Carotid artery stenosis: diagnosis and guidelines for management
Article information
Abstract
In carotid artery stenosis, the carotid arteries become blocked by fatty cholesterol deposits. Older individuals with high cardiovascular risk are disproportionately susceptible to this condition, for which risk factors include smoking, high cholesterol, male sex, and older age. When the vascular endothelium is damaged by the above-mentioned causes, low-density lipoproteins invade the inside of the endothelium and undergo an oxidation process. Monocytes infiltrate the endothelium in response to oxidized low-density lipoproteins and transform into lipid-laden macrophages, thereby activating inflammatory responses. As this inflammatory reaction progresses further, various decomposing enzymes are secreted, causing the atherosclerotic plaque to rupture and various thrombogenic materials to be secreted into the blood, resulting in the formation of blood clots and vascular stenosis or occlusion. This can cause symptoms ranging from mild, such as blurred-vision, to severe, such as life-threatening stroke. Carotid artery stenosis accounts for approximately 10% of all strokes. Therefore, early diagnosis and appropriate management are very important. When choosing between medical and surgical treatment, it is necessary to consider various factors, such as patient characteristics, symptoms, risk factors, and imaging results. In this review, we discuss the pathophysiology of carotid artery stenosis, risk factors, and the importance of prompt diagnosis and treatment. In particular, we focus on how to determine the need for treatment and select management methods for each individual patient.
Introduction
Stroke is one of the leading causes of high mortality in worldwide [1]. In South Korea, the mortality rate due to stroke is gradually decreasing, but the proportion of stroke in total medical expenses is increasing. And the proportion of ischemic stroke is increasing compared to hemorrhagic stroke [2]. Carotid artery stenosis is the cause of approximately 10% of stroke patients [3].
Carotid artery stenosis occurs when the carotid artery becomes blocked by plaque consisting of fatty cholesterol deposits. This condition, known as atherosclerosis, interferes with blood flow and increases the risk of stroke [4]. A observe at the exact pathophysiology of carotid plaque formation may reveal how carotid artery occlusion can lead to severe symptoms of carotid artery stenosis. Occlusion of the internal carotid artery occurs due to the following processes: Thrombotic events such as embolism and other hemodynamic related problems, mainly atherosclerosis and hypertension contribute to occlusion. The endothelial of the carotid artery has been damaged over a long period of time. Risk factors include hyperlipidemia, high blood pressure, smoking, and immune response. As a result, the permeability of the vascular endothelium increases and the adhesion of leukocytes and monocytes increases. Macrophages are activated and a fibrous cap containing smooth muscles, collagen, and elastin is formed. Macrophages and smooth muscles attract lipids. Smooth muscles proliferate quickly, extracellular matrix deposition is occurring. In this series of inflammatory reactions, various decomposition enzymes are secreted, and these decomposition enzymes rupture the atherosclerotic plaque and various thrombogenic materials are discharged into the blood, resulting in the formation of blood clots and stenosis or occlusion of carotid artery [5–7].
The annual stroke rate in individuals with carotid artery stenosis greater than 75% is 3.3%. Moreover, patients with severe carotid stenosis have a higher rate of cardiac events (8.3%) and mortality (6.5%). However, if carotid artery stenosis is less than 75%, the stroke incidence rate is minimal at 1.3% per year [8]. These statistics emphasize the importance of early detection and treatment of carotid artery stenosis to prevent complications.
Treatment modality depends on the type of carotid artery stenosis, the degree of luminal obstruction, and whether the patient has already had a stroke. For patients with symptomatic carotid artery stenosis (SCAS), immediate invasive treatment, including medical treatment, may be the gold standard, including either carotid angioplasty and stenting or carotid endarterectomy (CEA) [9]. On the other hand, for patients with asymptomatic carotid artery stenosis (ACAS), medication is the first treatment option. Drugs used include antihypertensive agents, antiplatelet agents, and anti-hyperlipidemia agents [10].
Clinical Features
Carotid bruit
It is a bruit generated by turbulent blood flow in the area of carotid artery stenosis and can be confirmed through auscultation. It is reported that this bruit occurs in 4% to 5% of the adult population aged 45 to 80 years, and in cases of severe stenosis (>75%), it is reported in 70% to 89% [11]. In general, the more severe the carotid artery stenosis, the greater the intensity of the bruit. There is also a report that the risk of stroke is 2.6 times higher in cases of carotid artery stenosis with bruit compared to cases without bruit [12].
Amaurosis fugax
The term "amaurosis fugax" is used when the symptoms are transient. It refers to temporary loss of vision caused by ophthalmic artery ischemia. There are many causes, but most cases are emboli caused by ipsilateral carotid artery stenosis. For patients with this symptom, the probability of having a stroke is reported to vary from 1.8% to 24.2%, depending on the number of stroke risk factors such as high blood pressure, hypercholesterolemia, diabetes, and smoking [13].
Cerebral infarction
The pathogenesis of cerebral infarction caused by carotid artery stenosis can be broadly classified into artery-to-artery embolism, acute thrombotic occlusion, and hemodynamic insufficiency. It is known that artery-to-artery embolism accounts for the largest proportion of cerebral infarctions, but in many cases, cerebral infarction occurs due to complex mechanisms. When large vessel occlusion occurs due to complex factors, various neurological symptoms appear and a life-threatening condition occurs [14,15].
Diagnostic Modalities
Efficient diagnosis and classification of carotid stenosis: 1st degree <50% mild stenosis, 2nd degree 51% to 69% moderate stenosis and 3rd degree 70% to 99% severe stenosis is one of the important steps for proper management. Scientific research and technological advancements have greatly improved diagnostic methods. However, the diagnostic process may differ for symptomatic and asymptomatic patients [16].
Ultrasonography
It is widely used as a screening test because of its non-invasive and easy-to-use advantages. However, there is a disadvantage that the results vary greatly depending on the operator. However, it has the advantage of being able to easily detect ulceration, echo-lucent, and intraplaque hemorrhage (Fig. 1) [17].
Magnetic resonance imaging
Magnetic resonance imaging (MRI) is commonly used to obtain high-contrast images of the internal anatomy of vessels. This is an appropriate method to confirm histopathological findings regarding the composition of atherosclerotic plaques on the blood vessel wall [18]. Magnetic resonance angiography (MRA) imaging can be used to reduce static tissue around blood vessels and obtain more relevant images of blood movement. Contrast agents compare diastolic and systolic velocity waveforms to provide high-contrast images, which are useful in locating injuries. There is also a time of flight MRA technique that can obtain high-quality images without using a contrast agent that is burdensome to the patient (Fig. 2) [19].
Computed tomography angiography
There are disadvantages to using contrast media and exposure to radiation. But the time it takes to obtain an image is short, and because images can be obtained using multi-planner reconstruction, the state of even curved blood vessels can be identified [17].
Digital subtraction angiography
It is a gold standard test that can determine the degree of stenosis of the carotid artery and is the test with the highest accuracy. A high-contrast picture of a blood vessel can be obtained by subtracting 2 X-ray images (one before the contrast agent is administered and one after). Digital subtraction angiography (DSA) has also been shown to be convenient for predicting cerebral hyperperfusion phenomenon with up to 75% sensitivity and 100% specificity. It is possible to clearly distinguish between complete occlusion and near total occlusion. Especially in cases where carotid artery stenosis and intracranial atherosclerosis and stenosis are present (tandem lesion), DSA can be the gold standard [18,19].
The degree of carotid artery stenosis is known to be related to the risk of stroke. However, guidelines based on the diagnostic test method used and the standards for stenosis rate are reported slightly differently. In fact, in many studies, the diagnostic techniques described above are used in combination [16,20]. Methods for calculating the stenosis rate are the widely known North American Symptomatic Carotid Endarterectomy Trial (NASCET) and European Carotid Surgery Trial (ECST) (Fig. 3) [21,22]. Recently, it is common to measure the degree of carotid artery stenosis using the NASCET method [23].
Management of Carotid Artery Stenosis
In the treatment of carotid artery stenosis, it is necessary to take a look about diet and lifestyle before medical or surgical management.
The main pathophysiology of carotid artery stenosis is atherosclerosis [5–7]. High blood pressure worsens atherosclerosis and increases the risk of stroke. Therefore, an antihypertensive lifestyle is necessary. The Dietary Approaches to Stop Hypertension diet, which is rich in fruits, vegetables, and low-fat dairy products and low in saturated fat and cholesterol, has been approved by the American Heart Association for improving the cardiovascular health of people. Adopting a Mediterranean diet was associated with a moderate but statistically significant reduction in blood pressure, and a meta-analysis found greater reductions in people with higher systolic blood pressure at baseline and in those who continued monitoring for longer periods of time [24, 25].
And active smoking cessation is recommended. Smoking is known to increase the intima-media thickness of the carotid artery and worsen carotid artery stenosis in proportion to the amount of smoking [26]. As a result of comparing patients who continue to smoke with those who quit smoking, a study reported that there was a significant difference in the degree of carotid artery stenosis and intima-media thickness [27]. and there was also a study that reported a decrease in the risk of stroke within 5 years after quitting smoking [28].
Lastly, active sugar control through exercise, medication, and dietary control is recommended. Hyperglycemia promotes cytotoxicity and atherosclerosis. Recent paper has shown that there is a significant increase in the intima-media thickness of the carotid artery and that the incidence of ischemic stroke increases 2 to 5 times [23].
Asymptomatic Carotid Artery Stenosis
Medical management
In general, the use of antiplatelet agents rather than anticoagulants is recommended for carotid artery stenosis, but in cases where anticoagulants must be taken due to atrial fibrillation, valvular disease, etc. in addition to carotid artery stenosis, it is appropriate to administer anticoagulants first [29–31]. The use of antiplatelet agents in asymptomatic patients is controversial due to concerns that incorrect treatment may increase the risk of serious bleeding without reducing the risk of stroke. Antiplatelet treatment for asymptomatic ACAS patients requires a clear analysis of risks and benefits [10]. A systematic review inferred that low-dose aspirin may alleviate the progression of ACAS, although it may not reduce vascular disease [32]. Additionally, in a randomized case-controlled trial of aspirin 325 mg or placebo in patients with ACAS with cervical murmurs with stenosis greater than 50%, no ischemic events or deaths occurred after a median of 2.3 years [33,34]. Other studies have also found no significant differences in the incidence of transient ischemic attack (TIA), ischemic stroke, unstable angina, myocardial infarction, and cardiovascular-related death between placebo and aspirin groups in randomized controlled trials regarding aspirin use [33]. However, another observational study found that aspirin significantly reduced the risk of ipsilateral stroke or TIA and the risk of stroke or death from cardiovascular events [35]. As such, the use of antiplatelets in ACAS patients seems to be still debated.
A review of 18 randomized controlled trials (56,934 participants) of statins for primary prevention of cardiovascular disease found significant reductions in all-cause mortality, fatal and nonfatal stroke [36]. The Asymptomatic Carotid Surgery Trial (ACST-1) found that participants who received lipid-lowering drugs had a significantly lower 10-year incidence of stroke or death and a relatively lower perioperative risk [37]. There is also a paper recommending that ACAS patients reduce their blood low-density lipoprotein levels to below 100 mg/dL through active statin treatment [38].
Surgical management
The decision to perform invasive treatment in patients with asymptomatic carotid stenosis is subject to debate. CEA complication recognition and management is important. In randomized trials, myocardial infarction has occurred at a slightly higher rate for CEA compared with carotid artery stenting (CAS), with a reported incidence between 0 and 2 percent [39]. A postoperative neck hematoma can be catastrophic and result in abrupt loss of the airway. In the International Carotid Stenting trial, the overall incidence of severe hematoma following CEA was 3.4 percent. Hematoma was associated with cranial nerve palsy in 28 of 45 patients [40]. Cranial nerve or other nerve injuries occur in approximately 5 percent of patients following CEA [41]. The most commonly encountered nerves during CEA including the following: Hypoglossal nerve, Facial nerve, mandibular nerve, Vagus/laryngeal nerves, Glossopharyngeal nerve, Sympathetic nerves. Cerebral hyperperfusion syndrome is an uncommon sequela of CEA occurring in only a small percentage of patients after carotid revascularization (from less than 1 to as high as 3 percent in various reports) [42,43]. It is probably the cause of most postoperative intracerebral hemorrhages and seizures in the first 2 weeks after CEA. Stroke is the second most common cause of death following CEA. Stroke rates associated with CEA in large trials are generally <3 percent for asymptomatic patients and <5 percent for symptomatic patients. Rates range from less than 0.25 percent to more than 3 percent depending upon the indication for CEA and other factors, including the experience of the surgeon [44,45]. The 2 largest randomized controlled trials comparing CEA with medical care in asymptomatic individuals showed a small benefit of surgery in preventing stroke [46]. One of these studies found that CEA reduced the risk of stroke from 2% per year to 1% per year [47]. It remains unclear whether reducing stroke incidence with current routine medical care could reduce the relative benefit of CEA in patients with asymptomatic carotid stenosis. In particular, patients over 75 years of age who underwent surgery were reported to have a higher mortality rate during follow-up [20]. Until now, CEA treatment methods for ACAS patients were based on the Veterans Administration Cooperative Study, the Asymptomatic Carotid Atherosclerosis Study, and the ACST study, targeting patients with stenosis of 60% or more. It was recommended that it be implemented. It has been recommended that it be performed by institutions or doctors with a postoperative mortality rate of less than 3% [47]. However, recent developments in drug treatment include inducing lifestyle changes such as diet control, appropriate exercise, and smoking cessation, thorough control of diabetes, low blood pressure, and dyslipidemia, and appropriate use of antiplatelet agents with various mechanisms. When the best medical treatment is administered, the incidence of stroke in patients with carotid artery stenosis is reported to be less than 1% per year [48]. The annual incidence of stroke in the drug treatment group was previously reported to be 2.2% in the Asymptomatic Carotid Atherosclerosis Study [49] and 2.4% in the American Symptomatic Carotid Endarterectomy Trial study [21]. However, the more recent Oxford study [50] and Second Manifestations of ARTerial disease study [51] reported stroke incidence rates of 0.35% and 0.5%, respectively. In other words, for invasive treatment methods such as CEA or CAS to be justified in asymptomatic carotid artery patients, the annual incidence of stroke after treatment must be less than 0.5% [48]. Recently, the 10-year long-term follow-up results of the Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) study were reported, where, excluding the occurrence of complications within 30 days after the procedure, the 10-year cumulative stroke incidence was 6.9% in the CAS group and 5.6% in the CEA group, which is an average of 0.5% per year (Table 1) [20,47,49–51]. It goes beyond. Of course, even considering that the patient group in this study included about 47.5% of symptomatic patients, stroke occurred in 4.4% and 2.3%, respectively, within 30 days after the procedure, and other complications must also be considered [51]. It is difficult to justify CEA and CAS methods in ACAS patients. However, this does not mean that all ACAS patients do not have indications for invasive treatment. Some papers estimate that CEA or CAS is required in approximately 10% of ACAS patients [52,53]. An important point of this study is that the patient group was not determined based on the degree of stenosis of the carotid artery. To determine whether or not to treat, the presence or absence of unstable atheromatous plaques was considered an important criterion. In order to select ACAS patients with unstable atheromatous plaques who are eligible for treatment, it is helpful to identify micro-emboli through trans-cranial doppler monitoring, identify bleeding within the atheromatous plaque on MRI, and identify ulceration or inflammation in the atheromatous plaque [52].
Symptomatic Carotid Artery Stenosis
Medical management
After experiencing a TIA or minor stroke, it is important to immediately evaluate your condition and begin early preventative treatment. This can significantly reduce the risk of early stroke recurrence by approximately 80% [54]. Invasive treatment method should be considered in patients with symptomatic severe carotid stenosis unless accompanied by significant risks such as serious cardiopulmonary disease, recent massive cerebral infarction, or hemorrhagic transformation. Antiplatelet therapy should be started immediately after carotid artery recanalization because it plays an important role in preventing stroke recurrence [55]. Aspirin is the most commonly prescribed antiplatelet agent and should be started immediately. Some studies suggest that taking aspirin and clopidogrel within 24 hours after a TIA or minor stroke may be more beneficial than aspirin alone [56].
A study examining the relationship between blood pressure and stroke risk in patients with carotid artery stenosis found that most patients can safely lower their blood pressure gradually over several days. However, individuals with severe bilateral or severe unilateral stenosis should avoid rapid drops in blood pressure and use antihypertensive agents carefully [54].
Randomized clinical trials have recommended statin therapy even in patients with mild or moderate hypercholesterolemia, with the goal of lowering low-density lipoprotein cholesterol levels to less than 70 mg/dL [38,57]. For long-term prevention of stroke and cardiovascular events in patients with symptomatic carotid stenosis and atherosclerotic cardiovascular disease, maintenance of low serum lipid levels with statins with or without ezetimibe is recommended. Statins have been shown to significantly reduce overall mortality of stroke [36,58]. If target lipid levels cannot be reached with full-dose statins, the addition of ezetimibe (10 mg daily) is considered a good alternative [58].
As such, the importance of basic lifestyle changes and medical treatment prior to surgical treatment is increasing in the treatment of CAS patients (Table 2) [54–58].
Surgical management
Medical treatment is rarely recommended as first-line treatment for symptomatic carotid stenosis patients with stenosis of more than 50%. Most studies recommend active treatment of CEA or CAS. However, there has been ongoing controversy over the past years as to which of the 2 should be considered primarily. Among many studies, 2 classical studies on CEA are NASCET [59] and ECST [60]. These 2 studies reported that CEA can reduce the incidence of cerebral infarction in patients with SCAS of more than 50%. When CEA was performed on 50% to 69% of patients with carotid artery stenosis, the absolute risk reduction rate could be lowered by 6.5% compared to medical treatment alone, in the patient group with a stenosis rate of 70% or more, the absolute risk reduction rate was reported to be reduced by 17% after 2 years in the NASCET study and by 14.9% after 3 years in the ECST study. If the degree of stenosis of the carotid artery is 70 to 99% based on NASCET, CEA results in an absolute risk reduction of about 15.3% (95% confidence interval [CI], 9.8 to 20.7) after 5 years. It has been reported that in cases with 50% to 69% stenosis, the absolute risk reduction can be reduced by 7.8% after 5 years. Meanwhile, the degree of benefit of CEA varies depending on gender and age. In the case of stenosis of 50% or more, it was reported that CEA is about 4 times more beneficial in men and about 3.6 times more beneficial in those over 75 years old than in those under 65 years old. In both studies, there was no benefit of CEA compared to medical treatment when stenosis was less than 50% according to NASCET criteria.
Recently many other studies have been conducted, one of the most reference currently is the CREST study [39,61]. Before this study, many studies supported consideration of CEA as primary treatment, but there have been many changes since the CREST study [62,63]. The CREST study was conducted on patients with SCAS who showed stenosis of more than 50% on angiography (Patients are included if they show stenosis of more than 70% on carotid ultrasound, or 50% to 69% stenosis on carotid ultrasound and more than 70% on computed tomography angiography [CTA] or MRA). When only the occurrence and death of stroke, excluding other complications, were considered as variables, the incidence rate within 30 days was 3.2% for the CEA method and 6.0% for the CAS method, which was advantageous to the CEA method (hazard ratio for stenting, 1.89; P=0.02). However, when comparing the 4-year cumulative frequencies, there was no significant difference between the 2 groups, with CEA at 6.4% and CAS at 8.0% (hazard ratio for stenting, 1.37; P=0.14). Meanwhile, the occurrence of stroke, death, or myocardial infarction within 30 days after treatment was investigated as the primary endpoint. And the incidence of stroke in the ipsilateral cerebral hemisphere after 30 days was investigated. In patients with symptomatic carotid stenosis, the incidence rate within 30 days was 5.4% in the CEA group and 6.7% in the CAS group (hazard ratio for stentingm, 1.26; 95% CI, 0.81 to 1.96). And the 4-year cumulative incidence rate was 8.4% in CEA and 8.6% in CAS, with no statistical significance between the 2 groups. Similar results were reported in another study, the International Carotid Stenting Study [64]. As a result of a study on a total of 1,713 patients, the cumulative risk rate for CEA was 5.1% for 1 year and 9.4% for 5 years in terms of the occurrence of all strokes regardless of the severity of the condition, and for CAS, it was 9.5% for 1 year and 15.2% for 5 years. Based on these results, the CEA method appears to have some advantages. However, if the occurrence of fatal or disabling stroke is considered as the primary endpoint, the results are different. In CEA, the rate was 3.2% for 1 year and 6.5% for 5 years, and in CAS, it was 3.9% for 1 year and 6.4% for 5 years, so there does not seem to be statistical significance between the 2 groups.
If symptoms have occurred within 2 weeks, if the patient is over 70 years of age, if the aorta has severe curvature and calcification, or if carotid artery calcification exists for a long segment, CEA may be considered first. On the other hand, if there is stenosis of more than 50% of the contralateral carotid artery, recurrent carotid artery stenosis, severe heart disease, or severe pulmonary disease, CAS can be considered first. In other words, they should be used complementary to each other according to the judgment of physicians.
Conclusions
We reviewed recent studies on diagnosis and treatment directions for carotid artery stenosis. Stroke, one of the complications caused by carotid artery stenosis, is very fatal and life-threatening, so prompt diagnosis and appropriate treatment are essential. To properly diagnose carotid artery stenosis, various diagnostic methods such as DSA, MRI, MRA, CTA, and ultrasonography can be used. For carotid artery stenosis with asymptomatic and mild or moderate symptoms, antiplatelet drugs and lipid-lowering drugs are the optimal medical treatments to prevent stroke. For patients with symptoms and moderate or severe stenosis, immediate invasive treatment is indicated. CEA and CAS can be treatment options, and we know from several papers that no treatment method is superior. It is necessary to accurately identify each patient's characteristics and risk factors to select a treatment tailored to the individual. In conclusion, although current medical and surgical treatments for carotid artery stenosis have been shown to reduce the risk of stroke and other complications, further research and development of preventive strategies to minimize the incidence and mitigate the complications of the disease are still needed.
Notes
Conflict of Interest
No potential conflict of interest relevant to this article was reported.