Author + information
- Received March 7, 2013
- Revision received June 7, 2013
- Accepted July 3, 2013
- Published online November 1, 2013.
- Manuel N. Cano, MD, PhD∗∗ (, )
- Antônio M. Kambara, MD, PhD∗,
- Silvia J.F. de Cano, MD∗,
- Luiz Antônio Pezzi Portela, MD, PhD∗,
- Ângela Tavares Paes, PhD∗,
- J. Ribamar Costa Jr., MD∗,
- Alexandre Antônio Cunha Abizaid, MD∗,
- Samuel Martins Moreira, MD, PhD∗,
- Amanda G.M.R. Sousa, MD, PhD∗ and
- J. Eduardo Moraes Rego Sousa, MD, PhD∗
- ↵∗Reprint requests and correspondence:
Dr. Manuel N. Cano, Rua Sampaio Viana, 203 Paraiso, São Paulo 04004-000, Brazil.
Objectives This study sought to randomly compare cerebral protection with ANGIOGUARD (Cordis Corporation, Bridgewater, New Jersey) with Mo.Ma (Invatec/Medtronic Vascular Inc, Santa Rosa, California) during carotid artery stenting (CAS), using diffusion-weighted magnetic resonance imaging (DW-MRI) to detect new ischemic cerebral lesions. The number, size, and location of lesions were analyzed.
Background The choice of the type of cerebral protection during CAS is controversial.
Methods From July 2008 to July 2011, 60 patients undergoing CAS were randomized to ANGIOGUARD or Mo.Ma, distributed by chance, 30 patients for each group. All patients underwent DW-MRI before and after CAS. An independent neuroradiologist blinded to the cerebral protection used analyzed the images. Univariate and multivariate logistic models were fitted to analyze new ischemic lesions. Alternatively, a propensity score approach was used to reduce the bias due to differences between the groups. For the number of lesions, we used Poisson regression models.
Results New ischemic lesions seen on DW-MRI were present in 63.3% of the ANGIOGUARD group versus 66.7% of the Mo.Ma cohort (p = 0.787). The number of ischemic cerebral lesions per patient, when present, was significantly lower in the Mo.Ma group (a median of 6 lesions per patient vs. a median of 10 in the ANGIOGUARD, p < 0.001). Most lesions were small (<0.5 mm) and localized in the ipsilateral territory. One patient in the ANGIOGUARD group had a minor stroke during CAS (1.66%).
Conclusions New ischemic lesions seen on DW-MRI were present in both groups in >60%, but the number of lesions per patient was greater in the ANGIOGUARD group. No death or disabling stroke occurred during at least 1 year of follow-up in both cohorts.
In recent years, carotid artery stenting (CAS) has become an alternative to surgery, especially in high-risk patients (1). The CREST (Carotid Revascularization Endarterectomy vs. Stenting) trial (2) showed that carotid endarterectomy (CEA) and CAS were comparable treatments, and the differences between the methods (more infarction and cranial nerve injury with CEA and increased risk of minor ipsilateral stroke with CAS) are counterbalanced.
In the Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Unanticipated or Rare Events (CAPTURE) registry, the authors analyzed timing, location, severity, and types of strokes after protected CAS in 3,500 patients (3). Stroke occurred in 168 (4.8%) patients (4% ipsilateral and 2% major stroke). The incidence of major stroke was greater in symptomatic than in asymptomatic patients (4.6% vs. 1.6%, respectively). This registry also revealed that the majority of symptoms occurred during the procedure (22.3%) or during hospitalization (57.7%), but 20% developed after discharge, aiding in the understanding of the different mechanisms of stroke.
The use of cerebral protection devices (CPDs) during CAS began with Theron et al. (4), who placed a distal balloon occlusion system during a carotid intervention. In a meta-analysis comparing CAS and CEA (5), the authors found that the CPDs did yield significant improvements in the occurrence of disabling stroke or death after CAS in 30 days, with a lower incidence in those patients with a CPD. Additionally, Bersin et al. (6), in a meta-analysis of 2,397 patients, showed that the benefits of proximal CPD extended to various subgroups of patients undergoing CAS, including symptomatic patients and octogenarians.
In the present study, the authors aimed to compare 2 different principles of CPD during CAS, using a surrogate imaging endpoint diffusion-weighted magnetic resonance imaging (DW-MRI) to assess the effectiveness of the devices.
Study design and population
This was a prospective, randomized, open-label, single-center trial in patients with symptomatic and asymptomatic carotid stenosis who underwent CAS with a proximal or distal CPD.
From July 2008 to July 2011, 60 patients with severe carotid lesions (symptomatic and asymptomatic), with indications for CAS in whom both distal filter ANGIOGUARD (Cordis Corporation, Bridgewater, New Jersey) or proximal occlusion Mo.Ma Ultra (Invatec/Medtronic Vascular Inc, Santa Rosa, California) could be used, were selected according to the inclusion and exclusion criteria and randomized to 1 of the CPDs. Table 1 presents the main inclusion/exclusion criteria.
Four cervical vessels angiography performed before randomization allowed us to classify whether patients with tight lesions >80% had collateral circulation. When cerebral circulation ipsilateral to the lesion was visualized during angiography of the contralateral carotid artery, or when the anterior communicating artery, was opacified during angiography, we considered the presence of collateral circulation.
Plaque characteristics were analyzed regarding the location, eccentricity, the presence of an ulcer, smoothness of its surface (i.e., regular vs. irregular) eccentricity, and the degree of calcification and tortuosity. Those patients with severe angulation between the carotid internal artery and common carotid artery (tortuosity index) (7) were excluded from randomization because greater tortuosity and angulation impaired the effectiveness of using a distal ANGIOGUARD CPD as well as increased complications (8).
During the randomization period, 250 carotid stenting procedures were performed at our institution, and 67 patients met the inclusion/exclusion criteria and were enrolled in the study. During the study, 2 patients withdrew their consent to participate in the study, and in 5 patients at the time of the procedure, the operators deemed their anatomy more suitable for 1 or the other CPD, violating the inclusion criteria. These patients were excluded for the final analysis.
Randomization was performed before the beginning of the procedure and done electronically using the complex samples module of SPSS for Windows, version 19.0 (SPPS, Inc., Chicago, Illinois). Block randomization of 6 patients (3 patients for ANGIOGUARD and 3 patients for Mo.Ma) was used to ensure a periodic balance in the number of patients assigned to each group.
The study protocol was in accordance with the Declaration of Helsinki for human research and was approved by the Ethics in Research Committee of our institution. The entire supporting infrastructure for conducting the research and monitoring the patients enrolled was offered by the hospital, and all patients gave their written informed consent. There was no sponsoring for this study.
CAS was performed according to the service routine, already described by Costa (9) and Cano (16) and followed international guidelines (10,11). For uniformity of the procedure, 1 type of carotid stent was used (PRECISE PRO RX carotid stent, Cordis Bridgewater, New Jersey), the same stent that was previously evaluated in the SAPPHIRE (Stent and Angioplasty with Protection in Patients at High Risk for Endarterectomy) trial (1). For the same reason, 1 type of distal CPD was chosen (ANGIOGUARD, Cordis). At the time of recruitment, a single type of proximal CPD was available for clinical use in our country (Mo.Ma, Invatec).
All patients were pre-medicated with clopidogrel 75 mg/day and aspirin 100 mg/day, at least 3 days before the intervention. Clopidogrel was continued for at least 1 month after CAS and aspirin indefinitely. Betablockers were discontinued at least 24 h before the procedure and other medications used were at the discretion of the referring physician.
Cerebral DW-MRI was performed before and 48 h after CAS on 3-T unit (Excite HD, GE Medical Systems, Milwaukee, Wisconsin) with a head coil of 8 channels. All imaging was performed at the Hospital do Coração and analyzed by an independent neuroradiologist blinded to the CPD used.
The primary endpoint of this study was comparison of the incidence, number, size, and location of new cerebral ischemic lesions using DW-MRI in patients treated with a distal (ANGIOGUARD) versus a proximal (Mo.Ma) CPD. Secondary endpoints included device success rate and the rate of major clinical events (death, major stroke, and myocardial infarction) up to 1 year.
Patients were considered symptomatic if they had an ipsilateral neurological ischemic event within 180 days before the procedure. The procedure was considered successful when residual stenosis after CAS was ≤30% without neurological complications. The ischemic lesions were considered ipsilateral when they occurred in the hemisphere supplied by the target vessel; otherwise they were contralateral. A transient ischemic attack was defined as a temporary alteration of the blood supply to an area of the brain, resulting in a sudden and brief (<24 h, usually <1 h) decrease in brain function. Symptoms varied depending on the area of the brain affected (12). Stroke was defined as a new focal neurological deficit with symptoms and signs consistent with focal ischemia lasting >24 h with the deficit corresponding to a vascular territory. The modified Rankin Scale score >2 was used to define classification as major and as minor when the score was ≤2. A minor stroke causes a neurological deficit that resolves completely within 30 days, whereas a major stroke causes a neurological deficit that does not resolve completely within 30 days and leads to a worsening of performance of daily activities (13,14).
Categorical variables were presented as frequency and percentage and quantitative variables were summarized as mean and SD, when normally distributed, or as median and interquartile range otherwise. The groups were compared using the Student t or Mann-Whitney test and the Pearson chi-square or Fisher exact test for numerical and categorical variables, respectively. To control the influence of confounding factors on the presence of new cerebral ischemic lesions, we used 2 approaches: conventional covariance analysis by simple and multiple logistic regression models (univariate and multivariate) (15) and propensity scores (16).
The multivariate model included variables with p < 0.10 in the univariate analysis and those with significant (or marginal) differences between groups. The same variables were selected for a logistic regression with group as a dependent variable to estimate the probability that a patient would be assigned to the ANGIOGUARD or Mo.Ma CPD. Inverse estimated probabilities (propensity scores) were used as individual weights in a weighted logistic regression model. Alternatively, the propensity score was included as a covariate in the unadjusted regression model.
For the number of new ischemic lesions (total and ipsilateral), we used the Poisson regression model (17). The propensity score approach (as a weighted model or as a covariate) was also applied.
The level of significance was p = 0.05. The statistical programs used were SPSS for Windows, version 19.0 (SPPS, Inc., Chicago, Illinois) and R software version 16.0 (R Foundation for Statistical Computing, Vienna, Austria).
Between July 2008 and July 2011, 60 patients were randomized to receive either an ANGIOGUARD or Mo.Ma CPD.
Clinical and angiographic characteristics of the enrolled patients are summarized in Table 2. The majority of patients were male (67%), and >20% in both groups had undergone a previous carotid intervention (7 [23%] patients in the ANGIOGUARD group vs. 6 [20%] in the Mo.Ma group, p = 0.753). Most previous carotid interventions (12 of 13) were performed in the contralateral carotid artery. Also, previous coronary revascularization was performed in 25% of the total number of study patients with no significant difference between groups (30% of the patients with distal CPD vs. 20% of the patients with proximal CPD [p = 0.371]).
The groups were also similar with regard to the lesion characteristics, except for the amount of calcified lesions, which were more prevalent in the ANGIOGUARD cohort (p = 0.004). Of the total study population, 22 (36.7%) patients had bilateral carotid lesions, equally divided in both groups.
DW-MRI performed before the procedure found no difference between the groups with regard to cerebral atrophy, leukoaraiosis, or the presence of previous cerebral microinfarction (Table 3).
The number of old infarcts per patient ranged from 1 to 9 in the ANGIOGUARD group and from 1 to 7 in the Mo.Ma group. Regarding the size of the old infarcts, most were <1.5 cm (90.5% in ANGIOGUARD and 74.4% in Mo.Ma). All 15 patients with a previous stroke (7 Mo.Ma, 8 ANGIOGUARD) were classified according to both modified Rankin Scale score and Barthel Index of Activities of Daily Living score, and most of them had no significant disability and were able to carry out all usual activities, with a modified Rankin Scale score between 0 and 1, and in five patients a score of 2; the Barthel Index score of all 15 patients was 100 points before CAS.
Only 1 patient in the ANGIOGUARD group and 2 in the Mo.Ma cohort had acute hyperintense Cerebral images on DW-MRI that probably occurred because of particles released either during or after diagnostic carotid angiography done a few days before CAS or spontaneously, although the patients remained completely asymptomatic.
Carotid angioplasty results
Clinical and procedural successes were achieved in 98.3% of the patients; 1 patient experienced a minor stroke during the procedure. In all of the patients, it was possible to complete CAS with the CPD according to randomization. There was no crossover between groups. Despite randomization, in the ANGIOGUARD group, a greater proportion of patients, the left carotid artery was treated (60% vs. 33% in the Mo.Ma group), with statistical significance (p = 0.038) (Table 4).
The procedure duration tended to be longer in the Mo.Ma group (29.5 min) compared with the distal CPD cohort (Δ24.2 min, p = 0.051).
There were no immediate deaths or major strokes. There were a low incidence of other complications, such as hypotension and bradycardia, and no statistical difference between groups. One patient (1.66%) required vascular surgery to stop bleeding at a puncture site. There was a late retinal infarction in a patient in the ANGIOGUARD group, and a patient with hyperperfusion syndrome in the Mo.Ma group, both of whom recovered quickly.
Results of DW-MRI after CAS
The findings of DW-MRI after CAS are shown in Table 5. The incidence of new microischemic lesions did not differ between groups (63.3% for the ANGIOGUARD group vs. 66.7% for the Mo.Ma group, p = 0.787).
CPD analysis according to the subgroups of interest did not point to any significant difference between the devices. However, when the number of new lesions per patients was analyzed, there was a statistically significant association between symptoms and the number of new lesions. Symptomatic patients had a greater number of lesions, with a significant p value = 0.001 for the whole group and for those with a the ANGIOGUARD CPD, and less significance with the Mo.Ma CPD (p = 0.039).
The majority of the new lesions were <0.5 cm, and >70% of the lesions were in a cortical location. There were no differences between groups with respect to lesion size (p = 0.950), anatomic location (p = 0.360), and vascular distribution (p = 0.915).
The total number of lesions seen on DW-MRI was significantly higher among patients with a distal CPD (424 lesions/19 patients vs. 167 lesions/20 patients in the Mo.Ma cohort, p < 0.001) as well as the number of lesions per patient (a median of 10 in the distal CPD group vs. a median of 6 in the proximal CPD group, p < 0.001). Overall, most new lesions were ipsilateral (>90% in both groups).
There were no independent predictors of acute ischemic event among these patients, regardless of the statistical model or correction (propensity score) applied.
Our results showed that regardless of the CPD used during CAS, new cerebral lesions developed in >60% of patients as seen on DW-MRI, but the number of lesions per patient was greater in the ANGIOGUARD group. Fortunately, most DW-MRI–detected embolizations did not have immediate clinical translation, even though the effect on cognitive function is still debated (18). The majority of lesions (>90%) were smaller (<0.5 mm). There was no major stroke or death during hospitalization and at least 1 year of follow-up.
The recently published PROFI (Prevention of Cerebral Embolization by Proximal Balloon Occlusion Compared to Filter Protection During Carotid Artery Stenting) trial (19), which also compared distal and proximal protection during CAS (n = 62), showed a higher incidence cerebral ischemic events after the use of a distal filter (87.1% vs. 45.2%, p = 0.001). Although in our study the number of ischemic events was insufficient to determine the difference between the groups, the number of particles per patient undergoing CAS was significantly lower in the proximal CPD group than in the distal CPD group (167 in 20 patients vs. 424 in 19 patients, respectively), which is in accordance with the PROFI trial findings, which also pointed to a significant reduction in the incidence, number, and volume of new cerebral ischemic lesions in patients who underwent CAS with a proximal balloon as compared with distal (filter) protection.
As previously demonstrated, microparticles embolized during CAS might be generated during all of the steps of the procedure. Montorsi et al. (20) compared the frequency of microparticles generated during CAS with the proximal Mo.Ma CPD and the distal FilterWire EZ Embolic Protection System (Boston Scientific, Natick, Massachusetts) in lipid-rich atherosclerotic plaques by transcranial Doppler imaging during the various phases of stenting: 1) lesion wiring; 2) pre-dilation; 3) stent crossing; 4) stent deployment; 5) stent dilation; and 6) device retrieval/deflation. The authors reported fewer signals (microembolic signals) detected by transcranial Doppler imaging in the Mo.Ma group compared with FilterWire EZ Embolic Protection System group in phases 3, 4, and 5 (27% vs. 100%, p < 0.0001) and higher in phase 6 (8.5% vs. 2%, p = 0.0036) with no difference in phase 2. Patients in the Mo.Ma group had a decrease in the number of microembolic signals compared with the FilterWire EZ, with statistical significance in patients with high-risk, lipid-rich plaque undergoing CAS.
In our study, ipsilateral lesions after CAS were observed in 395 of 424 patients (93%) with the ANGIOGUARD CPD and 145 of 167 patients (87%) with the Mo.Ma CPD. The presence of ipsilateral lesions can be attributed to the release of particles from the treated plaque during CAS. Stojanov et al. (21) assessed the correlation between carotid plaque composition and the risk of distal embolization during CAS. They studied a group of 50 patients using a distal CPD filter. Plaque morphology was differentiated by sonography as fibrolipid or fibrocalcific. They found 14.89% of new lesions on DW-MRI, 8.51% in the ipsilateral territory, and those with fibrolipid plaques had significantly more new lesions compared with fibrocalcific plaques (p = 0.041). The absolute risk of new lesions in the fibrolipid group was 18.18%. Most of the patients with lesions had no clinical symptoms, and no significant relationship was found between new lesions and factors related to CAS.
The source of contralateral lesions was described by Barbato et al. (22), who showed that the occurrence of microemboli during CAS was not prevented by the use of distal filter, and in one fifth of patients, embolization occurred in the contralateral hemisphere. They found a correlation between age, increasing amount of calcium in the aortic arch, and the presence of aortic arch type II and the occurrence of new lesions. Other previous studies have also shown that both aortic arch anatomy and a tortuous carotid artery proximal to a plaque significantly increased the risk of technical failure and neurological complications during CAS (7,23).
Major technical and technological advances are taking place with the introduction of appropriate dedicated stents, better patient selection, improvement in physicians expertise and new cerebral protection devices (24). Even though we believe that CPDs have made a great contribution to the development of carotid intervention, we cannot forget that CAS still has the inherent risk of potential stroke.
The relatively small sample size might preclude definite conclusions about the efficacy of the tested devices in this clinical scenario. Also, only 2 types of CPDs were tested, and, therefore, the results do not apply to the various proximal and distal CPDs currently available.
New ischemic lesions seen on DW-MRI were present in >60% of both groups, but the number of lesions per patient was greater in the ANGIOGUARD than in the Mo.Ma cohort. There were no deaths or disabling strokes in the one-year follow-up of the entire population.
All authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- carotid artery stenting
- carotid endarterectomy
- cerebral protection device
- diffusion-weighted magnetic resonance imaging
- Received March 7, 2013.
- Revision received June 7, 2013.
- Accepted July 3, 2013.
- American College of Cardiology Foundation
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