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Asymptomatic Carotid Artery Stenosis: Time to Rethink Our Therapeutic Options?

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Asymptomatic Carotid Artery Stenosis: Time to Rethink Our Therapeutic Options? Neurosurg Focus 36 (1):E2, 2014 ©AANS, 2014 Asymptomatic carotid artery stenosis: time to rethink our therapeutic options? SAUL F. MORALES-VALERO, M.D., AND GIUSEPPE LANZINO, M.D. Department of Neurologic Surgery, Mayo Clinic, Mayo Medical School, Rochester, Minnesota Asymptomatic carotid artery stenosis is a well-recognized risk factor for ischemic stroke, and its prevalence increases with age. In the late 1980s and in the 1990s, well-designed randomized trials established a definite advan- tage for carotid endarterectomy in reducing the risk of ipsilateral stroke when compared with medical therapy alone. However, medical treatment of cardiovascular disease has improved significantly over the past 2 decades, and this has, in turn, resulted in a decline of the stroke risk in patients with asymptomatic carotid artery stenosis treated medi- cally. This improvement in medical therapy casts doubts on the effectiveness of large-scale invasive treatment in pa- tients with asymptomatic carotid artery stenosis. Several studies have been conducted to identify possible subgroups of patients with asymptomatic stenosis who are at higher risk of stroke in order to maximize the potential benefits of invasive treatment. Ongoing large-scale trials comparing best current medical therapy to available invasive treat- ments, such as carotid endarterectomy and carotid artery stenting, are likely to shed some light on this debated topic in the near future. In this review, the authors summarize the current controversy surrounding the ideal management of asymptomatic carotid artery stenosis. (http://thejns.org/doi/abs/10.3171/2013.10.FOCUS13389) KEY WORDS • carotid artery stenosis • stroke • carotid endarterectomy HE prevalence of asymptomatic carotid artery ste- marginal but definite benefit for CEA in reducing the risk nosis varies according to age and sex. In a recent of stroke after 5 and 10 years when compared with “best” systematic review of population-based studies, medical therapy alone. However, these studies were con- Tmod erate stenosis (≥ 50%) was found in 4.8% of men ducted in the late 1980s and in the 1990s, and since their and 2.2% of women younger than 70 years. The percent- completion, progress in the medical management of car- ages increase to 12.5% in men and 6.9% in women if pa- diovascular diseases has led to a progressive decrease in tients older than 70 years are considered.8 Data regarding the yearly risk of stroke in patients with asymptomatic severe asymptomatic stenosis (≥ 70%) indicate that its carotid artery stenosis managed with medical treatment prevalence ranges from 0% to 3.1% of the general popu- alone. Thus, some have questioned the effectiveness of lation.9 Given the increase in prevalence with age and the large-scale invasive treatment (CEA or CAS) in view of aging population, asymptomatic carotid artery stenosis the significant improvement of medical therapy. In this can be expected to be very common in modern medical review, we summarize the available data and the ongoing practices. controversy related to this issue. About one-third of all strokes are related to large artery thromboembolism,4,12 and it is well recognized that carotid artery stenosis is a risk factor for ischemic Evidence Supporting Surgical Intervention for stroke.26,34 Large randomized, multicenter studies have Asymptomatic Carotid Artery Stenosis been conducted to assess the role and efficacy of carotid endarterectomy (CEA) and, more recently, carotid artery Two main studies have shaped the surgical treatment stenting (CAS) in patients with asymptomatic carotid ar- of asymptomatic carotid artery stenosis in the past 20 tery stenosis. These seminal trials have demonstrated a years: the Asymptomatic Carotid Atherosclerosis Study (ACAS) in North America and the Asymptomatic Ca- rotid Surgery Trial (ACST), conducted mostly in Europe. In ACAS, the main objective was to assess whether CEA Abbreviations used in this paper: ACAS = Asymptomatic Carotid Atherosclerosis Study; ACSRS = Asymptomatic Carotid Stenosis (in addition to medical therapy) reduced the 5-year risk and Risk of Stroke; ACST = Asymptomatic Carotid Surgery Trial; of ipsilateral stroke in individuals with hemodynamically CAS = carotid artery stenting; CEA = carotid endarterectomy; significant asymptomatic carotid artery stenosis (defined CREST = Carotid Revascularization Endarterectomy vs Stenting as ≥ 60% reduction in lumen diameter) when compared Trial; TCD = transcranial Doppler; TIA = transient ischemic attack. with medical therapy alone. “Best medical therapy” at the Neurosurg Focus / Volume 36 / January 2014 1 Unauthenticated | Downloaded 09/25/21 03:10 AM UTC S. F. Morales-Valero and G. Lanzino time of this trial was fairly simple and consisted mostly patients come from the Carotid Revascularization End- of daily aspirin combined with “reduction” of modifiable arterectomy vs Stenting Trial (CREST).6,36 During this risk factors. A total of 1662 patients were randomized study, both symptomatic and asymptomatic patients were from different medical centers across the United States randomized to undergo either CEA or CAS, and after a and Canada. The study was stopped early, after a medi- median follow-up period of 2.5 years the initial results an follow-up of 2.7 years, due to a significant difference were reported. Among the asymptomatic patients, the es- favoring CEA. The estimated 5-year risk of ipsilateral timated 4-year risk of stroke or death (including periop- stroke was reduced from 11% in individuals treated with erative events) was 2.7% with CEA and 4.5% with CAS. medical therapy alone to 5.1% in those undergoing CEA, However, this difference was not found to be statistically for an absolute risk reduction of 5.9% (or 1.2% per year).43 significant (p = 0.07) because the study was not powered The ACST was initiated in 1993 and enrolled a much to perform subgroup analysis. (Among the 2502 patients larger number of patients than ACAS. The primary ob- studied, there were 1181 asymptomatic patients; 594 in jective of ACST was to assess the long-term effects of the CAS group and 587 in the CEA group, with a small CEA on any stroke in patients with significant (defined number of endpoint events.) as > 60% lumen reduction on Doppler ultrasonography) asymptomatic carotid artery stenosis. It is important to mention that, in ACST, asymptomatic patients were con- Evidence Supporting Medical Therapy Alone sidered those without any relevant neurological symp- In the past 2 decades, important advances in medical toms during the 6 months preceding enrollment. A total therapy for cardiovascular diseases have taken place. An- of 3120 patients were randomized to undergo immediate tiplatelet, antihypertensive, and lipid-lowering agents are CEA while receiving intensive medical management or commonly used in patients at risk for atherosclerosis, and medical management alone; the mean follow-up period great emphasis is placed on the importance of exercise, was 3.4 years. An absolute risk reduction of 5.4% was weight loss, and smoking cessation. All of these interven- seen in the rate of any stroke and perioperative events tions, aimed at achieving specific clinical or biochemical when comparing immediate versus deferred surgery targets, have ultimately led to a reduction in the rate of (6.4% vs 11.8%). There was also a significant difference cardiovascular events, including stroke.20 Improvement in the risk of carotid territory stroke and fatal or disabling in medical therapy and cardiovascular risk-factor modi- stroke between both groups. The overall perioperative fication are the main reasons why many clinicians argue stroke and death rate in this study was 3.1%.16 against the widespread use of CEA and CAS for asymp- The 10-year data from ACST were published in tomatic patients.25,31,38 2010.15 The 10-year risk of any stroke and periopera- A number of studies and observations have indeed tive events was 13.4% in the CEA group and 17.9% in confirmed a progressive reduction in the yearly risk of the medical arm, representing an absolute risk reduction stroke in patients with asymptomatic carotid artery steno- of 4.6%. During this period, substantial improvement in sis since completion of the above-mentioned CEA trials. medical therapy was noted among individuals enrolled, These studies have methodological limitations, as many especially in regard to the increased use of lipid lower- variables such as weight loss, smoking, and physical ac- ing agents. The benefit of immediate CEA was not pres- tivity were not adequately controlled. However, they pro- ent across all age groups, being significant for men and vide convincing data to support a decreased rate of stroke women up to 75 years of age at the time of enrollment. with modern medical therapy in patients with asympto- Surgical intervention did not benefit patients older than matic carotid artery stenosis. 75 at the time of enrollment due to their increased prob- A prospective, cohort study of 101 patients was con- ability (> 50%) of dying from a variety of causes rather ducted from 2002 to 2009 to determine the risk of ipsi- than stroke during the 10-year follow-up period.15 lateral stroke in patients with at least 50% asymptomatic It is often said that ACAS and ACST reported a carotid artery artery stenosis on intensive medical treat- similar overall stroke risk reduction favoring CEA, but ment. In this study, intensive therapy consisted of anti- this is not true. A fundamental difference between the platelet, lipid-lowering, and antihypertensive medications two studies is the primary end-point: ipsilateral stroke in more than 80% of patients, as well as appropriate glu- in ACAS and any territory stroke in ACST. As we will cose control measures and lifestyle modifications. After elaborate later, careful analysis of the two studies actually a mean follow-up of 3 years, 6 ischemic events occurred does confirm a progressive decrease in the risk of ipsi- in the territory of the asymptomatic carotid artery ste- lateral stroke in parallel with improvements of medical nosis, and 5 of these events were transient ischemic at- therapy.
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