7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Management of symptomatic carotid atherosclerotic disease : Michael T Mullen, MD, Jeffrey Jim, MD, MPHS, FACS : Scott E Kasner, MD, John F Eidt, MD, Joseph L Mills, Sr, MD : John F Dashe, MD, PhD, Kathryn A Collins, MD, PhD, FACS All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Jul 03, 2023. INTRODUCTION The location most frequently affected by carotid atherosclerosis is the carotid bifurcation, often with extension into the proximal internal carotid artery (ie, the origin). Atherosclerosis of the internal carotid artery at the bifurcation accounts for 10 to 12 percent of all ischemic strokes [1,2]. This topic will review the treatment of symptomatic extracranial carotid atherosclerotic disease. The management of asymptomatic carotid disease is discussed separately. (See "Management of asymptomatic extracranial carotid atherosclerotic disease".) Other aspects of carotid occlusive disease are reviewed elsewhere. (See "Evaluation of carotid artery stenosis" and "Carotid endarterectomy" and "Overview of carotid artery stenting" and "Percutaneous carotid artery stenting" and "Transcarotid artery revascularization".) CHARACTERIZATION Definition of symptomatic disease Symptomatic extracranial carotid atherosclerotic disease is defined as neurologic symptoms that are sudden in onset and referable to the appropriate internal carotid artery distribution (ipsilateral to significant carotid atherosclerotic pathology), including one or more transient ischemic attacks (TIAs) characterized by focal neurologic dysfunction or transient monocular blindness, or one or more ischemic strokes [3]. https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 1/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate The definition is contingent on the occurrence of carotid symptoms within the previous six months [3,4]. Remote carotid symptoms should not be considered as indicative of "symptomatic" carotid disease. Vertigo and syncope are not generally caused by unilateral carotid stenosis. Therefore, patients with these symptoms in isolation should be considered as asymptomatic with regard to carotid disease even if they are found to have carotid artery stenosis. Mechanism of stroke Progression of atheromatous plaque at the carotid bifurcation results in luminal narrowing, often accompanied by ulceration. This process can lead to ischemic stroke or TIA from embolization, thrombosis, or reduced brain perfusion (more likely in the setting of bilateral disease). Location and severity of stenosis Treatment of symptomatic extracranial carotid atherosclerotic disease depends upon the location and severity of the carotid lesion. Location In nearly all cases, symptomatic atherosclerosis of the extracranial internal carotid artery (ICA) occurs at its origin or just distal to the bifurcation of the common carotid artery ( figure 1) and typically involves the carotid bulb. The benefit of carotid endarterectomy and carotid stenting for this type of ICA stenosis was established by the randomized trials described below. (See 'Patients appropriate for CEA' below and 'Patients appropriate for CAS' below.) Common carotid artery stenosis located proximal to the carotid bulb is a less frequent cause of stroke or TIA and is less well studied. Atherosclerosis of the common carotid most often occurs at the origin of the artery. Common carotid artery lesions that do not involve the origin can occur as a late complication of radiation treatment. (See 'Common carotid artery lesions' below.) Lesion severity The benefit of carotid endarterectomy (CEA) for patients with symptomatic carotid disease was established by clinical trials designed in the 1980s that used conventional contrast arteriography to determine the degree of internal carotid stenosis. Lesion severity is generally graded as mild (<50 percent), moderate (50 to 69 percent), severe (70 to 99 percent), near occlusion (eg, with severe long segment luminal narrowing from bifurcation to skull base, which is sometimes referred to as a "string sign" on angiographic imaging), and occlusion. Estimates of percent stenosis differ depending upon the definition used and imaging modality. Comparison of the two major trials of endarterectomy, the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST), https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 2/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate requires an understanding of how carotid artery stenosis was measured since these studies used different methodologies ( figure 2) [5]. NASCET measured the residual lumen diameter at the most stenotic portion of the vessel and compared this with the lumen diameter in the unaffected internal carotid artery segment distal to the stenosis [6]. ECST measured the lumen diameter at the most stenotic portion of the vessel, but compared this with the estimated diameter at the carotid bulb [4]. The maximum stenosis is generally in the carotid bulb, a wider portion of the artery than the distal segment. As a result, a given stenosis would be more severe using the ECST method compared with that of NASCET. ECST methodology also requires an estimation of the true bulb diameter, which increases the risk of interobserver variability. Despite these differences, the results of different methods have a nearly linear relationship to each other and provide data of similar prognostic value. A 50 percent stenosis with the NASCET method is equivalent to a 65 percent stenosis for the ECST method, while a 70 percent stenosis with the NASCET method is equivalent to an 82 percent stenosis for the ECST method. (See "Evaluation of carotid artery stenosis".) Imaging modality Catheter-based contrast digital subtraction arteriography (DSA) has been considered the gold standard for measuring the severity of internal carotid artery stenosis. However, noninvasive vascular imaging studies including carotid duplex ultrasound (CDUS), magnetic resonance (MR) angiography, and computed tomographic (CT) angiography are preferred in clinical practice because DSA is invasive and associated with a risk of stroke and other complications. (See "Neuroimaging of acute stroke", section on 'Digital subtraction angiography'.) Duplex ultrasound, CT angiography, and MR angiography can all be used to identify symptomatic carotid stenosis in patients who could benefit from carotid revascularization with CEA or carotid artery stenting (CAS). Some experts note that MR angiography is less accurate for evaluating a moderate stenosis, particularly when performed without contrast [7]. Additionally, CT and MR angiography may provide additional anatomic data that could be useful for surgical planning. For patients who undergo CAS, DSA will necessarily be performed as a part of the procedure. Comparisons of the various imaging studies for the evaluation of carotid stenosis are discussed separately. (See "Evaluation of carotid artery stenosis" and "Carotid endarterectomy", section on 'Preoperative evaluation'.) Epidemiology Atherosclerosis of the internal carotid artery at the bifurcation accounts for 10 to 12 percent of all ischemic strokes [1,2]. Evidence from population-based and hospital-based https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 3/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate studies suggests that TIA or stroke associated with ipsilateral carotid stenosis is associated with a high risk of recurrent ipsilateral stroke [8-11]. INTENSIVE MEDICAL MANAGEMENT Optimal medical management includes antithrombotic therapy, high-potency statin therapy, and risk factor modification, including blood pressure control, glucose control, weight control, and lifestyle modification with smoking cessation, exercise, and recommended dietary modifications. (See "Overview of secondary prevention of ischemic stroke", section on 'Lifestyle modification'.) Intensive medical therapy is recommended for all patients with atherosclerotic carotid artery stenosis in any location and regardless of symptoms, but particularly for those with an ipsilateral transient ischemic attack (TIA) or ischemic stroke [12]. The goal is to reduce the risk of future cardiovascular events, including stroke. Recommendations for medical treatment are provided separately. (See "Early antithrombotic treatment of acute ischemic stroke and transient ischemic attack" and "Overview of secondary prevention of ischemic stroke" and "Long-term antithrombotic therapy for the secondary prevention of ischemic stroke".) At the time when most of the major carotid endarterectomy (CEA) trials were underway (the late 1980s to mid-1990s), the best medical therapy for carotid disease was generally considered to be antiplatelet treatment with aspirin. Since the completion of these trials, medical regimens emerged that reduced the risk of stroke. These therapies include aggressive treatment with statins, antiplatelet agents, and antihypertensive agents. It is unknown if medical therapies that were introduced after the major trials would change the relative risk reduction afforded by CEA for carotid disease, but they might increase the number of patients needed to treat to prevent one stroke. CAROTID REVASCULARIZATION Treatment of symptomatic extracranial carotid atherosclerotic disease includes medical management and may or may not include carotid revascularization. A decision to offer carotid revascularization for extracranial internal carotid artery stenosis weighs the baseline risk of stroke (see 'Baseline risk of stroke' below) against the potential benefits (lowered risk of future stroke) and harms (eg, perioperative stroke or other complications) associated with the selected revascularization procedure. https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 4/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Patients likely to benefit In general, for patients with severe (70 to 99 percent) or moderate (50 to 69 percent) symptomatic internal carotid stenosis, the benefits of carotid revascularization for stroke risk reduction outweigh the risks, particularly when performed within two weeks of the presenting event. However, the benefit varies based upon the degree of stenosis. The benefit for females may be less than for males. Stenosis 70 to 99 percent For patients with recently symptomatic carotid stenosis of 70 to 99 percent who have a life expectancy of at least two years, we recommend revascularization in addition to medical management. Revascularizations should occur within two weeks of symptom onset, when possible. Stenosis 50 to 69 percent For patients with recently symptomatic carotid stenosis of 50 to 69 percent who have a life expectancy of at least three years, we suggest carotid revascularization in addition to medical management, when revascularization can be done within two weeks of symptom onset. Beyond two weeks from symptom onset, the benefit is less certain overall, and females, in particular, may not benefit from revascularization beyond two weeks from symptom onset. These recommendations are in general agreement with guidelines from the American Heart Association/American Stroke Association (AHA/ASA) [12]. For patients who are candidates for revascularization, we suggest carotid endarterectomy rather than transfemoral carotid artery stenting when there is a surgically accessible carotid artery lesion; no clinically significant cardiac, pulmonary, or other disease that would greatly increase the risk of anesthesia and surgery; and no prior ipsilateral endarterectomy. (See 'Patients appropriate for CEA' below.) Patients unlikely to benefit It is important to exclude those who are unlikely to benefit from carotid revascularization. These include patients with the following conditions [13,14]: Stenosis less than 50 percent. Severe comorbidity due to other surgical or medical illness. Stroke associated with persistent, severe neurologic deficits and disability that precludes preservation of useful function. Near occlusion of the symptomatic ipsilateral internal carotid artery; note that distinguishing between a very high-grade stenosis and near occlusion is not necessarily straightforward; the management of such patients should be individualized along with expert guidance. For patients with total occlusion, revascularization is not an option. https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 5/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Risk factors for morbidity and mortality associated with carotid revascularization should be identified to avoid procedures in those who may face unacceptably high surgical risk [15]. Specific factors are discussed separately. (See "Carotid endarterectomy", section on 'Preoperative evaluation' and "Carotid endarterectomy", section on 'Risk factors for poor outcome'.) CHOICE OF PROCEDURE Treatment options Carotid revascularization options include carotid endarterectomy (CEA) or carotid artery stenting (CAS). CEA is established as safe and effective by randomized controlled trials for reducing the risk of ischemic stroke in symptomatic patients with carotid artery atherosclerosis. CAS may be useful in selected patients but with risks that differ depending on the technique selected. The choice between CEA and CAS also depends upon the patient's medical comorbidities and the anatomic characteristics of the symptomatic carotid. Regardless of technique, the perioperative risk of stroke and death for the surgeon or center should be <6 percent to provide an overall benefit to the patient. Combined morbidity and mortality that exceeds 6 percent for patients with symptomatic stenosis could eliminate the benefit gained from CEA or CAS [16-18]. Thus, it is important for individual surgeons and stroke centers to track their outcomes and to be transparent about this information. Patients appropriate for CEA For patients who are candidates for carotid revascularization due to moderate (50 to 69 percent) or severe (70 to 99 percent) symptomatic carotid stenosis, we suggest CEA rather than CAS when the following conditions are met: An ipsilateral transient ischemic attack (TIA) or nondisabling ischemic stroke as the symptomatic event A surgically accessible carotid artery lesion No prior ipsilateral endarterectomy No contraindications to revascularization (see 'Patients unlikely to benefit' above) In addition, the risk of perioperative stroke and death with CEA for the surgeon or center should be <6 percent. Some patients who are appropriate candidates for carotid revascularization but who do not meet these conditions may be appropriate candidates for CAS. (See 'Patients appropriate for CAS' below.) https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 6/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate CEA is performed through a neck incision. An arteriotomy is performed at the carotid bifurcation (longitudinal or transverse depending on the technique), and the carotid plaque is then freed and removed and the arteriotomy closed either primarily (direct suture repair) or using a carotid patch. CEA can be performed using local/regional anesthesia or general anesthesia. The choice of anesthesia is generally determined by surgeon and anesthesiologist skill and preference, as well as patient characteristics and preference. The preoperative evaluation, surgical technique, and complications of CEA are reviewed in detail separately. (See "Carotid endarterectomy" and "Complications of carotid endarterectomy".) Antiplatelet treatment, generally with aspirin (81 to 325 mg/day), is recommended for all patients who are undergoing CEA. Other antiplatelet agents (eg, clopidogrel) may be selected for patients with contraindications to aspirin. Antiplatelet agents should be started prior to surgery and continued indefinitely after surgery in the absence of contraindications. (See "Carotid endarterectomy", section on 'Antiplatelet therapy'.) Randomized controlled trials have established CEA as safe and effective for reducing the risk of ischemic stroke in patients with symptomatic internal carotid artery atherosclerosis and moderate (50 to 69 percent) or severe (>70 percent) stenosis [3,4,19]. Patients appropriate for CAS Based upon the available data, we suggest CAS rather than CEA for select patients with recently symptomatic carotid stenosis of 50 to 99 percent who have one or more of the following conditions: A carotid lesion that is not suitable for surgical access Radiation-induced stenosis Carotid restenosis after endarterectomy Clinically significant cardiac, pulmonary, or other disease that greatly increases the risk of anesthesia and surgery Unfavorable neck anatomy including contralateral vocal cord paralysis, open tracheostomy, or prior radical surgery Carotid artery stenting can be performed using the following approaches, which are compared and reviewed in more detail elsewhere: (See "Overview of carotid artery stenting", section on 'Selecting an approach'.) Transfemoral carotid artery stenting (TF-CAS) TF-CAS has been the standard for endovascular carotid intervention [15]. Percutaneous vascular access is typically obtained via the right or left common femoral artery. (See "Overview of carotid artery stenting", section on 'Transfemoral carotid revascularization' and "Percutaneous carotid artery stenting".) https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 7/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Transcarotid artery revascularization (TCAR) TCAR uses a hybrid surgical approach that accesses the carotid artery through a small transverse neck incision, which avoids passing wire/catheters across the aortic arch. (See "Overview of carotid artery stenting", section on 'Transcarotid revascularization' and "Transcarotid artery revascularization".) 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. For high-risk patients (anatomic and physiologic), TCAR may be preferable to TF-CAS and CEA [20,21]. Further evidence from large controlled clinical trials is needed before drawing firm conclusions about the safety and effectiveness of CAS in these various subgroups. Factors that may affect periprocedural outcomes of CAS are discussed elsewhere. (See "Overview of carotid artery stenting", section on 'Risk assessment'.) In the absence of the conditions listed above, CEA remains the preferred treatment for most patients with symptomatic internal carotid atherosclerosis (see 'Patients appropriate for CEA' above). This preference for CEA is in general agreement with major society guidelines [12,20]. If CAS is considered, the periprocedural risk of stroke and death with CAS for the operator or center should be <6 percent. Note that older patients have worse outcomes with transfemoral CAS compared with CEA (see 'Older age and worse outcomes with CAS' below). For patients age 70 years and older in all these subgroups, the benefit-to-risk ratio of CAS is unknown. Patients undergoing CAS are generally treated with a dual antiplatelet regimen (aspirin and clopidogrel) prior to the procedure and continued for at least 30 days after the procedure, followed by long-term single-agent antiplatelet therapy. CEA trials Several major trials evaluated CEA for patients with TIA or nondisabling ischemic stroke attributed to symptomatic internal carotid artery stenosis. All were initiated in the 1980s and first published in 1991. These were the North American Symptomatic Carotid Endarterectomy Trial (NASCET) ( figure 3 and figure 4) [6,22], the European Carotid Surgery Trial (ECST) ( figure 5) [4,19,23], and the Veterans Affairs (VA) trial [24]. In a pooled analysis of patient-level data from the ECST, NASCET, and VA trials, CEA was beneficial for patients with 70 to 99 percent symptomatic stenosis (but not near occlusion) [14,25]. Prerandomization carotid angiograms from ECST were reassessed by the NASCET method, and outcomes were standardized to achieve comparability among the trials. To prevent one event at five years for ipsilateral carotid territory ischemic stroke and operative stroke or death, the number needed to treat (NNT) was 6 (95% CI 5-9) and the absolute risk reduction (ARR) was approximately 17 percent; to prevent one event at five years for disabling or fatal https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 8/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate ipsilateral ischemic or operative stroke and operative death, the NNT was 14 (95% CI 8-35) and the ARR was approximately 7 percent. CEA was also beneficial for patients with 50 to 69 percent symptomatic stenosis. The NNT to prevent any stroke or operative death at five years was 13 (95% CI 8-28, ARR approximately 7.7 percent), while the NNT to prevent any ipsilateral carotid territory ischemic stroke or operative stroke or death at five years was 22 (95% CI 12-80, ARR approximately 4.5 percent) [14,25]. CEA was not beneficial for symptomatic carotid stenosis of 30 to 49 percent, and CEA was harmful for symptomatic patients with less than 30 percent stenosis [14,25]. As an example, patients in the ECST with mild stenosis had little risk of ipsilateral ischemic stroke; possible benefits of CEA were small and were outweighed by the early risks [4]. In NASCET, patients with stenosis of less than 50 percent did not benefit from surgery [3]. There was no benefit of CEA for patients with near occlusion of the internal carotid artery, but there were few patients in this category [14,25]. Trials comparing CAS with CEA Data from randomized controlled trials suggest that CAS and CEA achieve similar long-term benefit for patients with symptomatic carotid occlusive disease. However, the periprocedural (30-day) stroke or death rate is greater with TF-CAS than with CEA, and while the risks of CAS and CEA are similar in the postprocedural period, the combined periprocedural and postprocedural risks still favor CEA. Note that CAS trials have involved predominantly transfemoral carotid artery stenting (TF-CAS). Whether TCAR reduces the risk of complications is unknown. Comparisons of the approaches to CAS are discussed separately. (See "Overview of carotid artery stenting", section on 'TCAR versus TF-CAS'.) A 2020 meta-analysis identified seven trials comparing endovascular treatment with CEA in patients with symptomatic carotid stenosis and four trials comparing endovascular treatment with CEA in patients with both symptomatic and asymptomatic stenosis [26]. None of the trials specifically included patients considered to be at high surgical risk. The patients assigned to the endovascular arms of the included trials were treated with TF-CAS. In the analysis of patients with symptomatic carotid stenosis, the following observations were made [26]: Compared with CEA, patients assigned to endovascular treatment had a higher rate of periprocedural stroke or death at 30 days (7.2 versus 4.4 percent, odds ratio [OR] 1.7, 95% CI 1.31-2.19). In subgroup analysis, patients 70 years of age had an increased risk of periprocedural stroke or death with endovascular treatment compared with CEA (OR 2.23, 95% CI 1.61-3.08). By contrast, the risk of periprocedural stroke or death for patients <70 years of age was similar for the two treatment groups (OR 1.11, 95% CI 0.74-1.64). https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 9/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Compared with CEA, the endovascular treatment group had a higher rate of death or any stroke during the periprocedural period or ipsilateral stroke during follow-up (10.2 versus 7 percent, OR 1.51, 95% CI 1.24-1.85). Compared with CEA, endovascular treatment was associated with lower periprocedural risks of myocardial infarction (OR 0.47), cranial nerve palsy (OR 0.1), and access site hematoma (OR 0.4). The rate of ipsilateral stroke after the periprocedural period was similar for the endovascular and CEA treatment groups (3 versus 2.9 percent, OR 1.05, 95% CI 0.75-1.47). Similar findings were noted in a 2019 pooled analysis of long-term patient-level data from the four largest trials comparing TF-CAS and CEA for symptomatic carotid stenosis, with median follow-up across the trials ranging from 2 to 6.9 years [27]. Most importantly, the combined periprocedural and postprocedural composite risk of stroke or death favored CEA at 1, 3, 5, 7, and 9 years from randomization, with differences ranging between 2.8 percent (95% CI 1.1-4.4) and 4.1 percent (95% CI 2.0-6.3). FACTORS INFLUENCING BENEFIT AND RISK Recommendations for treating symptomatic carotid stenosis are largely based upon findings of major randomized trials (eg, the North American Symptomatic Carotid Endarterectomy Trial [NASCET], the European Carotid Surgery Trial [ECST]), but remain predicated on carotid endarterectomy (CEA) providing a greater benefit to the patient in terms of stroke reduction compared with the risk of performing the procedure. The baseline risk of stroke in symptomatic patients is reviewed above. (See 'Baseline risk of stroke' below.) In addition to the perioperative complication rate and the timing of surgery (see 'Timing of revascularization' below), a number of additional factors appear to impact benefit and risk of CEA in patients with symptomatic carotid stenosis. These include age, sex, retinal versus hemispheric ischemia, and the presence of contralateral carotid stenosis or occlusion. Baseline risk of stroke Since any benefit of carotid revascularization (ie, endarterectomy and stenting) is dependent upon the absolute risk of adverse outcome with or without treatment, it is useful to systematically consider the risks and benefits of revascularization based on individual patient characteristics whenever possible [28]. A risk model for patients with recently symptomatic carotid stenosis was derived from the ECST trial data and validated by showing that the predicted stroke risk for patients assigned to medical treatment in the NASCET trial was close to the observed risk [28]. https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 10/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate While the model does not account for the risk and benefit of surgery, it may be useful for assessment of baseline stroke risk and patient selection for carotid revascularization. The baseline ipsilateral stroke risk for patients with recently symptomatic extracranial carotid atherosclerotic disease is calculated based upon the following factors [28]: Patient age Patient sex Degree of carotid stenosis Type of presenting symptomatic event (eg, ocular transient ischemic attack [TIA], hemispheric TIA, minor stroke, or major stroke) Time since last symptomatic event Carotid plaque morphology (eg, smooth versus ulcerated or irregular) These factors can be entered into the model to estimate the absolute risk of ipsilateral stroke for individual patients with symptomatic carotid disease who are candidates for carotid revascularization ( figure 6) [28]. As an example, a 70-year-old man who presents with an ocular TIA, a 70 to 99 percent ipsilateral carotid stenosis, an ulcerated irregular plaque, and time greater than 12 weeks since the last symptomatic event has a predicted absolute five-year stroke risk of 15 to 20 percent. However, if the same patient presents with a cerebral (hemispheric) TIA and time less than two weeks since the last symptomatic event, the predicted absolute five-year stroke risk increases to 35 to 40 percent. Retinal versus hemispheric ischemia Among patients with symptomatic carotid disease, transient retinal ischemia (ie, transient monocular blindness [TMB]; also called amaurosis fugax) portends a lower risk of ipsilateral carotid stroke than hemispheric TIA. In a subset analysis from NASCET, 198 medically treated patients with TMB had a three-year risk of ipsilateral stroke that was approximately one-half that of 417 medically treated patients with hemispheric TIA [29]. Older age and benefit with CEA Subgroup analysis of the NASCET trial found that patients who were age 75 years and older with 50 to 99 percent stenosis benefited more from CEA than younger patients [30]. Others have reported similar findings [31]. These results suggest that CEA should not be withheld from appropriately selected patients over the age of 75 years. Older age and worse outcomes with CAS Older adult patients have worse outcomes with transfemoral carotid artery stenting (TF-CAS) compared with CEA, even though older age was originally proposed to be associated with high risk for surgery and therefore a potential indication for CAS rather than CEA. https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 11/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate This point is illustrated by the findings of a 2016 meta-analysis that evaluated pooled patient- level data from subjects with symptomatic carotid disease in the EVA-3S, SPACE, ICSS, and CREST trials [32]. For patients assigned to TF-CAS, the overall periprocedural risk of stroke and death increased with age. Compared with patients aged <60 years, the risk was higher for patients aged 65 to 69 years (hazard ratio [HR] 2.2, 95% CI 1.1-4.1), 70 to 74 years (HR 4, 95% CI 2.2-7.3), 75 to 79 years (HR 3.9, 95% CI 2.1-7.3), and 80 years (HR 4.2, 95% CI 2.2-7.8). For patients assigned to CEA, the periprocedural risk was similar for these age groups. Compared with CEA, the periprocedural risk of stroke and death with TF-CAS was increased for patients aged 70 to 74 years (HR 2.1, 95% CI 1.3-3.3), 75 to 79 years (HR 1.9, 95% CI 1.2-3.0), and 80 years (HR 2.4, 95% CI 1.4-4.4). Similar findings were reported in other meta-analyses of randomized trials [26,33]. The risk of stroke associated with TF-CAS appears to increase linearly with patient age [33,34]. For patients 70 years of age with stroke or TIA being considered for carotid revascularization, 2021 guidelines from the American Heart Association/American Stroke Association (AHA/ASA) stated that it is reasonable to select CEA over CAS to reduce the periprocedural stroke rate [12]. These guidelines noted that the usefulness of TCAR for prevention of recurrent stroke and TIA is uncertain. By contrast, the 2021 Society for Vascular Surgery guidelines noted that, based on the available evidence (predominantly observational data from 2017 onward), TCAR appears to be equivalent to CEA, there are no differences in outcomes with TCAR relative to older age, and the periprocedural risk of stroke may be lower with TCAR compared with TF-CAS [20]. Older age as a risk factor for periprocedural complications of CAS is reviewed in more detail separately. (See "Overview of carotid artery stenting", section on 'Risk assessment'.) Benefit of CEA varies by sex The benefit of CEA may be greater for males than for females. Results from analyses that pooled data from two or more of the major trials (ECST, NASCET, VA, and ASA and Carotid Endarterectomy [ACE] trials [31,35,36]) found that the risk of stroke ipsilateral to a symptomatic carotid stenosis in medically treated patients was lower for females compared with males, while the perioperative risk of death in patients treated with CEA was higher for females compared with males. Nevertheless, CEA was beneficial for both males and females with 70 to 99 percent symptomatic carotid stenosis, with similar five-year absolute risk reduction in stroke for males and females (17.3 and 15.1 percent, respectively). Surgical benefit in females was confined to those who had CEA within two weeks after their last event. As discussed above, for females with 50 to 69 percent symptomatic carotid stenosis, the benefit of carotid revascularization is also less certain. However, an analysis that incorporates time from ischemic event has suggested a similar benefit for males and females with moderate stenosis if https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 12/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate CEA is performed within two weeks of symptom onset (five-year ARR in males of 15.2 percent and in females 13.8 percent) [35]. Beyond two weeks, the benefit is less clear overall, and particularly in females ( figure 5). (See 'Patients likely to benefit' above and 'Timing of revascularization' below.) Contralateral carotid stenosis or occlusion CEA is likely to be beneficial for patients who have symptomatic ipsilateral carotid stenosis and coexisting severe contralateral carotid stenosis or occlusion. However, such patients are at higher perioperative risk than those without a severe contralateral carotid artery stenosis [37]. These points were illustrated in a report from the NASCET cohort that analyzed medical versus surgical therapy in 659 patients with a recent ischemic event attributed to a 70 to 99 percent stenosis of an ipsilateral carotid artery [38]. The contralateral carotid artery had a 70 to 99 percent stenosis in 8.6 percent and was totally occluded in 7 percent. After a two-year follow-up, medically treated patients with an occluded contralateral carotid were twice as likely to have an ipsilateral stroke compared with those with severe or mild to moderate contralateral carotid stenosis (HR 2.36 and 2.65, respectively). Among surgically treated patients, the perioperative risk of stroke and death was higher in those with a totally occluded or mild to moderately stenotic contralateral vessel (4 and 5 percent, respectively) compared with those without contralateral disease. Despite this increased risk, patients who had CEA still had better outcomes compared with patients treated medically. Factors associated with increased surgical risk In data from NASCET, predictors of medical complications with CEA were a history of myocardial infarction or angina and hypertension [39]. Patients with a recent history of myocardial infarction, unstable angina pectoris, or heart failure were excluded from NASCET, perhaps in part explaining the low perioperative medical complication rate. The NASCET study examined rates of perioperative stroke and death at 30 days, stroke severity at 90 days, variables that influenced perioperative risk, and the durability of CEA [40]. Five baseline variables were predictive of increased surgical risk: hemispheric (versus retinal) TIA as the qualifying event; left-sided procedure; contralateral carotid occlusion; ipsilateral ischemic lesion on CT scan; and irregular or ulcerated ipsilateral plaque. It bears repeating that combined perioperative morbidity and mortality that exceeds 6 percent could eliminate the benefit gained from CEA for patients with symptomatic stenosis [16-18]. Timing of revascularization For patients with carotid stenosis and a nondisabling stroke or transient ischemic attack (TIA), we suggest that carotid revascularization with carotid endarterectomy (CEA) or carotid artery stenting (CAS) be performed within two weeks of the last symptomatic event rather than a later time; for patients with ischemic stroke, an exception is https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 13/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate that very early CEA (within the first two days after stroke onset) may be associated with increased operative risk. However, the optimal timing of revascularization in patients with symptomatic carotid atherosclerosis has been the subject of considerable debate. No high- quality prospective, randomized trials have specifically evaluated outcomes related to the timing of CEA after a recent stroke or TIA [41], and data for outcomes related to the timing of CAS are notably lacking. Timing of revascularization has been better studied for CEA than for CAS. Below we provide the evidence and recommendations for CEA, which can generally be extrapolated to timing of CAS. However, available data show that early CAS (TF-CAS, TCAR) is associated with worse outcomes after an index event compared with CEA. After mild stroke or TIA A pooled analysis of the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST) trials, representing the largest experience to date, found that CEA within two weeks of a nondisabling stroke or TIA significantly improved outcomes compared with later surgery ( figure 7) [31]. In the subgroup of patients with 70 percent or greater carotid stenosis, CEA was associated with a 30.2 percent reduction in absolute risk of stroke in patients randomized within two weeks of their last event, compared with a 17.6, 11.4, and 8.9 percent absolute reduction in those randomized 2 to 4, 4 to 12, and more than 12 weeks from their last event. For patients with 50 to 69 percent stenosis, clinically important benefits from CEA were noted only in patients randomized within two weeks of their last event. Further analysis of the pooled NASCET and ECST data showed that the decline in benefit of CEA over time was more rapid in females than in males [35]. Surgical benefit in females was confined to those who had CEA within two weeks after their last event, irrespective of the degree of stenosis, while CEA within two weeks of a nondisabling hemispheric stroke was not associated with an increased operative risk. When CEA is indicated for patients with TIA or stroke, guidelines from the American Heart Association/American Stroke Association (AHA/ASA) state that it is reasonable to perform the surgery within two weeks rather than delaying surgery [12]. Very early or emergency CEA Very early CEA (eg, within two days of stroke) or emergency CEA for progressing/fluctuating stroke or crescendo TIA may have a high operative risk, as suggested by findings from a meta-analysis of 47 studies (mostly observational or registry studies) published between August 2008 and March 2015 that evaluated early carotid intervention for recently symptomatic stenosis [42]. For CEA