Asymptomatic carotid stenosis (ACS) is estimated to affect between 0% and 3% of the general population [1], and comprises 72% of all carotid endarterectomies (CEAs) performed in the United States [2]. Management of ACS includes best medical therapy (BMT) with antiplatelet agents, lipid-lowering therapy, and lifestyle modification [3]. Screening and patient selection for revascularization in asymptomatic participants has been the subject of debate over the past decade. There are three randomized clinical trials on the management of ACS that largely influenced our current guidelines and practice: the Asymptomatic Carotid Surgery Trial-1 (ACST-1), Asymptomatic Carotid Atherosclerosis Study (ACAS), and Veterans Affairs Cooperative Study (VACS).

The VACS recruited male participants from 1983 to 1991 from 11 VA medical centers. Patients with asymptomatic stenosis of ≥ 50% were randomized to BMT alone, which included aspirin, versus BMT and CEA. The study had a mean follow-up of 48 months and found an incidence of ipsilateral neurologic events of 8% in the CEA group vs 20.6% in the CEA plus medical therapy group, without differences between groups in all strokes and death. The ACAS trial was conducted between 1987 and 1993. All patients received daily aspirin and risk factor modification. Patients with > 60% carotid stenosis were randomized to undergo CEA versus medical management alone. The study found a 53% reduction in ipsilateral stroke or any perioperative stroke or death in patients who underwent surgical intervention compared with medical management alone (5% v 11% risk). Their findings achieved significant results after a median follow-up of 2.7 years [4]. Shortly after, the ACST trial recruited and randomized patients to immediate CEA versus deferral from 1993 to 2003. As with ACAS, all patients received medical therapy, including antihypertensive and aspirin. Over the course of the study, the ACST trial introduced lipid-lowering therapy, with an increase in use from < 10% at the beginning of the study to > 80% at the completion. The rate of nonperioperative stroke decreased 46% in patients who had immediate CEA versus deferral. The authors also found that absolute stroke rates were lower in patients who were receiving lipid-lowering therapy, supporting their use as a key component of BMT. Benefits from early CEA were apparent after 5 years and continued until 10 years and, based on these findings, the authors concluded that surgery should be considered in patients with a life expectancy of more than 10 years [5]. One limitation of these randomized controlled trials (RCTs) is that they were conducted before lipid-lowering therapy was widely utilized [6]. Statins have been found to reduce the risk of stroke [7] and are a main component of modern BMT. Aside from their lipid-lowering properties, statins promote plaque stabilization and have been found to decrease inflammation and platelet aggregation [8].

The Carotid Revascularization Endarterectomy Versus Stenting Trial (CREST) is another landmark randomized clinical trial, conducted between 2000 and 2008. Patients with symptomatic carotid stenosis were randomized to CEA versus carotid artery stenting (CAS). In 2005, the investigators extended the eligibility criteria to include asymptomatic patients with high-grade stenosis detected on imaging, contributing to our knowledge of the management of ACS. The primary end point was a composite of myocardial infarction, death, or stroke in the perioperative period, or ipsilateral stroke within 4 years after randomization. The authors found no difference according to symptomatic status in the general population. Their results revealed CAS had greater efficacy in the younger cohort, and endarterectomy had greater efficacy in older adults, which became more pronounced after age 70 years [9]. These data shifted practice by validating CAS as an evidence-based alternative for asymptomatic patients who are younger than 70 years, have favorable arch/lesion anatomy, or elevated surgical cardiac risk, and reaffirming CEA as the preferred choice in most older adult patients. Proposed mechanisms for this include advanced atherosclerotic disease and complex anatomy in older adults, resulting in superior outcomes with an open approach [1]. The ongoing CREST-2 trial is composed of two multicenter RCTs comparing CEA plus BMT with BMT alone, and CAS plus BMT with BMT alone. This upcoming landmark study will provide contemporary data to support guidelines on patient selection for intervention and choice of revascularization.

Current Society for Vascular Surgery guidelines do not support screening in asymptomatic and low-risk patients (grade 1B), and recommend screening only for those who are at an increased risk of carotid stenosis and would benefit from intervention (grade 2B) [10]. The US Preventive Services Task Force does not recommend screening in asymptomatic patients in general [11]. In terms of management for asymptomatic patients with carotid stenosis of ≥ 70%, a life expectancy of 3 to 5 years, and low surgical risk, the Society for Vascular Surgery recommended BMT along with surgical intervention (grade 1 B) [10]. The guidelines also recommend consideration in asymptomatic patients with 60% to 99% stenosis and high-risk factors. Clinical and imaging features that are associated with high risk include presence of an echolucent plaque on ultrasound, progression of stenosis, intraplaque hemorrhage on magnetic resonance imaging, silent infarct on magnetic resonance imaging, and carotid ulceration [12]. The European Society for Vascular Surgery’s 2023 guidelines also recommended CEA in asymptomatic patients with 60% to 99% stenosis, a life expectancy exceeding 5 years, and one or more imaging or clinical characteristics associated with increased risk of stroke (grade IIA) [13].

To date, there is no consensus that carotid revascularization, whether CEA or CAS, is superior to modern BMT, and there is high variability in our current practice in the management of ACS. Although some studies have demonstrated superiority of CEA over traditional BMT [4,5], others have shown a similar decrease in stroke and mortality compared with modern BMT with lipid-lowering therapy [[14], [15], [16]]. The Second European Carotid Surgery Trial (ECST-2) enrolled participants with asymptomatic and symptomatic carotid stenosis of ≥ 50% and < 20% predicted risk of ipsilateral stroke. Participants were randomized to BMT alone or BMT plus revascularization. After 2 years, interim analysis found no difference in outcomes, including stroke, all-cause death, transient ischemic attack, and new silent cerebral infarction [17]. A study investigating the absolute risk of fatal and nonfatal strokes in older adults with ACS in a 5-year follow-up period found that there was no statistically significant difference between early CEA treatment and medical therapy alone [18]. In a community-based retrospective cohort study of 3,737 patients with asymptomatic severe (70% to 99%) carotid stenosis receiving medical therapy alone, the estimated rate of ipsilateral acute stroke related to carotid disease over 5 years was 4.7% [19]. The latter two studies, although not exclusive to octogenarians and nonagenarians, suggested that surgery is not necessarily superior to medical therapy alone. Multicenter RCTs with subgroup analyses of octogenarians and nonagenarians are needed to establish the best treatment strategy for ACS, standardize our guidelines, and homogenize our practice.