Embolic protection devices for carotid artery stenting: better results than stenting without protection?

Ralf Zahna,*, Bernd Marka, Nikolaj Niedermaierb, Uwe Zeymera, Peter Limbourgc, Thomas Ischingerd, Klaus Haertene, Karl Eugen Hauptmannf, Enz-Rüdiger von Leitnerg, Wolfgang Kasperh, Ulrich Tebbei and Jochen Sengesa for the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte (ALKK)

a Herzzentrum, Kardiologie, Ludwigshafen, Germany
b Städtisches Klinikum, Neurologie, Ludwigshafen, Germany
c Stadtkrankenhaus, Kardiologie, Worms, Germany
d Städtisches Klinikum, Kardiologie, München-Bogenhausen, Germany
e Marienkrankenhaus, Kardiologie, Wesel, Germany
f Krankenhaus der Barmherzigen Brüder, Kardiologie, Trier, Germany
g Klinikum Siloah, Kardiologie, Hannover, Germany
h St. Josefs Hospital, Kardiologie, Wiesbaden, Germany
i Klinikum Lippe-Detmold, Kardiologie, Detmold, Germany

Received March 6, 2004; revised June 1, 2004; accepted June 10, 2004 * Corresponding author. Tel.: +49-621-503-4000; fax: +49-621-503-4002 (E-mail: erzahn{at}aol.com).


    Abstract
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 Appendix: Institutions and...
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AIMS: Carotid artery stenting (CAS) for carotid artery stenoses has become an alternative to carotid endarterectomy. However, CAS itself can cause cerebral ischaemic events. Embolic protection devices (PD) promise to reduce the incidence of these events.

METHODS AND RESULTS: From July 1996 to March 2003, 1483 patients from 26 hospitals were included in the prospective CAS Registry of the ALKK study group. A PD was used in 668 of 1483 patients (45%). The use of a PD has grown rapidly over the years and reached 100% in 2003. Patients treated with a PD had prior carotid artery dilatation more often (3.5% versus 1%, p<0.001), a prior myocardial infarction (34% versus 27.4%, p=0.007) and a history of arterial hypertension (89.9% versus 78.6%, p=0.007) compared to patients treated without a PD. A thrombus was more often visible in patients treated under distal protection (16.5% versus 8%, p<0.001). The use of a PD led to a 10-min longer intervention (45 min versus 35 min median, p<0.001). Patients treated with a PD had a lower rate of ipsilateral stroke (1.7% versus 4.1%, p=0.007) and a lower rate of all non-fatal strokes and all deaths (2.1% versus 4.9%, p=0.004) during the hospital stay. This was confirmed by multiple logistic regression analysis (adjusted OR=0.45, 95% CI: 0.23–0.91, p=0.026). A similar reduction could be found for symptomatic as well as asymptomatic carotid artery stenoses.

CONCLUSION: Since 1996 there has been a steady increase in the use of PDs for CAS, with a 100% use in 2003. The use of a PD may lower the rate of ipsilateral strokes during CAS.


    Introduction
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Symptomatic, as well as high grade asymptomatic carotid artery stenoses are associated with an increased risk of ipsilateral ischaemic events. Carotid endarterectomy (CEA) was the first intervention which showed a reduction of the risk of further ischaemic events on top of optimal medical therapy.1–6

Carotid artery balloon dilatation, and over the last few years carotid artery stenting (CAS), has become the preferred alternative to CEA in special high risk subgroups of patients.7 Its value compared to CEA for the majority of patients with carotid stenoses still remains to be determined. However, current data from a randomised controlled clinical trial comparing the two interventions are promising.8

CAS is still an evolving intervention with a rapid development of new techniques, such as specialised and miniaturised diagnostic and guiding catheters and guide wires, new stents and new adjunctive therapies. The major problem of CAS, as well as CEA is the occurrence of procedure-related cerebral ischaemic events. Cerebral embolic protection devices (PD) were introduced to reduce the risk of ipsilateral ischaemic events during CAS. There are different types of PD, such as filter systems and occlusive systems, with or without reverse flow.9–11 The concept of the PDs seems to be so persuading that they are already integrated in current clinical practice as well as in ongoing randomised controlled clinical trials comparing CEA with CAS. However, there are few data from registries and no data from randomised trials on the effect of the use of PDs compared to no PDs during CAS.12,13

To determine the use and value of PDs compared to no PD during CAS we analysed the data of the prospective Carotid Artery Stent (CAS) Registry of the German Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte (ALKK).


    Methods
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 Methods
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 Appendix: Institutions and...
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The Carotid Artery Stent (CAS) Registry of the ALKK is an ongoing registry which was initiated 1996 to document current indications and outcome of CAS as well as to improve quality of CAS by simple quality measurements.

All interventions were prospectively enrolled in the registry. All complications occurring in the catheter room and during the in-hospital phase were prospectively documented. All data from the initiation in 1996 until the end of March 2003 were analysed for this report. All data were collected prospectively and analysed centrally.

Patient selection
All patients undergoing CAS for a carotid stenosis at the participating hospitals were considered for this analysis. In symptomatic patients, with a history of an ipsilateral stroke, at least one transient ischaemic attack (TIA) or an episode of amaurosis fugax, an angiographically documented stenosis ⩾70% according to the diagnostic criteria of the North American Symptomatic Carotid Endarterectomy Trial (NASCET)3 was suggested to be an indication for an intervention. In the case of asymptomatic patients, a stenosis ⩾80% according to the diagnostic criteria of the NASCET study was suggested as an indication for an intervention, especially in the presence of contralateral occlusion, before major surgery or documented progression of the stenosis. The decision to treat a given patient was left to the treating physician. The risks and benefits of CAS were explained to the patients; an operator informed them, that they were undergoing an investigational procedure and told them about the proven efficacy of CEA in randomised trials, and offered them this treatment as an alternative.

Although intended, the CAS procedure could not be performed in 1.3% of cases because of technical failures. The following analysis is based on those patients, in whom the CAS procedure was completed.

Definitions
Amaurosis fugax was defined as a retinal ischaemia with transient monocular blindness and a transient ischaemic attack (TIA) as a focal neurological deficit that resolved spontaneously within 24 h. Stroke was defined as loss of neurological function caused by an ischaemic or haemorrhagic event with residual symptoms at least 24 h after onset; a minor stroke was diagnosed if symptoms disappeared within 1 week after onset and a major stroke if symptoms persisted for at least more than 1 week after onset.

No differentiation between ischaemic, haemorrhagic and strokes with unknown aetiology and no quantification of the severity of stroke (such as the National Institute of Health (NIH) classification)14, besides its reversibility, was made.

Endpoints were evaluated by a neurologist either immediately at the occurrence of symptoms or routinely at the end of the hospital stay. We did not separately evaluate 30-day follow-up endpoints. The combined clinical endpoint of all death and all strokes was prospectively defined as the primary endpoint.

Different angiographic appearances of the stenosis were defined as follows: (1) ulcer: an excavation at the site of the stenosis; (2) visible thrombus: a round-shaped filling defect at the stenosis site, either mobile or not mobile. Quantification of the severity of the stenosis was performed by using the NASCET method.3 The use of a quantitative angiographic measurement or simply by the naked eye was left to the discretion of the treating physician.

CAS procedure
The CAS procedure was performed according to the standard protocol of each participating centre. The ALKK is an association of cardiologists. Therefore, the "cardiological technique" to treat carotid artery stenoses was preferred, that is the use of guiding catheters and 0.014 in. guide wires with continuous pressure monitoring, as described by Satler et al.15


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Data collection
Every participating centre was committed by written consent to include each patient with CAS during the study period. The patients gave informed consent for the processing of their anonymous data. All data sheets were sent to the central data processing centre, which was initially located in Kassel. In 2002 case report forms were modified and all data were transferred to the new Karl-Ludwig Neuhaus Datenzentrum of the ALKK in Ludwigshafen.

Data analysis
Absolute numbers and percentages were computed to describe the patient population. Medians and quartiles were computed as appropriate. Categorical values were compared by chi-square test and crude odds ratios with 95% confidence intervals were computed. Continuous variables were compared by the two-tailed Wilcoxon rank sum test. Logistic regression analysis was used to analyse selection for the use of PDs. The following variables were examined: age (dichotomised to age ⩾70 and <70 years), gender, presence of thrombus, symptomatic of carotid stenosis, prior carotid intervention (CAS or surgery), case-load of the hospitals for CAS and year of inclusion. Logistic regression analyses were also used to adjust for factors influencing the combined clinical endpoint of all death and all strokes and to compute the corresponding adjusted odds ratios with confidence limits. The following variables were examined: Age (dichotomised to age ⩾70 and <70 years), gender, presence of coronary heart disease, presence of symptomatic carotid stenosis, prior carotid intervention (CAS or CEA), presence of thrombus, presence of calcified lesions, presence of a carotid ulcer, case-load of the hospitals (dichotomised to ⩽35 and >35 reported CAS/hospital) and the use of a PD. A second regression analysis on this endpoint was performed with age and the case-load as continuous variables. We used the C statistic to assess the association of predicted probabilities and observed response of each logistic regression model. P-values <0.05 were considered significant. All p-values are the results of two-tailed tests. The tests were performed using the SAS© statistical package, version 8.2 (Cary, North Carolina, USA).


    Results
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From July 1996 to March 2003, 1483 patients from 26 hospitals were included in the prospective CAS Registry. The development in the numbers of participating centres and the numbers of included patients is shown in Fig. 1. The median hospital stay from CAS until hospital discharge was 3 days (quartiles: 2–6 days).



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Fig. 1 Development of participating centres and recruitment of patients.

 
Out of these 1483 patients, 668 patients (45%) were treated using a PD. Fig. 2 shows the development in the use of the PDs over time. In the year 2003 a PD was used in 100% of interventions. The year of inclusion of the patients remained by far the most powerful predictor for the use of a PD in the logistic regression model: Wald Chi Square: 301.80, OR (95% CI) per year: 4.82 (4.04–5.76), p<0.001. Out of the group of patients with a PD, a filter system was used in 476 (71%) and an occlusive system in 181 (27%). In 11 (2%) of cases, no information was given concerning the type of PD used.



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Fig. 2 Development in the use of protection devices.

 
As shown in Table 1, there were only small differences in baseline characteristics and concomitant diseases between the patients treated with, compared to those without, a PD. Patients treated with a PD more often had prior carotid artery dilatation (3.5% versus 1%, p<0.001), a prior myocardial infarction (34% versus 27.4%, p=0.007) and a higher prevalence of arterial hypertension (89.9% versus 78.6%, p=0.007) compared to patients treated without a PD.


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Table 1. Baseline characteristics and concomitant diseases
 
Concerning the carotid lesion and interventional characteristics, we found no differences in location and degree of stenosis before intervention between the 2 groups (Table 2). However, a thrombus was more often visible in patients treated under distal protection (16.5% versus 8%, p<0.001) and the residual stenosis after the intervention was slightly higher (median 10% versus median 5% residual stenosis). The rate of pre-dilatation before the use of a PD in the PD group was 9.8%. The use of a PD resulted in a 10-min longer intervention (median 45 min versus median 35 min, p<0.001).


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Table 2. Carotid lesion and interventional characteristics
 
The following non-neurological complications were observed: false aneurysms in 0.2%, no AV fistulae, severe local bleeding (requiring surgery or extended hospital stay) in 1.4% and arterial occlusions in 0.2% of cases.

There were no major differences in the hospital medication between the 2 groups. As shown in Table 3, patients treated with a PD had a lower rate of any ipsilateral ischaemic event during the hospitals stay (4.4% versus 7.4%, p=0.016, OR=0.57, 95% CI: 0.36–0.91) and a lower rate of the combined endpoint of all non-fatal strokes and all deaths (2.1% versus 4.9%, p=0.004, OR=0.41, 95% CI: 0.22–0.77). These differences are the results of a substantial lower rate of ipsilateral stroke in patients treated with PDs (1.7% versus 4.1%, p=0.007, OR=0.40, 95% CI: 0.20–0.79). In patients with symptomatic stenoses, the rates for all non-fatal strokes and all deaths were 3.7% versus 6.0%, p=0.137 and in patients with asymptomatic stenoses the corresponding rates were 0.3% versus 3.7%, p=0.003 in favour of the use of a PD.


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Table 3. Hospital medication and hospital events
 
After adjusting for possible confounding parameters by the use of a logistic regression model the presence of a symptomatic carotid stenosis (OR=2.49, 95% CI: 1.20–5.19, p=0.014), an age ⩾70 years (OR=2.66, 95% CI: 1.28–5.53) and the use of a PD (OR=0.45, 95% CI: 0.23–0.91, p=0.026) were independent predictors of the combined endpoint of all non-fatal strokes and all deaths (Table 4). The C statistic for the analysis of the primary endpoint was 0.75. The significance of the single variables did not change if age and case-load were included as continuous variables in the logistic regression model.


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Table 4. Multivariable model of predictors of in-hospital death or stroke
 

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Major findings of the current analysis
The data of the CAS Registry of the ALKK show that PDs, which were rarely used in 1996, were integrated as a standard tool for CAS in 2003 (used in 100% of cases). Therefore the selection criteria for the use of a PD identified in our registry lose their significance in current clinical practice. The use of a PD during CAS was associated with a significant lower rate of ipsilateral stroke (1.7% versus 4.1%, p=0.007) and a lower rate of the combined endpoint of all non-fatal strokes and all deaths (2.1% versus 4.9%, p=0.004).

Need of protection devices
As it is true for carotid endarterectomy, CAS itself also carries a substantial risk of cerebral ischaemic events during and shortly after the procedure. The Carotid and Vertebral Artery Transluminal Angioplasty Study (CAVATAS) showed a 10% incidence of death or stroke after CAS, which was identical with the event rate of the surgical group.8 The patients of the CAVATAS study were recruited from 1992 to 1997. Since then there has been a rapid development in the technique and concomitant medication of the CAS procedures. Nowadays the use of self-expanding stents is standard as is the combination of aspirin with ticlopidine or clopidogrel, whenever possible before the procedure and continued for about 4 weeks after. Together with the ongoing miniaturisation of the guiding catheters, and growing experience of the investigators, these factors should contribute to lower complication rates.

However, peripheral embolisation during the procedure, especially during and shortly after the balloon dilatation remains a major problem. The introduction of protection devices,11,16 which are designed to reduce the risk of intraprocedural emboli, promised to further reduce the rate of ischaemic complications.

Selection of CAS patients to be treated with a protection device
Patients receiving a CAS procedure under distal protection were only slightly different to CAS patients not treated under distal protection. CAS patients treated with a PD more often had prior carotid artery dilatation (3.5% versus 1%, p<0.001), a prior myocardial infarction (34% versus 27.4%, p=0.007) and a higher prevalence of arterial hypertension (89.9% versus 78.6%, p=0.007) compared to patients treated without a PD. A thrombus was more often visible in patients treated under distal protection (16.5% versus 8%, p<0.001). However, the strongest independent predictor to use a PD was the year of inclusion. Our data clearly show the rapid growth in the use of PDs since 1996. In 2003, almost all CAS procedures were performed under distal protection. Therefore in 2003 there are no more predictors for the use of a PD during CAS because it is already standard therapy in clinical practice.

Effectiveness of protection devices
Initial clinical series showed the safety and feasibility of different types of PDs.9,12,17–19 The study of Al-Mubarak et al.20 demonstrated that the use of a PD during CAS reduces the rate of microembolisations as detected by transcranial Doppler.

Our registry data showed a lower ipsilateral stroke rate in patients treated under embolic protection as compared to patients not treated under embolic protection (1.7% versus 4.1%, p=0.007, OR=0.40, 95% CI: 0.20–0.79). This reduction in ipsilateral stroke rate was the main reason that the combined endpoint of all non-fatal strokes and all deaths was also lower in the PD group (2.1% versus 4.9%, p=0.004, OR=0.41, 95% CI: 0.22–0.77). A similar reduction could be found for symptomatic as well as asymptomatic carotid artery stenosis to be treated. Surprisingly, we found no reduction in the rate of ipsilateral TIAs if a PD was used. One reason for the difference in the occurrence of stroke and TIAs with a PD may be that larger emboli are more reliably prohibited with a PD, whereas smaller particles might be missed.21

There are two other analyses of the effectiveness of a PD from registry data. Wholey et al., reported on behalf of The Multi-Centre World Carotid Registry22–25 and their data suggested a 50% reduction in peri-operative stroke event rate with distal protection versus without it: 5.3% death or stroke in 6753 patients without a PD compared to 2.2% in 4221 patients with a PD. In patients with a symptomatic stenosis, the rates of the combined endpoint of death or stroke were 6% versus 2.7% and in patients with asymptomatic stenoses the rates were 4% versus 1.8%.25 However, in this analysis of a retrospective registry no comparison between the two treatment modalities was made, neither was tried to adjust for confounding parameters.

Kastrup et al.,13 performed a literature review on data of CAS with and without PDs. They analysed data on 2357 patients treated with CAS without a PD and 839 patients treated with CAS under distal protection. The combined rate of death or stroke within 30 days after the procedure was 1.8% in the PD group compared to 5.5% in the group without a PD (p<0.001).

Overall, the data of these three analyses from registry data are well in-line, suggesting a reduction of about 50% in the stroke rate by using a PD during CAS.

Most recently a clinical alert from the Endarterectomy Versus Angioplasty in Patients With Symptomatic Severe Carotid Stenosis (EVA-3S) trial was published.26 In this randomised trial comparing CEA with CAS, the safety committee stopped the inclusion of CAS patients without the use of protection devices, because of an excess of 30-day stroke rate in CAS patients treated without PDs compared to patients treated with PDs (unadjusted OR=3,9; 95% CI: 0.9–16.7); a decision which may be questionable according to the published data.27

Limitations of protection devices and limitations of registry data
PDs will not reduce the rate of ischaemic complications during CAS to zero. During a CAS procedure there are 3 time frames of risk: Phase A="diagnostic phase": passage of the aortic arch, intubation of the target vessel and introduction of the guiding catheter or sheath. Phase B="interventional phase": placement of the guide wire, PD, pre-dilatation, stent implantation, post-dilatation, recovery of the PD. Phase C="early post-intervention phase": first hour(s) after leaving the catheterisation table.

A PD is designed to reduce the risk of emboli during phase B. It cannot reduce the risks of phase A or C. On the other hand a PD may itself elevate the risk of an intervention by the need for larger catheters and by irritating the carotid artery with the basket or the balloon.12 Therefore the expected horizon of the effectiveness of a PD is a reduction but not an elimination of ipsilateral peri-procedural ischaemic complications. Furthermore contralateral strokes, as observed in 8/1483 (0.5%) of our patients, may occur during CAS, which cannot be prevented by PDs.

In the absence of a randomised controlled clinical trial comparing the use of a PD with no PD during CAS, we should be cautious in the interpretation of data from registries on the effectiveness of PDs. Although we found no influence of the case-load of the hospitals on the complication rates, it seems to be reasonable that growing experience with CAS as well as continuing development of technical equipment besides the PDs will result in lower complication rates. Roubin et al.,28 found a significant reduction of the overall 30-day minor stroke rate during CAS without protection with increasing experience in the largest single-centre registry reported today. This possible effect on outcome must be taken into account when the favourable effect of CAS with PDs is interpreted.

Limitations of the study
Since the CAS Registry of the ALKK is an observational study it is not possible to totally control for the selection of patients to be treated with one of the two therapies. Therefore this analysis suffers from the limitations faced by all registries and it is not possible to draw definitive conclusions for the mechanism responsible for the differences in short-term outcome between CAS procedure with and without distal PDs. The influence of the increasing experience in CAS, which cannot be adjusted for, may have particularly contributed to the favourable effects of the PDs.

We only obtained data until hospital discharge. Therefore it may be difficult to compare our data to 30 days outcome data of other studies. However, clinical events are extremely low after the first days of stent implantation and a recent study showed no difference in the event rate at hospital discharge compared to 30-day event rate.29

No differentiation between ischaemic, haemorrhagic and strokes with unknown aetiology was made in our registry. Also, we cannot differentiate the time of the occurrence of events according to the different phases of the stent implantation (Phase A="diagnostic phase"; Phase B="interventional phase" and Phase C="early post-intervention phase"). This analysis might be of special value, because the PDs are designed to reduce the risk of emboli during phase B. It cannot reduce the risks of phase A or C.


    Appendix: Institutions and people who participated in the ALKK CAS Registry (numbers of included patients)
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 Appendix: Institutions and...
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Stadtkrankenhaus Worms, Prof. Limbourg (234), Städt. Krankenhaus München-Bogenhausen, Prof. Ischinger (195), Marienhospital Wesel, Prof. Haerten (151), Städt. Krankenhaus Siloah Hannover, Prof. von Leitner (147), Krankenhaus Barmherzige Brüder Trier, Dr. Hauptmann (121), Klinikum Ludwigshafen, PD Dr. Zahn (82), St. Josefs Krankenhaus Wiesbaden, Prof. Kasper (77), Kath. Kliniken Essen Nord, Dr. Jaksch (68), Städt. Klinikum Osnabrück, Prof. Treese (63), Herzzentrum Duisburg, Prof. Heinrich (62), Klinikum Offenbach, Prof. Klepzig (52), Elisabeth Krankenhaus Essen, Prof. Sabin (49), Klinikum Ernst von Bergmann Potsdam, Dr. Ohlmeier (36), Krankenhaus Siegburg GmbH, Prof. Grube (32), Evangelisches. Krankenhaus Oberhausen, Dr. Oberheiden (30), Klinikum Heilbronn, Prof. Cyran (25), St. Vincentius Krankenhaus Karlsruhe, Prof. Mehmel (16), Karl-Olga-Krankenhaus Stuttgart, PD Dr. Störk (13), Klinikum Lippe-Detmold, Prof. Tebbe (10), Klinikum Hoyerswerda, Prof. Park (6), Kreiskliniken Traunstein-Trostberg, Prof. Moshage (3), Leopoldina Krankenhaus der Stadt Schweinfurt gGmbH, Prof. Seggewiß (3), Klinikum Kempten, Dr. Seidel (2), Klinikum Wolfsburg, Prof. Engberding (2), Krankenhaus Düren gGmbH, Prof. Gulba (2), Westpfalz-Klinikum GmbH Standort – Kaiserslautern, Dr. Glunz (2).


    References
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 Abstract
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 Methods
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 Results
 Discussion
 Appendix: Institutions and...
 References
 

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