide]   Figure 3a. Lateral angiographic views of the left carotid artery in an 80-year-old man who presented with recurrent left hemispheric transient ischemic attacks. Carotid Doppler US (not shown) suggested an occluded right internal carotid artery and high-grade stenosis of the left internal carotid artery. An occluded right internal carotid artery and (a) a high-grade stenosis of the left internal carotid artery (straight arrow) were confirmed at angiography. Note also a focal stenosis (approximately 60%) of the left external carotid artery origin (curved arrow). (b) The high-grade stenosis was treated by means of endovascular placement of an 8-mm diameter 20-mm-long Wallstent. Arrows indicate the proximal and distal margins of the stent.

View larger version (93K): [in this window] [in a new window] [Download PPT slide]   Figure 3b. Lateral angiographic views of the left carotid artery in an 80-year-old man who presented with recurrent left hemispheric transient ischemic attacks. Carotid Doppler US (not shown) suggested an occluded right internal carotid artery and high-grade stenosis of the left internal carotid artery. An occluded right internal carotid artery and (a) a high-grade stenosis of the left internal carotid artery (straight arrow) were confirmed at angiography. Note also a focal stenosis (approximately 60%) of the left external carotid artery origin (curved arrow). (b) The high-grade stenosis was treated by means of endovascular placement of an 8-mm diameter 20-mm-long Wallstent. Arrows indicate the proximal and distal margins of the stent.

View larger version (72K): [in this window] [in a new window] [Download PPT slide]   Figure 4a. Lateral angiographic views of the left carotid artery in a 57-year-old man with hypertension and diabetes presenting with left-sided amaurosis fugax. (a) Critical stenosis (arrow) of the left internal carotid artery a few centimeters above the bifurcation was demonstrated at angiography. (b) Endovascular treatment was performed by using an 8-mm-diameter 20-mm-long Wallstent. Arrows indicate the proximal and distal margins of the stent.

View larger version (77K): [in this window] [in a new window] [Download PPT slide]   Figure 4b. Lateral angiographic views of the left carotid artery in a 57-year-old man with hypertension and diabetes presenting with left-sided amaurosis fugax. (a) Critical stenosis (arrow) of the left internal carotid artery a few centimeters above the bifurcation was demonstrated at angiography. (b) Endovascular treatment was performed by using an 8-mm-diameter 20-mm-long Wallstent. Arrows indicate the proximal and distal margins of the stent.

Compression of balloon-expandable stents has been found to be an important cause of restenosis in the superficial femoral arteries and hemodialysis grafts (126). The 1998 global survey of 3,047 carotid stent placement procedures by Wholey et al (85) included 3,033 endovascular carotid stents placed. Balloon-expandable Palmaz stents were used in 47% of cases; self-expandable Wallstents were used in 46%; and other stents, including Strecker (Medi-tech), Integra (Medi-tech), Symphony (Medi-tech), and SMART (Cordis Endovascular) stents, were used in the remaining 7% of cases (85). In this series, 28 stent deformations occurred exclusively with the Palmaz stent (2%).

However, Bergeron et al (81) reported no instances of compression, with a mean 13-month follow-up, among 96 patients with carotid stenosis treated with Palmaz stents. Nevertheless, the Palmaz stent may not be an ideal choice for superficially exposed arteries such as the internal carotid artery; however, in nonexposed locations such as the vertebral artery or great vessel origins, the superior positional accuracy of deployment may be advantageous. Self-expanding nitinol stents offer the purported advantage of crush recoverability or springlike behavior. If an external force compresses or deforms a nitinol stent, it will reassume its expanded shape on removal of the external stress.

Future Developments
In reviewing the current literature on carotid artery stent placement, the technical success rate, procedure-related morbidity and mortality, and restenosis rates compare favorably with those for carotid endarterectomy. However, the validity of comparisons between such disparate clinical data is unsound. In the case of carotid endarterectomy, there exists class I evidence of efficacy, whereas the bulk of the endovascular data is derived from nonrandomized, uncontrolled studies, usually from single institutions (127,128). Class I evidence is that which is proved by a prospective, randomized trial with a small chance of false-negative or false-positive values. The pertinent question may therefore be why bother with comparison of an alternative therapy at all. According to Freedman (129), a randomized prospective comparison is ethically justifiable if a state of clinical equipoise exists, defined as a lack of consensus among experts as to the optimum therapy for a single disease process.

Currently, three prospective, randomized, multicenter trials comparing carotid endarterectomy with carotid angioplasty (Carotid and Vertebral Transluminal Angioplasty Study [CAVATAS]) or carotid stent placement (Carotid Revascularization Endarterectomy versus Stent Trial [CREST] and Wallstent Trial) have been undertaken. The CAVATAS, a large, prospective, randomized, multicenter trial comparing carotid endarterectomy with carotid angioplasty, was recently completed. In the CAVATAS, patients with symptomatic stenoses (at least 30% luminal diameter reduction) whose conditions were suitable for surgery were randomly assigned to undergo either angioplasty or surgery (130). Patients whose conditions were unsuitable for endarterectomy were randomly assigned to undergo percutaneous transluminal techniques and medical treatment alone. In the CAVATAS, 504 patients were randomly assigned to undergo surgery or angioplasty over 5 years. There was no significant difference in the risk of stroke or death related to the procedure between carotid endarterectomy and angioplasty. The rate of any stroke lasting more than 7 days or death within 30 days of first treatment was approximately 10% in both the surgery and angioplasty groups. The rate of disabling stroke or death within 30 days of first treatment was 6% in both groups. Preliminary analysis of long-term survival showed no difference in the rates of ipsilateral stroke or any disabling stroke in patients up to 3 years after randomization.

The rates of stroke or death within 30 days in CAVATAS in both groups are higher than in many previous reports but are not significantly different from the ECST rate of 7%. Cranial nerve injury and myocardial ischemia were reported at the time of treatment only in the surgical group. Long-term follow-up is not yet available (131).

The CREST, a North American, multicenter, randomized controlled trial comparing the efficacy of surgical endarterectomy with that of carotid stent placement is currently in its initial developmental stage. In the CREST, patients with symptomatic extracranial carotid stenosis of at least 50% are randomly assigned to undergo stent-supported angioplasty or endarterectomy. To demonstrate a clinically important difference between the treatments, the CREST will potentially require at least 2,500 patients; this excludes comparison between various clinical subgroups (eg, recurrent stenosis), for which an even greater number will be required. An industry-supported (Wallstent; Schneider), prospective, randomized trial comparing endarterectomy and carotid stent placement for symptomatic stenosis of at least 60% is currently in progress (132).

The potential for further improvement in endovascular equipment and hence technique remains immense. Currently, carotid stents are mainly adaptations of coronary or peripheral stent designs. Dedicated carotid stent designs that taper in diameter distally to accommodate the size discrepancy between the common and internal carotid arteries may be advantageous, particularly with nitinol stents, which in time fully expand to their shape-memory diameter.

Other potential areas of innovation include providing cerebral protection by using intravascular filters or balloons; smaller-diameter, more flexible, and hence less traumatic delivery systems; lowering rates of restenosis secondary to intimal hyperplasia by using local catheter brachytherapy or radiation-emitting stents (133–135); and improving adjuvant pharmacologic regimens by using antiplatelet agents such as the glycoprotein IIb/IIIa inhibitors, which might reduce the incidence of acute thromboembolism and improve long-term patency (136). This genuine potential for future improvement has prompted some authors to suggest that a direct comparison with carotid endarterectomy is premature (88,137–139).

It remains unclear whether carotid artery stent placement helps reduce the number of particulate emboli by trapping them beneath the metallic meshwork. Current stent designs may trap larger fragments but may not efficiently prevent microemboli because the interstitial size is too large (116). A recent prospective study in which patients undergoing carotid artery stent placement were examined pre- and postprocedurally with MR imaging failed to show evidence of abnormal brain signal intensity referable to emboli; however, a similar prospective study in which 17 patients were examined with diffusion-weighted MR imaging showed new (clinically silent) lesions in three cases (140,141).

The problem of distal embolization during balloon angioplasty and carotid stent placement has spurred interest in providing methods of cerebral protection. A triple-coaxial catheter system designed to provide cerebral protection has been described by Theron et al (142). This consists of an 8-F guiding catheter primed with a 5-F balloon angioplasty catheter that contains a 300-cm length, 2.6-F catheter, with a latex balloon attached to its end. The latex balloon allows distal internal carotid artery protection during angioplasty. Atherosclerotic debris is then aspirated through the guide catheter or flushed into the external carotid artery.

Theron et al (51) reported distal embolic complications in three of 38 patients (8%) undergoing internal carotid artery balloon angioplasty without distal protection versus zero of 43 patients (0%) undergoing the same procedure with distal balloon protection. Theron et al (116) recently described two embolic complications when using this system. In the first case, flushing of debris into the external carotid artery resulted in monocular blindness due to an unrecognized connection between the middle meningeal artery and the ophthalmic artery. In the second case, vigorous flushing resulted in proximal reflux of debris from the right common carotid artery into the right vertebral artery. The rate of flush injection should therefore not exceed 2 mL/sec.

Henry et al (78) used Theron’s distal occlusion balloon technique in 32 of 163 carotid stent placement cases. However, two of the three major strokes that occurred in this series were in conjunction with use of this device. The authors cited prolonged procedure time and increased embolism risk when traversing ulcerated lesions as potential problems associated with its use.

A number of commercial devices aimed at reducing the microembolic burden associated with carotid angioplasty and/or stent placement, by using filters or guide wire–attached balloons, are currently under development (Fig 5). These include a low-profile embolic filter deployed and retrieved on a 0.014- or 0.018-inch shaft that serves as the guide wire for balloon and stent-delivery catheters. A study (143) with ex vivo models has shown more than 90% capture of particles larger than 200 µm and 100% capture of particles larger than 500 µm. Alternatively, a 0.014-inch guide wire with a protection balloon incorporated into the tip has been used. Following angioplasty and stent placement with the protection balloon inflated, an over-the-wire aspiration catheter is passed through the dilated area to clear debris (144). This balloon-protection method has the disadvantage of temporary occlusion of carotid flow, whereas filter devices allow constant cerebral perfusion.

View larger version (38K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Diagram illustrates the principle of cerebral protection during carotid angioplasty and stent placement by using a balloon attached to the end of a 0.014-inch guide wire (left) or a filter device deployed and retrieved with a 0.018- or 0.014-inch guide wire (right). ECA = external carotid artery, ICA = internal carotid artery.

In conclusion, the preeminent position of carotid endarterectomy for the treatment of carotid occlusive disease is under challenge. Retrospective data that suggest the feasibility and comparable safety of the endovascular approach have instigated direct comparison in the form of a multicenter, randomized, controlled trial. Indeed, the long-term durability of carotid stents in preventing stroke and the long-term patency rates of carotid stents are not as yet established. However, the potential for continued evolution in endovascular stent technology and clinical experience bodes well for further reduction in procedure-related complications and improved long-term patency rates.

	FOOTNOTES

 
Abbreviations: ACAS = Asymptomatic Carotid Atherosclerosis Study, ECST = European Carotid Surgery Trial, NASCET = North American Symptomatic Carotid Endarterectomy Trial

R.T.H. is a consultant for Cordis Endovascular. V.V.H. is a consultant for Target Therapeutics.

Author contributions: Guarantor of integrity of entire study, C.C.P.; study concepts and design, C.C.P.; definition of intellectual content, C.C.P.; literature research, C.C.P.; data acquisition and analysis, C.C.P.; statistical analysis, C.C.P.; manuscript preparation, C.C.P., A.M.M., P.M.M., T.E.L.; manuscript editing, C.C.P., R.T.H.; manuscript review, C.C.P., R.T.H., C.F.D., V.V.H.

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