Ramdas G. Pai, MD is a Professor of Medicine and the Cardiology Fellowship Program Director, Loma Linda University Medical Center, Loma Linda, CA.

Carotid endarterectomy (CE) is a well-established treatment for the prevention of stroke. However, CE has inherent limitations that make it applicable only to treatment of the surgically accessible internal carotid artery. Recently, percutaneous transluminal carotid artery stenting (CAS) deployment has emerged as an alternative modality for the treatment of carotid artery disease. Current data for CAS are comparable with CE. Trials comparing CE with CAS are under way. The results of these studies will not reflect the state-of-the-art technology as new stents and new embolic protective devices will become available during these studies. Therefore, the decision to use CAS will depend on patient risks and lesion characteristics.

Stroke remains the leading cause of disability in the industrialized world, and carotid artery disease (CAD) is a major cause of stroke. Given the tragedy and morbidity of stroke, any additional treatment modalities that will enable us to improve the care we provide are welcome. In the United States alone, the incidence of strokes is approximately 600,000 per year, of which 60% are due to CAD. This leads to approximately 160,000 deaths and leaves many more patients with major disabilities. ¹

Carotid endarterectomy (CE) is a well-established treatment of extracranial carotid atherosclerotic disease in symptomatic and asymptomatic lesions. Approximately 200,000 CEs are performed annually. However, CE is limited to treatment of surgically accessible lesions.

The technology used for endovascular interventions has undergone a rapid evolution over the past decade in that coronary and peripheral arterial interventional techniques have been used for carotid, vertebral, and other cerebral interventions.

The progress in the treatment of cerebrovascular disease has been much slower than that of CAD. This is probably related to the more intractable nature of cerebrovascular disease and the diversity of specialists involved in the care of these patients.

Carotid artery stenosis

The treatment of stroke resulting from atherosclerotic stenotic lesions can be categorized as medical, surgical, or endovascular. The first two types of treatments have been available traditionally. The medical therapy centers on antiplatelet and antithrombotic agents and aggressive risk-factor modification. Currently, the antiplatelet agents available for stroke prevention include aspirin, ticlopidine, clopidogrel, and an aspirin/dipyridamole combination. The oral anticoagulant, warfarin, has been used mainly in the context of cardiogenic brain embolism.

For extracranial carotid atherosclerosis, the studies that will be discussed showed the superiority of surgical therapy compared with the best medical therapy. In addition, the lessons learned from these landmark studies have allowed the construction of an evidence-based measure against which future medical and ongoing interventional trials should be compared. The degree of the stenosis and whether the lesions are associated with symptoms significantly challenge the approach to treatment.

Symptomatic carotid artery stenosis

Two large trials and other small ones that were conducted in the 1980s and 1990s involved a total of approximately 6000 patients with cerebral or retinal symptoms and corresponding atherosclerotic CAD. ^2-5 The European Carotid Surgery Trial (ECST) ³ and the North American Symptomatic Carotid Endarterectomy Trial (NASCET) ⁴ stopped recruiting patients with severe stenosis (70% to 99%) after fewer than 700 patients had been randomized in each trial. Positive results favoring surgery were evident for patients with 70% to 90% stenosis measured angiographically. However, at that time, the benefit had not been detected for symptomatic patients with lesser degree of stenosis (moderate stenosis 50% to 69%, mild stenosis <50%). In these large trials, patients with nonathe-rosclerotic disease, organ failure, unde-rlying potentially fatal cancers, embolic cardiac lesions, and remote (>6 months) ischemic symptoms were excluded.

It is important to realize that ECST and NASCET used different denominators to assess the degree of stenosis (Figure 1). Barnett and colleagues ⁶ remeasured the degree of the stenosis of the ECST patients using the NASCET method. Similar treatment results and long-term benefits were identified. ^6,7 NASCET found CE to be beneficial in patients with 50% to 99% stenosis with the greatest benefits for lesions with 70% to 99% stenosis. ⁵ ECST found that CE was beneficial if the degree of stenosis was above 80% (NASCET 60%). ³

Extrapolation of the results of NASCET and ECST into clinical practice requires the acknowledgment of two facts. First, the reported surgical complication rate of stroke and death was the result of the care taken by the investigators to select surgeons with proven expertise. In NASCET, surgeons were required to provide evidence that they had achieved a perioperative complication rate of <6%. When the results of the 328 patients with severe carotid artery stenosis who underwent CE were analyzed, the perioperative rate of death or stroke was 5.8%. Substituting a hypothetical perioperative complication rate above that observed in NASCET shows that the higher surgical complication rates soon negate benefits. The second fact is that the results were acquired from angiographic data. Extrapolation of the results to patients investigated using noninvasive methods remains unproven.

What about the patients with less than 70% stenosis? In NASCET, 226 patients were randomized to medical therapy or surgical therapy and followed up for an average of 5 years. The patients were stratified into two groups: those with 50% to 69% stenosis, and those with <50% stenosis. Benefits of CE were less dramatic in the 50% to 69% group than in the severe group with >70% stenosis. No benefits could be seen in patients with <50% stenosis. Similarly negative results came from the ECST for patients with what ECST calls 70% stenosis and NASCET measures at 50% stenosis.

Patients with a moderate degree of stenosis and high operative risks should be managed medically with close follow-up. This includes patients with an occluded carotid artery on the opposite side of the symptoms, diabetes, thrombus containing stenotic artery, ulcerated lesions, ⁸ diastolic blood pressure >90 mm Hg, and objective evidence of brain infarction in the territory affected by the stenosis.

No strong evidence is available currently to support the use of CE to prevent stroke in patients with nonspecific, nonhemispheric, or vertebrobasilar symptoms. Similarly, no data are available to support the use of CE in patients with symptoms related to fibromuscular dysplasia, postradiation fibrosis, or carotid artery dissection.

Asymptomatic carotid artery disease

The frequency of asymptomatic athe-rosclerotic carotid artery stenosis increases with age. It has been estimated that 2 million individuals in the United States older than 50 years have >50% stenosis of the carotid artery on one or both sides. ⁹ The Asymptomatic Carotid Atherosclerosis Study (ACAS) randomized half the patients to the medical therapy arm and the other half to the CE arm. ¹⁰ Individuals with >60% stenosis had a benefit at 5 years favoring CE. Ipsilateral stroke occurred in 11% of the patients in the medical arm compared with 5.1% in the surgical group (Table 1).

Limitations of CE

The benefit of CE holds true only if the risk of death and stroke from the procedure is <6% for symptomatic patients and <3% for asymptomatic patients. ^4,10 Furthermore, in routine clinical practice, these numbers are widely quoted as they set the standard for whether or not patients are referred for surgery based on the institution's experience with CE. ¹¹ However, postoperative complications of CE are not only limited to stroke and death. For example, in NASCET, the incidence of cranial nerve injury was 7%, resulting in a group of patients with new neurologic deficits related to the surgery. In ECST, the rate of major stroke and death was approximately 7%. Although this trial used somewhat different methodology than NASCET, this 7% rate of major stroke and death reported by ECST is three times the 2.1% rate reported by the NASCET group. The rate of CE complications reported is dependent on the specialty of the study investigators. Having a neurologist among the investigators of CE studies may result in a higher rate of neurologic complications because other specialists may have difficulty in acknowledging subtle neurologic changes. ¹²

Another important issue regarding CE is whether the patient population in these large trials represents the patients seen in daily practice. In NASCET, the majority of patients were below the age of 80 and their clinical comorbidities lacked significant coronary artery disease--only 19% had a previous myocardial infarction, 2.6% had congestive heart failure, 2% had valvular heart disease, and 5% had cardiac arrhythmias; patients with renal failure, liver failure, or cancer were excluded from entry into the study. Also, <20% were diabetics and hyperlipidemics and approximately 30% were smokers. ¹³ The ACAS participants were extremely low-risk, relatively healthy patients. ¹⁰ Therefore, it is obvious that the results of these trials cannot be applied to patients at higher risk or those with complex lesions ¹⁰ (Table 2). In NASCET, the existence of contralateral carotid artery occlusion and tandem siphon lesions was associated with a higher risk of postoperative complications, 14% and 9%, respectively. ¹⁴

Carotid angioplasty and stenting: Evolving experience

The advent of percutaneous treatment of significant carotid artery stenosis dates back to the early 1980s with several groups reporting their experience in a handful of cases with reasonable success for both atheromatous and nonatheromatous lesions. ^15-21

In 1987, Theron and colleagues ²² reported the first large series of carotid angioplasty including 6 patients with atherosclerotic lesions and 5 postsurgical restenotic lesions. In 1990, the same investigators treated 13 patients with significant carotid artery stenosis with distal protection devices. ²³

The Carotid and Vertebral Artery Transluminal Angioplasty Study was a prospective randomized study that compared carotid angioplasty with CE. Stents were not used routinely. Only 26% of patients received a stent. The 30-day risk of stroke and death was 10% in both groups. The surgical group had significantly more cranial nerve palsies, 8.7% versus 0%, and had more hematomas requiring treatment, 6.7% versus 1.2%. ²⁴ In 1995, several groups published their experiences with carotid artery stenting. ^25-27 Roubin and colleagues published 5-year prospective data on carotid artery stenting (CAS) in 528 patients with either symptomatic (>50% stenosis) or asymptomatic (>60% stenosis). ²⁸ Three-year follow-up data were available for 518 patients. Results are summarized in Table 3. ²⁸

An international registry was formed that compiled the experiences of the centers involved in carotid stenting. Data for a total of 5200 carotid stenting procedures were presented. Most of these series included patients that would have been excluded from randomized surgery versus medical treatment trials because of additional risk factors. The technical success rate was >98%. The 30-day mortality was 0.84% and all stroke rates (major and minor) were 3.94%. In addition, the follow-up data from the international registry showed a stroke rate of 3% during a period of 24 to 36 months and a restenosis rate of approximately 4%. ²⁹ These numbers seem to be very competitive with those of CE. In NASCET, the stroke rate in the surgical arm over 3 years was 14% and that of ACAS was 10% over 5 years. ²⁹

The enthusiasm and interest in CAS has grown tremendously in recent years. This has paralleled the development of stent and catheter technology dedicated to the carotid arteries. These technologic advances pose challenges not limited to stents suitable for carotid use but also to carotid access systems and embolic protection devices (EPDs). Eventually, this will lead to successful performance of safe and less traumatic carotid procedures.

Fundamentals of stent angioplasty in carotid artery stenosis

The procedural goal of stent angioplasty of the carotid artery is the elimination of the stenosis and the prevention of embolism and stroke. In principle, the technique is similar to that used in coronary and peripheral interventions.

Diagnostic studies

Carotid artery ultrasound or magnetic resonance imaging (MRI) can provide information about the severity and the composition of the atherosclerotic plaque. Head computed tomography or MRI should be obtained before the procedure to ascertain the extent of the previous infarctions and rule out any other structural abnormalities, particularly any evidence of intracranial hemorrhage. Four-vessel cerebral angiography is essential to plan for CAS. The information that should be obtained is the best angiographic view for the intervention, the significance of any arch disease if present, and the extent of the collateral cerebral circulation.

Standard transcranial Doppler (TCD) monitoring during the procedure provides real-time information about ipsilateral middle cerebral artery perfusion and embolization. ^30,31 It may also be useful in showing the amount of blood flow during dilatation and in obtaining information about the efficiency of the collateral blood flow. ³²

Antiplatelet and anticoagulant therapy

Patients who are to undergo CAS should receive aspirin (325 mg) daily starting at least 1 week before the procedure. Patients should also receive clopidogrel (75 mg) 5 days before CAS.

Carotid access and general procedural techniques

The common femoral vein is accessed in order to facilitate prompt infusion of medications and fluid as needed in anticipation of hypotension and bradycardia as a result of the carotid sinus baroreceptor reflex. The vein access also is important because a temporary pacer wire needs to be inserted occasionally to address the bradycardia.

To access the arterial system, usually the transfemoral approach is used. After visualization of the target internal carotid artery (ICA) and the intracranial arteries, an extra long (125 cm) 5F diagnostic catheter is inserted into the lumen of a regular length (110 cm) 7F (eg, multipurpose type) guiding catheter, protruding from it distally and used as a "search" catheter. This search catheter is engaged into the ostium of either the left or right common carotid artery (CCA). Heparin (100 U/kg) is administered intra-arterially to maintain the activated clotting time between 200 and 250 seconds. A regular 0.035-inch guidewire is advanced close to or into the external carotid artery (ECA), and the diagnostic search catheter is advanced over it to a position just proximal to the CCA bifurcation or the stenosis. Using the search catheter and the guidewire as a support, the guide catheter is advanced to position in the distal CCA and the search catheter and the guidewire are withdrawn. It may be necessary to predilate the lesion with a coronary balloon over an angioplasty wire or the wire of an EPD. One or more stents are then deployed across the lesion as necessary. The stents are further dilated at higher pressures to firmly embed them into the vessel wall (Figure 2).

Severe hypotension and bradycardia may occur during the poststent dilatation. The frequency of the hemodynamic instability is less if the balloon does not stretch the carotid sinus. Atropine (0.5 mg) and norepinephrine should be available for immediate administration. In most cases, the stented area of the ICA involves the takeoff of the ECA and it ends caudally in the CCA. It is important not to have the distal end of the stent come to lie in a prominent vessel curvature because this may induce arterial spasm or dissection. Treatment (dilatation or stenting) of the ECA is not usually necessary, unless the ECA is providing significant collaterals or unless the patient develops symptoms due to the occlusion of the ECA, such as jaw pain. In this situation, the flow can be restored using common balloon techniques through the stent mesh.

Clopidogrel is continued for 4 to 6 weeks and aspirin is continued indefinitely. The patient is fully awake during the procedure with little or no sedation, as constant neurologic monitoring is essential. ³³

Procedure-related cerebral embolization

In CE, embolism is still the most common cause (55%) of all the cerebrovascular complications, followed by hyperperfusion syndrome (29%), and hypoperfusion (17%) in a series of 500 patients with CE who had a neurologic complication rate of 4.8%. ³⁴

Neurologic deficits during carotid stenting are infrequent and are usually transient and resolve in minutes to hours. Echolucent carotid plaques and lesions with >90% stenosis produce a higher number of embolic particles. ³⁵

Jordan and colleagues ³⁶ reviewed 105 patients who underwent TCD monitoring during CE (n = 75) or CAS (n = 40). In the CAS group, there was a mean of 7.4 emboli per stenosis and 4 neurologic events. In the CE group, there was a mean of 8.8 emboli per stenosis with 1 neurologic event. The mean number of microemboli was 56.8 in patients with neurologic complications and 31.2 in those without ( P <0.02). ³⁶

A study by Mathur et al ³⁷ showed that the independent predictors of procedural stroke are advanced age, lesion severity, and long or multiple stenotic lesions. No correlation was found for plaque ulceration, sex, presence of coronary artery disease, diabetes, hypercholesterolemia, smoking, prior CE, contralateral carotid occlusion, or type of stent used.

However, when a clinically symptomatic embolism occurs, a loading dose of 10 mg of recombinant tissue plasmin activator (rt-PA) is administered in the ICA followed by an immediate cerebral angiogram. If an embolus is evident at a major branch of the middle cerebral artery, a microcatheter is advanced over a hydrophilic 0.014-inch wire to the occluded branch to restore a minimal blood flow. Then rt-PA is continued to a maximum of 50 mg. If the angiogram did not reveal an embolus, rt-PA is administered into the ICA. The risk of intracerebral bleeding in these patients is substantial.

Cerebral protection

It cannot be emphasized enough that, unlike other organs, the brain is very unforgiving when microembolization occurs. Embolic particles can be created at any time during carotid angioplasty. Cerebral protection should reduce embolization risks, and therefore, should widen the indications for carotid angioplasty to include high-risk lesions.

Theron and colleagues ^38,39 have introduced a concept that involves the use of a distally placed protection balloon designed to catch and remove embolic material. Wholey et al ⁴⁰ were issued the first patent on the design of a filter device that was positioned between the dilating balloon and the distal end of the catheter. Currently, not one of the devices is approved for routine use in CAS in the United States.

There are three different classes of EPDs: the balloon occluders, the filters, and the circulatory control devices (Table 4, Figures 3 and 4).

Data from a subset of 2038 cases from the Carotid Artery Stenting Global Registry showed that EPDs decreased the risk of procedure-related death from 4.1% (unprotected) to 2.4% (protected). ⁴¹

The preliminary clinical data on the application of the GuardWire Plus (Medtronic AVE; Santa Rosa, CA) system in the Carotid Angioplasty Free of Emboli (CAFE) study are promising. Seventy-five patients were treated; 56% had symptomatic disease and 31% had severe contralateral carotid disease. In addition, 36% of patients had angina and 28% had suffered cerebrovascular accidents. Procedural success was achieved in all cases. No strokes were recorded and only 1 patient suffered from a wire-related dissection. Patients tolerated a mean balloon occlusion time of 15.3 ± 5.5 min. ⁴² Data from the PercuSurge Global Registry are even more impressive. Of 463 procedures performed in 19 institutions, only 7 (1.5%) resulted in death or stroke. ^42,43

Filter devices have high capture efficiency with unparalleled particle retention and do not interrupt cerebral blood flow. Armor ⁴⁴ presented the experience of 3 institutions on 138 carotid interventions. The 30-day death and stroke rate with filter devices was 0.4%. ⁴⁴

Published clinical data with the Parodi Anti-Embolization System (PAES; ArteriA Medical Science, Inc.; San Francisco, CA) consist of an international series of 60 patients. Angiographic evidence of carotid artery stenosis with thrombus or ulceration was present in 45% of patients. The deployment of the PAES was successful in all the patients. There was no periprocedural stroke or death. ⁴⁵ Potential advantages of the flow reversal technique include no distal problems, such as spasm and dissections (Figure 5). In addition, embolic protection starts before crossing the lesion. PAES allows for the treatment of tight tortuous lesions and captures particles of all sizes. However, some patients may not tolerate retrograde flow, and it requires the insertion of an 11F sheath, which may lead to more vascular complications (Table 5).

Roubin et al ⁴⁶ presented data on 329 CAS procedures using PercuSurge GuideWire (Medtronic AVE; Santa Rosa, CA) (n = 232), PAES (n = 10), NeuroShield (MedNova, Inc.; Galway, Ireland) (n = 74), Accunet (Guidant; Indianapolis, IN) (n = 9), and AngioGuard (Cordis Corp.; Warren, NJ) (n = 4). They reported 30-day event rates of 0% for major stroke, 2% for minor stroke, and 0.9% for retinal emboli; for a total embolic event rate of 3%. ⁴⁶

Current limitations of EPD

Seizures, altered sensorium, transient ischemic attacks, and stroke resulting from transient cerebral ischemia have been documented for all three types of EPD. ^46-48 The series reported by Henry et al, ⁴³ the largest single-center study of PercuSurge EPD, showed intolerance to balloon occlusion of the cerebral flow in 4.9% of the patients. This was in the context of a mean occlusion time of 422 seconds. In the PAES series, 5% of the patients were intolerant to flow reversal. ⁴⁵ Filters occasionally accumulate enough debris to plug up the pores and impede the cerebral flow. Patients with contralateral carotid artery occlusion are likely to be intolerant to EPD. The EPDs add additional bulk to the guidewire and require manipulations and the traversal of the target lesions. Bulkiness occasionally results in failure to pass these devices across tight lesions, negating the benefit of devices in the patient subsets that would potentially benefit most from cerebral protection. Microscopic furrows in the carotid artery intima and vasospasm may occur with some filters. Filters with much smaller pore sizes may come at the cost of more pore plugging and cessation of flow. Spillage or overflow of debris can also occur with filters. Clot formation on the distal surface of the device is possible. This is especially true in cases in which the procedural time is increased or the distal flow is absent.

The current generation of EPDs does not offer protection from embolic phenomena that precede the deployment. In addition, they may add to blood loss, procedural time, and the complexity of the technique. At this time, no devices are approved by the Food and Drug Administration for cerebral protection. There are no studies that compare the strategies of CAS with EPD versus CAS without cerebral protection. This assumption is based on EPDs being all-protective, which may not be the case.

Who should be offered CAS?

It is quite obvious, as with other endovascular therapies, that CAS could potentially benefit patients by causing less risk, trauma, and patient discomfort. At this time, CAS may be considered in poor surgical candidates or patients who refuse surgery and understand their treatment options and associated risks. ^49,50 What is not yet clear is the comparison of CE and CAS in low-risk patients.

The future of CAS

Carotid angioplasty and stenting is rapidly becoming an alternative to traditional CE. The potential complications and their management will require a multispecialty team approach. In the global carotid stent survey, surveys were sent to 36 major carotid stenting centers in the world. Information was obtained regarding the number of procedures, the stents used, the complications rate, and follow-up information. The results showed that cardiologists performed 63% of the cases, radiologists 25%, and surgeons 12%. ⁵¹ Cerebral protection devices will play a major role in the future. The rapid technologic improvements should further refine these devices and should improve outcomes. Elimination of embolic debris, inflammation, or oxidative cellular damage represents an additional therapeutic goal. The role of platelet glycoprotein receptor antagonists as an adjunctive therapy is not yet clear.

The key issue will be the results of the study of Carotid Endarterectomy Versus Stent Trial (the CREST trial), funded by the National Institutes of Health. ⁵² It is conceivable that if this study confirms that CAS is not inferior to CE, then the interest in and the number of CAS procedures will be further enhanced. Some leaders in this field have argued that this trial is premature because CAS is still evolving.

Conclusion

Carotid angioplasty and stenting is evolving from its initial controversial status to that of an acceptable alternative for the treatment of CAD. The procedure is feasible and safe even in high-risk patients. As stents, guide catheters, and EPDs improve technical success and patency, complication rates should diminish. Current results of CAS in nonrandomized control trials are comparable to CE.

Acknowledgment

The authors are indebted to Dr. Felipe Cecena for providing the advice and images for this report.