Carotid Artery Stenting: What Have We Learned from the Clinical Trials and Registries and Where Do We Go from Here?

Article Outline

• Abstract
• Introduction
• Early Development of CAS
• Early Expansion of Indications
• What Have We Learned Thus Far? Case Series, Industry-Sponsored Registries, and Randomized Trials
  • Case Series
  • Industry-Sponsored Registries
  • Randomized Trials
  • EPDs
• Approval and Reimbursement in the United States
• Variation in Reporting
• Future Directions
• Conclusions
• References
• Copyright

As with other minimally invasive surgical procedures, carotid angioplasty and stenting (CAS) has developed rapidly over the last decade. Although many believe equivalency with carotid endarterectomy has been established in high-risk patients, the effectiveness of CAS in lower-risk patients is not yet established. This report aims to provide a comprehensive and critical review of the trials and registries of CAS and to offer insight into future directions of this emerging technology.

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Introduction 

The indications, optimal techniques and equipment, and outcomes of carotid artery stenting (CAS) remain controversial topics. This is not for lack of investigation as more than 20 case series studying over 24,000 patients, 12 industry-sponsored registries, and more than 12 randomized trials comparing CAS and carotid endarterectomy (CEA) have been initiated since 1998. Results have varied over time, depending on the population studied and the technology used. Even within the best level 1 evidence, at present it remains unknown if CAS can be considered “equivalent” to CEA.

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Early Development of CAS 

Several groups first described single case reports or carotid angioplasty in the late 1970s and 1980s.¹, ², ³, ⁴ One of the first and most widely reported large series for cerebrovascular occlusive disease that included angioplasty and stenting was reported by Roubin et al.⁵ at the University of Alabama. They studied 126 arteries in 107 patients judged too medically or anatomically risky to undergo open endarterectomy. This report demonstrated a nearly 10% combined stroke or death rate. However, it did demonstrate the feasibility of the technique.

Several reports of large case series and self-reported registries followed. Mathias et al.⁶ reported the results of over 3,000 CAS procedures performed in Germany in an ongoing clinical registry since 1999. Their report demonstrated a self-reported stroke rate of approximately 2% as well as an overall combined complication rate of just under 3%. Wholey et al.⁷ reported another large collection of patients obtained from surveys of providers of CAS. These investigators pooled data from 36 centers throughout Europe, North and South America, and Asia from self-reported survey data. They collected information on 5,210 cartoid stent procedures in 4,757 patients. They reported a technical success rate of 98.4%, successfully completing stent placement in 5,129 arteries. Complication rates were acceptable in this large, self-reported series. The “minor stroke” rate was 2.72% (129 patients) and the “major stroke” rate was reported as 1.49% (71 patients). Forty-one deaths occurred in the 30-day postprocedure period, for a combined stroke/death rate of 5.07%. This report has been updated on several occasions by the authors and most recently has collated data from over 10,000 patients.⁸

Other series⁹, ¹⁰ later in the 1990s and early 2000s built on this emerging body of evidence. Consistently, these case series and self-reported registries demonstrated that percutaneous CAS was feasible and could be performed with reasonable stroke and restenosis rates.

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Early Expansion of Indications 

Initial series of CAS were often limited to symptomatic patents deemed to be poor surgical candidates. However, as experience grew and techniques were refined, indications expanded to include the use of CAS in patients with asymptomatic carotid stenosis.¹¹ Similarly, as experience grew, the use of CAS was expanded to asymptomatic patients and patients who already had undergone carotid revascularization procedures. A large multicenter report utilizing data from 14 groups across the United States reported their results in 2000.¹² They treated 358 arteries in 338 patients with restenosis following CEA, and patients were followed for an average of 5 years. The overall stroke rate was 3.7%, mortality was 1.1%, and the overall adverse event rate was 4%. Additional reports by Hobson et al.¹³, ¹⁴ documented the use of CAS to treat restenosis following CAS. In 46 patients who had interventions on 50 arteries, they noted a 100% technical success rate in achieving revascularization in all patients who already had undergone percutaneous revascularization. These reports, along with others,¹⁰, ¹⁵ documented the feasibility of CAS in the treatment of restenosis following carotid revascularization.

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What Have We Learned Thus Far? Case Series, Industry-Sponsored Registries, and Randomized Trials 

Over the last 10 years, evidence surrounding CAS has emerged in three main categories: case series (either single or multi-institutional), industry-sponsored registries, and randomized trials. Each of these has varied in patient populations, quality, and duration of follow-up. Listed below are the main categories of clinical information available to date.

Case Series 

Since the advent of CAS in the mid 1990s, more than 20 case series of at least 99 patients have been published, reporting over 24,000 patients in total (Table I). A weighted average of these studies indicates that 51% of patients treated were symptomatic and >97% received the planned stent. Independent outcome evaluation by a neurologist was performed in 64% of series. After 2002, embolic protection devices (EPDs) were widely utilized. In terms of outcomes, 30-day stroke rates varied from 1% to 8%, but there was a trend toward lower rates as experience increased with time and EPD use became more widespread. Overall, the average 30-day stroke rate was 3% across all studies and the average combined 30-day stroke/myocardial infarction (MI)/death rate was 4%. However, these outcomes should be interpreted with caution as rates varied with year of procedure, EPD use, neurologist examination, and patient characteristics. Lastly, early restenosis rates appeared low (1-8%), albeit only reported in about half the studies.

Table I. Case series of CAS

This list represents case series reported in peer-reviewed journals with ≥99 patients or arteries. An earlier version of this table was used in our prior work.³⁸ The table has been updated. Stent type or EPD type reported as “variable” if stents or EPDs were not used on each patient in the series. Stent type or EPD type reported as “multiple” if there was not a dominant type used. In some registries, individual patients experienced multiple adverse events. Therefore, combined rate is not always additive.

Neuro MD, independent neurological evaluation by a neurologist.

Industry-Sponsored Registries 

Results from more than 10 industry-sponsored trials of specific CAS systems have been presented at national meetings, but far fewer have been published in peer-reviewed journals. All of these registries (except Acculink for Revascularization of Carotids in High-Risk Patients [ARCHeR 1]) routinely used EPDs (Table II). Stoke rates varied 2-7% at 30 days, and combined adverse outcome measures (stroke, death, or MI) varied 3-8% at 30 days. Based on a weighted average across these registries, 27% of patients were symptomatic, 4% of patients experienced periprocedure strokes, and combined adverse outcome measures were 6% at 30 days.

Table II. Industry-sponsored registries of CAS

Trials reported in chronological order of when results were presented. In some registries, individual patients experienced multiple adverse events. Therefore, combined rate is not always additive. An earlier version of this table was used in our prior work.³⁸ The table has been updated.

Neuro MD = independent neurological evaluation by a neurologist.

Two registries have led to device approval by the U.S. Food and Drug Administration (FDA). The ARCHeR registry was utilized by Guidant to obtain FDA approval for the Accunet/Acculink™ system, and the SECURITY registry allowed Abbott to obtain FDA approval for the Xact/Emboshield™ system. These registries achieved low stroke rates for CAS. However, it is important to note that in the process of achieving FDA approval, these results were compared to historical controls of CEA in high-risk patients. For example, in ARCHeR the estimated stroke rate for high-risk patients undergoing CEA was 14.5%. In many centers of excellence, combined adverse event rates following CEA in high-risk patients were much lower than that assumed by these registries, between 5% and 7%¹⁶, ¹⁷ at 1 year.

Randomized Trials 

At least 12 trials directly comparing CAS and CEA have been initiated (Table III). All except Carotid Revascularization Using Endarterectomy and Stenting Systems (CARESS)¹⁸ were randomized controlled trials. All used independent neurologist examinations to determine outcomes. Nearly all trials initiated after 2001 utilized EPDs. Unlike the other trials, CARESS assigned patients to CAS or CEA via “selection criteria reflective of broad clinical practice.”¹⁸ CARESS achieved some of the lowest stroke and overall complication rates reported across all trials for both CAS and CEA, indicating the possibility that careful patient selection may be one of the most important determinants of outcome for both CAS and CEA.

Table III. Randomized trials of CAS

Stent type or EPD type reported as “multiple” if there was not a dominant type used. An earlier version of this table was used in our prior work.³⁸ The table has been updated.

Neuro MD, independent neurological evaluation by neurologist.

^dCAS stroke rate based on first 80 patients in CAS arm.

While seven of the 12 trials have publicly reported outcomes, the Stenting and Angioplasty with Protection for Patients at High Risk for Endarterectomy (SAPPHIRE) trial is most widely cited because it reported 2-year results with uniform usage of EPDs. In this trial, 334 patients who were considered at high risk for CEA were randomized to CEA or CAS.¹⁹ “High risk” was defined as having at least one of the following risk factors: clinically significant heart disease, severe pulmonary disease, contralateral carotid occlusion, contralateral laryngeal nerve palsy, previous radical neck surgery or radiation therapy to the neck, recurrent stenosis after endarterectomy, or age >80 years. The combined 30-day end point of stroke, death, or MI was 4.4% for CAS vs. 9.8% for CEA (p = 0.06). At 1 year, this combined end point was 12% for CAS vs. 20% for CEA (p = 0.05). The authors concluded that carotid stenting using embolic protection is not inferior to CEA in high-risk patients.

Two other large randomized trials have recently reported their results. The Stent-Supported Percutaneous Angioplasty of the Carotid Artery vs. Endarterectomy (SPACE) collaborative group analyzed 1,183 symptomatic patients who were randomized to either CAS or CEA.²⁰ The rate of death or ipsilateral ischemic stroke at 30 days was 6.84% in patients undergoing CAS and 6.34% in patients with CEA. The authors concluded that the SPACE trial failed to prove noninferiority of CAS compared with CEA. Whether or not these results remain unchanged over the longer interval remain unknown. Similar findings were reported by the Endarterectomy vs. Angioplasty in Patients with Symptomatic Severe Carotid Stenosis (EVA-3S) investigators. They studied 527 high-risk patients randomized to CAS or CEA. This trial was stopped prematurely for “reasons of safey and futility.”²¹ The 30-day incidence of stroke or death was 3.9% after endarterectomy and 9.6% after stenting, and at 6 months, the incidence of stroke or death was 6.1% after endarterectomy and 11.7% after stenting. The authors concluded that the rates of stroke or death after endarterectomy were lower than after stenting in this population.

There are multiple ongoing randomized controlled trials that are focused on both high- and lower-risk patients, including the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST),²² International Carotid Stenting Study (ICSS),²³ and Asymptomatic Carotid Trial (ACT I).²⁴ CREST is a randomized trial comparing CEA and CAS in low-risk patients with both symptomatic stenoses ≥50% and asymptomatic stenoses ≥80%. As part of the lead-in phase to this study, 749 patients (31% symptomatic) underwent CAS. Thirty-day stroke/death rates increased with age such that there was a 12.1% 30-day stroke/death rate for patients ≥80 years old compared with 3.2% for patients <80 years of age. ICSS is randomizing symptomatic patients, while ACT I is randomizing asymptomatic patients. The results of these randomized trials, as well as the long-term results of the SAPPHIRE, SPACE, and EVA-3S patients, will hopefully provide the best quality of evidence upon which to make clinical decisions regarding patient selection for carotid revascularization procedures.

EPDs 

Most current data suggest that CAS can be performed with acceptable stroke rates only with the use of EPDs.²⁵ The first use of an EPD in CAS was described in France in the 1990s.²⁶ Since then, many different devices have been developed (Table IV). Most of these are wire-based filters that trap embolic debris. Currently, the Accunet Filterwire™²⁷ and the Abbott Emboshield²⁸ are the only FDA-approved EPDs for use with CAS in the United States.²⁹ In addition to filters, distal ICA balloon occlusion with subsequent aspiration can be used for embolic protection (Guardwire™, Medtronic³⁰) as well as flow blockage in the internal carotid artery (ICA) with common and external carotid balloon occlusion (MOMA™, Invatec³¹), or flow reversal in the ICA with the Parodi Anti-Emboli System™ (Gore³²). Different devices may have advantages in selected patients based on device size, lesion characteristics, ICA tortuosity, and other factors; but this has not been established by comparison studies, so EPD selection is currently based on individual practitioner experience.

Table IV. EPDs commonly utilized in CAS

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Approval and Reimbursement in the United States 

The FDA approved the Guidant Acculink/Accunet CAS system in August 2004²⁹ and the Abbott Xact/Emboshield CAS system in September 2005.³³ These devices were approved for limited application, specifically for symptomatic patients with ≥50% ICA stenosis or asymptomatic patients with ≥80% ICA stenosis, who are considered to be at high risk for CEA. In this regard, patients can be at high physiological risk for CEA based on risk factors such as severe coronary artery or pulmonary disease, end-stage renal disease, and uncontrolled diabetes.²⁹ Patients can also be at high anatomic risk for CEA based on risk factors such as contralateral ICA occlusion, radiation treatment to the neck, distal ICA location, spinal immobility, tracheostomy stoma, or contralateral laryngeal nerve paralysis.²⁹ Ongoing randomized trials will determine the effectiveness of CAS in lower-risk populations, but until these results are available, precise definitions of high-risk patients appropriate for CAS are being determined by these broad guidelines combined with individual practitioner experience. A current summary of indications and contraindications to CAS is shown in Table V.

Table V. Center for Medicare and Medicaid Service (CMS) reimbursement guidelines for CAS, medical and anatomic high-risk criteria, and contraindications to CAS

NYHA, New York Heart Association; LVEF₁, left ventricular ejection fraction; CCS, critical care service; DL_CO, carbon monoxide diffusing capacity of the lungs.

Currently, CAS is reimbursed by the Center for Medicare and Medicaid Services (CMS) only for FDA-approved devices. In addition, CMS will reimburse only for treatment of symptomatic, high-risk patients with >70% stenosis in CMS-approved centers. Despite consideration in early 2007, CMS does not provide reimbursement for the treatment of asymptomatic carotid stenosis with CAS.³⁴ However, in approved clinical trials, CMS will reimburse for symptomatic, high-risk patients with 50-69% stenosis as well as asymptomatic patients with >80% stenosis. Furthermore, all such cases must be entered into a registry to track outcome for potential CMS review. In this regard, the Society for Vascular Surgery has established a registry that meets these requirements.³⁵

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Variation in Reporting 

Evaluation of current case series, industry-sponsored registries, and randomized trials reveals variation in study design and outcome measurement. Duration of follow-up varies from 30 days in the Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS-I),³⁶ 1 year in SAPPHIRE,¹⁹ and up to 2 years in the Prospective Registry of Carotid Angioplasty and Stenting (Pro-CAS),³⁷ albeit some of this variation simply represents differences in the current stage of result reporting. While inherent differences in follow-up duration are likely, it becomes difficult to compare outcomes across trials with such distinct differences. Second, outcome event measurement has not been standardized. For example, SAPPHIRE classified strokes as minor and major, according to the National Institutes of Health Stroke Scale. CAVATAS, meanwhile, divided major adverse outcomes into “disabling stroke or death” and “stroke lasting more than 7 days.” Primary end points have also varied. While ARCHeR 1 and 2 considered all deaths, strokes, and MIs at 30 days and ipsilateral strokes until 1 year as primary end points, ARCHeR 3 reported only all deaths, strokes, and MIs at 30 days. Reporting standards need to be standardized to allow comparison and interpretation across studies.

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Future Directions 

Over the last decade, CAS has grown from an experimental procedure performed with technology “borrowed” from other vascular beds to a procedure routinely performed in both academic and community settings and has experienced significant increase in annual volume. However, serious concerns remain unsettled in terms of which patients should be candidates for percutaneous carotid revascularization and how that procedure should be performed. To this end, future directions in CAS will likely address (at least) three main concerns: patient selection, device design, and imaging techniques.

Patient selection is probably the most controversial issue surrounding CAS. One particularly controversial aspect is the concept of medical comorbidities and carotid revascularization. Many have recommended CAS in patients deemed “medically high risk”¹⁹ for CEA. However, our recent work³⁸ as well as the work of others²² challenges the notion that high-risk patients fare better with stenting rather than endarterectomy in long-term follow-up. Many recent reports, both in institutional case series and multi-institutional collaborative databases,³⁹, ⁴⁰, ⁴¹ have demonstrated excellent long-term results with endarterectomy, with stroke rates of 1-2%, even with patient populations deemed “medically high risk.” Whether or not optimal stenting outcomes will match these outcomes of endarterectomy remains uncertain; therefore, we believe the optimal carotid revascularization plan for patients with severe comorbidity burden will likely remain the subject of continued debate.

Second, many believe device design is likely to be an important influence on outcome. Hart et al.⁴² studied 701 consecutive patients undergoing CAS. In their analysis, stroke rates in symptomatic patients were significantly higher if patients received an open-cell design versus a closed-cell design (11% vs. 3%, p < 0.01). Similarly, patients who underwent stenting with a concentric embolic protection system had higher stroke rates than those with an eccentric protection system (10.4% vs. 3.4%). Similarly, lower stroke rates in patients with echolucent plaque were noted with the use of closed-cell stent designs and eccentric EPDs. Whether or not these differences in outcome depend upon device characteristics remains to be seen.

Third, preoperative imaging may offer a decided benefit in patient selection.⁴³ In a recent study of 59 patients who routinely underwent preoperative computed tomography (CT) angiography with three-dimensional reconstruction, 37 were found to be suitable anatomic candidates for carotid stenting, while the remaining were found to be intermediate or poor candidates for percutaneous carotid revascularization. In nine of 59 patients, stenting plans were abandoned after noninvasive imaging, without incurring the risk of a diagnostic cervical and cerebral angiogram. Formidable arch anatomy, circumferential calcifications, or lack of acceptable landing zones for EPDs (see Fig. 1, Fig. 2, Fig. 3) all led to consideration of alternative access techniques such as carotid cutdown and direct access or even change to CEA. In patients with intermediate or poor anatomy, technical success rates were slightly lower and intraoperative “unanticipated maneuvers” were more common. However, it remains unknown if CT angiography will emerge as a required planning tool prior to percutaneous carotid revascularization.

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• Fig. 1 

  Prohibitive aortic arch.

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• Fig. 2 

  Circumferential calcification at carotid bifurcation.

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• Fig. 3 

  Poor landing zones for EPDs.

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Conclusions 

As with other minimally invasive surgical procedures, CAS has developed rapidly over the last decade. Although equivalence with CEA has been established in high-risk patients, the effectiveness of CAS in lower-risk patients is not yet established. Currently, the choice of CEA versus CAS in individual patients is based more on individual practitioner experience than on clear evidence-derived guidelines. Nonetheless, the popularity of less invasive therapy combined with marketing of new CAS systems has increased the utilization of CAS. Ongoing randomized trials will help determine optimal carotid revascularization strategies in the future.

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