Author + information
- Received December 30, 2017
- Revision received June 6, 2018
- Accepted June 26, 2018
- Published online December 3, 2018.
- Eugenio Stabile, MD, PhDa,∗ (, )
- Gianmarco de Donato, MD, PhDb,
- Piotr Musialek, MD, PhDc,
- Koen De Loose, MDd,
- Roberto Nerla, MDe,
- Pasqualino Sirignano, MDf,
- Salvatore Chianese, MDa,
- Adam Mazurek, MDc,
- Tullio Tesorio, MDg,
- Marc Bosiers, MDd,
- Carlo Setacci, MDb,
- Francesco Speziale, MDf,
- Antonio Micari, MDd and
- Giovanni Esposito, MD, PhDa
- aDivision of Cardiology, Department of Advanced Biomedical Sciences, University of Naples “Federico II,”, Naples, Italy
- bDepartment of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy
- cJagiellonian University, Department of Cardiac and Vascular Diseases, John Paul II Hospital, Krakow, Poland
- dA.Z. Sint-Blasius, Dendermonde, Belgium
- eInterventional Cardiology Unit, Maria Cecilia Hospital, Cotignola, Italy
- fVascular and Endovascular Surgery Division, Department of Surgery “Paride Stefanini,” Policlinico Umberto I, “Sapienza” University of Rome, Rome, Italy
- gDivision of Invasive Cardiology, Clinica Montevergine, Mercogliano, Italy
- ↵∗Address for correspondence:
Dr. Eugenio Stabile, Division of Cardiology, Department of Advanced Biomedical Sciences, University of Naples “Federico II,” Naples, Italy.
Objectives The aim of this study was to evaluate the clinical efficacy of dual-layered mesh-covered carotid stent systems (DLS) for carotid artery stenting (CAS).
Background The need to minimize the risk for plaque debris prolapsing between stent struts following CAS has resulted in the development of DLS. Small clinical studies evaluating 2 available devices, Roadsaver and CGuard, have been recently published; none of these studies is sufficiently powered to test the role of common risk factors on the occurrence of stroke at 30 days post-CAS.
Methods A search was performed of multiple electronic databases for studies larger than 100 cases of CAS with DLS. Four single-arm prospective studies were identified, and individual patient data were collected. The primary endpoint was the occurrence of stroke at 30 days; secondary endpoints were technical and procedural success, periprocedural stroke, and in-hospital and 30-day rates of death.
Results The Roadsaver and CGuard stents were used in similar proportions, and technical success was achieved in all procedures (100% [n = 556]). There were 6 periprocedural strokes (1.08%; all minor). During 30-day follow-up, there was 1 death (0.17%) from myocardial infarction and 1 additional minor stroke (0.17%). The cumulative 30-day mortality rate was 0.17%, and the incidence of stroke at 30 days was 1.25%. No predictors of stroke at 30 days could be identified.
Conclusions This meta-analysis suggests that DLS can be safely used for CAS, and their use minimizes the incremental risk related to symptomatic status and other risk factors.
Procedural and post-procedural cerebral ischemic events still represent the Achilles’ heel of carotid artery stenting (CAS) (1,2). Although the occurrence of periprocedural events has been minimized by the use of embolic protection devices (EPDs), particularly when tailored to specific anatomic and clinical characteristics (3), large-scale clinical data indicate that post-procedural ipsilateral strokes still account for a significant proportion of all CAS-related adverse events (1,2), a phenomenon that has been related to plaque protrusion through the struts of conventional (i.e., single-layer) carotid stents (4).
The risk for post-procedural adverse cerebral events has been supposed to be linked to the size of the carotid stent free cell area, suggesting a possible role of carotid stent design on CAS outcome (5,6). The need for increased plaque coverage to decrease the risk for debris dislodgement through the stent struts has resulted in the development of a new generation of dual-layered mesh-covered carotid stent systems (DLS). These devices basically consist of novel thin-strut nitinol stents combined with mesh covering (which can be made of nitinol or of polyethylene terephthalate). This design allows the device to trap and exclude thrombus and/or plaque debris in order to prevent embolic events from the target lesion (7).
Several clinical studies evaluating these devices demonstrated safety and suggested clinical efficacy (8–12). Unfortunately, these studies are not sufficiently powered to test for device-related and clinical endpoints, and no randomized comparison between the 2 available devices have been reported yet.
The aim of this patient-based meta-analysis is to report the clinical efficacy of DLS in clinical practice.
Study design and patients
A systematic review of published research on the use of DLS for CAS was conducted in accordance with the guidance and reporting items specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement (13). A computerized search was performed to identify all relevant publications from PubMed and Embase. The following keywords or terms were used: “carotid angioplasty,” “carotid stent,” “carotid stenosis,” “CAS,” “dual layer stent,” “mesh-stent,” “Roadsaver/Casper” (Terumo, Tokyo, Japan), and “CGuard” (InspireMD, Boston, Massachusetts).
Only full-length published studies were considered for inclusion in the meta-analysis. Databases were last accessed on May 30, 2018. In addition to the computerized search, we manually reviewed the bibliographies of all included papers to ensure complete inclusion of all possible studies. Only prospective studies including population cohorts larger than 100 patients were included. Figure 1 shows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram. To date, 4 single-arm prospective studies meeting the inclusion criteria have been published (9–12). Access to anonymized patient-level data was granted from the investigators of these 4 studies. Data on baseline patient characteristics, procedural information, and clinical events were crosschecked against previous publications. Data from each of the 4 studies were pooled and analyzed in a single dataset. The local ethics committee of each participating center approved all studies, and patients provided written informed consent to participate in the trials.
A patient-level database was created by merging single study databases, provided by the studies’ coordinators, and used for the study. A total of 556 patients who underwent CAS stenting with the use of DLS (Roadsaver or CGuard) were included in the study.
The database collects data on clinical risk factors and anatomic and procedural characteristics.
For each patient, data were collected on periprocedural clinical events and at 30-day follow-up.
Inclusion criteria considered the degree of stenosis and related symptoms: 1) symptomatic stenosis of the internal carotid artery ≥50%; and 2) asymptomatic stenosis ≥80% and life expectancy >5 years.
Patients with amaurosis fugax, hemispheric transient ischemic attack, or ipsilateral ischemic stroke without major disability (Barthel Index ≤60, National Institutes of Health Stroke Scale [NIHSS] score <15, Rankin Scale score >3) were considered symptomatic if these events occurred in the 6 months before intervention.
Patients were considered at high risk if they met at least 1 of the high-risk criteria, whether clinical (age >80 years, Canadian Cardiovascular Society class III or IV angina or unstable angina, congestive heart failure [New York Heart Association functional class III or IV], left ventricular ejection fraction <30%, severe stenosis of the common coronary artery of the left or 2 or more epicardial coronary arteries, need for cardiac surgery in <30 days, recent myocardial infarction, and severe chronic lung disease) or anatomic (high cervical lesions, subclavicular lesions, previous radical neck surgery or radiotherapy treatment, restenosis after carotid endarterectomy, obstruction of the carotid contralateral, tracheostomy, and paralysis of the larynx and the contralateral nerve) (14).
All patients received dual-antiplatelet therapy at a standard dose for at least 2 days before the CAS procedure (alternatively, intraprocedural clopidogrel loading was performed). After the procedure, clopidogrel therapy was continued for at least 1 month and aspirin indefinitely. For intraprocedural anticoagulation, unfractionated heparin (70–100 IU/kg) was administered to maintain an activated clotting time >250 s.
All procedures were performed percutaneously, according to the therapeutic standard of each operating unit.
The primary endpoint was the occurrence of stroke at 30 days; secondary endpoints were technical and procedural success, the occurrence of periprocedural stroke, and in-hospital and 30-day rates of death.
Technical success was defined as success of stent implantation with residual stenosis <30%. Procedural success was defined as technical success in the absence of cardiac and cerebral adverse events during the hospitalization period.
At each institution, a neurologist or NIHSS-certified physician evaluated all patients before the procedure, after the procedure, and following an event that occurred during follow-up.
Neurological complications were classified as follows: 1) minor stroke was defined as a new neurological deficit that completely resolved in 30 days or increased the NIHSS score by ≤3 points compared with the pre-procedural evaluation; and 2) major stroke was defined as a new neurological deficit that persisted for >30 days and increased the NIHSS score by ≥4 points compared with the pre-procedural evaluation.
The databases from the 4 studies were combined for an overall pooled analysis. Continuous variables are expressed as mean ± SD and were compared using the paired or unpaired Student’s t-test or Wilcoxon rank sum test as appropriate. Categorical variables are expressed as counts and percentages and were compared using the Fisher exact test or the chi-square test. Odds ratios and risk ratios to study the primary endpoint were calculated for clinical and procedural variables. A 2-sided p value <0.05 was considered to indicate statistical significance. All analyses were performed using SPSS version 23.0 (IBM, Armonk, New York).
The general and procedural characteristics of the study population (n = 556) are reported in Table 1. There is a strong prevalence of cardiovascular risk factors. Octogenarians are quite numerous (21.94% of the total), and in the vast majority of the patients (92.44%) procedures were performed with the use of EPDs.
The 2 types of stents were used in similar proportions (nearly 1:1), and technical success was achieved in all the procedures (100%). During their in-hospital stays, 6 patients experienced minor strokes; consequently procedural success was achieved in 98.93% of the patients (Table 2). No statistically significant predictors of in-hospital stroke could be observed (Table 3).
During 30-day follow-up, there was 1 death (0.17%) from myocardial infarction, and 1 additional minor stroke (0.17%) occurred in a patient treated with a Roadsaver stent. The 30-day cumulative mortality rate was 0.17% (1 patient), and the incidence of stroke, study’s primary endpoint, was 1.25% (7 patients) (Table 2). No statistically significant predictors of stroke and/or death at 30 days could be identified (Table 4). No patients were lost to follow-up.
This patient-level meta-analysis suggests the following: 1) DLS can be safely used for guideline-based treatment of symptomatic or asymptomatic extracranial carotid artery stenosis, allowing a low rate of periprocedural complications and of post-procedural adverse events by 30 days; and 2) there are no clinical, anatomic, or procedural characteristics that could be identified in relation to increased risk for peri- or post-procedural adverse events, including lack of the effect of symptomatic status on peri- or post-procedural adverse event risk.
Procedural and post-procedural cerebral ischemic events still represent the most frequent complications of endovascular carotid revascularization. Although the occurrence of periprocedural events has been reduced by the proper use of EPDs and by operator training (15), large-scale clinical data have shown that adverse neurological events in the post-procedural period still account for a significant proportion of all CAS-related neurological events (5,16).
At present, the average annual risk for post-procedural ipsilateral stroke is still quite important (i.e., 0.4%) (1,2). Events during the stent healing phase play a substantial role, and evidence suggests that they may be largely related to plaque protrusion through stent struts, which occurs in up to two-thirds of cases and is dependent not only on plaque morphology and/or symptomatic status but also stent design. In particular, the risk for post-procedural adverse cerebral events has been linked to the size of the carotid stent free cell area, suggesting a possible effect of device design on CAS outcome and proposing that increased plaque coverage could decrease the risk for debris dislodgement through the stent struts (5).
However, at present, the advantage of a closed- over an open-cell stent design has not been proved in a randomized fashion, and the lowest clinical event rates from symptomatic patients to date were observed in the CREST study, which used an open-designed stent with very large cell areas (1). Moreover, other investigators have not found a difference in CAS outcomes according to stent design (17).
The clinical need to reduce procedure-related strokes has resulted in the development of DLS. These devices consist of a thin-strut nitinol stent covered by a nitinol or polyethylene terephthalate mesh. The presence of the mesh makes it possible to achieve a minimal free cell area (500 μm2 in case of nitinol mesh and 165 μm2 in case of polyethylene terephthalate mesh). This specific stent design should allow the device to trap and exclude thrombus and plaque debris to prevent acute and late embolic events from the treated lesion (6,8).
The first series of clinical studies evaluating these devices demonstrated device safety, but (being small to moderate in size) those studies were not powered to evaluate the role of specific clinical, anatomic, and procedural risk factors on the occurrence of post-procedural adverse clinical events (8–12). The outcome of this meta-analysis, combining together the routine use of dual-layer polyethylene terephthalate or nitinol mesh-covered carotid stent systems in the clinical practice of carotid revascularization, suggests that these systems could be used in almost every CAS procedure independent of patient and procedural characteristics.
Because the use of a dual-layer stent has been advocated to reduce post-procedural cerebral embolization by reducing plaque material prolapsing between stent struts, some investigators have assessed the amount of plaque prolapsing from the struts using optical coherence tomography (4,10,18). Using a DLS, plaque prolapse occurred in less than one-tenth of patients, and in most cases, plaque material was trapped between the 2 layers of struts, thus explaining the sustained antiembolic action of the stent, which is clinically demonstrated by the lack of cerebrovascular events at 30-day follow-up (19). This effect has been confirmed by the clinical outcome of this meta-analysis and seems to be independent of the specific device used.
In the CLEAR-ROAD trial (10), almost one-half of the patients enrolled were treated without cerebral protection, but the moderate study size with a low rate of clinical events did not permit evaluation of the role of EPD use (vs. nonuse) in that study. Because none of the other studies’ protocols were liberal regarding EPD use, this meta-analysis can provide no further insights in this respect.
In this meta-analysis, no events occurred in the group of patients in which proximal EPDs were adopted, thus suggesting that the combination of proximal EPDs and dual-layered carotid stent systems could be considered a very effective approach for the endovascular treatment of extracranial carotid atherosclerosis, combining maximized intra- and post-procedural cerebral protection; this mandates further research to verify this hypothesis.
It should be noted that there was only a single post-procedural ipsilateral stroke (0.17%). This occurred in the group of patients receiving the Roadsaver stent and could be related to the fact that the differences in the design of the 2 devices, including the mesh material and mesh position in relation to the stent frame, translate into a completely different type of plaque prolapse prevention.
Finally, it must be noted that, as in many other European studies, the proportion of symptomatic patients treated in each of the studies is quite low. This aspect may have dampened the potential benefit of using dual-layer stents that could better prevent unstable plaque prolapse compared with conventional carotid stents.
A potential clinical impact of DLS design differences requires testing in a large-scale clinical trial powered for differences in clinical endpoints.
This meta-analysis was inherently limited to the evaluation of 30-day outcomes, as only such outcomes have been reported to date. Although it allows the evaluation of periprocedural (in-hospital) versus post-procedural outcomes at 30 days, potential differences in the experience of operators in the particular studies may have affected procedural outcomes.
The reported data come from single-arm prospective studies and not from randomized controlled trials, so the study findings cannot support the idea that DLS perform better in a routine clinical setting compared with the stents used in the CREST and ACT-1 trials (1,2).
Furthermore, this meta-analysis cannot rule out the problem of potential selection bias and the issue of underreporting of (minor) strokes, and the sample size is still too small to provide a definitive answer regarding predictors of clinical outcomes.
Finally, a word of caution must be added with regard to the lack of available data on long-term performance (i.e., restenosis and thrombosis rates) of dual-layered stents.
Consequently, information derived from this study should be considered hypothesis generating for future large-scale clinical trials.
The present meta-analysis suggests that the use of carotid DLS can make it possible to achieve a low rate of periprocedural adverse events and near elimination of post-procedural adverse events independent of clinical, anatomic, and procedural characteristics. This is consistent with the supposed embolic prevention efficacy of the DLS during the stent healing phase and might eventually result in a clinically relevant benefit in relation to conventional carotid stents.
WHAT IS KNOWN? The risk for post-procedural adverse cerebral events has been linked to the size of the carotid stent free cell area, indicating a significant impact of carotid stent design on CAS outcome. The need for increased plaque coverage to decrease the risk for debris dislodgement through the stent struts has resulted in the development of DLS, able to trap and exclude thrombus and/or plaque debris to prevent embolic events from the target lesion.
WHAT IS NEW? Several small clinical studies evaluating these devices have recently been reported. In this patient-level meta-analysis, including 4 studies enrolling more than 100 cases of CAS with DLS, both procedural complications and 30-day stroke and death rates were very low, thus demonstrating that DLS can be safely used for CAS and that their use makes it possible to combine the incremental risk related to symptomatic status and other risk factors.
WHAT IS NEXT? These data should be considered hypothesis generating to inform the design of large-scale clinical trials to definitively prove the relative role of this modern endovascular technique of carotid revascularization and contemporary medical therapy to prevent stroke in patients with significant carotid artery stenosis.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- carotid artery stenting
- dual-layered mesh-covered carotid stent system(s)
- embolic protection devices
- National Institutes of Health Stroke Scale
- Received December 30, 2017.
- Revision received June 6, 2018.
- Accepted June 26, 2018.
- 2018 American College of Cardiology Foundation
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