Overview of current treatment options

Today, the treatment of carotid stenosis is interdisciplinary and individualized. Findings from earlier studies cannot be readily applied to today’s situation because medical advances have changed the boundary conditions. What are the therapeutic options? What do current guidelines say?

Stroke, or apoplexy, is one of the leading causes of mortality and morbidity in industrialized countries. Apart from sometimes serious consequences for the patients and their environment, strokes cause high costs for society. From the data of the Swiss Federal Statistical Office, the incidence of stroke can be estimated to be about 16,000 cases per year [1]. Of these, approximately 18% are due to atherosclerotic changes in the extracranial cerebral arteries and here predominantly to lesions in the carotid stromal territory. This means that between 3000 and 5000 strokes per year in Switzerland can be attributed to stenoses in the internal carotid artery.

Until the 1950s, treatment of carotid stenosis was based only on prevention of stroke and rehabilitation for persistent neurologic deficits. In 1954, surgical carotid thromboendarterectomy (CEA) was first published. At that time, there could be no talk of evidence-based treatment. For another 30 years, surgery failed to demonstrate superiority over conservative therapy. This changed in the 1990s when large randomized multicenter trials were published. These provided evidence for the superiority of surgical over conservative therapy, first for symptomatic (NASCET, ECST^)* and later for asymptomatic (ACAS, ACST^)** carotid stenoses [2].

Of course, a critical analysis also requires consideration of perioperative complication rates, which were comparatively low in the studies mentioned. Strict selection criteria and the expertise of the centers involved are other factors that were ultimately critical to the recognition of the prophylactic benefit of CEA. For example, the American Heart Association (AHA) requires a detectable perioperative complication rate (death or stroke in the first 30 days after surgery) of <6% for symptomatic and <3% for asymptomatic carotid stenosis.

Therapy approaches in transition

As a result of the rapid development in medicine and the new findings in pharmacotherapy, the results of the above-mentioned studies cannot be easily transferred to the present day. For example, at the time of the first large randomized trials, statin therapy was not yet part of the BMT (Best Medical Treatment) concept. On the other hand, people smoked much more back then than they do today. As a result, the incidence of strokes in the affected population is now lower than in the past. For example, a meta-analysis of 41 studies [3] found an annual stroke rate of 2.3 per 100 persons before 2000 and of about 1 per 100 persons between 2000 and 2010. This results in a 39% reduction in stroke incidence as a result of improvement in drug treatment and nicotine abstinence. The question therefore rightly arises as to whether the therapy recommendations in the guidelines, which are based on the studies mentioned, are still up-to-date. Further studies are needed to answer this question. In the ACST-2 trial comparing BMT with CEA or BMT with stent, patient enrollment is expected to be completed in one to two years.

Despite convincing results of the aforementioned studies of asymptomatic carotid stenosis with ARR (Absolute Risk Reduction) for stroke in the surgical group of 7.8% in <75-year-olds, caution is advised regarding recommendations for therapy in clinical practice. During a 5-year period, “only” 46 strokes per 1000 CEA can be prevented, according to the study. In other words, 95% of the patients were operated on for nothing. Due to advances in drug therapy, this number could be even higher nowadays. Ideally, among patients with high-grade stenoses, those with additional risks for stroke must be selected. However, current recommendations do not precisely define high-risk patients because there are not yet evident data for them. It remains to be seen which new algorithm for patient selection will be provided by the currently ongoing studies. The possible factors that increase the risk of stroke are silent infarcts on CT/MRI, progression of stenosis, extensive plaques, heterogeneity of plaques with high hypodense (thrombotic) content, hemorrhage into the plaque, plaque exulceration, impaired cerebrovascular reserve, or spontaneous embolization on transcranial Doppler [4].

According to the current guidelines [5], surgery may be considered for asymptomatic higher-grade carotid stenosis (>70%) if at least one of the above risk factors is present. A life expectancy of at least five years and a documented perioperative complication rate for stroke or death <3% in the respective hospital are further criteria that must be met for the surgical indication. Surgical therapy is generally recommended for moderate- and high-grade symptomatic stenoses. Symptomatic are the stenoses leading to stroke or TIA (transient ischemic attack) with corresponding neurological deficits in the contralateral half of the body, cognitive and perceptual alterations, or ipsilateral “amaurosis fugax”.

Carotid artery surgery (CEA) or carotid stenting for high-grade stenosis?

Against the background of the convincing study results of surgical therapy, its not uncommon limitations in patients with unfavorable conditions, but also due to complications typical for surgery, percutaneous angioplasty with stent implantation has become established in the last decades. Angioplasty as a less invasive procedure for the treatment of vascular pathologies has been on the rise for about 30 years and has now overtaken open vascular surgery in terms of numbers, at least in industrialized countries. On the one hand, due to the seductive concept of minimally invasive treatment, but also due to pressure from the multi-billion dollar medical device industry, which is doing massive public relations work advertising its products, angioplasty with stenting continues to be pushed to the forefront in carotid treatment as well.

The question now is whether carotid stenting confers a benefit in high-grade stenosis and without additional risk factors (average risk for stroke). Five randomized controlled trials of carotid stenting versus open surgery (CEA) have been conducted to date with the aim of answering this question (Lexington, CREST-1, ACT-1, SPACE-2, and Mannheim). A meta-analysis of these studies showed no statistically significant difference in the primary outcome parameters, that is, the combined end point of death and/or stroke by 30 days after the procedure, although there was a trend in favor of CEA.

The CREST study [6], sponsored by Abbott, stands out among this group. In this prospective study, classic CEA was compared with carotid stent surgery in 2522 patients. Particularly unusual in the design of the study was that myocardial infarction was determined as the primary end point in addition to death and stroke. Classical CEA was significantly superior to stenting with respect to stroke prophylaxis. However, once myocardial infarction is included, there is no longer a statistically significant difference between the primary endpoints of the two treatment arms. The conclusion of the study was that carotid stenting is equivalent to classic CEA. However, the big question is whether it is justified to include myocardial infarction, which was defined as troponin increase in this study, as an end point in the study, or whether this inclusion was aimed at putting the carotid stent in a better light.

Current guidelines and clinical experience

The current guidelines of the European Society for Vascular Surgery make the following recommendations regarding treatment indications and procedures for symptomatic carotid stenosis:

Surgery is generally recommended for symptomatic high-grade (70-99%) carotid stenosis if the event occurred six months or less ago. Surgery should be considered for moderate (50-69%) stenosis. In >70-year-olds with symptomatic moderate- and high-grade stenosis, surgery is preferred (rather than stenting). In <70-year-olds with symptomatic stenosis, stenting may be offered as an alternative to surgery.

Particularly in the case of moderate symptomatic stenoses, the plaque condition is often decisive for the indication. High calcium content and homogeneity of the plaques indicate a certain “stability” and thus a rather lower risk of further cerebral embolization. Before the indication for intervention is given, the BMT should first be expanded in such a case. In contrast, hypodense, atheromatous plaques with ulceration or hemorrhage, as well as floating thrombi, require surgery/intervention even in the absence of hemodynamically relevant stenosis.

However, there are situations in which the stent has distinct advantages over surgery. The classic example is the “hostile neck” or “difficult neck” in symptomatic recurrent stenosis after CEA, neck dissection or radiation has already taken place. The stent is also preferred in cases of extremely cranial localization of the stenosis because surgical access is difficult there. Tandem stenoses, especially downstream intracranial stenoses, often require cerebral angiography for further evaluation. In such a case, treatment with stenting in the same session is an option, since one is “already on site”. It should also be noted that dual platelet aggregation inhibition must be started before stent placement. For this reason, in case of already ongoing anticoagulation (^Marcoumar® or New Oral Anticoagulants), surgery is undoubtedly the better procedure. With a stent, triple anticoagulation would be associated with high bleeding risk. However, if neither procedure is expected to have significant disadvantages, patients are offered a choice of both alternatives in everyday clinical practice.

If surgery is indicated for symptomatic stenosis, the procedure should be performed within 14 days of the initial event. In this time window, patients are better served by surgery than by stenting [7]. In case of progression of symptoms, so-called “stroke-in-evolution”, however, surgery must be performed within 24 hours. In contrast, surgery should be refrained from in cases of severe vigilance reduction or unconsciousness and/or extensive infarction because of the risk of postoperative hemorrhagic transformation.

Postoperatively (after CEA or stenting), patients must be monitored closely (intensive care, intermediate care, stroke unit). It is important to consistently control blood pressure (BP) with a target systolic pressure of 140-150 mmHg. Uncontrolled hypertension carries the risk of cerebral edema postoperatively, which is associated with high (up to 50%) mortality. Normotonia should also be aimed for in the first postoperative weeks. Unfortunately, this vulnerable time window is not precisely defined. Unfortunately, strict normotension in elderly patients can often only be achieved at the expense of quality of life. Affected individuals may then be “proud” of a competitive athlete’s BP of 110/70 mmHg, yet complain of fatigue, dizziness, lassitude, and other symptoms associated with relative hypotension. If patients do not tolerate the “optimal” pressure setting, a higher blood pressure can be accepted as early as two months postoperatively. The quality of life should be in the foreground here.

Another hotly debated topic is a possible association of carotid stenting with cognitive deterioration as a result of periinterventional, clinically inapparent microemboli. These can occur during manipulation with guide wires and catheters and are then detectable on MRI. The current systematic review of 15 studies failed to show evidence that carotid interventions, whether classic CEA or stenting, have an impact on cognitive function. However, it must be emphasized that the studies investigated were not designed for this question at all, with mostly short follow-up, weak statistical power, irregular use of protective devices, or inappropriate neuropsychological tests. It remains to be seen whether the ongoing CREST-2 study investigating these aspects will provide new insights.

Prevention of risk factors

What is still considered certain in the prevention and treatment of carotid stenosis? What is certain is that smoking is associated with a threefold risk for the prevalence of high-grade stenosis. Recent meta-analyses have also demonstrated 1.5- to 2-fold increases in risk for stroke in obesity and diabetes [8,9].

The risk of stroke is not affected by aspirin® itself in asymptomatic stenoses. However, because carotid stenosis is associated with cardiovascular pathology, ^Aspirin® is still recommended in these patients because it reduces the likelihood of myocardial infarction. The combination of Aspirin® and clopidogrel shows no benefit. Clopidogrel alone is recommended only in case of ^Aspirin® intolerance. Statins are also recommended as primary prophylaxis in asymptomatic carotid stenosis, with the goal of lowering LDL to <1.8 mmol/l or to 50% of baseline [10].

The benefit of antihypertensive therapy (target BP 140/90 mmHg) was also clearly demonstrated. One of the most recent meta-analyses [11] shows a 45% relative risk reduction for subsequent stroke. For diabetics, the European Society of Cardiology even sets the limit for diastolic pressure at 85 mmHg. Diabetes itself increases the risk of stroke twofold. And although even optimal glycemic control does not affect this risk, it is known to reduce diabetes-associated complications.

Screening for carotid stenosis in the overall population is not recommended and may be considered only in selected patients with associated comorbidities.

Take-Home Messages

The therapy of carotid stenosis should be determined in an interdisciplinary manner (neurology, vascular surgery, and interventional neuroradiology). Recommendations of the Guidelines must not be implemented blindly. The individual patient situation should be taken into account when deciding on therapy.
Findings from previous studies cannot be readily applied to the current situation. Medical advances have changed the boundary conditions (e.g., decreased stroke incidence due to better prophylaxis).
Current large-scale trials (e.g., CREST-2) include the question of whether carotid artery surgery (CEA) or carotid stenting leads to better outcomes in high-grade stenosis. In both cases, postoperative follow-up is important.
Regarding prevention, control of risk factors (smoking, obesity, hypertension, and elevated blood glucose levels) and drug intervention, if necessary, are recommended.

^* NASCET = North American Symptomatic Carotid Endarterectomy Trial; ECST = European Carotid Surgery Trial.
^** ACAS = Asymptomatic Carotid Atherosclerosis Study; ACST = Asymptomatic Carotid Surgery Trial.

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