Asymptomatic Carotid Artery Stenosis

Introduction

Carotid artery stenosis accounts for 8% to 15% of acute stroke,¹ the importance of which is magnified by the high rate of early recurrence after an initial event, up to 21% at 2 weeks and 32% at 12 weeks.² Understanding and maximizing primary prevention strategies for asymptomatic carotid stenosis is therefore critical. Over the past decade, there has been a shift in thinking about management of patients with asymptomatic carotid artery disease, including reassessment of carotid endarterectomy (CEA) vs carotid artery stenting (CAS) vs medical management alone. Surgical trials in the 1990s demonstrated benefit in patients with more than 50% stenosis for patients with symptoms and more than 60% for patients who are asymptomatic; however, improving outcomes with statin use and more aggressive blood pressure control has since equalized the playing field and generated new questions about ideal treatment strategies.^3,4 In addition, cognitive function has emerged as an important outcome in carotid artery disease.

Prevalence and Risk Factors

Asymptomatic carotid stenosis of more than 50% has an age-dependent prevalence in men of 0.5% to 5.7% and in women of 0.3% to 4.4%. Among those with severe (≥ 70%) stenosis, rates are 0.1% to 1.7% in men and 0% to 0.9% in women.^5,6 Stroke rates among those with high-grade carotid stenosis were calculated to be 2% to 4% per year in 2002,⁷ but dropped to 0.5% per year in 2013, largely owing to better medical management.⁸ In a recent multicohort analysis that included 23,706 participants, age, male sex, history of vascular disease, systolic and diastolic blood pressure, total cholesterol/high-density lipoprotein (HDL) ratio, diabetes mellitus, and current smoking were independent predictors of moderate and severe stenosis.⁷

Diagnosis

Duplex Doppler (DD) ultrasound is the most common diagnostic modality for carotid stenosis worldwide and combines brightness/grayscale imaging of the vascular structures (B-mode) and quantitative representation of intraluminal flow velocities and waveforms (pulse-wave analysis). In an accredited laboratory with experienced technicians, DD ultrasound is accurate, safe, reliable, and inexpensive. Pulse-wave calculations of intraluminal flow velocities provide a highly replicable means of monitoring the degree of stenosis (Table). Additional information can be derived from the B-mode images of plaque morphology including intraplaque hemorrhage and plaque ulceration and mobile thrombi (Figure). Sensitivity and specificity of DD ultrasound screening is approximately 94% and 92%, respectively, for detecting stenosis of 60% to 99%.⁹ Magnetic resonance angiography (MRA) and CT angiography (CTA) are alternatives to ultrasound and, in many settings, may be preferable if a Doppler lab is not available. The accuracy of MRA and CTA are similar to DD ultrasound and can provide additional information about plaque morphology and vascular pathology.

Risk Stratification

Several factors that mediate stroke risk in carotid artery stenosis have been used to stratify risk and guide management.¹⁰ Higher degrees of stenosis are associated with higher risk of stroke.^11,12 At the highest levels of stenosis (80%-99%) strokes are more likely to have hemodynamic etiology, as flow restriction increases ischemic injury risk in the distal field of the internal carotid artery (ICA).¹³ In both hemodynamically significant lesions and in lower degrees of stenosis, morphologic characteristics of the plaque may determine risk. Strategies to stratify risk use direct imaging and physiologic measurements.

Progression of Stenosis

Progression of stenosis is associated with increasing stroke risk. A study showed the 8-year cumulative ipsilateral ischemic stroke rate was 0% in patients with regression of stenosis, 9% if stenosis was unchanged, and 16% if there was stenosis progression.¹⁴ This risk may not hold for the very highest degree of stenosis, however. A recent large cohort analysis reported that the incidence of stroke among patients moving from asymptomatic carotid artery stenosis to complete occlusion was 0.3%.¹⁵

Plaque Morphology

Certain morphologic features of the carotid plaque are associated with increased stroke risk. The so-called vulnerable plaque includes a lipid-rich necrotic core, a thin fibrous cap, intraplaque hemorrhage, and plaque ulceration.¹⁶ A lipid core is discernable by B-mode ultrasound as hypoechoic or hypoechoic with small hyperechoic areas.¹⁷ Ulcerations and plaque hemorrhage can also be seen on Doppler ultrasound. With MRI carotid-wall imaging, presence of intraplaque hemorrhage, fibrous cap thinning or rupture and lipid-rich necrotic core are all predictive of future ipsilateral stroke or transient ischemic attack (TIA), and have been associated with ipsilateral cryptogenic stroke.^18,19 In a study of 114 patients with a spectrum of carotid stenoses who underwent multicontrast sequences for carotid wall imaging, a lipid rich necrotic core and carotid wall volume were associated with greater volume of acute stroke, regardless of the degree of stenosis.²⁰ This finding was replicated as part of a larger, event-driven clinical trial investigating atherosclerotic risk in patients with metabolic syndrome.²¹ Among 232 subjects with asymptomatic carotid stenosis, high lipid content volume in the plaque (hazard ratio [HR] = 1.57, P = .002), and a thin or ruptured fibrous cap (HR = 4.32, P = .003) were associated with the combined endpoint of fatal and nonfatal myocardial infarction, ischemic stroke, acute coronary syndrome, and symptom-driven revascularization. Although 8.4% of subjects reached some endpoint over 3 years of observation, the incidence of stroke was 0.9%.

Microemboli Detection

Another way of stratifying risk in patients with asymptomatic carotid stenosis is to use transcranial ultrasound (TCD) to detect microemboli released from high-grade carotid stenosis. A TCD headframe holds a 2-Hz ultrasound probe in place during monitoring. Detection of 2 or more microemboli over 1 hour is considered positive.²² In a large prospective cohort study of 467 patients with asymptomatic carotid stenosis, the 2-year ipsilateral stroke risk was 3.62% in patients with embolic signals and 0.70% in those without (HR = 6.37; CI: 1.59-25.57; P = .009).²³ In contrast, a similar earlier study showed a 1-year stroke risk of 15.6% in patients with embolic signals compared with a risk of only 1% among patients who were embolus-negative (P < .001).²⁴ The higher risk of stroke at the earlier time point occurred before adoption of more aggressive blood pressure control and use of statins.

Cerebral Hemodynamics

For higher-grade stenosis (≥70%), hemodynamic measurements can stratify risk. Here again, DD ultrasound offers a reliable and inexpensive approach. The most commonly used technique, cerebral vasomotor reactivity (CVR) with TCD, involves continuous monitoring of the middle cerebral artery (MCA) bilaterally or on the side of the carotid stenosis during a vasodilatory challenge. Patients hold their breath for 30 seconds to increase the PCO₂ in the bloodstream. Alternatively, 5% CO₂ can be administered via face mask. Because CO₂ is a potent vasodilator, the flow velocity will rise in the proximal MCA in response to vasodilation in the more distal arterioles. If the arterioles are already maximally vasodilated because of a chronic stenosis, response to CO₂ will be low or absent. Thus, this technique can be said to measure cerebrovascular reserve. Breath holding index (BHI) is calculated as:

where MFV_(bh) is mean flow velocity (MFV) during breath holding and MFV(base) is MFV at baseline. A BHI of less than 0.69 is abnormal.²⁵ A capnometer is required when using the CO₂ inhalation technique. For this method, the CVR calculation is the same as above, but the change in MFV is divided by the rise in PCO₂, calculated as percent rise in MFV per mm Hg rise in PCO₂. Abnormal CVR is less than 2.0%.²⁶ The percentage cerebral blood flow velocity increase (pCi) during any hypercapnic challenge should be 20% or more.²⁷

Measures of CVR are predictive of cerebrovascular ischemia. Among 94 patients with greater than 70% asymptomatic stenosis, those with impaired BHI had an annual ipsilateral stroke rate of 13.9% vs 4.1% among those with normal BHI.²⁵ Using the CO₂ inhalation technique, among 46 patients with 80% or more ICA stenosis or complete occlusion who were followed for 6 months, impaired CVR was associated with stroke or TIA (Fisher’s exact test, P=.03).²⁶ In a meta-analysis from 9 studies comprising individual data from 754 patients with 70% or more carotid stenosis, CVR was independently associated with an increased risk of ipsilateral ischemic stroke among asymptomatic patients (HR = 2.90, [95% CI: 1.02-8.30]; P = .047).²⁸

Management

Medical Management

The mainstay in treating patients with carotid artery disease for any degree of stenosis is aggressive medical treatment. Managing atherosclerotic risk factors is familiar to the general practitioner and the neurologist. Better control of blood pressure^29,30 and cholesterol,^31,32 attention to diet, and adopting a nonsedentary lifestyle have resulted in improved outcomes for patients with stroke and for asymptomatic carotid stenosis in particular. For asymptomatic patients with stenosis greater than 60%, surgical revascularization had historically been proven advantageous. A meta-analyses comparing treatment arms of carotid disease intervention trials over 15 years demonstrated that medical treatment of carotid artery disease has improved to the point of matching surgical outcomes among patients who are asymptomatic, with an annual stroke rate of 1.13% in 2010 compared with between 2% and 3% among patients who were recruited to randomized clinical trials before 2000.³³ This finding has resulted in clinical practice moving toward medical management for asymptomatic ICA stenosis. With improved outcomes under new medical guidelines, surgical revascularization is being retested for efficacy.

Surgical Management

Patients with symptomatic carotid artery stenosis benefit from early intervention with mechanical endarterectomy or stenting because of the high risk of early recurrence; the approach to these patients is unlikely to change substantially. Those with asymptomatic carotid stenosis, however, carry a lower overall stroke risk, and may no longer gain better outcomes with surgical vs medical treatment. The seminal asymptomatic carotid stenosis surgery trials were completed in the 1980s. The ACAS^a in the United States, and the ACST^b in Europe established the benefit of surgery over medical management. In ACAS, patients with 60% to 99% stenosis were enrolled and randomly assigned to receive CEA or medical therapy. Those with CEA had a 5-year ipsilateral stroke rate of 5.1% vs 11.0% for patients receiving medical therapy alone.³⁴ In ACST, similar results were seen in 3,120 patients randomly assigned to CEA vs deferred surgery until symptoms occurred. At 5 years, 6.9% of those who had CEA, experienced a stroke, compared with a stroke rate of 10.9% among those who did not have CEA. At 10 years, strokes had occurred in 17.9% of subjects in the medical-only group vs 13.4% in the group that had CEA.³⁵ Because these trials were completed before modern medical management and before the emergence of CAS, there was a need for additional trials. There was also a paucity of information about patients over age 80 years, and about women and minorities with carotid disease.

The CREST^c trial compared CEA with CAS in 2,522 patients with 70% or more carotid stenosis who were symptomatic or asymptomatic. There was no significant difference in the composite endpoint of any stroke, myocardial infarction, death during the periprocedural period or ipsilateral stroke in the 4-year follow up period (HR=1.18 [95% CI: 0.82-1.68], P = .38]). Minor ipsilateral stroke was higher in patients who had CAS and myocardial infarction was higher in those who had CEA. Prespecified analysis did not show modification of the treatment effect by symptomatic status. In post hoc analysis, younger patients had slightly better outcomes with CAS, and older patients did slightly better with CEA.

Although CREST showed equivalence between stenting and surgery, it did not address whether either intervention would do better compared with aggressive medical therapy alone. To address this question, the CREST-2^d trial was initiated³⁶ and combines 2 multicenter randomized trials, which randomly assign patients to receive CEA plus intensive medical management (IMM) vs IMM alone or to receive CAS plus IMM vs IMM alone. The primary risk factor targets for IMM are systolic blood pressure lower than 130 mm Hg and low-density lipoprotein (LDL) cholesterol less than 70 mg per dL. The primary outcome is the composite of stroke and death within 44 days of randomization, and stroke ipsilateral to the target vessel thereafter, up to 4 years. Change in cognition and differences in major and minor stroke are secondary outcomes. It is anticipated that this trial will answer the question of whether revascularization can still improve outcomes for asymptomatic carotid stenosis patients in the current environment of improved medical management for atherosclerosis.

Cognition

In face of our aging population, cognitive status has emerged as an important outcome measure in stroke studies.³⁷ Carotid artery stenosis is known to impact cognition through a number of mechanisms. General cerebrovascular risk factors such as hypertension, diabetes, and metabolic syndrome are associated with vascular cognitive impairment (See Vascular Cognitive Impairment in this issue). Maximizing control of these factors can help prevent recurrent stroke that is associated with cognitive decline.³⁸ Plaque vulnerability and hemodynamic status have specific effects on cognitive function.

Plaque Vulnerability

Microemboli correlate with cognitive decline in patients with dementia, both among those with Alzheimer’s disease (AD) and with vascular dementia (VaD).³⁹ Microemboli are known to occur with high-grade carotid stenosis, and are associated with silent infarction. In one population-based prospective cohort study, decline in cognitive function was associated with the appearance of new silent infarcts on follow up MRI, independent of the presence of silent infarcts at baseline.⁴⁰ In patients with asymptomatic carotid stenosis, a recent study showed that among 27 patients with more than 60% stenosis, those with a strain pattern on ultrasound—a measure of plaque instability—had high rates of microemboli. The strain measure correlated with cognitive dysfunction, particularly with executive function measures.⁴¹

Hemodynamic Impairment

Hemodynamic failure in high-grade carotid artery stenosis is associated with cognitive impairment. In a study of 210 patients with unilateral asymptomatic severe carotid stenosis, there was increased probability of developing cognitive deterioration compared with 109 subjects without carotid stenosis (odds ratio [OR] = 14.66, 95% CI 7.51-28.59; P<.001).⁴² Among 83 of these patients with unilateral high-grade carotid stenosis, impaired CVR was associated with cognitive impairment. This finding was demonstrated with cognitive tests specific to the ipsilateral hemisphere, further supporting the relationship between hypoperfusion and cognitive dysfunction.⁴³

Cognitive impairment associated with high-grade carotid stenosis may also be reversible with revascularization. A recent case series showed that among 137 patients with 70% to 99% carotid artery stenosis with TIA only in the prior 6 months, both CVR and cognitive performance improved 3 months after CEA.⁴⁴ A meta-analysis reviewed 16 studies for the impact of carotid stenting on cognition and found overall improvements in the modified Mini-Mental State Examination (MMSE) and tests of attention/psychomotor speed and memory.⁴⁵ Reversibility of cognitive decline would represent an important clinical outcome because vascular cognitive impairment, along with other causes of dementia, are generally not reversible. In order to test the reversibility hypothesis more rigorously, an ancillary study to CREST-2, the CREST-H^e has begun and will test the hypothesis that the hemodynamically impaired subset of CREST-2 patients would benefit cognitively from revascularization.⁴⁶ A baseline perfusion MRI or CT, performed at baseline, will categorize patients into hemodynamically impaired or hemodynamically normal status. The primary outcome is cognitive status at 1 year, comparing those who get revascularized with those who receive IMM alone.

What Do We Tell Our Patients?

Management of asymptomatic carotid stenosis has evolved over the past 10 years. The seminal surgical studies that suggested revascularization would reduce stroke rate more than modern medical management may no longer be true. Aggressive medical management that includes controlling blood pressure to a target of 130/80 mm Hg, treating atherosclerosis with high potency, high-dose statins, and managing lifestyle choices of diet and exercise has become standard of care. Many vascular neurologists are eschewing CEA and CAS for patients with asymptomatic carotid stenosis and focusing on medical management alone. For clinical decision making for who should be sent for revascularization, testing for plaque instability, microemboli, and hemodynamic status may help determine which asymptomatic patients are at highest risk for stroke. With the CREST-2 trial, we now have a chance to rigorously retest our assumptions about surgical and interventional revascularization. Finally, cognitive function has emerged as an important outcome consideration. If cognitive impairment exists among a subset of our patients with asymptomatic carotid stenosis, we may need to re-assign them to symptomatic status, and consider the possibility that the cognitive impairment may be reversible with revascularization.

a Asymptomatic carotid atherosclerosis study.

b Asymptomatic carotid surgery trial.

c. Carotid revascularization endarterectomy versus stenting trial (NCT00004732).

d. Carotid revascularization and medical management for asymptomatic carotid stenosis (NCT02089217).

e. Carotid revascularization endarterectomy and stent trial–hemodynamics (NCT03121209).

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