Author + information
- Received October 18, 2005
- Revision received November 29, 2005
- Accepted December 5, 2005
- Published online June 20, 2006.
- Robert D. Safian, MD⁎,⁎ (, )
- John F. Bresnahan, MD†,
- Michael R. Jaff, DO‡,
- Malcolm Foster, MD§,
- J. Michael Bacharach, MD∥,
- Brijeshwar Maini, MD¶,
- Mark Turco, MD#,
- Subbarao Myla, MD⁎⁎,
- Gustav Eles, MD††,
- Gary M. Ansel, MD‡‡,
- CREATE Pivotal Trial Investigators
- ↵⁎Reprint requests and correspondence:
Dr. Robert D. Safian, Cardiac and Vascular Intervention, William Beaumont Hospital, Heart Center-3rd Floor, Royal Oak, Michigan 48073.
Objectives The purpose of this study was to determine the safety of carotid artery stenting with a unique distal embolic protection system in high-risk patients with severe carotid stenosis.
Background Previous studies suggest that some patients with carotid stenosis and serious comorbid conditions are at high risk for carotid endarterectomy, and may be safely treated by carotid artery stenting.
Methods A prospective non-randomized multicenter registry of 419 patients with severe carotid stenosis and high-risk features for carotid endarterectomy was conducted between April 2004 and October 2004. Carotid artery stenting was performed with the Protégé Self-Expanding Nitinol Stent and the SPIDER Embolic Protection System (ev3 Inc., Plymouth, Minnesota). Aspirin and clopidogrel were prescribed at least 24 h before and three months after revascularization. The primary outcome was the combined incidence of major adverse cardiac and cerebrovascular events at 30 days after intervention, including death, stroke, and myocardial infarction. A secondary outcome was the technical success, defined as successful deployment of all devices, filter retrieval, and final diameter stenosis <50%.
Results Technical success was achieved in 408 of 419 patients (97.4%). The primary end point was observed in 26 patients (6.2%), including death in 8 (1.9%), nonfatal stroke in 14 (3.3%), and nonfatal myocardial infarction in 4 (1%). Independent predictors of death or stroke at 30 days included duration of filter deployment, symptomatic carotid stenosis, and baseline renal insufficiency.
Conclusions For some patients with severe carotid stenosis and high-risk features for carotid endarterectomy, carotid artery stenting with distal embolic protection is a reasonable alternative for revascularization.
Carotid artery stenting (CAS) is emerging as a reasonable therapeutic alternative to carotid endarterectomy (CEA) for some patients with severe carotid artery stenosis who are at high risk for surgery based on the presence of concomitant severe cardiovascular, pulmonary, and cerebrovascular diseases (1). Although several studies have evaluated the use of self-expanding stents and distal embolic protection systems in high-risk patients with asymptomatic and symptomatic carotid stenosis, the results of these high-risk registries have not yet been published. The purpose of this study was to evaluate the safety of carotid artery revascularization using a unique stent and distal embolic protection system.
The Carotid Revascularization with ev3 Arterial Technology Evolution (CREATE) pivotal trial was approved by the institutional review boards at each of the 32 participating institutions (Appendix), and was in compliance with the Declaration of Helsinki. Interventional operators were required to submit a written statement documenting performance of at least 30 successful CAS procedures, before participation in this study.
Study design and end points
This study was a prospective multicenter registry of CAS in high-risk patients with severe carotid stenosis. The primary end point of the study was the composite of major adverse cardiac and cerebrovascular events (MACCE) at 30 days after revascularization, defined as the occurrence of death, ipsilateral stroke, procedure-related contralateral stroke, and myocardial infarction (MI). Strokes were further classified as major or minor strokes based on the National Institutes of Health Stroke Scale, the Rankin Score, and the Barthel Index (Appendix). Myocardial infarction was defined as any elevation of creatine kinase more than three times the upper limit of normal, and elevation of cardiac isoenzymes, with or without associated electrocardiographic changes. The secondary end point was technical success, defined as successful deployment and retrieval of the distal protection device system, successful stent deployment, and final diameter stenosis <50%.
Patient eligibility and study requirements
The major eligibility criteria are described in Table 1.Patients with suspected cervical carotid stenosis generally underwent carotid artery duplex ultrasound evaluation, but criteria for stenosis severity were defined angiographically. Patients who met all general inclusion criteria, one or more high-risk inclusion criteria (Table 2),and none of the exclusion criteria (Table 3)were considered for participation in this study. Written informed consent was obtained in all patients according to protocols approved by the institutional review boards at each institution. Patients underwent evaluation by an independent neurologist or approved surrogate before and during intervention, before hospital discharge, and at 30 days. Patients with persistent neurological deficits after CAS underwent imaging of the brain with computerized tomography or magnetic resonance imaging. All clinical events were reviewed and adjudicated by an independent clinical events committee. Methodology for monitoring cardiac enzymes, blood counts, renal function, and antiplatelet therapy have been described previously (2). After CAS, patients were treated with aspirin (325 mg daily or 81 mg daily if they were taking warfarin, and clopidogrel 75 mg daily) for three months. Details of the angiographic procedure and deployment of the SPIDER Embolic Protection System and the Protégé GPS Self-Expanding Nitinol Stent (ev3 Inc., Plymouth Minnesota) have been described previously (2). Unlike other distal protection devices, the Capture Wire in the SPIDER system is not used to cross the target lesion. Instead, the operator may select an independent guidewire to cross the target lesion and access the distal carotid artery, which may increase the opportunity for successful crossing.
Data acquisition, study oversight, and statistical methods
Angiographic and ultrasound data were acquired by independent core laboratory analyses. All adverse events were evaluated by an independent clinical events committee; were categorized as being related to the investigational devices, the procedure, or not; and were reported to an independent data and safety monitoring committee. Data are reported as mean (±SD) for continuous variables and frequency for categorical variables. Univariate analysis by logistic regression (Version 9.1, SAS Institute, Cary, North Carolina) was performed on 35 variables to identify correlates of death or stroke within 30 days. Those variables with p < 0.20 were entered into a multiple logistic regression model to identify independent predictors of outcome, and odds ratios (OR) for these variables were expressed with 95% confidence intervals (CI). Values of p ≤ 0.05 were considered statistically significant.
Patient characteristics and high-risk inclusion criteria
Baseline demographics and high-risk characteristics of the 419 patients are shown in Table 4.High-risk anatomical criteria were present in 221 (52.7%), high-risk clinical criteria in 319 (76.3%), and both high-risk anatomical and clinical criteria were present in 122 patients (29.1%). Two or more high-risk criteria were present in 217 patients (51.7%). The three most frequent criteria for inclusion were age >75 years, multivessel coronary artery disease, and recurrent stenosis after prior CEA. Baseline angiographic characteristics are shown in Table 5.
Procedural and 30-day outcomes
Technical success (the secondary end point of the study) was achieved in 408 of 419 patients (97.4%), and grossly visible debris was observed in the SPIDER filter in 151 patients (36%) (Tables 6 and 7).⇓⇓Technical failure occurred in 11 patients (2.6%), and was due to final residual stenosis of 50% to 60% in 2 patients and failure to deploy the SPIDER Capture Wire in 9 patients (no intervention was performed in 6 patients and a stent was deployed without distal protection in 3 patients) due to anatomic limitations such as vessel tortuosity and calcification. The primary end point (MACCE) occurred in 26 patients (6.2%), and included death in 8 (1.9%), nonfatal stroke in 14 (3.3%), and MI in 4 (1%; non–ST-segment elevation MI in 3, ST-segment elevation MI in 1). Among the eight patients who died within 30 days, causes of death were fatal stroke in five patients (1.2%), due to intracranial hemorrhage in four and thromboembolic stroke in one; non–ST-segment elevation MI, access site hemorrhage, compartment syndrome, and multisystem failure in one; progressive hypotension and ventricular fibrillation in one; and development of a femoral artery pseudoaneurysm leading to lower extremity gangrene and multisystem failure in one (Table 7).
Thus, there were a total of 19 strokes (4.5%) within 30 days of intervention, including fatal major stoke in five (4 hemorrhagic, 1 thromboembolic). The thromboembolic major stroke occurred immediately after a long CAS procedure requiring filter deployment for 50 min, and was further complicated by respiratory failure and death within 2 days (Table 7, Patient #4). All four hemorrhagic strokes occurred 4 to 28 days after CAS (Table 7, Patients #5 to #8), including one patient on day 28 after uncomplicated CAS, one patient with possible hyperperfusion syndrome 7 days after CAS, one patient on warfarin therapy who died 4 days after CAS despite emergency craniotomy, and one patient with cerebellar hemorrhage who died 14 days after a difficult CAS procedure (filter deployment for 43 min, failure to dilate the stent after deployment). Nonfatal stroke in 14 patients (3.3%) was classified as major stroke in 10 (2.3%) and minor stroke in 4 (1%); all patients with minor stroke and 4 patients with major stroke had no residual disability at 30 days after CAS (Table 7), including 1 patient who received intraarterial tissue-type plasminogen activator immediately after onset of neurological symptoms. Nonfatal strokes were due to thromboembolism in 13 patients and intracranial hemorrhage in 1 patient who received concomitant warfarin for deep venous thrombosis. Among the 10 thromboembolic major strokes (1 fatal, 9 nonfatal), 7 occurred during complex interventional procedures characterized by one or more of the following features: dissection of the internal carotid artery requiring multiple stents, prolonged (>30 min) deployment of the SPIDER capture wire, and technical difficulty retrieving the capture wire. Intracranial hemorrhage occurred in five patients (1.3%) within 4 to 28 days of CAS, and none were associated with excessive procedural anticoagulation. Concomitant warfarin therapy was administered in two patients, and poorly controlled hypertension was observed in another patient.
Other non-neurological events included vasovagal or vasodepressor reactions in 68 patients (16.2%), all treated by administration of intravenous fluids, atropine, and/or vasopressors; access site complications in 14 patients (3.3%); and minor gastrointestinal bleeding in 7 patients (1.7%).
Predictors of outcome
Thirty-five clinical and anatomical variables were analyzed using a logistic regression to determine their association with death or stroke within 30 days of CAS. Factors associated with adverse outcome by univariate analysis included baseline renal insufficiency, symptomatic carotid stenosis, severe pulmonary disease, lesion calcification, absence of an anatomical high-risk feature, and duration of filter deployment. Whereas there was no difference in the duration of filter deployment in patients without stroke compared with those with minor stroke (18.8 ± 9.3 min vs. 17.7 ± 7.8 min, p = NS), patients with major stroke had significantly longer duration of filter deployment compared with patients without stroke (25.7 ± 16.6 min, p = 0.004). When divided into four 10-min increments (<10 min, 10 to 20 min, 21 to 30 min, >30 min), there was a significant relationship between duration of filter deployment and the risk of death and stroke (5.1%, 5.0%, 10.3%, and 10.8%, respectively; p = 0.02). Using a forward stepwise multivariate analysis, independent predictors of death and/or stroke were symptomatic carotid stenosis (OR 2.88, 95% CI 1.2 to 6.8, p = 0.015), baseline renal insufficiency (OR 2.92, 95% CI 1.2 to 6.9, p = 0.015), and filter deployment time (p = 0.035).
The standard of care for symptomatic and asymptomatic patients with carotid artery stenoses has been established by the results of four large prospective randomized trials of medical therapy and CEA (North American Symptomatic Carotid Endarterectomy Trial [NASCET], European Carotid Surgery Trial [ECST], Asymptomatic Carotid Atherosclerosis Study [ACAS], and Asymptomatic Carotid Surgery Trial [ACST]) (3–6). These studies suggest that patients with symptomatic carotid stenosis >50% (NASCET and ECST) and asymptomatic carotid stenosis >70% (ACAS and ACST) have a significant reduction in the risk of ipsilateral stroke at five years after CEA compared with patients treated conservatively with aspirin. However, CEA is commonly performed in patients who would have been excluded from these randomized trials because of advanced age or the presence of serious comorbid medical conditions (7). In fact, the risk of perioperative death and stroke after CEA may be two- to four-fold higher in high-risk patients with serious cardiopulmonary disease compared with low-risk patients without such comorbidity (7).
In a recent randomized trial of CEA and CAS with distal protection in high-risk patients (Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigation [SAPPHIRE]) (1), more than half the patients who were screened were considered too high risk for CEA, and underwent CAS as part of a high-risk non-randomized registry. The results of this high-risk registry have not yet been published, but these patients have a higher risk profile than those in the randomized trial. Among high-risk patients who were considered satisfactory candidates for both revascularization procedures, CAS was associated with a 56% reduction in perioperative death, stroke, and MI compared with CEA, and a 39% reduction in death and ipsilateral stroke at one year (1). The 6.2% risk of death, stroke, and MI in our high-risk registry is higher than the 5.8% risk reported in the SAPPHIRE stent arm, but lower than the 7.6% to 8.5% risk in Acculink for Revascularization of Carotids in High-Risk Patients (ARCHER) trial (phases 1, 2, and 3) and the 8.5% risk in Registry Study to Evaluate the Neuroshield Bare Wire Cerebral Protection System and X-Act Stent in Patients at High Risk for Carotid Endarterectomy (SECURITY) (8,9). In addition, the risk of periprocedural death and stroke after CAS was 5.2% in our high-risk patients, which is similar to the 5.6% risk of death and stroke after CEA in symptomatic low-risk patients (10), but higher than the 3% threshold of perioperative death and stroke established by the American Heart Association for CEA in asymptomatic low-risk patients (11).
Because carotid artery revascularization is most often recommended to prevent stroke in asymptomatic patients, the risk of neurological complications after CAS is particularly important. The 4.5% risk of stroke in this study was lower than the 6.9% risk in the SECURITY trial (9), and was similar to the 4.4% to 5.5% risk in the ARCHER studies (8). The 3.5% risk of major stroke in this study was slightly higher than the 2.6% risk in the SECURITY trial and the 1.1% to 1.4% risk in the ARCHER studies, and these differences may be due to differences in clinical or angiographic characteristics, differences in the definition of major stroke, or chance. It is unlikely that these differences are due to the larger pore size of the SPIDER filter, because the risk of major stroke was 1.9% in the study of the rapid-exchange version of the SPIDER filter (12). Furthermore, although distal embolic protection devices have been widely accepted as necessary adjuncts during CAS, failures may be due to the inability to deliver the device, device-induced complications such as vessel dissection, and incomplete capture or retrieval of debris leading to acute stroke; all of these complications were observed in this study. However, the clustering of strokes after prolonged and complex interventional procedures, and the relationship between filter deployment duration and stroke, suggests that some adverse events may be potentially avoidable by careful patient selection. Duration of filter deployment may be a marker for complex arch and carotid artery anatomy (type C arch, severe carotid artery tortuosity), because these anatomical features often add to procedural complexity. Because these features are often found in the elderly, they may partially explain why advanced age was reported as a high-risk feature in another registry of low-risk patients (13).
The observation of intracranial hemorrhage in 1.3% of patients raises some concern. Concomitant administration of warfarin and dual antiplatelet therapy may predispose elderly patients to serious bleeding complications, including intracranial hemorrhage. Because similar rates of early intracranial hemorrhage have not been reported in coronary stent patients receiving concomitant warfarin and dual antiplatelet therapy, it is possible that hyperperfusion may play an incremental role. Further study is needed.
Although neurological complications are the most devastating, the most common complications are vasovagal or vasodepressor responses, possibly due to stretching the carotid baroreceptor during balloon inflation and stent deployment. These complications occurred in nearly 20% of our patients, and were readily managed with intravenous fluids, atropine, and vasopressors in most patients. However, patients with poor myocardial reserve due to severe left ventricular dysfunction may be poorly tolerant of hypotension, so prompt and effective treatment is appropriate.
In conclusion, in some patients with severe carotid stenosis and high-risk features for CEA, revascularization with CAS and distal embolic protection is a safe and reasonable alternative to CEA. In high-risk patients with renal insufficiency or complex anatomy of the aortic arch and carotid artery, in whom prolonged filter deployment may be anticipated, the risk of stroke after CAS may be higher, and the best therapy in these patients is unknown.
For a list of the investigating institutions, principal investigators, and number of patients enrolled, as well as the definitions of major and minor stroke after CAS, please see the online version of this article.
This study was funded by an educational research grant from ev3 Inc. (Plymouth, Minnesota), which was also responsible for data collection, data analysis, and manuscript review. The investigators for the CREATE pivotal trial are listed in Appendix.
- Abbreviations and Acronyms
- Asymptomatic Carotid Atherosclerosis Study
- Asymptomatic Carotid Surgery Trial
- Acculink for Revascularization of Carotids in High-Risk Patients trial
- carotid artery stenting
- carotid endarterectomy
- confidence interval
- Carotid Revascularization with ev3 Arterial Technology Evolution trial
- European Carotid Surgery Trial
- major adverse cardiac and cerebrovascular events
- myocardial infarction
- North American Symptomatic Carotid Endarterectomy Trial
- odds ratio
- Stenting and Angioplasty with Protection in Patients at High Risk for Endarterectomy Investigation trial
- Registry Study to Evaluate the Neuroshield Bare Wire Cerebral Protection System and X-Act Stent in Patients at High Risk for Carotid Endarterectomy
- Received October 18, 2005.
- Revision received November 29, 2005.
- Accepted December 5, 2005.
- American College of Cardiology Foundation
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