Abstract: Background. Use of the dual-filter cerebral embolic protection (CEP) device has been linked to a lower stroke rate in patients undergoing transfemoral transcatheter aortic valve replacement (TAVR). Captured debris is found in almost every filter. The impact of repositioning on number and area of captured debris has not been studied. Methods. Consecutive patients (n = 200) undergoing transfemoral TAVR with double-filter CEP device were included. A total of 400 filters were analyzed. Histopathologic assessment and histomorphometric analyses of debris were compared for TAVR procedures with vs without repositioning. Analyses were differentiated by particle size, particle count, and total particle area. Results. Repositioning was used in 23/200 TAVR procedures (11.5%). Baseline data including sex, diabetes mellitus, and predilation were similar between patients with and without repositioning. Repositioning was associated with a significantly higher number of embolized debris (349 ± 326 vs 509 ± 495; P<.04) and larger debris area in both filters (15.56 ± 22.13 mm² vs 38.9 ± 25.57 mm²; P<.001) when compared with patients with no valve prosthesis repositioning. Periprocedural stroke rate was statistically not different between the two groups (0.0% vs 2.8%; P=.41), with use of CEP in all patients. Renal failure occurred significantly more often with repositioning of the TAVR prosthesis (8.7% vs 1.7% in patients without repositioning; P<.05) due to a significantly higher volume of contrast (139 ± 181 mL in patients with valve repositioning vs 85 ± 35 mL in patients without valve repositioning; P<.001). Conclusions. Repositioning of the valve prosthesis during TAVR is associated with a larger number and higher total area of embolized debris captured with the dual-filter CEP device.
J INVASIVE CARDIOL 2019;31(10):282-288. (Epub 2019 August 15).
Key words: debris, embolic protection, stroke, TAVR
Periprocedural stroke during transfemoral transcatheter aortic valve replacement (TAVR) is a major complication with a tremendously negative impact on morbidity and mortality.1-7 The brain may be protected by use of a double-filter cerebral embolic protection (CEP) device.8-10 Use of a double-filter device during transfemoral TAVR was associated with a lower lesion volume on cerebral magnetic resonance imaging.9,11-13 In addition, clinically overt strokes were reduced from 8.2% in transfemoral TAVR patients without CEP to 3.0% in patients undergoing protected transfemoral TAVR with CEP within the first 72 hours post valve implantation (P=.05).14 Recent data from large registries and a meta-analysis demonstrated a lower risk of periprocedural stroke in transfemoral TAVR patients with use of CEP compared with patients undergoing transfemoral TAVR without CEP.10,15-17
The embolized debris captured by the two filters was histologically analyzed. Debris was found in the filters in up to 99% of patients.9,18-20 The size of captured debris and the number of particles may serve as a surrogate marker for risk of stroke in patients undergoing transfemoral TAVR. Particles >1 mm were found in 53% of patients,19 with some debris up to 9 mm in diameter.21 Recently, the United States Food and Drug Administration approved the Sentinel Cerebral Protection System (CPS; Boston Scientific).22
Different valve types can be used to treat severe aortic stenosis (AS) by transfemoral TAVR. In order to improve the acute outcome with respect to paravalvular leakage and atrioventricular block, the majority of the present implanted valve types can be partly or even completely repositioned. This repositioning feature has been used in 23.8%,23 25.8%,24 29.2%,25 and up to 60.8% of patients.26
The impact of repositioning on clinical overt stroke has been controversial,26,27 and has not been studied by histological analysis of captured debris.18,19,21 The aim of this study was therefore to evaluate the impact of repositioning on embolic debris captured with the dual-filter Sentinel CPS in patients undergoing transfemoral TAVR.
Patient selection. We analyzed the embolized debris captured with the Sentinel CPS by histopathology and histomorphometry with respect to repositioning during the TAVR procedure in 200 consecutive patients. Patients were treated with the following devices: CoreValve Evolut/Evolut R valve (Medtronic), Lotus valve (Boston Scientific), or Sapien 3 valve (Edwards Lifesciences). The Evolut/Evolut R and Lotus valves feature a repositioning option. The Sentinel CPS is a dual-filter, intraluminal CEP device inserted through a 6 Fr sheath introduced via the right radial, ulnar, or brachial artery prior to passage of any other device across the aortic arch. The proximal filter consists of a radiopaque nitinol frame with a 140 µm pore polyurethane filter that is positioned in the brachiocephalic trunk.
TAVR procedures were performed transfemorally, as described elsewhere.10 The protocol complied with the Declaration of Helsinki and was approved by the local ethics committee (clinicaltrials.gov identifier, NCT02162069). Written informed consent was obtained from all patients. Baseline data included age, sex, Society of Thoracic Surgeons (STS) score, diabetes mellitus, body mass index, renal insufficiency, history of atrial fibrillation, coronary artery disease, history of percutaneous coronary intervention or cardiac surgery, history of stroke or transient ischemic attack, chronic lung disease, history of myocardial infarction, porcelain aorta, aortic valve area index, and mean aortic valve gradient. The interdisciplinary heart team made the decision for transcatheter approach.
Grossing and processing. A total of 400 filters (200 proximal and 200 distal) from the dual-filter Sentinel device containing embolic debris captured during transfemoral TAVR were fixed in 10% neutral buffered formalin and shipped to CVPath Institute.8 Each filter was digitally photographed with the EOS Rebel Xsi (Canon) prior to any physical alteration. The samples were carefully opened using scissor blades and all contents were removed and then filtered through a 40 µm nylon cell strainer (Falcon). The material collected by the cell strainer was photographed again, then carefully folded and placed in a Shandon nylon biopsy bag (Fisher Scientific), which was then transferred to an appropriately barcode-labeled biopsy cassette and submitted for processing. Samples were processed in a graded series of ethanol and xylene (Tissue-Tek VIP 6; Sakura) and embedded in paraffin. Each paraffin block was serially cut at 4 to 5 microns, with two consecutive sections affixed per charged slide. Slides from each sample were stained with hematoxylin and eosin (H&E) and Movat pentachrome (MP) stain. The first, sixth, and twelfth slides cut were stained with H&E, and the second and seventh slides cuts were stained with MP.
Histological analysis and histomorphometry. Each sample was evaluated for the presence of thrombus (acute vs organizing) and its composition, determined by including presence of platelets, red blood cells, inflammatory cells, necrotic core, foamy macrophages, calcification, valve tissue, arterial wall, collagenous tissue, foreign material, and myocardium. These values and all combinations were recorded and reported for both filters separately.
In histomorphometric analysis, particle size (<150 µm, 150 to <500 µm, 500 to <1000 µm, 1000 to <2000 µm, and ≥2000 µm), number of particles, and total particle area were automatically measured.
Statistical analysis. Categorical parameters are presented as counts and percentages and were compared by Pearson’s Chi-square test and the Fisher’s exact test, as appropriate. Continuous variables are presented as mean ± standard deviation and were analyzed with t-test or Wilcoxon test. A P-value <.05 was considered to be statistically significant and tests were two-sided. Statistical analysis was performed using Statistica (StatSoft).
Out of 200 consecutive patients undergoing transfemoral TAVR with the Sentinel CPS device, a total of 23 patients (11.5%) had valve repositioning and 177 patients (88.5%) had no valve repositioning during TAVR. Baseline data of patients with and without device repositioning were similar (Table 1). There were no statistical differences with respect to predilation, postdilation, activated clotting time, and need for additional percutaneous coronary intervention (Table 2). The amount of contrast was significantly higher in patients with repositioning (Table 2), with a subsequent significantly higher rate of renal failure. In the 200 patient population There was no difference in periprocedural clinical stroke rate between the two patient groups (2.8% in the 177 patients without repositioning vs 0.0% in the 23 patients with repositioning).
Histopathology and histomorphometry. Histopathological data are based on 394 filters and histomorphometric data are based on 400 filters. Histopathological analyses stratified by the proximal filter, distal filter, and both filters are shown in Figure 1. Calcification, foreign material, and myocardium were more often observed in the embolized debris of the patients with valve repositioning (Figure 1).
Total object area was significantly larger in the group with valve repositioning vs the group without repositioning, both for the proximal filter placed in the brachiocephalic trunk and in the distal filter placed in the left common carotid artery (Table 3). Detailed analysis of particle sizes (<150 µm, 150 to <500 µm, 500 to <1000 µm, 1000 to <2000 µm, and ≥2000 µm) showed significantly more particles in patients with valve repositioning vs patients with no valve repositioning for almost every particle size group (Figure 2).
Number and area of particles seen in the proximal and distal filter were also summarized. Again, the total area of embolized debris (Table 4 and Figure 3), number of embolized particles (Table 4), and detailed analysis of particle sizes consistently demonstrated significantly higher numbers in patients with valve repositioning vs patients with no valve repositioning.
Repositioning of the valve prosthesis during TAVR is associated with a significantly larger number and greater area of embolized particles based on 400 analyzed filters derived from the Sentinel dual-filter CPS. In addition, repositioning was associated with a higher degree of calcification, foreign material, and myocardium in the captured debris. In this population of 200 TAVR patients, the rate of periprocedural stroke was similar between patients with valve repositioning versus patients without valve repositioning.
There are only a few data from histopathological and histomorphometric analyses of captured debris using a dual-filter CEP device, with no focus on repositioning to date.18-21 In an early experience by van Mieghem et al,21 captured debris was seen in 63% of patients, with the largest particle 9 mm in diameter. In a study of 322 filters,20 debris was found in 97% of patients with no difference between the proximal filter placed in the brachiocephalic trunk and the distal filter placed in the left common carotid artery. The authors found female sex (odds ratio, 1.364) and diabetes mellitus (odds ratio, 1.474) to be significant predictors for embolized debris. In addition, valve tissue embolized more often in patients with predilation. In the present study including 400 filters, the baseline data (including sex, diabetes mellitus, and predilation) were not statistically different between patients in the two study groups. However, the number and area of the embolized particles were significantly higher in the group with valve repositioning. Although the occurrence of periprocedural clinical stroke in the 200 patients in our study was statistically not different in the two groups, the impact of repositioning on clinical stroke has been controversially discussed based on TAVR studies without the use of a CEP device.26,27 Based on our data, repositioning during TAVR is associated with significantly more and larger embolized particles.
In a 246-patient study on embolized debris with the dual-filter Sentinel CPS, the authors found significantly larger particles with use of self-expandable and mechanically implantable valves (with repositioning feature) compared with balloon-expandable valves without the option of repositioning.19 The impact of repositioning was not addressed by the authors. In addition, particle count, total particle area, and maximum largest dimension were significantly higher in self-expandable and mechanically implantable valves compared with balloon-expandable valves,19 which could have been influenced by use of the repositioning feature. In a previous analysis of 200 filters, we were able to demonstrate that area and number of captured particles were lower with a mechanically implantable valve compared with self-expandable or balloon-expandable valves.18 The repositioning feature with a mechanically implantable valve might put less shear stress on the calcified annulus than the implantation of a balloon-expandable device or a self-expandable device. In our present analysis, repositioning was only used in 11.5% of 200 consecutive patients. Although we show that repositioning is associated with a significantly higher number and larger area of captured debris, this feature allows the elimination of relevant paravalvular regurgitation, which has been linked to a higher mortality rate in TAVR patients.28 The observed higher number and area of embolized particles with repositioning should not be used as an argument against repositioning in order to eliminate paravalvular regurgitation and to receive an optical hemodynamic result after TAVR.
Our study population of 200 patients was too small to demonstrate a clinical impact on stroke from device repositioning. However, all of our patients were protected with the dual-filter Sentinel device, which could have eliminated a potential negative impact of repositioning in our study population. In addition, very small particles may pass the filter and we did not protect the left vertebral artery with an additional filter. A complete filter-based CEP with protection of all arteries supplying the brain showed captured debris in every artery.29 CEP has been routinely used in all TAVR patients at our institution since 2016. The randomized Sentinel trial has demonstrated a trend toward a lower stroke rate within the first 72 hours post procedure. In a large patient-level meta-analysis including two randomized trials and large registry data,30 we were recently able to show a significant reduction in periprocedural stroke and the combined endpoint of mortality and stroke within 48 hours post procedure. There is no independent predictor to identify a patient at a higher risk of stroke.10 The only independent predictor of a patient being stroke free was the use of a CEP device, justifying the higher costs of its routine use in clinical practice with all valve types.
Almost all modern TAVR prostheses include a repositioning feature to enable optimal valve positioning. Future studies have to address whether repositioning with modern valve types is associated with an increase in cerebral ischemia and whether the use of dual-filter CEP devices in patients with device repositioning is also effective in reducing clinical stroke rate.
Study limitations. This is a single-center experience. Only 400 filters were analyzed, which represents the largest number of analyzed filters so far. The number of patients was limited to 200. The results are confined to the dual-filter Sentinel CPS device and cannot be translated to other CEP devices.31-33
Valve repositioning during TAVR is associated with a larger number and higher total area of embolized debris captured with a dual-filter CEP device.
1. Bernick C, Kuller L, Dulberg C, et al. Cardiovascular Health Study Collaborative Research Group. Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. Neurology. 2001;57:1222-1229.
2. Fairbairn TA, Mather AN, Bijsterveld P, et al. Diffusion-weighted MRI determined cerebral embolic infarction following transcatheter aortic valve implantation: assessment of predictive risk factors and the relationship to subsequent health status. Heart. 2012;98:18-23.
3. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol. 2007;6:611-619.
4. Eggebrecht H, Schmermund A, Voigtländer T, et al. Risk of stroke after transcatheter aortic valve implantation (TAVI): a meta-analysis of 10,037 published patients. EuroIntervention. 2012;8:129-138.
5. Mastoris I, Schoos MM, Dangas GD, Mehran R. Stroke after transcatheter aortic valve replacement: incidence, risk factors, prognosis, and preventive strategies. Clin Cardiol. 2014;37:756-764.
6. Steinvil A, Benson RT, Waksman R. Embolic protection devices in transcatheter aortic valve replacement. Circ Cardiovasc Interv. 2016;9:e003284.
7. Freeman M, Barbanti M, Wood DA, Ye J, Webb JG. Cerebral events and protection during transcatheter aortic valve replacement. Catheter Cardiovasc Interv. 2014;84:885-896.
8. Haussig S, Mangner N, Dwyer MG, et al. Effect of a cerebral protection device on brain lesions following transcatheter aortic valve implantation in patients with severe aortic stenosis: the CLEAN-TAVI randomized clinical trial. JAMA. 2016;316:592-601.
9. Kapadia SR, Kodali S, Makkar R, et al. SENTINEL trial investigators. Protection against cerebral embolism during transcatheter aortic valve replacement. J Am Coll Cardiol. 2017;69:367-377.
10. Seeger J, Gonska B, Otto M, Rottbauer W, Wöhrle J. Cerebral embolic protection during transfemoral aortic valve replacement significantly reduces death and stroke compared with unprotected procedures. JACC Cardiovasc Interv. 2017;10:2297-2303.
11. Bagur R, Solo K, Alghofaili S, et al. Cerebral embolic protection devices during transcatheter aortic valve implantation: systematic review and meta-analysis. Stroke. 2017;48:1306-1315.
12. Giustino G, Mehran R, Veltkamp R, et al. Neurological outcomes with embolic protection devices in patients undergoing transcatheter aortic valve replacement: a systematic review and meta-analysis of randomized controlled trials. JACC Cardiovasc Interv. 2016;9:2124-2133.
13. Wang N, Phan K. Cerebral protection devices in transcatheter aortic valve replacement: a clinical meta-analysis of randomized controlled trials. Thorac Dis. 2018;10:1927-1935.
14. Kapadia SR. Routine use of embolic protection during transcatheter aortic valve replacement. JACC Cardiovasc Interv. 2017;10:2304-2306.
15. Mohananey D, Sankaramangalam K, Kumar A, et al. Safety and efficacy of cerebral protection devices in transcatheter aortic valve replacement: a clinical end-points meta-analysis. Cardiovasc Revasc Med. 2018;19:785-791.
16. Testa L, Latib A, Casenghi M, et al. Cerebral protection during transcatheter aortic valve implantation: an updated systematic review and meta-analysis. J Am Heart Assoc. 2018;7:e008463.
17. Schäfer U. Safety and efficacy of protected cardiac intervention: clinical evidence for Sentinel cerebral embolic protection. Interv Cardiol. 2017;12:128-132.
18. Seeger J, Virmani R, Romero M, et al. Significant differences in debris captured by the Sentinel dual-filter cerebral embolic protection during transcatheter aortic valve replacement among different valve types. JACC Cardiovasc Interv. 2018;11:1683-1693.
19. Schmidt T, Leon MB, Mehran R, et al. Debris heterogeneity across different valve types captured by a cerebral protection system during transcatheter aortic valve replacement. JACC Cardiovasc Interv. 2018;11:1262-1273.
20. Schmidt T, Akdag O, Wohlmuth P, et al. Histological findings and predictors of cerebral debris from transcatheter aortic valve replacement: the ALSTER experience. J Am Heart Assoc. 2016;5:e004399.
21. Van Mieghem NM, El Faquir N, Rahhab Z, et al. Incidence and predictors of debris embolizing to the brain during transcatheter aortic valve implantation. JACC Cardiovasc Interv. 2015;8:718-724.
22. Rogers T, Alraies C, Torguson R, Waksman R. Overview of the 2017 US Food and Drug Administration circulatory system devices panel meeting on the Sentinel cerebral protection system. Am Heart J. 2017;192:113-119.
23. Manoharan G, Linke A, Moellmann H, et al. Multicentre clinical study evaluating a novel resheathable annular functioning self-expanding transcatheter aortic valve system: safety and performance results at 30 days with the Portico system. EuroIntervention. 2016;12:768-774.
24. Grube E, Van Mieghem NM, Bleiziffer S, et al; FORWARD Study Investigators. Clinical outcomes with a repositionable self-expanding transcatheter aortic valve prosthesis: the International FORWARD study. J Am Coll Cardiol. 2017;70:845-853.
25. Falk V, Wöhrle J, Hildick-Smith D, et al. Safety and efficacy of a repositionable and fully retrievable aortic valve used in routine clinical practice: the RESPOND study. Eur Heart J. 2017;38:3359-3366.
26. Rashid HNZ, Gooley R, McCormick L, et al. Safety and efficacy of valve repositioning during transcatheter aortic valve replacement with the Lotus valve system. J Cardiol. 2017;70:55-61.
27. Kleiman NS, Maini BJ, Reardon MJ, et al; CoreValve Investigators. Neurological events following transcatheter aortic valve replacement and their predictors: a report from the CoreValve trials. Circ Cardiovasc Interv. 2016;9:e003551.
28. Kodali S, Pibarot P, Douglas PS, et al. Paravalvular regurgitation after transcatheter aortic valve replacement with the Edwards Sapien valve in the PARTNER trial: characterizing patients and impact on outcomes. Eur Heart J. 2015;36:449-456.
29. Van Gils L, Kroon H, Daemen J, et al. Complete filter-based cerebral embolic protection with transcatheter aortic valve replacement. Catheter Cardiovasc Interv. 2018;91:790-797.
30. Seeger J, Kapadia SR, Kodali S, et al. Rate of peri-procedural stroke observed with cerebral embolic protection during transcatheter aortic valve replacement: a patient-level propensity-matched analysis. Eur Heart J. 2019;40:1334-1340.
31. Samim M, van der Worp B, Agostoni P, et al. TriGuard™ HDH embolic deflection device for cerebral protection during transcatheter aortic valve replacement. Catheter Cardiovasc Interv. 2017;89:470-477.
32. Baumbach A, Mullen M, Brickman AM, et al. Safety and performance of a novel embolic deflection device in patients undergoing transcatheter aortic valve replacement: results from the DEFLECT I study. EuroIntervention. 2015;11:75-84.
33. Lansky AJ, Schofer J, Tchetche D et al. A prospective randomized evaluation of the TriGuard™ HDH embolic DEFLECTion device during transcatheter aortic valve implantation: results from the DEFLECT III trial. Eur Heart J. 2015; 36:2070-2078.
From the 1Department of Internal Medicine II, University of Ulm, Ulm, Germany; and 2CV Path Institute, Inc, Gaithersburg, Maryland.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted December 8, 2018, provisional acceptance given March 11, 2019, final version accepted April 30, 2019.
Address for correspondence: Jochen Wöhrle, MD, University Hospital of Ulm,
Albert-Einstein-Allee 23, 89081 Ulm, Germany. Email: firstname.lastname@example.org