INTRODUCTION — This topic will review the treatment of asymptomatic extracranial carotid atherosclerotic disease. The management of symptomatic extracranial carotid disease is discussed separately. (See "Management of symptomatic carotid atherosclerotic disease".)
Other aspects of carotid atherosclerotic disease, including technical aspects of carotid revascularization, are reviewed elsewhere:
(See "Evaluation of carotid artery stenosis".)
(See "Percutaneous carotid artery stenting" and "Carotid endarterectomy".)
(See "Overview of carotid artery stenting".)
(See "Percutaneous carotid artery stenting" and "Carotid endarterectomy".)
(See "Transcarotid artery revascularization".)
EXTRACRANIAL CAROTID ATHEROSCLEROSIS — Extracranial carotid atherosclerosis most frequently involves the origin of the internal carotid artery and the common carotid artery bifurcation (ie, carotid bulb). This is distinguished from intracranial carotid atherosclerosis. (See "Intracranial large artery atherosclerosis: Epidemiology, clinical manifestations, and diagnosis" and "Intracranial large artery atherosclerosis: Treatment and prognosis".)
Asymptomatic disease — Asymptomatic carotid atherosclerotic disease, as discussed in this topic, refers to the presence of atherosclerosis in individuals with no history of ipsilateral carotid territory ischemic stroke or transient ischemic attack (TIA) within the preceding six months. Symptoms associated with carotid atherosclerotic disease are discussed separately. (See "Definition, etiology, and clinical manifestations of transient ischemic attack" and "Clinical diagnosis of stroke subtypes", section on 'Brain ischemia'.)
Note that isolated unilateral carotid stenosis does not cause vertigo, diplopia, lightheadedness, or syncope. Therefore, in patients with these symptoms, but no other focal neurologic symptoms, the carotid lesion should be considered asymptomatic.
Prevalence — The prevalence of asymptomatic carotid atherosclerotic disease varies by population studied and demographics, with age and sex as the most important factors. The prevalence is low in the general population. In a meta-analysis of four population-based studies with individual data from over 23,000 participants, the prevalence estimates of asymptomatic carotid stenosis (≥50 percent of the lumen diameter) for males and females aged <50 years were 0.2 and 0 percent, respectively [1]. The prevalence estimates for males and females aged ≥80 years were 7.5 and 5 percent, respectively. (See "Screening for asymptomatic carotid artery stenosis", section on 'Prevalence'.)
Detection — General population screening for carotid stenosis in asymptomatic individuals is not warranted, as reviewed elsewhere. (See "Screening for asymptomatic carotid artery stenosis".)
However, asymptomatic carotid stenosis due to atherosclerosis may be identified incidentally when a carotid bruit is detected on physical examination or when patients undergo carotid imaging during evaluation of atherosclerotic disease, or for the evaluation of an unrelated condition, including a stroke or TIA involving an unrelated vascular territory. Some patients will come to attention following private health screening studies.
Counseling — Once extracranial carotid atherosclerosis has been identified, patients should be screened for signs or symptoms of prior stroke or TIA to ensure that they are asymptomatic. They should also be counseled on the symptoms and signs of stroke and instructed to seek emergency care if a stroke is suspected (eg, by calling 911 in the United States or other phone number appropriate to their location). In addition, patients should be screened for treatable cardiovascular risk factors [2,3].
Degree of stenosis and clinical significance — Once asymptomatic carotid stenosis is identified, it is important to determine the severity of carotid stenosis both to identify individuals who may be candidates for revascularization and, if revascularization is not performed, to monitor for disease progression over time.
The severity of carotid stenosis can be determined by a variety of imaging modalities (ultrasound, computed tomographic angiography, magnetic resonance angiography, and catheter-based angiography). In addition, interpretation of ultrasound-derived physiological parameters (eg, velocity and turbulence) and plaque may be used to further characterize carotid stenosis. For angiographic imaging studies, the severity of stenosis is recorded as the percent diameter reduction by comparing the residual lumen at the site of stenosis with the diameter of the normal distal internal carotid artery. Stenosis greater than 50 percent is generally regarded as potentially significant, though lesser degrees of stenosis may serve as embolic sources. (See "Evaluation of carotid artery stenosis".)
RISK OF STROKE AND CARDIOVASCULAR EVENTS — Progression of atherosclerotic plaque at the carotid bifurcation results in luminal narrowing, often accompanied by plaque ulceration. This process can lead to ischemic stroke or transient ischemic attack from embolization, thrombosis, or reduced brain perfusion (more likely in the setting of bilateral disease). Asymptomatic carotid atherosclerosis also serves as a marker of increased risk for myocardial infarction and vascular death [4-6]. Thus, asymptomatic carotid atherosclerosis is considered a risk equivalent for cardiovascular disease. (See "Overview of established risk factors for cardiovascular disease", section on 'Noncoronary atherosclerotic disease'.)
Ipsilateral stroke risk — Ischemic stroke is the most feared outcome of carotid atherosclerosis, although the risk is low in asymptomatic patients. The annual risk of ipsilateral stroke in patients with asymptomatic extracranial carotid atherosclerosis with stenosis ≥50 percent is estimated to be 0.5 to 1.0 percent annually [4,7,8]. In a retrospective cohort study of over 3700 participants diagnosed between 2008 and 2012 with severe (70 to 99 percent) asymptomatic carotid stenosis who did not undergo carotid revascularization, the estimated annual rate of ipsilateral ischemic stroke was 0.9 percent (95% CI 0.7-1.2 percent) [9]. This finding is consistent with other studies suggesting that the risk of ipsilateral stroke in patients with medically treated asymptomatic carotid stenosis is lower than the risk in surgically treated patients who participated in the landmark endarterectomy trials from the late 1980s through the early 2000s. (See 'Is revascularization beneficial?' below.)
Factors potentially associated with stroke risk — Potential factors that might identify patients with asymptomatic extracranial carotid disease who have a high risk of ischemic stroke include the following [10-12]:
●Initial degree of carotid stenosis (see 'Initial degree of carotid stenosis' below)
●Progression in the severity of asymptomatic carotid stenosis (see 'Progressive stenosis despite optimal medical therapy' below)
●Asymptomatic embolism detected on transcranial Doppler ultrasound (see 'Asymptomatic embolism' below)
●Ipsilateral silent embolic infarcts on neuroimaging (see 'Silent embolic infarcts' below)
●High-risk morphologic features of the carotid plaque (see 'Carotid plaque morphology' below)
●Reduced cerebral blood flow reserve (see 'Reduced cerebrovascular reserve' below)
The utility of using these factors to select patients with asymptomatic extracranial carotid stenosis for revascularization remains to be proven; treatment of those who exhibit one or more of these features should be individualized [10].
Initial degree of carotid stenosis — The relationship between the degree of asymptomatic extracranial carotid stenosis at baseline and the risk of stroke is uncertain, as the data are inconsistent.
●Randomized controlled trials comparing carotid endarterectomy (CEA) with medical therapy in patients with 60 to 99 percent carotid stenosis (the Asymptomatic Carotid Atherosclerosis Study [ACAS] and the Asymptomatic Carotid Surgery Trial [ACST]) found that stroke rates for patients assigned to medical therapy were not clearly related to the severity of carotid stenosis, and that the benefit of carotid revascularization was not increased with more severe degrees of stenosis (see 'Endarterectomy trials' below). This is in contrast to symptomatic carotid stenosis, in which CEA trials have consistently found an increased risk of stroke and a greater benefit with revascularization with higher degrees of stenosis. (See "Management of symptomatic carotid atherosclerotic disease", section on 'Patients appropriate for CEA'.)
●By contrast, observational data suggest that ipsilateral stroke risk increases with the degree of asymptomatic carotid stenosis, as shown in a population-based cohort study of 207 patients with asymptomatic 50 to 99 percent carotid stenosis [13]. The five-year ipsilateral stroke risk was greater among 53 patients with 70 to 99 percent carotid stenosis (14.6 percent, 95% CI 3.5-25.7) compared with 154 patients with 50 to 69 percent stenosis, none of whom had a stroke. Similarly, the five-year ipsilateral stroke risk was greater among 34 patients with 80 to 99 percent stenosis (18.3 percent, 95% CI 7.7-29.9) compared with 173 patients with 50 to 79 percent stenosis (1 percent, 95% CI 0.0-2.9).
The investigators also performed a systematic review and meta-analysis of studies done from 1980 to 2020 and identified 23 studies with data for ipsilateral stroke risk among 8419 medically treated patients with asymptomatic carotid stenosis [13]. Stroke risk during follow-up (generally three to five years) increased linearly with the degree of ipsilateral stenosis, being greater for 70 to 99 percent stenosis compared with 50 to 69 percent stenosis (10.2 versus 4.8 percent, odds ratio [OR] 2.1, 95% CI 1.7-2.5), and greater for 80 to 99 percent stenosis compared with 50 to 79 percent stenosis (10.6 percent versus 5.1 percent, OR 2.5, 95% CI 1.8-3.5).
Progressive stenosis despite optimal medical therapy — Natural history studies of asymptomatic extracranial carotid stenosis found that progression of stenosis over time was associated with an increased stroke risk [14-22].
●As an example, one study analyzed the natural history of asymptomatic carotid disease in 714 patients who had serial carotid ultrasound examinations biannually for a mean follow-up of 3.2 years [14]. Progression to carotid stenosis of ≥80 percent was associated with a higher risk for cerebrovascular events and death.
●In the prospective ACSRS cohort study of 1121 patients with asymptomatic carotid stenosis of 50 to 99 percent who were followed by serial duplex ultrasonography biannually for a mean follow-up of four years, there was regression of carotid stenosis in 4 percent, no change in 76 percent, and progression of stenosis in 20 percent of patients [17]. The corresponding eight-year cumulative ipsilateral stroke rate was 0 percent in the subgroup with regression, 9 percent in the subgroup with no change, and 16 percent in the subgroup with progression of stenosis.
●In a retrospective analysis of data from the ACST trial, the annual incidence of progression of carotid luminal narrowing was 5 percent [23]. A high rate of progression over one year was significantly associated with ipsilateral neurologic events, though only a small number of patients had such progression.
These data have been used to support the use of CEA for patients with progression of asymptomatic carotid disease, particularly as the degree of carotid stenosis approaches 70 to 80 percent [18,21,24-26]. However, this approach has not been confirmed by randomized controlled trials.
Asymptomatic embolism — Evidence from observational studies suggests that asymptomatic cerebral embolism, detected by transcranial Doppler (TCD) ultrasound, is associated with an increased risk of ischemic stroke in patients with asymptomatic extracranial carotid atherosclerosis [27-30].
Some experts advocate using TCD emboli detection to identify patients with asymptomatic carotid stenosis who are at high and low risk of stroke and thus to help select those most likely to benefit from carotid revascularization [27,31]. However, the utility of this approach has not been tested in a randomized trial, and TCD is not widely available.
Silent embolic infarcts — The presence of silent embolic infarcts ipsilateral to asymptomatic carotid stenosis on neuroimaging may predict the risk of ipsilateral stroke [11]. In the prospective ACSRS study, 462 patients with asymptomatic 60 to 99 percent carotid artery stenosis by duplex ultrasound had a baseline head computed tomography (CT) scan and were monitored every six months for up to eight years [32]. At a mean follow-up of 3.7 years, the rate of ipsilateral stroke was significantly higher for patients with silent embolic infarcts on baseline CT (n = 86) compared with patients without embolic infarcts (annual event rate 3.6 versus 1.0 percent, hazard ratio [HR] 3.0, 95% CI 1.46-6.29). Previous studies have found that the presence of silent brain infarcts on CT or magnetic resonance imaging (MRI) scans were associated with an increased risk of ischemic stroke in the general population (see "Clinical diagnosis of stroke subtypes", section on 'Silent brain infarcts'), but these studies did not consider the status of the carotid arteries [32].
Carotid plaque morphology — Limited data suggest that ultrasound or MRI determination of carotid plaque morphology (eg, ulceration, plaque area, intraplaque hemorrhage, plaque echogenicity) may be useful to identify patients with asymptomatic carotid occlusive disease who are at higher risk of stroke and therefore likely to benefit from carotid revascularization. However, this approach requires additional study.
In patients with asymptomatic carotid stenosis, several imaging features on ultrasonography or MRI have been associated with elevated stroke risk [11,31,33]:
●Carotid ulceration – In a report of 253 patients with asymptomatic carotid stenosis, the carotid arteries were scanned with three-dimensional (3D) ultrasound, and the risk of stroke or death at three years was significantly higher for patients with three or more carotid plaque ulcers (the sum of both carotid arteries) compared with those who had less than three ulcers (18 versus 2 percent) [29].
●Large plaque area – In the ACSRS study, increased plaque area was independently associated with an increased risk of ipsilateral cerebrovascular or retinal ischemic events [34].
●Plaque echolucency on ultrasonography – Echogenicity refers to the appearance of plaque based on whether ultrasound waves pass through or are reflected, ranging from purely hypoechoic (ie, echolucent; no echoes, black) to hyperechoic (white). A standardized method for evaluating plaque echogenicity has been described [35]. Several studies have reported an increased stroke risk for purely echolucent plaques [30,36,37].
In a report of 435 patients with asymptomatic carotid stenosis, echolucent plaques were independently associated with an increased risk of ipsilateral stroke even after controlling for the presence of embolic signals at baseline [30].
●Increased size of juxtaluminal black (ie, hypoechoic) area on ultrasonography – The size of the plaque core (hypoechoic; juxtaluminal black area [JBA]) and position relative to the carotid lumen may predict stroke risk [38-40]. In the ACSRS study, the JBA on ultrasound images of asymptomatic carotid plaque demonstrated a linear relationship with stroke risk [39]. With a JBA <4 mm2, the mean annual stroke rate was <1 percent; with a JBA 4 to 8 mm2, the rate was 1.4 percent; with a JBA 8 to 10 mm2, the rate was 3.2 percent; and with JBA >10 mm2, the stroke rate was 5 percent.
●Intraplaque hemorrhage on MRI – In a meta-analysis of individual patient data from seven cohort studies, intraplaque hemorrhage detected by MRI was present in 40 of 136 patients (29 percent) with ≥50 percent asymptomatic carotid stenosis and was associated with an increased annualized rate of ipsilateral stroke compared with no intraplaque hemorrhage (5.4 percent versus 0.8 percent, unadjusted hazard ratio [HR] 7.9, 95% CI 1.3-47.6) [41].
Reduced cerebrovascular reserve — Several reports have found that a reduction in cerebrovascular reserve (CVR), also called cerebral blood flow reserve, is associated with increased risk of ischemic stroke in patients with asymptomatic carotid stenosis [11]. However, the utility of using this measure to select patients for carotid revascularization is unproven. In most studies, CVR is estimated using transcranial Doppler measurements of middle cerebral artery blood flow velocity change in response to a vasodilatory stimulus with acetazolamide, inhaled carbon dioxide, or breath holding [11,42,43]. A normal CVR reflects an increase in middle cerebral artery blood flow of 15 to 40 percent, while the CVR is considered impaired if blood flow increases by <10 percent. Other methods involve direct cerebral blood flow measurement with imaging modalities such as positron emission tomography, CT perfusion, MR perfusion, or nuclear medicine techniques. A meta-analysis of four studies evaluating patients with asymptomatic carotid stenosis reported that impaired CVR increased the risk of ischemic stroke or TIA (OR 4.07, 95% CI 2.00-11.07) [42]. The clinical availability of all these methods of measuring CVR is generally limited.
INTENSIVE MEDICAL THERAPY AND FOLLOW-UP — Asymptomatic carotid atherosclerosis is a risk equivalent for cardiovascular disease, and patients are at increased risk for future cerebrovascular (eg, transient ischemic attack [TIA], stroke) and cardiovascular (eg, myocardial infarction, limb ischemia) events.
All patients with carotid stenosis should undergo intensive medical therapy, which includes several strategies to reduce their cardiovascular risk. Periodic clinical follow-up to evaluate compliance with medical therapies and to evaluate for symptoms and signs of TIA or stroke is also important.
Risk reduction strategies — Importantly, intensive medical therapy lowers the risk of stroke in patients with asymptomatic carotid stenosis. With intensive medical therapy, the risk of stroke is low enough that the benefit of carotid revascularization for asymptomatic disease is disputed by some experts [7,8,28,44-47]. However, since this level of intensive medical therapy was not available during the trials of revascularization for asymptomatic carotid disease, we await further trials that aim to reassess the relative benefits and risks of carotid endarterectomy and carotid artery stenting compared with intensive medical therapy. (See 'Role of carotid revascularization' below.)
Intensive medical therapy includes rigorous and compliant use of the following risk reduction strategies; each is discussed in detail separately:
●Statin treatment (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Statins and other lipid-lowering agents')
●Antithrombotic therapy, generally using aspirin monotherapy unless there is an indication for anticoagulation (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Adjunctive therapies')
●Treatment of hypertension (see "Overview of hypertension in adults", section on 'Treatment')
●Glycemic control in patients with diabetes (see "Glycemic control and vascular complications in type 2 diabetes mellitus", section on 'Macrovascular disease')
●Smoking cessation (see "Cardiovascular risk of smoking and benefits of smoking cessation")
●Healthy diet (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Diet')
●Regular physical activity and exercise (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Physical activity')
●Weight reduction in patients with obesity (see "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk", section on 'Weight reduction')
Imaging surveillance — Patients with asymptomatic carotid stenosis can be followed with noninvasive vascular imaging of the carotid artery, particularly if they may be candidates for revascularization in the setting of stenosis progression. This is most easily accomplished using duplex ultrasonography performed annually by a qualified technologist in an accredited vascular laboratory with the goal of assessing the progression or regression of disease [48]. Magnetic resonance angiography and computed tomographic angiography are alternatives if duplex ultrasonography cannot be done, but they are more burdensome and expensive. (See "Evaluation of carotid artery stenosis", section on 'Carotid duplex ultrasound'.)
ROLE OF CAROTID REVASCULARIZATION
Is revascularization beneficial? — As already noted, intensive medical management is indicated for all patients with asymptomatic carotid atherosclerosis. (See 'Intensive medical therapy and follow-up' above.)
Optimal patient selection for carotid revascularization is controversial given the periprocedural risk relative to the low absolute risk reduction associated with revascularization.
Three large randomized trials have compared carotid endarterectomy (CEA) with medical therapy in asymptomatic carotid stenosis (50 to 99 percent stenosis in the VA trial and 60 to 99 percent in the Asymptomatic Carotid Atherosclerosis Study [ACAS] and the Asymptomatic Carotid Surgery Trial [ACST]) [49-51]. In these studies, CEA was associated with a 2.9 percent risk of perioperative stroke or death. CEA reduced the risk of subsequent stroke, but the benefit was small with an absolute risk reduction of approximately one percent per year [52]; the corresponding number needed to treat (NNT) to prevent one stroke at three years was approximately 33. (See 'Endarterectomy trials' below.)
On the basis of these data, older United States guidelines stated that it was reasonable to consider CEA in patients with asymptomatic carotid stenosis of 60 to 99 percent with five or more years of expected life expectancy at centers where the perioperative risk of stroke or death could be reliably documented to be <3 percent [53]. However, these trials enrolled from the late 1980s through the early 2000s and used medical therapy that was suboptimal compared with contemporary standards [44].
Multiple studies have shown that intensive medical therapy has lowered the stroke risk in patients with asymptomatic carotid stenosis who are managed without carotid revascularization. Importantly, with contemporary intensive medical therapy, the risk of stroke in medically treated patients is now as low, or lower, than the stroke risk in surgically treated patients from the CEA trials, with reported stroke rates of 0.5 to 1 percent per year [7-9,28,44-46]. As a result, some experts have suggested that medical therapy alone, without carotid revascularization, is the preferred treatment for most patients with asymptomatic carotid stenosis [4,7,8].
Other experts believe that CEA remains the best approach for treating asymptomatic carotid stenosis of 70 to 99 percent; they do not agree that the available data establish the equivalence of medical therapy, noting that the inclusion of many patients with low-risk 50 to 69 percent asymptomatic carotid stenosis may have skewed the results of studies, asserting that stroke risk reduction with modern medical therapy negates the benefit of CEA for all patients with asymptomatic carotid stenosis [54].
Unfortunately, cross-study comparisons may introduce bias, and improvements in surgical techniques in the years since the CEA trials were done may have reduced the risk of perioperative stroke and death associated with carotid revascularization [55]. As a result, the benefit of carotid revascularization in asymptomatic carotid stenosis is uncertain, and contemporary randomized controlled trials comparing carotid revascularization with intensive medical therapy are needed to know which approach is truly the best [56].
Our approach to patient selection — In the absence of more contemporary data, we present our approach to the management of asymptomatic carotid stenosis below. Treatment decisions should account for the patient's comorbid conditions, life expectancy, and preferences, as well as the local experience of the center and surgeon.
Note that the two largest trials comparing CEA and medical therapy enrolled patients with a stenosis of 60 to 99 percent. However, in practice, many ultrasound laboratories report carotid stenosis as <50 percent, 50 to 69 percent, and 70 to 99 percent stenosis, and so we will present our recommendations in these categories.
Stenosis less than 50 percent — Patients with asymptomatic internal carotid artery atherosclerotic disease who have <50 percent carotid stenosis do not require carotid revascularization. However, such patients should be screened for treatable risk factors for stroke and cardiovascular disease, with institution of appropriate lifestyle changes and medical therapies. Annual carotid duplex surveillance to evaluate for plaque progression may be reasonable. (See 'Intensive medical therapy and follow-up' above.)
Stenosis 50 to 69 percent — For patients with asymptomatic carotid atherosclerotic disease who have 50 percent to 69 percent internal carotid artery stenosis, we suggest intensive medical therapy and follow-up using all available risk reduction strategies. (See 'Intensive medical therapy and follow-up' above.)
Although patients with 60 to 69 percent stenosis meet the criteria for the ACAS and ACST trials, we believe it is reasonable to forego revascularization and use intensive medical therapy based on the overall low potential benefit of carotid revascularization and evidence that carotid stenosis does not become hemodynamically or clinically significant until it is >70 percent or with a residual lumen diameter of 1.5 mm or less [18,21,24-26,57]. For these patients, we pursue carotid artery follow-up and surveillance with the goal of detecting patients with progression of stenosis to >70 percent despite compliance with intensive medical therapy. This is most easily accomplished using duplex ultrasonography performed annually by a qualified technologist in an accredited vascular laboratory [48]. (See 'Imaging surveillance' above.)
Stenosis 70 to 99 percent — For medically stable patients with asymptomatic carotid atherosclerotic disease at baseline who have a life expectancy of at least five years and have a severe (70 to 99 percent) internal carotid artery stenosis, either intensive medical therapy alone or intensive medical therapy plus carotid revascularization is reasonable. Many vascular surgeons have adopted a more conservative approach and would only consider carotid revascularization for someone with a more severe stenosis of 80 to 99 percent. (See 'Alternative approaches' below.)
If carotid revascularization is considered, the combined perioperative risk of stroke and death for carotid revascularization should be less than 3 percent for the surgeon and center (See 'Is revascularization beneficial?' above.).
We advise a shared decision-making approach that incorporates the patient's values and preferences. It is critical that the patient understand that with intensive medical therapy the risk of stroke is relatively low, and the benefit of carotid revascularization is uncertain. We encourage patients with this degree of asymptomatic carotid stenosis to participate in ongoing randomized controlled trials comparing carotid revascularization with contemporary medical management, such as the CREST-2 trial [58].
Occlusion — There is no role for revascularization to prevent recurrent stroke in the setting of complete carotid chronic occlusion. Intensive medical therapy is indicated. (See 'Intensive medical therapy and follow-up' above.)
Alternative approaches — The management of asymptomatic carotid atherosclerotic disease is controversial. The following strategies are advocated by different experts:
●Avoidance of carotid revascularization regardless of the degree of asymptomatic carotid stenosis, with reliance on intensive medical management as described above using statins, antiplatelet agents, treatment of hypertension and diabetes, and healthy lifestyle changes [59]. (See 'Intensive medical therapy and follow-up' above.)
●Intensive medical management for most patients, with carotid revascularization only for a subgroup of patients with asymptomatic carotid stenosis who have a particularly high risk of stroke [12,31]. This approach relies on the use of markers to determine high stroke risk, such as those with progression of carotid stenosis, the detection of asymptomatic carotid embolism, the presence of silent embolic infarcts, increased carotid plaque burden or high-risk plaque morphology, and reduced cerebrovascular reserve. Some vascular surgeons recommend medical therapy for stenosis <80 percent but recommend revascularization when stenosis exceeds 80 percent. (See 'Factors potentially associated with stroke risk' above.)
●Revascularization with CEA for most medically stable patients with asymptomatic carotid stenosis of 60 to 99 percent, rather than reserving CEA for more severe degrees of stenosis (ie, ≥70 or ≥80 percent) [2,31,60,61]. This approach relies on prior data from randomized clinical trials, which showed a benefit in patients who were not receiving optimal medical therapy (see 'Carotid endarterectomy' below) without accounting for the uncertainty introduced by subsequent data, which show a lower risk of stroke with contemporary intensive medical therapy. For this reason, we advocate a more conservative approach. (See 'Intensive medical therapy and follow-up' above and 'Our approach to patient selection' above.)
Patients unlikely to benefit from revascularization — Patients unlikely to benefit from carotid revascularization include those with severe comorbidity due to other medical or surgical illnesses that increase their perioperative risk, limited life expectancy, a prior disabling ipsilateral stroke, or patients with total occlusion of the internal carotid artery (contraindication). Risk factors for morbidity and mortality associated with carotid revascularization techniques (ie, carotid endarterectomy, carotid artery stenting) should be evaluated to identify those who may face unacceptably high risk [62]. These risk factors are discussed separately. (See "Carotid endarterectomy", section on 'Preoperative evaluation' and "Overview of carotid artery stenting".)
Most other asymptomatic atherosclerotic lesions affecting the inflow to the internal carotid artery or its outflow are best managed medically, including stenosis involving the brachiocephalic artery (ie, also not causing extremity symptoms or subclavian steal syndrome), the common carotid artery, or stenosis of the distal internal carotid artery beyond the bifurcation. Likewise, conditions causing asymptomatic nonatherosclerotic carotid stenosis (eg, fibromuscular dysplasia, dissection, vasculitis, or prior radiotherapy) are best managed medically.
Choice of procedure — The optimal carotid revascularization procedure, whether CEA or carotid artery stenting (CAS), and for CAS, the optimal approach (transfemoral [TF-CAS] versus transcarotid artery revascularization [TCAR]) is controversial. However, there is agreement that the short-term (periprocedural) risk of stroke and death is generally higher with TF-CAS, while long-term outcomes are similar for CEA and CAS. The risk of stroke may be lower for TCAR compared with TF-CAS. (See 'Carotid endarterectomy' below and 'Carotid stenting' below.)
Carotid endarterectomy — Randomized controlled trials had found that CEA was beneficial for selected patients with asymptomatic internal carotid artery stenosis of 60 to 99 percent [49-51]. However, the absolute benefit was low. In addition, the evidence from these trials supporting CEA for asymptomatic carotid disease was less compelling for females compared with males.
For those who are not already receiving antiplatelet therapy, treatment with aspirin (81 to 325 mg/day) is recommended for all patients who are having CEA. Aspirin should be started prior to surgery and continued indefinitely for patients with asymptomatic atherosclerosis (see "Carotid endarterectomy", section on 'Antiplatelet therapy'). In addition, patients with atherosclerotic carotid disease, including those who undergo CEA, should receive intensive medical management that includes LDL-lower therapy and treatment of hypertension, cigarette smoking, and diabetes. (See 'Intensive medical therapy and follow-up' above and "Overview of secondary prevention of ischemic stroke".)
Endarterectomy trials — The efficacy of CEA, compared with no surgery, for patients with asymptomatic high-grade carotid stenosis was evaluated in three high-quality randomized controlled trials. These were the VA trial [49], ACAS [50], and ACST [51].
In a meta-analysis of these three trials, including 5268 subjects with a mean follow-up of 3.3 years per subject, CEA was associated with a 2.9 percent risk of perioperative stroke or death. CEA reduced the risk of any stroke, but the benefit was small with an overall absolute risk reduction of approximately one percent per year [52]; the corresponding number needed to treat (NNT) to prevent one stroke at three years was approximately 33. The outcome of any stroke or death was not significantly lower with CEA compared with medical therapy alone (20.5 versus 22.6 percent, relative risk [RR] 0.92, 95% CI 0.83-1.02).
Findings of the individual CEA trials are as follows:
●The VA trial randomly assigned 444 males with 50 to 99 percent asymptomatic carotid stenosis to CEA plus aspirin or aspirin alone [49]. The mean duration of follow-up was 48 months. The incidence of stroke or TIA was significantly lower for the CEA plus aspirin group compared with the aspirin alone group (8 versus 21 percent, RR 0.38, 95% CI 0.22-0.67) (figure 1). The difference in incidence for ipsilateral stroke was nonsignificantly lower for the CEA plus aspirin group (4.7 versus 9.4 percent). The composite outcome of all stroke and death at 30 days and 48 months was similar (41 and 44 percent, respectively); most of the deaths were due to coronary heart disease. This trial was criticized for including TIA in the primary endpoint, since by definition TIA does not result in any persistent neurologic deficit [53].
●The ACAS trial randomized 1662 adults with 60 to 99 percent asymptomatic carotid stenosis to CEA plus aspirin (325 mg/day) or aspirin alone [50]. At a median follow-up of 2.7 years, the incidence of ipsilateral stroke and any perioperative stroke or death was lower for the CEA plus aspirin group compared with the aspirin group (5 versus 11 percent; RR 0.53, 95% CI 0.22-0.72). The incidence of major ipsilateral stroke, major perioperative stroke, and perioperative death was nonsignificantly lower for the CEA plus aspirin group (3.4 versus 6 percent) (figure 2). This study was not powered to determine sex differences. However, subgroup analysis suggested that CEA was less effective in females. Males had an absolute risk reduction of 8 percent, whereas the absolute risk reduction in females was only 1.4 percent, perhaps due to a higher incidence of perioperative complications in females compared with males (3.6 versus 1.7 percent).
●The ACST trial randomly assigned 3120 patients with ≥60 percent asymptomatic carotid stenosis to immediate CEA or to deferred CEA (until a definite indication occurred) [51,63]. The main analysis for ACST combined ipsilateral and contralateral strokes [64]. In the immediate CEA group, one-half were treated with CEA by one month and 88 percent by one year. In the deferred CEA group, approximately 4 percent of patients per year underwent CEA. At a mean of 3.4 years of follow-up, the five-year risk for all strokes or perioperative death in the immediate CEA group was reduced compared with deferred CEA group (6.4 versus 11.8 percent, absolute risk reduction [ARR] 5.4 percent, 95% CI 2.96-7.75) (figure 3). Benefit with immediate CEA was also found for fatal or disabling stroke (3.5 versus 6.1 percent). Approximately one-half of the strokes in the trial were fatal or disabling (figure 4). The CEA group had a perioperative risk of stroke or death of 3.1 percent within 30 days of surgery.
The ACST subgroup analyses reported the results of risk reduction for non-perioperative stroke (ie, the benefit) separately from perioperative risk (ie, the risk) but did not report the overall balance of benefit and risk, which is of most importance to patients and clinicians [65]. While CEA was beneficial for preventing non-perioperative stroke in the entire cohort, the risk reduction over five years was significant for males (ARR 8.2 percent, 95% CI 5.64-10.78) but not females (ARR 4.1 percent, 95% CI 0.74-7.41).
The benefit of CEA was maintained at long-term follow-up (median nine years) in the ACST cohort [63]. The risk for all stroke or perioperative death in the immediate CEA group was significantly reduced compared with the deferred CEA group at five years (6.9 versus 10.9 percent) and at 10 years (13.4 versus 17.9 percent).
Factors influencing outcome
●Delay to benefit – CEA for patients with asymptomatic carotid atherosclerosis is a long-term investment [51]. The ACAS and especially the ACST trials showed that the net benefit of CEA is delayed for many months to nearly two years because of perioperative morbidity. In the ACST, the net benefit of CEA was delayed for approximately two years after surgery (figure 3) [51,63]. (See 'Endarterectomy trials' above.)
●Perioperative complications – CEA for patients with asymptomatic carotid atherosclerosis should be performed only at institutions in which the perioperative stroke and death rate is <3 percent. Combined morbidity and mortality that exceed 3 percent could eliminate the small benefit gained from revascularization for patients with asymptomatic carotid disease [66-68]. Surgeons participating in the ACAS trial were required to have a perioperative complication rate of <3 percent in asymptomatic patients [69]. Similarly, the ACST reported a 3.1 percent perioperative complication rate [51]. (See 'Endarterectomy trials' above.)
A review of Medicare recipients undergoing CEA found a higher mortality rate in hospitals that did not participate in major carotid surgery trials, particularly in those centers performing fewer procedures (2.9 percent, versus 1.4 percent in North American Symptomatic Carotid Endarterectomy Trial [NASCET] and ACAS trial hospitals) [70]. Low patient volume (less than three CEAs performed every two years) and a greater number of years since licensure of the surgeon have also been associated with worse outcomes following CEA [71]. (See 'Endarterectomy trials' above.)
●Sex – The potential benefit of CEA may be greater for males compared with females with asymptomatic carotid disease. Nevertheless, we use the same approach for managing asymptomatic carotid stenosis regardless of sex, but include a discussion of the difference in the data when counseling female patients.
A meta-analysis of data from the ACAS and ACST trials (figure 5) found no benefit for females with respect to the five-year risk of any stroke or perioperative death (odds ratio [OR] 0.96, 95% CI 0.63-1.45) [65]. By contrast, there was significant benefit for males (OR 0.49, 95% CI 0.36-0.66). In the ACST trial, the benefit of surgery for females with asymptomatic carotid disease was reported as significant, although less robust than the benefit for males [51]. However, this analysis excluded perioperative events.
The 10-year data from ACST found a similar benefit for the outcome of any stroke or perioperative death for males and females <75 years of age (males: ARR 5.5 percent, 95% CI 0.9-10.0; females: ARR 5.8 percent, 95% CI 0.1-11.4). In addition, a cohort study that included over 1.2 million patients treated primarily with CEA (but also CAS) from 2005 to 2015 reported no difference in outcome for asymptomatic carotid stenosis in males versus females [72].
Carotid stenting — Although overall outcomes with CAS have improved over time, CEA remains the preferred method of revascularization for most patients with asymptomatic carotid atherosclerosis with standard surgical risk. Based upon the data from randomized trials comparing CEA with predominantly carotid artery stents placed using a transfemoral approach (ie, TF-CAS), we suggest not treating asymptomatic carotid disease with CAS unless both of the following conditions are met (see 'Stenting versus endarterectomy trials' below):
●The patient's anatomy or risk factors suggest a prohibitively high risk for CEA
●The local center and operator have demonstrated a low (<3 percent) periprocedural risk
The available evidence suggests that CAS and CEA provide similar long-term outcomes for patients with asymptomatic and symptomatic carotid occlusive disease, but the periprocedural risk of stroke and death has been higher with TF-CAS. An alternative to TF-CAS, TCAR uses a neck incision to deliver the stent directly into the carotid artery, which avoids passing wires and catheters across the aortic arch and possibly reduces the risk for embolism. Observational data suggest that TCAR has a lower risk of perioperative stroke or death compared with TF-CAS. However, there are no trials directly comparing these techniques. The approach to CAS, including a comparison of transfemoral and transcarotid carotid stenting and their advantages and disadvantages, is reviewed separately. (See "Overview of carotid artery stenting".)
Most major guidelines note that the advantage of revascularization with CAS over intensive medical therapy alone is not well established for patients with asymptomatic carotid disease [2,60,61]. Nevertheless, some experts consider CAS as an alternative to CEA for the treatment of patients with asymptomatic carotid atherosclerotic disease, particularly in patients younger than age 70 years who are considered to be poor candidates for surgery due to high risks for perioperative complications.
Risk factors for periprocedural complications of CAS are discussed separately. (See "Overview of carotid artery stenting".)
Stenting versus endarterectomy trials — Most clinical trial data regarding carotid stenting compared CEA with CAS in patients with either symptomatic or asymptomatic carotid disease. These trials suggest that the periprocedural (30-day) stroke or death rate is higher with TF-CAS compared with CEA, while the risk of stroke or death beyond 30 days is similar for both techniques [73,74]. A 2017 meta-analysis of five trials (ACT1, CREST, EVA-3S, ICSS, SAPPHIRE) compared CEA with CAS in 6526 patients with symptomatic or asymptomatic carotid disease [73]. In a subgroup analysis limited to patients with asymptomatic carotid disease, the risk of any periprocedural stroke was higher for CAS compared with CEA (2.8 versus 1.6 percent, OR 1.86, 95% CI 1.05-3.31). However, the risk of periprocedural stroke plus ipsilateral stroke during long-term follow-up was similar for CAS and CEA (5.3 versus 4.5 percent, OR 1.26, 95% CI 0.86-1.84). The composite outcome of death, stroke, or myocardial infarction during the periprocedural period plus ipsilateral stroke during long-term follow-up was also similar for CAS and CEA (6.0 versus 8.2 percent, OR 0.92, 95% CI 0.68-1.26) [73].
No randomized trials have compared CAS (TF-CAS or TCAR) with medical therapy alone. Note that the trials discussed below have involved TF-CAS. Data regarding TCAR or other approaches to CAS are reviewed separately. (See "Overview of carotid artery stenting", section on 'Approach to carotid artery stenting'.)
●The ACST-2 trial, conducted from 2008 to 2020, randomly assigned 3625 patients with asymptomatic carotid stenosis of 70 to 99 percent to either CAS or CEA in a 1:1 ratio [75]. The procedural (ie, 30-day) rate of death or any stroke was higher with CAS compared with CEA (3.7 versus 2.7 percent), but the difference was not statistically significant. The five-year rate of procedural death or any stroke during follow-up was also higher with CAS compared with CEA (8.6 versus 7.1 percent), but again the difference did not achieve statistical significance. These results largely reflected a slightly higher incidence of nondisabling stroke in the CAS group; the five-year rate of procedural death or any fatal or disabling stroke was similar for CAS and CEA (3.3 versus 3.5 percent).
●The ACT I trial, halted early due to slow recruitment, randomly assigned 1453 patients with asymptomatic carotid stenosis of 70 to 99 percent to either CAS or CEA in a 3:1 ratio [76]. For the primary composite endpoint (death, stroke, or myocardial infarction within 30 days after the procedure or ipsilateral stroke within one year), event rates for CAS and CEA were 3.8 and 3.4 percent, respectively, achieving the prespecified statistical margin for noninferiority of CAS compared with CEA. The rates of stroke or death within 30 days for CAS and CEA were 2.9 and 1.7 respectively, and the difference was not statistically significant.
●The CREST trial randomly assigned 2502 patients with carotid atherosclerotic disease to endarterectomy or stenting [77,78]. The proportion of enrolled patients with asymptomatic and symptomatic carotid disease was 47 and 53 percent, respectively. The overall effectiveness and safety of CAS and CEA were similar, and the benefits were equal for males and females and for patients with asymptomatic and symptomatic carotid disease. The primary endpoint for the trial, a composite of any stroke, myocardial infarction, or death within 30 days following treatment plus any ipsilateral stroke during 10-year follow-up (median 2.5 years), was similar for CAS and CEA (11.8 versus 9.9 percent, hazard ratio [HR] 1.11, 95% CI 0.83-1.44). In addition, the overall rate of ipsilateral stroke, including the periprocedural period through 10 years of follow-up, was similar for CAS and CEA (10.8 versus 7.9 percent, HR 1.33, 95% CI 0.98-1.80). However, there was a clear trade-off, with higher rates of perioperative stroke or death (and lower rates of perioperative myocardial infarction) for CAS compared with CEA. A CREST substudy found that at one year, stroke had a large detrimental impact on quality of life, while both MI and cranial nerve palsy had small impacts on quality of life that were not statistically significant [79]. Despite the higher rate of stroke with CAS, there were no differences at one year after the procedure between the CEA and CAS groups in any quality-of-life measure.
●The SAPPHIRE trial compared CAS with CEA in patients considered at high risk for surgery due to clinically significant cardiac disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal nerve palsy, previous radical neck surgery, cervical radiation therapy, recurrent stenosis after CEA, and age greater than 80 years [80,81]. SAPPHIRE randomly assigned 334 patients to CAS or CEA and enrolled symptomatic patients with ≥50 percent carotid stenosis or asymptomatic patients with ≥80 percent carotid stenosis. More than 70 percent of patients had asymptomatic carotid disease. At one year, CAS was not inferior to CEA [80]. The primary endpoint was the cumulative incidence of periprocedural (30 day) death, stroke, or myocardial infarction, and/or death or ipsilateral stroke between 31 days and one year. There was near significant reduction in the primary composite endpoint for CAS compared with CEA (12.2 versus 20.1 percent, absolute difference 7.9 percent, 95% CI -0.7 to 16.4 percent). At three years, follow-up data was available for 78 percent of the subjects. The major secondary endpoint (ie, primary endpoint events plus death or ipsilateral stroke between one and three years) was similar for CAS compared with CEA (24.6 versus 26.2 percent) [82].
A number of methodologic and statistical problems with SAPPHIRE have made the conclusions problematic and controversial, with bias that favored the CAS group [62,83-86]. In addition, the periprocedural complication rates in both the CAS and CEA treatment groups were higher than the recommended rate of ≤3 percent [2,60], which might negate any potential advantages of CAS. Despite these shortcomings, the conclusion that CAS is not inferior to CEA in patients with asymptomatic disease is probably valid for the patient group that was studied, that is, those considered "high risk" for carotid surgery [83].
Stenting in specific subgroups — Older adults appear to have worse outcomes with CAS than with CEA [87-89], even though older age was originally proposed to be a condition associated with high surgical risk and therefore a potential indication for stenting rather than endarterectomy. In the prospective CREST trial, the rate of poor outcome in patients age 70 and older was higher with stenting than with endarterectomy [87]. (See 'Stenting versus endarterectomy trials' above.)
In a meta-analysis of 41 studies in patients ≥80 years old, the relative risks of death or myocardial infarction at 30 days were similar for patients having CAS or CEA, but the stroke rate was significantly higher for CAS (7.0 percent, versus 1.9 percent for CEA) [88]. Based upon an acceptable 3 percent stroke rate at 30 days, the pooled RR for stroke was more than threefold higher after CAS (RR 2.18 versus 0.63 with CEA). Most of the included studies were retrospective, so the results of this meta-analysis are not definitive.
In data drawn largely from registries and case series, subgroups suggested to have tolerated CAS with relative safety included patients with prior neck irradiation, high cervical carotid bifurcations, and those with complete occlusion of the contralateral internal carotid artery. Further evidence from large controlled clinical trials is needed before drawing firm conclusions about the safety and effectiveness of CAS in these various subgroups. (See "Overview of carotid artery stenting", section on 'Risk assessment'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Carotid artery disease (The Basics)" and "Patient education: Atherosclerosis (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition and implications – Asymptomatic carotid atherosclerotic disease refers to the presence of atherosclerotic narrowing of the extracranial internal carotid artery in individuals without a history of ipsilateral carotid territory ischemic stroke or transient ischemic attack in the last six months. The most feared outcome of carotid atherosclerosis is ischemic stroke. The estimated risk of ipsilateral stroke in patients with asymptomatic carotid atherosclerosis (stenosis ≥50 percent) is approximately 0.5 to 1.0 percent annually. Asymptomatic carotid atherosclerosis is also a marker of increased risk for myocardial infarction and vascular death. (See 'Extracranial carotid atherosclerosis' above.)
●Intensive medical therapy for all patients – All patients with carotid stenosis should receive intensive medical therapy to reduce the risk of future stroke and myocardial infarction. These interventions include antiplatelet and statin therapy and other measures to address risk factors for atherosclerosis. Specific recommendations are discussed separately. (See 'Intensive medical therapy and follow-up' above and "Overview of secondary prevention of ischemic stroke" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke" and "Overview of primary prevention of cardiovascular disease".)
●Role of revascularization – The approach to asymptomatic carotid stenosis due to atherosclerosis depends upon the severity of stenosis and the comorbid conditions and life expectancy of the patient. In addition, the local experience of the center and surgeon or interventionalist is important if carotid revascularization is desired. (See 'Role of carotid revascularization' above.)
•Less than 50 percent stenosis – Patients with asymptomatic internal carotid artery atherosclerotic disease with <50 percent carotid artery stenosis do not require carotid revascularization. (See 'Stenosis less than 50 percent' above.)
•Fifty to 69 percent stenosis – For patients with asymptomatic carotid atherosclerotic disease with 50 to 69 percent carotid artery stenosis, we suggest no revascularization procedure (Grade 2C). Patients should be managed with intensive medical therapy alone and followed with interval surveillance carotid ultrasound imaging. (See 'Stenosis 50 to 69 percent' above.)
•Seventy to 99 percent stenosis – For medically stable patients with a severe 70 to 99 percent asymptomatic carotid stenosis, either intensive medical therapy alone or intensive medical therapy plus carotid revascularization are reasonable. For patients to potentially benefit from carotid revascularization, their life expectancy should be at least five years, and the combined perioperative risk of stroke and death should be ≤3 percent. We advise a shared decision-making approach that incorporates the patient's values and preferences. Patients must understand both that the risk of stroke with intensive medical therapy is relatively low and that the benefits of carotid revascularization are limited. We encourage patients with asymptomatic carotid stenosis of 70 to 99 percent to participate in ongoing randomized controlled trials comparing carotid revascularization with modern medical management. (See 'Stenosis 70 to 99 percent' above and 'Carotid endarterectomy' above and 'Factors influencing outcome' above.)
●Endarterectomy compared with stenting – Carotid artery angioplasty and stenting (CAS) and carotid endarterectomy (CEA) provide similar long-term outcomes for patients with carotid occlusive disease, but the periprocedural risk of stroke and death is higher with transfemoral carotid artery stenting (TF-CAS) compared with CEA. The periprocedural risk may be lower for transcarotid artery revascularization (TCAR) compared with TF-CAS.
TF-CAS should generally be reserved for patients with unacceptably high surgical risk and performed only in centers with demonstrated low (<3 percent) periprocedural risk for combined stroke and death. (See 'Carotid stenting' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Ronald M Fairman, MD, who contributed to an earlier version of this topic review.
The UpToDate editorial staff also acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review.
