Carotid artery stenoses, both symptomatic and asymptomatic, increase the risk for ischemic cerebrovascular events. The long-standing gold standard for invasive treatment of these lesions has been surgical carotid endarterectomy (CEA). CEA reduces the risk of stroke for both severe asymptomatic carotid stenosis1-4 and moderate or severe symptomatic stenosis5-7 when compared with medical management alone.

Surgery, however, is not without limitations. The risk of stroke associated with CEA ranges from 2.9% to 10.7% in major trials.1-3,5-7 Additionally, the coronary artery disease (CAD) that frequently accompanies carotid atherosclerosis increases the risk of perioperative myocardial infarction (MI), complicating even further the management of these patients. Moreover, several groups of patients have a prohibitively high surgical risk for CEA due to comorbid conditions such as severe coronary atherosclerotic disease, severe left ventricular dysfunction, severe aortic stenosis, a history of head or neck radiation, previous ipsilateral CEA, or contralateral carotid occlusion.

Because of these factors, along with the inherent invasiveness and recovery time associated with surgery, nonsurgical alternatives are an important tool in the management of carotid artery stenosis.

In most individuals, the right common carotid artery (CCA) originates from the innominate (brachiocephalic) artery, which is typically the first branch of aortic arch, and the left CCA arises as the second branch of the arch. There are, however, many anatomic variants. Up to one fourth of patients have a common origin of the left common carotid and innominate arteries, and in one-fifth of patients, the left CCA arises directly from the innominate artery.8 Although historically referred to as bovine arch configurations, these two variants do not actually resemble the arch of cattle.9

Elongation of the aorta with aging, atherosclerosis, and different shapes of the chest cavity all impart tortuosity to arch vessels and alter the relationship of their origins to descending aorta. These changes are important for an interventionalist to recognize because they determine the accessibility of these vessels for percutaneous interventions. Figure 108–1 demonstrates the commonly used anatomic classification of the origins of the great vessels. Aortic arch classification is based on the relationship of the innominate artery to the top of the arch. In the type I arch, all three great vessels originate from the same horizontal plane (Fig. 108–1A); the origin of the innominate artery lies between the horizontal planes of the inner and outer curvature of the aortic arch in the type II arch (Fig. 108–1B); and in the type III arch, the innominate artery arises inferior to the horizontal plane of the inner curvature of the aortic arch (Fig. 108–1C).10

The CCA bifurcates into the internal carotid artery (ICA) and the external carotid artery at the level of the C4 to C5 intervertebral space. The ICA continues superiorly and gives rise to its first major branch, the ophthalmic artery, in the subarachnoid space. It then bifurcates into the anterior and middle cerebral arteries. The ICA is divided into the prepetrous, petrous, cavernous, and supraclinoid segments (Fig. 108–2).

The carotid sinus is located in the ICA just distal to the bifurcation of the CCA and measures approximately 7 mm in diameter in most adults. The sinus contains mechanoreceptors, which are responsible for the carotid sinus reflex.

The external carotid artery has an extensive collateral network; therefore, unilateral stenosis is rarely symptomatic. Severe stenosis or obstruction, however, may cause jaw claudication in patients with concomitant contralateral occlusion.

Epidemiology

Stroke is the third leading cause of death in the United States, causing almost 150,000 deaths in the year 2005. Approximately 800,000 people experience either an initial or recurrent stoke each year. An estimated 50,000 more women than men suffer a stroke annually, and the risk for a first-ever stroke is almost two times greater for blacks. Ischemic strokes, which are closely related to vascular stenosis, account for 87% of all strokes.11 Overall, the estimated prevalence of carotid stenosis is 0.5% at 50 years of age and 10% at 80 years of age.12 In 2009, it is estimated that the costs of diagnosis and treatment for stroke will exceed $68 billion. In addition to the acute clinical and financial consequences, there are significant long-term effects related to stroke. Stroke is the number one cause of long-term disability, with 20% of victims needing institutional care 3 months after the event. Furthermore, nearly a quarter of all stroke patients will die within 1 year following the event, and this number is even higher for those who are above age 65.11

Risk Factors

The atherosclerotic disease responsible for carotid artery stenosis is similar to that in CAD. Atheromatous plaque accumulates most frequently at sites of turbulent flow, such as the bifurcations. Examination of material collected after carotid stenting with distal emboli prevention devices has demonstrated that the microemboli from these lesions contain lipid vacuoles, fibrin, platelets, and foam cells.13 Because the disease processes are very similar, it is not surprising that concomitant CAD is a significant problem for patients with carotid stenosis. However, only 5% to 10% of patients with CAD will also have severe carotid atherosclerosis.14

There are several risk factors for the development of carotid atherosclerosis and its associated clinical sequelae. Stroke rates increase in a stepwise fashion with age. Tobacco use imparts a significant risk of stroke that is correlated to usage. Heavy smokers have twice the relative risk (RR) of stroke compared with light smokers, and the risk of stroke is significantly reduced within 2 years of smoking cessation, with a return to baseline at 5 years.15 Race has also been shown to impart risk. Blacks have twice the age-adjusted risk for stroke compared with non-Hispanic whites, and both male and female blacks are more likely to die secondary to strokes when compared with non-Hispanic whites.16 Hypertension, diabetes, the metabolic syndrome, male sex, and hypercholesterolemia are additional risk factors that have been shown to impart an elevated risk of carotid disease.17-19 Similar to recent work in the coronary realm, inflammation has been shown to be associated with an increased risk of both carotid atherosclerosis and carotid plaque instability.20-22

Natural History

The physical examination hallmark of carotid atherosclerosis is the carotid bruit. Although carotid bruits are poor predictors of the severity of atherosclerosis, they are associated with an increased risk of stroke, MI, and death.15,23 More specifically, once carotid atheromatous lesions have formed, the severity of stenosis and associated symptoms are predictive of the risk of stroke.23 In asymptomatic carotid stenosis of ≥60%, the annual risk of stroke is approximately 2.1%.1 The addition of symptoms such as transient ischemic attack (TIA) significantly increases the risk of stroke in patients with even moderate stenosis, and this risk increases in a stepwise fashion with the severity of stenosis. The risk of stroke following a TIA was 40% in the Framingham Study, and two-thirds of these strokes occurred within the first 6 months.18 The North American Symptomatic Carotid Endarterectomy Trial (NASCET) demonstrated the risk of ipsilateral stroke to be 18.7% over 5 years in medically treated patients with >50% symptomatic stenosis and 22.2% in patients with 50% to 69% symptomatic stenosis.24 There is also a direct correlation between the severity of stenosis and the risk of death. The adjusted RR of death is 1.32 for stenoses <45%, 2.22 for stenoses of 45% to 74%, and 3.24 for stenoses of 75% to 99%.25 Progressive carotid stenoses are more likely to be associated with adverse events.26,27

Clinical Presentation

Carotid bruits can be auscultated over one or both carotid arteries and have a harsh blowing quality associated with them. Evidence of a carotid bruit on physical examination is the most common finding leading to the diagnosis of asymptomatic carotid stenosis. The severity of the bruit, however, has not been shown to be consistently associated with the degree of stenosis, having sensitivity in some series of <30%.28-30

A TIA is the most common presentation of symptomatic carotid stenosis. By definition, a TIA lasts for <24 hours and typically resolves within 30 minutes. Symptoms from a TIA are related to the distribution affected by the area of ischemia. Importantly, TIAs caused by vertebrobasilar insufficiency must be differentiated from those secondary to carotid origin, which can be done with careful history taking and physical examination. Carotid-related symptoms include aphasia and dysarthria. Visual disturbances, such as ipsilateral amaurosis fugax or contralateral homonymous hemianopia, may also be present. Sensory and motor deficits are typically contralateral. Conversely, symptoms related to vertebrobasilar insufficiency include transient cranial nerve findings, diplopia, vertigo, and dysarthria. Motor deficits are ipsilateral, and visual losses are frequently bilateral.31

Noninvasive Techniques

Ultrasonography

Stenosis Severity

The standard noninvasive method for the evaluation of carotid artery stenosis is duplex ultrasonography. Several studies have encouraged diagnosis of the severity of carotid artery stenosis based on ultrasound alone, without the need for angiography.32-36 Results concerning the diagnostic accuracy of carotid ultrasound in the centers participating in the NASCET study, however, cast some doubt on the validity of ultrasound by showing that the sensitivity and specificity of carotid ultrasound were 68% and 67%, respectively.37 This poor correlation has been attributed to many factors, including variations in patient selection, imaging device performance, and the imaging protocols used.

Ultrasound evaluation fared better in the Asymptomatic Carotid Atherosclerosis Study (ACAS). In this study, centers had to show evidence of Doppler measurements and carotid arteriography correlation; a standard protocol was adopted, which played a part in the specificity of carotid ultrasound being measured above 95%.38 Corroborating these results, Jahromi and colleagues39 reported a sensitivity of 98% and a specificity of 88% for diagnosing an angiographic stenosis of >50% using ultrasound. Recent data suggest that carotid ultrasound also has a high accuracy for carotid restenosis after endarterectomy.40 Nonetheless, despite the overall high sensitivity and specificity for carotid ultrasound, accuracy varies widely according to laboratory.39 Therefore, properly trained sonographers and a routine quality assurance program are critical to the sensitivity and specificity of results obtained from sonography.

Various criteria have been proposed to diagnose severe carotid stenosis with a high level of accuracy. Different cutoff points for peak systolic and diastolic velocities from the ICA and the ratio of peak systolic velocity from the ICA and CCA have been correlated with severe stenosis.41 Typically, a >80% stenosis correlates with a systolic velocity >300 to 400 cm/s, a diastolic velocity >100 to 135 cm/s, and an ICA/CCA systolic velocity ratio of >4 to 6. Contralateral occlusion, severe left ventricular (LV) dysfunction, aortic stenosis, and common carotid stenosis are some of the variables that make these measurements less reliable and should be factored in when interpreting carotid ultrasound information.

Carotid Intima-Medial Thickness

Carotid intima-medial thickness (CIMT) is a measure of the thickness of the intima and media and provides a measure of subclinical atherosclerosis. As such, it has been associated with an increased risk of MI, stroke, and cardiovascular death.42-46 Furthermore, it is increasingly being used as a trial end point and even as a surrogate marker for clinical events in large studies.47 The use of CIMT in routine clinical practice, however, is still being established. At this time, it is recommended for patients without established atherosclerotic disease and an intermediate probability of cardiovascular events, in whom the use of preventive therapies is unclear and further risk assessment would be beneficial.48

Magnetic Resonance Angiography

Magnetic resonance angiography (MRA) can be performed using two different techniques: time-of-flight (TOF) and contrast-enhanced imaging. TOF imaging is useful in patients with contraindications to the use of gadolinium-based contrast agents. The relative inaccuracy of this method is in large part due to the lengthy time of acquisition (10-15 minutes), which increases the susceptibility to artifacts and flow disturbances. Some investigators have reported sensitivities as high as 90% but specificities as low as 64%.49,50 A study comparing the sensitivity and specificity of noninvasive imaging with angiography on 569 patients demonstrated that noncontrast MRA was associated with a sensitivity of 75% and specificity of 88%.51 However, concordant Doppler ultrasound measurement resulted in an improved sensitivity of 96% and specificity of 85%. Therefore, the authors suggest that surgical decisions should be made cautiously if based solely on the results of individual noninvasive studies.

The advent of three-dimensional contrast-enhanced MRA provided advancement in the noninvasive examination of the aortic arch and carotid arteries. Advantages of gadolinium-enhanced (GE) MRA for carotid angiography include the ability to image plaque ulcerations, which are often not seen on TOF imaging; lack of flow-related artifacts, which can degrade tortuous vessels by in-plane saturation; short imaging times with excellent signal-to-noise ratio; and the ability to image from the aortic arch to circle of Willis in approximately 30 seconds.52-54 The GE MRA technique is limited by interference from contrast in the jugular vein, which may impair visualization of the carotid artery and thereby decrease the sensitivity for measuring stenoses when a long scan time is used. Conversely, using the shorter scan time decreases the spatial resolution.

Multiple investigators have demonstrated sensitivities of 88% to 97% and specificities of 89% to 96% for GE MRA.54 A recently published meta-analysis comparing GE MRA and TOF found better sensitivity (94.6% vs 91.2%) and specificity (91.9% vs 88.3%) for GE MRA in diagnosing severe (>70%) carotid stenosis.55 The accuracy of both techniques was relatively poor in diagnosing moderate (50%-69%) stenosis (sensitivities of 65.9% and 37.9% for GE MRA and TOF MRA, respectively), a finding that has been demonstrated by other investigators.52,56

Ultimately, magnetic resonance imaging (MRI) has established itself as a useful noninvasive imaging tool in the evaluation of carotid stenosis. Improved sensitivity and specificity may be provided by concomitant MRA and Doppler ultrasound examination, possibly reducing the need for invasive angiography.57 Future improvements in MRA technology are also likely to improve its diagnostic capabilities and accuracy.58

Computed Tomography Angiography

First-generation computed tomography (CT) scanners obtained images by rotating the x-ray tube around the patient once, returning the x-ray tube back to the starting position while moving the patient, and starting the process over again.59 These scanners obtained noncontiguous single slices of patients after long scan times. Spiral CT scanners improved imaging by continuously rotating the x-ray tube with the patient moving, allowing contiguous slices to be obtained in less time. Initially, these scanners had single detectors, and only one slice could be captured at a time. The development of multislice detectors (256-slice detectors are currently in use) greatly improved resolution and scan time.

Thus, multislice CT angiography (CTA) matured to become a promising form of noninvasive angiography for numerous vascular beds—coronary, peripheral, and carotid arteries. In one of the first studies evaluating CTA for carotid imaging, Sameshima and colleagues60 examined 128 carotid bifurcations, comparing CTA to Doppler ultrasound and MRA, using conventional angiography as the standard. MRA tended to overestimate stenosis, whereas CTA strongly correlated with conventional angiography (r = 0.987, P < .0001).

A more recently published meta-analysis, however, reported a lower accuracy for CTA.56 In 684 arteries in 362 patients, CTA demonstrated a sensitivity of 77% and specificity of 95% in diagnosing severe carotid stenosis, a finding that is more consistent with other investigators using strict methodologic criteria.61 Calcium blooming artifact is the major limiting factor decreasing the ability of CT scan to measure accurate stenosis severity in calcified lesions. Sensitivity (67%) and specificity (79%) in diagnosing moderate stenosis, similar to both MRA and Doppler ultrasound, were much lower. With the advent of more advanced multislice CT scanners and more ready availability of CTA than MRA, this technique is quickly gaining favor as a noninvasive diagnostic modality.

Invasive Techniques

Angiography

The gold standard for assessing the severity of carotid stenosis severity remains the angiogram. In most situations, digital subtraction angiography is applied when imaging the cervicocerebral circulation. By “subtracting” the bones and soft tissues, the arteries are more clearly visualized. There are several factors that make angiography unique and attractive in its detection of atherosclerotic plaque. It provides high-resolution images of the stenosis and plaque surface and is able to distinguish easily between a high-grade stenosis and occlusion. It allows the simultaneous study of the origin of the neck vessels and intracranial circulation. This is important for the detection of tandem stenoses, which pose diagnostic problems for Doppler ultrasound. The ability to assess collateral circulation as well as the speed of blood flow is quite useful in clinical decision making, particularly in predicting the safety of temporary carotid occlusion associated with either CEA or carotid artery stenting. Additionally, angiography provides information regarding the atherosclerotic lesion and surrounding reference vessel. The risk of transient and permanent neurologic complications with invasive digital subtraction angiography is estimated at 1.3% to 1.8% and 0.5% to 0.6%, respectively.62,63

Therapies with antiplatelet agents, anticoagulant agents, lipid lowering agents, and antihypertensive agents have all been studied for reducing the risk of stroke.

Antiplatelet Agents

Aspirin

The long-standing foundation of antiplatelet therapy in the management of atherosclerotic disease has been aspirin. Aspirin exerts its antiplatelet effect by acetylating platelet cyclooxygenase, thereby irreversibly inhibiting the formation of platelet-dependent thromboxane A2, a potent effector of platelet activation, vasoconstriction, and smooth muscle proliferation. Multiple investigators have demonstrated the efficacy of aspirin in the prevention of stroke.64-66 The Antithrombotic Trialists’ Collaboration documented, in their meta-analysis of >200,000 patients from 287 randomized trials, the powerful effect of antiplatelet agents (primarily aspirin) in the primary and secondary prevention of both fatal and nonfatal strokes.67 Specifically, they noted a 25% reduction in nonfatal stroke and a 30% reduction in fatal or nonfatal ischemic stroke. They also found that low doses of daily aspirin (75-150 mg) were just as effective as higher doses (up to 1500 mg). The authors also comment that daily doses of <75 mg may be as effective as higher doses based on their meta-analysis, but they caution that this has been less widely studied and thus remains uncertain. A subanalysis of small groups of patients in five CEA trials and one asymptomatic carotid disease trial demonstrated a 19% reduction in vascular events, which, although it did not reach statistical significance, demonstrated a consistent trend with that seen in other high-risk patient populations in the overall meta-analysis.

It should be noted that the use of aspirin in low-risk women was called into question by the Women’s Health Study, which noted an increased risk of hemorrhagic stroke.66 In women with documented carotid disease, however, the benefits are likely to outweigh this risk. Therefore, aspirin is recommended for the primary prevention of cardiovascular events in men >45 years old and women >55 years old for whom the benefits are likely to outweigh the risks.68,69 All patients with documented carotid disease, stroke, or TIA should receive aspirin, in the absence of a contraindication, to reduce the risk of stroke and other cardiovascular events.68,70

Thienopyridines

Clopidogrel and ticlopidine are thienopyridines that irreversibly bind the P2Y12 subunit of the adenosine diphosphate (ADP) receptor. This blocks ADP-mediated activation of the glycoprotein IIb/IIIa receptor complex, thereby inhibiting fibrinogen activity and platelet aggregation, as well as the action of other platelet agonists such as thrombin and thromboxane A2.71 The Ticlopidine Aspirin Stroke Study compared the use of ticlopidine and aspirin in patients with a history of TIA, reversible ischemic neurologic deficit, or minor stroke. Ticlopidine significantly reduced the risk of fatal and nonfatal stroke by 24% (P = .011) compared with aspirin. This effect was even greater during the first year, with a 48% reduction in the risk of stroke.72 In The Canadian American Ticlopidine Study, patients with a history of previous atherothrombotic stroke were treated with ticlopidine or placebo for up to 3 years. Ticlopidine significantly reduced the RR of stroke by 24% over 3 years (P = .017).73 However, due to the complications associated with its use, such as neutropenia and thrombotic thrombocytopenic purpura, the use of ticlopidine has been supplanted by clopidogrel.

The Clopidogrel Versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial was a randomized, double-blind trial that compared clopidogrel versus aspirin in patients with a history of recent MI, ischemic stroke, or peripheral vascular disease. Clopidogrel demonstrated an 8.7% RR reduction for the primary outcome of stroke, MI, or vascular death (P = .04). In the subgroup of patients with a history of a previous stroke, there was a trend toward reducing the risk of adverse events with a RR reduction of 7.3% in favor of clopidogrel (P = .26).74

The role of dual antiplatelet therapy (aspirin plus clopidogrel) has been studied by multiple investigators. The Clopidogrel in Unstable Angina to Reduce Ischemic Events (CURE) study included patients with acute coronary syndrome without ST-segment elevation.75 All patients were treated with aspirin and were randomized to receive clopidogrel or placebo for up to 1 year. There was a 20% RR reduction in the occurrence of cardiovascular death, MI, or stroke for the clopidogrel-treated group. Similar to findings in the CAPRIE trial, there was a trend favoring clopidogrel for the reduction of ischemic stroke (1.2% with clopidogrel vs 1.4% with placebo; P = not significant).

The Management of Atherothrombosis With Clopidogrel in High-Risk Patients With Recent Transient Ischaemic Attack or Ischaemic Stroke (MATCH) trial evaluated dual antiplatelet therapy in 7599 patients with recent stroke or TIA.76 All patients received clopidogrel 75 mg daily and were randomized to aspirin (75 mg daily) or placebo. After a follow-up of 18 months, the primary end point, a composite of ischemic stroke, MI, vascular death, or rehospitalization for acute ischemia, was insignificantly lower for the dual therapy group (15.7% vs 16.7%; P = not significant), although life-threatening bleeding was higher (2.6%) than in the clopidogrel-only group (1.3%; P < .0001).

The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) investigators evaluated dual antiplatelet therapy in patients with either clinically overt vascular disease (cardiovascular, cerebrovascular, or peripheral vascular disease) or multiple risk factors.77 In this study, 15,603 patients were randomized to clopidogrel (75 mg daily) plus aspirin (75-162 mg daily) or to aspirin alone. After a median follow-up of 28 months, the primary end point, which was a composite of cardiovascular death, stroke, or MI, did not differ between the aspirin plus clopidogrel group (6.8%) and the aspirin-only group (7.3%; P = .22). The subgroup of patients enrolled with prior stroke similarly did not benefit. As seen in MATCH, the risk of bleeding was significantly increased with dual antiplatelet therapy.

Taken together, studies of clopidogrel in the prevention of stroke have established its efficacy when used as monotherapy as an alternative to aspirin. However, the increased risk of bleeding with dual antiplatelet therapy (aspirin plus clopidogrel) and a lack of consistent benefit in clinical outcomes have resulted in a class III (not recommended) designation for use of the combination in stroke or TIA.70

Dipyridamole

Dipyridamole (DP) is an inhibitor of adenosine deaminase and phosphodiesterase, resulting in the accumulation of adenosine, adenine nucleotides, and cyclic adenosine monophosphate (cAMP), which in turn inhibit platelet aggregation and cause vasodilation. The first major trial of extended-release DP (ER-DP) in the secondary prevention of stroke, the European Stroke Prevention Study 2 (ESPS-2), randomized 6602 patients with previous stroke or TIA to aspirin, ER-DP, aspirin plus ER-DP, or neither.78 Compared with placebo, the risk of stroke was decreased by 18% with aspirin (P = .013); by 16% with DP alone (P = .039); and by 37% with combination therapy (P < .001). The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) study group randomized 2739 patients with recent (<6 months) TIA or minor stroke to aspirin with or without (n = 1376) DP and found a less robust effect from the addition of DP.79 The primary outcome (composite of death from all vascular causes, nonfatal stroke, nonfatal MI, or major bleeding complication) occurred in 13% of patients on combination therapy and 16% of patients on aspirin alone (hazard ratio [HR] = 0.80; 95% confidence interval [CI], 0.66-0.98) over a period of 3.5 years, or a 1% absolute risk reduction annually (95% CI, 0.1-1.8).

A recent meta-analysis by De Schryver and colleagues80 studied the safety and efficacy of ER-DP in 29 trials enrolling a total of 23,019 patients. They found that the addition of ER-DP to aspirin had no significant effect on the rate of vascular death (RR = 0.99; 95% CI, 0.87-1.12) but, in patients with prior ischemic stroke, did provide a reduction in overall vascular events (RR = 0.88; 95% CI, 0.81-0.95). A recent study by the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) study group compared aspirin/ER-DP versus clopidogrel in a group of patients with ischemic stroke. The rate of recurrent stroke was not significantly different (HR = 1.01; 95% CI, 0.92-1.11). Although the rate of major bleeding was higher with the aspirin/ER-DP combination (HR = 1.15; 95% CI, 1.00-1.32), the net risk of recurrent stroke or major bleeding was not significantly different (HR = 1.03; 95% CI, 0.95-1.11)

The use of an aspirin/ER-DP combination is recommended by the American Heart Association/American Stroke Association as an alternative first-line treatment for patients with a history of stroke or TIA.70

Cilostazol

Through the inhibition of phosphodiesterase III, cilostazol decreases the degradation of cAMP, resulting in impaired platelet activation and aggregation.81 There is also the suggestion that cilostazol decreases smooth muscle proliferation, delays the formation of atherosclerosis, and promotes vasodilation.82,83 The Cilostazol Stroke Prevention Study randomized 1062 patients with ischemic stroke (<6 months prior to study) to cilostazol or placebo.84 The active treatment arm experienced a 41.7% reduction in recurrent stroke compared with placebo (P = .015). Although this was a significant reduction, the comparison to placebo makes the results less applicable to clinical practice.

More recently, Huang and colleagues85 performed a pilot study on 720 patients with recent (<6 months) ischemic stroke randomized to aspirin or cilostazol. There was no difference between the treatment groups in the incidence of the primary end point of recurrent stroke (HR = 0.62; 95% CI, 0.30-1.26; P = .185). Of note, the incidence of cerebral hemorrhage was significant less in patients taking cilostazol (seven events vs one event; P = .034). Unfortunately, the study findings are limited by a low number of clinical events and short follow-up.83

Ultimately, these trials raise the possibility that cilostazol is at least as effective as aspirin and possibly safer. However, larger phase III trials will be necessary before definitively establishing a role for cilostazol in the secondary prevention of stroke.

Anticoagulants

Although there is evidence that warfarin reduces the risk of stroke in specific subsets of patients, such as those with atrial fibrillation, there is no convincing evidence that it is superior to aspirin in patients with a history of ischemic stroke from a noncardioembolic source.86 The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) evaluated the use of warfarin (with a target international normalized ratio [INR] of 3.0-4.5) compared with aspirin for the prevention of adverse events in patients with a history of noncardioembolic TIA or stroke.87 Warfarin was associated with twice the risk of vascular death, stroke, MI, or major bleeding complications compared with aspirin (12.4% vs 5.4%; P < .05). This poor outcome was mainly attributable to excess bleeding complications, including 27 intracranial bleeds associated with warfarin.

The Warfarin Aspirin Recurrent Stroke Study (WARSS) compared warfarin (with a lower target INR of 1.4-2.8) with aspirin in 2206 patients with a history of ischemic, noncardioembolic stroke.88 The rates of complications, including major hemorrhage, were not statistically different between the two treatment groups with the more conservative dosing of warfarin, and there was no difference between aspirin and warfarin for the prevention of recurrent ischemic stroke or death (17% vs 16%; P = .25).

The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) Trial randomized symptomatic patients (TIA or stroke within 90 days) with a 50% to 99% major intracranial artery stenosis to warfarin (INR 2-3) or aspirin (1300 mg/d).89 During a mean follow-up of 1.8 years, 4.3% of aspirin patients died compared with 9.7% of warfarin patients (P = .02), resulting in early termination of the trial. Warfarin patients had a higher incidence of major hemorrhage (8.3% vs 3.2%; P = .01) and MI or sudden death (7.3% vs 2.9%; P = .02).

Taken together, these clinical trials fail to demonstrate a significant benefit for warfarin over aspirin in decreasing the incidence of recurrent stroke in patients with noncardioembolic stroke. Furthermore, the risk of complications such as major bleeding is significantly higher with anticoagulation. Therefore, the use of warfarin to prevent stroke is reserved for patients with a cardioembolic source (eg, mechanical heart valve, atrial fibrillation). Patients with recurrent stroke while on antiplatelet therapy may be another group that benefits from anticoagulation, but this has not been extensively studied.90

Antihyperlipidemics

The treatment of hyperlipidemia confers a cardiovascular and mortality benefit.91-93 Statins are potent inhibitors of 3-hydroxy-3-methylglutaryl–coenzyme A reductase. They have been shown to decrease levels of low-density lipoprotein (LDL) and C-reactive protein, a potent marker of inflammation; upregulate nitric oxide synthase; decrease expression of endothelin-1 mRNA; improve platelet function; and decrease the production of detrimental free radicals.94-97 These effects (and likely others still to be discovered) contribute to improved endothelial function and may decrease the progression of atherosclerosis. There are a number of investigators who have demonstrated the beneficial effect of statin therapy on carotid disease.

Corti and colleagues98 monitored a total of 35 aortic and 25 carotid artery plaques using serial MRIs (0, 6, and 12 months) after the initiation of simvastatin.98 Statin therapy was associated with significant reductions in vessel wall thickness and vessel wall area over 12 months of follow-up in both aortic and carotid arteries (P < .001). Further work by the same group on 44 aortic and 32 carotid artery plaques detected by MRI in 21 asymptomatic hypercholesterolemic patients demonstrated not only a decrease in vessel wall thickness and vessel wall area after treatment with simvastatin, but also an increase in lumen area ranging from 4% to 6% at 18 and 24 months in both carotid and aortic lesions.99

The Carotid Atherosclerosis Italian Ultrasound Study (CAIUS) was performed to test the effect of lipid lowering on the progression of CIMT in 305 asymptomatic patients.100 Progression of CIMT was less in the pravastatin-treated group compared with the control group (P < .0007). A meta-analysis by Kang and colleagues101 of 10 trials with >3000 patients found slowing of CIMT progression in 8 of these studies. Another meta-analysis by Amarenco and coworkers102 evaluated >2700 patients from nine trials. They found that each 10% reduction in LDL cholesterol was estimated to decrease CIMT by 0.73% per year (95% CI, 0.27-1.19).

The salutary effect of statins on carotid atheroma is a product of more than just changes in plaque volume. Watanabe and colleagues103 randomized 60 nonhypercholesterolemic patients with CAD to placebo or pravastatin and found a significant increase in the echogenicity of carotid plaques with statin treatment, suggesting a decrease in plaque vulnerability. Similarly, carotid plaques retrieved at the time of CEA from patients on statins have significantly fewer matrix metalloproteinases and interleukin-6, both of which are proteins associated with plaque instability.104

These changes in the size and composition of atheroma are associated with substantial clinical benefit. Several large meta-analyses have demonstrated a role for statins in the primary prevention of stroke. Bucher and coworkers105 analyzed the results from >100,000 patients treated with statins, fibrates, resins, or dietary intervention. Only statins were associated with a reduction in the risk of stroke (P < .05).105 Cheung and colleagues106 examined outcomes for >47,000 patients from 10 major statin trials, finding an 18% risk reduction of stroke (95% CI, 10%-25%). The Cholesterol Treatment Trialists’ (CTT) Collaborators evaluated >90,000 patients from 14 randomized trials of statins, finding a 17% risk reduction of stroke (95% CI, 22%-12%).107 This risk reduction is robust, occurring in patients with and without CAD. Briel and colleagues108 demonstrated this by evaluating outcomes for >200,000 patients from 65 trials. They found risk ratio of 0.75 (95% CI, 0.65-0.87) for patients with CAD compared with 0.77 (95% CI, 0.62-0.95) for patients without CAD.

The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators provided the first major randomized trial of intensive statin use after recent stroke or TIA (1-6 months prior to entry) in patients without a documented history of CAD.109 They randomly assigned 4731 patients to atorvastatin 80 mg daily versus placebo with a mean follow-up of 4.9 years. LDL levels were significantly reduced with statin therapy (72.9 vs 128.5 mg/dL; P < .001). The treatment group experienced a 2.2% absolute risk reduction at 5 years (adjusted HR = 0.84; 95% CI, 0.71-0.99; P = .03) in the primary end point of fatal or nonfatal stroke. Subgroup analysis suggested that the group with carotid stenosis may have had an even greater degree of benefit (HR = 0.67; 95% CI, 0.47-0.94; P = .02) and experienced a 56% reduction (HR = 0.44; 95% CI, 0.24-0.79; P = .006) in the need for later carotid revascularization.110

In summary, statins have demonstrated an abrogation of plaque progression and stabilization in plaque morphology. These effects (and likely others to be discovered) have translated into significant clinical benefits in the primary and secondary prevention of stroke. Currently, patients with high-risk features such as diabetes, as well as those with documented atherosclerotic disease, are prescribed statin therapy with a goal LDL of <100 mg/dL and consideration of a goal LDL of <70 mg/dL.68,70

Antihypertensives

Approximately 50,000,000 Americans have hypertension, a well-established risk factor for a first or recurrent ischemic stroke.11,111 A number of trials and meta-analyses have demonstrated a consistent decrease in the risk of stroke or stroke recurrence with antihypertensive treatment.112,113

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