Carotid Occlusive Disease

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CHAPTER 349 Carotid Occlusive Disease

Natural History and Medical Management

Christopher M. Loftus, Robert E. Harbaugh

Stroke is a leading cause of death and disability. It is estimated that about 600,000 people suffer a new or recurrent stroke each year in the United States. Strokes killed an estimated 160,000 people in the United States in 1996 and rank behind only heart disease and cancer as the third leading cause of death.¹ Ischemic stroke accounts for about 80% to 85% of all strokes.² Although the causes of ischemic stroke may vary with the demographic characteristics of the patient population, the most common causes are large artery atherosclerotic disease and cardioembolic and small vessel or penetrating artery disease. Certainly, carotid artery occlusive disease or extracranial carotid disease is an important risk factor for and cause of stroke. This chapter focuses on the natural history and medical management of carotid atherosclerotic disease.

Pathologic Mechanisms of Atherosclerosis

The word carotid, derived from the Greek word karos, means deep sleep. Hippocrates, around 400 BC, was one of the first to describe the symptoms of stroke.³ Chiari is credited as being the first to propose that occlusive disease of the extracranial blood vessels could be responsible for neurological symptoms. In 1905, in a series of 400 autopsies, Chiari found seven patients who had thrombus superimposed on atherosclerosis near the carotid bifurcation. Four of these patients had suffered a cerebral embolism, and he presumed the source was the extracranial carotid artery.⁴ In 1927, Egas Moniz described the first successful cerebral angiogram.³ Initially, this technique was used predominantly to visualize the intracranial cerebral circulation; however, it represented an opportunity to visualize the carotid artery before direct visualization at surgery. Published in 1951, C. Miller Fisher’s article, Occlusion of the Internal Carotid Artery, is unquestionably the landmark publication describing the relationship between carotid artery disease and transient ischemic attacks (TIAs) and stroke. Fisher described the clinical history, available premortem studies, and available postmortem examinations of the carotid arteries in eight patients with stroke.⁵ Interestingly, the clinical descriptions of previous symptoms included several patients with transient monocular blindness ipsilateral to the diseased carotid artery. Fisher later reported the clinicopathologic results of 45 more patients with occlusion or near occlusion of the carotid arteries.⁶

The pathology of the atherosclerotic plaque is quite complex. Essentially, however, it represents a disease of the arterial intima that, in subsequent stages, progresses to luminal narrowing. Over the years, various theories regarding the genesis and growth of atherosclerotic lesions have been promoted, usually concentrating on endothelial injury, smooth muscle cell proliferation, lipid accumulation, and more recently, inflammatory cells.^7,⁸

Infectious agents such as Chlamydia pneumonia and cytomegalovirus have been associated with carotid atherosclerosis. Evidence of C. pneumonia organisms has been found in atherosclerotic plaques removed at the time of carotid endarterectomy by both reverse-transcriptase polymerase chain reaction and immunohistochemical techniques.^9,¹⁰ A population-based cohort study showed a graded relation between the odds of intimal-medial carotid artery thickening measured by carotid ultrasonography and the levels of cytomegalovirus antibody titers in sera.¹¹ Whether these agents cause carotid atherosclerosis, contribute to its progression, or simply represent a superimposed infection remains to be studied.

A combination of these elements causes the development of significant plaque. Atherosclerosis is likely initiated by injury to or dysfunction of the endothelium.

The reactive endothelium allows the inward migration of mononuclear cells and lymphocytes and stimulates medial smooth muscle cells to migrate and proliferate. Lipids are deposited or taken up by monocytes or macrophages through lipoproteins, most notably low-density lipoproteins (LDLs). Lipid-laden macrophages, or foam cells, continue to accumulate, as do various connective tissue elements and smooth muscle cells.

Inflammatory cells also likely play a role in the progression of atherosclerotic plaque. Oxidative stress and free radical production also play a role in the pathogenesis of atherosclerosis. As the various elements accumulate, the lesion grows, and the diameter of the vessel narrows. Eventually, a complicated lesion with a fibrous cap overlying a core of lipid and necrotic tissue is formed. Certainly, the atherosclerotic plaque is a complex environment of cells, connective tissue elements, lipids, cytokines, growth factors, and calcium. The plaque may fissure, ulcerate, or rupture, exposing thrombogenic nonendothelial cells and substances. The adherence of platelets and the formation of fibrin clot are precursors for further narrowing or occlusion of the artery and distal embolization.

Typically, the mechanism of ischemic stroke in atherosclerosis of the proximal internal carotid artery (ICA) is attributed to either “hemodynamically consequential” narrowing of the vessel lumen, proximal carotid artery–to–distal vessel embolus, or thrombosis of the proximal vessel leading to perhaps both hemodynamic compromise and potential artery-to-artery embolization. Blood flow in a larger artery like the ICA remains fairly constant until its internal diameter is reduced to about 70% of its normal diameter.¹² Further diminution in blood flow follows higher levels of stenosis. Some authors, however, argue that true cerebral hemodynamics cannot be assumed on the basis of the degree of carotid stenosis and that other factors, especially the adequacy of collateral circulation, play important roles.^13,¹⁴

Carotid atherosclerosis develops in regions of low wall shear stress. Symptomatic carotid artery plaque involves primarily the carotid artery bulb. Plaque morphology and, specifically, plaque ulceration may also play a role in the risk for stroke. Ulcerated, echolucent, and heterogenous plaque with a soft core may be unstable with a high risk for arterioarterial embolization.¹⁵ Cranial computed tomography (CT) of patients with carotid artery plaque shows a sixfold increase in the frequency of cerebral infarction in patients with echolucent carotid artery plaque compared with patients with echogenic carotid artery lesions.¹⁶ However, it is quite difficult to determine the exact risk associated with ulcerations given the various radiographic modalities used to image the carotid artery, the various definitions for the severity of ulcerations, and the various degrees of stenosis that accompany ulcerations.¹⁷ In an analysis of patients with severe carotid stenosis (70% to 99%) in the North American Symptomatic Carotid Endarterectomy Trial (NASCET), the presence of angiographically defined ulceration for medically treated patients was associated with an increased risk for stroke.¹⁸

Clinical Manifestations of Atherosclerosis

Recognition of the symptoms and signs of TIAs or strokes related to carotid artery atherosclerotic disease is important in evaluating patients (Table 349-1). About 10% to 15% of those who experience a stroke have a history of preceding TIAs. Among patients with a TIA who survive 5 years, a third will experience a stroke. Estimates indicate that the risk for stroke after a TIA is about 5% during the first month after the event and 12% during the first year.¹⁹ Patients with hemispheric TIAs have a greater risk for ipsilateral stroke than patients with retinal TIAs.²⁰ The ICA and its branches supply blood to the eye and the largest portions of the cerebral hemispheres. Therefore, it is almost impossible to describe one or a few sets of syndromes related to cerebral ischemia in its territory. The type and severity of symptoms depend on the location of the occlusion, the amount of brain or retinal tissue affected, and the availability of collateral circulation. The important clinical features of lesions of the carotid artery or its branches, including the ophthalmic artery, middle cerebral artery (MCA), anterior cerebral artery (ACA), anterior choroidal artery, and sometimes the posterior cerebral artery (PCA), are summarized.

TABLE 349-1 Symptoms of Carotid Artery Territory Transient Ischemic Attacks

Ipsilateral monocular blindness (amaurosis fugax)

Contralateral weakness, clumsiness, or paralysis

Contralateral numbness, paresthesias, including loss of sensation

Dysphasia

Dysarthria

Contralateral homonymous hemianopia

Combinations of the above

The only feature that truly differentiates the ICA syndrome from the MCA syndrome is transient monocular blindness or amaurosis fugax. Patients describe the abrupt and painless onset of a visual disturbance in one eye, usually lasting 1 to 30 minutes. The classic description is one of a shade being pulled down over the eye, but it occurs only in a minority of patients. Blackout, graying, dimming of vision, or even a general constriction of the visual field in one eye can be described. Marginal perfusion causing diminished retinal blood flow or microemboli to the retinal circulation are the causes. Different types of microemboli may be seen on funduscopic evaluation of the retinal vessels, including bright plaques (Hollenhorst), so-called white plugs, or calcium. Hollenhorst plaques are composed of cholesterol crystals, whereas “white plugs” typically consist of platelets and fibrin.²¹

The MCA is the most common site of ischemic stroke. The manifestations of an infarction in its territory can be extremely varied, depending on the site of occlusion. Contralateral weakness and sensory loss can occur. Often, the face and arm are more severely affected than the leg. Various types of aphasia are associated with lesions in the dominant hemisphere; hemineglect and apractic syndromes are associated with damage to the nondominant hemisphere. Contralateral visual field deficits can occur, and paresis and apraxia of conjugate gaze to the opposite side are occasionally noted. Infarctions of the ACA typically lead to contralateral leg weakness more so than weakness of the arm. Various cognitive or psychiatric disturbances have also been associated with unilateral or bilateral medial frontal lobe infarctions.

Anterior choroidal artery infarctions typically result in contralateral hemiparesis caused by involvement of the posterior limb of the internal capsule, hemisensory loss caused by involvement of the posterolateral thalamus or its connections, and hemianopia related to involvement of the lateral geniculate body or its connections in the visual pathways. The classic deficit in PCA infarctions is contralateral visual field disturbances. Other symptoms and signs may occur, depending on site of occlusion and the extent of the cerebral hemisphere supplied by the PCA.

Natural History of Extracranial Carotid Disease

As a prelude to discussing the medical management of extracranial carotid disease, knowledge of its prevalence, the importance of detecting carotid bruits, and its natural history can provide a helpful perspective. Some insight into the history of proposed treatments for extracranial carotid disease is necessary as a background to a discussion of the natural history. Armed with the thought that extracranial carotid artery disease might be a mechanism for stroke, surgeons began using carotid endarterectomy in the 1950s as a way to remove offending plaque, hoping to prevent strokes. In the 1970s, platelet antiaggregating agents such as aspirin were found to help prevent strokes. Several studies on the efficacy of aspirin in preventing stroke excluded patients who were to undergo surgical treatment such as carotid endarterectomy. Adequate prospective randomized controlled studies that compared carotid endarterectomy with “best medical care” did not appear until the 1990s. Also, initial observational studies did not control for the use of platelet antiaggregants or anticoagulants. Therefore, it is difficult to determine the actual natural history of carotid artery occlusive disease using data from these years.

Typically, patients with extracranial carotid disease reach a physician’s attention in one of three ways: (1) an asymptomatic lesion is found on some type of noninvasive screening test, most often carotid ultrasonography; (2) a carotid bruit is auscultated on physical examination; or (3) extracranial carotid disease is found during the evaluation of a patient with a previous stroke or TIA symptoms. In unselected adult populations, the frequency of ICA stenosis of more than 50% on carotid duplex scanning was less than 5% but increased with age.^22,²³ The incidence is higher in patients with coronary artery disease, peripheral vascular disease, and high-risk factors for atherosclerosis.²⁴

The prevalence of asymptomatic carotid artery bruits increases with age and has been assessed in two large population-based studies. In Evans County, Georgia, 4.4% of 1620 asymptomatic individuals at least 45 years of age had a carotid bruit.²⁵ In the Framingham study, 3.5% of asymptomatic people aged 44 to 54 years and 7% of those aged 65 to 79 years had a carotid bruit.²⁶ In both studies, the incidence of TIAs and strokes was higher in individuals with carotid bruits than in those without bruits, but the correlation between the location of the bruit and the location and proposed etiology of the cerebral ischemia was poor. In two studies that correlated cerebral angiographic findings and carotid bruits, the predictive value of carotid bruit for ipsilateral extracranial carotid atherosclerosis was about 75%,²⁷ and the false-positive rate was 10%.²⁸ In the Asymptomatic Carotid Artery Study (ACAS), only about 10% of the randomized patients had an ipsilateral carotid bruit.²⁹ Auscultation of the carotid artery is useful and easy to accomplish at the bedside. Some patients, however, have no carotid bruit but have significant extracranial carotid disease, and not all patients with a carotid bruit have significant extracranial carotid disease.

The risk for stroke depends on the degree of carotid artery stenosis. Asymptomatic carotid artery stenosis of less than 75% carries an annual stroke risk of about 1%. When the stenosis is greater than 75%, the combined 1-year risk for TIA or stroke is about 10%. Most events are ipsilateral to the stenosed artery. The natural history of asymptomatic carotid artery occlusive disease was reported in studies from the 1980s. In a retrospective study of 640 neurologically asymptomatic patients with either pressure-significant ICA lesions determined by oculoplethysmography or carotid bruits without pressure-significant lesions, the annual stroke rates were 3.4% and 1.5%, respectively. However, only 56% of the strokes and TIAs occurred in a distribution ipsilateral to the oculoplethysmographic abnormality.³⁰ In a prospective study of 339 patients using serial Doppler examinations with a median follow-up of 29 months, the number of strokes varied with the degree of carotid stenosis. Two percent of those with 50% to 80% carotid stenosis, 8.3% of those with 80% to 99% stenosis, and 12.2% of those with a carotid occlusion had strokes.³¹ Again, not all strokes occurred in the distribution of the abnormal carotid artery. Neither of these studies controlled for the use of platelet antiaggregants, and both excluded patients who had undergone carotid artery surgery.

Two large randomized prospective studies evaluated the effects of carotid endarterectomy in neurologically symptomatic patients, the European Carotid Surgery Trial (ECST) and NASCET. Both studies had patients with some degree of asymptomatic carotid stenosis contralateral to the symptomatic, randomized carotid, and the risk for stroke in the distribution of the asymptomatic artery has been published. ECST found that higher degrees of stenosis tended to have a higher risk for stroke; the 3-year risk for stroke was 1.8% in the 0% to 29% stenosis group, 2.1% in the 30% to 69% stenosis group, and 5.7% in the 70% to 99% stenosis group.³² In NASCET, the risks for stroke over a 4-year period were 4.5%, 8.3%, and 14.5% for stenosis of less than 30%, 30% to 69%, and 70% to 99%, respectively.³³ These numbers should be compared carefully because the degree of carotid stenosis was measured differently in the two trials (50% NASCET stenosis equals 75% ECST stenosis).

Patients with a TIA or minor nondisabling stroke in the distribution of a carotid stenosis appear to have a higher risk for subsequent ipsilateral stroke compared with patients with no neurological symptoms with known carotid stenosis. Data from the control or medically treated arms of NASCET and ECST provided stroke rates ipsilateral to the symptomatic carotid stenosis. In NASCET, the ipsilateral stroke rates were 26%, 22%, and 19% for 70% to 99%, 50% to 69%, and less than 50% stenosis, respectively. The major ipsilateral stroke rates were 13%, 7.2%, and 4.7% for 70% to 99%, 50% to 69%, and less than 50% stenosis, respectively.^34,³⁵ In ECST, the ipsilateral major stroke rates were 17.4%, 10.6%, and 6% for 70% to 99%, 50% to 69%, and less than 50% stenosis, respectively.³⁶ Again, interpretation must be cautious. Not only was the degree of carotid stenosis measured differently in ECST and NASCET, the duration of follow-up also varied. The mean follow-up was about 6 years in ECST, 2 years in the severe stenosis NASCET group, and 5 years in the mild and moderate stenosis NASCET group.

Medical Management of Extracranial Carotid Disease

This discussion of the medical management of carotid occlusive disease concentrates on secondary prevention rather than acute interventions. First, risk factors for stroke and carotid artery occlusive disease are considered, followed by various medical treatments that have been used to prevent complications of carotid artery occlusive disease (i.e., ischemic strokes). The risk factors for ischemic stroke are discussed in general and applied specifically to carotid artery occlusive disease when applicable. Most patients with significant cerebrovascular disease are likely to have other cardiovascular diseases or to be predisposed to develop them. Patients have no control over risk factors such as advancing age, gender, race, and previous TIA or stroke. Certain risk factors, however, are modifiable, and both patients and physicians must be aware of them: arterial hypertension, diabetes mellitus, tobacco smoking, heavy alcohol use, and hyperlipidemia, among others.

Risk Factors

Hypertension is the most prevalent and modifiable risk factor for stroke.³⁷ Its treatment substantially reduces the risk for stroke. Several prospective randomized controlled trials indicate that a 5 to 6 mm Hg decrease in diastolic blood pressure reduces the risk for stroke by 42%.³⁸ The treatment of isolated systolic hypertension in the elderly decreases the risk for stroke by 36%.³⁹ In this population of elderly patients, isolated systolic hypertension greater than 160 mm Hg strongly correlated with carotid stenosis, as measured by carotid ultrasonography.⁴⁰ In general, recommendations state that systolic blood pressure (BP) should be less than 140 mm Hg, and diastolic BP should be less than 90 mm Hg. In patients with heart failure, renal insufficiency, diabetes, or other evidence of target organ damage or clinical cardiovascular disease (including stroke or TIA), drug therapy combined with lifestyle modifications should be considered when BP is high-normal (systolic BP, 130 to 139 mm Hg or diastolic BP, 85 to 89 mm Hg).^41,⁴²

Diabetes mellitus, a well-established risk factor for stroke, may increase the risk for stroke by several mechanisms: acceleration of large artery atherosclerosis, adverse effects on plasma lipoprotein levels, and promotion of plaque formation through hyperinsulinemia. Although it has been difficult to show conclusively that tight control of serum glucose levels reduces the risk for stroke, it does reduce some of the other microvascular complications of diabetes.^37,⁴³ Controlling elevated blood sugars, perhaps at less than 126 mg/dL,⁴¹ is desirable.

Heavy alcohol consumption appears to be a risk factor for ischemic stroke.⁴⁴ However, light or moderate alcohol use may exert a protective effect.⁴⁵ This J-shaped curve also appears to hold true for early carotid atherogenesis. Light drinkers face a lower risk for incident carotid atherosclerosis detected by carotid ultrasonography than heavy drinkers or those abstaining from alcohol.⁴⁶

Cigarette smoking is another ischemic stroke risk factor. Smokers have an approximate risk of 1.5.⁴⁷ The impact of cigarette smoking on the risk for stroke also applies to young adults (between 15 and 45 years old).⁴⁸ It also appears that smoking is an independent determinant of severe carotid artery stenosis in patients with previous strokes.⁴⁹ Therefore, all patients should be encouraged to quit smoking.

The relationship of hypercholesterolemia to stroke has been controversial, mainly because the outcomes of lipid-lowering regimens in preventing strokes have been inconsistent.⁵⁰ However, recent, large-scale, randomized, double-blind, placebo-controlled trials have shown that the hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, or statins, can lower rates of myocardial infarction and fatal coronary events in patients with a history of coronary artery disease and various levels of total cholesterol and LDL cholesterol.⁵¹^–⁵³ Two of these studies specified stroke as a secondary end point, and it appears that these medications lower the risk for stroke in these patients with coronary artery disease by 19% to 32%.^53,⁵⁴ Two meta-analyses of the data from reported clinical trials on the effectiveness of HMG CoA reductase inhibitors in patients with coronary artery disease also showed a 27% to 32% reduction in stroke rate.^55,⁵⁶ Several studies have shown that lovastatin or pravastatin reduce the development or progression of carotid atherosclerosis as measured by the thickness of the vessel intima-media complex on carotid ultrasonography.⁵⁷^–⁶¹ We await the results of trials evaluating the effectiveness of these medications in lowering cholesterol and in preventing strokes in patients with primary cerebrovascular disease. At this time, we recommend following the guidelines on the detection, evaluation, and treatment of high blood cholesterol published by the National Cholesterol Education Program.⁶²

Homocysteine (specifically, hyperhomocystinemia) is a risk factor for atherosclerosis and endothelial dysfunction and, therefore, likely for stroke as well. Proposed mechanisms for its proatherogenic effects are endothelial cell injury, increased platelet aggregation, enhancement of a prothrombotic environment, and smooth muscle cell proliferation.^63,⁶⁴ A case-control study in a group of British men aged 40 to 59 years showed that hyperhomocystinemia was a strong risk factor for stroke even after adjusting for multiple other risk factors.⁶⁵ A graded increase in the number of strokes was noted as homocysteine levels increased. Elderly subjects with an elevated homocysteine level also appear to be at higher risk for cardiovascular disease, including strokes.⁶⁶ Plasma homocysteine concentrations and extracranial carotid artery disease appear to be associated.^67,⁶⁸ In a cohort of patients from the Framingham Heart Study, the odds ratio of a carotid stenosis greater than or equal to 25% was 2.0 for subjects with the highest plasma homocysteine concentrations compared with those with the lowest concentrations.⁶⁷ Treatment with vitamins, specifically B₁₂, B₆, and folate, may lower plasma homocysteine concentrations, but their effectiveness in preventing stroke has not yet been determined. Ongoing trials of vitamins in preventing strokes are underway and should help answer that question.

Platelet Antiaggregant Therapy

This discussion of the medical management of carotid artery occlusive disease focuses on platelet antiaggregating drugs, which are mainstays in the prevention of stroke in arterial atherothromboembolic disease. Aspirin works by irreversibly inhibiting platelet cyclooxygenase, which prevents the formation of thromboxane A₂, a potent vasoconstrictor and inducer of platelet aggregation. In healthy individuals, a single aspirin results in a 98% inhibition of thromboxane A₂ production within 1 hour of ingestion. Several large, randomized controlled clinical trials have found aspirin to be beneficial in the secondary prevention of cardiovascular events and death.⁶⁹ An overview of randomized trials of platelet antiaggregant therapy in patients with a history of TIA or stroke showed about a 25% reduction in the risk for nonfatal stroke, nonfatal myocardial infarction, and death from vascular causes.⁷⁰ This risk reduction was independent of age, gender, and other risk factors.

Another advantage of aspirin is its effect on reducing cardiovascular deaths, a helpful feature for patients with carotid disease given their frequent combination of carotid and coronary atherosclerosis. Aspirin also helps reduce mortality rates after carotid endarterectomy.⁷¹ In a retrospective analysis of the medically treated patients from the Veterans Administration Cooperative Study on Asymptomatic Stenosis, patients not taking aspirin had a higher incidence of stroke and death than those taking aspirin. This finding provides some indirect evidence that aspirin may be useful in asymptomatic patients with significant carotid stenosis.⁷² Higher doses of aspirin slowed the growth of carotid plaque in 27 patients, although this finding has not been duplicated in larger patient populations.⁷³

The appropriate dose of aspirin in preventing stroke remains controversial. Studies showing its effectiveness in the secondary prevention of stroke have used doses ranging from 30 to 1500 mg/day. Some authors have advocated higher doses of aspirin, given that these doses may have useful effects unrelated to cyclooxygenase inhibition.⁷⁴ In the Aspirin in Carotid Endarterectomy (ACE) trial, 2804 patients who had a carotid endarterectomy were randomly assigned to compare the benefits of low-dose aspirin (81 to 325 mg/day) with high-dose aspirin (650 to 1300 mg/day). The primary end points in the ACE trial were stroke, myocardial infarction, and death. Three months after surgery, the risk for stroke, myocardial infarction, or death was 6.2% in the low-dose aspirin group compared with 8.4% in the high-dose aspirin group. The difference was less apparent when only stroke or death was evaluated as the end point.⁷⁵ Recently, the U.S. Food and Drug Administration recommended a dose of 50 to 325 mg/day of aspirin.⁷⁶

Ticlopidine is a platelet antiaggregant agent that works by inhibiting the adenosine phosphate pathway of platelet aggregation. Although it has not been studied specifically in patients with carotid atherosclerosis, it has been shown to reduce the risk for stroke, myocardial infarction, or vascular death in patients with recent noncardioembolic stroke.⁷⁷ Ticlopidine reduces the relative risk for death or nonfatal stroke by 12% compared with aspirin.⁷⁸ The recommended dose of ticlopidine is 250 mg twice daily. Ticlopidine has more side effects than aspirin, including diarrhea, nausea, dyspepsia, and rash. Its use, however, has been limited by significant hematologic side effects, including a reversible neutropenia and thrombotic thrombocytopenic purpura. The drug must be discontinued if the neutrophil count falls below 1200/mm³.

Clopidogrel is also a platelet adenosine diphosphate receptor antagonist. In a study enrolling more than 19,185 patients with atherosclerotic vascular disease, which manifested as either recent ischemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease, clopidogrel (75 mg/day) was more effective than 325 mg of aspirin in reducing the combined risk for ischemic stroke, myocardial infarction, or vascular death.⁷⁹ After almost 2 years of follow-up, the absolute risk reduction was modest (annual risk of end points in clopidogrel-treated patients 5.32% versus 5.83% in aspirin-treated patients) although statistically significant. In the group of more than 6400 patients who entered the study with a stroke, there was a nonsignificant relative risk reduction of 7.3% in favor of clopidogrel. Most of these patients developed a recurrent stroke as their first outcome measure. The side-effect profile of clopidogrel is relatively benign. There is no increased incidence of neutropenia, and the incidence of gastrointestinal hemorrhage and gastric or duodenal ulcers is lower compared with that of aspirin. Its use has not been tested specifically in patients who have carotid artery occlusive disease only.

Dipyridamole is a phosphodiesterase inhibitor that increases the levels of cyclic adenosine monophosphate (cAMP). Previous studies failed to demonstrate the benefit of adding dipyridamole to aspirin. A large, randomized placebo-controlled double-blind trial, however, was published in 1996. This European Stroke Prevention Study-2 (ESPS-2) randomized patients with prior TIA or stroke to treatment with aspirin alone (25 mg twice daily), modified-release dipyridamole (200 mg twice daily), the two agents in combination, or a placebo. The ESPS-2 investigators reported an additive effect of dipyridamole when it was coprescribed with aspirin. The stroke rate decreased in the combined treatment arm compared with either agent alone. Both low-dose aspirin and high-dose dipyridamole in a modified release form alone were associated with better outcomes than the placebo.⁸⁰ The main side effects of dipyridamole are gastrointestinal distress and headaches.

Platelet glycoprotein IIb-IIIa receptor inhibitors have been evaluated in cardiovascular disease, but their benefit in preventing ischemic stroke awaits randomized studies. Combinations of platelet antiaggregant therapy (aspirin + ticlopidine or aspirin + clopidogrel) are also used by clinicians, but no data have demonstrated their benefit over single agents alone in preventing ischemic stroke in general or carotid artery occlusive disease specifically.

Warfarin has also been used in the primary and secondary prevention of stroke in patients with nonvalvular atrial fibrillation. Warfarin is unequivocally effective in reducing the recurrence of stroke in patients with selective cardiac sources of emboli, especially nonvalvular atrial fibrillation. However, its relative efficacy compared with antiplatelet therapy in patients with atherothrombotic TIA or stroke has not been studied adequately. Many clinicians use warfarin to treat patients with high-grade intracranial stenosis and severe ICA stenosis, but randomized clinical data are not available to support its use. Trials comparing warfarin to aspirin in the secondary prevention of noncardioembolic stroke are ongoing. When available, these data, including subgroup analysis, may help define the usefulness of warfarin in treating carotid artery occlusive disease.

Surgical and catheter-based procedures such as angioplasty and stenting are also used to treat carotid artery occlusive disease. Numerous well-designed studies defining the effectiveness of carotid endarterectomy in preventing strokes in both neurologically symptomatic and asymptomatic patients have been published since 1990,^29,³⁴^–³⁶ ^,81 ^,82 and carotid endarterectomy (CEA) is well established as the standard treatment for severe symptomatic internal carotid artery stenosis. Carotid angioplasty and stenting (CAS) has also been advocated for stroke prevention in patients with atherosclerotic carotid artery disease,⁸³ particularly in patients who are deemed to be at high risk for complications with CEA. The role of CAS in the treatment of patients with carotid artery disease remains controversial.

A review ⁸⁴ of randomized trials comparing CAS and CEA^83,⁸⁵^–⁸⁹ did not support CAS as a preferable treatment to CEA for carotid artery stenosis. In addition, a recent randomized trial of CEA versus CAS was stopped when the data monitoring committee recommended discontinuing enrollment in the trial because of statistically superior results with CEA.⁹⁰ Patients in this trial were eligible if they had a symptomatic stenosis of 60% to 99% as determined by the NASCET method. The severity of stenosis was confirmed by catheter angiography or a combination of duplex scanning and magnetic resonance angiography. Patients who were suitable candidates for either CEA or CAS were randomly assigned to treatment. CEA was carried out according to the usual practice of the operating surgeons. CAS was done through the femoral artery using approved distal protection devices. Patients were treated with aspirin (100 to 300 mg) and clopidogrel (75 mg) or ticlopidine (500 mg) for 3 days before and 30 days after CAS. Study neurologists performed follow-up evaluations 48 hours, 30 days and 6 months after treatment and at 6-month intervals thereafter. The primary end point was a composite of any stroke or death occurring within 30 days of treatment. Secondary outcomes included myocardial infarction, transient ischemic attack, cranial nerve injury, major local complications, and systemic complications within 30 days of treatment. Five hundred twenty patients were included in the analysis of the 30-day risk for stroke or death. The CEA and CAS groups were similar with respect to baseline characteristics, except for a greater proportion of patients older than 74 years of age and more patients with a history of stroke in the CEA group and a higher proportion of contralateral carotid occlusion in the CAS group.

In this trial, the 30-day incidence of any stroke or death was 3.9% (95% confidence interval [CI], 2.0 to 7.2) after CEA and 9.6% (95% CI, 6.4 to 14.0) after CAS. The 30-day incidence of disabling stroke or death was 1.5% (95% CI, 0.5 to 4.2) after CEA and 3.4% (95% CI, 1.7 to 6.7) after CAS. There were more cardiopulmonary complications after CEA and more severe local complications after CAS, but these differences did not reach statistical significance. Cranial nerve injury was significantly more common after CEA (7.7% versus 1.1%, P < .001). The results of this trial offer evidence in patients who are candidates for either CEA or CAS that CEA remains the preferred treatment.

Other trials comparing CEA and CAS are in progress.⁹¹^–⁹³ These trials may help clarify the roles of these procedures in the treatment of patients with atherosclerotic carotid artery disease.

At present, there are no data to prove superiority of CAS over CEA in either asymptomatic or symptomatic disease, and there is serious doubt about whether CAS is even an equivalent treatment, except for patients who are simply unable to undergo CEA because of medical comorbidities.