Highlights
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Cerebral embolic protection (CEP) devices have the potential to reduce embolic burden to the cerebral circulation during transcatheter aortic valve replacement (TAVR); however, their effectiveness in real-world patients at high risk of stroke remains insufficiently studied.
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In a prespecified imaging study of the prospective Sentinel registry (NCT 05217888), we have evaluated the effect of CEP on new cerebral embolism as determined by brain magnetic resonance imaging (MRI) in patients undergoing transfemoral TAVR who were considered at high risk for stroke.
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A total of 219 patients were included (49 in the SENTINEL registry and 170 patients in the ADAPT-TAVR trial). As the primary imaging endpoint, the number and volume of new cerebral lesions in the protected brain area was significantly lower in the CEP group than in the control group.
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In patents at high risk for cerebral embolic events undergoing TAVR, the use of CEP was associated with a significant reduction of new cerebral embolism in protected brain territories. However, the study was not powered to assess differences in clinically relevant outcomes and therefore, the results cannot be considered clinically directive.
ABSTRACT
Background
Cerebral embolization is a common complication following transcatheter aortic valve replacement (TAVR). Cerebral embolic protection (CEP) devices have the potential to reduce embolic burden to the cerebral circulation; however, their effectiveness in real-world patients at high risk of stroke remains insufficiently studied.
Methods
As part of imaging study of the prospective Sentinel registry (NCT 05217888), we evaluated the effect of CEP on new cerebral embolism as determined by brain magnetic resonance imaging (MRI) in patients undergoing transfemoral TAVR who were considered at high risk for stroke. The primary endpoint was the number and volume of new cerebral lesions on brain MRI at postprocedure (2 to 7 days) compared to baseline in protected brain territories. The control group consists of enrolled patients in the ADAPT-TAVR trial (NCT03284827), in which TAVR was performed without the use of a CEP device.
Results
A total of 219 patients was included (49 in the SENTINEL registry and 170 patients in the ADAPT-TAVR trial). For the primary endpoint, the number and volume of new cerebral lesions was significantly lower in the CEP group than in the control group: the median no. of lesions; 1 (interquartile range [IQR], 1 to 2) vs 6 (IQR, 3 to 10), respectively; difference,-4 [IQR,-6 to-3]; P <.001, and the median volume of lesions; 113.5 mm 3 (IQR, 42.4-206.9) vs 283.5 mm 3 (IQR, 129.7-682.4), respectively; difference,-145.9 [IQR,-296.7 to-67.1]; P <.001). Strokes at 30 days occurred in 1 patient (2.0%) in the CEP group and 2 patients (1.2%) in the control group ( P =.64).
Conclusions
Among patients who are at high risk for stroke undergoing TAVR, the use of CEP was associated with a significant reduction of new cerebral embolism in protected brain territories. Because the study was underpowered to detect clinically relevant events, the results cannot be considered clinically directive.
Clinical Trail Registration
http://ClinicalTrials.gov (Identifier: NCT05217888).
Background
Transcatheter aortic-valve replacement (TAVR) is an established treatment for symptomatic patients with severe aortic stenosis (AS) across the diverse spectrum of surgical risk. , Despite the remarkable improvements in TAVR devices and procedural techniques, embolization of debris from the valve or the vasculature during the procedures can cause periprocedural stroke, which still remains a significant potential complication leading to increased morbidity and mortality. , Although the clinical relevance is still uncertain, the majority of patients (approximately, 70%-90%) undergoing TAVR may have cerebral embolic defects identified on diffusion-weighted magnetic resonance imaging (MRI). ,, To capture embolic debris and reduce the risk of periprocedural ischemic injury to the brain, the Sentinel cerebral embolic protection (CEP) device (Boston Scientific) is commonly used in contemporary TAVR practice.
Prior imaging-dedicated randomized clinical trials (RCTs) using Sentinel CEP device have reported conflicting results. ,, The CLEAN-TAVI (Claret Embolic Protection and TAVI) trial demonstrated a significant reduction of new ischemic cerebral lesions on brain MRI. By contrast, the SENTINEL trial did not achieve a significant reduction of cerebral embolism, although embolic debris was captured in 99% of the patients. Subsequently, large-sized patient-centered RCTs of the PROTECT-TAVR and the BHF PROTECT-TAVI (British Heart Foundation Randomized Trial of Routine Cerebral Embolic Protection in Transcatheter Aortic Valve Implantation) demonstrated that routine use of CEP did not significantly reduce the incidence of periprocedural stroke. , In a real-world nationally representative registry, the relationship of sentinel CEP use with a reduction of in-hospital stroke was also not evident.
Given the conflicting evidence regarding the effect of a sentinel CEP on the risk of cerebral embolism and its associated clinical outcomes, in this dedicated imaging study of the prospective registry, we sought to evaluate the effect of sentinel CEP on new cerebral embolism as detected by serial brain MRI among patients who were at high risk for stroke undergoing TAVR in real-world practice.
Methods
Study design and patient population
This study was designed as a dedicated imaging study of the prospective Sentinel registry (NCT 05217888). In brief, the Sentinel registry is an investigator-initiated, multicenter, prospective observational registry to evaluate the safety and efficacy of Sentinel CEP device among patients undergoing transfemoral TAVR who are at high risk for cerebral embolic events. The anatomical or clinical criteria for high cerebral embolic risk in this registry included bicuspid aortic valve, heavily calcified aortic valve, severe calcified or atherosclerotic ascending aorta and/or aortic arch, chronic kidney disease, prior history of stroke, or concomitant high-risk comorbidities for stroke events at the discretion of the treating physician. Key exclusion criteria were incompatible anatomical structure of the carotid and brachiocephalic artery anatomy for the placement of the CEP device, as determined by multislice Computed Tomography (CT) scan or an equivalent imaging modality, vasculature in the right extremity precluding radial or brachial access, or severe occlusive carotid disease. Detailed information regarding the inclusion and exclusion criteria are provided in Supplementary Table 1. Enrolled patients fulfilled all of the eligibility criteria and provided written informed consent. This study was supported by the Cardio Vascular Research Foundation (Seoul, Korea) and the Boston Scientific, which provided the Sentinel CEP device in this registry. The sponsor did not have any role in the design, conduct, analysis, or reporting of the results from the imaging study. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper and its final contents.
The control group consisted of enrolled patients in the ADAPT-TAVR (Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement) trial (NCT03284827); all of whom underwent TAVR without CEP and had serial brain MRI evaluations at the identical time frame (baseline, postprocedure [2–7 days after TAVR], and 6-month follow-up). In brief, the ADAPT-TAVR trial was a multicenter, open-label RCT comparing direct oral anticoagulants (DOAC), edoxaban vs dual-antiplatelet therapy for the occurrence of leaflet thrombosis and new cerebral thromboembolism on serial brain MRI and neurological or neurocognitive functions.
TAVR procedure and follow-up
For the experimental group (CEP use in the Sentinel registry) or the control group (no CEP use in the ADAPT-TAVR trial), the TAVR procedure was performed according to standard clinical practice with commercially available TAVR devices with balloon-expandable valve (SAPIEN 3 or SAPIEN 3 Ultra, Edwards Lifesciences) or self-expandable valve (Evolut or Evolut Pro, Medtronic). In the Sentinel group, prior to the TAVR procedure, the SENTINEL CEP device was advanced with a black-load floppy tip 0.014 guidewire via the radial or brachial artery of the patient’s right arm using a standard interventional technique. , A proximal filter was placed at the brachiocephalic trunk and a distal filter was positioned at the left common carotid artery before TAVR. After TAVR, the proximal and distal filters were withdrawn into the catheter and removed. All of the investigators in the Sentinel registry were experienced in deploying the Sentinel CEP device.
After enrollment, patients were followed immediately after TAVR, 1 month and 6 months. Data collected during follow-up visits include clinical symptoms, health status, and any related clinical events, including rehospitalization or unintended hospital visits. For all patients, a transthoracic echocardiogram was routinely performed immediately after TAVR before discharge and at 1 and 6 months.
Brain MRI studies
Patients enrolled in the Sentinel registry (the CEP group) and those in the ADAPT-TAVR study (the control group) were routinely scheduled for serial brain MRI scans within the same time frame; at baseline, postprocedure (2-7 days after TAVR and before discharge) and 6-month follow-up. All brain MRI scans obtained, including diffusion-weighted imaging, fluid-attenuated inversion recovery and T2* gradient echo sequence, which are important sequences for the brain imaging endpoint. These brain MRI scans were analyzed for the occurrence, number and volume of new cerebral lesions at postprocedure (2-7 days) and at 6-month follow-up on the diffusion-weighted imaging, fluid-attenuated inversion recovery and T2 gradient echo sequence compared to the baseline MRI, respectively. The study-specific brain MRI protocol and methodology are provided in Supplementary Table 2.
All MRI imaging data were matched with baseline scans, and subtraction analyses were performed to identify new cerebral lesions. Based on the anatomical location of the circle of Willis, the brain was divided into protected, partially protected, and nonprotected areas. , The measurement of the new lesion number and volume was calculated in these predefined vascular territories (ie, the protected, partially protected, and nonprotected areas) and in the whole brain area. Brain MRI imaging measurements were performed at a central imaging core laboratory (Asan Image Metrics) in a blind manner by independent neuroradiologists who were not aware of the patients’ identities.
Study endpoints
The primary endpoint of the present study was the number and volume of new cerebral lesions on a post-TAVR brain MRI (2-7 days) relative to the baseline in protected brain territories. Because the device does not protect the entire brain, the primary focus was on the territory where a potential filter effect could most reliably be detected. Secondary endpoints included new cerebral lesions in the partially protected and whole brain areas, serial changes in cerebral lesions on brain MRI at 6-month follow-up, as well as the efficacy and safety of clinical outcomes at 30 days, which included all deaths, all strokes (disabling and nondisabling, Valve Academic Research Consortium [VARC]-3), acute kidney injury (stage 3, VARC-3), bleeding events, major vascular complications, permanent pacemaker implantations, and urgent rehospitalizations. All clinical outcomes were adjudicated by an independent clinical events committee according to the VARC definitions. , Predefined definitions of clinical outcomes are provided in Supplementary Table 3.
Statistical analysis
Categorical variables were expressed as numbers (percentages) and were compared using the χ 2 test or the Fisher exact test as appropriate. Continuous variables were expressed as mean (SD) values or median interquartile (IQR) ranges and compared using an appropriate parametric (Student t) test or nonparametric (Mann-Whitney U) test.
The primary efficacy endpoint, consisting of the new median lesion numbers and volume differences in the CEP and control arms, were compared using the Wilcoxon rank sum test and linear regression analysis after log transformation. Differences between medians were estimated with the independent-samples Hodges-Lehmann estimator. Given the potential imbalance in baseline characteristics between the CEP group and the control group, multivariable analysis was also undertaken to adjust clinically relevant covariates, including age, sex, Society of Thoracic Surgeons (STS) score, atrial fibrillation, antithrombotic medications, and pre-TAVR balloon valvuloplasty.
The clinical outcomes at 30 days were compared with the use of the chi-square test or Fisher’s exact test, as appropriate. All reported P values were 2-sided, and P<0.05 was considered significant. No adjustment for multiple testing was undertaken and thus all findings of this study should be interpreted as exploratory given the potential for type I error due to multiple comparisons. All statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute), and R software, version 4.0 (R Foundation for Statistical Computing).
Results
Study population and baseline characteristics
The flow of study participants is depicted in Figure 1 . From May 2022 through September 2023, 59 patients were enrolled in the dedicated imaging study of the Sentinel registry. Among them, 49 patients had a complete set of serial MRI evaluations at baseline and postprocedure (the primary analytic cohort), and 35 had a complete set of serial MRI evaluations at baseline, postprocedure, and 6-month follow-up. From March 2018 through April 2021, 229 patients were enrolled in the ADAPT-TAVR trial. Among them, 170 patients were included in the control group, who had a complete set of serial brain MRI evaluations at baseline and postprocedure.
Study flow diagram. This diagram showed flow of study participants from the SENTINEL registry (the CEP group) and the ADAPT-TAVR trial (the control group without CEP use). CEP, cerebral embolic protection; MRI, magnetic resonance imaging; TAVR, trans-aortic valve replacement.
Baseline clinical and hemodynamic characteristics between the CEP group and the control group are summarized in Table 1 . Most of the baseline characteristics did not differ significantly between the 2 groups. However, more patients in the CEP group were men and had a higher prevalence of atrial fibrillation and carotid disease as compared with those in the control group. In addition, given that the ADAPT-TAVR trial randomized patients to receive edoxaban or dual-antiplatelet therapy post-TAVR, the use of DOAC after TAVR was more frequent in the control group. Procedural characteristics were summarized in Table 2 . Overall, there were no significant differences between the CEP and control groups with respect to procedural characteristics regarding the TAVR valve type, valve size, and procedural success. A balloon-expandable TAVR device was mostly used in both groups. The Sentinel CEP device was successfully deployed in all patients in the CEP group. The amount of contrast dye was higher in the CEP group than in the control group.
Table 1
Baseline characteristics of the patients at baseline
| Characteristic | CEP group (n = 49) | Control group (n = 170) | P value |
|---|---|---|---|
| Age, yrs | 80.0 ± 4.3 | 80.5 ± 4.2 | .467 |
| Male | 30 (61.2) | 70 (41.1) | .013 |
| BMI, kg/m 2 | 23.6 ± 2.8 | 24.4 ± 3.7 | .467 |
| BSA | 1.6 ± 0.1 | 1.6 ± 0.1 | .416 |
| STS risk score | |||
| Mean | 3.0 ± 2.0 | 3.3 ± 2.3 | .323 |
| Category | .523 | ||
| Low | 40 (81.6) | 124 (72.9) | |
| Intermediate | 8 (16.3) | 41 (24.1) | |
| High | 1 (2.0) | 5 (2.9) | |
| EuroSCORE II value | 1.8 ± 1.0 | 2.1 ± 1.8 | .301 |
| NYHA Class III or IV | 14 (28.5) | 40 (23.5) | .473 |
| Diabetes mellitus | 12 (24.5) | 53 (31.2) | .367 |
| Hypertension | 37 (75.5) | 119 (70) | .453 |
| Hyperlipidemia | 39 (79.6) | 139 (81.7) | .731 |
| Previous hear failure | 0 (0) | 9 (5.3) | .213 |
| Previous CAD | 8 (16.3) | 43 (25.3) | .191 |
| Previous MI | 1 (2.0) | 2 (1.2) | .534 |
| Previous CABG | 0 (0) | 5 (2.9) | .590 |
| Atrial fibrillation | 4 (8.1) | 3 (1.7) | .046 |
| Peripheral artery disease | 2 (4.1) | 16 (9.4) | .375 |
| Cerebrovascular disease | 7 (14.3) | 13 (7.6) | .165 |
| Carotid disease | 9 (18.7) | 9 (5.3) | .006 |
| Chronic lung disease | 5 (10.2) | 53 (31.2) | .003 |
| Chronic kidney disease | 4 (8.5) | 8 (5.0) | .409 |
| Serum creatinine, mg/dL | 1.0 ± 0.3 | 0.9 ± 0.3 | .112 |
| Antithrombotic medication | .004 | ||
| NOAC | 14 (28.6) | 82 (48.2) | |
| Dual antiplatelet therapy | 35 (71.4) | 88 (51.8) | |
| Echocardiographic data | |||
| EOA, mm 2 | 0.65 ± 0.14 | 0.61 ± 0.14 | .031 |
| Peak velocity, m/s | 4.8 ± 0.75 | 4.9 ± 0.72 | .535 |
| Maximal pressure gradient | 94.3 ± 32.0 | 96.7 ± 29.2 | .682 |
| Mean pressure gradient | 57.0 ± 19.9 | 57.9 ± 19.0 | .822 |
| LVEF, % | 61.4 ± 7.6 | 60.2 ± 9.8 | .418 |
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