15.1 Goals

1. 
   

   Understand the risk profile of a patient with asymptomatic carotid stenosis. Review medical and anatomical risk factors for stroke in patients with asymptomatic carotid stenosis and understand how medical, surgical, or interventional management can alter this risk profile.

   
   
2. 
   

   Review the literature on medical, surgical, and interventional treatment of patients with asymptomatic carotid stenosis.

   
   
3. 
   

   Understand the risks and benefits of all the three management strategies.

15.2 Case Example

15.2.3 Follow-up

Working with her primary physician, the patient was able to successfully stop smoking. Cholesterol goals were targeted initially with simvastatin, and ultimately the patient achieved her cholesterol goals with the addition of ezetemibe. Aspirin therapy was continued. No symptoms of ischemia developed. A repeat carotid ultrasound study showed decreased velocities in the ICA.

15.3 Case Summary

1. 
   

   What is the risk of stroke in a patient with asymptomatic carotid stenosis without surgical or endovascular treatment? How have changes in the medical treatment changed the clinical course of patients with asymptomatic carotid stenosis treated with medical therapy alone?

   
   

   Atherosclerotic stenosis of the extracranial carotid arteries is a relatively common disease of older adults, affecting approximately 7% of women and > 12% of men aged 70 years or above. ¹ Our knowledge of the risk posed by asymptomatic carotid stenosis has evolved considerably in the last 20 years, largely due to the advances in medical therapies. Several landmark papers, reviewed in greater detail later in this chapter, have contributed to this progression in understanding. The two largest trials that have addressed the issue of asymptomatic carotid stenosis are the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST). ^{2 , 3} These studies, both performed in the 1990s, were two randomized trials of carotid endarterec-tomy (CEA) versus medical therapy. In both studies, the annual risk of stroke from asymptomatic stenosis greater than 60% was found to be approximately 2% in the nonsurgical arms.

   
   

   While these studies are important as a foundation for our understanding of this disease process, it is important to bear in mind that they were performed over 20 years ago, prior to widespread use of aggressive medical management including statins and newer antiplatelet agents. Newer studies suggest that the risk of stroke from asymptomatic stenosis treated medically has fallen in the last 30 years. ⁴ Several recent studies suggest that the annual stroke risk of nonsurgical treatment of asymptomatic carotid stenosis ranges from 0.3 to 12%.5.6.7.8 Thus, _whiie ACAS and ACST remain important studies in the history of the disease, they have largely been eclipsed by contemporary data which show a very low risk in asymptomatic patients treated with medical therapy alone. Despite this overall low risk, certain patients may benefit from intervention if properly selected on the basis of certain anatomical and medical factors.

   
   
2. 
   

   What clinical or radiological variables can aid in risk stratification and decision making for intervention?

   
   

   Our understanding of the risk of asymptomatic carotid stenosis has become more nuanced in recent years. Several clinical and radiological features have been identified as risk factors for stroke in these patients. These risk factors provide a means for risk stratification and may allow clinicians to select patients for which an alteration in medical therapy or an intervention may be beneficial. The simplest means of risk stratification which is widely available is the percentage of stenosis. Though this method is simple and available, it demonstrates a lack of understanding of the pathogenesis of stroke due to carotid disease, which is overwhelmingly thromboembolic rather than related to hemodynamic failure. Accordingly, study data on the degree of stenosis as an accurate predictor of ipsilateral stroke risk are mixed. ^{9 , 10} Thus, more specific risk factors are likely to prove helpful for decision making. These include progression of stenosis on serial carotid ultrasound, plaque features, and findings on additional cranial studies including transcranial Doppler (TCD) ultrasound and standard axial imaging.

   
   

   The overall plaque burden (which includes the cross-sectional area of plaque from the clavicle to the mandible) has been shown to predict ipsilateral stroke significantly better than the degree of stenosis. ¹⁰ In addition, approximately 25% of patients will show progression of stenosis on annual carotid ultrasound studies. This progression has been shown to increase the risk of stroke to as high as 27% over a mean follow-up period of 42 months. ¹¹ Other features of the plaque itself have been shown to increase the risk of stroke. A systematic review showed that plaque echolucency on ultrasound, which is suggestive of lipid-rich necrotic core, raised stroke risk to approximately 10%, a roughly 2.5 relative risk increase, over a follow-up period of 30 months. ¹² In addition to echolucency, motion within the plaque is suggestive of plaque instability. This finding has also been shown to increase the risk of stroke in one study (hazard ratio ~5). ¹³ Other findings suggestive of plaque instability that are thought to increase the risk of stroke include the volume of plaque ulceration on three-dimensional ultrasonography, as well as enhancement of the carotid bulb on CT angiography. ^{14 , 15}

   
   

   In addition to features of the carotid plaque itself, TCD can be used to stratify stroke risk. ¹⁶ Approximately 10% of patients with asymptomatic carotid stenosis have evidence of emboli on TCD. ¹⁷ TCD recording showing two or more embolic signals over 1 hour has been shown to elevate the absolute annual risk of stroke to 7%. ¹⁸ In this study, the hazard ratio for ipsilateral stroke in patients who had emboli detected on TCD was > 6. ¹⁸ Finally, as might be expected, evidence of previous silent stroke on CTor magnetic resonance imaging (MRI) predicts ischemia, raising the annual event rate of stroke or TIA to 4.6%. ¹⁹

   
   

   In this particular patient’s case, though the degree of stenosis was severe, the plaque was heavily calcified, dense, and though somewhat heterogeneous in appearance, did not have evidence of ulceration (Fig. 15.1 and Fig. 15.2). Thus, the patient’s risk of stroke was deemed relatively low. TCD studies were not performed.

   
   
3. 
   

   What are the key aspects of maximal medical management for patients with asymptomatic carotid stenosis? What is the optimal antiplatelet strategy in these patients?

   
   

   The medical management of asymptomatic carotid stenosis focuses on modifiable risk factors for stroke including cholesterol reduction, treatment of hypertension, and antiplatelet medication. Hypertension is the most prevalent risk factor for stroke and is increasing with increasing age and obesity. ^{20 , 21} More than two-thirds of the U.S. population above 65 years of age is hypertensive. ²² The treatment of hypertension has been shown to decrease the risk of stroke and is recommended for primary stroke prevention. ²³ With the advent of multiple antihypertensive medications and sophisticated risk stratification, the treatment of hypertension has become complex and algorithm based with recommendations often in flux. ^{22 , 24} Patients with high-grade stenosis and longstanding untreated hypertension are at risk for hemodynamic failure if hypertension is overcorrected or corrected too rapidly. It is recommended that neurointerventional specialists coordinate antihypertensive care for prevention of stroke with involvement of the primary care physician.

   
   

   Smoking has been clearly established in numerous longitudinal studies to increase stroke risk. A systematic review assessing the risk for ischemic stroke in smokers showed a nearly twofold relative risk increase compared to nonsmok-ers. ²⁵ Furthermore, it has been shown that smoking cessation rapidly decreases stroke and other cardiovascular risk to a level that approaches but does not quite reach that of the nonsmoking population. ^{26 , 27 , 28} Numerous strategies are available to assist patients in smoking cessation including FDA-approved medications. These treatments should be offered to smokers with asymptomatic carotid stenosis. ^{23 , 29 , 30} In this case, the patient had attempted smoking cessation but was initially unsuccessful. Working with the primary physician, this patient was able to stop smoking without the use of adjunctive medications.

   
   

   Elevated total cholesterol, as well as elevation of low-density lipoprotein (LDL) relative to high-density lipoprotein (HDL) have been established as risk factors both for atherosclerosis and ischemic stroke. ^{31 , 32} More specifically, hyperlipidemia has been established as a risk factor for both carotid atherosclerosis and stenosis with lipid-rich plaque. ^{33 , 34} Treatment of these conditions with statin drugs has been shown to both slow the progression of carotid atherosclerosis and reduce the relative risk for ischemic stroke by 21 %. ^{35 , 36} Research on other lipid-lowering agents is nascent; however, a clinical trial demonstrated a reduction in the risk of ischemic stroke in patients with diabetes with the addition of ezetimibe to statin therapy (as used in this patient). ³⁷ Specific guidelines for the management of hypercholesterolemia are regularly updated by the National Institutes of Health through the National Cholesterol Education Program Adult Treatment Panel (NCEP-ATP).

   
   

   The benefit of antiplatelet therapy for patients with carotid atherosclerotic disease is well established. The Mayo Asymptomatic Carotid Endarterectomy Study, which did not use aspirin in the surgical arm, was terminated early due to the higher number of coronary and cerebral ischemic events in the surgical arm. ³⁸ This underscores the importance of antiplatelet therapy in this disease. Aspirin is the mainstay of antiplatelet therapy for asymptomatic carotid stenosis; however, the optimal dose of aspirin in this setting is not well established. ³⁹ Several large trials have examined dual antiplatelet therapy or alternative antiplatelet agents for patients with carotid stenosis, but the majority have included only those patients with prior stroke or TIA. ^{40 , 41} At present, there is a lack of clinical trial data to support the use of dual antiplatelet therapy, or antiplatelet therapy other than aspirin for the prevention of a first stroke in asymptomatic patients. ³⁹ In this case, the patient was treated with aspirin 81 mg daily.

   
   
4. 
   

   What are the benefits ofCEA? What is the risk of surgery in patients with asymptomatic carotid stenosis? What factors serve to alter this risk?

   
   

   The largest studies of the surgical management of asymptomatic carotid stenosis, ACAS and ACST, found an approximately 50% risk reduction with CEA as compared to medical therapy. These studies showed perioperative stroke and death rates of 2.3 and 3.1%, respectively. ²³ More recently, the Carotid Revascularization Endarterectomy versus Stent Trial (CREST) found 30-day perioperative stroke and death rates in asymptomatic patients undergoing CEA of 1.4%, much lower than the aforementioned trials. However, CREST was notable for the rigorous credentialing and lead-in period for operators and thus may underestimate procedural risk. ⁴² A recent study using data on Medicare beneficiaries in New York State undergoing CEA for asymptomatic stenosis used a multivariate logistic regression analysis to identify clinical features predictive of perioperative stroke and death. These findings were then developed and validated as the CEA-8 Risk Score ( Table 15.1), which ranges from 0.6 to 9.6%. ⁴³ Current guidelines recommend CEA only in those patients with a perioperative risk of stroke and death less than 3%; thus, this tool may prove helpful in selecting patients who may benefit from CEA. ³⁹

   
   
5. 
   

   What are the benefits of carotid angioplasty and stenting (CAS) for asymptomatic stenosis? What is the risk? In which patients might this therapy be offered?

   
   

   Most major noninferiority trials comparing CAS to CEA, including the Stent Supported Percutaneous Angioplasty of the Carotid versus Endarterectomy (SPACE), Endarterectomy versus Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S), and the International Carotid Stenting Study (ICSS) trials, enrolled patients with symptomatic carotid stenosis. ^{44 , 45 , 46} One major study to date, the Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial included asymptomatic patients with at least 80% stenosis deemed high risk for surgery. Though this study was stopped prematurely, stenting was found to be noninferior to endarterectomy and a trend toward benefit for stenting was noted at 1 year. ⁴⁷ The perioperative complication rate was 4.8% in the stenting group, but it should be noted that patients in SAPPHIRE were selected to have high-risk comorbidities. The benefits of stenting as demonstrated in the CREST study are similar to that demonstrated with CEA in ACAS. ⁴⁸ The perioperative risk for CAS in asymptomatic patients in CREST was 2.5%. Interestingly, the risk of CAS was slightly higher in older patients (see below). Relative indications for CAS are provided in ▶ Table 15.2.