CHAPTER 95: CAROTID ARTERY STENTING

Stroke is the fifth¹ leading cause of death in the United States and represents the single most important cause of long-term physical and intellectual disability. Each year in the United States, approximately 795,000 people experience a new or recurrent stroke (87% ischemic, 13% hemorrhagic), and roughly 610,000 (75%) of these strokes are first events. On average, every 40 seconds someone in the United States experiences a stroke; there are close to 130,000 annual deaths related to stroke, and the cost of managing stroke patients in the United States in 2012 was approxinately $33 billion.¹ Unfortunately, despite important advances and progress in several areas of medicine, the treatment options for an established stroke are limited and the expectation for reversibility or improvement of stroke-related neurological deficits is both guarded and unpredictable.

Extracranial (cervical) carotid disease (“carotid stenosis”) is responsible for up to 20% of strokes^2,3 and the intent of treatment for carotid stenosis (medical, surgical, or stenting) is to prevent a future ipsilateral stroke. In the past, carotid artery stenting (CAS) was considered to be investigational or experimental and outcomes of this new procedure were constantly compared and benchmarked with the outcomes of carotid endarterectomy (CEA), long considered the gold standard for treatment of carotid stenosis. The results of three large prospective multicenter randomized trials with head-to-head comparisons of CAS and CEA are now available^4,5,6,7,8,9 and provide Level 1 evidence to support treatment recommendations in both symtpomatic and asymptomatic patients (Table 95–1). Although the US Food and Drug Administration (FDA) provided regulatory device approvals for CAS in high surgical risk and standard surgical risk patients in 2004 and 2011, respectively,¹⁰ as of 2016, the Centers for Medicare and Medicaid Services (CMS) only reimburse CAS when the procedure is performed in symptomatic patients with > 70% stenosis and who are at high risk for CEA.

In this chapter, we will review invasive treatment approaches for the treatment of carotid stenosis, address the critical issue of how to identify the standard-risk CAS patient, summarize key aspects of the stenting technique, and provide analysis of the clinical trial data that support the current indications for this procedure.

Surgical Carotid Endarterectomy

CEA is the most frequently performed surgical procedure to prevent stroke. Although the first surgical procedure for treating carotid stenosis was reported in the early 1950s,¹¹ it took another 30 years before large prospective randomized trials (with the intent of testing the benefit of CEA for stroke reduction) were initiated. These studies, including the North American Symptomatic Carotid Endarterectomy Trial (NASCET),^12,13,14,15 the European Carotid Surgery Trial (ECST),¹⁶ the Asymptomatic Carotid Atherosclerosis Study (ACAS),¹⁷ and the Asymptomatic Carotid Surgery Trial (ACST),^18,19 confirmed the benefits of CEA for stroke reduction when compared to best available medical treatment during the trial period, in both symptomatic (NASCET, ECST) and asymptomatic (ACAS, ACST) patients.

It is important to recognize that the patients included in these surgical studies were carefully selected and subjects who were at high risk for CEA were excluded from participation, and medical therapy in this time period was not nearly as good as it is in 2016. The types of high CEA risk patients excluded from these trials were those over 80 years of age, patients with recurrent stenosis following prior ipsilateral endarterectomy, intracranial stenosis that was more severe than the surgically accessible lesion in the neck, patients with severe/symptomatic coronary artery disease (CAD), those on long-term anticoagulation therapy, and patients with surgically inaccessible lesions.^12,17 The rates of CEA have decreased over the past 15 years, and in 2010 approximately 100,000 endarterectomy procedures were performed in the United States.¹

Endovascular Approaches to Treat Carotid Stenosis

Carotid Angioplasty

Initial clinical reports of carotid angioplasty involved small series of patients and were limited to single centers.²⁰ Kachel²¹ summarized the results of carotid angioplasty published through 1995 and noted that 503 of the 523 (96%) procedures were technically successful. There were no deaths, major strokes occurred in 2.1%, and minor complications were in the single digits (6.3%).²¹

Two complications most feared among patients undergoing CAS in the 1990s included acute vessel closure (resulting from dissection caused by the barotrauma of balloon dilatation plus vessel recoil following deflation of the balloon) and distal embolization. The introduction of stents and embolic protection devices (EPDs) provided effective solutions to both of these key limitations and plain balloon angioplasty for treating extra-cranial carotid disease has been essentially reduced to a historical footnote.

Carotid Artery Stenting

The contemporary, percutaneous, interventional approach for the treatment of extracranial, cervical, bifurcation carotid stenosis centers around the use of a device that can capture and remove emboli generated during the procedure—EPDs—and the practice of primary elective stenting, ie, stenting independent of the angiographic results of balloon angioplasty.

Balloon expandable stents are rarely used during carotid intervention because these stents are prone to deformation or “stent crush.” This occurs in approximately 15% of the cases and is a consequence of the superficial location of the carotid artery and the associated movements of the neck.^22,23 This led to testing and rapid adoption of self-expanding stents such as the Wallstent (Elgiloy) and a variety of nitinol stents. Primary stenting has virtually eliminated the risk of acute carotid closure and fortunately acute stent thrombosis and in-stent restenosis are not significant issues.

Indications for Carotid Artery Stenting

The indications for carotid artery revascularization are well described in the Guidelines for the Management of Patients with Extracranial Carotid and Vertebral Artery Disease²⁴ and are guided by two important variables: the symptomatic or asymptomatic status of the patient and the severity of stenosis in the target carotid artery. Before providing a recommendation for intervention (CEA or CAS), it is critically important for patients and their physicians to understand the individual operator's experience as well as the center's procedural outcomes.

The term “symptomatic carotid stenosis” refers to ischemia or infarction in the distribution of the internal carotid artery resulting in neurological abnormalities that include, but are not limited to, contralateral motor and/or sensory events and speech and/or visual problems (monocular blindness, field defects). “Amaurosis fugax” refers to transient monocular visual loss typically described by the patient as a “shade being drawn down or across the eye” (amaurosis = fleeting in Latin; fugax = dark in Greek). The symptomatic event may present as a transient ischemic attack (TIA) or a major or minor stroke. A TIA is the most common symptomatic presentation and approximately 15% of strokes are heralded by a TIA.²⁵ By definition, a TIA lasts for less than 24 hours (typically under 30 minutes) and following resolution of the episode there are no clinically recognizable neurological deficits. A recent meta-analysis²⁶ reported that the risk of recurrence of cerebrovascular events in patients with symptomatic carotid stenosis within 2 weeks of the index event is 26%. The stroke risk may be lower in patients presenting with amaurosis as the sole symptom in comparison to patients who present with a hemispheric TIA. A patient is considered symptomatic for 6 months after the initial event.

It is important to distinguish ischemic symptoms caused by vertebrobasilar insufficiency (VBI) from those secondary to carotid origin. VBI symptoms include transient cranial nerve dysfunction, diplopia, vertigo, and dysarthria. Motor deficits are ipsilateral and visual symptoms may be bilateral.²⁷ Dizziness and problems with balance are symptoms that typically result from ischemia or infarction in the vertebrobasilar system; dizziness is very rarely a symptom of carotid artery disease.

In symptomatic patients, the periprocedural (CAS or CEA) risk of stroke or death should be under 6%.²⁸ The NASCET study¹² demonstrated the benefit of CEA over medical treatment for reducing the risk of a stroke in symptomatic patients with carotid stenosis between 70% and 99%. Hence, it is well accepted that revascularization should be offered to all symptomatic patients with a 70% or greater internal carotid artery (ICA) stenosis. The NASCET results also showed that the magnitude of the benefit is less for patients with a stenosis between 50 and 70% and revascularization is typically not recommended unless there are additional unfavorable features on the angiogram (Table 95–2). Although stroke risk in symptomatic patients scales with the degree of stenosis, there is no such definite correlation in asymptomatic patients.²⁴

An important issue in the treatment of symptomatic patients relates to the timing of the revascularization procedure after the index, symptomatic event.^{26,29,30,31,32,33} The risk of a recurrent neurological event after a TIA or stroke is estimated to be between 15% and 20%, and this elevated risk persists for approximately 6 months after the initial event (hence the 6-month time limit when defining symptomatic patients). An important reason underlying the reluctance of operators to perform revascularization (CEA or CAS) soon after a stroke is the concern that “early treatment” increases the risk of hemorrhagic transformation of the culprit, nonhemorrhagic infarct. The practice of waiting and thereby delaying intervention in symptomatic patients has been challenged.²⁹ Proponents of “early intervention,” ie, treatment within a few days of the symptomatic event, argue that the highest risk of a recurrent event is during this early period. Therefore, any delay in treatment will significantly diminish its therapeutic value because a substantial portion of the patients would have already experienced a neurological event during the waiting period. Meschia and colleagues³⁴ analyzed 1180 symptomatic patients in the CREST trial who received their assigned procedure and had clearly defined timing of symptoms. Patients were classified into three groups based on time from symptoms to procedure: < 15, 15 to 60, and > 60 days. For both CEA and CAS, the risk of periprocedural stroke or death was not significantly different for the two later time periods relative to the earliest time period, leading the authors to conclude that time from symptoms to CEA or CAS did not alter periprocedural safety, supporting early revascularization regardless of modality. In the United States, the percentage of patients undergoing CEA within 2 weeks of the onset of stroke increased from 13% in 2007 to 47% in 2010.³⁵

The detection of a carotid bruit during a clinical exam often leads to the diagnosis of asymptomatic carotid stenosis. However, neither the presence nor the severity of the bruit correlate with the severity of the stenosis.^36,37,38 The absence of symptoms in patients with severe, hemodynamically significant stenosis signals the presence of robust collaterals to the culprit hemisphere—most often from the contralateral carotid artery via a patent anterior communicating artery or from the vertebro-basilar circulation via a posterior communicating artery. The stroke risk in these patients is mainly from embolization from the stenotic plaque in the extracranial ICA to the intracranial vessel(s) rather than from complete occlusion of the carotid artery in the neck.

Two important issues impact treatment decisions in a patient with asymptomatic carotid stenosis:

1. The severity of stenosis. Per current guidelines, it is reasonable to consider revascularization for patients with > 80% asymptomatic stenosis and low periprocedural risk (see Table 95–2).²⁴

2. Choice of treatment. In the event revascularization is to be performed, should the patient be referred for CEA or CAS? The CREST^6,7 and ACT I⁹ trials provide prospective, randomized comparative outcomes of CEA and CAS in asymptomatic patients (see Table 95–1).

Medical Treatment Versus Intervention (CAROTID ENDARTERECTOMY or CAROTID STENTING) for Asymptomatic Carotid Disease

The Case for Medical Treatment

Because the annualized risk of a stroke in patients with asymptomatic carotid artery disease treated with contemporary medical treatment is likely around 2% to 3%, and treatment with CEA or CAS is always prophylactic—ie, a procedure done with the intent of preventing a future stroke, based on the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines, the peri-procedural complications should be < 3%.²⁴ Not surprisingly, there has been intense debate, controversy, scrutiny, and oversight surrounding the issue of selection of the asymptomatic patient appropriate for carotid revascularization.

Proponents of medical treatment for asymptomatic disease argue that asymptomatic carotid stenosis is essentially a medical condition, and should be treated as such³⁹; revascularization treatment subjects the patient to periprocedural risks that are immediate as opposed to the small risks with medical treatment that happen in the future and are spread out over time^40,41; and there are too many carotid interventions being performed on patients who have a small risk of stroke on contemporary medical therapy. Therefore, in addition to the procedurally related risks, an interventional approach (CEA or CAS) is not cost effective.⁴¹

Proponents of “only medical treatment for asymptomatic patients” point out that in the past 20 years (since the publication of the ACAS results in 1995), the stroke risk in asymptomatic patients managed solely with medical treatment using antihypertensives,⁴² antiplatelet agents,⁴³ and statins^44,45,46 together with smoking cessation, has shown a gradual, but appreciable, reduction.

Further, because statin treatment was infrequently used during the ACAS trial, the stroke outcomes in the early trials may not be representative of contemporary medical treatment outcomes. For example, in ACAS,¹⁷ with best medical therapy, the annual ipsilateral stroke was 2.2% and incidence of any stroke was 3.5%. In the HOPE-3 trial,⁴⁴ treatment with rosuvastatin at a dose of 10 mg per day for a period of 5.6 years in intermediate-risk patients who did not not have cardiovascular disease and who had baseline lipid levels within the normal range resulted in signficantly lower risks of stroke and myocardial infarction compared to those treated with placebo. Many investigators argue that there is an urgent need for a three-arm, randomized clinical trial for asymptomatic carotid disease that includes not only CEA and CAS, but also a well-controlled medical treatment arm. The CREST II study, currently enrolling patients, is a two-arm study comparing best medical treatment with CEA and best medical treatment with CAS in asympomatic patients with 70% or greater carotid stenosis.

The Case for Intervention

Even though the ACAS and ACST trials included patients with 60% carotid stenosis, today most physicians will only consider interventional treatment for asymptomatic patients with ≥ 80% stenosis, the diagnosis based on appropriate duplex ultrasound velocities and corroborated by angiography (see Table 95–2). Important considerations supporting the case for intervention include:

1. Extracranial carotid stenosis accounts for approximately 12% to 21% of all anterior circulation ischemic strokes.^2,3 A TIA is a heralding symptom only in approximately 15% of patients.²⁵

2. Treatment of an acute stroke essentially consists of supportive therapy, institution of pharmacological and/or interventional measures to contain the initial event, secondary prevention measures to prevent a recurrence, and rehabilitation. Unfortunately, none of these measures can guarantee recovery of any or all of the lost neurological function. Because the first presentation in a patient with asymptomatic disease can be a major devastating stroke, there is no active treatment that will predictably reverse the neurological deficit of a stroke, and response to treatment of an established stroke is unpredictable, significant efforts have been directed at primary stroke prevention.

3. The cornerstone of this primary preventative approach is centered on control and/or modification of risk factors. An equally important aspect of this primary prevention approach involves prescribing revascularization treatment for a subset of asymptomatic patients with significant (usually accepted to mean ≥ 80%) carotid stenosis because these patients represent a major treatable cause of ischemic stroke.

4. The management of an established stroke is expensive and is connected to the direct costs of hospitalization and rehabilitation and indirect costs stemming from loss of wages.¹

5. Although risk-factor modification as part of the overall management strategy is important for all patients with atherosclerotic vascular disease, adopting the extreme position that all asymptomatic patients—including those with severe (≥ 80%) stenosis—should be managed exclusively with conservative medical treatment and not offered intervention should be tempered by the following observations:

   1. Lipid-lowering drugs have been used and studied extensively in patients with CAD, less so in patients with asymptomatic carotid disease.⁴⁷ A number of studies have shown beneficial effects of statins on plaque composition, plaque morphology, and plaque progression.^48,49,50,51 Although there are no studies demonstrating a decrease in major stroke in asymptomatic patients administered a statin, the SPARCL⁴⁵ study randomized 4731 patients who had a stroke or TIA within 1 to 6 months before study entry and no known CAD to 80 mg daily of atorvastatin or placebo. There was a significant reduction in the primary end point of fatal and nonfatal stroke (hazard ratio [HR] 0.84, P = 0.03), fatal stroke (HR 0.57, P = 0.003), stroke or TIA (HR 0.77, P = 0.001), and major cardiovascular events (HR 0.80, P = 0.002). There was no difference in nonfatal stroke or all-cause mortality. A meta- analysis⁵² of randomized trials in asymptomatic patients found that statins were effective in decreasing the total number of strokes, but not fatal strokes.

   2. Only a small proportion (< 30%) of the patients in the ACAS study¹⁷ had severe (> 80%) stenosis—the current threshold²⁴ for treatment with intervention (see Table 95–2). Hence, the low stroke risks in the medically treated arms of the ACAS and ACST trials must be interpreted with caution. It is not clear that the annualized stroke risk of < 3% applies equally to all degrees of stenosis, especially to patients with > 80% stenosis.

   3. Medical treatment requires a lifelong patient commitment and, hence, its value and impact on outcomes are completely dependent on shared decision making between the patient and physician and ultimately on patient compliance. Medication cost, side effects, and a perceived lack of any immediate benefit (because patients are asymptomatic) all compromise patient compliance. Because the dropout from medical treatment is random, it is entirely possible that the patients who need treatment the most, may end up not receiving it, compromising and undermining the value of this approach.

6. Revascularization: A critical message from the asymptomatic CEA trials¹⁷ was that for surgical revascularization to be beneficial in reducing the future stroke risk in asymptomatic patients (Table 95–3), the periprocedural risk of the revascularization should not exceed 3%. If the risk breaches this threshold, the difference in stroke risk between the medically treated arm and the surgical arm will not be significant, ie, the benefit of stroke reduction from the intervention no longer accrues to the patient. This low tolerance for periprocedural complications constitutes what the authors have framed as the 3% Rule of Carotid Stenting.⁵³ How to avoid breaching this rule is central to the theme of patient selection for carotid stenting and underlies the critical, all important task of identifying the standard risk patient for carotid stenting. It is equally important to recognize that all patients considered high risk for CEA (Table 95–4) do not automatically become standard risk for stenting.

Identifying the Asymptomatic Patient at High Stroke Risk on Medical Treatment

Much of the controversy surrounding the treatment of asymptomatic carotid stenosis could be resolved if physicians had a method of reliably identifying the subset of asymptomatic patients who are at high risk for a stroke on medical treatment; interventional treatment could then be selectively directed at these patients.⁵⁴ Such an approach would greatly improve the justification, the yield, as well as the cost effectiveness of prophylactic invasive treatment with either CEA or CAS.⁵⁵ Some of the metrics that have been proposed as predictors of increased risk of ipsilateral ischemic events in asymptomatic patients with carotid stenosis include severity of stenosis, progression to a higher grade,^56,57 unfavorable plaque characteristics/composition including plaque ulceration and echolucency,^58,59 and verifying the presence or absence of microemboli by transcranial Doppler.^60,61,62 Other clinical and radiological markers for predicting an increased stroke risk in asymptomatic patients include occult cerebral infarction on brain imaging studies,⁶³ patients with contralateral carotid occlusion,⁶⁴ and detection of intraplaque hemorrhage by magnetic resonance imaging (MRI).⁶⁵ Nicolaides and colleagues⁶⁶ have suggested that combining clinical risk factors such as diabetes and smoking together with high-risk ultrasound features such as the presence of an echolucent plaque may also help identify the high-risk asymptomatic patient (Table 95–5).

Although one cannot dispute the clinical importance and practical usefulness of being able to identify the asymptomatic patient at high risk for a stroke, none of the approaches outlined above have been validated to justify using them in making clinical decisions. Hence, at the present time, the degree of severity of carotid stenosis continues to remain the basis for deciding whether or not to treat asymptomatic patients.

In contemporary practice, most clinicians will (should) only consider interventional treatment options for an angiographically ≥ 80%, unilateral, incidentally discovered asymptomatic carotid stenosis, ie, diagnosed on routine duplex ultrasound screening or diagnosed following the identification of a carotid bruit. Patients with stenosis less than 60% are managed medically, with periodic, usually annual, ultrasound surveillance to monitor stenosis progression. Although stenosis between 60% and 80% is typically managed with conservative medical treatment, this recommendation may need to be altered (see Table 95–2) based on individual circumstances. Examples include the following:

1. Contralateral carotid occlusion and a stenosis between 60% and 80% in the index carotid artery, which also supplies the territory of the occluded carotid artery via collaterals.

2. MRI or computed tomography (CT) findings of “clinically silent” (asymptomatic) prior ipsilateral stroke(s).

The decision to treat based on the degree of stenosis is an approach supported and validated by the large prospective clinical trials (see Table 95–3). Although standard risk-factor modification approaches should be implemented in all these patients, there is no convincing evidence to date that these risk-modifying measures by themselves will reduce the stroke risk in patients with severe degrees of stenosis, and invasive/interventional approaches should be considered in these patients, assuming, of course, that the periprocedural risk is 3% or less. Hopefully the ongoing CREST II trial will enroll an adequate number of patients with > 80% stenosis to test the value of medical versus invasive treatments. On the other hand, if the majority of patients in CREST II have only a modest degree of stenosis (70%-80%), the trial may fail in its mission.

Prior to recommending CAS, it is important for the physician and the patient to understand the natural history of the condition without intervention; the procedure-related risks, which can immediately erode the benefits of a procedure done purely with the intent of future benefit, and the durability of the stenting procedure.

Natural History

Our understanding of the natural history of extracranial carotid artery disease is based on the stroke outcomes of patients in randomized clinical trials, performed more than 15 years ago and assigned to the medical or conservative arm in the symptomatic NASCET and ECST studies,^12,16 and the stroke outcomes in the asymptomatic ACAS and ACST trials.^17,18,19 The risk of stroke is approximately 15% in the first 6 months following a symptomatic event and between 2% to 3% per year in asymptomatic patients,¹⁷ translating into a 5-year cumulative risk of around 11%; approximately half of these events will be major strokes (Table 95–3).

Procedure-Related Risks

Perhaps the most important advance in the past 15 years relates to our understanding of what constitutes “high stent risk.”⁵³ It is important to remember that CEA was first performed in the 1950s, and over the course of three decades, surgeons defined high CEA risk patients by identifying anatomical features and comorbidities that would increase the risk of CEA. These high CEA risk patients were excluded from the major randomized CEA trials.

Evolution in Our Understanding of the Concept of “High and Standard Stent Risk"

To help the interventionist decide whether stenting is the appropriate treatment choice for a particular patient, it is important for the operator to understand, recognize, and differentiate the standard-risk from the high-risk CAS patient (Table 95–6). This determination based on an individualized analysis is the single most important element of the CAS risk-stratification process, and should be performed for every patient. The attributes that define high CEA risk are distinct from those that define high stent risk; hence, a patient who is high risk for CEA does not automatically become suitable (ie, standard risk) for CAS.

The designation of high stent risk has evolved over time as operators became more experienced. The high event rates observed in the early CAS stent registries that enrolled high CEA risk patients (Table 95–7) resulted in large part from the unintentional inclusion of high stent risk patients; exclusion of these high-risk patients from later clinical trials resulted in a corresponding improvement in procedural outcomes. The protocol for the CREST study was developed in 1998 and did not specifically call out high stent risk exclusions. By 2005, halfway through the trial enrollment, the concept of high stent risk was better established, and in the second half of the CREST study, many of these high stent risk patients were excluded, with corresponding better outcomes.

Standard Stent Risk

Age is a very important determinant of risk in patients undergoing CAS (see Table 95–6). Similar to patients with poor left ventricular function, patients with poor “brain reserve” and brain function are more likely to clinically manifest neurological events related to periprocedural embolization. Embolization is a universal occurrence during CAS procedures and happens despite the routine use of EPDs. Examples of patients with poor brain reserve include those who have experienced a prior large stroke, multiple small strokes or lacunar infarcts, and those with dementia. In patients with dementia, there are anecdotal reports wherein despite having a perfectly acceptable angiographic and acute clinical result (ie, no procedure related events), in the follow-up period, there is a marked deterioration in memory and other cognitive functions. The reason(s) for this is unclear, but dementia should be at least a relative contraindication for CAS.

Figures 95–1, 95–2, 95–3, 95–4 illustrate lesion and vessel features that are ideal for stenting using distal embolic protection. These features include:

1. A narrow, acute angle between the ICA and the external carotid artery (ECA). The wider this bifurcation (ie, approaching or exceeding 90^o), the greater is the anticipated technical difficulty in advancing a distal embolic protection filter device with a fixed-wire system (Figs. 95–5 and 95–6). This difficulty imparted by an open ICA/ECA angle is compounded if there is additional tortuosity in the ICA distal to the stenosis.

2. Minimal calcification and no ulceration. Some degree of calcification is nearly always found at the carotid bifurcation, but heavy concentric calcification in association with a severe stenosis is a major problem. Although the diagnosis of carotid calcification is straightforward and requires only fluoroscopy (Fig. 95–7), the distinction between deep, vessel-wall calcium and superficial calcium encroaching on the vessel lumen may be challenging, and the decision to declare the case unsuitable for CAS is largely subjective. We arbitrarily define heavy calcification as calcification ≥ 3 mm in width with concentricity defined by imaging in two orthogonal views. The unyielding nature of calcium along with the stiffness it imparts to the involved vessel segment makes it very difficult to pre-dilate and advance the EPD and stent delivery system through the lesion. Forcing these devices in an attempt to “cross” the stenosis not only increases the chances of prolapsing the sheath out of the common carotid artery (CCA), it also increases the risk of embolization, spasm, and dissection. Inability to completely dilate and expand a deployed stent, despite using larger and/or high-pressure balloons, results in a stent with a “hourglass” appearance, leading to accelerated velocities of blood flow and turbulence through the stented areas.

3. The artery cephalad to the stenosis should be free of any significant kinks or bends. The presence or absence of this unfavorable feature is extremely important to note on the pre-procedure magnetic resonance angiography (MRA), CT angiography (CTA), or invasive angiogram because it increases the degree of difficulty when attempting to place a distal EPD. Excessive vascular tortuosity is defined as two or more bend points that are 90 degrees or greater. At times the tortuosity is in the carotid artery proximal to the stenosis, and when extreme may impart a hairpin bend to the carotid artery (Fig. 95–8). Such severe tortuosity makes it impossible to position a sheath in the CCA. Milder degrees of tortuosity in the CCA may be straightened with a stiff wire; however, once the sheath is placed in the CCA, the kink is transferred more cephalad and introduces an iatrogenic tortuosity in the ICA. Worsening grades of tortuosity increase the difficulty when attempting to cross the stenosis and may make device delivery difficult or impossible. Additionally, the straightening of the tortuous vessel segment by stiff wires or devices may result in vessel spasm and reduce antegrade flow. Thus, despite filter placement, the patient does not receive the benefit of brisk antegrade flow, and in the absence of adequate collaterals may manifest ischemic symptoms. Additionally, slow flow increases the risk of fibrin deposition within the filter. The longer the dwell time of the EPD, the higher the risk of an “iatrogenic thrombus.” Iatrogenic tortuosity can be introduced by the placement of the sheath in a redundant carotid artery—hence tortuosity should be reassessed after the sheath is in place below the carotid bifurcation.

The degree of stenosis severity and eccentricity/concentricity are not problems as long as the flow in the vessel is normal (Thrombolysis In Myocardial Infarction [TIMI] grade III). A severe stenosis in association with less than TIMI III flow (“string sign,” Fig. 95–9) and an occluded carotid artery are contraindications for CAS. Ulceration is often noted—even on angiograms from asymptomatic patients—and although not a contraindication, operators should be aware that the risk of embolization may be higher, particularly during stent post-dilatation. Angiographic filling defects that are consistent with a thrombus are a contraindication to CAS.

Although both calcium and thrombus may appear as filling defects, the differentiation is based on the clinical presentation. Whereas a filling defect in a symptomatic patient should be presumed to be thrombus, filling defects in asymptomatic patients are frequently a result of calcium encroaching on the vessel lumen (see Fig. 95–7).

These unfavorable anatomical features—heavy calcification, visible thrombus, string sign, and carotid occlusion (see Figs. 95–7 and 95–9)—as a rule should be considered contraindications for CAS. Although special techniques (eg, use of a heavy gauge buddy wire to straighten tortuous vessel segments, use of cutting balloons to dilate unyielding lesions) may result in a satisfactory angiographic outcome, the risk of a procedure-related neurological event will likely be higher and can breach the acceptable periprocedural complication threshold.

Initial Evaluation

Most, if not all, carotid revascularization procedures are elective and there is no justification for an ad hoc carotid procedure, ie, proceeding to perform a carotid intervention during another scheduled invasive procedure (eg, coronary angiography). A comprehensive history and physical, including a detailed neurological exam, is a mandatory first step when evaluating a patient for a possible carotid intervention. Often patients referred for treatment of “symptomatic” carotid artery stenosis have other reasons for their symptoms including posterior circulation (vertebrobasilar) disease, or the culprit may be a cardioembolic source (eg, a patient with atrial fibrillation with thrombus in the atrial appendage). These patients have incidental, ie, asymptomatic, carotid disease and their risk assessment and treatment differs from the patient with true, symptomatic carotid artery stenosis. Another frequently encountered problem relates to suboptimal images resulting in unreliable noninvasive diagnostic studies.

The standard noninvasive method for the evaluation of carotid artery stenosis is duplex ultrasonography. Despite the overall high sensitivity and specificity, diagnostic accuracy varies widely between laboratories.⁶⁷ Therefore, trained, certified sonographers working in a quality-accredited laboratory are important for reliable and consistent diagnostic studies. Although ultrasound criteria corresponding to a > 80% stenosis on angiography (NASCET,⁶⁸ Fig. 95–10) vary considerably among different vascular laboratories, as a general rule if the peak systolic velocity is > 300 cm/s, end diastolic velocity is > 120 cm/s and ICA/CCA ratio is > 4,⁶⁹ the stenosis will typically qualify to be labelled > 80%.

The quality of the MRA study is influenced not only by the generation of the equipment, but also by the scanning protocol (with or without gadolinium), the correct timing sequence, as well as the skill and the experience of the interpreting physician. CTA is less operator dependent; however, it exposes the patient to iodinated contrast and radiation. Moreover, the majority of carotid bifurcations are calcified, which may interfere with accurate interpretation of stenosis severity on CTA. Noninvasive diagnostic accuracy and reliability are important, especially in the patient with asymptomatic carotid stenosis.

The goal of the clinical exam and diagnostic testing is to provide answers to the following questions:

1. Is the patient symptomatic or asymptomatic?

2. If symptomatic, are symptoms referable to the stenosis at the carotid bifurcation?

3. What is the severity of the stenosis?

4. Risk assessment:

   1. Is the patient suitable for carotid stenting?

   2. Is the patient suitable for CEA?

   3. Overall recommendation: CAS, CEA, or continued medical management?

Preprocedure Issues

Patients are admitted the day of the procedure and consented for brachiocephalic angiography and possible stent placement. An independent neurologist should document preprocedure neurological status and functional scores (typically using National Institutes of Health [NIH] and Rankin scales). All symptomatic patients, those with a prior history of stroke, and patients with an abnormal neurological examination should have a brain CT or MRI scan.

It is preferable to schedule the interventional procedure during the early part of the day. Patients are usually nil per os overnight, and prolonging this state, especially in the elderly, can exaggerate the hemodynamic disturbances resulting from carotid sinus stimulation. Since these hemodynamic perturbations are treated by prophylactic administration of atropine and volume expansion with isotonic fluids, a preprocedure 2D echocardiogram to help define left ventricular function and exclude significant aortic stenosis is advised. Likewise, knowledge of the coronary anatomy is very helpful. In the absence of prior evaluation of the coronary arteries, diagnostic coronary angiography at the time of the carotid study should be considered. Often, especially in the elderly, asymptomatic patient, diagnostic carotid and cerebral angiography is performed as a stand-alone, first-stage procedure. This approach, although not convenient to the patient and the family, provides the operator an opportunity to more accurately assess the anatomy, compute the risks, and discuss the findings with the patient and the family before electively scheduling the intervention.

Antiplatelet Agents and Anticoagulants

In the clinical protocol, great emphasis is placed on dual antiplatelet therapy before and after carotid stenting. The nonevent of stent thrombosis and the low rates of periprocedural and postprocedural embolic events are predicated upon the administration of the correct doses of adjunctive antiplatelet therapy. All patients should receive aspirin 81 mg and clopidogrel 75 mg orally for a week prior to the procedure, and both of these medications are continued for a minimum of 8 weeks after procedure to allow healing and stent endothelialization. If a patient has not received aspirin and clopidogrel before the procedure for a week, a 600-mg loading dose of clopidogrel should be given at least 4 hours prior to the procedure. If this is not possible, the procedure should be rescheduled. There is no experience using prasugrel or ticagrelor in patients undergoing CAS. The approach to patients who are on chronic anticoagulation with warfarin should be individualized, with the recognition that in some cases the bleeding risk on triple therapy may be prohibitive and CAS may be contraindicated.

Antihypertensive Agents and Beta-Blockers

In general, these medications are withheld the day of the procedure to avoid exaggerating the bradycardia and hypotension resulting from carotid baroreceptor stimulation. After the procedure, the blood pressure and heart rate need to be followed closely, and these medications can be given as soon as the clinical situation permits. In patients with restenosis following prior CEA (denervated carotid bulb) or in cases where the location of the stenosis is such that balloon inflations and stent deployment are clearly cephalad to the carotid bifurcation, there may not be a need to discontinue these medications, and blood pressure in the postprocedure period needs to be carefully managed to minimize the risk of cerebral hyperperfusion syndrome.

Procedural Considerations

Table 95–8 lists the 10 steps in the CAS procedure.

Diagnostic Angiographic Evaluation

It is important to have a high-quality, complete diagnostic cerebral and extracranial carotid angiogram prior to initiating the stenting procedure. State-of-the art digital subtraction angiography with the ability to vary the field of view is available in all modern-day catheterization laboratories; neurovascular procedures should not be performed in angiography suites equipped solely with a C-arm. Aortic arch angiography is not routinely performed at our center; the amount of contrast required to perform this single angiogram is equivalent to what is needed to complete the entire selective angiographic study. Many of our patients have had MRA, which helps identify not only the degree of stenosis at the carotid bifurcation, but also tortuosity of the carotid vessels. MRA can also define issues such as anomalous origins of the vessels (eg, independent origin of the left vertebral artery from the arch and origin of the left carotid artery from the innominate artery). However, neither MRA nor CTA can accurately define the extent of unfolding and elongation of the aortic arch and posterior displacement of the origin of the great vessels. This assessment of unfavorable aortic arch anatomy is best made during the invasive angiographic procedure, one important advantage of separating the diagnostic procedure from the intervention (see Fig. 95–11 for classification of the aortic arch).

A complete cerebral angiogram requires anatomical definition of both intracranial as well as extracranial arterial anatomy as well as the dominant vertebral artery (usually the left vertebral artery). Although in our center we often selectively image the dominant vertebral artery, the decision to perform selective cannulation and angiograms of the vertebral artery should be individualized. The vertebral arteries not infrequently have a tortuous course and the vessel is prone to spasm—features that can predispose to dissection with potentially catastrophic sequalae. Brachiocephalic angiography has several advantages in that it is a reliable and reproducible method for measuring the degree of carotid stenosis. Anatomical conditions that would increase the risk of CAS, such as a dilated aortic arch, heavily calcified stenosis, and marked vessel tortuosity, can be easily identified. This approach allows accurate assessment of the cerebral circulation along with collaterals.

The term “isolated hemisphere” describes the anatomical situation where the cerebral hemisphere of interest is entirely dependent on the ipsilateral ICA for its blood supply because of the absence of the anterior and posterior communicating arteries. Angiography reliably demonstrates significant flow-limiting stenosis distal to the carotid bifurcation. Although the bifurcation stenosis may be treatable, the ultimate benefit of stroke reduction may not accrue to the patient because of this additional disease and may influence the decision to proceed with CAS for bifurcation disease.

In the event there is an intraprocedural neurological event, the post-event intracranial angiograms can be compared with the baseline images. The main risks of invasive cerebral angiography relate to the use of contrast and the risk of a neurological event which in experienced hands is very small (0.1%).

The typical sequence of acquisition of the angiographic images is described next. We first selectively image the left subclavian artery in a posterior-anterior (PA) view. The ostium of the left vertebral artery is usually seen well in the frontal projection; if not, the right anterior oblique (RAO)-cranial projection is recommended. If a selective angiogram of the left vertebral artery is to be acquired, a roadmap to facilitate entry and selective placement of the catheter is recommended. Selective or nonselective intracranial views of the vertebrobasilar system are acquired in the lateral and steep anterior-posterior (AP) cranial views. Next the left carotid artery is imaged. The bifurcation is imaged in left anterior oblique (LAO) 45 as well as lateral projections. If the bifurcation is “over-rotated,” an AP caudal view usually separates the ECA and ICA very well. Intracranial images of the left carotid artery are acquired in the lateral and AP cranial (15-30 degree) views. An innominate angiogram is performed in the RAO caudal view. This view is optimal for separating the CCA and the right subclavian artery and hence very useful for defining the origin of the right subclavian artery. Finally, selective angiograms of the right carotid artery are acquired. The bifurcation is imaged in the RAO 45 as well as the lateral projections. Intracranial images of the right carotid artery are obtained in the lateral and AP cranial (15-30 degree) projections.

Emboli Protection Devices

In 1984, Vitek and his neuroradiology colleagues from the University of Alabama at Birmingham⁷⁰ reported angioplasty of the innominate artery aided by distal occlusion balloon protection of the CCA. This early report represents the first percutaneous supra-aortic intervention performed with the benefit of distal embolic protection. Because placement of the sheath occurs prior to the deployment of the EPD and release of emboli occurs to some degree during all stages of the carotid intervention, all steps of the carotid intervention can never be completely “emboli protected.” The risk of embolization appears to be highest during stent deployment and post-stent balloon dilatation.⁷¹

A number of EPDs are available and can be broadly categorized as flow-interrupting (occlusive) and flow-preserving devices. Flow-interrupting EPDs can be subdivided into distal occlusion and proximal occlusion types. An example of a distal flow-interrupting EPD is the Percusurge GuardWire (Medtronic, Minneapolis, MN. Proximal occlusion devices include those developed by Gore (Flagstaff, AZ) and the Mo.Ma device (Medtronic). Although flow-interrupting, occlusive-type embolic protection devices are intuitively appealing (no blood flow = no emboli), there have been some issues with their use. For example, it is mandatory to demonstrate a robust collateral circulation to the hemisphere that is being treated to permit occlusion and interruption of antegrade flow in the ipsilateral carotid artery. Device preparation and testing of the GuardWire is very different from that of a coronary balloon. Infrequent use of the Percusurge wire as well as occasional device failure resulting from inadequate balloon inflation and suboptimal seal of the carotid artery and/or premature deflation, has resulted in virtual abandonment of this device for carotid intervention. The rationale for use of the proximal occlusion devices is based on interruption of antegrade flow and “flow-reversal” in the ipsilateral ICA. This combination is achieved by balloon occlusion of the CCA as well as the ECA. The multicenter ARMOUR Trial⁷² evaluated the 30-day safety and effectiveness of the MO.MA proximal cerebral protection device (Medtronic) for CAS in 262 high surgical risk patients. Mean age was 75 years, 29% were older than 80 years, and 15% were symptomatic. The 30-day incidence of stroke, death, or myocardial infarction was 2.7%, with a 30-day major stroke rate of 0.9%

The system from Silk Road Medical involves introduction of a sheath via a small incision made in the CCA, low down in the neck, just above the clavicle. The sheath is connected to a system that will reverse blood flow from the ipsilateral carotid artery and any embolic debris will be captured in a filter outside the body. The filtered blood is then returned through a second sheath placed in the femoral vein in the groin. Thus, the system allows stenting and balloon angioplasty to be performed while blood flow is reversed (TCAR, or transcarotid artery revascularization procedure). After the stent has been deployed, flow reversal is turned off and blood flow to the brain resumes in its normal direction. This device and strategy was tested in the Roadster multicenter trial.⁷³ Of the 141 patients enrolled in the pivotal study, 25% were symptomatic. Stroke and death were noted in 2.8% (4 of 141). Strokes were seen in 1.4% (2 of 141), and stroke, death, and myocardial infarction occurred in 3.5% (5 of 141). Cranial nerve injury was observed in one patient.

Although procedural outcomes using these devices appear favorable,^72,73,74 since the catheters are larger or require surgical incision of the carotid artery (TCAR), these will likely be used as “niche devices.” They are particularly useful in cases with tortuous distal ICA and/or unfavorable aortic arch anatomies, as well as for lesions with filling defects that may embolize during wire passage, prior to deployment of distal EPDs.

The nonocclusive, flow-preserving devices are the filters. Depending on their construction, the body of the filter can be supported by a nitinol frame or it may be unsupported and resemble a windsock. The underlying principle and rationale of use is the same for all filter EPDs: preserving antegrade flow while preventing passage of the embolic debris. As may be expected, each of these EPDs has certain unique features and familiarity with their construction and attributes will allow rational selection of the device most appropriate for use with a particular anatomy.

EPDs are standard of care for CAS procedures in clinical practice. Given the wide choices, devices are selected based on operator familiarity, preference, experience, and compatibility with the clinical situation and vascular anatomy.

The procedure is performed under local anesthesia; we do not recommend sedation. The heart rate, rhythm, blood pressure, and neurological status should be closely monitored throughout the intervention. The femoral approach is preferred, and either unfractionated heparin (target activated clotting time [ACT] around 250 seconds) or bivalirudin⁷⁵ is used for systemic anticoagulation. A 6-Fr, 90-cm-long sheath is placed in the CCA below the bifurcation, and accomplishing this step in a safe and expeditious manner is critically important. Recognizing and responding appropriately to difficult access situations (which may include procedure termination prior to a complication) constitute a large and important part of the learning curve.

Wires ranging from soft, atraumatic 0.014-inch coronary wires to 0.038-inch stiff Amplatz wires may be needed in various stages of the procedure. The operator and the assistant must exercise excellent wire control and should be aware of the position of the distal wire tip at all times. This will minimize the risk of wire-induced perforation, spasm, and dissection. A suitable distal EPD (our preference) is placed cephalad to the stenosis, and the dwell time of the EPD should be tracked. The median dwell time in an experienced lab should be approximately 7 minutes. The longer the EPD is in the body, the higher the chance of fibrin accumulation and (iatrogenic) thrombus formation within the filter. The lesion is dilated with a small-diameter (generally 3.0 mm) low-profile coronary balloon; the goal is to create enough room to allow easy passage of a 5- or 6-Fr stent delivery system without major plaque disruption and creation of a flow-limiting dissection. A self-expanding nitinol stent (typically closed cell, 40 mm in length and 8-10 mm in diameter) is deployed across the bifurcation. The stent is postdilated using a 5.0-mm balloon, restricting this step to a single inflation. Balloon deflations should be performed gradually, typically over 30 to 45 seconds. The EPD device is retrieved, and control extracranial and intracranial angiograms in views comparable to baseline images are performed using the 90-cm sheath, which is then exchanged for a short 6Fr sheath, sutured in place, and removed when the ACT is subtherapeutic. Routine prophylactic placement of a temporary pacing wire is not necessary except in patients with severe aortic stenosis, left main disease, or severe left ventricular dysfunction. Use of glycoprotein IIb/IIIa inhibitors is contraindicated.

Patients are monitored in a telemetry unit, and although we have reported the feasibility and safety of ambulatory CAS,⁷⁶ our routine practice is to admit patients post-procedure for an overnight stay to allow periodic neurological evaluation and close hemodynamic monitoring. Although “low blood pressure” is not unusual in the post-procedure period, other causes such as retroperitoneal hemorrhage related to access site bleeding should be excluded as a cause of any unexplained, persistent hypotension. Before discharge, the patient should be reevaluated by the same neurologist who examined the patient pre-procedure and the NIH and Rankin stroke scale scores should be calculated. More than 95% of patients will be ready for discharge approximately 24 hours following the procedure. Follow-up visits for clinical evaluation and carotid duplex ultrasound are scheduled for 1 month, 6 months, and 12 months after the procedure. Subsequently, the patient is followed on an annual basis with a carotid duplex ultrasound.

Stents

To eliminate the risk of deformation and crushing^22,23 seen with balloon expandable stents, self-expanding stents are exclusively used for CAS with the following notable exceptions:

1. When treating an aorto-ostial stenosis of the CCA.

2. When the stenosis and treatment involves the distal portion of the cervical carotid artery (close to the skull base). There is minimal risk of stent deformation of a balloon expandable stent deployed at this level and advancing the bulkier 5- or 6-Fr self-expanding stent delivery systems to the distal ICA can be technically difficult.

3. On rare occasion, if despite predilatation with a 5.0-mm balloon the self-expanding stent cannot be advanced without resistance through the stenosis (eg, when dealing with a rigid, heavily circumferentially calcified stenosis of the carotid artery), a 5.0-mm balloon expandable stent is first deployed at the bifurcation. This prevents recoil at the lesion site and permits passage of a self-expanding stent. The latter functions as the definitive stent and the constant, externally directed radial force of nitinol prevents deformation of the balloon expandable stent.

Although the elgiloy (a cobalt chromium alloy) tracheobronchial Wallstent (Boston Scientific, Natick, MA) was initially used, currently most operators worldwide use nitinol (an alloy of nickel and titanium) self-expanding stents.

Management of Hemodynamics

The carotid sinus baroreceptor, innervated by the glossopharyngeal nerve (cranial nerve IX), is located in the adventitia of the carotid artery and is stimulated by balloon inflation and stent expansion stretching the vessel wall. The physiological role of this baroreceptor is to detect, respond, and thereby regulate the systemic blood pressure. Stretching of the carotid sinus baroreceptor stimulates the glossopharnygeal nerve, which in turn stimulates the vasomotor center in the medulla via the tractus solitarius, which then modulates the activity of the autonomic nervous system (suppresses sympathetic and stimulates parasympathetic output). The net effect of stimulation of the carotid baroreceptor is bradycardia (negative chronotropy) as well as some reduction in cardiac contractility. Additionally, the decreased sympathetic output results in vasodilatation, causing hypotension. As might be expected, carotid sinus stimulation with the resultant hemodynamic perturbations are most profound when the lesion and the stretch from the postdilatation balloon involves the carotid bifurcation, less so if the stenosis is cephalad to the bifurcation; these changes are not seen (or occur with much less intensity and frequency) in the post CEA patient whose carotid bulb is denervated. The bradycardia and hypotension can be profound and worse in younger patients as well as in patients with highly calcified stenosis (where higher pressures are used for postdilating the stent).

β-B, diuretics, and other antihypertensive agents are typically withheld on the morning of the procedure. The patient must be well hydrated, and procedure-related hypotension and bradycardia are treated with fluids 1.0 mg of prophylactic atropine, and small aliquots of alpha agonists. Close attention should also be paid to the management of the blood pressure after the procedure. Although the hemodynamic effect of the atropine and any alpha agonists used during the procedure will wear off quickly, in the postprocedure phase, unless the patient is symptomatic (which is the exception), there is usually no need to treat bradycardia or hypotension even though the blood pressures may be as low as 70 or 80 mm Hg. The systolic blood pressure will typically increase by 15 to 30 points by next morning. There are two main problems with persistent hypotension: (1) on occasion, patients with a periprocedural embolic event or a severe contralateral carotid stenosis can become symptomatic; and (2) patients with baseline renal insufficiency typically have an elevation of creatinine. Even though on average less than 30 mL of contrast is used for the stenting procedure, the combination of contrast exposure and persistent postprocedure hypotension results in worsening of renal function.

On the other hand, if the drop in blood pressure is less than expected and continues to be high following postdilatation (eg, in the post-endarterectomy patient with severe post-CEA restenosis), this situation increases the risk of hyperperfusion syndrome. Unfortunately, it is difficult to provide precise recommendations at what level the blood pressure needs to be maintained, and it is not clear as to what medications should be used to dial down the blood pressure. In the poststenting period, patients are very sensitive to nitroglycerine because it overcomes the compensation and/or exaggerates the vasodilatation mediated via the autonomic system in the stented patient.

Management of Neurological Complications

During the procedure, the neurological status of the patient should be monitored at frequent intervals. In our interventional suite, we follow a simple protocol—asking the patient to squeeze a toy placed in the contralateral hand. Conversing with the patient and judging the speed and the appropriateness of the response to simple questions is also very useful. Any departure from baseline, including frequent yawning in a nonsedated patient, all point to a neurological event (which at times can be very subtle) that should not be ignored.

In our experience, corroborated by the outcomes of the large prospective randomized trials like CREST, the risk of a major stroke during CAS is low, a benefit of using EPDs to trap the “larger” emboli. TIAs and minor strokes may be the result of embolic particles that are able to evade the filters, or the result of embolization that occurs during the “unprotected” phases of the procedure.

If the patient develops a neurological deficit during the procedure, the procedure should be completed, the EPD removed, and normal flow established. Patients should be hydrated with isotonic fluids and adequate blood pressure should be maintained (both hypotension and relative dehydration worsen the effects of small emboli that otherwise may be clinically silent). At the conclusion of the procedure, the patient should be reassessed clinically and intracranial angiograms should be repeated in views comparable to baseline projections. The angiographer should look for any occlusion of a proximal vessel segment, which requires intervention to lessen the likelihood of a major stroke; distal occlusion of a small branch, which can usually be managed with observation; and slow flow and/or identification of emboli in multiple branches, which generally has a poor prognosis.

In circumstances where neurovascular rescue is required, mechanical recanalization techniques may be utilized in an attempt to restore flow in the involved area of the brain. It is generally not advisable to use intraarterial thrombolysis as the risk of intracranial bleeding is quite high.

On rare occasions, a patient may develop ipsilateral partial or complete loss of vision as a result of retinal infarction. Unless there is spontaneous recovery of the vision soon after the event, the prognosis for full recovery of vision is poor.

The risk of a clinically significant intracerebral bleed is approximately 0.5%—a complication that cannot be prevented by the best EPDs. Downward modulation of the dose of anticoagulants targeting a lower ACT (around 250 seconds), recognizing that the use of glycoprotein IIb/IIIa inhibitors during CAS is contraindicated, and with careful monitoring of the hemodynamics, the chances of an intracerebral bleed can be minimized.

Cerebral hyperperfusion is defined as an increase in blood flow of more than 100% from baseline and cerebral hyperperfusion syndrome (CHS) is hyperperfusion associated with a neurological deficit. Although CHS does not occur frequently, its consequences can be devastating. An increase in ipsilateral blood flow to the affected cerebral hemisphere may occur after CAS (or CEA); it is usually asymptomatic.⁷⁷ Although there are a host of possible mechanisms responsible for the failure of auto-regulation at the cerebral microcirculatory level (the basic mechanism underlying cerebral hyper-perfusion),^{78,79,80,81,82} the pathophysiology is not completely understood.

Patients with severe (> 90%, subocclusive stenosis) and limited collateral supply (isolated hemisphere) are at the greatest risk for hyperperfusion.⁸³ Baseline severe hypertension and persistence of this increased blood pressure in the postprocedure period (not uncommon in patients after endarterectomy) can result in hyperperfusion that can last several days after the procedure.⁸³ Hyperperfusion resulting in a major intracerebral bleed is a concern. The most common clinical symptom of cerebral hyperperfusion is headache; several patients report this symptom on the table soon after the procedure is completed and it never progresses beyond this symptom. The headache may last a few days and is typically unilateral with a nonfocal neurological exam. A more serious presentation, possibly related to cerebral edema, is seizure activity, again with an otherwise normal exam. Patients with CHS can present with a variety of neurological deficits including isolated speech disturbance. In patients who develop neurological symptoms following carotid revascularization, a number of etiologies must be considered in the differential diagnosis. Differentiation must be made between procedure-related embolic complications, resulting in an ischemic infarct—a manifestation of a low-flow state, and a high-flow state characteristic of CHS. The diagnosis of CHS is best confirmed with MRI.⁷⁸

Lowering blood pressure and anticonvulsant therapy are the most important treatments to reduce the degree of cerebral edema and seizures. As vasorelaxation may further increase cerebral blood flow, calcium antagonists and nitrates are contraindicated in the treatment of CHS. Hence, the operator must resist the urge to administer nitrates to relieve spasm; for example, at the site of deployment of the EPD noted on the postprocedure angiogram. The spasm will resolve gradually with time, and although nitrates will rapidly resolve the spasm, they can also predispose to the development of hyperperfusion. Because of their ability to reduce cerebral perfusion pressure, labetalol and clonidine^78,84 are the preferred agents. The duration of therapy may be for several days or even months after procedure.⁸⁵ There is no evidence to support the treatment of cerebral edema, although corticosteroids and barbiturates have been used to good effect. Prophylactic anticonvulsant treatment is not recommended, but should be introduced if seizures occur.⁷⁸ As a result of the relative infrequency of this condition and the heterogeneity of presentations, it is hard to generalize the outcomes following CHS. However, the limited data from the CEA literature suggest that one-third of the patients may have some residual disability following CHS,⁸⁶ with others reporting mortality of up to 50%.⁸⁷

As was the case with other arterial percutaneous interventions, the availability of stents for treatment of carotid disease resulted in predictable outcomes and soon stenting became the standard of care. Prospective observational studies of CAS were initiated in the mid 1990’s,⁸⁸ and even during this early period, the outcomes were good when assessed in terms of outcomes of disabling stroke or death. Nondisabling neurologic events were more frequent in patients with advanced age, complex aortic arch and ICA anatomies, and severe ICA stenosis.^89,90

Numerous case reports and clinical series of CAS without embolic protection have been published.^{89,90,91,92,93,94,95,96,97,98,99,100,101,102} These were mixed series of symptomatic and asymptomatic patients, with varying degrees of arterial stenosis. Asymptomatic patients were generally required to have more severe stenosis or additional evidence of compromised cerebral circulation.^89,94,99 Some reports included CCA lesions, which are not easily accessible by surgical techniques.^{89,94,100,101} These early studies reported procedural success of > 95% with periprocedural minor stroke rates of 1.6% to 4.8% and major stroke and death rates between 1% and 1.5%.

Reviews of the status of carotid artery stent placement prior to the introduction of EPDs were published in 1998¹⁰² and 2000.⁹² Thirty-six centers participated in the survey, which included 5210 stenting procedures with a technical success rate of 98.4%. The 30-day rates of TIAs, minor strokes, major strokes, and death were 2.6%, 2.5%, 1.4%, and 0.8%, respectively.⁹² Technical failures were usually related to inability to access the CCA (2%-7% of patients) and prolonged procedural time was associated with increased morbidity.¹⁰² It is important to note that these were observational studies and the outcomes were not audited, and so the reported results were probably better than the outcomes obtained when a neurologist examined each patient after CAS.

Neurologic events related to embolization during CAS were not unexpected. Transcranial Doppler studies showed that the majority of particles were released from the atheromatous plaque during stent deployment and postdilation of the stent; however, it should be recognized that embolization can occur during any phase of the procedure.⁷¹ The embolized fragments consist of plaque debris, fibrin and platelet aggregates, lipid vacuoles, and calcium fragments.^103,104 Evidence of embolization on transcranial Doppler provided the rationale for use of embolic protection systems during CAS.^105,106

Table 95–4 lists anatomical characteristics and comorbidities that are used to define high CEA risk. In the NASCET study involving symptomatic patients, contralateral occlusion was not an exclusion for entry, and 30-day risk of stroke and death in this cohort was 9.4% (approximately 2.2 times the risk without contralateral occlusion).¹⁵ The surgical outcomes in high CEA risk patients have never been tested in a large multicenter prospective trial with independent neurological assessment and event adjudication, rendering conclusions about benefit of CEA in this population unclear.

Initial studies of CAS with embolic protection were not randomized (registry data) trials and only included patients who were at high risk for CEA. The large number of registries of CAS in high-risk CEA patients was a result of the fact that the FDA required reporting the results of each carotid stent and EPD as a condition of marketing approval (see Table 95–7).^{107,108,109,110,111,112,113} The study design, study hypothesis, and statistical approach were largely similar for all the registries: the goal was to determine whether outcomes in high CEA risk patients treated with a particular sponsor's stent in conjunction with their EPD were less than or equal to those of an objective performance criteria (OPC) derived from historic controls undergoing CEA. An OPC of 15% for patients with comorbidities and 11% for patients with anatomical risk factors was negotiated a priori and agreed to by the FDA. The SAPPHIRE study¹¹⁰ was the only one that included a randomized arm comparing outcomes of CAS and CEA in patients at high risk for CEA.

This multicenter, noninferiority, randomized study was conducted in 29 centers across the United States and enrolled symptomatic patients (≥ 50% stenosis on duplex ultrasound, 29% of the patient population) and asymptomatic patients (≥ 80% stenosis on duplex ultrasound). The primary end point was the cumulative incidence of death, stroke, and myocardial infarction within 30 days of treatment or death and ipsilateral stroke between day 31 and 1 year from the time of the procedure. Although the inclusion criteria included high CEA-risk patients, prior to randomization, all members of the team (neurologist, vascular or neurosurgeon, and interventionalist) had to agree that the patient was a suitable candidate for either endarterectomy or stenting. If the surgeon assessing the patient concluded that endarterectomy could not be safely performed, but the interventional physician judged that stenting was feasible, the patient was not randomized, but entered into a stent registry (n = 406). Likewise, if the surgeon deemed the patient suitable for surgery, but the interventional physician did not think that stenting was feasible, the patient was entered into a surgical registry (n = 7).

Between August 2000 and July 2002, 747 patients were enrolled in the study, and 334 patients underwent randomization. Of the 167 patients randomly assigned to stenting, 159 received the assigned treatment; of the 167 patients assigned to surgery, 151 received the assigned treatment; all 334 patients were followed. Patients undergoing CAS received the nitinol self-expanding Precise stent and the AngioGuard filter (Cordis, Johnson and Johnson, New Brunswick, NJ). In early 2002, the pace of enrollment abruptly slowed because several carotid-stent registries (nonrandomized) had become available and were competing for the same group of patients. The trial was therefore terminated (original goal was 600 randomized patients) and the primary end point was analyzed with respect to the noninferiority of CAS compared with CEA, using interval-censored survival data at 1 year.

By intention to treat analysis, the primary end point at 1 year occurred in 20 CAS patients (12.2%) and 32 CEA patients (20.1%; P = 0.05). Cranial nerve injuries were seen in 5% of the patients undergoing CEA. The investigators concluded that CAS with embolic protection was not inferior to CEA in a high surgical-risk population. The clinical durability of CAS in this patient group (freedom from stroke during follow-up) was demonstrated by the 3-year follow-up data, which showed that there was no significant difference in long-term outcomes between patients who underwent CAS using an EPD and those who underwent CEA.¹¹⁴

Postapproval Registries

Postapproval studies are required by the FDA as part of the condition for marketing approval of stents and EPDs. The purpose of this is to identify any unanticipated events related to the devices. Additionally these studies allow the assessment of stenting in the “real-world environment” as opposed to a controlled study environment. Gray and colleagues¹⁰⁷ reported the outcomes of two such prospective multicenter (280 US sites, 672 operators) postmarket surveillance studies wherein CAS was performed with distal embolic protection using filters in high CEA risk patients (CAPTURE 2 and EXACT). These studies had pre- and postprocedure neurological evaluation and independent adjudication of neurological events. There were 3500 patients in CAPTURE,¹¹¹ 4175 in CAPTURE-2,¹⁰⁷ and 2145 in EXACT.¹⁰⁷ Among these three postsurveillance studies, 86% to 90% of the patients were asymptomatic. The 30-day stroke and death rate for symptomatic patients was 12.1%, 6.2%, and 7.0% in CAPTURE, CAPTURE-2, and EXACT, respectively. The 30-day stroke and death rate for asymptomatic patients was 5.4%, 3.0%, and 3.7% in CAPTURE, CAPTURE-2, and EXACT. Symptomatic patients 80 years and older had a 30-day stroke and death rate of 10.5% (compared to 5.3% in younger patients), and asymptomatic octogenarians (or older) had a 4.4% risk compared to 2.9% in the younger cohort.

In subjects with anatomical features unfavorable for surgery, independent of age, the 30-day death and stroke rates were 1.7% among 60 symptomatic patients and 2.7% among 371 asymptomatic patients.

In patients with physiological factors unfavorable for surgery, the combined 30-day rate of death and stroke for 574 symptomatic patients was 6.4%, and for the 4603 asymptomatic patients it was 3.3%.

Operator Experience

The CAPTURE-2¹¹⁵ investigators analyzed the CAS outcomes of 3388 patients (representing 64% of the total number of patients) to determine if physician or site-related factors impacted outcomes of CAS.

Two-thirds of the sites (118 of 180, 66%) had no death and stroke events. Within the remaining sites, an inverse relationship between adverse event rates and hospital patient volume as well as individual operator volume was observed. The German registry analysis¹¹⁶ and a meta-analysis of published studies¹¹⁷ reported similar findings. In the CAPTURE 2 study, it was shown that site and operator volume were the most important determinants of perioperative events, and defined a threshold of 72 cases for consistently achieving a 30-day death and stroke rate of < 3%. This 72-case number is higher than the entry threshold for operators who participated in randomized trials like the CREST⁶ or ACT I⁹ (Carotid Stenting versus Surgery of Severe Carotid Artery Disease and Stroke Prevention in Asymptomatic Patients) trials.

Analysis

1. With the exception of SAPPHIRE, all studies testing CAS in high CEA risk patients were designed as registry studies. Unlike the majority of registry studies which are characterized by self-reported events with no opportunity for adjudication, the “high-risk CAS registries” were performed under FDA scrutinized clinical protocols, with prospective data collection and event adjudication. The importance of prospective, independent clinical review was demonstrated by Rothwell and Warlow,¹¹⁸ who looked at adverse event rates following CEA. They found a threefold difference in neurological events between operator self-reported and independent neurologist-assessed events.

2. Individually and collectively, a large number of patients, mainly asymptomatic, have been studied within the context of these registries and provide a robust data set for analysis of high CEA risk patients undergoing CAS in the United States. Cumulatively, a total of more than 10,000 patients were included and analyzed in the three post-marketing studies (90% asymptomatic), and analysis of the data has helped provide answers to important questions concerning CAS in a “real-world” setting.

3. CAS outcomes have shown a steady and continuous improvement since the initial introduction of these devices in US trials (Fig. 95–12). For example, compared with outcomes in the ARCHeR and the original CAPTURE registries, the combined results of the CAPTURE 2 and EXACT studies showed improvement in 30-day death and stroke outcomes: 6.9%, 5.7%, and 3.6%, respectively, and these improved outcomes meet AHA guidelines in the < 80 years age group. In the CREST study, the majority of the neurological events were “minor strokes” with substantial resolution of the neurological deficits during the follow-up period.^6,7

4. Factors contributing to the improvement in the results of CAS include:

   1. The recognition of the features that define the “high stent risk patient.” This was not appreciated at the time these registry studies were initiated in the year 2000, and stenting with distal embolic protection was attempted in most, if not all, high CEA risk patients, a subset of whom had high stent risk features who were excluded from studies later in the decade. Exclusion of these patients resulted in better outcomes.

   2. The pool of qualified, experienced operators increased as multiple specialties now perform CAS.

   3. There have been improvements in the devices, such as smaller EPDs and the use of nitinol stents. Additionally, changes in the procedure itself, such as limiting post-inflation to a single inflation, may have contributed to improved outcomes.

5. CAS outcomes in nonoctogenarian, high surgical risk patients, both symptomatic and asymptomatic, are within the acceptable thresholds of AHA standards. Additionally, in patients deemed high CEA risk because of unfavorable anatomic features, the outcomes meet the AHA guidelines in symptomatic as well as asymptomatic patients, irrespective of age.

6. The higher event rates in the pre-2005 high CEA risk carotid stent registries may explain the lack of CMS reimbursement for asymptomatic patients undergoing CAS, despite FDA approval for this indication. The outcomes of the CAPTURE-2 and the EXACT postmarketing registry are compelling because at least in the nonoctogenarian high CEA risk population (both symptomatic and asymptomatic), the death and stroke outcomes were within the AHA guidelines. The results of large prospective randomized trials in standard CEA risk patients (ICSS, CREST, and ACT I) are all directionally similar and should hopefully help support a favorable coverage decision from CMS when the issue comes up next for review.

7. The octogenarian and older population continues to be a challenge, and the decision to recommend and perform CAS (or CEA), especially in the asymptomatic patient older than 80 years of age, has to be individualized.

There are four completed randomized trials in patients with symptomatic carotid disease: the Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Cartoid Stenosis (EVA-3S) trial^119,120; the Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterctomy (SPACE) trial^121,122; the International Carotid Stenting Study (ICSS)^4,5; and the Carotid Revascularization Endartectomy versus Stenting Trial (CREST).^6,7 The CREST study also included asymptomatic patients.

EVA-3S,¹¹⁹ a noninferiority study, was conducted in 30 centers across France and recruited and randomized standard CEA risk patients. These patients were within 120 days of either a TIA or a nondisabling stroke and had a ≥ 60% internal carotid artery stenosis in symptomatic carotid artery. The primary end point was any stroke or death within 30 days of treatment. Although the enrollment target was 872 patients, the trial was stopped prematurely by the data safety monitoring board after 527 patients had been enrolled, for reasons of safety and futility. The primary end point was seen in 9.6% of patients in the stenting group compared to 3.9% in those undergoing endarterectomy (P = 0.01). Later analyses demonstrated that the difference between the two groups persisted out to 4 years, the difference being driven by procedural events.¹²⁰

SPACE¹²¹ was a multicenter (n = 35), multinational (German, Austrian, and Swiss) noninferiority study. This trial recruited and randomized standard CEA risk patients within 180 days of either a TIA or moderate stroke (Rankin score < 4). Patients had a stenosis severity of 70% or greater by ECST criteria (≥ 50% by NASCET) in the index carotid artery determined by catheter angiography or by duplex ultrasound. The primary end point was ipsilateral stroke and death within 30 days of treatment. The trial was stopped after data from 1183 patients had been analyzed, which led to the conclusion that a larger sample size (almost 2500 patients) would be needed; however, additional funding was not available. Event rates were 6.84% in the stenting group compared with 6.34% in patients undergoing endarterectomy. Although the outcome rates were similar between the two groups, the trial failed to demonstrate the noninferiority of CAS (ie, the study failed to prove that the outcomes in patients undergoing stenting were no worse when compared to the outcomes of CEA).

The ICSS,^4,5 a multicenter (n = 50), multinational (Europe, Australia, New Zealand, and Canada participation) superiority study, recruited and randomized 1713 standard CEA risk patients to either CAS (n = 855) or CEA (n = 858) within 12 months of symptoms. Patients older than 40 years of age with a stenosis severity of 50% or greater (by NASCET criteria) in the index carotid artery were eligible for enrollment. Stenosis severity and study entry eligibility were determined by duplex ultrasound or other noninvasive imaging of the carotid artery; approximately 90% of patients in both groups had > 70% stenosis. Patients were followed for a median of 4.2 years. The median time from the symptomatic event to CAS and CEA was 35 and 40 days, respectively (P < 0.013), and 25% of CAS patients and 18% of the CEA patients underwent treatment within 14 days of the event.

The primary end point was long-term incidence of death or disabling stroke in any territory. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the CAS and CEA groups (6.4% vs 6.5%; HR 1.06, P = 0.77). Although any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs. 72 events; intention-to-treat population, 5-year cumulative risk 15.2% vs 9.4%, P < 0.001), this difference was contributed by nondisabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups. The ICSS study, the largest randomized study comparing CAS and CEA in symptomatic patients, concluded that long-term functional outcomes and the risk of fatal or disabling strokes are similar for stenting and endarterectomy.⁵

Analysis

Inclusion and Exclusion Criteria

For the outcomes comparison between the two treatment strategies, CAS and CEA, to be valid, the two patients groups should be comparable. Specifically, for the patients enrolled in these studies it should not matter if they were in the CAS or CEA arms since, in a well-designed, adequately enrolled clinical trial, the process of randomization should “cancel the noise” and even out the imbalances between the two arms. However, despite randomization, an important imbalance continued to persist between the two treated groups related to the inclusion and exclusion criteria that handicapped the outcomes in the CAS arm. For example, in each one of these trials, patients with known anatomical characteristics that would render them “high risk” for CEA (tandem lesions, additional intracranial high grade stenosis, “hostile necks” as a result of prior surgery or radiation) were all excluded from trial participation. On the other hand the trial protocol did not specify exclusions for high stent risk. Additionally, when the trial protocol permits trial entry and randomization on the basis of duplex imaging, anatomical features that render stenting high risk (extended, type III aortic arch, tortuous extracranial carotid anatomy, obvious lesion filling defect(s) as a result of a fresh, friable, and loose thrombus) cannot be identified/excluded. Whereas inclusion of these patients made little or no difference to the outcomes for CEA, it negatively impacts CAS outcomes, and this imbalance cannot be corrected by the randomization process. In their defense, it is important to recognize that the EVA-3S, SPACE, and ICSS studies developed their protocols and started recruiting patients during a period wherein the concept of high stent risk was not well understood.

Antiplatelet Regimen

Contemporary CAS results are predicated on mandatory administration of adequate doses of dual antiplatelet medications in all patients prior to initiation of the stenting procedure and continuing them for around 8 weeks post-CAS.^123,124 In all three of the above trials, dual antiplatelet agent use was recommended but not mandated. Approximately 20% of patients in the EVA-3S and SPACE studies did not receive adequate antiplatelet medications.

Inconsistent Use of Embolic Protection Devices

In EVA-3S, during the first 3 years of enrollment (2000-2003), EPDs were used in approximately three-quarters of the procedures. In 2003, after a Data and Safety Monitoring Board review, EPD use became mandatory. Analysis of the outcomes with and without use of EPDs reveals much higher complication rates for CAS performed without EPDs. In SPACE, EPDs were used in only 27% of the cases. In ICSS, use of EPDs was recommended, but not mandatory. Less than three quarter, of the cases were performed using an EPD. Since the protocol was silent with respect to the need for familiarity with these devices prior to use within the trial, experience and expertise with the use of these devices was very variable and in some centers, minimal if any. In contemporary CAS practice, careful, critical analysis of the carotid anatomy as it relates to its suitability for placing a distal EPD is an important component of the risk stratification process. If the anatomy cephalad to the stenosis is markedly tortuous and/or there is no “adequate” landing zone (ie, there is insufficient room between the caudal extent of the EPD and the area where the distal tip of the stent delivery system is expected to land), unless the case is suitable for a proximal (flow reversal) EPD, the case should be considered high stent risk, and the operator should not proceed with “unprotected” CAS.

Operator Experience

Among practitioners of CAS, a major concern with these studies has been the lack of experience of the investigators. Whereas the surgeons were experienced CEA operators and needed to have performed a minimum of 25 CEA surgeries in the year preceeding study participation (EVA-3S and SPACE), the entry barrier for CAS operators was much lower.^125,126 In EVA-3S, for example, a total stenting experience of 12 CAS procedures or 5 CAS procedures plus 30 non-CAS supra- aortic stent procedures was sufficient for entry qualification.¹²⁷ Surprisingly, first-ever CAS cases in the presence of a proctor in the room were allowed within the trial. In the ICSS study,⁵ randomization was suspended at two centers; one of them enrolled 11 CAS patients but had 5 disabling strokes or deaths. In ICSS, the hazard ratio for the combined outcomes of procedural stroke or procedural death or ipsilateral stroke during follow-up was lower for centers that enrolled 50 or more patients. A disproportionately high number of patients underwent CAS using general anesthesia or conscious sedation, a reflection of operator inexperience and unfamiliarity with the CAS procedure and contrary to contemporary CAS practice. This has led many investigators^128,129 to question the validity of establishing clinical criteria and guidelines for CAS on the basis of these trials.

The CREST Trial

The CREST study^6,7 was conducted in 107 US and 9 Canadian centers and randomized standard risk CEA patients to either CAS or CEA. The trial, which commenced in 2000, started by enrolling symptomatic patients, ie, patients with TIA, amaurosis fugax, or nondisabling stroke, who were within 6 months from the index event. In 2005, enrollment criteria were modified to include asymptomatic patients. Symptomatic patients needed to have a stenosis severity of ≥ 50% on conventional angiography (NASCET criteria) or ≥ 70% stenosis on duplex ultrasonography, CTA, or MRA in the index carotid artery. For asymptomatic patients, the stenosis eligibility criteria were ≥ 60% on conventional catheter angiography, ≥ 70% by duplex ultrasonography, or ≥ 80% stenosis on CTA or MRA. The trial was sponsored by the NIH as well as Abbott Vascular, whose devices, the Accunet filter and Acculink stent, were utilized in the study. Secondary end points included all death, any stroke, or myocardial infarction at 30 days (periprocedural); a 1-year composite end point stratified by symptomatic status and age (octogenarian status), acute procedural success, target lesion revascularization at 12 months, access site complications requiring treatment, cranial nerve injury unresolved at 1 and 6 months, and a prespecified interaction analyses involving gender and symptomatic status.

Data analysis was performed with four prespecified analysis populations: intent to treat, as treated, modified as treated, and per protocol.

The sample size of 2500 symptomatic patients in the initial proposal was based on a noninferiority analysis for a study with 80% power and one-sided alpha of 0.05, assuming a composite end point rate of 7.48% and a noninferiority margin of 2.6. When asymptomatic patients were added in 2005, the assumption was that 50% of the patient population would be asymptomatic. The assumed composite event rate was ratcheted down to 6.76%, and the study power increased marginally to 82% with a one-sided alpha of 0.05.

Of the 2307 patients in the per-protocol population, 1219 (52.8%) were symptomatic and 1088 (47.2%) were asymptomatic. The demographics of the two groups were well matched; approximately 9% of the patients were octogenarians, 30% were diabetic, and cardiovascular disease was present in about 45% of the patients.

The primary end point of the CREST study was the composite of any stroke, myocardial infarction, or death from any cause during the periprocedural period or ipsilateral stroke within 4 years after randomization. The data were also analyzed using a composite end point that included any stroke, myocardial infarction, and all death within 30 days of the procedure plus ipsilateral stroke between day 31 and day 365 (Table 95–9). This end point was used by the industry sponsor for FDA submission for device approval. CAS was shown to be noninferior to CEA based on a prespecified noninferiority margin of 2.6%. There were no significant differences between CAS versus CEA by symptomatic status for the primary CREST end point.⁸

During the periprocedural period, there was a greater risk of stroke with stenting (4.1% vs 2.3%; P < 0.01), a difference that was driven by the increased number of minor strokes in the CAS group (3.2% vs 1.7%; P = 0.01). It is worth noting and emphasizing that for the end points of death and major stroke, not only was there no significant difference between the two groups, the event rates for these two key end points was low with both CEA and CAS.⁶ For both CAS and CEA, the overall stroke and death rates were below or comparable to those of previous randomized trials and were within the complication thresholds suggested in current guidelines for both symptomatic and asymptomatic patients.⁸

Minor Strokes

All interventions for extracranial carotid artery disease (CEA or CAS) are prophylactic and the specific goal of the procedure is to reduce the patient's future risk of a stroke. Although survival free of a major stroke is the principal goal of the therapeutic intervention, minor strokes cannot be simply ignored. In fact, especially when treating asymptomatic patients, operators should have an extremely low tolerance for any procedure-related neurological event, be it major or minor stroke or cranial nerve injuries. In the CREST study, an increased incidence of minor strokes contributed to the excess stroke hazard in the CAS arm. Analysis of the NIH stroke scale data of patients suffering a periprocedural minor stroke reveals that although residual defects were disproportionately higher in the CAS arm at 1 month (1.10% vs 0.60%), this difference was no longer evident at the 6-month time point (0.62% vs 0.6%). A similar trend to equalization was noted when objective classification of the residual deficits was performed using the Rankin scale. Importantly, the occurrence of a minor stroke did not negatively impact the patients’ long-term survival.

Myocardial Infarction

In CREST, myocardial infarction was defined by biomarker elevation (creatine kinase-MB [CK-MB] or troponin > twice the upper limit of normal) plus either chest pain or electrocardiographic (ECG) evidence of ischemia (> 1 mm ST-segment elevation or depression in two contiguous leads). An additional prespecified category included biomarker elevation without chest pain or ECG abnormality (biomarker positive only). When compared to patients without biomarker elevation, mortality was higher over 4 years for those with a myocardial infarction (HR 3.40) or biomarker positive only (HR 3.57). After adjustment of baseline risk factors, the occurrence of myocardial infarction or the elevation of biomarkers only remained independently associated with increased mortality.¹³⁰

The negative impact on survival in patients experiencing a periprocedural myocardial infarction is consistent with observations from other cardiac and noncardiovascular procedures. It has been previously shown that small periprocedural elevations of cardiac enzymes were associated with increased future mortality.^{131,132,133,134}

Cranial Nerve Injuries and Their Sequalae

Cranial nerve injuries occur in 4.9% to 7.7% of patients undergoing CEA. Although uncommon, cranial nerve deficits can be permanent and cause significant morbidity. In the ICSS study, two of the cranial nerve injuries (out of 857 endarterectomies) were classified as disabling—both patients required gastrostomies. In the CREST study, 5.3% of patients undergoing CEA had a cranial nerve injury. Two percent of the cranial nerve injuries were unresolved at 6-month follow-up. In future trials, consideration should be given to the inclusion of cranial nerve injuries as part of a composite primary end point together with death, stroke, and myocardial infarction.

Durability of Carotid Stenting

Clinical durability, ie, freedom from an ipsilateral stroke during long-term follow-up in both symptomatic and asymptomatic patients with extracranial carotid artery disease undergoing CEA, was established by the NASCET¹² and ACAS¹⁷ trials.

The 10-year follow-up results from the CREST study were recently reported⁷ (see Table 95–9). Postprocedural ipsilateral stroke over the 10-year follow-up occurred in 6.9% (95% CI, 4.4%-9.7%) of the patients in the CAS group and in 5.6% (95% CI, 3.7%-7.6%) of those in the CEA group; these rates were not significantly different (HR, 0.99; 95% confidence interval [CI], 0.64-1.52). There were no between-group differences when symptomatic and asymptomatic patients were analyzed separately. These results are similar to the observations in the EVA-3S¹²⁰ and SPACE¹²² trials, suggesting excellent durability on longer-term follow-up. The durable benefits of CAS, ie, freedom from ipsilateral stroke, in these large randomized studies reinforce the long-term results published by the authors (SI, GR) almost 15 years ago.⁸⁹

Restenosis Following Carotid Stenting

Although duplex ultrasound is an excellent noninvasive method of following these patients, as a result of mechanical changes in the carotid artery following stenting, velocity criteria conventionally applied to diagnose stenosis in nonstented arteries are not the same in stented carotid arteries. It has been suggested that a peak systolic velocity greater than 300 cm/s be used to define a stenosis > 70%^135,136,137 in the stented patient. Although CTA may be used for noninvasive imaging,¹³⁸ MRA is not useful in a stented patient because of metallic interference from the implanted stent.

In the CREST trial,⁷ restenosis was defined as the time from the procedure to either ipsilateral revascularization or the detection of a 70% to 99% stenosis or occlusion on a duplex exam performed annually after CAS or CEA, with the degree of stenosis determined by the norms of the local laboratory. There was no significant difference between the two treatment groups in the proportion of patients who had restenosis or underwent revascularization. Restenosis occurred or revascularization was performed in 12.2% of the patients treated with CAS and in 9.7% of those treated with CEA (HR, 1.24; 95% CI, 0.91-1.70)

Summary

The results of the CREST trial showed that both CEA and CAS are excellent treatment options. There was no difference in the outcomes in women versus men. The primary composite end point of periprocedural stroke, myocardial infarction, or death was similar between CEA and CAS. The incidence of major disabling strokes or death was extremely low and was not different between the two treatment modalities. Periprocedural minor strokes were greater in the CAS group, but by 6 months, the deficits were not different. There was no survival disadvantage in patients with minor strokes. However, myocardial infarction occurred more frequently in the CEA cohort, and this negatively impacted survival. At 1 year, stroke had a greater adverse effect on quality of life than did myocardial infarction.¹³⁹ Over a follow-up period that extended to 10 years, freedom from ipsilateral stroke and the risk of restenosis were similar for the CEA and CAS groups, supporting the clinical and device durability of CAS.

ACT I,⁹ a randomized prospective study, compared CAS performed with embolic protection (n = 1089) and CEA (n = 364) in patients 79 years of age or younger who had severe (≥ 70%) asymptomatic carotid stenosis and who would be considered standard risk for CEA. The trial was designed to enroll 1658 patients, but was halted after 1453 patients underwent randomization because of slow enrollment. Subjects were randomized in a 3:1 ratio to the CAS and CEA groups, respectively. Patients were followed for up to 5 years. The primary composite end point of death, stroke, or myocardial infarction within 30 days after the procedure or ipsilateral stroke within 1 year was tested at a noninferiority margin of 3%.

The mean age was approximately 67 years, more than half were male, close to 90% were white, and approximately 40% had contralateral carotid disease. The mean angiographic stenosis was > 70%. Other than lesion length (19 ± 5.8 mm in the CAS group vs 18.0 ± 6.2 mm in the CEA group; P < 0.05) and lesions with thrombus (0.9% in the CAS group vs 2.8% in the CEA group; P < 0.05), none of the other baseline characteristics were different between the two groups

The study outcomes showed that CAS was noninferior to CEA with regard to the primary composite end point (3.8% vs 3.4%; P = 0.01 for noninferiority). The 30-day rate of death or major stroke was low in both groups (0.6%); the 30-day rate of minor stroke was numerically higher in the CAS group (2.4% vs 1.1%; P = 0.20). Hence, the overall rate of stroke or death within 30 days was 2.9% in the stenting group and 1.7% in the CEA group (P = 0.33). The rate of cranial nerve injury in the CEA group was 1.1%.

Between 30 days and 5 years after the procedure, the rate of freedom from ipsilateral stroke was 97.8% in the CAS group and 97.3% in the CEA group, and the overall survival rates were 87.1% and 89.4%, respectively. The cumulative 5-year rate of stroke-free survival was 93.1% in the CAS group and 94.7% in the CEA group. None of these differences were significant. Freedom from clinically driven target lesion revascularization at 1 year was 99.4% for CAS and 97.4% for CEA. These results support the durability of CAS when treating asymptomatic patients.

The Elderly

Patients older than 80 years with carotid stenosis pose several challenges for revascularization. The association between advanced age and increased risk of adverse events after CAS was observed in the CREST lead-in cohort,¹⁴⁰ the SPACE trial,¹²¹ and the ICSS.⁴ ACT I did not enroll patients older than 80 years of age. Octogenarian patients are more likely to be excluded because they have one or more features deemed high risk for CAS (see Table 95–6). By excluding patients with adverse features, it has been shown that event rates comparable to those seen following CEA¹⁴¹ can be achieved.

In the CREST study,⁶ an interaction between age and treatment efficacy was detected with a crossover at approximately 70 years of age. This led the CREST investigators to conclude that “carotid-artery stenting tended to show greater efficacy at younger ages, and carotid endarterectomy at older ages.” Treatment recommendations in the elderly patient need to be individualized and must take into account high-risk features that will make either CAS or CEA (or both) unsuitable. Elderly patients with severe asymptomatic carotid stenosis who have high-risk anatomic features or comorbidities that increase risk of CAS and CEA are often best managed with medical treatment and risk-factor optimization.

Concomitant Carotid and Coronary Arterial Disease

The prevalence of > 50% carotid stenosis in patients undergoing coronary artery bypass grafting (CABG) is approximately 25%¹⁴² and perioperative stroke risk following CABG may be as high as 11%.¹⁴³ Meta-analyses showed that stroke as a complication of CABG occurred in 1.7% of all cases.^144,145 The risk of stroke is 3% in patients with unilateral carotid stenosis 5% for patients with bilateral > 50% stenosis, and 7% to 11% for patients with carotid artery occlusion.¹⁴⁴ However, pathological and radiological examination revealed that only 40% of such strokes could be attributed to the ipsilateral stenosis. Therefore, even if it were 100% effective at preventing ipsilateral ischemia, carotid intervention can only reduce stroke rates by less than half.

Observational studies have shown that the perioperative stroke/death rate was 8.7% for combined CEA and CABG and 6.1% when a sequential approach of CEA followed by CABG¹⁴⁶ was used. There was an increased risk of myocardial infarction with either strategy—3.6% for the synchronous procedure and 6.5% for the staged approach.¹⁴⁶

When 64 patients with severe carotid and coronary stenoses treated with CAS followed by CABG were compared to 112 patients who underwent combined CEA and CABG, despite the CAS group being a higher risk group, there was a lower incidence of strokes (2% vs 9%; P = 0.05) and strokes and myocardial infarction (6% vs 19%; P = 0.02).¹⁴⁷ In 356 patients with severe, asymptomatic carotid stenosis who underwent CAS prior to CABG, 30-day follow-up showed rates of stroke, TIA, myocardial infarction, and death of 3.1%, 3.7%, 2.0%, and 3.7%, respectively.¹⁴⁸ In a meta-analysis of 11 trials¹⁴⁹ enrolling 760 patients (87% asymptomatic) who underwent staged CAS and CABG, the rates of ipsilateral stroke, myocardial infarction, and death at day 30 were 3.3%, 1.8%, and 5.5%, respectively.

There are no guidelines or consenus as to the optimum approach to treating a patient with asymptomatic carotid artery stenosis who requires CABG. Patients with bilateral severe carotid artery disease or a contralateral occlusion may benefit from carotid revascularisation prior to CABG and CAS when feasible may be a safer alternative. Careful monitoring of hemodynamics is important and consideration should be given for placing a temporary venous pacemaker; an intra-aortic balloon pump during the CAS procedure may be required in patients with severe three-vessel CAD, left main disease, aortic stenosis, or severe left ventricular dysfunction.

Prior Neck Irradiation

Carotid artery stenosis can present as a delayed complication of neck irradiation (radiation arteritis).¹⁵⁰ Patients with prior neck radiation frequently have long smooth lesions that are high (at or above the C2 vertebra) or low (at the level of the clavicle in the common carotid artery). Stenosis at multiple locations within the same artery may also occur. The typical interval between the radiation treatment and the detection of stenosis is 10 years or more.

Because radiation-induced vascular stenosis may be associated with fibrosis and scaring of the skin and subcutaneous tissue, surgical therapy is more complicated and may lead to postoperative necrosis, infections, wound breakdown, and cranial nerve injuries.¹⁵¹

For these reasons, CAS is safer and more effective in the post-radiated patient.^152,153 Reported periprocedural stroke and death rates have been low and have not exceeded those observed in general patient cohorts undergoing CAS. One limitation of stenting in this group is the possible increased risk of in-stent restenosis following the procedure. Restenosis rates from 5%¹⁵² to 41%¹⁵³ have been reported at intervals from 12 to 24 months. Restenosis is often clinically asymptomatic and generally amenable to repeat percutaneous intervention.

The guidelines provide CAS a Class IIa recommendation²⁴ in this setting. There may be incomplete endothelialization of the stent struts; therefore patients with prior neck radiation who undergo stenting should be given dual antiplatelet treatment for an extended period, preferably lifelong.

Restenosis Following Prior CAROTID ENDARTERECTOMY

If restenosis occurs in the early years after CEA, it is typically caused by intimal hyperplasia, whereas in later years, atherosclerosis is likely responsible.¹⁵⁴ Revision CEA is technically challenging and is associated with higher complication rates than primary surgery, with increased rates of stroke (4.8% vs 0.8%), TIA (4.0% vs 1.1%), and cranial nerve injury (17.0% vs 5.3%).¹⁵⁵

CAS following prior CEA is associated with low complication¹⁵⁶ rates, and stent restenosis is not significantly higher than that seen with primary CAS.¹⁵⁷

Restenosis Following Carotid Stenting

Noncompliant balloons¹⁵⁸ are generally used for dilating in-stent restenosis; an additional stent may be required especially if the stenosis involves the distal edge of the index stent. Zhou and colleagues utilized cutting balloons in five of seven patients, and two required further stent implantation.¹⁵⁹ The use of an EPD remains mandatory when intervening on these lesions. Rates of target lesion revascularization in recently reported randomized prospective CAS trials have been in the low single digits.⁹

CAS or CEA can be scientifically and ethically justified as a treatment option for symptomatic and asymptomatic patients if the operators and centers are experienced and have a verifiable periprocedural stroke risk that is less than 6% and 3%, respectively. Making decisions and providing treatment recommendations are very challenging in centers where interventional and surgical expertise and outcomes cannot be verified.^160,161 Carotid duplex diagnostic testing should only be performed in Intersocietal Accreditation Commission (IAC) accredited labs. All patients should be on at least one antiplatelet agent and a statin, and risk factors should be appropriately modified.

In symptomatic patients, there is consensus that most if not all patients with a ≥ 70% stenosis and a certain proportion of patients with a 50% to 70% stenosis on angiography should be offered a definitive revascularization procedure. Level I support for recommending CAS or CEA is provided by the results of the ICSS and CREST trials. The risk of procedural death and major stroke is low and similar with either procedure. Long-term follow-up has shown clinical durability. Although timing of the revascularization procudure in relation to the symptomatic event is still debated, data from the CREST study seem to indicate that risks with either procedure are equivalent even when the intervention is done within 2 weeks of the event.

For asymptomatic patients, the results of CREST as well as the ACT I trial reveal that both CEA and CAS are equivalent in terms of acute and 30-day outcomes and both procedures have clinical durability. It would seem reasonable to offer revascularization for asymptomatic patients with a ≥ 80% stenosis provided the periprocedural risk is less than 3%.

Despite the data from these large prospective randomized clinical trials, in 2016, the issue of which asymptomatic patient needs treatment and if invasive approaches are better than contemporary medical therapy is not settled because of the speculation that the stroke risk in all asymptomatic patients treated with modern medical therapy is much lower. The ongoing Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial (CREST-2) will test this hypothesis by addressing the question of the relative benefits of revascularization over nonrevascularization in asymptomatic patients in the context of contemporary, intensive medical therapy. The European Carotid Surgery Trial 2 (ECST-2) is also comparing revascularization with nonrevascularization in asymptomatic patients and includes symptomatic patients who have been deemed at low risk for stroke. Assuming adequate numbers of asymptomatic patients with > 80% stenosis are enrolled in these trials, they will help define the optimum treatment for these patients.

Patient selection remains the single most important predictor of complications. Although EPDs are routinely used, no protection device can replace critical risk analysis and sound operator judgment. In general, it is reasonable to recommend CAS over CEA in patients who are younger than 70 years of age. For patients between 70 and 80 years of age and certainly for those older than 80 years, the decision needs to be individualized and the recommendation for revascularization should be reached after critical analysis of the risks and benefits. Technological device-related improvements can be expected, and these may further reduce the periprocedural risk and improve the safety of carotid stenting.