Author + information
- Received May 24, 2018
- Revision received November 20, 2018
- Accepted November 28, 2018
- Published online February 18, 2019.
- Ralf Langhoff, MDa,∗ (, )
- Joachim Schofer, MDb,
- Dierk Scheinert, MDc,
- Andrej Schmidt, MDc,
- Gerald Sedgewick, BAd,
- Elizabeth Saylors, MSce,
- Ravish Sachar, MDf,
- Horst Sievert, MDg,h and
- Thomas Zeller, MDi
- aDepartment of Angiology, Sankt Gertrauden Krankenhaus GmbH, Berlin, Germany
- bDepartment of Cardiology, Medical Care Center Prof. Mathey, Prof. Schofer, Hamburg, Germany
- cClinic for Angiology, University Hospital Leipzig, Leipzig, Germany
- dImaging and Analysis, LLC, St. Paul, Minnesota
- eContego Medical, LLC, Raleigh, North Carolina
- fHeart and Vascular Services, UNC REX Healthcare, Raleigh, North Carolina
- gCardioVascular Center Frankfurt, Frankfurt am Main, Germany
- hAnglia Ruskin University, Chelmsford, United Kingdom
- iDepartment of Angiology, Universitats Herzzentrum Freiburg–Bad Krozingen, Bad Krozingen, Germany
- ↵∗Address for correspondence:
Dr. Ralf Langhoff, Sankt Gertrauden Krankenhaus GmbH, Paretzer Straße 12, 10713 Berlin, Germany.
Objectives This study evaluated the safety and performance of the Paladin System, a novel angioplasty balloon with an integrated embolic protection filter designed to increase embolic protection during post-dilation.
Background The risk of major adverse events during carotid artery stenting (CAS) is equivalent to carotid endarterectomy. However, the risk of minor stroke remains higher with CAS. Much of this risk occurs during post-stent dilation.
Methods A total of 106 patients were enrolled in 5 centers in Germany. The study’s primary endpoint was all-cause death, myocardial infarction, and stroke at 30 days post-procedure. Pre- and post-procedural diffusion-weighted magnetic resonance imaging evaluated new ischemic lesions in 30 subjects. Filter histomorphometric analysis was performed in 23 patients. Retrospective analyses compared outcome rates to historical controls.
Results Device and procedural success rates were 100%. The combined major adverse event rate (death, myocardial infarction, and stroke) at discharge and at 30 days was 0% and 1.0%, respectively. The single adverse event was a stroke, which occurred at day 12 and was believed unrelated to the device or procedure. New ischemic lesions were found in 11 (36.7%) patients in the diffusion-weighted magnetic resonance imaging subset. New ipsilateral lesions were seen in 9 (30.0%) patients. Mean lesion volume per patient was 0.010 cm3. Debris was present in all filters, and approximately 90% of captured particles were <100 μm.
Conclusions Use of the Paladin System for post–stent dilation during CAS appears safe, and it may effectively decrease the number of embolic particles reaching the brain, which may help reduce the risk of procedure-related stroke. (A Multi-Center Study to Evaluate Acute Safety and Clinical Performance of Paladin® Carotid Post-Dilation Balloon System With Integrated Embolic Protection; NCT02501148)
Although carotid artery stenting (CAS) has emerged as an effective alternative to carotid endarterectomy (CEA) for carotid artery revascularization, several trials have shown that the risk of minor stroke during CAS remains higher when compared with CEA (1–6). The CAS procedure can be broadly categorized into the access phase, periprocedural phase (embolic protection device [EPD] placement, pre-dilation, stent deployment, and post-dilation), and post-procedural phase. A significant portion of the risk for stroke is periprocedural, mostly occurring during the post-dilation phase among those patients needing additional stent expansion (7–10).
During post-dilation, a balloon forces the stent into the plaque at high pressure, leading to extrusion and distal embolization of atheromatous particles (upon balloon deflation) (9). With the presence of a distal EPD, the risk of embolic particles reaching the brain is reduced (9). However, the risk of ipsilateral stroke during CAS remains, especially minor stroke. Diffusion-weighted magnetic resonance imaging (DW-MRI) and transcranial Doppler data show that despite the use of EPDs, microemboli reach the middle cerebral artery in nearly every case (11,12).
There are several reasons why emboli reach the brain, despite the presence of a distal EPD. Particles smaller than the filter pore size may travel through the filter uninhibited. Size and shape mismatch between the filter and the artery may result in malapposition of the filter against the arterial wall (13,14). In some cases, the carotid anatomy necessitates filter placement in a curved segment of the vessel, resulting in malapposition. Finally, patient and filter movement during the procedure can result in transient periods of malapposition. Thus, the risk of cerebral embolization during the post-dilation phase is not completely eliminated by distal or proximal EPD use alone (15). Several centers avoid post-dilation as much as possible, and double filtration during CAS (using either 2 distal filters or 1 distal filter and proximal occlusion balloon) has been proposed to reduce this risk (16–19).
Currently available EPDs are beneficial in preventing large embolic particles from reaching the brain, but they are not effective in preventing all particles from entering the intracranial circulation. We hypothesized that increasing the degree and efficiency of embolic protection during the post-dilation phase would reduce the number of particles reaching the brain and thereby reduce the risk of stroke. Here we present the first real-world study findings of the Paladin Carotid Post-Dilation Balloon System with Integrated Embolic Protection (Contego Medical, Raleigh, North Carolina), a novel device designed to provide additional embolic protection and reduce the number of particles reaching the brain during the post-dilation phase of CAS.
A prospective, multicenter, nonrandomized observational study was performed to evaluate the safety and procedural success of the Paladin System. Following protocol approval by the local ethics committees, the Paladin System was used in 106 patients meeting study selection criteria and willing to provide written informed consent in 5 German centers from July 2015 to September 2016. Symptomatic and asymptomatic patients were treated, with the degree of stenosis (measured by visual estimate using NASCET [North American Symptomatic Carotid Endarterectomy Trial] criteria) of at least 50% for symptomatic patients and 70% for asymptomatic patients. Patients having a history of major ipsilateral stroke with residual deficit, a total occlusion of the target carotid artery, a previously placed stent in the ipsilateral carotid artery, or a >50% stenosis of the common carotid artery proximal to target lesion were not included in this study.
Clinical assessments and endpoints
The primary endpoint was 30-day occurrence of major adverse events (MAE) (all-cause death, myocardial infarction [MI], and stroke). The primary device endpoint was the technical success of the Paladin System, defined as delivery (to the target lesion), deployment, and retrieval of the device as intended per the Instructions for Use. Procedural success was defined as successful completion of the CAS procedure using the Paladin System. All patients underwent clinical and neurological examination before and after the procedure (before discharge and at 30 days) by a National Institutes of Health Stroke Scale–certified evaluator. Likewise, all patients were evaluated for procedure-associated MI by either the development of new Q waves in 2 or more leads in a post-procedure electrocardiogram (ECG) before discharge, or an elevation of creatine kinase-myocardial band levels >3 times the upper limit of normal or elevation of troponin levels greater than the MI decision limit within 24 h after the index procedure.
The Paladin System is a rapid-exchange, percutaneous transluminal balloon angioplasty catheter. Uniquely, it incorporates a nitinol-based distal embolic filter, which catches and prevents debris from being expelled when collapsed. The filter is adjustable in vivo up to 7 mm, and its filter membrane contains 40-μm pores. Radiopaque markers on the balloon and filter aid in positioning under fluoroscopy (Figure 1).
Angiography confirmed the degree of stenosis according to NASCET criteria. Lesion pre-dilation, type of carotid stent, and choice of distal or proximal primary EPD were all at the discretion of the operator. Following deployment of the stent, the operator was instructed to position the post-dilation balloon entirely within the stented segment, such that the filter was immediately distal to, and the angioplasty balloon was positioned within, the stent. The Paladin filter was then deployed, and wall apposition was confirmed angiographically. Following deflation of the balloon, the filter was collapsed, and the Paladin System was removed.
MRI and filter content analysis
Cerebral DW-MRI scans were obtained in 30 patients following CAS to assess the presence of new ischemic lesions. MR images included T1, T2, and DW-MRI, and were evaluated by an independent radiologist without knowledge of the patients’ symptom status. Each set of images was analyzed for the number, volume, and location of new ischemic lesions (post-procedure as compared with baseline). Using a method described by Sims et al. (20), lesion volume was calculated as follows: if 3 lesion dimensions were visible, the volume was determined by multiplying all 3. In cases in which only 2 dimensions were visible, the third dimension was set at 1 mm in size. If only 1 dimension was visible, the volume was calculated to be that of a sphere, using the formula V = 4/3πr3, where r (radius) was equal to the size of the lesion.
A histomorphometric analysis was performed on 46 filters from 23 patients who had a distal filter used as the primary EPD. Contents from both the Paladin System and the primary filters were analyzed by an independent emboli analysis lab. Upon receipt, each specimen was analyzed to remove nonbiological particles and red blood cells manually or via computer-aided methods. High-resolution scans determined the size and number of remaining particles, which were subsequently recorded and categorized according to length: 40 to 100 μm, 101 to 200 μm, and 201 to 400 μm.
Descriptive statistics were used to assess the overall cohort and make comparisons among subgroups. A 2-sided p value of 0.05 was used to determine statistical difference among subgroups. Continuous variables were compared by Wilcoxon or Student’s t-test; categorical variables were compared by chi-square analyses. Differences in particle counts captured by the Paladin System and primary EPD were analyzed using Student’s t-test. Correction for unequal variances was employed as appropriate.
Retrospective analyses were also performed, comparing rates of safety and clinical performance outcomes to evaluate whether results from this study fall within an acceptable margin of historical control rates using conventional stenting and embolic protection. Relevant studies were selected based on outcomes and rates of clinical performance and safety. Three safety outcomes and 1 efficacy outcome were tested against event rates derived from historical controls (death, stroke, MI, procedural success). Of note, some studies measured MAE using the 2 components of death or stroke whereas other studies used a 3-component definition of MAE consisting of death, MI, or stroke (as defined in this study). From these variable definitions, historical control rates were determined for both endpoint definitions (MAE-2 and MAE-3, respectively). The average of the ratio MAE-2/MAE-3 across studies for both definitions was used to derive a weighting factor for MAE-2 among those studies that only reported results for MAE-3, resulting in a weighted factor of 0.86 (e.g., if a study reported a MAE-3 rate of 5.0%, and no MAE-2 rate, this interpolated as 5.0% • 0.86 = 4.3%).
Angiographic and procedural results
Patient demographics are shown in Table 1. The target lesion was in the left internal carotid artery in 43.1% and in the right internal carotid artery in 56.9% of patients. Mean reference vessel diameter was 5.3 ± 0.7 mm, with an average lesion length of 14.90 ± 6.21 mm. The average pre-procedure stenosis was 83.5%, which decreased to a mean of 5.9% post-intervention. Pre-dilation was performed in 45 (42%) cases. Proximal balloon occlusion was used in 7 (6.6%) patients; distal EPDs were used in the remaining. The post-dilation balloon was inflated at a maximum pressure of 9.0 ± 2.3 atm and averaged 8.8 ± 3.8 s in duration. Most cases were completed with 1 inflation (88.3%). The Paladin System was used successfully in all cases.
Post-procedure and 30-day outcomes
Procedural success, defined as residual target lesion diameter stenosis <50% by angiography, was achieved in all patients. Device technical success was achieved in 99% (105 of 106) of patients. In 1 case, it was difficult to withdraw the Paladin System, but it was successfully withdrawn with additional manipulation by rotating the device. No damage to the filter or stent occurred, and there were no adverse procedural events associated with any case. Before discharge, 100 patients had post-procedure cardiac enzymes drawn, and post-procedure ECG was performed on 79 patients. No enzyme assays or ECG tracings demonstrated evidence of acute MI. In the 6 patients in whom cardiac enzymes were not drawn, post-procedure ECG was normal, and there was no report of chest pain or clinical evidence of myocardial ischemic events; there were no MAE reported through discharge.
At 30 days, 1 patient had withdrawn consent; no patient died, had MI, or was lost to follow-up. The 30-day primary endpoint of MAE was observed in 1.0% (1 of 105) of patients. One patient who was noncompliant with dual antiplatelet medications experienced stent thrombosis and stroke at day 12. The patient was treated with systemic thrombolytic therapy and recovered completely with a 30-day National Institutes of Health Stroke Scale of 0.
Results of the DW-MRI analysis are summarized in Table 2. New ischemic lesions were found in 11 (36.7%) patients, and new ipsilateral lesions were seen in 9 (30.0%) patients. The number of new ischemic lesions per patient was 0.53 ± 0.73. No new ipsilateral ischemic lesions were detected in any of the symptomatic patients. The mean lesion volume per patient was 0.010 cm3.
Of the 46 paired filters that underwent morphometric and histological analysis, microscopic debris was present in 100% of filters, with 95% more particles present in the Paladin System filter than in the primary filter (Figure 2). Ninety-two percent of the particles captured in the Paladin System filter were between 40 and 100 μm. Lesions were pre-dilated in 52% of filter analysis subset (12 of 23). The mean number of particles in the primary filter was not significantly higher in patients who underwent pre-dilation as compared with those who did not (1,394 vs. 1,043; p = NS). The histological particle count by size in the primary filter compared with the Paladin System filter are summarized in Table 3.
Safety and efficacy in relation to historical controls
Parallel analyses compared the results of this study to corresponding historical control rates (Table 4) using both MAE-2 and MAE-3, producing the following control rates: 30-day MAE (MAE-3) 4.9% (95% confidence interval [CI]: 4.4% to 5.5%); 30-day MAE (MAE-2) 3.7% (95% CI: 3.2% to 4.2%); 30-day stroke 3.7% (95% CI: 3.2% to 4.2%); and procedural success 98.0%. Our 100% procedural success rate was essentially identical to the historical control rate.
Considering safety outcomes and 95% CIs from the historical control studies, our 1.0% event rate (1 stroke) fits well within the CI of reported events whether considering MAE-3, MAE-2, or stroke at 30 days.
CAS has emerged as a minimally invasive alternative to CEA among patients undergoing carotid artery revascularization (5,21–24). However, CAS carries a higher risk of minor stroke while CEA carries a higher risk of MI and cranial nerve palsy (5,6,36). The highest risk of stroke is during post-dilation, despite the use of traditional wire-based distal embolic protection filters. Double filtration during post-dilation with the Paladin System may reduce the risk of minor stroke as well as in the number, size, and incidence of new DW-MRI lesions in the brain during CAS. It is encouraging that in the present study there was only 1 stroke at 30 days (likely unrelated to device or procedure), and there were no major or minor strokes at the time of the procedure through discharge. These results compare favorably with other published multicenter studies of more than 100 patients (1–6,24,36).
Filter histomorphometric analysis showed considerably more particles in the Paladin System filter than the primary filter, confirming that the majority of embolic particles are released during the post-dilation phase. Furthermore, most of the particles captured in the Paladin System filter were the smallest in size. It is plausible these particles are more efficiently captured in Paladin System filter as compared with currently available distal filters due to its smaller pore sizes and adjustable filter circumference.
MRI analysis revealed the occurrence and total number of new ischemic lesions during CAS performed with the Paladin System is lower than distal filtration systems, and appears to be in the same range as proximal occlusion systems (37,38). Mean lesion volume was very low as compared with other published data (37,39). These embolic events are significant, as a growing body of evidence correlates microembolization with a higher risk of long-term cognitive dysfunction (40–42).
In aggregate, our clinical, MRI substudy, and filter histology results suggest that as compared with CAS performed with 1 distal EPD, double filtration with the Paladin System is effective in reducing the number of microemboli reaching the brain during CAS. Additionally, as compared with historic controls we found evidence that the Paladin System may be superior regarding freedom from stroke, MI, and death at 30 days.
While not a consistent finding, several studies have shown that embolic protection using proximal occlusion strategies results in a lower periprocedural risk of stroke, and also a lower risk of new ischemic cerebral lesion by DW-MRI (43–46). However, proximal protection requires a larger arteriotomy, is more complex, and patients can develop neurological symptoms due to occlusion of flow. The Paladin study shows that double filtration with the Paladin System achieves similar clinical and DW-MRI results as proximal occlusion, without the attendant disadvantages.
The use of double filtration addresses the periprocedural risk of stroke during CAS. Some authors have suggested that post-procedural neurological events are the main contributor to the overall 30-day risk of stroke after CAS due to late protrusion and embolization of plaque through the stent struts (47). However, Kotsugi et al. (48) recently reported a low 2.6% incidence of plaque protrusion by intravascular ultrasound and angiography in a cohort of 328 patients undergoing CAS, calling into question the significance of post-procedural embolization. Indeed, if post-procedural plaque protrusion through the stent struts and embolization into the cerebral circulation was a significant contributor to the risk of 30-day stroke, then such emboli would likely be of various sizes, and thus increase the risk of major stroke at 30 days. Yet several studies have shown that there is not a higher risk of major stroke with CAS as compared with CEA (5,15,18,19). Furthermore, when proximal protection is used during CAS, there is a very low risk of post-procedural stroke and 30-day stroke (43–45). These findings suggest that most of the 30-day risk of stroke is due to inadequate embolic protection during the index CAS procedure. It is possible that some of the neurological deficits noted after the index procedure but before discharge represent late adjudication of a procedural event.
This study was not randomized, and there was no active control group to directly assess for a reduction in clinical or surrogate endpoints with the Paladin System. While the number of patients with MRI data is similar to other CAS studies that have included MRI analyses, the sample size is not sufficient to draw certain conclusions. Also, patients were not consecutively enrolled, and thus there may be a bias in the type and complexity of patients enrolled in the study.
The use of the novel Paladin Carotid Post-Dilation Balloon System with Integrated Embolic protection appears safe, and the clinical, MRI, and filter histology analyses, as well as comparison with historical controls, suggest that the system is a feasible treatment to reduce the number of embolic particles reaching the brain during CAS, hopefully reducing the risk of stroke.
WHAT IS KNOWN? Currently available EPDs are beneficial in preventing large embolic particles from reaching the brain; however, they are not effective in preventing all embolic particles from entering the intracranial circulation. MRI and transcranial Doppler data show that despite the use of EPDs, microemboli reach the middle cerebral artery in nearly every intervention.
WHAT IS NEW? In the current study, we found that use of the Paladin System for post-dilation during CAS is safe and appears to reduce the number of embolic particles reaching the brain. This is evidenced by the low clinical stroke rate, as well as by the MRI and filter histology analyses.
WHAT IS NEXT? The new Paladin System appears to be a promising addition in the field of carotid intervention, but additional studies should be conducted to further validate these results.
The authors would like to thank Jordan Bauman for his advice and recommendations on the statistical analysis of this work.
The work was funded by Contego Medical, LLC (Raleigh, North Carolina). Dr. Langhoff has served as a consultant for Biotronik, B. Braun, Kardionet, and Contego Medical; has served on the Speakers Bureau for Boston Scientific, Terumo, and Medtronic; and has received speaking honoraria from Contego Medical. Prof. Scheinert has served on advisory boards and/or as a consultant for Abbott, Bayer, Boston Scientific, Cook Medical, Cardionovum, CR Bard, Gardia Medical/Allium, Medtronic, Philips, and Upstream Peripheral Technologies. Dr. Schmidt has received consulting or speaker honoraria from Abbott Vascular, Cordis, Cook Medical, and Medtronic. Ms. Saylors is an employee of Contego Medical. Dr. Sachar is the founder and a significant shareholder of Contego Medical; has served as a consultant for Boston Scientific and Medtronic; has received research support from Medtronic, Boston Scientific, Microvention, Gore, Surmodics, and Abbott Vascular; and has served on the Speakers Bureau for Spectranetics. Prof. Sievert has received consulting fees from Abbott Vascular, Ablative Solutions, Ancona Heart, Bioventrix, Boston Scientific, Carag, Cardiac Dimensions, Celenova, Cibiem, CGuard, Comed BV, Contego Medical, CVRx, Edwards, Hemoteq, Inspire MD, Kona Medical, Lifetech, Maquet Getinge Group, Medtronic, Occlutech, pfm Medical, Recor, St. Jude Medical, Terumo, Trivascular, Vascular Dynamics, Venus, and Veryan Medical. Prof. Zeller has received honoraria from Abbott Vascular, Bard Peripheral Vascular, Biotronik, Boston Scientific, Cook Medical, Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme, VIVA Physicians GLG, Philips, and Veryan Medical; and he is a consultant for Abbott Vascular, Boston Scientific, Cook Medical, Gore & Associates, Medtronic, Spectranetics, and Veryan Medical. All other 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
- confidence interval
- diffusion-weighted magnetic resonance imaging
- embolic protection device
- major adverse event(s)
- myocardial infarction
- Received May 24, 2018.
- Revision received November 20, 2018.
- Accepted November 28, 2018.
- 2019 American College of Cardiology Foundation
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