Evaluation and Management of Atherosclerotic Carotid Stenosis

Abstract

Medical therapies for the prevention of stroke have advanced considerably in the last several years. There can also be a role for mechanical restoration of the lumen by endarterectomy or stenting in selected patients with high-grade atherosclerotic stenosis of the extracranial carotid artery. Endarterectomy is generally recommended for patients with high-grade symptomatic carotid stenosis. Stenting is considered an option for patients at high risk of complications with endarterectomy. Whether revascularization is better than contemporary medical therapy for asymptomatic extracranial carotid stenosis is a subject of several ongoing randomized clinical trials in the United States and internationally.

Atherosclerosis is not merely a byproduct of the sedentary life style and adverse dietary habits typical of the twenty-first century, as it has afflicted humanity for millennia. A whole-body CT scanning study of mummies found that about one third of pre-industrial populations, including pre-agricultural hunter-gatherers, had evidence of atherosclerosis.¹ Atherosclerosis is common in the modern asymptomatic middle-aged population. In one study of asymptomatic individuals between ages 40 and 54 years, nearly one third had ultrasonographic evidence of atherosclerosis in the carotid arteries.² When the burden of atherosclerosis becomes severe enough to cause stenosis of the carotid artery, it may act as a source of embolism and, by extension, a cause of ischemic stroke. When cerebral infarction or reversible cerebral ischemia occurs in the perfusion zone distal to a carotid stenosis, the carotid stenosis is said to be symptomatic. The risk of future stroke increases with greater degree of stenosis in patients for whom the stenosis is symptomatic.³ About 8 to 15% of ischemic strokes are attributable to carotid atherosclerosis.^4-6 In this narrative review, we summarize the data regarding the evaluation and management of asymptomatic and symptomatic carotid stenosis.

Methods

The review and our recommendations are supported by a formal search of the medical literature updated since a prior publication on this topic in 2007 in this Journal.⁷ The Appendix describes the specific approach used to identify the relevant medical literature.

Identifying and Characterizing Carotid Stenosis

The most common non-invasive ways of screening for carotid stenosis are duplex ultrasonongraphy, computed tomographic angiography (CTA), and magnetic resonance angiography (MRA). In the case of carotid ultrasonography, the degree of carotid stenosis is largely determined by measuring the velocity of blood flow at various segments of the artery. Criteria have been established for translating velocity measurements into clinically useful stenosis cut-points.^8,9 For example, one meta-analysis found a peak systolic velocity of 200 cm/s or greater on ultrasound to have a sensitivity of 90% and specificity of 94% for diagnosing angiographic stenosis ≥70%.⁸ However, measurement properties vary considerably between laboratories. Factors that can affect sensitivity of ultrasound include heavy calcification of the artery, and selected contours of the neck. Distal and proximal segments of the extracranial carotid artery cannot be visualized on ultrasonography.

CTA generally correlates well with carotid ultrasonography, though, unlike ultrasonography, it exposes patients to radiation and contrast.¹⁰ With the recent demonstration of the efficacy of mechanical thrombectomy for treating acute ischemic stroke in selected patients,¹¹ CTA is being used with greater frequency in the initial evaluation of patients.¹² Thus, patients with non-disabling stroke who are being considered for carotid revascularization may have a CTA available for review.

Catheter angiography traditionally has been considered the gold standard for stenosis assessment in patients with carotid disease. However, MRA fairs well by comparison. A study of 103 patients undergoing endarterectomy had their plaque sectioned transversally and assessed planimetrically.¹³ All patients had preoperative catheter angiography and MRA. Overall, catheter angiography underestimated histological stenosis by 14.5%, whereas MRA underestimated histological stenosis by only 0.7%. Among catheter angiography-defined severe stenosis patients, MRA overestimated stenosis by 12.1%.

The risk of modern digital subtraction angiography is low. The rate of permanent neurological complications is about 0.5%.¹⁴ Rates of transient neurological complications range from 0 to 2.4% and rates of major non-neurological complications range from 0.26 to 4.3%.¹⁵ Nonetheless, there is little justification to expose asymptomatic patients to the risk of catheter-based angiography prior to treatment decisions.

Cost of carotid imaging should be considered. A prospective study of 167 patients found that the most cost-effective approach to carotid imaging for evaluating patients prior to endarterectomy was carotid ultrasonography and contrast-enhanced MRA, proceeding to digital subtraction angiography only in cases of discrepancy in which the MRA is positive for high-grade stenosis and the ultrasound is negative.¹⁶

A challenge regarding the use of revascularization for preventing stroke in patients with asymptomatic carotid stenosis is the generally low risk of stroke in untreated patients. Various imaging techniques are being used and developed to stratify risk of stroke in asymptomatic stenosis. MRI techniques can be used to characterize plaque beyond degree of stenosis. Intraplaque hemorrhage, lipid-rich necrotic core, and thinning and rupture of fibrous cap predict risk of stroke.¹⁷ Statistical modeling suggests that detection of intraplaque hemorrhage by MRI may be cost-effective for identifying asymptomatic patients most likely to benefit from carotid endarterectomy.¹⁸ Transcranial Doppler can also stratify risk.^19,20 The Asymptomatic Carotid Emboli Study (ACES) study involving 482 patients across 26 centers found that transcranial Doppler detected microembolic signals are associated with ipsilateral ischemic stroke in patients with asymptomatic carotid stenosis (HR, 6.37).²¹

Screening for Asymptomatic Carotid Senosis

Clinically significant carotid stenosis is not rare. Ultrasound studies have found the prevalence of moderate to severe atherosclerotic stenosis to range from 2 to 8% among adults in North America, Europe and East Asia (Table 1^22-35). The US Preventive Services Task Force issued an updated recommendation against screening for asymptomatic carotid stenosis in the general population.³⁶ The Task Force raised concerns that no randomized trial has specifically demonstrated the value of screening for carotid disease as a first step in the prevention of ischemic stroke. Further concerns were raised about false positive detection of stenosis and of potential complications in patients undergoing revascularization. In clinical populations, carotid ultrasonography is done for diverse indications. A review of Veterans Health Administration patients who had a revascularization procedure for asymptomatic carotid stenosis found that about half had initial ultrasonography for carotid bruit or follow-up of carotid disease.³⁷

Table 1.

Prevalence of atherosclerotic carotid stenosis of 50% or greater detected by ultrasonography.

Author, Year of Publication	Subjects examined (n)	Age (years)	Prevalence rate (%)	Country
Colgan, 198822	348	24-91	4	United States
Ricci, 199133	328	> 49	5	Italy
O'Leary, 199231	5201	≥ 65	6	United States
Pujia, 199232	239	> 65	5	United States
Fine-Edelstein, 199423	1116	66-93	8	United States
Kiechl, 199426	909	40-79	8	Italy
Harer, 199624	529	36-84	4.2	Russia
Mannami, 199727	1694	50-79	4.4	Japan
Meissner, 199929	567	≥ 45	8	United States
Mineva, 200030	500	50-79	6.4	Bulgaria
Mathiesen, 200128	6727	25-84	2.2	Norway
Suri, 200834	5449	≥65	4.2	United States
Huang, 201525	5349	>40	6.7	China
Yan, 201635	1375	>60	7.0	China

Several clinical features point to populations with a high pretest probability for detecting carotid stenosis on ultrasonography. Patients with peripheral artery disease (PAD) are at increased risk of having coexisting carotid stenosis. A review of Life Line Screening data from 3.67 million US adults found that the presence of PAD, defined as an ankle-brachial index of <0.9, had a 3.28 odds ratio for detection of carotid stenosis.³⁸ Further, increasing severity of PAD increased the odds of carotid stenosis. Patients with ophthalmoscopic evidence of a cholesterol embolus within a retinal artery (Hollenhorst plaque) have a 13% prevalence of high-grade extracranial carotid stenosis, and patients with both Hollenhorst plaque and carotid bruit have a 37% prevalence of high-grade carotid stenosis.³⁹ Patients undergoing coronary artery bypass grafting at one referral center had a 38% prevalence of carotid stenosis on ultrasonography.⁴⁰ A multi-society evidence-based guideline recommended that screening for carotid stenosis could be considered for asymptomatic patients with either: 1) symptomatic PAD, coronary artery disease, or atherosclerotic aortic aneurysm, or 2) two or more of the following risk factors: hypertension, hyperlipidemia, tobacco smoking, a family history of early-onset (less than 60 years) atherosclerotic disease in a first-degree relative, or a family history of ischemic stroke.⁴¹

Medical Management

Though there have been numerous successful clinical trials of various medical strategies for primary and secondary stroke prevention,^42,43 surprisingly few trials have specifically focused on the prevention of stroke by medical means in patients with carotid stenosis. Nonetheless, several evidence-based recommendations can be made.

Antiplatelet and anti-thrombotic therapy

Aspirin, the combination of aspirin and extended-release dipyridamole, and clopidogrel all have efficacy for secondary prevention of ischemic stroke in patients with non-cardioembolic stroke.⁴³ While long-term aspirin monotherapy is not indicated for primary stroke prevention in low-risk individuals,⁴² the AHA recommends that patients with obstructive or non-obstructive extracranial carotid disease take aspirin at a daily dose of 75 to 325 mg.⁴⁴ Aspirin clearly reduces the risk of stroke in patients who have had prior ischemic stroke or transient ischemic attack.⁴⁵ However, aspirin has not been clearly shown to prevent stroke in asymptomatic patients with carotid bruit and stenosis.⁴⁶ Aspirin is recommended in asymptomatic carotid patients to prevent coronary events. Long-term dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is not generally indicated for secondary stroke prevention due to increased risk of hemorrhage⁴³ and is not typically used for primary stroke prevention.

For patients undergoing revascularization, antiplatelet therapy is routinely used pre- and post-procedure, though the practice varies considerably depending on the nature of the revascularization procedure. In the Asymptomatic Carotid Surgery Trial (ACST)-2, survey data indicate that for patients undergoing stenting, 82% of centers used DAPT pre-procedure and 86% of centers used DAPT post-procedure, with a mean post-procedure duration of 3 months.⁴⁷ For patients undergoing endarterectomy, only 31% of centers used DAPT pre-operatively and 24% centers used DAPT post-operatively, with a mean post-operative duration of therapy of 3 months.⁴⁷ In the Vascular Quality Initiative, using propensity score matching, DAPT was associated with a lower risk of stroke and a higher risk reoperation for bleeding in patients undergoing endarterectomy.⁴⁸ When it comes to perioperative aspirin therapy, more is not always better. The randomized double-blind ASA and Carotid Endarterectomy (ACE) Trial involving 2849 patients found that the rate of stroke, myocardial infarction and death at one and three months was lower in patients taking low-dose aspirin (81 mg or 325 mg per day) compared to patients taking high dose aspirin (650 mg to 1300 mg per day).⁴⁹

Antihypertensive therapy

Blood pressure control is essential for preventing stroke, coronary heart disease, and heart failure.⁵⁰ Trials of antihypertensive therapy at the time of an acute stroke have not shown significant effects on short or long-term outcomes.^51,52 Nonetheless, there remains concern that rapid lowering of blood pressure immediately following stroke in a patient with symptomatic carotid disease might increase infarct volume and worsen neurological deficit. For asymptomatic patients, the AHA strongly recommends maintaining blood pressure below 140/90 mm Hg.⁴⁴ Beyond the several hours to days following a stroke or transient ischemic attack, patients with symptomatic stenosis should be treated to a similar target as patients with asymptomatic stenosis.⁴⁴

Lipid-lowering therapy

Most patients with carotid stenosis will benefit from statin therapy for cholesterol lowering. Current guidelines regarding the use of statins for primary prevention focus on adjusting the intensity of therapy based on projected risk of cardiovascular disease. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial randomized patients with an LDL cholesterol of 100 to 190 mg/dL within 1 to 6 months following a stroke or TIA to placebo or atorvastatin at 80 mg/d. The subgroup of patients with known carotid stenosis in the trial had a 33% reduction in all strokes and a 43% reduction in major coronary events with atorvastatin.⁵³ Moderate evidence supports lipid lowering with a statin to a target LDL cholesterol below 100 mg/dL in all patients with extracranial atherosclerotic stenosis and, for those who have had symptoms, lowering to a more aggressive target LDL below 70 mg/dL.⁴⁴

Cigarette smoking

Smoking increases the risk of stroke in a dose-dependent manner and quitting smoking decreases the risk.⁵⁴ Smoking is also associated with the prevalence of carotid plaque.⁵⁵ Smokers should be encouraged to quit, and, if necessary, prescribed drugs to assist in quitting. Higher pack-years increases inflammatory markers like highly sensitive C-reactive protein in active smokers, and time from quitting in former smokers reduces inflammatory markers as well as subclinical vascular disease, including carotid disease.⁵⁶

Interventions for other risk factors

Increasing regular physical activity should be encouraged in patients with carotid atherosclerosis. In a study involving over 3 million carotid ultrasound tests, the intensity of self-reported physical activity was associated with lower odds of carotid atherosclerotic stenosis.⁵⁷ Obesity is another modifiable risk factor. As proof of principle, bariatric surgery has been shown to reduce the risk of stroke by 50%.⁵⁸ Intensive glucose control is generally recommended in patients with diabetes mellitus, though the benefits regarding stroke prevention are not clear.⁵⁹

Carotid Endarterectomy

Carotid endarterectomy, a procedure with over half a century history,⁶⁰ is one of the most studied surgeries in clinical practice. As a technique that can both cause and prevent stroke, it became clear that only properly powered trials with long duration follow-up could provide reliable evidence as to the net benefits of the procedure. Historically, randomized clinical trials have focused on treating either symptomatic or asymptomatic patients (Table 2^61-69).

Table 2.

Major randomized trials of carotid endarterectomy.

Study, year	Stenosis (%)	No. randomized patients	Average Follow-up (years)	Median time randomization to surgery (days)	Endpoint	Medical Therapy (%)	Surgical therapy (%)	RRR (%)	ARR (%)	P value	NNT
Symptomatic CEA
NASCET, 199162	70-99	659	1.5	3	Ipsilateral stroke	26	9	65	17	<0.001	6¥
NASCET, 199865	50-69	858	5	3	Ipsilateral stroke	22.2	15.7	29	6.5	0.045	15§
VACSP, 199161*	50-99	189	1	2	Stroke/TIA	19.4	7.7	60	11.7	0.011	9¤
ECST, 200367	≥70**	429	6.1	14	Ipsilateral stroke, surgical stroke or death	-	-	-	21.2	<0.0001	5§
	50-69	646	6.1	14	Ipsilateral stroke, surgical stroke or death	-	-	-	5.7	0.05	18§
CETC, 200366†	70-99	1095	5.4	6	Ipsilateral stroke	-	-	-	16	<0.001	6§
	50-69	1549	5.4	6	Ipsilateral stroke	-	-	-	4.6	0.04	22§
Asymptomatic CEA
VACSP, 199363*	50-99	444	4	10	Stroke/TIA	24.5	12.8	48	11.7	<0.002	9£
ACAS, 199564	≥60	1662	2.7	11	Ipsilateral stroke, surgical stroke or death	11	5.1	53	5.9	0.004	17§
ACST, 200468	≥60	3120	3.4	30	Any stroke or surgical death	11.8	6.4	46	5.4	<0.0001	19§
ACST, 201069	≥60	3120	9	30	Any stroke or surgical death	17.9	13.4	25	4.5	0.009	22§§

^*Only males included

^**Without near occlusion

^†Pooled analysis of NASCET, ECST, and VACSP trials

^¥At 2 years

^§At 5 years

^¤At 1 year

^£At 4 years

^§§At 10 years

ACAS = Asymptomatic Carotid Atherosclerosis Study; ACST = Asymptomatic Carotid Surgery Trial; ARR = Absolute Risk Reduction; CETC=Carotid Endarterectomy Trialists' Collaboration; ECST=European Carotid Surgery Trial; NASCET = North American Symptomatic Carotid Endarterectomy Trial; NNT=Number Needed to Treat; RRR=Relative Risk Reduction; VACSP = Veterans Affairs Cooperative Studies Program.

Symptomatic patients

There is little controversy regarding the net benefit of carotid endarterectomy in patients with symptomatic moderate- to high-grade stenosis. A key finding was that the benefits are greater for patients with higher degrees of stenosis. A meta-analysis of the three major clinical trials pooled individual patient data on 6092 patients and 35,000 patient-years.⁷⁰ The analysis demonstrated that endarterectomy was marginally beneficial for patients with 50 to 69% stenosis, with an annual absolute risk reduction of ipsilateral ischemic stroke of 4.6%. The procedure was substantially more beneficial for patients with 70 to 99% stenosis, with an annual absolute risk reduction of ipsilateral ischemic stroke of 16%. Subgroup analysis demonstrated the greatest benefits for men, patients 75 years of age or older, and patients randomized within two weeks after their last ischemic event. A separate pooled analysis of trial data from ECST and NASCET concluded that the greatest benefit from endarterectomy comes from early surgery, preferably within 2 weeks.⁷¹ Early revascularization has become commonplace, such that by 2013, 73% of patients in Florida, California, and New York had their procedure (either endarterectomy or stenting) within 14 days of stroke.⁷² It should be noted, however, that early revascularization in an unstable patient with either stroke-in-evolution or crescendo TIAs carries a high risk of stroke and death.⁷³

Asymptomatic patients

While the effectiveness of timely endarterectomy for symptomatic high-grade carotid stenosis is well established, the benefits of endarterectomy in patients with asymptomatic carotid stenosis is less certain. Two pivotal randomized trials support endarterectomy for asymptomatic stenosis: the Asymptomatic Carotid Atherosclerosis Study (ACAS)⁶⁴ and the ACST.⁶⁹ Both trials enrolled patients with at least 60% stenosis. ACAS followed patients for an average of 2.7 years and found surgery resulted in an absolute reduction in the risk of ipsilateral stroke or surgical stroke or death of 5.9%. ACST followed patients for an average of 9 years and found surgery resulted in an absolute reduction in the risk of any stroke or surgical death of 4.5%.

Those who argue against endarterectomy in this patient population today point to the steady decline in risk of stroke in medically treated patients from the 1980s to 2010, with recent studies reporting ipsilateral stroke rates of less than 1% per year.⁷⁴ Trials are underway to clarify the role of endarterectomy compared to intensive medical therapy in patients with asymptomatic carotid stenosis. Stent-protected Angioplasty in Asymptomatic Carotid Artery Stenosis vs. Endarterectomy (SPACE)-2 trial, with centers in Germany, Austria, and Switzerland, is comparing best medical therapy to revascularization by either endarterectomy or stenting. Slow recruitment into the SPACE-2 trial led to halting of recruitment after randomization of 513 patients, however, patients continue to be followed for endpoints.⁷⁵ The National Institute of Neurological Disorders and Stroke Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial CREST-2 is also comparing best medical therapy to revascularization by either endarterectomy or stenting. As of January 11, 2017, a total of 454 patients had been randomized and recruitment and follow-up are ongoing.

Carotid Angioplasty and Stenting

Carotid angioplasty and stenting evolved as a potentially safer alternative to endarterectomy. A series of randomized trials ensued, mostly in patients with symptomatic stenosis (Table 3 ^7,76-91).

Table 3.

Randomized trials of carotid endarterectomy compared to carotid angioplasty^α Adapted from Meschia et al.⁷ and Perkins et al.⁸⁷

Study, year	No. randomized patients	Stenosis (%)	Patient status	Embolic protection	Findings
Naylor et al., 199876β	17	70-99	Symptomatic	No	Stopped early: 0/10 strokes CEA, 5/7 strokes CAS
CAVATAS, 200177	504	50-99	Symptomatic	Optional	No significant difference in 30-day rate of stroke or death
Brooks et al., 200178β	104	70-99	Symptomatic	No	No stroke in either treatment group
Brooks et al., 200479β	85	80-99	Asymptomatic	No	No stroke or death in either treatment group
SAPPHIRE, 200480	334	50-99	Both, high risk	Yes	Primary endpoint: 12.2% CAS, 20.1% CEA (p=0.004 for non-inferiority, p=0.053 for superiority
SAPPHIRE, 200883	334	50-99	Both, high risk	Yes	No significant difference in long-term outcomes between CAS and CEA
EVA-3S, 200682	527	60-99	Symptomatic	Yes	30-day incidence of disabling stroke or death: 1.5% CEA, 3.4% CAS
SPACE, 200681	1200	50-99	Symptomatic	Optional	Failed to prove non-inferiority. 30-day rate of death or ipsilateral stroke: 6.84% CAS, 6.34% CEA
CREST, 201085	2502	50-99	Both	Yes	No significant difference in 4-year rates of primary endpoint between CAS (7.2%) and CEA (6.8%)
CREST, 201690	2502	50-99	Both	Yes	No significant difference in 10-year rates of primary endpoint between CAS (11.8%) and CEA (9.9)
ICSS (CAVATAS-2), 201086	1713	50-99	Symptomatic	Optional	CAS has a 3.3% higher risk of stroke, death, or procedural myocardial infarction v. CEA in the short term (120 days)
ICSS (CAVATAS-2), 201589	1713	50-99	Symptomatic	Optional	No significant difference in 5-year risk of fatal or disabling stroke between CAS (6.4%) and CEA (6.5%)
ACT I, 201691	1453	70-99	Asymptomatic	Yes	CAS was non-inferior to CEA for primary composite endpoint (event rate 3.8% and 3.4%, respectively)
Ongoing trials					Study Design
SPACE-2	Goal: 3640	70-99	Asymptomatic	Optional	Two arm trial: CEA +OMT v. OMT alone; CEA +BMT v. BMT alone
ACST-2	Goal: 5000	70-99	Asymptomatic	Optional	CEA compared to CAS
ECST-2	Goal: 2000	50-99	Both	Optional	Revascularization (CEA or CAS) compared to OMT alone
CREST-2	Goal: 2480	70-99	Asymptomatic	Yes	Two parallel trials: CEA +OMT v. OMT alone; CEA +OMT v. OMT alone

^αAngioplasty may or may not have been done with stenting,

^βSingle center study

ACST = Asymptomatic Carotid Surgery Trial; ACT=Asymptomatic Carotid Trial; OMT= Optimal Medical Treatment; CAS = carotid angioplasty and stenting; CAVATAS = Carotid and Vertebral Artery Transluminal Angioplasty Study; CEA = carotid endarterectomy; CREST = Carotid Revascularization Endarterectomy vs Stenting Trial; EVA-3S = Endarterectomy vs Angioplasty in Patients with Symptomatic Severe Carotid Stenosis; ICSS =International Carotid Stenting Study; SAPPHIRE = Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy; SPACE = Stent-protected Percutaneous Angioplasty of the Carotid vs Endarterectomy

Patients at high risk for endarterectomy

The Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial tested whether stenting was non-inferior to endarterectomy for patients at high-risk for complications following endarterectomy.⁸³ Patients were considered high-risk for complications with endarterectomy for a number of reasons, including: history of contralateral carotid occlusion or laryngeal nerve palsy; significant coronary artery disease; and radical dissection or radiation therapy to the neck. In this non-inferiority trial, carotid stenting was found to be non-inferior to endarterectomy for the primary endpoint (the composite primary endpoint of death, stroke, or myocardial infarction within 30-days after the intervention, or ipsilateral stroke between 31 days and 1 year).⁸⁰ The three-year rates for the secondary composite outcome of death, stroke or myocardial infarction within 30 days or ipsilateral stroke thereafter were 26.2% for stenting and 30.3% for endarterectomy, a difference that was not significant.⁸³

Symptomatic patients

Using data from three randomized trials, the Carotid Stenting Trialists' Collaboration found that any stroke or death occurred significantly more often in the stenting group than the endarterectomy group (risk ratio, 1.53).⁹² Using data from four trials, the Collaboration found that endarterectomy was clearly superior to stenting in symptomatic patients over age 70 to 74 years due to a rising risk of stroke with age for stenting but not for endarterectomy.⁹³ The long-term results of the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST), which extended follow-up to 10 years, did not demonstrate a significant difference between endarterectomy and stenting when including perioperative myocardial infarction in the primary outcome.⁹⁰

Carotid stenting generally has shown higher procedural stroke rates than endarterectomy in randomized trials. However, the picture is slightly more complex than implied by simple counts of stroke. In the International Carotid Stenting Study (ICSS)-MRI substudy, patients were scanned using a 1.5 T or 3.0 T MRI at 1 to 7 days before treatment, 1 to 3 days after treatment and 27 to 33 days after treatment. Patients who had stenting had higher lesion counts than patients who had endarterectomy, but the lesions tended to be smaller and were more likely to involve cortex and subjacent white matter.⁹⁴ Furthermore, the total lesion volume was not significantly different between treatment groups. The functional implications of these topographic differences are unknown.

Asymptomatic patients

About half of the patients in CREST were asymptomatic at randomization. An analysis stratified by symptomatic status showed no significant difference for the primary endpoint in CREST for asymptomatic patients.⁹⁵ The Asymptomatic Carotid Trial (ACT)-1 randomized 1453 patients at standard risk of complications with endarterectomy to either endarterectomy or protected stenting.⁹¹ There was non-inferiority for the primary endpoint of perioperative stroke, death, or myocardial infarction or ipsilateral infarction within 1 year.

Factors influencing approach to revascularization

Many patients with carotid stenosis can be safely and effectively revascularized by either endarterectomy or stenting. However, some anatomic and clinical considerations should influence which approach is preferred (Table 4). It has been argued that carotid artery stenting is less invasive, and thus one might suspect that stenting would be less expensive. However, formal cost-effectiveness studies have not shown this to be the case. In ICSS there was no significant difference in adjusted costs between endarterectomy and stenting.⁹⁶ Stenting had slightly higher costs in the CREST trial than endarterectomy.⁹⁷

Table 4. Factors to consider in choice of carotid revascularization method.

Factor	Favors
Age >70 years	CEA
Recently symptomatic patient (<2 weeks)	CEA
Tortuous and/or heavily calcified vessels	CEA
Contralateral carotid occlusion	CAS
Restenosis after prior CEA	CAS
Previous neck surgery and/or radiation	CAS
Laryngeal nerve palsy	CAS
Periprocedural risk of:
Myocardial infarction	CAS
Cranial nerve injury	CAS
Stroke	CEA
Death	CEA
Long-term risk of:
Myocardial infarction	No difference
Stroke	No difference
Death	No difference

Effect of Experience on Outcomes

With a caveat to be discussed below, experience matters both for endarterectomy and stenting. A Canadian hospital registry found that low hospital and surgeon case volumes are risk factors for complications following endarterectomy.⁹⁸ A 10-year Maryland statewide audit found surgeon volume to inversely correlate with risk of death following endarterectomy.⁹⁹ Operator experience, as measured by average time interval between carotid stenting cases, was an independent predictor of death, stroke, or myocardial infarction in the Carotid Stenting for High Surgical-risk Patients; Evaluating Outcomes Through the Collection of Clinical Evidence (CHOICE) registry.¹⁰⁰ The Nationwide Inpatient Sample showed that case volume rather than operator training specialty predicted stenting outcomes.¹⁰¹ Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events (CAPTURE) 2 prospective, independently adjudicated registry showed an inverse relationship between perioperative event rates and hospital and operator volumes.¹⁰² The Carotid Stenting Trialists' Collaboration showed that the 30-day risk of stroke or death was inversely related to the in-trial operator volumes.¹⁰³ The caveat to operator experience being the cause of good outcomes, rather than a marker, is the given operator's threshold to operate or stent. For example, the busy surgeon or interventionist could be busier than his or her colleagues in part, or in large part, because of lower a threshold to intervene. Hence, his or her patients would be less often symptomatic and so less often high-risk. The operative or stenting outcomes would be expected to be more favorable, because of the lower threshold to intervene and not because of experience. In addition, neurologically trained surgeons and interventionists may be more likely to be referred symptomatic patients than vascular surgeons or interventionists trained in vascular surgery or cardiology. The pool of symptomatic patients is much lower than the pool of asymptomatic patients. The ratio of the prevalence of high-grade asymptomatic carotid stenosis to recently (within 6 months) symptomatic carotid stenosis may be as high as 38:1 (estimated using: a 3% prevalence of carotid stenosis in the general population over age 65 years, an estimate of 345,825 prevalent recent ischemic strokes,¹⁰⁴ an 8% rate of carotid stenosis among patients with ischemic stroke,⁶ an estimate of 120,000 prevalent recent TIAs,¹⁰⁵ and a 13% rate of carotid stenosis among patients with TIA.¹⁰⁶) Of course, not every patient with asymptomatic carotid stenosis will be detected and not every patient with recent ischemic stroke will be suitable for carotid intervention due to acquired disability.

The neurosurgeon or neuro-interventiontist could have both a lower frequency of procedures performed overall and have a higher proportion of procedures performed on a more at-risk cohort of patients. This circumstance, which is consistent with practice patterns, would be a confounder of cause and effect for experience and improved outcomes.

Conclusions

Patients with recent non-disabling ischemic stroke or TIA need prompt evaluation for possible high-grade carotid stenosis and, if detected, referral for revascularization. Patients with asymptomatic stenosis may also be candidates for revascularization, but the net benefit is likely to be low even under the best of circumstances. This is because unselected asymptomatic patients are at low long-term risk of stroke without revascularization. Techniques like transcranial ultrasonographic assessment for microemboli and MR plaque imaging may help to stratify risk in asymptomatic patients and thereby identify patients most likely to benefit from endarterectomy or stenting, but further research is needed. Patients who are at high risk for complications with endarterectomy may be at lower risk for complications with stenting, as shown in SAPPHIRE. However, in these high-risk patients, neither procedure may be the preferred course of action due to an unacceptably high absolute risk of complications with either one. Making decisions regarding whether and how to revascularize patients is only part of the management of carotid stenosis, and should not distract from the importance of control of medical risk factors, including hypertension, hyperlipidemia, and smoking cessation.

Abbreviations

ACAS

Asymptomatic Carotid Atherosclerosis Study

ACE

Aspirin and Carotid Endarterectomy Trial

ACES

Asymptomatic Carotid Emboli Study

ACST

Asymptomatic Carotid Surgery Trial

ACT

Asymptomatic Carotid Trial

CAPTURE

Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events

CHOICE

Carotid Stenting for High Surgical-risk Patients; Evaluating Outcomes through the Collection of Clinical Evidence

CREST

Carotid Revascularization Endarterectomy Versus Stenting Trial

CREST-2

Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial

CT

Computed Tomography

CTA

Computed Tomographic Angiography

DAPT

Dual Antiplatelet Therapy

HR

Hazard Ratio

ICSS

International Carotid Stenting Study

LDL

Low-Density Lipoprotein

MRA

Magnetic Resonance Angiography

MRI

Magnetic Resonance Imaging

PAD

Peripheral Artery Disease

SAPPHIRE

Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy

SPACE-2

Stent-protected Angioplasty in Asymptomatic Carotid Artery Stenosis vs. Endarterectomy

SPARCL

Stroke Prevention by Aggressive Reduction in Cholesterol Levels

TIA

Transient Ischemic Attack

US

United States

Appendix

Database

Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations and Ovid MEDLINE(R) <1946 to Present>

Search Strategy

1. exp *Carotid Stenosis/(10685)

2. exp Angioplasty/(57482)

3. exp Endarterectomy, Carotid/(7586)

4. (carotid adj2 stent$).mp. [mp= Title, Original Title, Abstract, Subject Heading, Name of Substance, and Registry Word] (3460)

5. 1 and 2 (2030)

6. 1 and 4 (2124)

7. 3 or 5 or 6 (9414)

8. limit 7 to (english language and humans and yr=“2007 - 2016” and “all adult (19 plus years)”) (2496)

9. 8 and (symptomatic$ or asymptomatic$).mp. [mp= Title, Original Title, Abstract, Subject Heading, Name of Substance, and Registry Word] (1097)

10. limit 9 to (clinical trial, all or controlled clinical trial or evaluation studies or meta-analysis or multicenter study or randomized controlled trial or validation studies) (288)

11. from 10 keep 1-288 (288)

Search ran on August 23, 2016 by Tara J. Brigham, MLIS.