The era of percutaneous or endovascular revascularization techniques was ushered in by Dotter in 1964, and then advanced by Gruentzig with the invention of the balloon angioplasty catheter. The technique of percutaneous transluminal angioplasty (PTA) has been used in both peripheral and coronary vessels to great success and, in many circumstances, has largely replaced surgical therapy as the treatment choice. The use of PTA in the extracranial carotid circulation began in Europe. In a worldwide survey of carotid intervention published in 1998, the specialty of cardiology was dominant, responsible for more than 60% of all the reported cases. Cardiologists have continued to lead this field with the development of embolic protection devices (EPDs); initially proven in saphenous vein graft intervention, cardiologists are already comfortable using this technology.

Pathophysiology

The majority of cerebral ischemic events are a focal manifestation of a systemic disease, atherosclerosis. Extracranial atherosclerotic carotid artery disease accounts for slightly more than half of the 731,000 strokes per year in the United States. Stroke is the third leading cause of death after coronary artery disease and cancer in the United States, and it is the leading cause of disability. In the Framingham study, 70% of all stroke patients had hypertension, 70% had coronary artery disease, and 30% had peripheral vascular disease.

There are 2 main types of stroke: ischemic and hemorrhagic. Ischemic stroke results from a reduction of blood flow due to emboli, thrombosis, or hypoperfusion. Hemorrhagic stroke includes primary cerebral hemorrhages or hemorrhage secondary to an ischemic event. Atherosclerotic carotid artery stenoses most often cause symptoms due to emboli events. A minority of ischemic strokes are caused by thrombotic occlusion, which is in contrast to acute coronary syndromes, which are usually due to thrombotic vessel occlusion.

Anatomically, the 2 internal carotid arteries and 2 vertebral arteries come together at the base of the skull to form the circle of Willis (Fig. 57-1), which is an ideal anastomotic network. In theory, a single vessel could supply the circulatory needs of the entire brain. However, although a circle of Willis is present in every brain, there is a huge amount of individual variability, and fewer than half are complete anastomotic networks.

Stroke Prevalence, Demographics, and Etiology

The third leading cause of death in the United States is stroke, with more than three-quarters of a million strokes per year. Stroke is a leading cause of functional impairment in adults with approximately 20% of survivors requiring institutional care and up to one-third having a permanent disability. More worrisome, however, is the fact that as the population ages, the number of patients experiencing strokes appears to be increasing.

The majority of strokes are ischemic and are caused by atherosclerotic emboli from the carotid artery or the aortic arch; more rarely, they are related to thromboembolism from the heart chambers. The incidence of asymptomatic extracranial carotid stenosis (≥50%) in persons >65 years of age is estimated to be between 5% and 10%, with fewer than 1% of patients having a critical stenosis (>80%). The annual risk of stroke is between 1% and 4.3% for asymptomatic patients with ≥50% stenosis of the carotid artery. The asymptomatic patients at highest risk of stroke are those with severe stenoses or those with progressive carotid narrowing. Unfortunately, the majority (~80%) of strokes have no warning symptoms. Therefore, identifying asymptomatic patients at highest risk for stroke is extremely important.

The current evidence supporting revascularization (carotid endarterectomy [CEA] or carotid artery stenting [CAS]) in asymptomatic patients is dated, with more current evidence creating debate among experts.¹ The strongest evidence favoring revascularization comes from randomized clinical trials (Asymptomatic Carotid Artery Surgery [ACAS]² and Asymptomatic Carotid Surgery Trial [ACST]³) that were performed prior to the widespread availability of modern multimodality medical therapy, particularly statins. The most conservative estimate is that the current incidence of an asymptomatic carotid stenosis leading to a stroke is <1% per year, which, if true, would make it difficult for revascularization to provide additional benefit for patients.¹ Unfortunately, there is little evidence upon which to base a treatment recommendation for patients with severe asymptomatic carotid stenosis. This has led to a proposal for a second Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST-2), which will randomize asymptomatic patients with significant carotid lesions to revascularization (CEA or CAS) versus multimodality medical therapy.

Pending the outcome of new trials, there continues to be reasons to consider revascularization of asymptomatic patients with significant carotid artery stenosis (>60%), such as prior to heart surgery to protect the brain from intraoperative hypoperfusion, rapidly progressing stenoses, patients with contralateral carotid occlusions, or patients with ulcerated or other high-risk plaque features that increase the incidence of stroke. Because the majority of strokes occur without warning, patient-centered care demands giving the asymptomatic patient’s preferences for revascularization (CAS or CEA), in the hands of an experienced team with proven quality outcomes, consideration.

Symptomatic patients have a worse prognosis compared to asymptomatic patients. The risk of atheroembolic stroke is directly related to the severity of carotid artery stenosis and the presence of symptoms. A transient ischemic attack (TIA), a neurologic event lasting <24 hours, predicted a 15% risk of stroke at 1 month and a 30% risk of recurrent TIA, stroke, or death within 3 months. In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the stroke rate was 16.2% among those with moderate (50%-69%) stenosis and 25.1% with a 70% to 99% carotid stenosis (Table 57-1).⁴ Patients with the very tightest lesions, near occlusions, which were defined in the European Carotid Surgery Trial (ECST) as a severe stenosis with evidence of reduced flow in the distal carotid artery and evidence of narrowing of the poststenotic carotid artery, did not benefit from CEA.^5,6

Cerebrovascular Symptoms

Symptomatic cerebrovascular events are classified as TIAs, if they completely resolve within 24 hours, or as strokes, if they leave a permanent deficit. Patients with minor strokes include those who symptoms resolve within 7 days or those with minimal disability (National Institute of Health Stroke Scale [NIHSS] ≤). Symptoms may be “hemispheric,” meaning they are related to a single carotid distribution, causing contralateral hemiparesis or hemiparesthesias, aphasia, and/or ipsilateral monocular blindness (amaurosis fugax), or they may be “nonhemispheric,” with symptoms of vertebrobasilar insufficiency (VBI) such as dysarthria, diplopia, vertigo, syncope, and/or transient confusion.

Noninvasive Imaging

Doppler ultrasound or duplex imaging of the extracranial carotid arteries is cost-effective, accurate, and reproducible. Duplex imaging of the carotids provides information about the location, extent, and severity of disease. Blood flow velocity measurements are translated into categories that have clinical relevance. There is controversy regarding the ability of ultrasound imaging to serve as the sole imaging criterion to determine suitability for carotid revascularization.⁵ A recent trial suggested that although ultrasound is an excellent screening tool, its accuracy in a community setting was not sufficient to replace angiography. As the resolution and speed of magnetic resonance angiograpy (MRA) and computed tomographic angiography (CTA) rapidly improve, they are being used to noninvasively image the extracranial carotid arteries and intracerebral vessels (Fig. 57-2). The cross-sectional images can be reconstructed into noninvasive angiograms that have the very important advantage of imaging the circle of Willis with excellent resolution and clarity.

Invasive Angiography

All of the revascularization trials upon which carotid artery treatment decisions have been based have used angiographic criteria for patient selection. Invasive angiography is the “gold standard” for the diagnosis of vascular pathology of the aortic arch, cervical, and cerebral vessels (Fig. 57-3). The major drawback for invasive angiography has been the risk of adverse events associated with the procedure. In the ACAS trial, there was a 1.2% risk of stroke related to angiography performed by radiologists.⁷ More recently, we have reported a much lower stroke rate (0.5%) for experienced interventional cardiologists performing carotid angiography.⁸ Clinical volume, technical skills, and patient selection are important elements in minimizing the risk for diagnostic angiography.

Stroke Prevention with Pharmacologic Therapy

Both primary and secondary stroke prevention require aggressive risk factor modification, specifically lipid management, blood pressure control, and smoking cessation.⁹ Aspirin therapy (81 mg daily) results in a 25% relative risk reduction compared to placebo. There is no evidence that doses of aspirin greater than 75 to 325 mg per day are more effective for stroke prevention. The CAPRIE (Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events) trial, comparing clopidogrel to aspirin, demonstrated a significant benefit for clopidogrel for the combined endpoint of ischemic stroke, myocardial infarction, or vascular death, but it did not show a reduction in stroke risk with clopidogrel compared to aspirin alone. The MATCH (Management of Atherothrombosis With Clopidogrel in High-Risk Patients) trial showed no stroke reduction benefit for aspirin and clopidogrel compared to clopidogrel alone, although the bleeding risk was increased with combination therapy.¹⁰ Despite isolated data from a single trial regarding secondary prevention, the preponderance of evidence is that the addition of dipyridamole to aspirin alone for primary or secondary stroke prevention is of marginal benefit. With the exception of patients with atrial fibrillation, there are no data to support the role of anticoagulation with warfarin to reduce the risk of stroke.

Primary prevention has consisted of primarily blood pressure control, tobacco cessation, and aspirin therapy, but recently, the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial demonstrated significant risk reduction for stroke with statins. Several other lipid-lowering trials in patients at increased risk for stroke due to cardiovascular disease have also shown efficacy for statin therapy to reduce stroke. Both the 4-S (Scandinavian Simvastatin Survival Study) trial with simvastatin and the CARE (Cholesterol and Recurrent Events) trial with pravastatin demonstrated a 30% relative risk reduction for stroke compared to placebo. Of note, the stroke benefit did not appear in these trials until after 3 years of therapy.

Surgical Treatment

CEA has been established as the surgical procedure of choice for stroke prevention in patients with extracranial carotid artery disease (see Table 57-1; Table 57-2) to prevent stroke for usual or average surgical risk symptomatic patients with ≥50% carotid stenosis^6,11,12 and average risk asymptomatic patients with ≥60% carotid stenosis^7,13,14 compared to medical therapy.

The applicability of clinical trial results to everyday patients has been questioned. Wennberg and colleagues¹⁵ demonstrated that the perioperative mortality rate for trial hospitals was 1.4% (95% confidence interval [CI], 1.2%-1.7%) and that the perioperative mortality rate was higher in nontrial hospitals (high volume: 1.7%; 95% CI, 1.6%-1.8%; average volume: 1.9%; 95% CI, 1.7%-2.1%; low volume: 2.5%; 95% CI, 2.0%-2.9%; P for trend <.001; Fig. 57-4). Patients undergoing CEA at trial hospitals had a mortality risk reduction of 15% (95% CI, 0%-31%) compared with high-volume nontrial hospitals, 25% (95% CI, 7%-40%) compared with average-volume hospitals, and 43% (95% CI, 25%-56%) compared with low-volume hospitals (P for trend <.001). The authors concluded that the perioperative mortality following CEA as practiced in the communities is substantially higher than that reported in the trials, even in those institutions that participated in the randomized studies. Caution is advised in translating the efficacy of carefully controlled studies of CEA to effectiveness in everyday practice.

Variability in the reporting of CEA results makes interpretation and comparison of studies difficult (Table 57-3). In a meta-analysis of CEA in symptomatic patients (n = 51 studies), the strongest predictor of stroke or death was who (neurologist or surgeon) performed the postoperative assessment.¹⁶ When a neurologist evaluated postoperative patients, the risk of stroke and death was 7.7%; however, when a single author surgeon performed the evaluation, the risk was reported as 2.3%.

The clinical benefit of CEA must be balanced against the perioperative risk associated with the procedure. An expert consensus panel suggested that CEA was beneficial if the perioperative risk of stroke and death did not exceed 3% for asymptomatic patients and 6% for symptomatic patients. However, an increased risk of perioperative stroke and death rates has been reported for repeat CEAs (10.9%) and in patients with contralateral carotid occlusions (14.3%). There is consensus among experts that there is a population of patients who are at increased risk of complications with CEA due to a variety of unfavorable anatomic features and/or medical comorbidities (Table 57-4). The comparative benefit of CEA in patients treated with modern anti-atherosclerotic therapy has not been established.

Carotid Artery Stenting

Extracranial CAS placement has evolved over the past 20 years to become an accepted method for revascularizing patients with selected carotid lesions (Fig. 57-5). Because the extracranial carotid artery is subject to external compression and rotation, self-expanding stents are used to avoid stent deformation. Concern over the potential release of cerebral emboli led to the development of EPDs. These protection systems fall into 3 categories: (1) distal balloon occlusion with aspiration, (2) proximal occlusion with aspiration, and (3) distal filter systems.

CAS is the preferred revascularization strategy in patients at increased risk for surgical complications of CEA if they have suitable anatomy (see Table 57-4). The SAPPHIRE trial randomized high surgical risk patients to CEA or CAS in a large multicenter trial.¹⁷ The investigators clearly demonstrated noninferiority (CAS = 12.2%, CEA = 20.1%; P = .004 for noninferiority) across the entire cohort at 1 year for major adverse events. In patients at increased risk for complications of CEA, randomized trial data (SAPPHIRE¹⁸) and pivotal registry evidence (ARCHeR,¹⁹ SECuRITY,²⁰ MAVErIC,²¹ SPIDERX,²² PRIAMUS,²³ BEACH,²⁴ CREATE,²⁵ CAPTURE,²⁶ CASES-PMS,²⁷ CABERNET,²⁸ EXACT,²⁹ CAPTURE-2,²⁹ ARMOUR,³⁰ EPIC,³¹ EMPIRE,³² and PROTECT³³) support CAS as an alternative to CEA (Fig. 57-6). The durability of CAS relative to CEA was maintained out to 3 years of follow-up.³⁴

The current multisocietal guidelines recommend CAS as an alternative to CEA for treating symptomatic patients at increased risk for complications of CEA, if performed by an experienced operator and an experienced team, with expected 30-day morbidity and mortality outcomes similar to those observed in clinical trials (4% to 6%).^35,36 This category of CAS patient (symptomatic with ≥70% carotid artery stenosis and at high risk of CEA complications) represents the only group eligible for noninvestigational Centers for Medicare and Medicaid Services (CMS) reimbursement.

There have been 3 international randomized controlled trials comparing CEA to CAS (SPACE,³⁷ EVA-3S,³⁸ and ICSS³⁹), each of which, unfortunately, had seriously flawed trial designs by failing to provide quality control for CAS operators and not requiring the use of an EPD, which is the standard of care in the United States.⁴⁰ The single common denominator among these trials was allowing inexperienced operators to participate in order to accelerate enrollment. These inexperienced operators were challenged by the additional complexity of using an EPD with CAS, leading many of them to abandon this important step and sacrificing patient safety.

The largest trial comparing CAS and CEA in average surgical risk patients was CREST,³⁶ which enrolled 1321 symptomatic patients (53%) and found no difference for the primary end point of stroke, myocardial infarction (MI), or death from any cause during the periprocedural period or any ipsilateral stroke within 4 years after randomization between CEA (8.4% ± 1.2%) and CAS (8.6% ± 1.1%). A potentially disabling cranial nerve palsy occurred in 5.5% (n = 36) of the CEA group. After 4 years of follow-up, there was no difference in stroke occurrence for either symptomatic or asymptomatic patients (Fig. 57-7).