What Is the Future of Asymptomatic Carotid Artery Disease?

Jun 16, 2015   |  Kamal Gupta, MBBS, FACC; Zubair Shah, MBBS

Expert Analysis

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Introduction

Asymptomatic carotid artery stenosis is a significant health concern, as out of the 135,701 carotid revascularizations performed in the U.S. in 2005, 122,986 (92%) were for asymptomatic carotid artery stenosis.1 Current societal guidelines recommend revascularization in most patients with severe asymptomatic carotid artery stenosis.2 However, these guidelines are based on older studies that may not reflect the changing natural history of asymptomatic carotid artery stenosis with current optimal medical therapy (OMT). The old paradigms for deciding the timing of revascularization need to be revisited.3 Thus physicians today are faced with a dilemma regarding who to treat and when. This article addresses the evolving natural history of asymptomatic carotid artery stenosis, ongoing attempts to identify those more likely to become symptomatic, and advances in revascularization techniques that may decrease the risk from revascularization.

Conventional Management Paradigm for Asymptomatic Carotid Artery Stenosis

Current recommendations for revascularization for asymptomatic carotid artery stenosis2 are predominantly based on two seminal studies performed in the 1990s. The Asymptomatic Carotid Artery Study (ACAS) was a well-conducted study that assessed carotid endarterectomy (CEA) in asymptomatic carotid artery stenosis (>60%) for stroke prevention.4 A total of 1,662 patients were randomized to CEA or medical therapy. The study was halted at 2.7 years because of a projected 5.9% absolute risk reduction (ARR) at five years favoring CEA. The perioperative stroke rate was 2.3%. The five-year projected rate of ipsilateral stroke was 11% for the medical group versus 5.1% for the surgical group (a 47% relative risk reduction [RRR]). The Asymptomatic Carotid Surgery Trial (ACST) randomized 3,120 asymptomatic carotid artery stenosis patients into immediate CEA or delayed surgery for symptoms only. The 30-day risk of stroke or death was 3.1%. The five-year rates were 6.4% for CEA and 11.7% for medical therapy arm.5,6

However, medical therapy in these trials was not up to current standards, with only a minority of patients receiving lipid-lowering therapy and blood pressure (BP) was also significantly higher than today's standards.3,7

Evolving Natural History of Asymptomatic Carotid Artery Disease

The annual risk of stroke in ACAS and ACST was 2-3%.4,6 This relatively high risk with medical therapy would likely still make revascularization a reasonable choice today as the more recent Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST) reported a four-year risk of stroke or death as 4.5% with carotid artery stenting (CAS) and 2.7% with CEA.8 However, recent evidence suggests that the natural history of asymptomatic carotid artery stenosis has improved remarkably, and the risk-benefit analysis of revascularization will need to be re-evaluated. Current OMT consists of high-dose statin drugs, optimal BP control, smoking cessation, antiplatelet therapy (generally aspirin alone), optimal diabetes control and other lifestyle changes.9 In ACST, in 2004, the five-year risk of any stroke in medically treated subjects was 11.8% (2.4% annually), while in 2010 the five-year risk was 7.2% (1.4% annually).3,10 Ipsilateral stroke risk was 5.3% (1.1% annual) and 3.6% (0.7% annually). In a sub-study of the Oxford Vascular Study, Marquardt et al. reported that in 101 patients with a mean follow-up of three years, the annual risk of any ipsilateral stroke was 0.34%.11 There are no large studies, but several meta-analysis have demonstrated a sustained trend towards a decline in the stroke.12-14 By most estimates, the annual risk of stroke with current OMT is likely <1%. Shah et al. recently showed that with OMT and risk factor control, the risk of progression of the degree of carotid stenosis is also significantly lower than in those with sub-optimal medical therapy.15

Current and Future Trials of Carotid Revascularization and OMT

There is an urgent need for studies that directly compare OMT with current revascularization techniques.

The Carotid Revascularization Endarterectomy Stenting Trial 2 (CREST 2) is currently recruiting subjects with asymptomatic carotid artery stenosis and ≥70% stenosis. The study will compare either OMT alone versus OMT plus CEA or OMT alone versus OMT plus CAS.16,17

The Stent-Protected Angioplasty in Asymptomatic Carotid Artery Stenosis versus Endarterectomy (SPACE-2) study aims to recruit about 3,500 patients and randomly assign them to OMT alone or CEA or CAS.18

Identifying the "High-Risk" Patient With Asymptomatic Carotid Artery Stenosis

Unarguably, the above-mentioned studies will help define the role of revascularization strategies in asymptomatic carotid artery stenosis patients. However, the reality is that the majority of patients with asymptomatic carotid artery stenosis will never become symptomatic and may undergo unnecessary procedures if these studies do show benefit of CEA or CAS. On the other hand, even if the studies show no benefit of OMT over CEA or CAS, there will still be patients who will become symptomatic. Thus, recognition of patients at higher risk would maximize the potential benefits of revascularization. However, there are several potential and promising tools that are being investigated.

Clinical Features

There are few clinical predictors of increased stroke risk in asymptomatic carotid artery stenosis. Certain clinical characteristics, such as male sex, current smoking, poorly controlled hypertension, and history of contralateral transient ischemic attack (TIA)/stroke impart a higher risk of future stroke. However these are too non-specific to serve as useful guides for deciding about revascularization.19

In addition to identifying clinical factors, risk stratification attempts have focused on other indirect methods as discussed below.

Stenosis Severity

Contrary to common belief, the stenosis severity in the 60-99% range has been an inadequate predictor of future events. The randomized ACAS and ACST trials did not show stenosis severity in this range as a predictor of future events.4,6 The ACSRS study did find that those with 50-69% stenosis had a lower risk compared to those with 70-89% and 90-99% stenosis (0.8% vs. 1.4% vs. 2.4%).20 However, stenosis severity alone is not a strong enough predictor to be used alone in decision making.

Progression of Stenosis

There is significantly stronger evidence in regard to the predictive value of progressively worsening stenosis. In a post-hoc analysis of the ACST data, incidence of ipsilateral neurologic events was four times higher for stenosis that had progressed by two categories.21 Kakkos et al. studied 1,121 patients with asymptomatic carotid artery stenosis and 50-99% stenosis (mean follow-up, four years).22 19.8% of patients showed stenosis progression of at least one grade and had twice the risk of ipsilateral stroke (21% vs. 12%). Balestrini et al. followed 535 patients with moderate asymptomatic carotid artery stenosis for a mean of 42 months.23 They found that 96.7% of subjects without progressive stenosis remained free from vascular events. Among those with progressive stenosis, 27.1% had an ipsilateral stroke. Thus, progressively increasing stenosis does identify patients with higher risk.

Plaque Characteristics

Using ultrasound, atherosclerotic plaques can be characterized based on their surface irregularity, ulcerations, echolucency and gray-scale values. The concept is to identify unstable plaque that is more likely to result in thromboembolic events. The ACSRS investigators have shown that those with predominantly echolucent, lipid-rich plaque had significantly higher stroke risk (3%) than those with mostly echodense, fibrotic plaque (0.8-0.4%).19,24,25 Ulceration on plaque surface detected by three-dimensional ultrasound has also been shown to identify high-risk subjects.26

Magnetic resonance imaging (MRI) has also been used to detect the presence of intraplaque hemorrhage as indicative of a high-risk plaque.27 In a retrospective study of 75 men with 98 asymptomatic carotid arteries of 50-70 % stenosis, intraplaque hemorrhage detected by MRI was present in 36 arteries (37 percent) and was associated with an increased risk of cerebrovascular events (hazard ration [HR] 3.59, 95% confidence interval [CI] 2.48-4.71).28

Looking for Silent Emboli

Since both progressive stenosis and high-risk imaging features identify unstable plaque more prone to atheroembolic events, another way to identify patients at risk is to assess for active silent emboli or evidence of prior asymptomatic cerebral emboli.

Silent Embolic Infarcts on Computed Tomography (CT) or MRI

Presence of ipsilateral silent embolic infarcts on neuroimaging may be predictive of increased risk of ipsilateral stroke.27 In the ACSRS study, among the 821 patients who had a baseline CT, the annual stroke rate was 3.6% when silent embolic infarcts were present at baseline and 1% when they were absent (log-rank P = 0.005).29

Microemboli on Transcranial Doppler (TCD)

Several observational studies demonstrate that detection of microemboli on TCD helps identify those at higher stroke risk.30,31 In the Asymptomatic Carotid Emboli Study (ACES),32 482 patients with asymptomatic carotid artery stenosis underwent six monthly TCDs. The annual risk of ipsilateral stroke was 3.62% in patients with embolic signals and 0.7% in those without them (HR 5.57). A meta-analysis of six reports involving 1,144 patients with asymptomatic carotid artery stenosis found that patients with embolic signals had a significantly higher risk of ipsilateral stroke (HR 6.6, 95% CI 2.9-15.4).33 However, most patients with these signals did remain stroke free at three years, and thus, this test lacks the specificity for stand-alone clinical use.30 Of note, consistently negative asymptomatic carotid artery stenosis patients are associated with an extremely low risk of subsequent stroke.31

Reduced Cerebrovascular Reserve

In patients with severe ipsilateral carotid stenosis, the presence of an incomplete circle of Willis or presence of intracranial or contralateral occlusive disease can reduce cerebral perfusion pressure. Cerebrovascular reserve in such patients can be assessed using TCD velocity measurements in response to acetazolamide or breathing 5% CO2.34-37 In a meta-analysis of 13 studies (991 patients, mean follow up 32.7 months), a strong association between impaired cerebrovascular reserve and ischemic events was seen (OR 3.86).38

Women

Women were underrepresented in most randomized studies of CEA and CAS.4,5 However, a combined analysis of the ACAS and ACST trials found that men with asymptomatic carotid artery stenosis had a 51% relative risk reduction of stroke, whereas women did not have a reduction in stroke risk.39 This has been mostly attributable to the higher risk of perioperative events in women though not borne out in the recent CREST trial.8,40,41 Thus, there is a concern that women may benefit less from revascularization than men and future clinical trials focusing on women are needed to clarify the issue.42

Elderly

The elderly (especially those over 80 years of age) is a group in which the benefit of revascularization for asymptomatic carotid artery stenosis is most controversial because in both the ACAS and ACST, the benefit from revascularization was seen after five-year follow-up.4,6 Further, ACAS did not enroll subjects greater than 75 years of age; in ACST, there was no benefit seen in those over 75 years (although this was not a pre-specified endpoint). However, age cannot be an absolute contraindication with increasing life expectancy of the overall population; certainly in carefully selected patients, excellent outcomes after both CEA and CAS have been demonstrated.43,44 In regards to the modality of revascularization, based on the CREST data, overall CEA had more favorable outcomes for those over 70 years of age and CAS for those under 70 years of age.8

Current State of Revascularization (Improving Outcomes)

In parallel with improved outcomes with OMT, there have been advances in revascularization techniques. The 30-day risk of stroke after CEA in the CREST study was 2.3 percent, which is lower than historical data.8

Similarly for CAS, most of the published randomized trials used the distal embolic protection devices (DEPD)8,45 and not the proximal embolic protection devices or flow reversal devices. These devices establish embolic protection before any wire/ hardware ever crosses the lesion and, thus, overcome one significant limitation of the DEPDs. Overall the proximal protection/flow reversal has been associated with less microemboli as detected by diffusion-weighted brain (DW-MRI).46-49 A recently published meta-analysis of seven studies with a total of 357 patients reported that following CAS, the incidence of new ischemic lesions/patient detected by DW-MRI was significantly lower in the proximal balloon occlusion group (effect size [ES]: 0.43; 95% CI: 0.84 to 0.02, I2 . 70.08,Q . 23.40).50

The ongoing ROADSTER trial involves an innovative technique with a limited proximal neck dissection to obtain direct carotid access and is paired with proximal reverse flow embolic protection.51,52 Direct carotid access is intended to minimize the risk of microemboli and stroke associated with arch navigation.

Conclusions and Recommendations for Clinical Practice

Both medical and surgical management arms of asymptomatic carotid artery stenosis are rapidly evolving and will continue to result in decreased stroke risk. Until results of CREST 2 and SPACE-2 trails are available, there will remain some uncertainty in regards to best management plan. We recommend that for asymptomatic carotid artery stenosis patients (even those with >80%) stenosis there is enough evidence for a more conservative approach and decisions regarding revascularization should be made after discussing the current available data on stroke risk with the patients. Serial ultrasounds should be performed and revascularization offered to those with >70% stenosis with evidence of progression of stenosis severity. All patients with asymptomatic carotid artery stenosis should be on OMT. For the very elderly (>80 years) and life expectancy less than five years, a conservative approach is most reasonable in most situations. Though more prospective data is needed (and not ready for "prime time" yet), it appears that in the future TCD and brain MRI will be part of the risk stratification process. Regarding optimal revascularization strategy, the authors of this Expert Analysis article believe that CREST is a well-conducted, contemporary trial done in multi-specialty collaboration and does represent current standards of care; based on its results, there is equipoise between the two modalities. Based on CREST results, younger patients (<70 years) may benefit more from CAS and older more from CEA. Individual patient and anatomic risks for CEA and CAS are different and should be considered and a multi-specialty approach should be followed.53

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Keywords: Acetazolamide, Aged, Angioplasty, Aspirin, Balloon Occlusion, Blood Pressure, Brain, Carotid Arteries, Carotid Stenosis, Circle of Willis, Confidence Intervals, Constriction, Pathologic, Cooperative Behavior, Diabetes Mellitus, Embolic Protection Devices, Endarterectomy, Carotid, Follow-Up Studies, Hypertension, Incidence, Intracranial Embolism, Ischemic Attack, Transient, Life Expectancy, Life Style, Lipids, Magnetic Resonance Imaging, Neck Dissection, Neuroimaging, Plaque, Atherosclerotic, Prospective Studies, Research Personnel, Retrospective Studies, Risk, Risk Factors, Smoking, Smoking Cessation, Standard of Care, Stents, Stroke, Tomography, Uncertainty, Unnecessary Procedures


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