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 https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 14/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate performed within 48 hours of the index event of stroke, the pooled periprocedural risk of stroke and death was 8.4 percent (95% CI 5.0-12.7); for the index event of TIA, the corresponding risk was 2.8 percent (95% CI 0.4-7.2). For CEA performed within 15 days of the index event of stroke, the pooled periprocedural risk of stroke and death was 4.9 percent (95% CI 3.4-6.7); for the index event of TIA, the corresponding risk was 1.9 percent (95% CI 0.8-3.3). A 2009 systematic review identified 18 nonrandomized studies of CEA for recently symptomatic carotid stenosis that reported data on time from presenting event to CEA and further stratified CEA into emergency (stroke-in-evolution or crescendo TIA) and nonemergency indications. The rate of perioperative stroke or death was significantly higher with emergency CEA (14 percent, versus 4 percent for nonemergency CEA, pooled relative odds 4.6, 95% CI 3.4-63) [43]. However, the rate of perioperative stroke or death for neurologically stable patients with recent TIA or nondisabling stroke was similar for early CEA (less than one week) and later CEA (one week or more). After moderate to severe stroke Intervention is often not indicated in the setting of very large infarcts with severe neurologic disability. In moderate infarcts, decision-making should be individualized, accounting for the size and severity of the index stroke, the potential for meaningful neurologic deterioration if another stroke were to occur, and the operative risk. The benefit of CEA for patients with moderate to severe ischemic stroke has not been evaluated in randomized clinical trials, as patients who had disabling strokes were not eligible for NASCET or ECST. Given that there have been no prospective trials addressing the question of timing of surgery, it is difficult to generalize observations from the NASCET and ECST trials to all patients undergoing CEA. In particular, patients who have a large infarction with brain swelling and/or significant hemorrhagic transformation have long been thought to have high perioperative risk with early CEA [44-46]. On the other hand, delay in CEA may expose the patient to an increased risk of recurrent stroke. A number of retrospective studies have evaluated the timing of CEA after moderate to severe ischemic stroke, and a 1997 review noted that patients undergoing CEA who have fixed neurologic deficits after a stroke probably represent a heterogeneous group whose risks vary according to clinical and radiological features [47]. Several included reports documented satisfactory outcomes in patients undergoing surgery within six weeks of cerebral infarction. An evidenced-based review of CEA published by the American Academy of Neurology (AAN) in 2005 identified six retrospective cohort studies comparing the timing of CEA (early versus late) in patients after stroke [48]. None of the studies found any https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 15/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate differences in outcomes of perioperative morbidity or longer-term follow-up. All six studies were limited by small size. After intravenous thrombolysis There are only limited retrospective data about the risk of complications with carotid revascularization for patients with acute ischemic stroke who were treated with intravenous thrombolysis. Most studies suggest that CEA or CAS is not associated with increased risk of complications in this setting, at least for patients with minor or moderate deficits [49-53]. However, some reports have found an association with an increased risk of poor outcomes, particularly for patients undergoing revascularization within 48 to 72 hours of intravenous thrombolysis [53,54]. (See "Approach to reperfusion therapy for acute ischemic stroke", section on 'Alteplase' and "Intravenous thrombolytic therapy for acute ischemic stroke: Therapeutic use".) Higher risk with urgent CAS and TCAR compared with CEA Early CAS and TCAR are associated with worse 30-day outcomes after an index event compared with CEA. CAS and TCAR performed within the first two days after carotid symptom onset are associated with an increased risk of stroke/death compared with CEA. The safety of CAS and TCAR compared with CEA from three to seven days after symptom onset is not entirely clear, but most data suggest a higher risk with CAS and TCAR [55-58]. In a 2017 pooled analysis of individual patient data from four randomized controlled trials comparing CEA and CAS that included 513 patients treated within seven days of symptom onset, the risk of stroke or death was higher for CAS compared with CEA (8.3 versus 1.3 percent, risk ratio 6.7, 95% CI 2.1-21.9) [55]. A 2022 systematic review of 71 studies (mainly retrospective) with over 200,000 patients found that CAS within two days of symptom onset was associated with higher 30-day stroke and mortality rates compared with CEA [56]. CAS from 3 to 14 days was associated with a similar 30-day stroke rate but higher mortality (odds ratio 2.76, 95% CI 1.39 5.50) compared with CEA. Nearly all of the CAS procedures were performed via the transfemoral route. The data for TCAR are more limited. In a retrospective review of 2608 symptomatic patients treated with TCAR, the procedure was performed after symptom onset within 48 hours (5.5 percent), from days 3 through 14 (35.6 percent), and 14 days or more (58.9 percent) [57]. On adjusted analysis, treatment within 48 hours was associated with a three-fold increased risk of in-hospital stroke/death compared with treatment after 14 days. In another retrospective analysis, performing a TCAR within 48 hours after a stroke was the strongest predictor (odds ratio 5.4) of a postoperative stroke/TIA [58]. However, TCAR within 48 hours after a TIA was not associated with an increased risk. https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 16/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate OTHER MANAGEMENT ISSUES Common carotid artery lesions There are limited data about the management of high-grade stenosis involving the common carotid artery (CCA). Treatment depends in part upon the severity and location of the CCA stenosis. Symptomatic stenosis localized to the distal CCA near the bifurcation or extending to the internal carotid artery (ICA) bulb can be treated much the same as proximal ICA stenosis with either carotid endarterectomy or carotid artery stenting. Isolated, proximal CCA lesions can be treated using either retrograde or antegrade stenting. (See "Surgical and endovascular techniques for aortic arch branch and upper extremity revascularization", section on 'Endovascular repair'.) Tandem lesions involving the ICA and the CCA may be treated with endarterectomy of the ICA stenosis, followed by retrograde stenting of the proximal CCA artery lesion. However, some surgeons first treat the proximal CCA stenosis before performing endarterectomy of the ICA lesion [59]. (See "Surgical and endovascular techniques for aortic arch branch and upper extremity revascularization", section on 'Endovascular repair'.) Carotid restenosis There is controversy about the appropriate management for patients who develop restenosis of the carotid artery following carotid endarterectomy (CEA) or carotid artery stenting (CAS). Restenosis due to intimal hyperplasia is usually benign. For patients who develop symptomatic cerebral ischemia due to recurrent carotid stenosis caused by intimal hyperplasia or atherosclerosis, multispecialty guidelines note that it is reasonable to either repeat CEA or perform CAS using the same criteria as recommended for initial revascularization [13]. There is no established benefit for revascularization of an asymptomatic restenosis [60]. Additional factors that should be considered in the decision include the degree of wound healing since surgery, the occurrence of local or cerebral perioperative complications with prior surgery, and the time since the prior surgery, since perioperative risk may change over time. In addition, patient preference is always important in such decisions. The approach to carotid restenosis is discussed in greater detail elsewhere. (See "Complications of carotid endarterectomy", section on 'Carotid restenosis' and "Overview of carotid artery stenting", section on 'Carotid thrombosis and restenosis'.) SOCIETY GUIDELINE LINKS https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 17/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults" and "Society guideline links: Occlusive carotid, aortic, renal, mesenteric, and peripheral atherosclerotic disease".) INFORMATION FOR PATIENTS UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." th th The Basics patient education pieces are written in plain language, at the 5 to 6 grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more th th sophisticated, and more detailed. These articles are written at the 10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.) Basics topics (see "Patient education: Carotid artery disease (The Basics)" and "Patient education: Stroke (The Basics)") SUMMARY AND RECOMMENDATIONS Definition of symptomatic extracranial carotid disease Symptomatic extracranial carotid atherosclerotic disease is defined as focal neurologic symptoms that are sudden in onset and referable to the carotid artery distribution within the previous six months. These symptoms may be transient ischemic attacks (TIAs), episodes of transient monocular blindness, or ischemic strokes. (See 'Definition of symptomatic disease' above.) Importance of medical management Treatment of symptomatic extracranial carotid atherosclerotic disease includes intensive medical management and may or may not include carotid revascularization with carotid endarterectomy (CEA) or carotid artery stenting (CAS). Optimal medical therapy includes antithrombotic therapy, statin therapy, and risk factor modification. It is recommended for all patients with atherosclerotic carotid artery stenosis in any location and regardless of symptoms. (See 'Intensive medical management' above.) https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 18/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Patients likely to benefit from revascularization 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 with CEA in addition to medical management (Grade 1A). (See 'Patients likely to benefit' above and 'Patients appropriate for CEA' above.) For patients with recently symptomatic moderate carotid stenosis of 50 to 69 percent who have a life expectancy of at least three years, we suggest carotid revascularization with CEA in addition to medical management (Grade 2A). Medical management alone is an appropriate alternative, especially in situations when the benefit is less certain, such as for female patients and if revascularization is delayed more than two weeks. (See 'Patients likely to benefit' above and 'Patients appropriate for CEA' above.) These recommendations apply to patients who are appropriate candidates for CEA, who meet the following conditions (see 'Patients appropriate for CEA' above): - - An ipsilateral TIA or nondisabling ischemic stroke as the symptomatic event A surgically accessible carotid artery lesion Absence of severe cardiac, pulmonary, or other disease that would greatly increase the risk of anesthesia and surgery - No prior ipsilateral endarterectomy CEA is performed by a surgeon or center where the risk of perioperative stroke and death with CEA is <6 percent Patients with symptomatic extracranial carotid atherosclerotic disease are most likely to benefit when carotid revascularization can be done within two weeks of symptom onset; for patients with ischemic stroke, an exception is that very early CEA (within the first two days after stroke onset) may be associated with increased operative risk. (See 'Timing of revascularization' above.) Patients unlikely to benefit from revascularization It is important to exclude those who are unlikely to benefit from carotid revascularization. This includes patients with severe comorbidity due to other surgical or medical illness, who may have unacceptably high risk for carotid revascularization, patients with stroke who have persistent, severe neurologic deficits and disability that precludes preservation of useful function, patients with less than 50 percent carotid stenosis, and patients with carotid occlusion or near occlusion. (See 'Patients unlikely to benefit' above.) https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 19/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate For patients with carotid stenosis that is 30 to 49 percent, we suggest against CEA or CAS (Grade 2B). There is no role for revascularization. For patients with near occlusion of the symptomatic ipsilateral internal carotid artery, there was no benefit of CEA in clinical trials, but there were few patients and events in this category. 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. Conditions favoring CAS rather than CEA For most patients, CEA is preferred over CAS because of a higher periprocedural stroke risk associated with CAS. Important exceptions include (see 'Patients appropriate for CAS' above): A carotid lesion that is not suitable for surgical access Radiation-induced stenosis Severe cardiac, pulmonary, or other disease that greatly increases the risk of anesthesia and surgery For these patients, CAS may be preferred and may be the only option. The approach to CAS, whether transfemoral carotid artery stenting (TF-CAS) or transcarotid artery revascularization (TCAR), is influenced by a variety of factors. For patients age 70 years and older with symptomatic carotid disease, outcomes are worse for TF-CAS compared with CEA; for TCAR, an age-related effect on outcomes has not been seen, but data are limited. (See 'Older age and worse outcomes with CAS' above.) ACKNOWLEDGMENTS The editorial staff at UpToDate acknowledges Ronald M Fairman, MD, who contributed to an earlier version of this topic review. The editorial staff also acknowledges Emile R Mohler, III, MD (deceased), who contributed to an earlier version of this topic review. Use of UpToDate is subject to the Terms of Use. REFERENCES https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 20/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate 1. Touz E. 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Editor's Choice - Timing of Carotid Intervention in Symptomatic Carotid Artery Stenosis: A Systematic Review and Meta-Analysis. Eur J Vasc Endovasc Surg 2022; 63:3. 57. Cui CL, Dakour-Aridi H, Eldrup-Jorgensen J, et al. Effects of timing on in-hospital and one- year outcomes after transcarotid artery revascularization. J Vasc Surg 2021; 73:1649. https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 24/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate 58. Elmously A, Rich N, Lazar AN, et al. Outcomes of early transcarotid artery revascularization versus carotid endarterectomy after acute neurologic events. J Vasc Surg 2022; 76:760. 59. de Borst GJ, Hazenberg CE. How should I treat a patient with a tandem carotid artery atherosclerotic stenosis involving the internal carotid artery and the innominate/proximal common carotid artery? Eur J Vasc Endovasc Surg 2015; 50:257. 60. Chung J, Valentine W, Sharath SE, et al. Percutaneous intervention for carotid in-stent restenosis does not improve outcomes compared with nonoperative management. J Vasc Surg 2016; 64:1286. Topic 1106 Version 43.0 https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 25/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate GRAPHICS Lateral view of the internal carotid artery Lateral view of a schematic drawing of the carotid arteries, vertebral arteries, and intracranial vessels and their relationships in the neck and brain. Reproduced with permission from: U acker R. Atlas Of Vascular Anatomy: An Angiographic Approach, Second Edition. Philadelphia: Lippincott Williams & Wilkins, 2007. Copyright 2007 Lippincott Williams & Wilkins. Graphic 63286 Version 1.0 https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 26/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Methods of measuring carotid stenosis in NASCET and ECST Modi ed from Donnan, GA, Davis, SM, Chambers, BR, Gates, PC, Lancet 1998; 351:1372. NASCET: North American Symptomatic Carotid Endarterectomy Trial; ECST: European Carotid Surgery Trial; CC: Common Carotid Method. Graphic 58353 Version 2.0 https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 27/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Benefit of carotid endarterectomy after recent ipsilateral nondisabling stroke or TIA in the NASCET trial The NASCET included 659 patients with a recent TIA or nondisabling stroke and a 70 to 99 percent carotid stenosis who were randomly assigned to carotid endarterectomy or medical therapy. After a two- year follow-up, the cumulative risk of any ipsilateral stroke was significantly lower in the endarterectomy group compared with the medical treatment group (9 versus 26 percent). The Kaplan-Meier survival curve shows the probability of event-free survival after randomization at six-month intervals. NASCET: North American Symptomatic Carotid Endarterectomy Trial; TIA: transient ischemic attack. Data from: North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991; 325:445. Graphic 75669 Version 7.0 https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 28/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Carotid endarterectomy reduces major stroke and death in symptomatic patients with severe stenosis The NASCET included 659 patients with a recent TIA or nondisabling stroke and a 70 to 99 percent carotid stenosis who were randomly assigned to carotid endarterectomy or medical therapy. At two-year follow-up, the cumulative risk of a major stroke or death was significantly lower in the endarterectomy group compared with the medical treatment group (8.0 versus 19.1 percent). The Kaplan- Meier survival curve shows the probability of event-free survival after randomization at six-month intervals. NASCET: North American Symptomatic Carotid Endarterectomy Trial; TIA: transient ischemic attack. Data from: North American Symptomatic Carotid Endarterectomy Trial Collaborators. N Engl J Med 1991; 325:445. Graphic 67964 Version 12.0 https://www.uptodate.com/contents/management-of-symptomatic-carotid-atherosclerotic-disease/print 29/34 7/5/23, 11:41 AM Management of symptomatic carotid atherosclerotic disease - UpToDate Sex difference in the effect of time from symptoms to surgery on benefit from c endarterectomy for TIA and nondisabling stroke Pooled data from the NASCET and the ECST showing the absolute reduction with surgery in the five-year risk