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There are four completed randomized trials in patients with symptomatic carotid disease: the Endarterectomy Versus Angioplasty in Patients with Symptomatic Severe Cartoid Stenosis (EVA-3S) trial119,120; the Stent-Supported Percutaneous Angioplasty of the Carotid Artery versus Endarterctomy (SPACE) trial121,122; the International Carotid Stenting Study (ICSS)4,5; and the Carotid Revascularization Endartectomy versus Stenting Trial (CREST).6,7 The CREST study also included asymptomatic patients.
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EVA-3S,119 a noninferiority study, was conducted in 30 centers across France and recruited and randomized standard CEA risk patients. These patients were within 120 days of either a TIA or a nondisabling stroke and had a ≥ 60% internal carotid artery stenosis in symptomatic carotid artery. The primary end point was any stroke or death within 30 days of treatment. Although the enrollment target was 872 patients, the trial was stopped prematurely by the data safety monitoring board after 527 patients had been enrolled, for reasons of safety and futility. The primary end point was seen in 9.6% of patients in the stenting group compared to 3.9% in those undergoing endarterectomy (P = 0.01). Later analyses demonstrated that the difference between the two groups persisted out to 4 years, the difference being driven by procedural events.120
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SPACE121 was a multicenter (n = 35), multinational (German, Austrian, and Swiss) noninferiority study. This trial recruited and randomized standard CEA risk patients within 180 days of either a TIA or moderate stroke (Rankin score < 4). Patients had a stenosis severity of 70% or greater by ECST criteria (≥ 50% by NASCET) in the index carotid artery determined by catheter angiography or by duplex ultrasound. The primary end point was ipsilateral stroke and death within 30 days of treatment. The trial was stopped after data from 1183 patients had been analyzed, which led to the conclusion that a larger sample size (almost 2500 patients) would be needed; however, additional funding was not available. Event rates were 6.84% in the stenting group compared with 6.34% in patients undergoing endarterectomy. Although the outcome rates were similar between the two groups, the trial failed to demonstrate the noninferiority of CAS (ie, the study failed to prove that the outcomes in patients undergoing stenting were no worse when compared to the outcomes of CEA).
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The ICSS,4,5 a multicenter (n = 50), multinational (Europe, Australia, New Zealand, and Canada participation) superiority study, recruited and randomized 1713 standard CEA risk patients to either CAS (n = 855) or CEA (n = 858) within 12 months of symptoms. Patients older than 40 years of age with a stenosis severity of 50% or greater (by NASCET criteria) in the index carotid artery were eligible for enrollment. Stenosis severity and study entry eligibility were determined by duplex ultrasound or other noninvasive imaging of the carotid artery; approximately 90% of patients in both groups had > 70% stenosis. Patients were followed for a median of 4.2 years. The median time from the symptomatic event to CAS and CEA was 35 and 40 days, respectively (P < 0.013), and 25% of CAS patients and 18% of the CEA patients underwent treatment within 14 days of the event.
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The primary end point was long-term incidence of death or disabling stroke in any territory. The number of fatal or disabling strokes (52 vs 49) and cumulative 5-year risk did not differ significantly between the CAS and CEA groups (6.4% vs 6.5%; HR 1.06, P = 0.77). Although any stroke was more frequent in the stenting group than in the endarterectomy group (119 vs. 72 events; intention-to-treat population, 5-year cumulative risk 15.2% vs 9.4%, P < 0.001), this difference was contributed by nondisabling strokes. The distribution of modified Rankin scale scores at 1 year, 5 years, or final follow-up did not differ significantly between treatment groups. The ICSS study, the largest randomized study comparing CAS and CEA in symptomatic patients, concluded that long-term functional outcomes and the risk of fatal or disabling strokes are similar for stenting and endarterectomy.5
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Inclusion and Exclusion Criteria
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For the outcomes comparison between the two treatment strategies, CAS and CEA, to be valid, the two patients groups should be comparable. Specifically, for the patients enrolled in these studies it should not matter if they were in the CAS or CEA arms since, in a well-designed, adequately enrolled clinical trial, the process of randomization should “cancel the noise” and even out the imbalances between the two arms. However, despite randomization, an important imbalance continued to persist between the two treated groups related to the inclusion and exclusion criteria that handicapped the outcomes in the CAS arm. For example, in each one of these trials, patients with known anatomical characteristics that would render them “high risk” for CEA (tandem lesions, additional intracranial high grade stenosis, “hostile necks” as a result of prior surgery or radiation) were all excluded from trial participation. On the other hand the trial protocol did not specify exclusions for high stent risk. Additionally, when the trial protocol permits trial entry and randomization on the basis of duplex imaging, anatomical features that render stenting high risk (extended, type III aortic arch, tortuous extracranial carotid anatomy, obvious lesion filling defect(s) as a result of a fresh, friable, and loose thrombus) cannot be identified/excluded. Whereas inclusion of these patients made little or no difference to the outcomes for CEA, it negatively impacts CAS outcomes, and this imbalance cannot be corrected by the randomization process. In their defense, it is important to recognize that the EVA-3S, SPACE, and ICSS studies developed their protocols and started recruiting patients during a period wherein the concept of high stent risk was not well understood.
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Contemporary CAS results are predicated on mandatory administration of adequate doses of dual antiplatelet medications in all patients prior to initiation of the stenting procedure and continuing them for around 8 weeks post-CAS.123,124 In all three of the above trials, dual antiplatelet agent use was recommended but not mandated. Approximately 20% of patients in the EVA-3S and SPACE studies did not receive adequate antiplatelet medications.
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Inconsistent Use of Embolic Protection Devices
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In EVA-3S, during the first 3 years of enrollment (2000-2003), EPDs were used in approximately three-quarters of the procedures. In 2003, after a Data and Safety Monitoring Board review, EPD use became mandatory. Analysis of the outcomes with and without use of EPDs reveals much higher complication rates for CAS performed without EPDs. In SPACE, EPDs were used in only 27% of the cases. In ICSS, use of EPDs was recommended, but not mandatory. Less than three quarter, of the cases were performed using an EPD. Since the protocol was silent with respect to the need for familiarity with these devices prior to use within the trial, experience and expertise with the use of these devices was very variable and in some centers, minimal if any. In contemporary CAS practice, careful, critical analysis of the carotid anatomy as it relates to its suitability for placing a distal EPD is an important component of the risk stratification process. If the anatomy cephalad to the stenosis is markedly tortuous and/or there is no “adequate” landing zone (ie, there is insufficient room between the caudal extent of the EPD and the area where the distal tip of the stent delivery system is expected to land), unless the case is suitable for a proximal (flow reversal) EPD, the case should be considered high stent risk, and the operator should not proceed with “unprotected” CAS.
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Among practitioners of CAS, a major concern with these studies has been the lack of experience of the investigators. Whereas the surgeons were experienced CEA operators and needed to have performed a minimum of 25 CEA surgeries in the year preceeding study participation (EVA-3S and SPACE), the entry barrier for CAS operators was much lower.125,126 In EVA-3S, for example, a total stenting experience of 12 CAS procedures or 5 CAS procedures plus 30 non-CAS supra- aortic stent procedures was sufficient for entry qualification.127 Surprisingly, first-ever CAS cases in the presence of a proctor in the room were allowed within the trial. In the ICSS study,5 randomization was suspended at two centers; one of them enrolled 11 CAS patients but had 5 disabling strokes or deaths. In ICSS, the hazard ratio for the combined outcomes of procedural stroke or procedural death or ipsilateral stroke during follow-up was lower for centers that enrolled 50 or more patients. A disproportionately high number of patients underwent CAS using general anesthesia or conscious sedation, a reflection of operator inexperience and unfamiliarity with the CAS procedure and contrary to contemporary CAS practice. This has led many investigators128,129 to question the validity of establishing clinical criteria and guidelines for CAS on the basis of these trials.
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The CREST study6,7 was conducted in 107 US and 9 Canadian centers and randomized standard risk CEA patients to either CAS or CEA. The trial, which commenced in 2000, started by enrolling symptomatic patients, ie, patients with TIA, amaurosis fugax, or nondisabling stroke, who were within 6 months from the index event. In 2005, enrollment criteria were modified to include asymptomatic patients. Symptomatic patients needed to have a stenosis severity of ≥ 50% on conventional angiography (NASCET criteria) or ≥ 70% stenosis on duplex ultrasonography, CTA, or MRA in the index carotid artery. For asymptomatic patients, the stenosis eligibility criteria were ≥ 60% on conventional catheter angiography, ≥ 70% by duplex ultrasonography, or ≥ 80% stenosis on CTA or MRA. The trial was sponsored by the NIH as well as Abbott Vascular, whose devices, the Accunet filter and Acculink stent, were utilized in the study. Secondary end points included all death, any stroke, or myocardial infarction at 30 days (periprocedural); a 1-year composite end point stratified by symptomatic status and age (octogenarian status), acute procedural success, target lesion revascularization at 12 months, access site complications requiring treatment, cranial nerve injury unresolved at 1 and 6 months, and a prespecified interaction analyses involving gender and symptomatic status.
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Data analysis was performed with four prespecified analysis populations: intent to treat, as treated, modified as treated, and per protocol.
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The sample size of 2500 symptomatic patients in the initial proposal was based on a noninferiority analysis for a study with 80% power and one-sided alpha of 0.05, assuming a composite end point rate of 7.48% and a noninferiority margin of 2.6. When asymptomatic patients were added in 2005, the assumption was that 50% of the patient population would be asymptomatic. The assumed composite event rate was ratcheted down to 6.76%, and the study power increased marginally to 82% with a one-sided alpha of 0.05.
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Of the 2307 patients in the per-protocol population, 1219 (52.8%) were symptomatic and 1088 (47.2%) were asymptomatic. The demographics of the two groups were well matched; approximately 9% of the patients were octogenarians, 30% were diabetic, and cardiovascular disease was present in about 45% of the patients.
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The primary end point of the CREST study was the composite of any stroke, myocardial infarction, or death from any cause during the periprocedural period or ipsilateral stroke within 4 years after randomization. The data were also analyzed using a composite end point that included any stroke, myocardial infarction, and all death within 30 days of the procedure plus ipsilateral stroke between day 31 and day 365 (Table 95–9). This end point was used by the industry sponsor for FDA submission for device approval. CAS was shown to be noninferior to CEA based on a prespecified noninferiority margin of 2.6%. There were no significant differences between CAS versus CEA by symptomatic status for the primary CREST end point.8
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During the periprocedural period, there was a greater risk of stroke with stenting (4.1% vs 2.3%; P < 0.01), a difference that was driven by the increased number of minor strokes in the CAS group (3.2% vs 1.7%; P = 0.01). It is worth noting and emphasizing that for the end points of death and major stroke, not only was there no significant difference between the two groups, the event rates for these two key end points was low with both CEA and CAS.6 For both CAS and CEA, the overall stroke and death rates were below or comparable to those of previous randomized trials and were within the complication thresholds suggested in current guidelines for both symptomatic and asymptomatic patients.8
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All interventions for extracranial carotid artery disease (CEA or CAS) are prophylactic and the specific goal of the procedure is to reduce the patient's future risk of a stroke. Although survival free of a major stroke is the principal goal of the therapeutic intervention, minor strokes cannot be simply ignored. In fact, especially when treating asymptomatic patients, operators should have an extremely low tolerance for any procedure-related neurological event, be it major or minor stroke or cranial nerve injuries. In the CREST study, an increased incidence of minor strokes contributed to the excess stroke hazard in the CAS arm. Analysis of the NIH stroke scale data of patients suffering a periprocedural minor stroke reveals that although residual defects were disproportionately higher in the CAS arm at 1 month (1.10% vs 0.60%), this difference was no longer evident at the 6-month time point (0.62% vs 0.6%). A similar trend to equalization was noted when objective classification of the residual deficits was performed using the Rankin scale. Importantly, the occurrence of a minor stroke did not negatively impact the patients’ long-term survival.
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Myocardial Infarction
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In CREST, myocardial infarction was defined by biomarker elevation (creatine kinase-MB [CK-MB] or troponin > twice the upper limit of normal) plus either chest pain or electrocardiographic (ECG) evidence of ischemia (> 1 mm ST-segment elevation or depression in two contiguous leads). An additional prespecified category included biomarker elevation without chest pain or ECG abnormality (biomarker positive only). When compared to patients without biomarker elevation, mortality was higher over 4 years for those with a myocardial infarction (HR 3.40) or biomarker positive only (HR 3.57). After adjustment of baseline risk factors, the occurrence of myocardial infarction or the elevation of biomarkers only remained independently associated with increased mortality.130
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The negative impact on survival in patients experiencing a periprocedural myocardial infarction is consistent with observations from other cardiac and noncardiovascular procedures. It has been previously shown that small periprocedural elevations of cardiac enzymes were associated with increased future mortality.131,132,133,134
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Cranial Nerve Injuries and Their Sequalae
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Cranial nerve injuries occur in 4.9% to 7.7% of patients undergoing CEA. Although uncommon, cranial nerve deficits can be permanent and cause significant morbidity. In the ICSS study, two of the cranial nerve injuries (out of 857 endarterectomies) were classified as disabling—both patients required gastrostomies. In the CREST study, 5.3% of patients undergoing CEA had a cranial nerve injury. Two percent of the cranial nerve injuries were unresolved at 6-month follow-up. In future trials, consideration should be given to the inclusion of cranial nerve injuries as part of a composite primary end point together with death, stroke, and myocardial infarction.
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Durability of Carotid Stenting
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Clinical durability, ie, freedom from an ipsilateral stroke during long-term follow-up in both symptomatic and asymptomatic patients with extracranial carotid artery disease undergoing CEA, was established by the NASCET12 and ACAS17 trials.
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The 10-year follow-up results from the CREST study were recently reported7 (see Table 95–9). Postprocedural ipsilateral stroke over the 10-year follow-up occurred in 6.9% (95% CI, 4.4%-9.7%) of the patients in the CAS group and in 5.6% (95% CI, 3.7%-7.6%) of those in the CEA group; these rates were not significantly different (HR, 0.99; 95% confidence interval [CI], 0.64-1.52). There were no between-group differences when symptomatic and asymptomatic patients were analyzed separately. These results are similar to the observations in the EVA-3S120 and SPACE122 trials, suggesting excellent durability on longer-term follow-up. The durable benefits of CAS, ie, freedom from ipsilateral stroke, in these large randomized studies reinforce the long-term results published by the authors (SI, GR) almost 15 years ago.89
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Restenosis Following Carotid Stenting
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Although duplex ultrasound is an excellent noninvasive method of following these patients, as a result of mechanical changes in the carotid artery following stenting, velocity criteria conventionally applied to diagnose stenosis in nonstented arteries are not the same in stented carotid arteries. It has been suggested that a peak systolic velocity greater than 300 cm/s be used to define a stenosis > 70%135,136,137 in the stented patient. Although CTA may be used for noninvasive imaging,138 MRA is not useful in a stented patient because of metallic interference from the implanted stent.
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In the CREST trial,7 restenosis was defined as the time from the procedure to either ipsilateral revascularization or the detection of a 70% to 99% stenosis or occlusion on a duplex exam performed annually after CAS or CEA, with the degree of stenosis determined by the norms of the local laboratory. There was no significant difference between the two treatment groups in the proportion of patients who had restenosis or underwent revascularization. Restenosis occurred or revascularization was performed in 12.2% of the patients treated with CAS and in 9.7% of those treated with CEA (HR, 1.24; 95% CI, 0.91-1.70)
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The results of the CREST trial showed that both CEA and CAS are excellent treatment options. There was no difference in the outcomes in women versus men. The primary composite end point of periprocedural stroke, myocardial infarction, or death was similar between CEA and CAS. The incidence of major disabling strokes or death was extremely low and was not different between the two treatment modalities. Periprocedural minor strokes were greater in the CAS group, but by 6 months, the deficits were not different. There was no survival disadvantage in patients with minor strokes. However, myocardial infarction occurred more frequently in the CEA cohort, and this negatively impacted survival. At 1 year, stroke had a greater adverse effect on quality of life than did myocardial infarction.139 Over a follow-up period that extended to 10 years, freedom from ipsilateral stroke and the risk of restenosis were similar for the CEA and CAS groups, supporting the clinical and device durability of CAS.