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Carotid stenosis: medical and surgical aspects
Cardiol Clin 20 (2002) 599–609
Carotid stenosis: medical and surgical aspects Gorav Ailawadi, MDa, James C. Stanley, MDa, Sanjay Rajagopalan, MDb, Gilbert R. Upchurch, Jr, MDa,* a
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA b Section of Vascular Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI 48103, USA
Stroke is the third leading cause of death in the United States, with more than 700,000 strokes and 150,000 deaths annually [1,2]. Of the three major causes of stroke (atherosclerotic cerebrovascular disease, atrial fibrillation, and embolic disease), atherosclerosis of the brachiocephalic trunk, including the carotid arteries, causes more than 50% of all strokes (see Box 1). Carotid plaques are complex structures with calcium deposits and a lipid-laden core. Events that initiate transformation of the benign carotid lesion into a stroke-producing hemorrhagic plaque are poorly understood. The initial plaque size, degree of stenosis, and chemical composition of the plaque are all relevant in this evolution. Risk factors and medical therapy for carotid disease The risk factors for stroke are similar to those that are operative in atherosclerosis in general. Hypertension has a strong correlation with stroke; both systolic and diastolic blood pressures are independently associated with primary and recurrent stroke risk [3]. A reduction in diastolic blood pressure of 6 mmHg can decrease the incidence of stroke by 42% [4]. Furthermore, cigarette smoking and diabetes increase the risk of stroke two- to three-fold, especially in conjunction with hypertension. Both primary and secondary prevention of ischemic stroke involves risk factor modification and institution of antiplatelet therapy (see Box 2).
Antiplatelet therapy Aspirin (ASA) therapy alone (81–325 mg) for primary and secondary prevention of strokes results in an approximately 25% relative reduction in the incidence of ischemic stroke versus placebo [5]. The second European Stroke Prevention Study-2 demonstrated in 6602 patients with a prior history of transient ischemic attack (TIA) or stroke that the combination of extended release dipyridamole (400 mg daily) and low-dose ASA (50 mg daily) in a specific dose ratio of 8:1 resulted in a 37% relative risk reduction compared with placebo [6]. ASA therapy alone in this trial resulted in an 18% reduction, which is comparable to previous studies using low-dose ASA [7,8]. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel (75 mg daily), a thienopyridine derivative structurally and pharmacologically similar to ticlopidine, was compared with ASA (325 mg). After an average of 1.91 years of follow-up, clopidogrel yielded an 8.7% relative risk reduction in major vascular outcomes (stroke, MI, or vascular death) compared with ASA (5.32% versus 5.83%, respectively) [8]. Stroke incidence alone was not statistically significant between the two groups. Thus, current data support the use of aspirin therapy as a stand-alone approach in primary and secondary prevention with potential for incremental benefits using ASA plus dipyradimole or clopidogrel alone for secondary prevention. Anticoagulation
* Corresponding author. E-mail address: [email protected] (G.R. Upchurch).
There are no data to support the use of warfarin in the primary prevention of stroke for
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Box 1. Common causes of ischemic stroke
Box 2. Prevention of stroke from carotid disease
Large artery atheroembolism (most common)
Primary
Artery to artery embolism Thrombosis in situ Cardioembolism Nonvalvular atrial fibrillation Post-myocardial infarction (MI) Dilated cardiomyopathy Prosthetic heart valves Aortic arch and innominate artery atheroma Infective endocarditis Rheumatic heart disease Patent foramen ovale
Modification of risk factors Antihypertensive therapy Control of diabetes Cessation of smoking Lowering lipid profile risk Antiplatelet therapy Consider carotid endarterectomy Secondary Modification of risk factors Antiplatelet therapy Treatment of cause of stroke Consider carotid endarterectomy Consider anticoagulation
Small vessel atheroembolism Lacunar disease associated with hypertension and diabetes Low-flow state Ischemic ‘‘watershed’’ areas
patients without atrial fibrillation. In addition, recent studies show no benefit to anticoagulation with warfarin in the prevention of recurrent stroke or death in patients who are not eligible for carotid endarterectomy [9]. Lipid-lowering therapy Despite the apparent lack of evidence from epidemiology studies to indicate that cholesterol is a surrogate marker for cerebrovascular disease, reductions in the incidence of stroke in patients with ischemic heart disease have been observed in large-scale endpoint trials of lipid lowering (Scandinavian Simulation Survival Study [10] and Cholesterol and Recurrent Events Trial [CARE]) with hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) [10,11]. In the 4S and the CARE studies, patients with coronary artery disease who were treated with simvastatin (20–40 mg) or pravastatin (40 mg) experienced an approximately 30% relative risk reduction for fatal and nonfatal strokes or TIAs during the follow-up period [10,11]. The Kaplan-
Meier curves for cerebrovascular events in these trials revealed that at least 3 years of exposure to these agents is necessary to discern a benefit for primary stroke prevention. In the Long-Term Intervention with Pravastatin in Ischaemic Disease study, administration of pravastatin resulted in a 19% relative reduction in the stroke rate (P ¼ 0.05) over a 6-year period without affecting the incidence of hemorrhagic stroke [12]. The Stroke Prevention by Aggressive Reduction of Cholesterol Levels trial has been designed to determine whether or not aggressive cholesterollowering therapy with atorvastatin (80 mg daily) can reduce the incidence of cerebrovascular disease in patients with previous stroke or TIA, but without coronary artery disease.
Diagnosis of carotid stenosis The workup for a patient who presents with symptomatic or incidental carotid stenosis should be systematic. History should be directed at identifying risk factors and prior ischemic events. Physical examination should note signs of cardiac and systemic vascular disease, including assessment of pulse volume at various sites, examination of bruits, and careful assessment for signs of prior clinical stroke on neurologic examination. Imaging tests should begin with a carotid duplex ultrasonography. The severity of an internal carotid artery (ICA) lesion can be reliably
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measured based on the internal carotid to common carotid artery ratio, peak systolic flow, or end diastolic velocity [13]. Three-dimensional contrast-enhanced Magnetic Resonance Angiography (3D-MRA) and two-dimensional time-offlight (2D-TOF) techniques are increasingly being used for the diagnosis of carotid disease, but they are significantly more expensive and are known to be prone to certain artifacts. Magnetic Resonance Imaging (MRI) is useful in cases in which ultrasonography yields contradictory results or in the elucidation of a concomitant intracranial lesion. The traditional ‘‘gold standard’’ test has been carotid angiography because of its utilization in randomized studies such as the North American Symptomatic Carotid Endarterectomy Trials (NASCET I and II) [14,15] and serves as the reference standard against which other modalities are measured. It is useful in its ability to identify coexisting lesions of the great vessels and intracerebral arteries, but it is not used routinely because of a stroke risk of 1% to 3% [16]. Few patients require angiographic evaluation prior to recommendation for endarterectomy because duplex ultrasonography is generally sufficient. MRA or catheter-based angiography should be considered in cases in which symptoms do not correlate with the severity of carotid disease, the distal extent of the plaque is not visualized on duplex, the vessel is extremely tortuous, the ipsilateral carotid artery is occluded, or there is a high carotid bifurcation.
Predictors of perioperative risk Sundt et al graded patient risk for carotid endarterectomy (CEA) based on the criteria listed in the Box 3. Grade 1 (0.9% risk): no angiographic or medical predictors and stable neurologically. Grade 2 (1.7%): no medical but angiographic risk predictors; stable neurologically. Grade 3 (3.1%): major medical or angiographic predictors; stable neurologically. Grade 4 (9.1%): neurologically unstable [17]. Importance of center endarterectomy volumes There is a direct correlation between center volume and operative outcomes from carotid endarterectomy [18]. Based on the above data for perioperative risk, it is apparent that to derive any benefit from the operation, complication rates at a hospital performing such surgeries should be less than 3% for asymptomatic patients and less than 9% for symptomatic patients.
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Box 3. Risk factors for perioperative complications from carotid endarterectomy Neurologic Deficit within past 24 h Stroke within past 7 d Crescendo TIA Global cerebral ischemia CT evidence of stroke Angiographic Ulcerated plaque on angiography [3 cm distal carotid stenosis [5 cm proximal carotid stenosis High bifurcation (at C2) Intraluminal thrombus Medical Age [50 y Hypertension Chronic obstructive pulmonary disease Severe obesity Diabetes mellitus
Asymptomatic disease and carotid endarterectomy Two million people in the United States over the age of 50 are estimated to have asymptomatic carotid artery narrowing of at least 50% of the luminal diameter. Previous studies have suggested high neurologic event rates in asymptomatic patients, progressing to an 80% carotid stenosis [19]. More recent data derived from the asymptomatic contralateral artery in patients enrolled in the NASCET I study suggest that although the overall event rate in individuals with a 60% to 90% stenosis is high (16.2% over 5 years or 3.2% annually), event rates in the territory of the stenosed artery are lower than the overall event rate (5-year risk of 9.9% versus 16.2%, respectively) [20]. The remaining events can be attributed to cardioembolic or lacunar strokes unrelated to the stenosed artery [20]. Three large clinical studies have been performed that assess the utility of endarterectomy in the setting of asymptomatic carotid disease: the Asymptomatic Carotid Atherosclerosis Study
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(ACAS) [21], the Veterans Affairs Cooperative Asymptomatic Trial (VA Cooperative Study) [22], and the Carotid Artery Stenosis with Asymptomatic Narrowing, Operation versus Aspirin (CASANOVA) [23] studies (Table 1). ACAS The most widely quoted of these studies is the ACAS [21], which randomized 1662 patients with documented carotid stenosis of at least 60% without antecedent ipsilateral cerebrovascular symptoms. Patients were randomized to ‘‘best medical therapy’’ (aspirin) or to aspirin plus CEA. The results of this study demonstrated a significant outcome advantage with aspirin plus CEA when compared with aspirin alone. With a mean follow-up period of 2.7 years, the 5-year risk by Kaplan-Meier projection of ipsilateral stroke following surgery was 5.1% compared with 11% in the nonoperative group (P\0.004). In this study, endarterectomy was performed by competent surgeons with less than a 3% combined perioperative morbidity and mortality rate. Intriguingly, men benefited substantially more than women and experienced a reduction in stroke with operative therapy from 12.1% to 4.1% compared with a reduction from 8.7% to 7.3% in women. This gender difference might be attributable to a higher presurgical stroke rate after arteriography in women. All patients in the surgical arm underwent cerebral angiography versus only 38% of patients in the medical arm. In the surgical arm, 1.2% of patients suffered a stroke as a complication of presurgical cerebral arteriography. Because evaluation by cerebral angiography is not necessary in many patients with asymptomatic carotid disease, eliminating this risk would have further reduced the stroke rate in the surgical arm from 5.1% to 3.9%. The 30-day perioperative mortality rate in this study was a commendable 1.5%.
VA Cooperative Study The VA Cooperative Study randomized 444 male patients with carotid stenosis of at least 50% by arteriography to medical therapy (aspirin) with endarterectomy or medical therapy alone [22]. During the mean follow-up period of nearly 4 years, the ipsilateral stroke rate decreased from 9.4% in the medical group to 4.7% in the surgical group and approached statistical significance (P ¼ 0.056). The surgical arm had a lower rate (8%) of ipsilated neurologic events (TIA or Stroke) versus medical therapy alone (20.6%, P\0.001). Presurgical arteriographic stroke and perioperative mortality rates in this study were a noteworthy 0.4% and 1.9%, respectively. CASANOVA The CASANOVA study randomized 410 patients with asymptomatic carotid stenosis of 50% to 90% by arteriography [23]. No benefit in stroke rate was found between the surgically treated and the medically treated groups (10.7% versus 11.3%). The major criticism of this study was the exceptionally high crossover rate, with more than 50% of the patients in the medical arm undergoing CEA. Analysis was performed on an intent-to-treat basis and likely accounts for the discrepancy between the CASANOVA study and the ACAS and VA Cooperative clinical trials. The three aforementioned studies documenting the role of carotid endarterectomy in asymptomatic patients with significant carotid stenosis were defined by a 50% to 70% narrowing by arteriography. These arteriographic measurements relate the size of the lumen within the bulb at the site of disease to the more normal distal internal carotid artery. Arteriographic studies should not be confused with duplex ultrasound studies, which measure the actual amount of atherosclerotic
Table 1 Randomized controlled trials in asymptomatic patients: CEA plus medical therapy vs. medical therapy alone Trial ACAS [21] VA Cooperative Study [22] CASANOVA [23]
Degree of stenosis
Number of patients enrolled
Absolute reduction in stroke risk
Relative reduction in stroke risk
P value
60% 50%
1662 444
5.9% at 5 y 4.7% at 4 ya
53% at 5 y 50% at 4 y
0.004 0.056
410
0.6% at 3 y
5.3% at 3 y
NS
50–90%
Abbreviations: NS, not significant. a Reduction in ipsilated event rate.
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material from the outside of the bulb to the remaining lumen. The difference in technique results in inexact correlation between duplex and angiography. For example, an 80% stenosis by ultrasound is equivalent to a 72% stenosis by arteriogram (Fig. 1). Similarly, a 64% stenosis by ultrasound is equivalent to a 50% stenosis by arteriogram. This discrepancy becomes important when relating these study data to clinical practice because today duplex ultrasound is often the only preoperative test that is performed in most patients. Based on these studies, carotid endarterectomy is indicated in asymptomatic patients with carotid stenosis of at least 60% by arteriography or approximately 80% by carotid duplex. The majority of patients with noncomplicated, asymptomatic carotid stenosis can be evaluated by duplex alone and need not undertake the risk of a periprocedural stroke with cerebral angiography. Centers and surgeons that perform endarterectomy for asymptomatic carotid disease should perform CEA with a low perioperative mortality rate (\3%).
Symptomatic disease and CEA Symptomatic carotid disease carries a higher risk for subsequent stroke than asymptomatic disease. Without treatment, patients experiencing TIAs incur a stroke risk of 7% per year [15].
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Patients with recurrent ipsilateral events have a 28% stroke rate within 2 years [24]. Having a prior history of a stroke from a carotid lesion confers a 14% to 20% risk of ipsilateral stroke [25,26]. Symptomatic ICA stenosis often presents with signs and symptoms that are referable to the middle cerebral artery, including contralateral weakness or sensory deficits (face and upper extremity[lower extremity), aphasia, neglect, ipsilateral monocular vision loss (amarosis fugax), and other visual difficulties. Following a neurologic event, a CT scan or MRI of the brain should be performed to evaluate the type of insult (ischemic versus hemorrhagic). Antiplatelet therapy should be initiated promptly if it is not contraindicated. An electrocardiogram followed by echocardiography should be performed to evaluate cardiac sources of thromboembolism such as atrial fibrillation. In addition, markedly elevated blood pressure should be controlled in an intensive care setting ([200/110 mmHg). Excessive reductions ([15–20 mmHg of mean arterial pressures) are not recommended. Three large randomized studies were performed to evaluate the efficacy of carotid endarterectomy in the setting of symptomatic carotid stenosis: the North American Symptomatic Carotid Endarterectomy Trials (NASCET I and II) [14,15], the European Carotid Surgery Trial (ECST) [27], and the Veterans Affairs Cooperative Symptomatic Trial (VA Cooperative Study; Table 2) [28].
Fig. 1. Discrepancy in method of measurement of stenosis leads to differing measurements between ultrasound and arteriography. (Courtesy of BS Knipp, MS, University of Michigan Medical School, Department of Vascular Surgery.)
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Table 2 Randomized controlled trials in symptomatic patients: CEA plus medical therapy vs. medical therapy alone Degree of stenosis
Trial NASCET I [14] ECST [27] VA Cooperative Study [28] NASCET II [15] NASCET II [15] a
70% 60% 50% 50–69% \50%
Number of patients enrolled 659 778 189 858 1368
Absolute reduction in stroke risk (%)
Relative reduction in stroke risk (%)
P value
17% at 1.5 y 9.6% at 2.7 y 11.7% at 1 ya
65% at 1.5 y 44% at 2.7 y 60.3% at 1 ya
\0.001 \0.001 0.01
6.5% at 5 y 3.8% at 5 y
29.2% at 5 y 20.3% at 5 y
0.045 0.16
Risk reduction in the VA Cooperative Study combined both stroke and TIAs.
NASCET I and II The NASCET I [14] study involved 2267 patients with symptomatic, severe stenosis of 70% to 99% by arteriography (equivalent to 80% by ultrasound) that were randomized to either best medical therapy (aspirin) or aspirin plus CEA. This study was halted prematurely after a mean follow-up of 1.5 years, when the risk of ipsilateral stroke following endarterectomy was 9% compared to a 26% stroke rate with nonoperative therapy (P\0.001). Similarly, the risk of major or fatal stroke was reduced from 13.1% in the medical treatment group to 2.5% in the surgical group (P\0.001). The 30-day perioperative morbidity and mortality rate was 5.8%. A subset of patients with contralateral carotid occlusion was found to have a 69% risk of stroke within 2 years if treated with aspirin alone [15]. NASCET II [13], which evaluated patients with 50% to 69% arteriographic stenosis, documented a 5-year ipsilateral stroke rate of 15.7% after CEA (3% per year) compared with a 22.2% stroke rate among patients not subjected to surgery (4% per year, P ¼ 0.045). This difference was not found in symptomatic patients with less than a 50% stenosis (14.9% stroke rate in endarterectomy group versus 18.7% in the medical group, P ¼ 0.16). Thus, in symptomatic patients with arteriographic stenosis greater than 50% (equivalent to ultrasound narrowing [64%), operative therapy is appropriate in the setting of low perioperative morbidity and mortality. ECST The ECST [27] randomized 778 patients with severe stenosis (70–99%) to medical therapy with or without endarterectomy. The technique used for calculating stenosis in this study was different than the method used for the NASCET studies. In the NASCET studies, the stenotic region of the carotid artery was compared to a normal-
appearing distal segment of carotid artery; in the ECST study, normal carotid diameter before plaque formation began was estimated and the stenosis calculation was based on this measurement (Table 3) [16]. All patients had ipsilateral symptoms within 6 months of study entry. During the 2.7-year mean follow-up period, the average stroke or death rate for the surgical group was 12.3%, which was significantly lower than the rate for the nonsurgical group (21.9%, P\0.001). Patients with mild or moderate stenosis (0–29% or 30–69%, respectively) did not show benefit from CEA [29]. ECST supported endarterectomy in symptomatic patients with severe stenosis (70–99%). VA Cooperative Symptomatic Study The VA Cooperative Symptomatic Study, also known as the Carotid Endarterectomy and Prevention of Cerebral Ischemia in Symptomatic Carotid Stenosis study [28], included 189 men with symptomatic carotid lesions of at least 50% by arteriography who were randomized to medical or surgical plus medical treatment groups. The study ceased after convincing data from the NASCET and the ECST were discovered. After just 1 year follow-up, the surgical group’s stroke or TIA rate of 7.7% was lower than that of medical group, which had a rate of 19.4% (P ¼ 0.01). This study supported findings from the two larger symptomatic trials. Based on this evidence, CEA plus aspirin is the optimal treatment in symptomatic patients with at least a 70% angiographic stenosis (80% by Table 3 Correlation of calculated stenosis based on techniques used in the NASCET and ECST studies Trial
Degree of angiographic stenosis (%)
NASCET [14,15] ECST [27]
90 97
80 96
70 91
60 84
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duplex). These results also support CEA in symptomatic patients who have at least a 50% angiographic lesion in centers that have excellent surgical outcomes. CEA after stroke in evolution/crescendo TIA A stroke in evolution is defined as a progressive neurologic deficit over the course of hours or days without complete resolution. Crescendo TIAs are recurrent, worsening episodes of cerebral ischemic attacks. In the 1960s and 1970s, results of CEA in the setting of acute stroke were poor, with a mortality rate of 42% and neurologic improvement in only 34% of patients who underwent CEA within 2 weeks of the acute event [30]. When endarterectomy was performed more than 2 weeks after the acute event, mortality decreased to 17%, and 72% of patients improved neurologically [30]. In a recent study with more rigorous patient selection and better perioperative care, early CEA in the setting of evolving stroke or crescendo TIA has led to improvement or resolution of symptoms in 93% of patients with a reduction in operative mortality to 2.9% [31]. Upon presentation with an acute, nonhemorrhagic stroke, the institution of thrombolytic therapy can be considered (Fig. 2). The results of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group support the use of intravenous tissue plasminogen activator (t-PA) if used within 3 hours of the acute onset of symptoms at the cost of
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a 6.4% incidence of intracranial hemorrhage [32,33]. For patients who do not present within the 3-hour window, intra-arterial thrombolytic therapy by way of a catheter placed in the middle cerebral artery (MCA) for patients presenting with MCA distribution symptoms can be considered [34–36]. Upon stabilization, a carotid endarterectomy can be performed when indicated. In situations in which thrombolytics are unavailable, emergent CEA should be considered. The benefit of waiting to perform a CEA after such events because of operative risk is counterweighed by the risk of recurrent stroke. CEA after a fixed stroke Patients suffering a stroke secondary to carotid disease continue to have a 5% to 10% yearly risk of recurrent stroke [37]. The primary goal of CEA after a completed stroke is to prevent further damage from recurrent stroke. Early series reported relatively high mortality rates when CEA was performed within 1 to 2 weeks of a stroke [38]. More recent studies have demonstrated much lower rates of perioperative morbidity and mortality (\3%) when CEA is performed with careful preoperative selection, improved perioperative anesthesia, and the selective use of shunts [39,40]. Acute internal carotid artery occlusion In symptomatic patients with suspected ICA occlusion, urgent MRAs or cerebral angiograms
Fig. 2. Algorithm for treating a patient with suspected carotid artery atherosclerosis who presents with an acute neurologic event.
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should be obtained for diagnosis. Consideration should be given to thrombolytic therapy followed by endarterectomy (Fig. 2). Surgery should generally be performed within 72 to 96 hours of an acute occlusion because operations performed after this window result in damage to endothelium during endarterectomy and high rates of reocclusion. If the patient does not have acute symptoms, consideration can be given to a carotid–subclavian or extracranial–intracranial bypass depending on the level of occlusion [41,42]. Carotid restenosis after endarterectomy Narrowing within 2 years is typically caused by myointimal hyperplasia, whereas restenosis occurring after more than 2 years is often a result of recurrent atherosclerotic disease. The incidence of recurrent disease in patients undergoing CEA has been reported to range from 1% to 37% in a compilation of 55 series [43]. Perioperative stroke and morbidity rates are reported to be slightly higher for redo-CEA than primary CEA. Because of scarred tissue planes, rates of permanent cranial nerve damage in redo-surgery are higher (1.0–7.3%). In cases of recurrent disease (restenosis or atherosclerotic), any symptomatic patient with recurrent carotid disease as the suspected source or any asymptomatic patient with stenosis [80% should be considered for intervention. In the setting of contralateral occlusion, many would argue that less stringent criteria should be entertained for ipsilateral redo-endarterectomy. Patch carotid angioplasty is advocated by most in recurrent disease. In patients where this is not possible due to the extent of recurrent stenosis, interposition grafting using saphenous vein or prosthetic material can be performed. Concomitant carotid and coronary disease Carotid disease and coronary disease are often concomitant because atherosclerosis is a systemic disease. The overall perioperative stroke rate with routine coronary artery bypass grafting (CABG) is 1% to 3% [44–46]. Patients with greater than 50% ICA stenosis carry a 9.2% risk of a perioperative neurologic event, whereas individuals with greater than 75% stenosis carry a perioperative stroke rate of 14.3% [47,48]. In this difficult patient population, controversy exists regarding in what order to perform the two operations: CEA followed by CABG (staged), CABG followed by CEA (reversestaged), or a combined approach at one setting
(Table 4). The majority of the reported literature is retrospective in nature. In the combined group there was a 2.8% to 3.3% stroke rate and a 3.4% to 4.2% mortality rate [49–51]. The reverse-staged approach reportedly had a 14% stroke rate and a 5.3% mortality rate [49]. The staged approach resulted in a 3% to 4% stroke rate and a 3% to 4% mortality rate [49,52]. In summary, retrospective reports show little difference between staged and combined approaches; however, the reversestaged approach appears to confer higher stroke and mortality rates. The more severe and symptomatic problem should generally be addressed initially. In the setting of severe carotid disease with normal to moderate coronary disease, a combined or staged procedure (CEA prior to CABG) should be undertaken. With severe, unstable coronary disease and asymptomatic, unilateral carotid disease without contralateral disease, combined or reverse-staged approaches should be considered. In the setting of severe coronary and carotid disease, any of the three approaches should be considered depending on the individual surgeon’s experience and morbidity rates. Technical controversies in carotid endarterectomy Anesthesia: general versus regional Anesthetic techniques and intraoperative monitoring have improved surgical outcomes. The primary goal of carotid endarterectomy is protection from cerebral ischemia during cross-clamping of the carotid artery. Multiple methods of intraoperative evaluation for cerebral ischemia are used with general anesthesia, including carotid stump pressure measurement, electroencephalogram, transcranial Doppler, and evoked potential monioring. If alteration in these parameters from baseline occurs, a carotid shunt is promptly placed Table 4 Stroke and mortality rates for concomitant CEA and CABG Order of procedure
Stroke rates
Mortality rates
Staged (CEA prior to CABG) [49,52] Reverse-staged (CABG prior to CEA) [48] Combined (simultaneous CEA and CABG) [49–51]
3–4%
3–4%
14%
5.3%
2.8–3.3%
3.4–4.2%
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to augment cerebral blood flow. Critics of general anesthesia cite poor correlation of the above methods of intraoperative monitoring with cerebral blood flow and unnecessary risk of mortality with general anesthesia. Under regional anesthesia, a local anesthetic is given to block levels C2 to C4. Because of the ease of intraoperative assessment of alterations in neurologic examination compared with baseline as assessed by speech, orientation, and contralateral motor function—which can readily prompt maneuvers to improve cerebral perfusion—this approach has gained popularity. Potential complications with regional anesthesia include hypotension, seizure, anesthetic toxicity, hoarseness, dysphagia, phrenic nerve palsy, and hematoma formation (Box 3). As more surgeons and anesthesiologists become familiar with regional anesthesia, it is becoming the standard approach for CEA. Intraoperative shunting When concerns regarding inadequate cerebral perfusion arise, maneuvers to restore perfusion include blood pressure manipulation with intravenous pressors and placement of a carotid shunt. The selection of patients for shunt use has been controversial. While some clinicians advocate the use of shunts in all patients, others cite unnecessary longer carotid clamp time and potential damage to the distal ICA as reasons against universal use. The incidence of ipsilateral ischemia during carotid cross-clamping appears to be related to the patency of the contralateral carotid artery. One study found a 20% incidence of ipsilateral ischemia during carotid cross-clamping when the contralateral artery was patent, but it increased to 50% with a contralateral carotid occlusion [53]. Not only does the anatomy appear to influence the rate of cerebral ischemia, but the indication for operation might also influence the use of a shunt. Forty percent of patients undergoing CEA after an ipsilateral stroke required a shunt [39]. A shunt should be placed in patients who show signs of ipsilateral ischemia during crossclamping. Patients with prior ipsilateral stroke or contralateral carotid occlusion should also be considered for a shunt.
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shear stress along the wall of the carotid artery, which can result in thrombosis, atherosclerosis, and accelerated intimal hyperplasia. Saphenous vein harvesting to create a patch lengthens operating time, introduces a leg wound, and might prohibit the future use of the saphenous vein for other procedures besides being associated with a tangible risk of patch rupture (0.5–4.0%) [54,55]. The use of synthetic material to create the patch is not risk-free either. There is a definite risk of infection, and follow-up carotid duplex studies are rendered difficult because of acoustic shadowing of the prosthetic material. A recent randomized study comparing saphenous vein versus synthetic patching did not reveal differences in perioperative stroke rate or early restenosis [56]. Advocates for patch closure argue that primary closure results in narrowing of the artery by as much as 15% [57]. Multiple randomized studies have been performed with mixed results. Several studies did not show any differences between patch closure and primary repair, while others showed some benefit with patch closure. In a meta-analysis of these studies, however, there appears to be a benefit to patch closure. The incidence of perioperative stroke decreased from 3.9% with primary closure to 1.2% with patch closure (P ¼ 0.008) [58]. Similarly, the incidence of restenosis of at least 50% at 1 year was significant between primary and patch closure (7.4% versus 2.1%, P\0.001) [57].
Summary Medical treatment for carotid disease is similar to the treatment of atherosclerosis, with some recent data suggesting that there is a benefit to an aspirin–dipyridamole combination. CEA has revolutionized the treatment of symptomatic and asymptomatic carotid stenosis. This approach remains the gold standard for the surgical treatment of carotid artery stenosis, against which emerging modalities such as percutaneous carotid stenting should be compared. Higher-risk, asymptomatic patients can safely undergo CEA in highvolume centers for stenosis greater than 80% as defined by ultrasound.
Primary repair versus patch closure The debate over primary repair and patch closure is ongoing. Proponents of primary repair argue that patching increases carotid occlusion time by 5 to 10 minutes and creates changes in
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[16] Sila CA. Carotid stenosis: current strategies for choosing between medical and surgical management. Clev Clin J Med 2000;67:851–61. [17] Sundt Jr TM, Meyer FB, Piepgras DG, et al. Risk factors and operative results. In: Weber FB, editor. Sundt’s occlusive cerebrovascular disease, 2nd edition. Philadelphia, PA: WB Saunders; 1994. p. 241–7. [18] Cebul RD, Snow RJ, Pine R, et al. Indications outcomes and provider volumes for carotid endarterectomy. JAMA 1998;279:1282–7. [19] Roederer GO, Langolois YE, Jager KA, et al. The natural history of carotid arterial disease in asymptomatic patients with cervical bruits. Stroke 1984;15:605–13. [20] Inzitari D, Eliaziw M, Gates P, et al. The causes and risk of stroke in patients with asymptomatic internal carotid artery stenosis. NEJM 2000;342: 1693–700. [21] Executive Committee for the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA 1995; 273:1421–8. [22] Hobson RW, Weiss DG, Fields WS, et al. Efficacy of carotid endarterectomy for asymptomatic carotid stenosis. The Veterans Affairs Cooperative Study Group. NEJM 1993;328:221–7. [23] Anonymous. CASANOVA. Carotid surgery versus medical therapy in asymptomatic carotid stenosis. Stroke 1991;22:1129–235. [24] Evans BA, Wieber DO, Barnett HJM. The importance of symptoms in predicting risk for subsequent stroke following an initial transient ischemic attack or minor stroke. In: Moore WS, editor. Surgery for cerebrovascular disease, 2nd edition. Philadelphia, PA: WB Saunders; 1996. p. 16–9. [25] Bardin JA, Bernstein EF, Humber PB, et al. Is carotid endarterectomy beneficial in prevention of stroke? Arch Surg 1982;117:1401–7. [26] Sacco RL, Foulkes MA, Mohr JP, et al. Determinants of early recurrence of cerebral infarction: the Stroke Data Bank. Stroke 1989;20:983–9. [27] European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (0–99%) or with mild (0–29%) carotid stenosis. Lancet 1991;337:1235–43. [28] Mayberg MR, Wilson SE, Yatsu F, et al, for the Veterans Affairs Cooperative Studies Program 309 Trialist Group. Carotid endarterectomy and prevention of cerebral ischemia in symptomatic carotid stenosis. JAMA 1991;266:3289–94. [29] European Carotid Trailists’ Collaborative Group. Endarterectomy for moderate symptomatic carotid stenosis: interim results from the MRC European Carotid Surgery Trial. Lancet 1996;347:1591–3. [30] Blaisdell WF, Clauss RH, Galbraith JG, et al. Joint study of extracranial arterial occlusion. JAMA 1969;209:1889–95.
G. Ailawadi et al / Cardiol Clin 20 (2002) 599–609 [31] Gertler JP, Blankensteijn JD, Brewster DC, et al. Carotid endarterectomy in neurologically unstable patients: do results justify endarterectomy in neurologically unstable patients? J Vasc Surg 1994;19: 32–42. [32] The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. NEJM 1995;333:1581–7. [33] The NINDS t-PA stroke study group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke 1997;28:2109–18. [34] Furlan A, Higashida R, Wechsler L, et al. Intraarterial prourokinase for acute ischemic stroke: the PROACT II study: a randomized controlled trial. JAMA 1999;282:2003–11. [35] del Zoppo GJ, Higashida RT, Furlan AJ, et al. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke 1998;29: 4–11. [36] Brott T, Bogousslavsky J. Treatment of acute ischemic stroke. NEJM 2000;343:710–22. [37] Beebe HG. Surgical treatment of fixed stroke secondary to carotid artery atherosclerosis. In: Ernst CB, Stanley JC, editors. Current vascular therapy, 3rd edition. St. Louis, MO: Mosby; 1995. p. 38–40. [38] Rob CG. Operation for acute completed stroke due to thrombosis of the internal carotid artery. Surgery 1969;65:862–5. [39] Whittemore AD, Ruby ST, Couch NP, et al. Early carotid endarterectomy in patients with small fixed neurological deficits. J Vasc Surg 1984;1:795–9. [40] Rosenthal D, Borrero E, Clark MD, et al. Carotid endarterectomy after reversible ischemic neurologic deficit or stroke: is it of value? J Vasc Surg 1988;8: 527–34. [41] Belkin M, Mackey WC, Pessin MS, et al. Common carotid artery occlusion with patent internal and external carotid arteries: diagnosis and surgical management. J Vasc Surg 1993;17:1019–28. [42] Diaz FG. Extracranial–intracranial bypasses. J Vasc Surg 1985;2:234–6. [43] Lattimer CR, Burnand KG. Recurrent carotid stenosis after carotid endarterectomy. Br J Surg 1997;84:1206–19. [44] Bojar RM, Najafi H, Dehana GA, et al. Neurological complications of coronary revascularization. Ann Thor Surg 1993;36:427–32.
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[45] Frye RL, Kronmal R, Schaff HV, et al. Stroke in coronary artery bypass graft surgery: an analysis of the CASS experience. Int J Cardiol 1992;26: 213–21. [46] Brener BJ, Brief DK, Alpert J, et al. The risk of stroke in patients with asymptomatic carotid stenosis undergoing cardiac surgery: a follow-up study. J Vasc Surg 1987;2:269–79. [47] Schwartz LB, Bridgman AH, Kieffer RW, et al. Asymptomatic carotid stenosis and stroke in patients undergoing cardiopulmonary bypass. J Vasc Surg 1995;21:146–53. [48] Faggioli GL, Curl GR, Ricotta JJ. The role of carotid screening before coronary artery bypass. J Vasc Surg 1990;12:724–31. [49] Hertzer NR, Loop FD, Beven EG, et al. Surgical staging for simultaneous coronary and carotid disease: a study including prospective randomization. J Vasc Surg 1989;9:455–63. [50] Akins CW, Moncure AC, Daggett WM, et al. Safety and efficacy of concomitant carotid and coronary artery operations. Ann Thor Surg 1995;60: 311–8. [51] Vermeulen FE, Hamerlijnck RP, Defauw JJ, et al. Synchronous operation for ischemic cardiac and cerebrovascular disease: early results and long-term follow-up. Ann Thor Surg 1992;53:381–90. [52] Curl GR, et al. Staged vs. combined carotid endarterectomy in coronary bypass patients. Abstract presented at Eastern Vascular Soc 1995;May:5–7. [53] Hobson RW, Goldstein JE, Jamil Z, et al. Carotid restenosis: operative and endovascular management. J Vasc Surg 1999;29:228–38. [54] O’Hara PJ, Hertzer NR, Krajewski LP, et al. Saphenous vein patch rupture after carotid endarterectomy. J Vasc Surg 1992;15:504–9. [55] Riles TS, Lamparello PJ, Giangola G, et al. Rupture of the vein patch: a rare complication of carotid endarterectomy. Surgery 1990;107:10–2. [56] O’Hara PJ, Hertzer NR, Mascha EJ, et al. A prospective, randomized study of saphenous vein patching versus synthetic patching during carotid endarterectomy. J Vasc Surg 2002;35:324–32. [57] Archie JP Jr. Patching with carotid endarterectomy: when to do it and what to use. Semin Vasc Surg 1998;11:24–9. [58] Archie Jr JP. Prospective randomized trials of carotid endarterectomy with primary closure and patch reconstruction: the problem is power. J Vasc Surg 1997;25:1118–9.
Carotid stenosis: medical and surgical aspects Gorav Ailawadi, MDa, James C. Stanley, MDa, Sanjay Rajagopalan, MDb, Gilbert R. Upchurch, Jr, MDa,* a
Department of Surgery, University of Michigan Medical School, Ann Arbor, MI 48109, USA b Section of Vascular Medicine, Division of Cardiology, University of Michigan, Ann Arbor, MI 48103, USA
Stroke is the third leading cause of death in the United States, with more than 700,000 strokes and 150,000 deaths annually [1,2]. Of the three major causes of stroke (atherosclerotic cerebrovascular disease, atrial fibrillation, and embolic disease), atherosclerosis of the brachiocephalic trunk, including the carotid arteries, causes more than 50% of all strokes (see Box 1). Carotid plaques are complex structures with calcium deposits and a lipid-laden core. Events that initiate transformation of the benign carotid lesion into a stroke-producing hemorrhagic plaque are poorly understood. The initial plaque size, degree of stenosis, and chemical composition of the plaque are all relevant in this evolution. Risk factors and medical therapy for carotid disease The risk factors for stroke are similar to those that are operative in atherosclerosis in general. Hypertension has a strong correlation with stroke; both systolic and diastolic blood pressures are independently associated with primary and recurrent stroke risk [3]. A reduction in diastolic blood pressure of 6 mmHg can decrease the incidence of stroke by 42% [4]. Furthermore, cigarette smoking and diabetes increase the risk of stroke two- to three-fold, especially in conjunction with hypertension. Both primary and secondary prevention of ischemic stroke involves risk factor modification and institution of antiplatelet therapy (see Box 2).
Antiplatelet therapy Aspirin (ASA) therapy alone (81–325 mg) for primary and secondary prevention of strokes results in an approximately 25% relative reduction in the incidence of ischemic stroke versus placebo [5]. The second European Stroke Prevention Study-2 demonstrated in 6602 patients with a prior history of transient ischemic attack (TIA) or stroke that the combination of extended release dipyridamole (400 mg daily) and low-dose ASA (50 mg daily) in a specific dose ratio of 8:1 resulted in a 37% relative risk reduction compared with placebo [6]. ASA therapy alone in this trial resulted in an 18% reduction, which is comparable to previous studies using low-dose ASA [7,8]. In the Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, clopidogrel (75 mg daily), a thienopyridine derivative structurally and pharmacologically similar to ticlopidine, was compared with ASA (325 mg). After an average of 1.91 years of follow-up, clopidogrel yielded an 8.7% relative risk reduction in major vascular outcomes (stroke, MI, or vascular death) compared with ASA (5.32% versus 5.83%, respectively) [8]. Stroke incidence alone was not statistically significant between the two groups. Thus, current data support the use of aspirin therapy as a stand-alone approach in primary and secondary prevention with potential for incremental benefits using ASA plus dipyradimole or clopidogrel alone for secondary prevention. Anticoagulation
* Corresponding author. E-mail address: [email protected] (G.R. Upchurch).
There are no data to support the use of warfarin in the primary prevention of stroke for
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Box 1. Common causes of ischemic stroke
Box 2. Prevention of stroke from carotid disease
Large artery atheroembolism (most common)
Primary
Artery to artery embolism Thrombosis in situ Cardioembolism Nonvalvular atrial fibrillation Post-myocardial infarction (MI) Dilated cardiomyopathy Prosthetic heart valves Aortic arch and innominate artery atheroma Infective endocarditis Rheumatic heart disease Patent foramen ovale
Modification of risk factors Antihypertensive therapy Control of diabetes Cessation of smoking Lowering lipid profile risk Antiplatelet therapy Consider carotid endarterectomy Secondary Modification of risk factors Antiplatelet therapy Treatment of cause of stroke Consider carotid endarterectomy Consider anticoagulation
Small vessel atheroembolism Lacunar disease associated with hypertension and diabetes Low-flow state Ischemic ‘‘watershed’’ areas
patients without atrial fibrillation. In addition, recent studies show no benefit to anticoagulation with warfarin in the prevention of recurrent stroke or death in patients who are not eligible for carotid endarterectomy [9]. Lipid-lowering therapy Despite the apparent lack of evidence from epidemiology studies to indicate that cholesterol is a surrogate marker for cerebrovascular disease, reductions in the incidence of stroke in patients with ischemic heart disease have been observed in large-scale endpoint trials of lipid lowering (Scandinavian Simulation Survival Study [10] and Cholesterol and Recurrent Events Trial [CARE]) with hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) [10,11]. In the 4S and the CARE studies, patients with coronary artery disease who were treated with simvastatin (20–40 mg) or pravastatin (40 mg) experienced an approximately 30% relative risk reduction for fatal and nonfatal strokes or TIAs during the follow-up period [10,11]. The Kaplan-
Meier curves for cerebrovascular events in these trials revealed that at least 3 years of exposure to these agents is necessary to discern a benefit for primary stroke prevention. In the Long-Term Intervention with Pravastatin in Ischaemic Disease study, administration of pravastatin resulted in a 19% relative reduction in the stroke rate (P ¼ 0.05) over a 6-year period without affecting the incidence of hemorrhagic stroke [12]. The Stroke Prevention by Aggressive Reduction of Cholesterol Levels trial has been designed to determine whether or not aggressive cholesterollowering therapy with atorvastatin (80 mg daily) can reduce the incidence of cerebrovascular disease in patients with previous stroke or TIA, but without coronary artery disease.
Diagnosis of carotid stenosis The workup for a patient who presents with symptomatic or incidental carotid stenosis should be systematic. History should be directed at identifying risk factors and prior ischemic events. Physical examination should note signs of cardiac and systemic vascular disease, including assessment of pulse volume at various sites, examination of bruits, and careful assessment for signs of prior clinical stroke on neurologic examination. Imaging tests should begin with a carotid duplex ultrasonography. The severity of an internal carotid artery (ICA) lesion can be reliably
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measured based on the internal carotid to common carotid artery ratio, peak systolic flow, or end diastolic velocity [13]. Three-dimensional contrast-enhanced Magnetic Resonance Angiography (3D-MRA) and two-dimensional time-offlight (2D-TOF) techniques are increasingly being used for the diagnosis of carotid disease, but they are significantly more expensive and are known to be prone to certain artifacts. Magnetic Resonance Imaging (MRI) is useful in cases in which ultrasonography yields contradictory results or in the elucidation of a concomitant intracranial lesion. The traditional ‘‘gold standard’’ test has been carotid angiography because of its utilization in randomized studies such as the North American Symptomatic Carotid Endarterectomy Trials (NASCET I and II) [14,15] and serves as the reference standard against which other modalities are measured. It is useful in its ability to identify coexisting lesions of the great vessels and intracerebral arteries, but it is not used routinely because of a stroke risk of 1% to 3% [16]. Few patients require angiographic evaluation prior to recommendation for endarterectomy because duplex ultrasonography is generally sufficient. MRA or catheter-based angiography should be considered in cases in which symptoms do not correlate with the severity of carotid disease, the distal extent of the plaque is not visualized on duplex, the vessel is extremely tortuous, the ipsilateral carotid artery is occluded, or there is a high carotid bifurcation.
Predictors of perioperative risk Sundt et al graded patient risk for carotid endarterectomy (CEA) based on the criteria listed in the Box 3. Grade 1 (0.9% risk): no angiographic or medical predictors and stable neurologically. Grade 2 (1.7%): no medical but angiographic risk predictors; stable neurologically. Grade 3 (3.1%): major medical or angiographic predictors; stable neurologically. Grade 4 (9.1%): neurologically unstable [17]. Importance of center endarterectomy volumes There is a direct correlation between center volume and operative outcomes from carotid endarterectomy [18]. Based on the above data for perioperative risk, it is apparent that to derive any benefit from the operation, complication rates at a hospital performing such surgeries should be less than 3% for asymptomatic patients and less than 9% for symptomatic patients.
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Box 3. Risk factors for perioperative complications from carotid endarterectomy Neurologic Deficit within past 24 h Stroke within past 7 d Crescendo TIA Global cerebral ischemia CT evidence of stroke Angiographic Ulcerated plaque on angiography [3 cm distal carotid stenosis [5 cm proximal carotid stenosis High bifurcation (at C2) Intraluminal thrombus Medical Age [50 y Hypertension Chronic obstructive pulmonary disease Severe obesity Diabetes mellitus
Asymptomatic disease and carotid endarterectomy Two million people in the United States over the age of 50 are estimated to have asymptomatic carotid artery narrowing of at least 50% of the luminal diameter. Previous studies have suggested high neurologic event rates in asymptomatic patients, progressing to an 80% carotid stenosis [19]. More recent data derived from the asymptomatic contralateral artery in patients enrolled in the NASCET I study suggest that although the overall event rate in individuals with a 60% to 90% stenosis is high (16.2% over 5 years or 3.2% annually), event rates in the territory of the stenosed artery are lower than the overall event rate (5-year risk of 9.9% versus 16.2%, respectively) [20]. The remaining events can be attributed to cardioembolic or lacunar strokes unrelated to the stenosed artery [20]. Three large clinical studies have been performed that assess the utility of endarterectomy in the setting of asymptomatic carotid disease: the Asymptomatic Carotid Atherosclerosis Study
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(ACAS) [21], the Veterans Affairs Cooperative Asymptomatic Trial (VA Cooperative Study) [22], and the Carotid Artery Stenosis with Asymptomatic Narrowing, Operation versus Aspirin (CASANOVA) [23] studies (Table 1). ACAS The most widely quoted of these studies is the ACAS [21], which randomized 1662 patients with documented carotid stenosis of at least 60% without antecedent ipsilateral cerebrovascular symptoms. Patients were randomized to ‘‘best medical therapy’’ (aspirin) or to aspirin plus CEA. The results of this study demonstrated a significant outcome advantage with aspirin plus CEA when compared with aspirin alone. With a mean follow-up period of 2.7 years, the 5-year risk by Kaplan-Meier projection of ipsilateral stroke following surgery was 5.1% compared with 11% in the nonoperative group (P\0.004). In this study, endarterectomy was performed by competent surgeons with less than a 3% combined perioperative morbidity and mortality rate. Intriguingly, men benefited substantially more than women and experienced a reduction in stroke with operative therapy from 12.1% to 4.1% compared with a reduction from 8.7% to 7.3% in women. This gender difference might be attributable to a higher presurgical stroke rate after arteriography in women. All patients in the surgical arm underwent cerebral angiography versus only 38% of patients in the medical arm. In the surgical arm, 1.2% of patients suffered a stroke as a complication of presurgical cerebral arteriography. Because evaluation by cerebral angiography is not necessary in many patients with asymptomatic carotid disease, eliminating this risk would have further reduced the stroke rate in the surgical arm from 5.1% to 3.9%. The 30-day perioperative mortality rate in this study was a commendable 1.5%.
VA Cooperative Study The VA Cooperative Study randomized 444 male patients with carotid stenosis of at least 50% by arteriography to medical therapy (aspirin) with endarterectomy or medical therapy alone [22]. During the mean follow-up period of nearly 4 years, the ipsilateral stroke rate decreased from 9.4% in the medical group to 4.7% in the surgical group and approached statistical significance (P ¼ 0.056). The surgical arm had a lower rate (8%) of ipsilated neurologic events (TIA or Stroke) versus medical therapy alone (20.6%, P\0.001). Presurgical arteriographic stroke and perioperative mortality rates in this study were a noteworthy 0.4% and 1.9%, respectively. CASANOVA The CASANOVA study randomized 410 patients with asymptomatic carotid stenosis of 50% to 90% by arteriography [23]. No benefit in stroke rate was found between the surgically treated and the medically treated groups (10.7% versus 11.3%). The major criticism of this study was the exceptionally high crossover rate, with more than 50% of the patients in the medical arm undergoing CEA. Analysis was performed on an intent-to-treat basis and likely accounts for the discrepancy between the CASANOVA study and the ACAS and VA Cooperative clinical trials. The three aforementioned studies documenting the role of carotid endarterectomy in asymptomatic patients with significant carotid stenosis were defined by a 50% to 70% narrowing by arteriography. These arteriographic measurements relate the size of the lumen within the bulb at the site of disease to the more normal distal internal carotid artery. Arteriographic studies should not be confused with duplex ultrasound studies, which measure the actual amount of atherosclerotic
Table 1 Randomized controlled trials in asymptomatic patients: CEA plus medical therapy vs. medical therapy alone Trial ACAS [21] VA Cooperative Study [22] CASANOVA [23]
Degree of stenosis
Number of patients enrolled
Absolute reduction in stroke risk
Relative reduction in stroke risk
P value
60% 50%
1662 444
5.9% at 5 y 4.7% at 4 ya
53% at 5 y 50% at 4 y
0.004 0.056
410
0.6% at 3 y
5.3% at 3 y
NS
50–90%
Abbreviations: NS, not significant. a Reduction in ipsilated event rate.
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material from the outside of the bulb to the remaining lumen. The difference in technique results in inexact correlation between duplex and angiography. For example, an 80% stenosis by ultrasound is equivalent to a 72% stenosis by arteriogram (Fig. 1). Similarly, a 64% stenosis by ultrasound is equivalent to a 50% stenosis by arteriogram. This discrepancy becomes important when relating these study data to clinical practice because today duplex ultrasound is often the only preoperative test that is performed in most patients. Based on these studies, carotid endarterectomy is indicated in asymptomatic patients with carotid stenosis of at least 60% by arteriography or approximately 80% by carotid duplex. The majority of patients with noncomplicated, asymptomatic carotid stenosis can be evaluated by duplex alone and need not undertake the risk of a periprocedural stroke with cerebral angiography. Centers and surgeons that perform endarterectomy for asymptomatic carotid disease should perform CEA with a low perioperative mortality rate (\3%).
Symptomatic disease and CEA Symptomatic carotid disease carries a higher risk for subsequent stroke than asymptomatic disease. Without treatment, patients experiencing TIAs incur a stroke risk of 7% per year [15].
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Patients with recurrent ipsilateral events have a 28% stroke rate within 2 years [24]. Having a prior history of a stroke from a carotid lesion confers a 14% to 20% risk of ipsilateral stroke [25,26]. Symptomatic ICA stenosis often presents with signs and symptoms that are referable to the middle cerebral artery, including contralateral weakness or sensory deficits (face and upper extremity[lower extremity), aphasia, neglect, ipsilateral monocular vision loss (amarosis fugax), and other visual difficulties. Following a neurologic event, a CT scan or MRI of the brain should be performed to evaluate the type of insult (ischemic versus hemorrhagic). Antiplatelet therapy should be initiated promptly if it is not contraindicated. An electrocardiogram followed by echocardiography should be performed to evaluate cardiac sources of thromboembolism such as atrial fibrillation. In addition, markedly elevated blood pressure should be controlled in an intensive care setting ([200/110 mmHg). Excessive reductions ([15–20 mmHg of mean arterial pressures) are not recommended. Three large randomized studies were performed to evaluate the efficacy of carotid endarterectomy in the setting of symptomatic carotid stenosis: the North American Symptomatic Carotid Endarterectomy Trials (NASCET I and II) [14,15], the European Carotid Surgery Trial (ECST) [27], and the Veterans Affairs Cooperative Symptomatic Trial (VA Cooperative Study; Table 2) [28].
Fig. 1. Discrepancy in method of measurement of stenosis leads to differing measurements between ultrasound and arteriography. (Courtesy of BS Knipp, MS, University of Michigan Medical School, Department of Vascular Surgery.)
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Table 2 Randomized controlled trials in symptomatic patients: CEA plus medical therapy vs. medical therapy alone Degree of stenosis
Trial NASCET I [14] ECST [27] VA Cooperative Study [28] NASCET II [15] NASCET II [15] a
70% 60% 50% 50–69% \50%
Number of patients enrolled 659 778 189 858 1368
Absolute reduction in stroke risk (%)
Relative reduction in stroke risk (%)
P value
17% at 1.5 y 9.6% at 2.7 y 11.7% at 1 ya
65% at 1.5 y 44% at 2.7 y 60.3% at 1 ya
\0.001 \0.001 0.01
6.5% at 5 y 3.8% at 5 y
29.2% at 5 y 20.3% at 5 y
0.045 0.16
Risk reduction in the VA Cooperative Study combined both stroke and TIAs.
NASCET I and II The NASCET I [14] study involved 2267 patients with symptomatic, severe stenosis of 70% to 99% by arteriography (equivalent to 80% by ultrasound) that were randomized to either best medical therapy (aspirin) or aspirin plus CEA. This study was halted prematurely after a mean follow-up of 1.5 years, when the risk of ipsilateral stroke following endarterectomy was 9% compared to a 26% stroke rate with nonoperative therapy (P\0.001). Similarly, the risk of major or fatal stroke was reduced from 13.1% in the medical treatment group to 2.5% in the surgical group (P\0.001). The 30-day perioperative morbidity and mortality rate was 5.8%. A subset of patients with contralateral carotid occlusion was found to have a 69% risk of stroke within 2 years if treated with aspirin alone [15]. NASCET II [13], which evaluated patients with 50% to 69% arteriographic stenosis, documented a 5-year ipsilateral stroke rate of 15.7% after CEA (3% per year) compared with a 22.2% stroke rate among patients not subjected to surgery (4% per year, P ¼ 0.045). This difference was not found in symptomatic patients with less than a 50% stenosis (14.9% stroke rate in endarterectomy group versus 18.7% in the medical group, P ¼ 0.16). Thus, in symptomatic patients with arteriographic stenosis greater than 50% (equivalent to ultrasound narrowing [64%), operative therapy is appropriate in the setting of low perioperative morbidity and mortality. ECST The ECST [27] randomized 778 patients with severe stenosis (70–99%) to medical therapy with or without endarterectomy. The technique used for calculating stenosis in this study was different than the method used for the NASCET studies. In the NASCET studies, the stenotic region of the carotid artery was compared to a normal-
appearing distal segment of carotid artery; in the ECST study, normal carotid diameter before plaque formation began was estimated and the stenosis calculation was based on this measurement (Table 3) [16]. All patients had ipsilateral symptoms within 6 months of study entry. During the 2.7-year mean follow-up period, the average stroke or death rate for the surgical group was 12.3%, which was significantly lower than the rate for the nonsurgical group (21.9%, P\0.001). Patients with mild or moderate stenosis (0–29% or 30–69%, respectively) did not show benefit from CEA [29]. ECST supported endarterectomy in symptomatic patients with severe stenosis (70–99%). VA Cooperative Symptomatic Study The VA Cooperative Symptomatic Study, also known as the Carotid Endarterectomy and Prevention of Cerebral Ischemia in Symptomatic Carotid Stenosis study [28], included 189 men with symptomatic carotid lesions of at least 50% by arteriography who were randomized to medical or surgical plus medical treatment groups. The study ceased after convincing data from the NASCET and the ECST were discovered. After just 1 year follow-up, the surgical group’s stroke or TIA rate of 7.7% was lower than that of medical group, which had a rate of 19.4% (P ¼ 0.01). This study supported findings from the two larger symptomatic trials. Based on this evidence, CEA plus aspirin is the optimal treatment in symptomatic patients with at least a 70% angiographic stenosis (80% by Table 3 Correlation of calculated stenosis based on techniques used in the NASCET and ECST studies Trial
Degree of angiographic stenosis (%)
NASCET [14,15] ECST [27]
90 97
80 96
70 91
60 84
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duplex). These results also support CEA in symptomatic patients who have at least a 50% angiographic lesion in centers that have excellent surgical outcomes. CEA after stroke in evolution/crescendo TIA A stroke in evolution is defined as a progressive neurologic deficit over the course of hours or days without complete resolution. Crescendo TIAs are recurrent, worsening episodes of cerebral ischemic attacks. In the 1960s and 1970s, results of CEA in the setting of acute stroke were poor, with a mortality rate of 42% and neurologic improvement in only 34% of patients who underwent CEA within 2 weeks of the acute event [30]. When endarterectomy was performed more than 2 weeks after the acute event, mortality decreased to 17%, and 72% of patients improved neurologically [30]. In a recent study with more rigorous patient selection and better perioperative care, early CEA in the setting of evolving stroke or crescendo TIA has led to improvement or resolution of symptoms in 93% of patients with a reduction in operative mortality to 2.9% [31]. Upon presentation with an acute, nonhemorrhagic stroke, the institution of thrombolytic therapy can be considered (Fig. 2). The results of the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group support the use of intravenous tissue plasminogen activator (t-PA) if used within 3 hours of the acute onset of symptoms at the cost of
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a 6.4% incidence of intracranial hemorrhage [32,33]. For patients who do not present within the 3-hour window, intra-arterial thrombolytic therapy by way of a catheter placed in the middle cerebral artery (MCA) for patients presenting with MCA distribution symptoms can be considered [34–36]. Upon stabilization, a carotid endarterectomy can be performed when indicated. In situations in which thrombolytics are unavailable, emergent CEA should be considered. The benefit of waiting to perform a CEA after such events because of operative risk is counterweighed by the risk of recurrent stroke. CEA after a fixed stroke Patients suffering a stroke secondary to carotid disease continue to have a 5% to 10% yearly risk of recurrent stroke [37]. The primary goal of CEA after a completed stroke is to prevent further damage from recurrent stroke. Early series reported relatively high mortality rates when CEA was performed within 1 to 2 weeks of a stroke [38]. More recent studies have demonstrated much lower rates of perioperative morbidity and mortality (\3%) when CEA is performed with careful preoperative selection, improved perioperative anesthesia, and the selective use of shunts [39,40]. Acute internal carotid artery occlusion In symptomatic patients with suspected ICA occlusion, urgent MRAs or cerebral angiograms
Fig. 2. Algorithm for treating a patient with suspected carotid artery atherosclerosis who presents with an acute neurologic event.
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should be obtained for diagnosis. Consideration should be given to thrombolytic therapy followed by endarterectomy (Fig. 2). Surgery should generally be performed within 72 to 96 hours of an acute occlusion because operations performed after this window result in damage to endothelium during endarterectomy and high rates of reocclusion. If the patient does not have acute symptoms, consideration can be given to a carotid–subclavian or extracranial–intracranial bypass depending on the level of occlusion [41,42]. Carotid restenosis after endarterectomy Narrowing within 2 years is typically caused by myointimal hyperplasia, whereas restenosis occurring after more than 2 years is often a result of recurrent atherosclerotic disease. The incidence of recurrent disease in patients undergoing CEA has been reported to range from 1% to 37% in a compilation of 55 series [43]. Perioperative stroke and morbidity rates are reported to be slightly higher for redo-CEA than primary CEA. Because of scarred tissue planes, rates of permanent cranial nerve damage in redo-surgery are higher (1.0–7.3%). In cases of recurrent disease (restenosis or atherosclerotic), any symptomatic patient with recurrent carotid disease as the suspected source or any asymptomatic patient with stenosis [80% should be considered for intervention. In the setting of contralateral occlusion, many would argue that less stringent criteria should be entertained for ipsilateral redo-endarterectomy. Patch carotid angioplasty is advocated by most in recurrent disease. In patients where this is not possible due to the extent of recurrent stenosis, interposition grafting using saphenous vein or prosthetic material can be performed. Concomitant carotid and coronary disease Carotid disease and coronary disease are often concomitant because atherosclerosis is a systemic disease. The overall perioperative stroke rate with routine coronary artery bypass grafting (CABG) is 1% to 3% [44–46]. Patients with greater than 50% ICA stenosis carry a 9.2% risk of a perioperative neurologic event, whereas individuals with greater than 75% stenosis carry a perioperative stroke rate of 14.3% [47,48]. In this difficult patient population, controversy exists regarding in what order to perform the two operations: CEA followed by CABG (staged), CABG followed by CEA (reversestaged), or a combined approach at one setting
(Table 4). The majority of the reported literature is retrospective in nature. In the combined group there was a 2.8% to 3.3% stroke rate and a 3.4% to 4.2% mortality rate [49–51]. The reverse-staged approach reportedly had a 14% stroke rate and a 5.3% mortality rate [49]. The staged approach resulted in a 3% to 4% stroke rate and a 3% to 4% mortality rate [49,52]. In summary, retrospective reports show little difference between staged and combined approaches; however, the reversestaged approach appears to confer higher stroke and mortality rates. The more severe and symptomatic problem should generally be addressed initially. In the setting of severe carotid disease with normal to moderate coronary disease, a combined or staged procedure (CEA prior to CABG) should be undertaken. With severe, unstable coronary disease and asymptomatic, unilateral carotid disease without contralateral disease, combined or reverse-staged approaches should be considered. In the setting of severe coronary and carotid disease, any of the three approaches should be considered depending on the individual surgeon’s experience and morbidity rates. Technical controversies in carotid endarterectomy Anesthesia: general versus regional Anesthetic techniques and intraoperative monitoring have improved surgical outcomes. The primary goal of carotid endarterectomy is protection from cerebral ischemia during cross-clamping of the carotid artery. Multiple methods of intraoperative evaluation for cerebral ischemia are used with general anesthesia, including carotid stump pressure measurement, electroencephalogram, transcranial Doppler, and evoked potential monioring. If alteration in these parameters from baseline occurs, a carotid shunt is promptly placed Table 4 Stroke and mortality rates for concomitant CEA and CABG Order of procedure
Stroke rates
Mortality rates
Staged (CEA prior to CABG) [49,52] Reverse-staged (CABG prior to CEA) [48] Combined (simultaneous CEA and CABG) [49–51]
3–4%
3–4%
14%
5.3%
2.8–3.3%
3.4–4.2%
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to augment cerebral blood flow. Critics of general anesthesia cite poor correlation of the above methods of intraoperative monitoring with cerebral blood flow and unnecessary risk of mortality with general anesthesia. Under regional anesthesia, a local anesthetic is given to block levels C2 to C4. Because of the ease of intraoperative assessment of alterations in neurologic examination compared with baseline as assessed by speech, orientation, and contralateral motor function—which can readily prompt maneuvers to improve cerebral perfusion—this approach has gained popularity. Potential complications with regional anesthesia include hypotension, seizure, anesthetic toxicity, hoarseness, dysphagia, phrenic nerve palsy, and hematoma formation (Box 3). As more surgeons and anesthesiologists become familiar with regional anesthesia, it is becoming the standard approach for CEA. Intraoperative shunting When concerns regarding inadequate cerebral perfusion arise, maneuvers to restore perfusion include blood pressure manipulation with intravenous pressors and placement of a carotid shunt. The selection of patients for shunt use has been controversial. While some clinicians advocate the use of shunts in all patients, others cite unnecessary longer carotid clamp time and potential damage to the distal ICA as reasons against universal use. The incidence of ipsilateral ischemia during carotid cross-clamping appears to be related to the patency of the contralateral carotid artery. One study found a 20% incidence of ipsilateral ischemia during carotid cross-clamping when the contralateral artery was patent, but it increased to 50% with a contralateral carotid occlusion [53]. Not only does the anatomy appear to influence the rate of cerebral ischemia, but the indication for operation might also influence the use of a shunt. Forty percent of patients undergoing CEA after an ipsilateral stroke required a shunt [39]. A shunt should be placed in patients who show signs of ipsilateral ischemia during crossclamping. Patients with prior ipsilateral stroke or contralateral carotid occlusion should also be considered for a shunt.
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shear stress along the wall of the carotid artery, which can result in thrombosis, atherosclerosis, and accelerated intimal hyperplasia. Saphenous vein harvesting to create a patch lengthens operating time, introduces a leg wound, and might prohibit the future use of the saphenous vein for other procedures besides being associated with a tangible risk of patch rupture (0.5–4.0%) [54,55]. The use of synthetic material to create the patch is not risk-free either. There is a definite risk of infection, and follow-up carotid duplex studies are rendered difficult because of acoustic shadowing of the prosthetic material. A recent randomized study comparing saphenous vein versus synthetic patching did not reveal differences in perioperative stroke rate or early restenosis [56]. Advocates for patch closure argue that primary closure results in narrowing of the artery by as much as 15% [57]. Multiple randomized studies have been performed with mixed results. Several studies did not show any differences between patch closure and primary repair, while others showed some benefit with patch closure. In a meta-analysis of these studies, however, there appears to be a benefit to patch closure. The incidence of perioperative stroke decreased from 3.9% with primary closure to 1.2% with patch closure (P ¼ 0.008) [58]. Similarly, the incidence of restenosis of at least 50% at 1 year was significant between primary and patch closure (7.4% versus 2.1%, P\0.001) [57].
Summary Medical treatment for carotid disease is similar to the treatment of atherosclerosis, with some recent data suggesting that there is a benefit to an aspirin–dipyridamole combination. CEA has revolutionized the treatment of symptomatic and asymptomatic carotid stenosis. This approach remains the gold standard for the surgical treatment of carotid artery stenosis, against which emerging modalities such as percutaneous carotid stenting should be compared. Higher-risk, asymptomatic patients can safely undergo CEA in highvolume centers for stenosis greater than 80% as defined by ultrasound.
Primary repair versus patch closure The debate over primary repair and patch closure is ongoing. Proponents of primary repair argue that patching increases carotid occlusion time by 5 to 10 minutes and creates changes in
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