Appropriateness of Care – Asymptomatic Carotid Stenosis Including TCAR

Abstract

Carotid artery stenosis remains one of the most commonly treated diagnoses by vascular specialists in the United States. The optimal management of carotid stenosis remains controversial however, with notable variation surrounding diagnostic imaging modalities, longitudinal surveillance, medical therapies, and procedural interventions. Data from high quality randomized controlled trials and observational studies form the foundation for current management paradigms and societal guidelines that inform clinical practice. Presently, a diagnosis of carotid disease is most often established with duplex ultrasound, and supplemental cross-sectional imaging using computed tomography or magnetic resonance angiography as needed to provide additional anatomic information. Currently, all patients with documented occlusive disease should receive goal directed medical therapy, with antiplatelet agents and a lipid reduction strategy, most commonly with a statin. Those patients with severe carotid stenosis and an acceptable life expectancy may be considered for carotid artery revascularization. The proceduralist should optimally consider a shared decision-making approach where the tradeoffs of revascularization can be carefully considered with the patient, to optimize informed therapeutic decision making. In current practice, three distinct procedure options exist to treat carotid artery stenosis, including carotid endarterectomy, transfemoral carotid artery stenting, and transcarotid artery revascularization. It should be noted that each procedure, while often used interchangeably in most clinical settings, carry technical nuances and outcome disparities. In this review, we explore each of these topics and outline various approaches surrounding the appropriate use of treatments for patients with asymptomatic carotid artery stenosis.

Introduction

Carotid artery stenosis remains an important underlying cause of stroke, the fifth leading cause of death in the United States.¹ While documented population-based epidemiology rates vary, it is currently estimated that carotid disease affects 5–7% of the adult population over 50, and its incidence increases linearly with advancing age.^{2, 3} Risk factors for carotid stenosis are those classically associated with atherosclerotic vascular disease, and include age, male sex, smoking, hypertension, dyslipidemia, and family history.⁴ These prevalent risk factors and co-morbidities make carotid disease one of the most common diagnoses prompting consultation by vascular specialists.

The treatment of carotid artery stenosis currently includes both procedural and non-procedural based management strategies. Guideline directed medical therapy (GDMT), described below, forms the basis for the treatment of carotid disease.⁵ In addition to GDMT, procedures for carotid revascularization can be performed to further reduce a patient’s longitudinal risk of stroke. Three primary procedure options exist in contemporary practice and include: carotid endarterectomy (CEA), transfemoral carotid artery stenting (TF-CAS), and transcarotid artery stenting (TCAR).⁶ Currently, more than 100,000 carotid revascularization procedures are performed annually in the U.S, with well documented clinical risks and benefits.^7–10

Nevertheless, the optimal management of asymptomatic carotid stenosis remains one of the most controversial topics in contemporary vascular practice. Interestingly, there are persistent advocates for both medical therapy and intervention. Notably, while some advocate for a more aggressive intervention-based treatment approach,¹¹ others maintain that advances in medical therapy have rendered procedures obsolete for patients with asymptomatic carotid stenosis.¹² This ongoing variation in practice transpires in the setting of dozens of randomized trials to inform practice and thus has led the Society for Vascular Surgery to consider the management of asymptomatic carotid disease as a top research priority.¹³ Accordingly, in this review, we will discuss the reasons for some of these controversies in management, the data underlying them, and some important points for treating patients.

Standards of Care for Asymptomatic Patients

Current guideline recommendations surrounding asymptomatic carotid disease are supported by abundant high-quality evidence. Patients who present for evaluation for atherosclerotic disease should undergo a full history and physical exam to elicit for signs of carotid stenosis, such as a carotid bruit on exam, or symptoms of carotid stenosis, such as pulsatile tinnitus or recent focal neurologic changes. Individuals who have known substantial vascular disease in the lower extremities or mesenteric circulation, or those with known coronary disease, also remain at risk of carotid occlusive disease. Patients with signs, symptoms, or otherwise who are at risk of carotid disease should be considered for carotid imaging to determine if there is significant carotid stenosis. Widespread screening, however, is generally not recommended for asymptomatic patients without known significant risk factors.¹⁴

Medical therapy remains the cornerstone of optimal therapy for patients with carotid artery stenosis. Patients with significant disease should be on an antiplatelet agent if not contraindicated.⁵ Treatment of modifiable risk factors, including hypertension, dyslipidemia, and diabetes are additionally important both for the management of carotid disease, but also for general cardiovascular health.⁵ Smoking cessation is paramount.¹⁵ HMG CoA reductase inhibitors (statins) have been repeatedly demonstrated to reduce the stroke risk of patients with carotid stenosis, and therefore should be considered in all people with documented carotid occlusive disease.^16–18 Individuals who are intolerant of statins, or who do not achieve sufficiently reduced cholesterol levels on high intensity therapy, may be considered for PCSK9-inhibotors.¹⁹ These components of GDMT represent the baseline standards of care for patients with asymptomatic carotid stenosis.

Controversies in the Management of Asymptomatic Carotid Disease

Despite relative consensus surrounding best medical therapy, the best approach for long term stroke prevention among patients with asymptomatic carotid stenosis remains a focus of persistent controversy. Specifically, debate persists surrounding the categorization of disease severity, and the appropriate threshold for procedural intervention, and the role and type of revascularization for such patients. Accordingly, we will next summarize the data most relevant for patients with asymptomatic carotid disease.

Diagnostic Imaging for Carotid Stenosis

The American Heart Association (AHA) currently recommends duplex ultrasound as the initial diagnostic imaging study to identify carotid stenosis, establish disease severity, and serve as the primary modality for longitudinal surveillance.^{5, 20} Carotid duplex ultrasound offers several advantages. It is non-invasive, does not require contrast administration, and is lower cost compared to computed tomography angiography (CTA) or magnetic resonance angiography (MRA). However, there are several nuances to duplex ultrasound which providers must be cognizant of when interpreting study results. Most importantly, while published duplex velocity criteria to determine stenosis severity exist, there remains wide variation in their across centers..^{21, 22} Currently, approximately 50% of centers that are accredited by the Intersocietal Accreditation Commission (IAC) use the duplex criteria recommended by the Society of Radiologists in Ultrasound Consensus Conference.^{21, 23} The remaining 50% use various alternative velocity permutations reflecting internally center validated criteria. While there are ongoing efforts to minimize some of these differences and establish better homogeneity, variation persists.^{21, 24, 25} This has led to a clinical landscape where a patient may present to one center and potentially be offered surgery, whereas at another center be offered surveillance.^{21, 22} Therefore, providers should optimally be wary of center variation and how carotid disease stenosis category is established at their respective center to best inform patients.

Cross-sectional imaging is also an important alternative to duplex ultrasound and has assumed a growing role to supplement imaging of the extracranial arterial anatomy. Most often, these studies are undertaken either to establish disease severity in the setting of severe calcification, or when a procedural intervention is being considered. Cross sectional-imaging provides important anatomic information about the aortic arch, plaque morphology and composition, and surrounding anatomy that is helpful for planning an intervention. CTA is most commonly used in this setting given its widespread availability. MRA is another option, though potentially less widely available. In addition, it should be noted that MRA has the potential to overestimate the degree of arterial stenosis compared to duplex ultrasound or CTA, and as such caution should be taken when interpreting MRA results of carotid stenosis severity.^{26, 27}

Currently, an evidence based approach for imaging patients with asymptomatic carotid occlusive disease can follow this pragmatic algorithm (Figure 1).⁵ Those with suspected or known carotid occlusive disease should undergo duplex ultrasound for either initial diagnosis, or ongoing surveillance, and to categorize disease severity. Patients with a heavily calcified stenosis which prohibits thorough interrogation with ultrasound, or those with a severe stenosis who are being considered for revascularization, may undergo additional cross-sectional imaging with CTA or MRA at the discretion of the treating provider. Finally, in patients where a carotid occlusion or near occlusion (string sign) is suspected or unclear, and/or when duplex ultrasound and cross-sectional imaging have discordant results, conventional invasive angiography may be considered as an additional imaging modality to establish diagnostic clarity. However, due to the inherent stroke risk associated with angiography, this should be used judiciously and when clinically necessary.²⁸

Figure 1:

Flow diagram of carotid imaging.

Threshold for Procedural Revascularization

The basis and clinical threshold for carotid revascularization currently remains predicated on a historical foundation of high quality level 1 evidence from randomized controlled trials (Table 1).^28–30 The results of such trials demonstrated that there was an incontrovertible clinical benefit among a subgroup of patients for carotid endarterectomy (CEA) over medical therapy. Specifically, these patients included asymptomatic individuals with 60–99% carotid stenosis, who have an anticipated 5-year life expectancy and who are free of any major life-threatening condition.^28–31 Subsequent analyses of these trials and more recent observational studies have led to broadened criteria in current societal guidelines such that revascularization may now be considered in patients who have greater than 70% carotid stenosis with a reasonable life expectancy.⁵

Table 1:

Randomized controlled trials of asymptomatic patients with carotid stenosis

Trial	Year	Population	Endpoint	Risk: Arm 1	Risk: Arm 2	Risk: Arm 3	p value
BMT versus CEA
VA Trial	1993	>50% stenosis	Ipsilateral TIA or stroke under follow up	BMT: 20.6%	CEA: 8.0%		<0.01
ACAS	1995	>60% stenosis	Perioperative stroke or death, ipsilateral stroke under follow up	BMT: 11.0%	CEA: 5.1%		<0.01
ACST	2004	>60% stenosis	Perioperative stroke or death, any stroke under follow up	BMT: 11.8%	CEA: 6.4%		<0.01
CEA versus TF-CAS
ACT-1	2016	>70% stenosis	Perioperative stroke, death, M1, or ipsilateral stroke at 1 year	CEA: 3.4%	TF-CAS: 3.8%		p=NS
ACST-2	2021	>60 stenosis	Perioperative stroke or death, any stroke under follow up	CEA: 7.2%	TF-CAS: 9.0%		p=0.09
CEA versus TF-CAS versus BMT
SPACE- 2	2022	>70 stenosis	Perioperative stroke or death, ipsilateral stroke within 5 years	CEA: 2.5%	TF-CAS: 4.4%	BMT: 3.1%	p=NS
CREST-2			Actively enrolling
ACTRIS			Actively enrolling

BMT, best medical therapy; CEA, carotid endarterectomy; TF-CAS, transfemoral carotid artery stenting, MI, myocardial infarction.

However, data from these landmark trials are now surprisingly 20–30 years old.^28–30 GDMT and procedural options have both advanced and broadened since these trials were conducted. Additional antiplatelet medications beyond aspirin such as p2y12 inhibitors (e.g., clopidogrel, prasugrel, ticagrelor) now exist. Statin use is both established and increasingly prevalent.³² These therapeutic advances in conjunction with initiatives to comprehensively mitigate risk factors appear to have led to a decrease in baseline stroke-risk associated with asymptomatic carotid artery stenosis. It is worth noting that recent meta-analyses suggest that the risk of stroke from asymptomatic carotid occlusive disease may approach 1% per year (Table 2).^{33, 34} Baseline documented cumulative stroke risks this low accordingly raise questions regarding the appropriate utility of carotid revascularization among asymptomatic patients, especially given a repeatedly documented approximately 1% annual stroke risk after carotid revascularization, and has been the fodder of ongoing debate among clinical experts.^{11, 22, 35–37} More recent randomized trials have sought to inform this knowledge gap but have faced challenges in doing so. The Stent-Protected Angioplasty versus Carotid Endarterectomy 2 (SPACE-2) trial compared TF-CAS, CEA, and GDMT but was stopped early due to patient enrollment challenges.³⁸ While it did not demonstrate a benefit for revascularization over GDMT, it was underpowered.³⁸ Two additional trials, the Carotid Revascularization Endarterectomy versus Stenting Trial 2 (CREST-2) and the Endarterectomy Combined With Optimal Medical Therapy (OMT) vs OMT Alone in Patients With Asymptomatic Severe Atherosclerotic Carotid Artery Stenosis at Higher-than-average Risk of Ipsilateral Stroke (ACTRIS), seek to add important data to inform whether patients benefit from surgery over GDMT.^{39, 40} Forthcoming results from CREST-2 and ACTRIS will have important implications for how patients with asymptomatic carotid stenosis are optimally managed.

Table 2:

Selected non-randomized prospective studies of medical therapy and carotid stenting for asymptomatic patients with carotid stenosis, or study subgroups of asymptomatic patients

Study or Author	Year	Population	Endpoint	Risk
Medical therapy recent systematic reviews (includes a variety of study designs)
Howard et al.	2021	>50% stenosis	Ipsilateral stroke risk	2.38% (before 2000), 0.88% (after 2010)
Poorthuis et al	2023	>50% stenosis	ipsilateral ischemic stroke	0.98% per year
Transfemoral carotid artery stenting
ARCHeR	2006	>80%, high surgical	30 day stroke or risk death	5.4%
BEACH	2006	>80%, high surgical risk	30 day stroke, death, MI	5.0%
CABERNET	2008	>60%, high surgical risk	30 day stroke, death, MI, 1 year ipsilateral stroke 30 day stroke,	13.0%
MAVErIC I & II	2010	>80% high surgical risk	30 day stroke, death, MI, 1 year ipsilateral stroke or MI	10.8%
Transcarotid artery rev ascu’arization
ROADSTER-1	2015	>70% stenosis, high medical or anatomic risk	Any perioperative stroke	1.9%
ROADSTER-2	2020	>80% stenosis, high medical or anatomic risk	Any perioperative stroke	1.0%
ROADSTER-3		Actively enrolling

MI, myocardial infarction.

The appropriate use of carotid revascularization procedures in asymptomatic patients remains contentious despite the aforementioned randomized trials and current Societal guidelines. Accordingly, a pragmatic clinical approach toward revascularization among asymptomatic patients includes first establishing an accurate degree of stenosis and defining a patient’s overall comorbidity profile and life expectancy. If the documented degree of stenosis is severe (generally ≥70 or ≥80% depending on the source), and the estimated life expectancy is good (generally 3–5 years depending on the source), then consideration for carotid revascularization is warranted.^{5, 8, 20, 28, 29} Patients with mild or moderate carotid stenosis, and those with significant comorbidity profiles or limited life expectancy, should likely be treated with GDMT alone. Patients who are ultimately considered for revascularization should undergo a thorough shared decision making assessment of the risks and benefits associated with GDMT versus revascularization.⁴¹ Individuals who choose to proceed with revascularization may then undergo one of the three primary procedural options discussed later in this review.

Types of Carotid Revascularization Procedures

To date, three primary procedures are used to treat extracranial carotid occlusive disease in contemporary practice, CEA, TF-CAS, and TCAR (Figure 2). Each procedure has a distinct signature of advantages and draw backs which must be considered for each patient.

Figure 2:

Procedures for Carotid Revascularization, A, carotid endarterectomy, B, transfemoral carotid artery stenting, C, transcarotid artery revascularization. Reproduced with permission, Columbo & Stone, NEJM Evidence.

Carotid Endarterectomy.

Since its first description in the 1950s, CEA has rightfully become a mainstay of therapy for durable stroke prevention among patients with carotid occlusive disease. Two primary techniques for CEA exist, eversion endarterectomy, and patch angioplasty. Both procedures are effective and excellent options for the treatment of severe carotid stenosis, and procedure selection should be based on the comfort and preference of the operating surgeon.⁴² CEA long antedates the advent of carotid stenting, and thus represents a primary fallback option for any patient in whom stenting fails or is not a technical option. Several adjunctive nuances exist to facilitate exposure, neuromonitoring, and cerebral perfusion during the conduct of the operation. As such, CEA is and remains an appropriate option for the vast majority of patients with severe carotid stenosis.

For these reasons, CEA remains one of the most comprehensively studied procedures in current practice. Several randomized trials have documented its efficacy in long-term stroke-risk reduction for patients with carotid stenosis, when compared to medical therapy, and TF-CAS.^{28–30, 36, 37} While potentially antiquated, prior comparisons to medical therapy suggested an approximately 50% relative risk reduction in favor of CEA versus medical therapy.^{8, 28, 29} More contemporary results from randomized trials suggest that the expected perioperative stroke rate among patients who undergo CEA are approximately 2%, with similar findings from observational registry-based studies.^{31, 36, 37, 43, 44} CEA remains a durable therapeutic intervention as well, with documented 10 year post procedural stroke rates of 5.6%.³⁶ Based on these findings, CEA arguably remains the gold standard for carotid revascularization.

Transfemoral Carotid Artery Stenting.

TF-CAS was first popularized in the 1990s as an alternative to CEA for medically high-risk patients with carotid stenosis. Performed primarily via transfemoral percutaneous access, TF-CAS offers several potential advantages over CEA that apply to different subgroups of patients. A percutaneous approach can be performed under local anesthesia, avoids re-operative or hostile neck anatomy, and facilitates treatment of high anatomic carotid lesions which can be more challenging to reach surgically.^45–48 These procedure associated characteristics have led to some enthusiasm for TF-CAS across provider specialties in certain settings.¹⁰

Accordingly, the outcomes of TF-CAS versus CEA have been well documented in several randomized controlled trials. These studies suggest that while the perioperative stroke risk for TF-CAS is slightly higher than CEA, the perioperative myocardial infarction risk remains slightly lower compared to CEA.^{37, 43} This persistent observation has led TF-CAS enthusiasts to cite composite endpoints (reflecting both stroke and MI) and conclude that the studies offer clinical equipoise.^{37, 43} In addition, it should be noted that the additional stroke risk observed with TF-CAS likely reflected minor strokes identified through routine neurologist adjudication in randomized trials, rather than major disabling strokes which appear to be similar between the two procedures in the perioperative period.⁴⁴ After the perioperative period, the rate of long-term stroke appears to be similar between TF-CAS and CEA.^{36, 37, 44} These acceptably low stroke rates among asymptomatic patients make TF-CAS an attractive therapeutic option in selected instances, particularly for patients who are at high risk for CEA.

It is important to emphasize however, that to date, the pivotal trials of TF-CAS have all been compared to CEA, not GDMT alone. There are three trials seeking to remedy this knowledge gap in the literature. One was stopped early due to lack of enrollment.³⁸ The other two are actively recruiting patients.^{39, 40} Results from these trials will yield important results to guide practice on the appropriate and optimal use of TF-CAS and its efficacy versus GDMT for longitudinal stroke risk reduction.

Transcarotid Artery Revascularization.

TCAR was approved by the Food and Drug Administration (FDA) in 2015 as an alternative mode of carotid stent delivery to TF-CAS for high medical and anatomic risk patients with carotid stenosis. Interestingly, in 2023, the FDA subsequently expanded TCAR’s indication to standard-risk patients. Accordingly, it has gained widespread therapeutic traction in current practice. TCAR is performed via a low-neck incision, and therefore obviates the need to traverse the aortic arch as required in TF-CAS. Stenting is then performed under flow-reversal embolic protection, which can be established without crossing the carotid lesion in an unprotected fashion, as is required for embolic filter protection commonly used with TF-CAS. TCAR can also be used to effectively treat restenosis after a prior CEA, which does not expose the patient to the risks of a reoperative neck incision and endarterectomy. These technical disparities between TF-CAS and CEA make TCAR a favorable alternative in many clinical situations.

It is important to highlight however that in stark contrast to CEA and TF-CAS, there is still no randomized controlled trial to support the use of TCAR. Rather, all data informing its use, and subsequent FDA approvals, are predicated on observational data. Available observational evidence suggests that stroke rates in the periprocedural period are similar to CEA, and approximately half that compared to TF-CAS. Moreover, these findings appear to persist to 1 year.^{31, 49–51} Furthermore, it is interesting and worthy to note that centers which offer TCAR in addition to CEA appear to have better results than centers which do not offer TCAR.⁵² This observation likely reflects the possibility that proceduralists can better align the optimal procedure to a patients’ specific anatomy and co-morbidity profile.⁵² Promising results and technical advantages over CEA and TF-CAS for certain clinical situations have led to TCAR’s rapid popularity and widespread adoption. As of March 2022, TCAR has been performed in over 30,000 patients across more than 600 centers (Figure 3).⁷

Figure 3:

Number of Vascular Quality Initiative Centers performing transcarotid artery revascularization (TCAR), and the total number of procedures performed over time. Reproduced with permission, Columbo et al., Circulation: Cardiovascular Interventions.

Appropriate Choice of Carotid Revascularization Modality

As noted previously, CEA remains the gold standard for carotid revascularization and is an appropriate surgical option for the majority of patients with carotid stenosis warranting intervention. To date, CEA is the only carotid revascularization strategy that has been rigorously demonstrated by randomized trials to confer a benefit over medical therapy for patients with carotid stenosis.^28–30 It continues to offer durable long-term stroke risk reduction, with concordantly low restenosis rates.³⁶ Accordingly, CEA should rightfully be considered as a good option for most patients considering carotid revascularization.

As already noted, there are some clinical scenarios where an alternative method of carotid revascularization may be beneficial. TF-CAS has been studied extensively and while stroke rates remain slightly higher than CEA, they remain acceptably low among asymptomatic patients.^{36, 37} Appropriately, TF-CAS is established as an important therapeutic alternative in the treatment of carotid stenosis in selected patients.^{37, 43} TF-CAS is a particularly attractive alternative among patients with hostile neck anatomy or among those with sufficiently high co-morbidity profiles, in whom local anesthesia would be preferred.

Likewise, TCAR, now offers additional nuanced benefits over CEA and TF-CAS in the treatment of carotid stenosis. TCAR allows direct carotid access via a low-neck incision, which can make stent delivery technically more facile than TF-CAS, particularly for patients with tortuous or atheromatous aortic arches. In addition, TCAR can be employed for patients with documented aorto-iliac occlusive disease, where TF-CAS may not be possible. TCAR is also an attractive alternative for patients who have had a prior neck surgery, avoiding a reoperative field and associated increased risks of potential nerve injury. Perioperative results for TCAR procedure appear encouraging to date, but long-term stroke rates and stent durability remain unknown.^49–51 Furthermore, all data surrounding TCAR is observational, and thus must be interpreted with comparative caution.

The choice of carotid revascularization procedures should remain at the discretion of the vascular specialist but may choose to reflect the following principles. Patients who have been selected to undergo a procedure should be considered for CEA given its highly studied and long proven record of stroke-risk reduction and durability. The roles for TCAR and TF-CAS can be considered but should be weighed against the benchmarked results of CEA. Patients who are at high risk for CEA but still wish to undergo carotid revascularization may then be considered for either TF-CAS or TCAR weighing the specific anatomic and medical risks. Certainly, one must consider that TCAR, appears to offer similar periprocedural stroke rates to CEA, which may be lower than observed in TF-CAS.^{31, 49} Patients who do not meet anatomic eligibility for TCAR or have co-morbidities and/or airway issues which preclude a general anesthetic should be preferentially considered for TF-CAS.

Summary

The management of patients with asymptomatic carotid stenosis remains a focus of controversy in current practice. Fortunately, there is ample high-quality data upon which to base most treatment decisions in these patients. Unquestionably, all patients with documented carotid stenosis should undergo GDMT. Those with severe stenosis, may be considered for revascularization, after a thorough discussion reflecting both the short- and long-term risks and benefits. If a procedure for carotid revascularization is sought, consideration of the long-standing safety profile and therapeutic efficacy of CEA must be considered, though the growing roles of TCAR and TF-CAS in selected cases offers significant advances in the effective management of carotid occlusive disease going forward.