Are the Current Risks of Asymptomatic Carotid Stenosis Exaggerated?: Further Evidence Supporting the CREST 2 Trial

In the past 2 decades, 2 large multicenter trials have demonstrated the efficacy of carotid endarterectomy (CEA) for patients with asymptomatic carotid stenosis: the Asymptomatic CarotidAtherosclerosisStudy (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST).1,2 These trials found thatCEA, comparedwithbestmedical therapy,was associated with a significant relative risk reduction of 50%during 5 years but only an absolute reduction in ipsilateral stroke of 0.5% to 1%peryear.With thenumberneededto treat toprevent 1 stroke in 1year approaching 100 to200,whether thisdegreeof stroke reduction is clinically significant has been debated.3 The trials have led toevidence-based recommendations supportingCEA for selectedpatientswith asymptomatic carotid stenosis anda surge in carotid revascularization procedures in recent years. Among Medicare patients in the period 2004-2006, 87% of carotid artery stenting (CAS) and 88%of CEAprocedureswere performed in asymptomatic patients.4 Medical therapy has advanced since the time these trials were conducted. These advances include the more widespread use of high-potency statins, newer antiplatelet agents, and expanded options for blood pressure control.5 In addition, there has been increased recognition of the value of lifestyle interventions, including exercise and dietary modification.6 Several small longitudinal studies7,8havedocumented that for patients with asymptomatic carotid narrowing treatedwithcontemporarymedical therapy, theannual risk of ipsilateral stroke has decreased to less than 1% per year. In this issueof JAMANeurology, Yanget al9 addsome“fuel to the fire” regarding the debate concerning the best treatment for asymptomatic carotid stenosis. They analyzed 3681 patients seen in an atherosclerosis clinic during a 20-year period.Thepatientswere followedupwith regular carotidduplex examinations. The study found that the risk of progression to internal carotid artery (ICA) occlusion decreased over time, corresponding tomore intensivemedical therapy.Of the 316 patients with documented progression to ICA occlusion, 80.4%of these cases occurredbefore 2002.Remarkably, only 1 patient had a stroke at the time of ICA occlusion. These low rates of ICA occlusion and stroke add to the increasing evidence for the value of contemporary medical therapies. Such a low risk of strokewith progression to occlusion has beenseeninotherworkaswell.10 IntheACST,among1469medically treated patients, 82 had progression to an asymptomatic occlusion, with only 12 individuals having a symptomatic ICA occlusion.10 Inthe12patientswithasymptomatic ICAocclusion, only 1hada stroke.The lower ratesofprogression to ICAocclusionandstrokeamongpatientstreatedwithcontemporarymedical therapyprovidefurthersupport for therationaleofnewtrials to reassess the evidence for revascularization in such cases. Selectionof thehighest-risk subgroups among thosewith asymptomatic carotid stenosis has remained difficult. In the current study, age, total plaque area, and male sex were the onlypredictors of ipsilateral stroke, transient ischemic attack, orstroke-relateddeath.Sexdisparities forcarotidstenosis treatments have been noted previously. A combined analysis of ACASandACSTfoundnobenefitofCEAinwomenwithasymptomatic carotid stenosis.11 Women tend to have less intraplaque hemorrhage and lower degrees of macrophage infiltration in carotid plaques.12,13 Themore benign prognosis for womenhas led to calls for “women-specific” carotid stenosis trials among symptomatic and asymptomatic women.14,15 Characteristics of the carotid stenosis, such as degree of stenosis, calcification, andulceration, havebeenevaluated to help risk stratify asymptomatic patients. Total plaque area, as suggested by Yang et al,9 was a predictor of adverse outcomes and can be used as a quantitative tool for tracking the success or failure of intensive medical therapy. Those patients with increases in total plaque area despite medical therapy may require further testing, such as monitoring for cerebral emboli,8 and provide further rationale for selecting patients for revascularization treatments. Asa single-center study, theanalysis byYanget al has limitations. The cause of deathwas unknown in 16 of 71 patients, raising the issues ofmisclassification and ascertainment bias. Furthermore, it isnotclearwhether therewasanyexternalvalidation of the listed causes of death. Finally, it is unclear what percentage of patients was evaluated by a neurologist after documentationof an ICAocclusion.All these limitations could have led to underestimations in the risk of stroke. Moreover, theaggressivemedicalmanagementprovided in thisclinicmay notbe typical of communitypractice settings, leading to issues of lack of generalizability. Ultimately,whether the improvements inaggressivemedical therapyare sufficient to reduce the rationale forCEAorCAS in asymptomatic patients will need to be determined by contemporary randomizedclinical trials.Fortunately, theNational Institute ofNeurological Disorders and Stroke has funded the Carotid Revascularization and Medical Management for Related article page 1261 Opinion