Overview of Carotid and Cerebrovascular Disease

Carotid endarterectomy has been the gold standard for the treatment of carotid disease, but recent data suggest that carotid stenting with embolic protection is a viable alternative.

By Jay S. Yadav, MD

To view the tables related to this article, please refer to the print version of our November/December issue, page 24.

Stroke remains the third leading cause of death in the US, and it is the leading cause of serious long-term disability.1 Each year, stroke affects approximately 750,000 people, and the annual cost to the health care system is more than $20 billion.

Most ischemic strokes (>85%) are due to atheroemboli, and approximately two thirds of these can be attributed to large-vessel stenosis.
2 Extracranial carotid disease is present in up to 30% to 40% of acute stroke patients. Intracranial atherosclerotic disease is present in 5% to 15% of acute ischemic stroke patients. The causal link between carotid atherosclerotic disease and stroke was first clearly delineated by C. Miller Fisher, MD, which led to the development of the surgical treatment of atherosclerotic disease.3

Risk Factors
There is close correlation between atherosclerotic disease in the carotids and the presence of coronary and peripheral atherosclerotic disease.4 Coronary disease and carotid disease share risk factors, but the relative contributions appear to be different. Men older than 75 years have a 50% risk of carotid atherosclerosis, as determined by ultrasound, but stenosis >50% is relatively uncommon and is present in only 5% of this population.5 White patients have predominantly extracranial carotid atherosclerosis, whereas black and Asian patients have predominantly intracranial vascular disease.6 Smoking remains the most important risk factor for carotid atherosclerotic disease, followed by hypertension, diabetes, and male sex.7

Hypercholesterolemia does not always show up as a risk factor for stroke, but this may be due to the fact that many epidemiologic studies do not separate out ischemic and hemorrhagic strokes.8 Many studies, however, have shown an association between elevated total cholesterol, low-density lipoprotein (LDL), and decreased high-density lipoprotein (HDL) with regard to carotid atherosclerosis.9 Low levels of HDL, even without elevation of LDL, have been associated with carotid disease in patients who have coronary disease.10 Clinical trials with HMG-CoA inhibitors have demonstrated a clear association between the degree of hypercholesterolemia and ischemic stoke.11

Studies of asymptomatic patients with ultrasound-diagnosed carotid atherosclerosis have demonstrated that the percentage of stenosis, the rate of progression of the stenosis, and the presence of ulceration all impact the risk of stroke.12 In patients with stenosis &Mac178;75%, the risk of stroke is only 1%. This increases to 2% to 5% in patients with stenosis &Mac179;75%.13 Silent brain infarction or embolization may also increase the risk for future symptomatic strokes.14 In patients with a transient ischemic attack (TIA) due to severe carotid disease, the risk of stroke is approximately 10% in the first year and increases to a cumulative risk of 30% to 35% at the end of 5 years. The presence of hemispheric TIAs, recent TIAs, frequent TIAs, or high-grade stenosis is associated with an increased risk of subsequent events.15

Anomalies of the aortic arch and great vessels are relatively frequent, with only 70% of patients demonstrating three separate ostia for the innominate, left common carotid, and left subclavian arteries. Origin of the left common carotid artery from the innominate artery (the bovine arch) is the most common anomaly and is seen in approximately 20% of patients. The common carotid artery typically divides into the internal and external carotid arteries at the C4-C5 intervertebral space. The internal carotid artery is situated posterolaterally to the external carotid artery and does not branch until it enters the subarachnoid space, where it gives rise to the ophthalmic artery before dividing into the anterior and middle cerebral arteries.

The internal carotid artery can be divided into the cervical, petrous, cavernous, and supraclinoid segments. The most significant brain collaterals are provided by the circle of Willis, which is composed of the anterior communicating artery. The anterior communicating artery connects the anterior cerebral arteries and the posterior communicating arteries, which connect the middle and posterior cerebral arteries. A symmetrical and normal circle of Willis, however, is present in less than one third of individuals undergoing cerebral angiography.16

As in other arterial locations, lesions are most commonly present at branch points and bends. The most common site of cerebrovascular disease is the carotid bifurcation, most typically occurring along the outer wall of the carotid bulb extending into the distal common carotid artery and the proximal internal carotid artery. Plaque hemorrhage leading to ulceration and thromboembolism is the most common cause of stroke.17,18 Ulcers are found much more commonly at pathologic examination than at angiography.19 In the North American Symptomatic Carotid Endarterectomy Trial (NASCET), plaque ulceration more than doubled the risk for stroke.20 During angiography, the ulcer size is defined as a multiple of the length and width of the ulcer in millimeters. The presence of a large ulcer (>40 mm) is an independent predictor of stroke risk and increases the risk of stroke to 7.5% per year.21

A TIA is the initial symptom of carotid disease in most patients and, if treatment is not instituted, 30% to 40% of these patients will develop a stroke. The diagnosis of TIA is made by history. It is important to differentiate vertebrobasilar symptoms from carotid distribution TIAs. The motor and sensory deficits of carotid disease typically involve the contralateral face and body, whereas posterior circulation events are often associated with bilateral or crossed deficits. Dysarthria, dysphasia, contralateral visual field loss, and amaurosis fugax are typical manifestations of carotid disease. Vertebrobasilar insufficiency is often associated with ataxia, dysarthria, diplopia, or bilateral visual field loss.

Ultrasound is the most commonly used technique for diagnosing carotid stenosis and is easily performed in an outpatient setting. A combination of B-mode and Doppler imaging is used. Ultrasound has a 90% specificity and sensitivity when performed by experienced sonographers. The intimal medial thickness has been used as a surrogate in many trials of risk factor modification and the severity of intimal medial thickness correlates well with the degree of coronary artery disease.22 Progression and regression of carotid lesions are correlated with the behavior of coronary atherosclerotic lesions.23

Magnetic Resonance Angiography
MRA is useful in the study of the carotid bifurcation, particularly in combination with MRA imaging of the brain. The specificity of MRA is somewhat less than ultrasound; only 70% due to artifacts, tortuous vessels, turbulent flow, and other technical reasons.24 MRA typically overestimates the degree of stenosis and is particularly poor at distinguishing between subtotal and total occlusions; however, this is also a limitation of ultrasound.

Angiography remains the gold standard for diagnosing carotid stenosis. It allows for accurate measurements of stenosis along the entire vessel length and is relatively free from artifact. It is also particularly useful for establishing the collateral circulation. However, because it is an invasive procedure, it does carry the risk of embolization and stroke.25 However, when performed using current modern techniques, angiography is a safe procedure.

Pharmacologic Management
Antiplatelet Drugs. A number of studies have been conducted in this area, but most of these did not specifically include patients with carotid stenosis. The Antiplatelet Trialists Collaboration was a meta-analysis of 164 randomized trials that included more than 100,000 patients.26 Among the primary prevention patients, there was approximately a 30% reduction in the risk of nonfatal MI, but there was no reduction in the risk of stroke. In the group with a history of stroke or TIA, the incidence of subsequent ischemic nonhemorrhagic stroke was reduced from 12.2% to 9.7% with the use of antiplatelet therapy (P <.01). Surprisingly, there was no difference in the effectiveness of different aspirin dosages or combination regimens.

In the Ticlopidine Aspirin Stroke Study (TASS), 3,069 patients with noncardiogenic TIAs or strokes were randomized to ticlopidine or aspirin (650 mg twice a day) therapy. There was a trend in favor of ticlopidine in preventing nonfatal stroke or death at 3 years (17% vs 19%; P = .048).27

Clopidogrel was studied in the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial. The CAPRIE trial randomized 19,185 patients who had atherosclerotic disease. The combined incidence of ischemic stroke, myocardial infarction, and vascular death at approximately 2 years favored clopidogrel (5.3% vs 5.8%; P = .043), although the absolute reduction in events was small (0.27% per year).28

The most specific data regarding outcomes for patients with carotid disease treated with antiplatelet drugs was derived from the medical management arms of the carotid endarterectomy randomized trials.29 In the Asymptomatic Carotid Atherosclerotic Study (ACAS), the annual risk for ipsilateral stroke in patients treated with aspirin alone was only 2.2% a year. However, the degree of stenosis was quite modest, at only 60%.30 In the Mayo Asymptomatic Carotid Endarterectomy Study, the trial was stopped due to an excessive rate of myocardial infarction in the surgical group that did not receive aspirin.31 In the Veterans Affairs Cooperative Study of asymptomatic carotid stenosis, the 4-year risk of TIA or stroke for asymptomatic patients with &Mac179;50% carotid stenosis was 37.8% when they did not receive aspirin versus 17.4% when they did receive aspirin (P = .005).32

Antiplatelet drugs, however, appear to be less effective in preventing recurrent strokes in symptomatic patients. In the NASCET study, symptomatic patients with >70% stenosis received 1,300 mg of aspirin a day, yet they experienced a 26% incidence of stroke at 2 years.33 In the European Carotid Surgery Trial (ECST), patients receiving aspirin had a >5% annual risk for a major ipsilateral stroke.34

Much fewer data are available about the role of anticoagulants. A meta-analysis of 16 randomized trials of anticoagulation after cerebral ischemia or infarction showed no benefit.35 The SPIRIT study randomized 243 patients with TIA or stroke of noncardiac origin to aspirin (30 mg) versus warfarin and found a higher incidence of death, stroke, myocardial infarction, and major bleeding in the warfarin group as compared to the aspirin group.36 Anticoagulation is not recommended in the management of carotid artery disease at this time.37

Lipid-Lowering Agents. HMG-CoA reductase inhibitors (statins) have been shown to be effective in stroke prevention.11,38,39 Statins have also been shown to reduce plaque progress

ion as measured by the carotid intimal medial thickness using serial ultrasound measurements.40
Three meta-analyses have focused on the effect of cholesterol reduction with the use of statins on stroke risk.11,39,41 In one meta-analysis, patients had a 29% reduction in the risk of stroke and a 22% reduction in the risk of total mortality.39

The other two meta-analyses showed similar dramatic reductions in the risk of fatal and nonfatal stroke.11,41 Importantly, fibrates, resins, and dietary modification did not reduce the incidence of stroke.11

Although carotid angioplasty was first proposed in the late 1970s, concern about embolization prevented significant development of this technique. Marks and Mathias published the first reports of the use of stents in treating carotid artery dissection in 1994.42,43 Subsequently, several observational studies have been published that describe the use of carotid stenting, particularly in high-surgical-risk patients (Table 1).44-52 The technical success rate in all of these studies was quite high (>99% in most series). These initial studies were all performed without embolic protection, and the stroke rates were quite variable due to varying definitions; they were surprisingly low given the early stage of the technology. Restenosis did not appear to be a major problem, at less than <5% in most series.53 Balloon-expandable stents were found to be problematic due to the risk of compression and are no longer used.

Embolic Protection Devices
Clearly, the major limitation of carotid stenting has been the unpredictable risk of embolization. We used transcranial Doppler in our initial cases to better understand the timing and risk of embolization. We found that embolization occurs during all carotid stent procedures and most typically occurs during stent placement and dilatation of the stent. Other studies have shown that embolization is quite frequent during carotid endarterectomy once patients are monitored by transcranial Doppler.54,55 A variety of embolic protection devices have been developed (Figure 1; Table 2)56,57 and they can be broadly classified into two types—occlusive and filter.

The most widely used occlusive device has been the PercuSurge Wire (Medtronic, Inc., Santa Rosa, CA), which has an occlusive balloon at the tip. Henry et al58 have reported a substantial reduction in neurological complications from 5.2% to 1.5% with the use of this device. The prototype filter device (AngioGuard; Cordis Corporation, a Johnson & Johnson company, Miami, FL) has been evaluated in the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial. In addition, the AngioGuard has been used in vein graft interventions in the Saphenous Vein Graft Intervention using AngioGuard in Reduction of Distal Embolization (GUARD) trial. The final results of both of these studies should be available this year.56

Symptomatic Disease
There have been three significant randomized trials comparing carotid endarterectomy in patients with symptomatic carotid disease to medical management. The European Carotid Surgery Trial (ECST) randomized patients who had symptoms within the previous 6 months, and found a 30-day perioperative stroke and death rate of 7%.34 In patients who had severe (&Mac179;70%) stenosis, surgery showed a substantial reduction in the risk of death or stroke at 3 years (12.3% vs 21.9%; P <.01).59 Patients with mild and moderate stenosis did not show benefit with surgery. The NASCET study found benefit from surgery in 662 patients with 70% to 99% stenosis. The perioperative 30-day risk of stroke or death was 5.8%. At 24 months, the risk for ipsilateral stroke was 9% in patients with endarterectomy versus 26% in patients treated with medical management. Ipsilateral stroke was found in patients with the most severe carotid disease, with absolute reductions of 26% in the 90% to 99% stenosis group, 18% in the 80% to 89% group, and 12% in the 70% to 79% group. In patients with 50% to 69% stenosis, there was a 6.5% reduction in the primary endpoint of ipsilateral stroke at 5 years of follow-up (15.7% vs 22.2%; P = .045) in the surgical group.60 A group with less than 50% stenosis did not have a significant reduction in the risk of stroke with surgery.

The Veterans Affairs Cooperative Studies Program Trialist Group study randomized 189 men to medical therapy or carotid endarterectomy.61 Patients had to have >50% stenosis and had to have neurologic symptoms. At 12 months of follow-up, significant reduction and the combined endpoint of stroke or TIAs was found in the endarterectomy group versus the medical group (7.7% vs 19.4%; P = .011). The complication rate for stroke and death was 6.6%.

Asymptomatic Disease
It has been more challenging to establish the value of carotid endarterectomy in asymptomatic carotid disease. The Asymptomatic Carotid Atherosclerosis Study (ACAS) trial randomized 1,659 patients with asymptomatic carotid stenosis of &Mac179;60% on the basis of ultrasound.30 The perioperative stroke and death rate was only 2.3%. The aggregate risk at 5 years for ipsilateral stroke and death was estimated to be 5.1% for the surgical group and 11% for the patients treated medically (P = .004). The remarkably low surgical complication rate was obtained by careful screening of the participating centers and has created questions about the ability to apply the results of this trial to the community setting.62,63

The Veterans Affairs Asymptomatic Carotid Stenosis study randomized 444 patients with &Mac179;50% asymptomatic stenosis.29 At approximately 4 years of follow-up, there was a reduction in the combined incidence of ipsilateral neurologic events, including TIAs (8% for the surgical group, 20.6% for the medical group; P = .001). However, the reduction in the incidence of stroke alone did not reach statistical significance (4.7% in the surgical group, 9.4% in the medical group).

The operation versus aspirin (CASANOVA) trial randomized asymptomatic patients with 50% to 99% stenosis.64 Because this trial had a complex design with many crossovers from medical to surgical therapy and exclusion of patients with &Mac179;90% stenosis, the results were difficult to interpret. No significant difference was found between the medical and surgical groups for stroke or death.65

Carotid Angioplasty and Stenting versus Carotid Endarterectomy
One substantial randomized trial has been reported—the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) comparing surgery to angioplasty.66 Five hundred four symptomatic patients with >70% stenosis were randomized to endarterectomy or best medical treatment. Only 25% of the patients received stents. Embolic protection devices were not used. At 30 days, the periprocedural event rates were identical (10% for death or any stroke in both groups). The secondary events were high for the surgical group, with a higher incidence of cranial nerve palsy and major hematoma. There was no difference in ipsilateral stroke or death and disabling stroke after 3 years between the two arms of the study.

The first randomized trial using current embolic protection device and stenting technology versus endarterectomy was the Stenting and Angioplasty in Patients at High Risk for Endarterectomy (SAPPHIRE) trial.67 This study randomized patients for increased risk of endarterectomy due to comorbid medical conditions such as congestive heart failure or previous carotid endarterectomy, to surgery versus carotid stenting. Patients who were symptomatic had to have &Mac179;50% stenosis, as determined by ultrasound, and patients who were asymptomatic had to have &Mac179;80% stenosis, as determined by ultrasound. All patients were seen by a team comprising a neurologist, a surgeon, and an interventionist, and a consensus was required for entering the trial and randomization. If a patient was believed to be unsuitable for surgery by the local surgeon, the patient was entered into the stent registry. If the interventionist did not believe the patient could be treated, the patient was entered into a surgical registry. Three hundred seven patients were randomized; 409 patients were entered in the stent registry and seven patients were entered into the surgical registry. Final 1-year data will be available this year.

Another major randomized study is the Carotid Revascularization Endarterectomy versus Stent Trial (CREST), which is randomizing patients at low surgical risk to stenting versus surgery. It utilizes the ACCULINK carotid stent and the ACCUNET embolic protection device (Guidant, Indianapolis, IN). This trial will enroll 2,500 patients and is not expected to finish for several more years.

Stroke remains the major preventable cause of morbidity and mortality in the US. Coronary disease and carotid disease share risk factors, and carotid stenosis is frequently encountered in cardiac patients. Carotid endarterectomy has been the gold standard for treating carotid disease, but recent data suggest that carotid stenting with embolic protection is a viable alternate, at least in high-risk patients and potentially also in the lower-risk patient population.

Jay S. Yadav, MD, is Director of Vascular Intervention in the Department of Cardiology at the Cleveland Clinic Foundation in Cleveland, Ohio. He is a consultant to Cordis and Guidant, and is inventor of the AngioGuard. Dr. Yadav may be reached at (216) 444-6160; yadavj@ccf.org.

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