Carotid Intervention
The Data
When discussing the clinical data for outcomes in carotid artery stenting (CAS), there are several important outcomes to be detailed: periprocedural (30 day) safety, which is composed of death, all stroke, and myocardial infarction; 1-year stroke prevention efficacy composed of ipsilateral stroke rates from 30 to 365 days; and durability, which is measured by restenosis >70% to 80% in severity and/or the need for repeat revascularization. All of these will necessarily be measured against carotid artery endarterectomy (CEA), the standard of care for carotid bifurcation disease requiring intervention.
Although the first reports of endovascular approaches to carotid artery disease were employed in nonatherosclerotic lesions and date back to the early 1980s, the use of stents to augment angioplasty results did not come into routine use until the mid- to late 1990s. When studied in the first large-scale, multicenter, Carotid and Vertebral Artery Transluminal Angioplasty Study started in 1995 (CAVATAS), balloon angioplasty was used alone in 75% of the trial participants randomized to endovascular approach for symptomatic carotid disease, with the last 25% of this enrollment employing stent implantation. The results of the U.K.-based CAVATAS suggested no short-term differences in safety and clinical efficacy between CEA and carotid angioplasty. But two important caveats to that conclusion are warranted. First, the restenosis rate in the angioplasty group was higher than CEA likely related to that lack of a stent scaffold in the majority of cases. Second, while the results between groups were not different, the rates (~10%) of 30-day death and stroke were higher than the standards established by the North American Symptomatic Carotid Endarterectomy Trial (NASCET) for symptomatic lesions —and not a good showing for either approach. Importantly, not only were stents not used in the majority of patients but emboli protection devices (EPD) were still not developed and therefore not employed at all in CAVATAS, thus making these results largely irrelevant in today’s era of “modern” CAS with standard EPD.
While CAS with EPD was introduced around 1999, the full penetration of this technology was not realized in Europe (EU) until several years later and was more delayed in the United States. The earlier approval of the technology in Europe did not translate into a deep pool of experienced operators capable of contributing expertly to studies of CAS and CEA early in the decade, when the EU trials were under way. In fact, of the three EU randomized trials, all in symptomatic patients, examining the relative safety and efficacy of these two treatments—Endarterectomy Versus Stenting in patients with Symptomatic Severe carotid Stenosis (EVA-3S), Stent-Protected Angioplasty versus Carotid Endarterectomy (SPACE), and International Carotid Stenting Study (ICSS)—two were severely cofounded by gross CAS operator inexperience, both on an absolute basis and relative to the CEA trial surgeon experience, making the results highly problematic. Additionally confounding all three of these studies was the failure to include and/or routinely measure myocardial infarction (MI) as an endpoint, in spite of ample data demonstrating that MI in the perioperative period has significant long-term mortality implications for the patient. Equally problematic, EPD were not mandated in any of the studies from the outset, although after a significant number of strokes had already occurred with CAS in EVA-3S in the first ~80 patients, EPD was finally made standard.
As a result of these and other construct and conduct issues within these EU trials, many of which can be ascribed to their premature initiation in an underdeveloped and novel therapy, their results are both predictable and unfortunate in that they are not helpful in determining the place of CAS in symptomatic patient management today. The French EVA-3S study was the first to report its data in 2006 and had to be halted early after approximately 500 patients due to safety concerns in the CAS arm. The primary endpoint of 30-day death and stroke was 3.9% in the CEA arm and 9.6% in the CAS arm. The second trial to report was the German SPACE (2007), which was also stopped early when a prespecified interim analysis at 1200 patients suggested the need for roughly another 1200 patients at the same event rates to reach a statistically meaningful endpoint, at which point the government funding agency withdrew support; nevertheless there was no difference detected in the 30-day endpoint of death and stroke between CEA and CAS, 6.3% versus 6.8%, respectively (EPD) was used only 27% of the time). Last to report was the U.K.-based ICSS trial, which reported an interim nonprimary endpoint in 2008 demonstrating more outcome events with CAS (8.5%) than CEA (5.2%) but which ultimately reported its 3-year primary endpoint of disabling stroke and death demonstrating no differences between the two therapies.
The progression of study followed a different course in the United States than in Europe. After several reports of reasonable outcomes in CAS in high surgical risk patients using off-label devices, including tracheobronchial stents (which had delivery systems long enough to reach the carotid from the transfemoral route), device development including dedicated nitinol stents and EPD got under way. Subsequently, the Food and Drug Administration (FDA) Investigational Device Exemption (IDE) approval process dictated that studies would need to be compared with CEA. Because the procedural safety profile of CAS using EPD had not been fully established, the comparator group was mandated to be those patients who were deemed to require CEA but were at high risk for the operation by virtue of either anatomic or physiologic co-morbidities. These conditions are listed in Table 24-1 . The first U.S. trial to use these inclusion criteria was the randomized Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy study (SAPPHIRE), which tested the Precise carotid stent and the Angioguard filter EPD (Cordis/Johnson and Johnson, Freemont, California). SAPPHIRE turned out to be the only multicenter prospective examination of CEA in this high surgical risk cohort, which had largely been excluded from the landmark CEA trials such as the NASCET, the Asymptomatic Carotid Atherosclerosis Study (ACAS), and the Asymptomatic Carotid Surgery Trial (ACST). Unfortunately, the SAPPHIRE trial did not go to completion, as it didn’t enroll a patient in its last 6 months, felt to likely be due to the availability of other competitive non-randomized IDE studies that guaranteed the interested subjects would get CAS. These other, single-arm, studies used objective performance criteria (OPC) to compare the CAS outcomes to and were constructed from a literature review of CEA outcomes in high surgical risk patients in the various categories of surgical risk (e.g., lung disease, congestive heart failure, prior CEA, etc.). They then weighted contributions according to the actual percentage of each category enrolled in the specific trial. While this may seem like an inexact science, in fact the high-risk surgical arm of SAPPHIRE had roughly the same 1-year outcomes that were modeled using the OPC method, which validated this approach; this method became the de facto standard for device trials in CAS for both IDE stent approval and 510(k) EPD clearance.
| HIGH-RISK CATEGORY | CRITERIA |
|---|---|
| Age (y) | >80 |
| Severe cardiac dysfunction | NYHA Class III/IV chronic heart failure |
| Left ventricular ejection fraction <30% | |
| Open heart surgery within 6 weeks | |
| MI within 4 weeks | |
| NYHA Class III/IV angina | |
| Cardiac stress test positive for ischemia | |
| Severe renal dysfunction | End-stage renal failure on dialysis |
| Severe chronic lung disease | Chronic oxygen therapy |
| pO 2 ≤60 mm Hg | |
| Baseline hematocrit ≥50% | |
| FEV 1 or DLCO ≤50% of predicted | |
| Anatomic co-morbidities | Prior cervical radiation therapy |
| Previous ipsilateral carotid endarterectomy | |
| C2 or higher carotid bifurcation | |
| Contralateral carotid occlusion | |
| Contralateral laryngeal nerve palsy | |
| Presence of a tracheostomy | |
| Common carotid artery lesion(s) below the clavicle |
Although it was not able to be completed, the SAPPHIRE study nevertheless enrolled enough subjects to demonstrate that in a mixed population of symptomatic and asymptomatic patients at high surgical risk for CEA CAS was noninferior to CEA in the primary endpoint of 30-day death, stroke, and MI plus ipsilateral stroke and death to 1 year with trends favoring CAS ( Figure 24-1 ).
The next high surgical risk population CAS study completed and reporting data was the ARCHeR trial, which tested the Acculink stent and Accunet EPD system (Abbott Vascular, Santa Clara, California) and was the first single-arm study to compare to an OPC. The ARCHeR study 30-day death, stroke, and MI plus ipsilateral stroke to 1 year was 8.3%, the upper limit of the 95% confidence interval (CI) of which was able to satisfy the OPC endpoint estimate of 14.4%. This study led to FDA approval for this carotid stent system, the first in the United States, in 2004. Thereafter, a series of single-arm studies led to FDA approval, or clearance, for a variety of stents and filters, respectively, which are listed in Table 24-2 . It is noteworthy that no device tested for use in CAS in the United States has failed to establish safety and efficacy by FDA standards.
| IDE TRIAL | N (CAS) | YEAR OF FDA ACTION | STENT SYSTEM APPROVAL/EPD 510(K) CLEARANCE | POSTMARKET SURVEILLANCE STUDY |
|---|---|---|---|---|
| ARCHeR | 581 | 2004 | Acculink PMA approval Accunet 510(k) clearance | CAPTURE ( N —4225) CAPTURE ( N —6361) CHOICE ( N —19,000) |
| SECURITY | 305 | 2005 | Xact PMA approval Emboshield 510(k) clearance | EXACT ( N —2145) CHOICE |
| SAPPHIRE | 565 | 2006 | Precise PMA approval Angioguard 510(k) clearance | CASES-PMS ( N —1493) SAPPHIRE WW ( N —15,000) |
| CABERNET | 488 | 2006 | Nexstent PMA approval FilterWire Carotid 510(k) clearance | None |
| CREATE | 419 | 2006 2007 | Protégé Carotid PMA approval SpiderFX Carotid 510(k) clearance | CREATE PAS ( N —3500) |
| MaVErIC | 449 | 2007 | Exponent PMA approval GuardWire Carotid 510(k) clearance | None |
| PROTECT | 320 | 2008 | Emboshield NAV6 510(k) clearance | CHOICE |
| BEACH | 480 | 2008 | Wallstent Carotid PMA approval FilterWire EX System clearance | CABANA ( N —1097) |
| EPIC | 237 | 2008 | Fibernet 510(k) clearance | None |
| EMBOLDEN | 250 | 2009 | GORE Embolic Filter clearance | None |
| EMPIRE | 245 | 2009 | Gore Flow Reversal 510(k) clearance | FREEDOM (planned N —5000) |
| ARMOUR | 228 | 2009 | Mo.Ma 510(k) clearance | None |
| CREST | 1131 | 2011 | Acculink PMA extension | CANOPY (planned N —1200) |
As a condition of approval for each device tested, the FDA mandated postmarket surveillance registries of approximately 1500 patients to assess devices for any rare or unanticipated events not seen in the smaller pivotal studies, as well as the ability to transfer the technology into the nontrial setting. These single-arm prospective multicenter studies, replete with independent procedural and 30-day neurologic assessment, along with independent clinical event committees, were voluntarily extended by the device manufacturers and have yielded high-quality data from real-world settings from hundreds of sites and operators. The same comparable volume and quality of data—high or standard surgical risk—has not been paralleled in the CEA experience and provides a great deal of unique insight into the evolution of CAS U.S. outcomes, to be discussed further on. These studies, among them CAPTURE (Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Unanticipated or Rare Events), CAPTURE 2, EXACT (Emboshield and Xact), SAPPHIRE WW, and CHOICE (carotid stenting for high surgical risk patients; evaluating outcomes through the collection of clinical evidence), have studied tens of thousands of patients across hundreds of U.S. operators and sites and have consistently demonstrated that CAS outcomes in the high surgical risk population of patients meets or exceeds the American Heart Association (AHA) guidelines for both symptomatic and asymptomatic patients ( Figure 24-2 ).
In the background (2000–2008), while these pivotal and postmarket trials were being completed and conducted in high-risk surgical patients, the National Institutes of Health/National Heart, Lung, and Blood Institute and Abbott Vascular sponsored the large (2500 subject) Carotid Revascularization Endarterectomy versus Stenting Trial (CREST), which was originally designed to randomize symptomatic patients with standard risk for surgery to either CEA or CAS in 1 : 1 ratio. As contrasted to the aforementioned European studies, CREST mandated the use of EPD, included MI as a component of the primary endpoint, and insisted on qualified operators. The strict qualification criteria for both surgical and endovascular operators used to select sites resulted in over 50% of endovascular applications being rejected and led to a slower than anticipated ramp up of the number of study sites from 2000 to 2004 since there were few U.S. sites with an adequate qualifying volume of CAS activity. Due to new data from the ACST trial published in 2004 demonstrating an advantage of immediate over deferred CEA in patients with asymptomatic carotid lesions, along with an effort to boost the slower than anticipated enrollment, asymptomatic patients were included in 2005 and the study completed in 2008. The final population was roughly evenly divided between symptomatic and asymptomatic subjects.
CREST demonstrated no differences between CEA and CAS for the primary composite endpoint of 30-day death, stroke, and MI, plus ipsilateral stroke to 4 years (7.2% vs. 6.8%; p = 0.51) in the intention-to-treat analysis (ITT) ( Figure 24-3 ). In the ITT analysis, periprocedural event rates were the lowest reported for CEA and CAS in a multicenter randomized controlled trial setting. Within these 30-day composite outcomes, there were small differences noted between the therapies: CEA had roughly twice the number of MIs (1.1% vs. 2.3%; p = 0.03) and CAS had roughly twice the number of strokes (4.1% vs. 2.3%; p = 0.01), the difference being related to the incidence of minor strokes; major strokes were not different between CAS and CEA. While the trial was not powered to assess these individual components, they serve as hypothesis-generating observations and opportunity for outcome improvements. In CREST, the long-term outcomes such as stroke prevention effectiveness, vessel patency, and target lesion revascularization were the same between the two treatment arms, observations that reinforced those also seen in the SPACE and ICSS studies.
The short-term competitive safety profile of CAS was combined with similar comparable longer term durability with CEA represents a unique profile in endovascular intervention. Most, if not all, other endovascular interventions are attractive alternatives to surgery because they can have immediate and similar therapeutic importance to the patient without nearly the morbidity associated with the parallel surgical approach (such as with abdominal aortic aneurysm repair or lower extremity bypass), but generally suffer from a lack of competitive durability (such as SFA stents). In CAS, the long-term durability and stroke prevention being spot on with CEA means that its value and attractiveness really come down to matching the acute safety profile of periprocedural stroke and death in CEA (which is quite good). If short-term safety outcomes can be matched, then the avoidance of nuisance complications like cranial nerve injury and access site re-operation become the only real differentiating features between CEA and CAS.
In a separate per protocol analysis (PP) presented to the FDA as part of a successful application for extension of indication (to standard surgical risk patients) of the study devices by the co-sponsor of the study (Accculink stent and Accunet filter, Abbott Vascular), several other findings were observed. First, whereas a best-fit line in the ITT analysis appeared to demonstrate an advantage of CEA over CAS in octogenarians, a direct FDA assessment of this cohort in the PP analysis found that although the adverse outcomes were indeed higher in octogenarians, there were no differences between CEA and CAS in this group ( Figure 24-4 ). Conversely, CAS was found to be safer in the under 60-year-old population.
Second, a follow-up assessment of all patients with minor stroke due to either CEA or CAS demonstrated no differences in the mean severity of neurologic and functional deficit at 1 month and 6 months as measured by National Institutes of Health Stroke Scales (NIHSS) and modified Rankin scale (MRS), suggesting that the CAS minor strokes, while more numerous, ultimately had very little lasting clinical impact ( Figure 24-5 ). This confirmed similar findings from previous smaller studies that demonstrated that patients with CAS-related minor stroke were likely to have an NIHSS of 0 or 1 by 1 year. These clinical observations are further bolstered by MRI data from ICSS that show that while there is a higher frequency of new but asymptomatic diffusion-weighted imaging (DWI) abnormalities after CAS compared with CEA, in fact the volume of abnormalities is similar. Not only are there fewer but larger CEA-associated defects than CAS in ICSS, the CEA lesions were more likely to convert from acute to persisting lesions (RR, 0.4; 95% CI, 0.2–0.8; p = 0.007). The clinical implication of these findings is unclear but seems to support the data on the increase in minor stroke events seen in CREST with CAS compared with CEA, but the relative lack of persistent symptoms.
The CREST PP analysis also found that there appeared to be an important trend of outcome improvement within the CAS operators over the 8 years of the study enrollment ( Figure 24-6 ), but that there was no similar trend within the CEA operators. These observations were not surprising given the 60-year experience with CEA and stable techniques and established patient selection criteria at the start of the study, but for CAS the lack of even FDA-approved and dedicated devices until the fourth year of the study.
This last finding in CREST, the improvements in CAS outcomes within the trial, cannot entirely be explained by the experience accrued within the trial, since the average number of CAS cases performed by interventionalists was around six. This is where an intersection of the unique reimbursement hurdles delaying a fuller adoption of CAS as an alternative to CEA or medical therapy requires comment for a fuller understanding of the therapy and its outcomes and status. Specifically, carotid intervention has been under a restrictive national coverage decision (NCD) since the 1980s as a result of a negative technology assessment of carotid PTA, which did not foresee the advent of CAS at the time. This NCD, which did not support coverage or payments for carotid, vertebral, or intracranial intervention, was modified in the early 2000s to allow for research in CAS, and then again in 2005 following FDA approval of the first CAS systems. This second NCD modification extended coverage to patients with high surgical risk with recent symptoms, which represents a small (estimated to be 10% to 15%) fraction of the overall population of patients requiring carotid intervention. The 2005 NCD also allowed for coverage of CAS postmarket registries mandated as a condition of FDA approval that were subsequently extended by the sponsors voluntarily to explore other scientific queries, and that ultimately allowed greater patient access to and operator activity in, CAS. During the time of this coverage of registry activity a great deal was learned and published about the technique and patient selection related to CAS that have been reflected in this chapter and have accrued to the benefit of patients not just in the United States. A recent analysis of the past decade of CAS outcomes strongly backs the concept that CAS outcome improvement seen in CREST was the result of FDA approval (2004) and CMS reimbursement (2005), which supported a much broader and deeper parallel CAS experience outside of CREST, gained primarily in the postmarket studies. These studies allowed the treatment and study of over 50,000 patients in the last half of the decade which generated high-quality prospective 30-day data across hundreds of sites and unparalleled in any CEA experience. This volume of activity dwarfs the first half of the decade when a few small (generally <400 patients) trials in only a few sites, and a few operators, provided the only experience for CAS using EPD in this country. This marked increase in the number of CAS cases being done in the second half of the decade resulted in dramatic improvements in not only the IDE trial results across stent systems but also within the same stent and EPD systems ( Figure 24-7 ).
In retrospect, much of the failure of the European trials to have adequate experience in their operators can be explained by the era in which they were both planned and executed; had the studies been done in the second half of the decade rather than the first, the results may have been appreciably different for analogous reasons. Similarly, had the CREST trial enrollment not lagged—the last 4 years of the trial (2005 to 2008) enrolled the significant majority of subjects—as a result of the lack of adequate operator experience due to the enforcement of stringent operator selection criteria, then outcomes may have more closely paralleled the EU’s.
Unfortunately, there has been a recent marked reduction of CAS activity in the United States as a result of a unique and persistent refusal by the Centers for Medicare and Medicaid Services (CMS) to expand coverage to devices approved or cleared by the FDA as safe and effective in spite of a number of national coverage determination processes and opportunities to do so. Given the data on outcome improvement in the United States with volume activity that have just been discussed, this has real implications not only for patient access to care but also the quality of their outcomes. It also may make recruitment of qualified sites for CAS research problematic as well as put a damper on spending for technology improvements that can further safeguard patient outcomes.
As has been detailed, the clinical event rates for CAS and CEA are quite low, a happy fact for patients and referring/treating physicians alike; however, this is an unfortunate fact for researchers seeking to compare outcomes across therapies or to improve outcomes within therapies since it means that very large trials are required to assess differences. As an example, an intervention that seeks to demonstrate a 1% difference in outcomes in stroke would mean several thousand patients, and recruitment for trials of this size—even with brisk enrollment—can take close to a decade by which time the technology or method can be obsolete. So in addition to the “classic” clinical outcome measures listed, attempts to define objective but nonclinical differences in techniques and equipment have used surrogate markers of safety. These have primarily centered around the detection—the microembolic signals detected on transcranial Doppler (TCD)—or consequence—new lesions seen on serial magnetic resonance diffusion weighted imaging (MR-DWI)—of microemboli. The former method is confounded by the lack of reliable ability to distinguish gaseous from solid emboli, which means that presumably innocuous microbubbles released from moving devices through sheaths, unsheathing filters and stents, and even contrast injection are counted among potentially harmful ones; even still, it can be useful in characterizing potentially vulnerable stages of the procedure even if it is a bit more difficult to use in a comparative way. In the case of the latter technique, it is preferred since these overwhelmingly clinically silent imaging findings—the result of the edema indicative of cellular ischemia—are counted with consistency and are frequent enough to be used to distinguish both between therapies (i.e., CAS and CEA) and within (e.g., differences among EPD systems) requiring a relatively small number of patients. It should nevertheless be emphasized that while these markers will likely have utility in determining such things as the effectiveness of EPD, or the effects various access approaches or tools have on these measures of microembolism, there has yet to be a clinical correlate directly linked to these strictly image-based findings. That said, the low but real rate of minor stroke excess seen in CAS as compared with CEA, especially in symptomatic patients, appears to roughly parallel in a proportional way the consistent excess in MR-DWI lesions noted postprocedure. Therefore, both intuitively and on a semi-empiric basis, the reduction of MR-DWI lesions is desirable.
Last, while there are several publications reporting the effects of CAS on subtle measures of cognition using the outcomes of neuropsychometric testing, the results have been mixed and far from conclusive, likely related to the difficulty in administering these tests reliably and multiple confounders, known and unknown.
The Procedure
The endovascular management of obstructive atherosclerotic bifurcation carotid disease is practiced by multiple specialties—interventional cardiology, vascular surgery, neurointerventional radiology, and interventional neurology—and so mandates a confluence of disparate skill sets and understanding of both the disease process as well as the exceptionality of the procedure. This section will endeavor to communicate the relevant elements of endovascular carotid intervention important to performing it expertly and safely.
The predicate of surgical plaque removal—carotid endarterectomy (CEA)—of atherosclerotic bifurcation carotid disease has been performed for over 60 years and has been demonstrated to reduce future stroke in both symptomatic and asymptomatic patients as compared with deferred therapy. While acknowledging that these trials lacked a programmed, monitored, and modern medical therapy component, they nevertheless represent the highest quality data available (prospective, randomized, controlled, multicenter) to both direct clinical decision making and, in the case of CAS, use as a comparator for the standard of care. As was seen in the first half of this carotid section, the progression of carotid testing and therapy has always been predicated on a comparison, direct or indirect, to CEA.
The carotid artery and associated atherosclerotic plaque are unique not only as pathophysiologic determinants of clinical ischemic syndrome but also in their response to intervention, surgical or endovascular. On the first point, it is only in the small minority of cases that symptoms related to carotid stenosis are due to an actual reduction in distal blood flow, as contrasted with all other atherosclerotic stenoses that create their associated clinical syndromes via restriction in distal bed perfusion—chronic or acute. As a further demonstration of its distinctive nature, an acute occlusion of the carotid artery can often be asymptomatic. All of these characteristic aspects are related to the maintenance of distal perfusion by the circle of Willis, which although complete in less than half the population, nevertheless provides perfusion adequate enough to avoid symptoms in many cases. As regards the second point, the carotid bifurcation plaque, in the significant majority of lesions, is reliably and discretely localized within ~2 cm of the bifurcation. This fact is a result of the flow dynamics within the carotid bulb that set up a flow-eddy responsible for lesion generation, and this allows for its easy and routine surgical removal—not true in many other atherosclerotic vascular territories. In addition, the durability of carotid intervention is unmatched in the arterial circulation: long-term rates of restenosis requiring re-intervention for both CEA and CAS are similar and low—1% to 2% per year. In the case of standard (not eversion) CEA, enlargement of the arteriotomy with a patch is associated with lower rates of restenosis especially in women, whereas in CAS no definitive association with residual stenosis or sex and long-term patency has been shown. Understanding these two unique qualities of the carotid bifurcation drives decision making in the procedural components of CAS.
Although an in-depth exploration of the subject is largely beyond the scope of an interventional chapter on CAS, it is important to at least acknowledge the indications for carotid intervention in general terms, and for CAS specifically, and that some of them are in evolution or testing. These were codified in a 2011 multi-society guidelines document that the following distillation references ( Table 24-3 ).
