Stroke is the third leading cause of death and a principal cause of long-term disability in much of the industrialized world.1 In the United States, at least 500,000 persons suffer new or recurrent stroke annually, and stroke is a contributing factor in 150,000 deaths each year.1 Over the past decades, advances in the understanding of the pathophysiology and epidemiology of stroke, which parallel research in the medical and surgical management of acute and threatened ischemic stroke, have led to an explosion of knowledge in the field of cerebrovascular disease.
Thromboses in coronary and cerebral arteries are complications of atherosclerosis, the most prevalent cause of mortality in the Western world. Carotid atherosclerosis develops in regions of low vessel-wall shear stress. Symptomatic carotid artery plaques primarily involve the carotid artery bulb and are characterized by increased cellular proliferation, lipid accumulation, calcification, ulceration, hemorrhage and thrombosis.2
Whether an association exists between carotid plaque composition and the pathophysiology of carotid artery disease is unknown. It has been postulated that plaque structure, in addition to the degree of carotid artery stenosis, may be a critical factor in determining stroke risk. Ultrasonographic carotid artery plaque morphology may identify a subgroup of patients at high risk for stroke. Ulcerated, echolucent and heterogeneous plaques with a soft core may represent unstable plaques at high risk for embolism.3 Inflammatory infiltration of the fibrous cap may contribute to rupture of the atherosclerotic plaque.4 However, among patients who have had carotid endarterectomy, plaque composition is similar, regardless of preoperative symptom status.5
Risk Factors for Ischemic Stroke
Ischemic strokes are generally predicted by a number of established risk factors. These include older age, male gender, African-American ethnicity, family history, arterial hypertension, diabetes mellitus, dyslipidemia, heart disease, cigarette smoking, excessive alcohol intake, abnormal body mass index and low socioeconomic status.
Arterial hypertension is a predisposing factor for ischemic stroke because it aggravates atherosclerosis and accelerates heart disease, thereby increasing the relative risk of stroke threefold to fourfold. Hypertension is the most important modifiable risk factor for stroke.
Cigarette smoking is an independent risk factor for ischemic stroke in men and women of all ages and a leading risk factor for carotid atherosclerosis in men. Like hypertension and cigarette smoking, diabetes mellitus and hyperlipidemia are modifiable risk factors for stroke. Other potential predictors of stroke include transient ischemic attacks (TIAs), previous stroke, asymptomatic carotid bruit or stenosis, polycythemia, increased fibrinogen level, high plasma homocysteine level, microalbuminuria and oral contraceptive use (Table 1).6–12
|Nonmodifiable risk factors|
|Race or ethnicity|
|Modifiable or treatable risk factors|
|Transient ischemic attacks|
|Asymptomatic carotid bruit or stenosis|
|Aortic arch atheromatosis|
|Increased fibrinogen level|
|Elevated homocysteine level|
|Low serum folate level|
|Elevated anticardiolipin antibody levels|
|Use of oral contraceptives|
Evaluation of Ischemic Cerebrovascular Disease
Accurate determination of the degree of carotid artery stenosis is important in the routine clinical assessment of patients with ischemic cerebrovascular disease. This information determines whether surgical referral and subsequent intervention are warranted.
High-resolution Doppler ultrasonography followed by three-dimensional time-of-flight magnetic resonance angiography (MRA) as needed provides excellent noninvasive assessment of the severity of carotid artery stenosis.13 The use of valid criteria for detecting advanced-grade carotid artery stenosis is of the utmost importance. The presence of a flow gap on MRA is a reliable marker of carotid stenosis greater than 60 percent.14 Duplex ultrasound criteria for a stenosis of 60 percent or greater result from combining a peak systolic velocity of 290 cm per second or more, or an end diastolic velocity of 80 cm per second or more.15
Carotid duplex ultrasound screening is useful in selected patients, primarily those with neurologic symptoms. Current evidence does not support the routine use of serial ultrasonography to determine the risk of stroke in unselected patients with asymptomatic carotid artery disease.16,17 The use of carotid ultrasound scanning in patients with vague symptoms is inappropriate and not cost-effective.
Because of lack of standardization as well as the availability of many different ultrasound machines, concordance between carotid ultrasonography and cerebral angiography is less than ideal. Overall agreement between the two modalities is reliable in normal vessels but less reliable when significant disease is present.
MRA is a useful complement to duplex ultrasonography for the noninvasive diagnosis of internal carotid artery occlusion. When the diagnosis is uncertain, angiographic confirmation may be necessary to exclude the possibility of internal carotid artery “pseudo-occlusion” (cervical internal carotid artery stenosis so severe that at first glance the vessel appears occluded).
Whether selected patients should undergo carotid endarterectomy on the basis of duplex ultrasound scanning alone (without cerebral angiography) or on the basis of duplex ultrasound scanning with MRA remains controversial. In one study,18 angiography performed in patients found to have significant stenosis by duplex ultrasonography did not change the plan to operate in 162 of 165 patients.
SYMPTOMATIC CAROTID ARTERY STENOSIS
Stroke is often caused by atherosclerotic lesions of the carotid artery bifurcation. The degree of internal carotid artery stenosis is the most important predictor of cerebral infarction among patients with extracranial carotid artery disease.19 The severity of carotid artery bifurcation stenosis is directly related to the risk of stroke.
Through the removal of atherosclerotic plaques, carotid endarterectomy restores cerebral blood flow and reduces the risk of cerebral ischemia. Results from three major prospective contemporary studies provide compelling evidence for the benefit of carotid endarterectomy, when performed by experienced surgeons, in improving the chance of stroke-free survival in high-risk symptomatic patients.19–21 Subgroup analysis identified patient subgroups at variable risk for stroke. Overall, an estimated eight carotid endarterectomies are required to prevent one stroke in symptomatic patients with severe (more than 70 percent) carotid artery stenosis.19
North American Symptomatic Carotid Endarterectomy Trial (NASCET). This trial19 confirmed the effectiveness of carotid endarterectomy in preventing stroke in 659 symptomatic patients who had TIAs or minor strokes with high-grade (70 to 99 percent), diameter-reducing carotid artery stenosis. A uniform and strict technique for measuring carotid artery stenosis from an arteriogram was used in the trial (percentage of stenosis = [1 − minimum residual lumen/normal distal cervical internal carotid artery diameter] × 100).
For different end points, absolute risk reductions in favor of surgery were 17 percent for ipsilateral stroke, 15 percent for all strokes, 16.5 percent for combined outcomes of all strokes and death, 10.6 percent for major ipsilateral stroke, 9.4 percent for all major strokes and 10.1 percent for major stroke and death.19
The number needed to treat may be calculated by dividing the absolute risk reduction into 100. Thus, to achieve an absolute risk reduction of 17 percent for ipsilateral stroke, approximately six patients would need to undergo carotid endarterectomy (100 divided by 17). To achieve an absolute basic reduction of 10.1 percent for major stroke and death, approximately 10 patients would need to undergo carotid endarterectomy. The relative risk of major stroke was reduced by at least 80 percent at two years of follow-up.19
Carotid endarterectomy was also beneficial and not more dangerous in symptomatic patients with atheromatous carotid artery pseudo-occlusion. In addition, longer term outcome was better for surgically treated patients who had an occluded contralateral carotid artery. Morbidity and mortality rates for early and delayed carotid endarterectomy were similar.19
European Carotid Surgery Trial (ECST). This trial20 also indicated benefit from carotid endarterectomy compared with medical therapy in 778 patients who had carotid-territory nondisabling ischemic stroke, TIA or retinal infarct associated with diameter-reducing proximal internal carotid stenosis between 70 and 99 percent. The risks of surgery were significantly outweighed by the subsequent benefits.
The cumulative risk of any ipsilateral stroke at three years was 10.3 percent in the surgical groups and 16.8 percent in the medical group.20 However, ECST used different criteria than NASCET for measuring carotid artery stenosis by angiography. Compared with NASCET, the ECST overestimates the degree of carotid artery stenosis. A diameter-reducing carotid artery stenosis of 70 to 99 percent by NASCET criteria is equivalent to a stenosis of 82 to 99 percent by ECST methodology; likewise, a stenosis of 70 to 99 percent by ECST criteria is equivalent to a stenosis of 50 to 99 percent by NASCET criteria.22 These methodologic differences were more important with mild carotid artery stenosis (Table 2).19,20
|NASCET (%)||ECST (%)|
|30 to 69||50 to 82|
|50 to 99||70 to 99|
|70 to 99||82 to 99|
Veterans Affairs Trial of Carotid Endarterectomy in Symptomatic Carotid Stenosis. This trial21 was terminated early because of the positive results of NASCET and ECST. The trial also showed that carotid endarterectomy improved outcome in selected symptomatic patients with high-grade extracranial carotid artery stenosis.
Summary Discussion. Among 374 symptomatic patients with mild stenosis (0 to 29 percent), the ECST results favor the use of medical therapy with platelet antiaggregants.20 The usefulness of carotid endarterectomy in symptomatic patients with carotid artery stenosis of 30 to 69 percent has not yet been unequivocally determined. The ECST results were analyzed separately for patients with stenosis of 30 to 49 percent and those with stenosis of 50 to 69 percent. Analyses of 1,599 patients treated in 97 hospitals in 15 countries suggest that carotid endarterectomy is not indicated in most of these patients.23
Recent results in 2,226 patients randomized to NASCET-224 show a relatively modest benefit favoring surgery in patients with stenosis of 50 to 69 percent, especially those with hemispheric ischemia or no history of diabetes. Carotid endarterectomy provided no benefit if stenosis was less than 50 percent. These results corroborate the observations made by ECST investigators23 (i.e., 50 percent stenosis by NASCET criteria is equal to 75 percent stenosis by ECST criteria).
Timely surgical intervention reduces the risk of recurrent cerebral ischemia or death from stroke in patients with hemispheric TIAs, amaurosis fugax or completed carotid-territory nondisabling strokes within the previous six months that were associated with diameter-reducing carotid stenosis of 70 to 99 percent.19,20
Other factors that increase the risk of ipsilateral stroke are the hemispheric (rather than retinal) site of ischemia, the ulcerative nature of the stenotic plaque and the presence of contralateral carotid artery occlusion. Benefits of carotid endarterectomy are slightly better in men than in women,24 perhaps because women have smaller arteries. Advanced age by itself should not be considered a contraindication for surgery in properly selected patients with symptomatic high-grade carotid artery stenosis.
ASYMPTOMATIC CAROTID ARTERY STENOSIS
Asymptomatic carotid artery atherosclerosis is highly prevalent in the general population, particularly the elderly. However, severe (more than 70 percent) carotid artery stenosis is rare, especially in asymptomatic persons. Compared with symptomatic stenosis, asymptomatic carotid artery stenosis is associated with a relatively low risk of ipsilateral cerebral infarction. About 4 percent of adults have asymptomatic neck bruits, but a carotid bruit is a poor predictor of extracranial carotid artery disease or high-grade stenosis.25
By actuarial analysis, persons with asymptomatic carotid bruits have an estimated annual risk of stroke of 1.5 percent at one year and 7.5 percent at five years.26 Asymptomatic carotid artery stenosis of 75 percent or less carries a stroke risk of 1.3 percent annually.27 When stenosis is more than 75 percent, the combined rate for TIA and stroke is 10.5 percent per year, with most events occurring ipsilateral to the stenosed carotid artery.27
Carotid Artery Surgery Asymptomatic Narrowing Operation Versus Aspirin (CASANOVA) Trial. The CASANOVA trial28 included asymptomatic patients with carotid artery stenosis of 50 to 90 percent. Patients with more than 90 percent stenosis were excluded on the basis of presumed surgical benefit. All patients were treated with 330 mg of aspirin and 75 mg of dipyridamole three times daily. Overall, the trial showed no difference between medically and surgically treated groups.
Mayo Asymptomatic Carotid Endarterectomy (MACE) Trial. The MACE trial29 was terminated early because of a significantly higher number of myocardial infarctions and TIAs in the surgical group than in the medical group. This result most likely reflected the avoidance of aspirin in the surgical group.
Veterans Affairs Asymptomatic Carotid Endarterectomy Trial. In this trial,30 the outcomes of surgery and medical treatment were compared in 444 asymptomatic patients with angiographically proven carotid stenosis of 50 to 99 percent. The study results showed a reduction in the relative risk of ipsilateral neurologic events with surgery when TIA and stroke were included as composite end points. However, when ipsilateral stroke was considered alone, only a nonsignificant trend favoring surgery was noted. For the combined outcome of stroke and death, no significant differences were found between the two treatment arms.
Asymptomatic Carotid Atherosclerosis Study (ACAS). The ACAS31 evaluated the combined use of carotid endarterectomy, aspirin therapy and medical risk factor management in patients younger than 80 years who had asymptomatic carotid artery stenosis of 60 percent or more. The degree of stenosis was determined by arteriography, by Doppler ultrasound scanning within 60 days (greater than 95 percent positive predictive value by frequency or flow velocity) or, in a separate study, by Doppler ultrasound scanning performed within 60 days and confirmed by oculopneumoplethysmography (more than 90 percent positive predictive value). The angiographic methods were similar to those used in NASCET.
Based on a five-year projection, the ACAS31 showed that carotid endarterectomy reduced the absolute risk of stroke by 5.9 percent (which corresponds to an absolute risk reduction of only 1 percent per year) and the relative risk of stroke and death by 53 percent. The surgical benefit incorporated a low aggregate perioperative stroke and death rate of only 2.3 percent, including a permanent arteriographic complication rate of 1.2 percent.
Despite the ACAS findings, some investigators still feel that insufficient evidence exists to recommend surgery in asymptomatic patients.17 It is estimated that 19 carotid endarterectomies must be performed to prevent one stroke or death over a five-year period among asymptomatic patients.
Because of the low risk of stroke in asymptomatic patients, some experts recommend surgery only when the degree of stenosis is more than 80 percent, as was demonstrated by ECST investigators. This is provided that the operation is performed by an experienced surgeon with a combined arteriographic and surgical complication rate of 3 percent or less.32
The overall benefit of carotid endarterectomy strongly depends on surgical risk. Appropriate patient selection and preoperative control of risk factors remain key issues for the family physician to consider. Medical strategies may include the use of platelet antiaggregants, risk factor modification and preoperative evaluation for coronary artery disease.
Because variability in outcome after carotid endarterectomy is well recognized, guidelines for the surgical risk of this procedure have been established.33 Mortality and morbidity rates associated with carotid endarterectomy are significantly lower in asymptomatic patients than in symptomatic patients. The acceptable level of surgical risk (i.e., the combined risk of stroke and death) varies with the indication for carotid artery surgery. Acceptable guidelines for operative risk are 3 percent for asymptomatic patients, 5 percent for patients with TIA, 7 percent for patients with stroke and 10 percent for patients with recurrent stenosis.33