Post on 06-Jun-2020
Accepted Manuscript
Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement
Samir R. Kapadia, MD, Susheel Kodali, MD, Raj Makkar, MD, Roxana Mehran, MD,Ronald M. Lazar, PhD, Robert Zivadinov, MD, PhD, Michael G. Dwyer, MD, HasanJilaihawi, MD, Renu Virmani, MD, Saif Anwaruddin, MD, Vinod H. Thourani, MD,Tamim Nazif, MD, Norman Mangner, MD, Felix Woitek, MD, Amar Krishnaswamy,MD, Stephanie Mick, MD, Tarun Chakravarty, MD, Mamoo Nakamura, MD, JamesM. McCabe, MD, Lowell Satler, MD, Alan Zajarias, MD, Wilson Y. Szeto, MD, LarsSvensson, MD, PhD, Maria C. Alu, MS, Roseann M. White, MS, Carlye Kraemer, MS,Azin Parhizgar, PhD, Martin B. Leon, MD, Axel Linke, MD
PII: S0735-1097(16)36768-7
DOI: 10.1016/j.jacc.2016.10.023
Reference: JAC 23128
To appear in: Journal of the American College of Cardiology
Received Date: 1 October 2016
Revised Date: 21 October 2016
Accepted Date: 22 October 2016
Please cite this article as: Kapadia SR, Kodali S, Makkar R, Mehran R, Lazar RM, Zivadinov R, DwyerMG, Jilaihawi H, Virmani R, Anwaruddin S, Thourani VH, Nazif T, Mangner N, Woitek F, KrishnaswamyA, Mick S, Chakravarty T, Nakamura M, McCabe JM, Satler L, Zajarias A, Szeto WY, Svensson L,Alu MC, White RM, Kraemer C, Parhizgar A, Leon MB, Linke A, Cerebral Embolic Protection DuringTranscatheter Aortic Valve Replacement, Journal of the American College of Cardiology (2016), doi:10.1016/j.jacc.2016.10.023.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service toour customers we are providing this early version of the manuscript. The manuscript will undergocopyediting, typesetting, and review of the resulting proof before it is published in its final form. Pleasenote that during the production process errors may be discovered which could affect the content, and alllegal disclaimers that apply to the journal pertain.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement Samir R. Kapadia, MD*a, Susheel Kodali, MD*b, Raj Makkar, MDc, Roxana Mehran, MDd, Ronald M. Lazar, PhDb, Robert Zivadinov, MD, PhDe, Michael G. Dwyer, MDe, Hasan Jilaihawi, MDf, Renu Virmani, MDg, Saif Anwaruddin, MDh, Vinod H. Thourani, MDi, Tamim Nazif, MDb, Norman Mangner, MDj, Felix Woitek, MDj, Amar Krishnaswamy, MDa, Stephanie Mick, MDa, Tarun Chakravarty, MDc, Mamoo Nakamura, MDc, James M. McCabe, MDk, Lowell Satler, MDl, Alan Zajarias, MDm, Wilson Y. Szeto, MDh, Lars Svensson, MD, PhDa, Maria C. Alu, MSb, Roseann M. White, MSn, Carlye Kraemer, MSo, Azin Parhizgar, PhDp, Martin B. Leon, MDb, and Axel Linke, MDj,q *co-first authors From: aCleveland Clinic, Cleveland, OH ; bColumbia University Medical Center, New York, NY; cCedars-Sinai Medical Center, Los Angeles, CA; dMount Sinai School of Medicine, New York, NY; eBuffalo Neuroimaging Analysis Center, Buffalo, NY; fNYU Langone Medical Center, New York, NY; gCV Path Institute, Gaithersburg, MD; hUniversity of Pennsylvania, Philadelphia, PA; iEmory University, Atlanta, GA; jHerzzentrum Leipzig GmbH –Universitätsklinik, Leipzig, Germany; kUniversity of Washington, Seattle, WA; lMedstar Washington Hospital Center, Washington, DC; mWashington University School of Medicine, St. Louis, MO; nDuke Clinical Research Institute, Durham, NC; oNAMSA, Minneapolis, MN; pClaret Medical Inc, Santa Rosa, CA; qLeipzig Heart Institute, Leipzig, Germany Short Running Title: Embolic protection in TAVR Sources of Funding: The SENTINEL Trial was funded by Claret Medical, Inc. Relationships with Industry: Authors disclose the following relationships with industry:Dr. Kodali is a consultant for Edwards Lifesciences. Dr. Makkar has received research support from Edwards Lifesciences and St. Jude Medical and is a consultant for Abbott Vascular, Cordis, and Medtronic. He also holds equity in Entourage Medical. Dr. Mehran receives research grant support from Eli Lilly/DSI, BMS, AstraZeneca, The Medicines Company, OrbusNeich, Bayer, and CSL Behring; is a consultant for Janssen Pharmaceuticals, Osprey Medical, Watermark Research Partners, and Medscape, a member of the Scientific Advisory Board of Abbott Laboratories, and holds Equity or Stock Options in Claret Medical Inc. and Elixir Medical Corporation. Dr. Zivadinov has received personal compensation from Teva Pharmaceuticals, Biogen Idec, EMD Serono, Genzyme-Sanofi, Claret Medical, IMS Health and Novartis for speaking and consultant fees. He received financial support for research activities from Teva Pharmaceuticals, Genzyme-Sanofi, Novartis, Claret Medical, Intekrin and IMS Health. Dr. Zivadinov serves on editorial board of J Alzh Dis, BMC Med, BMC Neurol, Vein and Lymphatics and Clinical CNS Drugs. He is Executive Director and Treasurer of International Society for Neurovascular Disease. Dr. Jilaihawi is a consultant for Edwards Lifesciences, St. Jude Medical, and Venus Medtech. Dr. Anwaruddin is a speaker, consultant, and proctor for Edwards Lifesciences and Medtronic and a consultant for the American College of Radiology. Dr. Thourani is a consultant for Edwards Lifesciences, Sorin Medical, St. Jude Medical, and DirectFlow. Dr. Nazif is a consultant for Edwards Lifesciences. Dr. Nakamura is a consultant for Edwards Lifesciences. Dr. McCabe is a consultant for Edwards Lifesciences. Dr. Zajarias is a
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
consultant for Edwards Lifesciences. Dr. Szeto is a consultant for MicroInterventional Devices. Dr. Svensson holds equite in Cardiosolutions and ValvXchange and Intellectual Property Rights for Posthorax. Ms. Alu is a consultant for Claret Medical. Ms. White is a consultant for Claret Medical through Duke Clinical Research Institute. Ms. Kraemer is a consultant for Claret Medical. Dr. Parhizgar is an employee of Claret Medical. The other authors report no relevant relationships with industry. Acknowledgements: The authors would like to thank Matthew T. Finn, MD (Columbia University Medical Center) for assistance with manuscript preparation. Address for Correspondence: Samir Kapadia, MD Cleveland Clinic 9500 Euclid Avenue, Desk J2-3 Cleveland, OH 44195 Tel: 216-444-6697 Email: kapadis@ccf.org
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Abstract Background Neurological events and brain infarction after transcatheter aortic valve replacement (TAVR) are concerns which may be reduced with transcatheter embolic protection (TEP). Objective Evaluate the safety and efficacy of TEP during TAVR. Methods Nineteen centers randomized 363 patients undergoing TAVR to safety (n=123), device imaging (n=121), and control imaging (n=119). The primary safety endpoint was major adverse cardiac and cerebrovascular events (MACCE) at 30 days and the primary efficacy endpoint was reduction in new lesion volume in protected brain territories on MRI scans at 2-7 days. Patients underwent neurocognitive assessments and the debris captured was analyzed. Results MACCE (7.3%) was non-inferior to the performance goal (18.3%, pnoninferior<0.001) and not statistically different from control (9.9%, p=0.41). New lesion volume was 178.0 mm3 in controls and 102.8 mm3 in the device arm (p=0.33). A post hoc multivariable analysis identified preexisting lesion volume and valve type to be predictors of new lesion volume. Strokes at 30d were 9.1% in controls and 5.6% in device patients (p=0.25). Although neurocognitive function was similar in control and device patients, there was correlation between lesion volume and neurocognitive decline (p=0.0022). Histopathologic debris, found within filters in 99% of patients, included thrombus, calcification, valve tissue, artery wall and foreign material. Conclusions TEP was safe, captured embolic debris 99% patients, and did not change neurocognitive function. Reduction in new lesion volume on MR scans was not statistically significant. Keywords: Cerebral embolic protection, transcatheter aortic valve replacement (TAVR), stroke, neuroimaging. Trial Registration: ClinicalTrials.gov #NCT02214277 Abbreviations ANOVA Analysis of Variance AS Aortic Stenosis DW-MRI Diffusion-weighted Magnetic Resonance Imaging FLAIR Fluid-attenuated Inversion Recovery ITT Intention to Treat MACCE Major Adverse Cardiac and Cerebral Events MMSE Mini Mental State Exam MRI Magnetic Resonance Imaging mRS Modified Rankin Score MSCT Multi Slice Computed Tomography NIHSS National Institutes of Health Stroke Scale STS Society of Thoracic Surgeons TAVR Transcatheter Aortic Valve Replacement TCEP Transcatheter Cerebral Embolic Protection
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Introduction
Transcatheter aortic valve replacement (TAVR) is an important new therapy for high and
intermediate-risk patients with severe aortic stenosis (AS).(1-8) However, strokes remain a
concerning complication after TAVR and are associated with increased mortality and
morbidity.(1,2,4,9-13) In addition, clinically “silent” brain infarctions seen on magnetic
resonance (MR) scans have been associated with neurocognitive function changes(14-17) and
are present in as many of 80% of patients after TAVR.(18-21) Although the etiology of strokes
and MR perfusion abnormalities is multifactorial in this elderly co-morbid population, the
majority are due to embolization of particulate debris during the procedure.(22,23) Previous
exploratory studies have attempted to minimize procedural embolization using either
transcatheter filters or deflection devices.(24-30) The present randomized trial was designed to
assess the safety of transcatheter cerebral embolic protection (TCEP) during TAVR and the
efficacy in reducing the effects of cerebral embolization.
Methods
Patients
The study population included 363 patients with severe symptomatic AS and planned TAVR
who were at high risk for surgery from 17 centers in the U.S. and 2 centers in Germany. All
patients had multi-slice computed tomography (MSCT) scans which were analyzed by a core
laboratory and reviewed by a committee to determine treatment eligibility using the Sentinel®
TCEP device (Claret Medical, Santa Rosa, CA, USA). Other exclusions included patients with
known contraindications for right radial or brachial artery access and patients unable to undergo
MRI evaluation of their brain for any reason.
Study Device and Procedure
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
The SentinelT TCEP device consists of 2 filters within a single 6 French delivery catheter
percutaneously placed from the right radial (preferred) or brachial artery over a 0.014” guide
wire (Figure 1). The filters are positioned in the brachiocephalic and the left common carotid
arteries before TAVR and are withdrawn into the catheter and removed after TAVR. Details of
the device and the procedure have been previously described.(26,31)
Study Design
In this prospective multicenter randomized trial, patients undergoing TAVR were randomized
1:1:1 into a safety arm (TCEP only) and two imaging cohorts, in which patients were randomly
treated with TCEP (device arm) or without TCEP (control arm) (Figure 2). TCEP safety was
assessed in the safety and device arms (device safety cohort). Reason to include safety arm was
show clinical safety without increasing cost of the trial by eliminating MRI cost. Patients were
blinded to treatment assignment. Blinded diffusion weighted MRI (DW-MRI) and
neurocognitive function assessments were performed in the device and control arms. Particulate
debris from the extracted filters was studied in the device arm. All patients underwent rigorous
neurologic evaluations post-TAVR, at 30 days and at 90 days.
Brain MRI Studies
Brain MRI using a 3 Tesla scanner was performed in both imaging arms (device and control) at
baseline, and post-TAVR at 2-7 days and at 30 days. All MRI studies were analyzed by a core
laboratory in a blinded manner. Appendix 1 in the Supplementary Appendix provides a
description of the methodology for MRI acquisition and analysis. Post-TAVR studies were
matched with baseline scans and subtraction analyses were performed to identify new lesions.
Protected territories were defined as brain territories entirely perfused by vessels protected by
TEP and “all” territories refers to the entire brain.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Neurocognitive Function
Device and control arms underwent comprehensive neurocognitive assessment tailored for
TAVR patients and designed to evaluate seven domains of neurocognitive function, including bi-
hemispheral and hemisphere-specific attention, executive function, processing speed, working
memory, visual memory, mental status, and depression (Appendix 2, Supplementary Appendix).
Trained and certified test administrators and neurocognitive core lab personnel were blinded to
randomization assignment.
Histopathologic Assessment of Debris
All filters from the device arm were stored in formalin and sent to a histopathology core lab for a
blinded analysis. Extracted debris was stained, examined with light microscopy and the debris
was catalogued as thrombus, calcium, valve tissue, or catheter fragments. A quantitative
analysis was also performed to measure the size of embolic debris.
Study Endpoints
The primary safety end point was the occurrence of major adverse cardiac and cerebrovascular
events (MACCE) at 30 days compared to a historical performance goal. MACCE was defined as
all death, all strokes (Disabling and Non-Disabling, VARC-2), and acute kidney injury (stage 3,
VARC-2).(32) The occurrence of stroke was assessed by neurologist-administered National
Institutes of Health Stroke Score (NIHSS) and modified Rankin score (mRS) at Baseline (< 14
days pre-procedure), Discharge, and 30 days. For those experiencing a stroke within 30 days, 90-
day NIHSS and mRS were also administered by a neurologist for the purposes of determining
stroke severity.
The primary efficacy endpoint was the reduction in median total new lesion volume in protected
territories between the device and control arms assessed by DW-MRI at 2-7 days after TAVR.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Minimum treatment effect of 30% reduction in median total new lesion volume in protected
territories was also pre specified as an observational success criteria. Total new lesion volume
was defined as the sum of all diffusion-positive new cerebral lesion volumes in post-procedural
scans relative to the pre-TAVR scans.
Other pre-specified secondary endpoints included device success, vascular complications,
new lesion number in protected and all territories, and the correlation of lesion volume with
neurocognitive function changes, and histopathology evaluations.
Statistical Analysis
Fisher’s exact test was used to compare categorical variables. Continuous variables, which are
presented as means with standard deviations or medians with interquartile ranges, as appropriate,
were compared with the use of analysis of variance (ANOVA), non-parametric ANOVA, or the
Wilcoxon rank-sum test. The point estimate for the historical performance goal for the primary
safety endpoint at 30 days post-TAVR was derived from a review of the published literature of
30-day TAVR outcomes.(1,2,4) The boundary was selected by first weighting the published
MACCE rates by the expected proportion of transfemoral and transapical cases using the
following formula: weighted MACCE Rate = [20.2% x 20% (TA) + 12.0% x 80%(TF)]*2/3 +
[12.62]*1/3 = 13.3%. The performance goal of 18.3% was derived by adding a conservative non-
inferiority margin of 5% to the weighted literature rate of 13.3%. Sample size estimates for
comparing the total new lesion volume from the protected territories between the two
randomized imaging arms were obtained based on a Wilcoxon-Mann-Whitney test, assuming
data with a lognormal distribution and the following means: Raw Mean (SD): Test 474.2 (813.6)
vs. Control 1029.7 (2424.12); Lognormal Mean (SD): Test 5.4 (1.2) vs. Control 6.0 (1.3). Under
these assumptions, seventy-two subjects per arm were required, with an 80% power and an alpha
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
of 0.05 (two-sided). With an estimated loss allowance of 35%, 120 subjects were planned to be
randomized to each imaging arm to achieve 75 evaluable subjects. The primary efficacy
endpoint, new median lesion volume differences in the test and control arms were compared
using the Wilcoxon rank-sum test.
A z-score for each neurocognitive function domain was calculated based on normative
means and standard deviations for each neurocognitive test. Change scores were calculated (by
domain) by subtracting baseline scores from the 30-day or 90-day post-TAVR scores.
Comparison of the change in composite neurocognitive z-scores was performed controlling for
mini mental state examination (MMSE), education, and the depression scores.
Multivariable analysis was undertaken to determine covariates of new lesion volumes,
starting with identifying all baseline univariate predictors with a p-value < 0.1. Stepwise linear
regression was performed to identify independent predictors. Adjustment models to account for
the effect of multivariable predictors on new lesion volume are described in Appendix 3,
Supplementary Appendix.
Statistical analyses were performed on the intention-to-treat (ITT) population using SAS
version 9.3 (SAS Institute, Cary, NC).
Results
Study Characteristics
240 patients were randomized to the imaging cohort (119 control and 121 device) and 123
patients to the safety arm (Figure 2). Within the imaging cohort, MRI studies at baseline and 2-
7 days post-TAVR were performed in 189 (78.8%) patients and neurocognitive assessments
were completed at baseline and 30 days in 185 (77.1%) patients. Baseline characteristics of the
primary safety cohort and of those with and without paired MRI studies (primary efficacy
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
cohort) are presented in Tables 1 and 2 of the supplementary appendix. Of note, there were no
significant differences between groups in the primary safety cohort and the only baseline
characteristics which differed between those with and without paired MRI were history of prior
coronary artery bypass graft and mean gradient.
Overall, the study population was elderly (median age 83.4 years), the majority (52.1%)
were females, median Society of Thoracic Surgeons (STS) score was 6.0%, and there were
frequent co-morbidities including atrial fibrillation (31.7%) and prior strokes (5.8%). Baseline
characteristics were generally well balanced for the entire population (Table 1) and for the paired
MRI and paired neurocognitive function cohorts (Tables 3 and 4, Supplementary Appendix).
Due to timing of FDA approval and operator choice, four different TAVR devices were used in
this trial; Sapien XT (17.8%) and Sapien 3 (52.4%) (both Edwards Lifesciences, Irvine, CA,
USA) as well as CoreValve (3.9%) and Evolut R (25.9%) (both Medtronic, Minneapolis, MN,
USA). TAVR systems were used with similar distribution across all three randomized treatment
groups.
Procedural Details and Clinical Outcomes
TAVR was performed via the femoral artery in 94.7% of cases and TCEP was delivered from the
radial and brachial arteries in 93.2% and 5.6% of cases. Delivery and retrieval of both filters was
successful in 94.4% of patients. In the device arm vs. control, there was an increase in total
procedure time (p=0.01) and fluoroscopy time (p=0.007) (Table 1).
MACCE in the device and safety arms was 7.3% and the upper bound of the 95%
confidence interval (11.4%) was less than the 18.3% performance goal (p<0.001 for non-
inferiority) (Figure 3, Table 2). MACCE in the control arm (9.9%) was not statistically different
compared with the device and safety arms (p=0.405). Strokes were not significantly different in
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
the device and safety arms vs. the control arm (5.6% vs. 9.1%, p=0.25). There were no
differences in other important endpoints including acute kidney injury or vascular complications
(Table 2).
MRI Efficacy Primary Outcomes
The median total new lesion volume in protected territories was 42% lower, meeting the 30% pre
specified treatment effect success criteria, but was not significantly different in device vs. control
arms (102.8 mm3 versus 178.0 mm3, p=0.33) (Figure 2). Total new lesion volume in all
territories was also not statistically different in device vs. control arms (294 mm3 vs. 309.8 mm3,
p = 0.81). New lesion number in device vs. control arms in both protected and all territories was
unchanged (Table 3). When analyzed by valve type, there were significant differences in new
lesion volume and number in both protected and all territories (Table 5, Supplementary
Appendix). The median total new lesion volume at 30 days was 0 for in both protected and all
territories for both the Device and Control arms (Table 6, Supplementary Appendix).
Post Hoc Multivariable Analysis
Univariate and multivariable analyses indicated that baseline T2/FLAIR lesion volume on MRI
(a marker of prior injury and gliosis, often called white matter disease) was the strongest baseline
predictor of new lesion volume after TAVR (Table 7, Supplementary Appendix). After
adjusting for valve type, baseline T2/FLAIR lesion volume, and an interaction between valve
type and treatment arm, there was a significant reduction in new lesion volume in both protected
and all territories in the device vs. control arms (p=0.025 for protected and p=0.050 for all
territories (Table 8, Supplementary Appendix). After similar adjustments for baseline
T2/FLAIR lesion volume, there were variable responses associated with specific valve types
(Table 9, Supplementary Appendix).
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Neurocognitive Function and Histopathology
Neurocognitive test batteries were similar in all 7 domains with no difference in overall
composite scores at baseline, 30 days or 90 days between device and control arms (Table 4).
However, the change in neurocognitive scores from baseline to 30-day follow-up correlated with
median new lesion volume in protected territories (r = -0.20275, R2 = 4.1, p = 0.0109) and all
territories (r = -0.23562, R2 = 5.6, P = 0.003) (Figure 1, Supplementary Appendix).
Histopathologic debris was found in retrieved filters in 99% of patients (Figure 4). Most
frequently captured debris components included acute thrombus with tissue elements, artery
wall, calcification, valve tissue, and foreign materials. More than 80% of the debris was 150–
500 microns (maximum diameter) and < 5% was greater than 1000 microns (Figure 4).
Discussion
The main results from this important multicenter randomized trial evaluating the role of embolic
protection using the Sentinel™ device during TAVR are as follows: (1) transcatheter placement
of a dual filter device was successful in most patients without safety concerns; (2) the primary
efficacy endpoint (reduction in median new lesion volume on MRI at 2-7 days in protected
territories) was not met; however, after adjusting for valve type and baseline T2/FLAIR lesion
volume in a post hoc analysis, there were significant differences in new lesion volumes favoring
embolic protection; (3) neurocognitive function was not significantly improved, but there was
correlation between new lesion volume and number and neurocognition at 30 days; (4)
particulate debris during TAVR was found in almost all patients including diverse biologic and
foreign materials.
The first hurdle of accessory therapies to improve TAVR outcomes is the demonstration
of technical feasibility and clinical safety. As suggested in prior smaller studies,(26,31) the
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Sentinel® dual filter device was easily delivered, usually from the right radial artery, and was
compatible with standard TAVR workflow. The total procedure was longer by approximately 13
minutes with an additional 3 minutes of fluoroscopy time. Importantly, clinical safety outcomes
were much lower than the pre-specified performance goal, and MACCE point-estimates were
lower in the device arms compared to control. Although the largest difference was in minor
strokes, it has been shown that all strokes, and even TIAs, confer increased risk of mortality risk
among TAVR. (9)
Historically, demonstration of clinical efficacy with embolic protection to reduce
deleterious target organ effects has been problematic. The proposed or accepted use of embolic
protection devices for the brain, heart, kidneys, and legs has been based largely on observational
studies indicating device safety combined with surrogate clinical efficacy endpoints.(18,19,33-
36) Early TAVR trials showing increased peri-procedural stroke frequency(1-3) and MRI
examinations revealing concordant ischemic deficits(18,19,21) heightened the need to develop
brain sparing therapies and encouraged the use of quantitative MRI analyses as a surrogate
endpoint. In the present trial, with embolic protection there was a 38% reduction in all strokes at
30 days, which did not reach statistical significance. There was a 42% reduction in MRI median
new lesion volume at 2-7 days in the device arm compared with controls, which also did not
reach statistical significance.
Several limitations of the study likely contributed to the lack of statistical significance
despite this observed 42% reduction in new lesion volume in protected territories. First, despite
the use of 3T MRI scanners to improve the accuracy of characterizing new lesions and
subtraction imaging methodology to provide unbiased quantitative analyses, there was
considerable variance in MRI post-procedure results, in part due to rapidly changing new lesion
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
volumes and numbers during the broad 2-7 day follow-up window. In addition, 3T MRI is
potentially more prone to scanner signal (B0 and B1) inhomogeneity across the brain,
particularly on FLAIR imaging, although the increased inhomogeneity is offset by the sensitivity
increase and by software correction using the N3 algorithm. Second, there was little benchmark
MRI data on which to base control arm assumptions and the observed new lesion volume and
number were less than predicted from the recently published CLEAN-TAVI trial.(25) This may
be the result of using CoreValve exclusively in Clean TAVI, whereas the use of self-expanding
valves was ~20% in the Sentinel trial. Third, the impact of baseline T2/FLAIR lesion volume on
subsequent new lesion volume was not accounted for in the trial design. Prior neurology studies
have demonstrated that baseline disease burden is an important predictor of subsequent clinical
events after interventions (37-39). Fourth, different TAVR devices were included in this trial and
the randomization scheme was not stratified according to valve category. Both the control arm
MRI results and the response to embolic protection appeared to differ with varying TAVR
systems.
At the time the Sentinel Trial was designed, only one device was commercially available
in the US, and therefore no stratification by device type was anticipated in the randomization
structure. However, several new devices became available over the course of trial. Additionally,
risk factors for stroke, especially findings on baseline MRI, were incompletely understood at the
time at the time the study was designed. When evaluation of univariate predictors of new lesion
volume revealed that device type and baseline T2/FLAIR lesion volume were potentially
important confounders or effect modifiers of the relationship between TCEP and new lesion
volume, we determined that is was necessary to perform multivariable analysis to adjust for the
unanticipated baseline differences in brain infarction volume and valve type. After adjusting for
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
these variables, there was a significant difference in new lesion volume favoring neuroprotection
in both protected (p = 0.025) and all territories (p = 0.050). The study provides a very interesting
observation regarding differences in MRI findings due to implanted valve type. In the control
group of patients, the volume of new MRI lesions was lower in S3 compared to Evolut R or
Sapien XT. The overall treatment effect, after adjustment for TAVR Device and the interaction
between TAVR and Treatment, is a 49% reduction in post procedure new lesion volume in
protected areas. However, SAPIEN 3 generated the lowest post procedure new lesion volume
(30% - 50% lower than the other TAVR devices (Supplemental Table 6). Therefore, SAPIEN 3
derived the least benefit from the use of the Sentinel device, resulting in little to no difference
between the treatment arms. This is responsible for the significant interaction effect between the
device and treatment. The treatment effect of the Sentinel device was significant in non-S3
valves. The reasons for these differences are not clear, but will be an important future question
for clinical trials. There may be other factors that may explain these differences like use of pre-
dilatation or post-dilatation, operator experience, or patient selection for different valves.
Although these variables did not reach statistical significance in multivariate modeling, limited
power of the study and possible interaction with valve types do not allow us to rule out their
contribution to observed differences between valve types. It is important to note that first
generation balloon expandable and self-expanding valves have reported similar stroke rates. The
clinical stroke rate reported from S3 has been very low, but has not been directly compared to
new generation self-expanding valves.
The neurocognitive function test domains utilized in this trial were rigorously obtained by
trained examiners and were customized to optimize the sensitivity of identifying changes
associated with diffuse cerebral embolization. Although there was no difference in
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
neurocognition at 30 days between the embolic protection and control arms, there was an
important relationship linking cumulative neurocognition scores with new lesion volumes and
numbers.
As has been noted in other trials using similar filters for neuroprotection during TAVR
(22,23), there was a striking consistency of retrieved materials in almost all patients in this study.
The observation of frequent thrombus, artery wall, valve tissue, and calcification suggests that
overly aggressive device manipulation within the aortic valvar complex should be avoided,
whenever possible.
There are several limitations associated with this clinical trial. The Sentinel® dual filter
device appears safe and feasible but the embolic protection afforded excludes the territory of the
left vertebral artery. The observation that residual new lesions are still present in protected
territories after neuroprotection indicates that either the current transcatheter devices are
suboptimal in debris capture or that post-procedure particulate embolization is ongoing and
occurs after removing the filters. Further, it is possible that that some of the retrieved material in
the filters was not directly related to TAVR, but rather was due to placement of TEP. Follow-up
MRI studies were not obtained in 25% of patients from the imaging cohort due to patient
compliance and the need for new pacemakers post-TAVR. Despite being the largest randomized
trial examining neuroprotection during TAVR, the sample size was clearly too low to assess
clinical outcomes, and in retrospect, was also too low to evaluate follow-up MRI findings or
neurocognitive outcomes. Finally, the analyses of valve type differences and multivariable
analysis to account for confounders should be viewed as hypothesis generating and non-
definitive.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
There are important lessons from this trial, which should impact future research on
neuroprotection during TAVR. In particular, the use of quantitative MRI analyses as a surrogate
endpoint must be further clarified, including stricter time windows for follow-up studies and
more accurate assumptions of expected control arm results, such that sample sizes can be
adjusted appropriately. The requirement of baseline MRI studies to account for prior lesion
volume and the need to adjust for differences in valve type (e.g. stratification of valve types
during randomization) cannot be overemphasized.
In conclusion, this randomized trial investigating the SentinelTM dual filter
neuroprotection therapy provides reassuring evidence of device safety and confirms the high-
frequency of embolic debris capture.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
REFERENCES
1. Leon MB, Smith CR, Mack M et al. Transcatheter aortic-valve implantation for aortic
stenosis in patients who cannot undergo surgery. N Engl J Med 2010;363:1597-607.
2. Smith CR, Leon MB, Mack MJ et al. Transcatheter versus surgical aortic-valve
replacement in high-risk patients. N Engl J Med 2011;364:2187-98.
3. Popma JJ, Adams DH, Reardon MJ et al. Transcatheter aortic valve replacement
using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme
risk for surgery. J Am Coll Cardiol 2014;63:1972-81.
4. Adams DH, Popma JJ, Reardon MJ et al. Transcatheter aortic-valve replacement with
a self-expanding prosthesis. N Engl J Med 2014;370:1790-8.
5. Leon MB, Smith CR, Mack MJ et al. Transcatheter or Surgical Aortic-Valve
Replacement in Intermediate-Risk Patients. N Engl J Med 2016;374:1609-20.
6. Thourani VH, Kodali S, Makkar RR et al. Transcatheter aortic valve replacement
versus surgical valve replacement in intermediate-risk patients: a propensity score
analysis. Lancet 2016;387:2218-25.
7. Reardon MJ, Kleiman NS, Adams DH et al. Outcomes in the Randomized CoreValve
US Pivotal High-risk Trial in Patients With a Society of Thoracic Surgeons Risk
Score of 7% or Less. JAMA Cardiology 2016 doi: 10.1001/jamacardio.2016.2257.
[Epub ahead of print].
8. Holmes DR, Jr., Nishimura RA, Grover FL et al. Annual Outcomes With
Transcatheter Valve Therapy: From the STS/ACC TVT Registry. J Am Coll Cardiol
2015;66:2813-23.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
9. Kapadia S, Agarwal S, Miller DC et al. Insights Into Timing, Risk Factors, and
Outcomes of Stroke and TIA After Transcatheter Aortic Valve Replacement in the
PARTNER Trial. Circulation Cardiovasc Interv 2016;9.
10. Athappan G, Gajulapalli RD, Sengodan P et al. Influence of transcatheter aortic valve
replacement strategy and valve design on stroke after transcatheter aortic valve
replacement: a meta-analysis and systematic review of literature. J Am Coll Cardiol
2014;63:2101-10.
11. Athappan G, Gajulapalli RD, Tuzcu ME, Svensson LG, Kapadia SR. A systematic
review on the safety of second-generation transcatheter aortic valves.
EuroIntervention 2016;11:1034-43.
12. Auffret V, Regueiro A, Del Trigo M et al. Predictors of Early Cerebrovascular Events
in Patients With Aortic Stenosis Undergoing Transcatheter Aortic Valve
Replacement. J Am Coll Cardiol 2016;68:673-84.
13. Gleason TG, Schindler JT, Adams DH et al. The risk and extent of neurologic events
are equivalent for high-risk patients treated with transcatheter or surgical aortic valve
replacement. J Thorac Cardiovasc Surg 2016;152:85-96.
14. Floyd TF, Giovannetti T. Neurocognitive outcomes in older adults after transcatheter
aortic valve replacement. J Thorac Cardiovasc Surg 2012;144:1539.
15. Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MM. Silent
brain infarcts and the risk of dementia and cognitive decline. N Engl J Med
2003;348:1215-22.
16. Vermeer SE, Longstreth WT, Jr., Koudstaal PJ. Silent brain infarcts: a systematic
review. Lancet Neurology 2007;6:611-9.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
17. Svensson LG, Blackstone EH, Apperson-Hansen C et al. Implications from
neurologic assessment of brain protection for total arch replacement from a
randomized trial. J Thorac Cardiovasc Surg 2015;150:1140-7.e11.
18. Ghanem A, Muller A, Nahle CP et al. Risk and fate of cerebral embolism after
transfemoral aortic valve implantation: a prospective pilot study with diffusion-
weighted magnetic resonance imaging. J Am Coll Cardiol 2010;55:1427-32.
19. Kahlert P, Knipp SC, Schlamann M et al. Silent and apparent cerebral ischemia after
percutaneous transfemoral aortic valve implantation: a diffusion-weighted magnetic
resonance imaging study. Circulation 2010;121:870-8.
20. 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.
21. Spaziano M, Francese DP, Leon MB, Genereux P. Imaging and functional testing to
assess clinical and subclinical neurological events after transcatheter or surgical aortic
valve replacement: a comprehensive review. J Am Coll Cardiol 2014;64:1950-63.
22. Van Mieghem NM, Schipper ME, Ladich E et al. Histopathology of embolic debris
captured during transcatheter aortic valve replacement. Circulation 2013;127:2194-
201.
23. Schmidt T, Schluter M, Alessandrini H et al. Histology of debris captured by a
cerebral protection system during transcatheter valve-in-valve implantation. Heart
2016; 102:1573-80.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
24. 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.
25. 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.
26. Van Mieghem NM, van Gils L, Ahmad H et al. Filter-based cerebral embolic
protection with transcatheter aortic valve implantation: the randomised MISTRAL-C
trial. EuroIntervention 2016;12:499-507.
27. Campelo-Parada F, Regueiro A, Dumont E et al. Embolic protection in patients
undergoing transaortic transcatheter aortic valve replacement: initial experience with
the TriGuard HDH embolic deflection device. J Card Surg 2016 doi:
10.1111/jocs.12822. (epub ahead of print).
28. Pagnesi M, Martino EA, Chiarito M et al. Silent cerebral injury after transcatheter
aortic valve implantation and the preventive role of embolic protection devices: A
systematic review and meta-analysis. Int J Cardiol 2016;221:97-106.
29. 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 2016 doi: 10.1002/ccd.26566. [Epub ahead of print].
30. Wendt D, Kleinbongard P, Knipp S et al. Intraaortic Protection From Embolization in
Patients Undergoing Transaortic Transcatheter Aortic Valve Implantation. Ann
Thorac Surg 2015;100:686-91.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
31. Naber CK, Ghanem A, Abizaid AA et al. First-in-man use of a novel embolic
protection device for patients undergoing transcatheter aortic valve implantation.
EuroIntervention 2012;8:43-50.
32. Kappetein AP, Head SJ, Genereux P et al. Updated standardized endpoint definitions
for transcatheter aortic valve implantation: the Valve Academic Research
Consortium-2 consensus document. EuroIntervention 2012;8:782-95.
33. Iqbal MB, Nadra IJ, Ding L et al. Embolic protection device use and its association
with procedural safety and long-term outcomes following saphenous vein graft
intervention: An analysis from the British Columbia Cardiac registry. Catheter
Cardiovasc Interv 2016;88:73-83.
34. Mendes BC, Oderich GS, Fleming MD et al. Clinical significance of embolic events
in patients undergoing endovascular femoropopliteal interventions with or without
embolic protection devices. J Vasc Surg 2014;59:359-367.e1.
35. Paul TK, Lee JH, White CJ. Renal embolic protection devices improve blood flow
after stenting for atherosclerotic renal artery stenosis. Catheter Cardiovasc Interv
2012;80:1019-22.
36. Roberts D, Niazi K, Miller W et al. Effective endovascular treatment of calcified
femoropopliteal disease with directional atherectomy and distal embolic protection:
final results of the DEFINITIVE Ca(+)(+) trial. Catheter Cardiovasc Interv
2014;84:236-44.
37. Ederle J, Davagnanam I, van der Worp HB et al. Effect of white-matter lesions on the
risk of periprocedural stroke after carotid artery stenting versus endarterectomy in the
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
International Carotid Stenting Study (ICSS): a prespecified analysis of data from a
randomised trial. Lancet Neurology 2013;12:866-72.
38. Mashour GA, Moore LE, Lele AV, Robicsek SA, Gelb AW. Perioperative care of
patients at high risk for stroke during or after non-cardiac, non-neurologic surgery:
consensus statement from the Society for Neuroscience in Anesthesiology and
Critical Care*. J Neurosurg Anesthesiol 2014;26:273-85.
39. Ng JL, Chan MT, Gelb AW. Perioperative stroke in noncardiac, nonneurosurgical
surgery. Anesthesiology 2011;115:879-90.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
FIGURE LEGENDS
Figure 1: Sentinel Device
Panel A shows the Sentinel device. Panel B shows the proximal filter is placed in the innominate
artery and the distal filter is placed in the left carotid artery. The pore size of the filters is 140
micron. Panel C shows fluoroscopic image of the device.
Figure 2: Study Flow
Sentinel study randomized patients in 3 arms including imaging control arm, imaging device arm
or safety arm with 1:1:1 randomization. Patients in the safety arm were followed for clinical
events without MRI (magnetic resonance imaging) or neurocognitive (NC) testing. The figure
shows the patients and reasons for not having MRI or NC testing. TAVR: Transcatheter aortic
valve replacement, F/U: follow-up, W/D: study withdrawal, PPM: Permanent pacemaker, TEP:
Thromboembolic protection.
Figure 3: Primary safety (a) and efficacy (b) endpoints
Panel A shows MACCE in the device and safety arms was 7.3% and the upper bound of the 95%
confidence interval (11.4%) was less than the 18.3% performance goal (p<0.001 for non-
inferiority). MACCE in the control arm (9.9%) was not statistically different compared with the
device and safety arms (p=0.405).
Panel B shows median total new lesion volume in protected territories in control and device arm.
The median total new lesion volume in protected territories was 42% lower, meeting the 30% pre
specified treatment effect success criteria, but was not significantly different in device vs. control
arms (102.8 mm3 versus 178.0 mm3, p=0.33). This is a box plot with central line representing
median and box representing the interquartile range (25th-75th percentile).
Figure 4: Histopathology Particulate Debris Analysis
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Study analyzed the particulate debris from filters. Panel A shows rate of debris capture by type
and panel B shows average number of particles captured by size in maximum diameter.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Table 1. Baseline Characteristics and Procedural Details
Control Arm (N=119)
Device Arm (N=121)
Safety Arm (N=123)
Total Randomized (N=363)
P-value1
Age 85.0 [78.4, 89.4] 83.1 [77.2, 87.2] 82.5 [76.4, 87.5] 83.4 [78.0, 88.2] 0.1371 Male 51.3% (61/119) 47.9% (58/121) 44.7% (55/123) 47.9% (174/363) 0.6062 BMI 27.0 [23.8, 30.5] 27.0 [23.7, 32.1] 26.2 [22.7, 30.4] 26.7 [23.4, 30.8] 0.3103 STS PROM Score 6.6 [4.5, 8.6] 5.6 [3.9, 8.0] 5.8 [3.9, 8.0] 6.0 [4.2, 8.1] 0.0860 History of Atrial Fibrillation
30.3% (36/119) 34.7% (42/121) 30.1% (37/123) 31.7% (115/363) 0.6932
History of PVD 15.1% (18/119) 14.0% (17/121) 16.3% (20/123) 15.2% (55/363) 0.9003 History of CAD 55.5% (66/119) 50.4% (61/121) 53.7% (66/123) 53.2% (193/363) 0.7341 Previous CABG 21.0% (25/119) 18.2% (22/121) 14.6% (18/123) 17.9% (65/363) 0.4289 Previous PCI 16.8% (20/119) 17.4% (21/121) 15.4% (19/123) 16.5% (60/363) 0.9367 History of Diabetes
37.8% (45/119) 40.5% (49/121) 26.8% (33/123) 35.0% (127/363) 0.0577
Previous Stroke2 5.0% (6/119) 4.1% (5/121) 8.1% (10/123) 5.8% (21/363) 0.4376 Previous TIA 6.7% (8/119) 7.4% (9/121) 8.1% (10/123) 7.4% (27/363) 0.9678 Heavily Calcified Aorta
2.5% (3/119) 1.7% (2/121) 3.3% (4/123) 2.5% (9/363) 0.7791
NYHA Class III/IV
82.8% (96/116) 84.9% (101/119) 81.7% (98/120) 83.1% (295/355) 0.8077
Lesion Volume as calculated on FLAIR (mm3)
7916.7 [3865.4, 17315.3]
7377.5 [2562.9, 19181.5]
N/A 7847.9
[3243.2, 17854.5] 0.43063
Echocardiographic Findings Valve Area (cm2) 0.7 ± 0.20 (118) 0.7 ± 0.17 (119) 0.7 ± 0.18 (122) 0.7 ± 0.18 (359) 0.6603 Mean aortic valve gradient (mmHg)
41.0 [33.0, 47.0] 42.7 [33.6, 52.0] 41.0 [31.9, 49.0] 41.0 [33.0, 49.0] 0.3334
Procedural Details Sentinel Device Access
0.4918
Radial N/A 91.2%(104/112) 95.0% (114/119) 93.2% (218/231) Brachial N/A 7.0% (8/112) 4.2% (5/119) 5.6% (13/231) Both Filters Deployed
N/A 92.0% (103/112) 96.6% (115/119) 94.4% (218/231) 0.1570
At Least One Filter Deployed
N/A 99.1% (111/112) 100.0% (119/119) 99.6% (230/231) 0.4848
Procedure Time4 68.0 [41.0,
96.0] 83.5 [54.0,
118.0] 78.0 [52.0,
101.0] 74.0 [52.0, 106.0] 0.0050
Fluoroscopy Time 15.0 [9.0, 20.0] 18.0 [12.0, 29.0] 14.0 [10.0, 27.0] 15.0 [10.0, 26.0] 0.0402 TAVR Device Used 0.7176 Sapien XT 16.9% (20/118) 17.5% (21/120) 19.0% (23/121) 17.8% (64/359) Sapien 3 53.4% (63/118) 55.8% (67/120) 47.9% (58/121) 52.4% (188/359) CoreValve 5.9% (7/118) 2.5% (3/120) 3.3% (4/121) 3.9% (14/359) CoreValve Evolut R
23.7% (28/118) 24.2% (29/120) 29.8% (36/121) 25.9% (93/359)
BMI, Body Mass Index; STS PROM, Society of Thoracic Surgeons Predicted Risk of Operative Mortality; PVD, peripheral vascular disease; CAD, coronary artery disease; CABG, coronary artery bypass graft; PCI, percutaneous coronary intervention; TIA, transient ischemic attack; NYHA, New York Heart Association Note: Continuous data presented as Mean ± SD (n) or Median [IQR]. Categorical data presented using % (n/N). 1 P-values are testing for statistical differences across randomized arms. Continuous data are compared using ANOVA for mean, non-parametric ANOVA for median; categorical data are compared using Fisher's exact test.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
2 Defined as neurological deficit lasting >24 hours confirmed by imaging. 3Based on two-sided Wilcoxon test 4Defined as time from first vascular access puncture to achievement of hemostasis at the TAVR access site.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Table 2. Clinical Outcomes
Control Arm Safety + Device Arm p-value 30-day Clinical Outcomes
Any MACCE† 9.9% (11/111) 7.3% (17/234) 0.40
Death (all-cause) 1.8% (2/111) 1.3% (3/234) 0.65
Stroke 9.1% (10/110) 5.6% (13/231) 0.25
Disabling 0.9% (1/109) 0.9% (2/231) 1.00
Non-disabling 8.2% (9/110) 4.8% (11/231) 0.22
AKI (Stage 3) 0% 0.4% (1/231) 1.00
TIA 0% 0.4% (1/231) 1.00
Major Vascular Complication 5.9% (7/119) 8.6% (21/244) 0.53
Radial/Brachial N/A 0.4% (1/244)
Femoral 5.9% (119) 8.2% (20/244) †MACCE defined as Death (any cause), Stroke (any), Acute Kidney Injury (Stage 3)
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Table 3. Median total new lesion volume and number of new lesions (unadjusted analysis, Day 2-7)
Control Arm
n=98 Device Arm
n=91 Hodges-Lehmann Estimate of Location Shift (95% CI) P-value
Median Total New Lesion Volume in Protected Territories, mm3
178.0 (34.3, 482.5)
102.8 (36.9, 423.2)
-21.1 (-94.9, 21.8) 0.33451
Median Total New Lesion volume in All Territories, mm3
309.8 (105.5, 859.6) 294 (69.2, 786.4)
-8.6 (-110.7, 68.6) 0.80761
Median Number of New Lesions in Protected Territories
3 (1, 6) 2 (1, 6) 0 (-1, 0) 0.89792
Median Number of New Lesions in All Territories
5 (2, 10) 3 (2, 10) -1 (-2, 1) 0.76672
Data are presented as median (IQR) 1 Based on Wilcoxon Test 2Based on negative binomial regression model
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Table 4. Neurocognitive Assessments
Control Arm Device Arm
Mean ± SD (n) Change from
Baseline Mean ± SD (min,
max), n Change from
Baseline P-value1
Attention Baseline -0.17 ± 0.88 (117) NA -0.14 ± 0.96 (117) NA NA
2 to 7 Days Post-TAVR
-0.28 ± 1.1 (65) -0.01 ± 0.59 (65) -0.5 ± 1.02 (65) -0.32 ± 0.7 (65) 0.0334
30 Day Follow-Up
0.03 ± 0.88 (92) 0.14 ± 0.51 (92) -0.14 ± 0.93 (93) 0.03 ± 0.55 (93) 0.1778
90 Day Follow-Up
0.11 ± 0.87 (76) 0.23 ± 0.55 (76) 0.06 ± 0.87 (77) 0.2 ± 0.49 (77) 0.6103
Executive Function Baseline -1.36 ± 1.36 (117) NA -1.28 ± 1.3 (117) NA NA
2 to 7 Days Post-TAVR
-1.36 ± 1.36 (63) 0 ± 1 (63) -1.7 ± 1.55 (65) -0.36 ± 1.19 (65) 0.0865
30 Day Follow-Up
-0.99 ± 1.34 (91) 0.25 ± 0.86 (91) -1.2 ± 1.4 (93) 0.14 ± 0.86 (93) 0.4692
90 Day Follow-Up
-0.79 ± 1.21 (76) 0.39 ± 0.86 (76) -0.94 ± 1.16 (77) 0.32 ± 0.79 (77) 0.4585
Processing Speed Baseline -0.23 ± 0.95 (117) NA -0.24 ± 0.91 (117) NA NA
2 to 7 Days Post-TAVR
-0.47 ± 0.87 (63) -0.05 ± 0.38 (63) -0.51 ± 0.94 (65) -0.06 ± 0.5 (65) 0.9698
30 Day Follow-Up
-0.01 ± 0.86 (90) 0.12 ± 0.39 (90) -0.11 ± 1 (92) 0.14 ± 0.43 (92) 0.5470
90 Day Follow-Up
0.14 ± 0.81 (76) 0.27 ± 0.43 (76) -0.05 ± 0.86 (77) 0.21 ± 0.46 (77) 0.7272
Verbal Memory Baseline -0.64 ± 1.07 (117) NA -0.85 ± 0.94 (117) NA NA
2 to 7 Days Post-TAVR
-1.06 ± 1.06 (66) -0.63 ± 0.79 (66) -1.34 ± 1.3 (66) -0.7 ± 1.03 (66) 0.8534
30 Day Follow-Up
-0.88 ± 1.18 (91) -0.32 ± 0.8 (91) -1.09 ± 1.13 (93) -0.28 ± 0.85 (93) 0.4644
90 Day Follow-Up
-0.61 ± 1.11 (76) -0.13 ± 0.78 (76) -0.86 ± 1.05 (77) -0.02 ± 0.78 (77) 0.2933
Visual Memory Baseline -0.72 ± 0.96 (117) NA -0.83 ± 0.85 (115) NA NA
2 to 7 Days Post-TAVR
-0.7 ± 1.01 (65) 0.06 ± 0.86 (65) -0.87 ± 0.94 (66) -0.19 ± 0.96 (65) 0.1340
30 Day Follow-Up
-1.02 ± 1.03 (92) -0.36 ± 0.79 (92) -1.28 ± 0.94 (93) -0.46 ± 0.91 (92) 0.4282
90 Day Follow-Up
-0.53 ± 0.98 (76) 0.12 ± 0.81 (76) -0.58 ± 0.98 (77) 0.17 ± 0.86 (77) 0.6942
Mental Status2 Baseline 26.07 ± 3.32 (116) NA 26.12 ± 2.95 (114) NA NA
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Control Arm Device Arm
Mean ± SD (n) Change from
Baseline Mean ± SD (min,
max), n Change from
Baseline P-value1
2 to 7 Days Post-TAVR
26.02 ± 2.81 (62) -0.25 ± 2.47 (61) 25.41 ± 3.58 (64) -0.73 ± 2.95 (63) NA
30 Day Follow-Up
26.82 ± 2.74 (89) 0.52 ± 2.55 (89) 26.24 ± 2.84 (92) 0.41 ± 2.67 (91) NA
90 Day Follow-Up
27.24 ± 2.47 (76) 0.96 ± 2.42 (76) 26.56 ± 2.6 (77) 0.3 ± 2.76 (76) NA
Depression2 Baseline 2.7 ± 2.28 (116) NA 3.33 ± 2.62 (114) NA NA
2 to 7 Days Post-TAVR
2.26 ± 2.53 (62) -0.48 ± 1.41 (61) 2.77 ± 2.83 (64) -0.57 ± 2.12 (63) NA
30 Day Follow-Up
2.07 ± 2.14 (89) -0.73 ± 1.57 (89) 2.38 ± 2.43 (91) -0.68 ± 2.02 (90) NA
90 Day Follow-Up
2.37 ± 2.75 (76) -0.49 ± 2.16 (76) 2.53 ± 2.66 (77) -0.75 ± 2.22 (76) NA
Overall Composite Score
Baseline -0.63 ± 0.79 (117) NA -0.66 ± 0.75 (117) NA NA
2 to 7 Days Post-TAVR
-0.81 ± 0.93 (66) -0.16 ± 0.58 (66) -1 ± 0.95 (66) -0.33 ± 0.65 (66) 0.1894
30 Day Follow-Up
-0.59 ± 0.79 (92) -0.03 ± 0.37 (92) -0.77 ± 0.82 (93) -0.09 ± 0.44 (93) 0.4207
90 Day Follow-Up
-0.34 ± 0.72 (76) 0.18 ± 0.35 (76) -0.47 ± 0.76 (77) 0.18 ± 0.38 (77) 0.9409
1P-values based on model adjusted for education, baseline Geriatric Depression Score, and baseline Mini Mental State Score. 2Raw score provided for Mental State and Depression.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Online Supplemental Appendix Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement
Kapadia, Kodali, et al.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPTTable of Contents
List of Study Sites and Investigators
Appendix 1: Description of the MRI acquisition and analyses techniques
Appendix 2: Description of the neurocognitive function domains and methods
Appendix 3: Multivariable modeling methodology
Table 1: Baseline characteristics of the Safety Cohort – ITT, evaluable for MACCE
Table 2: Baseline characteristics of patients with and without paired baseline and 2-7 day MRI
Table 3: Baseline patient characteristics for the paired MR imaging population
Table 4: Baseline patient characteristics for the paired neurocognitive function population
Table 5: MR new lesion volume and number data by valve type (2-7 days)
Table 6: MR new lesion volume (30 days)
Table 7: Univariate and Multivariable analysis of predictors of new lesion volume
Table 8: Multivariable adjustment model new lesion volume
Table 9: Multivariable adjustment model new lesion volume by valve type
Figure 1: Correlation of neurocognitive function and MRI new lesion volume
References
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPTThe SENTINEL Trial Site and Investigator Listing
Cedars-Sinai Medical Center PI: Raj Makkar
Sub-I: Hasanian Al-Jilaihawi Los Angeles, CA United States
Cleveland Clinic
PI: Samir Kapadia Sub-I: Amar Krishnaswamy
Sub-I: E. Murat Tuzcu Sub-I: Stephanie Mick
Cleveland, OH United States
Columbia University Medical Center
PI: Susheel Kodali Sub-I: Tamin Nazif
New York, NY United States
Emory University Hospital Midtown
PI: Vinod Thourani Sub-I: Vasilis Babaliaros
Sub-I: Chandan Devireddy Sub-I: Kreton Mavromatis
Atlanta, GA United States
MedStar Washington Hospital Center
PI: Ron Waksman Sub-I: Lowell Satler
Sub-I: Augusto Pichard Washington, DC
United States
University of Pennsylvania PI: Wilson Szeto
Sub-I: Saif Anwaruddin Sub-I: Prashanth Vallabhajosyula
Sub-I: Jay Giri Sub-I: Howard Herrmann
Philadelphia, PA United States
Barnes - Jewish Hospital
PI: Alan Zajarias Sub-I: John Lasala
St. Louis, MO United States
Henry Ford Health System PI: Adam Greenbaum Sub-I: William O’Neill
Sub-I: Marvin Eng Detroit, MI
United States
Morton Plant Hospital PI: Joshua Rovin Sub-I: Lang Lin
Sub-I: Douglas Spriggs Clearwater, FL United States
Weill Cornell Medical Center
PI: Shing-Chiu Wong Sub-I: Geoffrey Bergman
Sub-I: Arash Salemi New York, NY United States
The University of Texas - Health Science Center
PI: Richard Smalling Sub-I: Biswajit Kar
Sub-I: Pranav Loyalka Houston, TX
United States
University of Virginia Health System PI: D. Scott Lim
Sub-I: Michael Ragosta Charlottesville, VA
United States
University of Washington PI: Mark Reisman
Sub-I: James McCabe Sub-I: Creighton Don
Seattle, WA United States
Icahn School of Medicine at Mount Sinai
PI: Samin Sharma Sub-I: Annapoorna Kini Sub-I: George Dangas
New York, NY United States
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Sentara Norfolk General Hospital PI: Paul Mahoney
Norfolk, VA United States
St. Thomas Hospital
PI: Andrew Morse Sub-I: Mark Stankewicz Sub-I: Evelio Rodriguez
Nashville, TN United States
Herzzentrum Leipzig GmbH -Universitätsklinik
PI: Axel Linke Sub-I: Norman Mangner
Sub-I: Felix Woitek Leipzig
Germany
Asklepios Klinik St. Georg PI: Christian Frerker
Hamburg Germany
St. Luke's Hospital
PI: David Cohen Kansas City, MO
United States
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Appendix 1: MRI acquisition and analysis methodology
STUDY PROCEDURES
Magnetic Resonance Imaging
Brain MRI assessments were performed at baseline, 2-7 days and 30 days post procedure. MRI scans were obtained
according to a protocol provided by the MRI reading center (Buffalo Neuroimaging Analysis Center, Buffalo, NY,
USA) that also performed all sequential co-registration of MRI scans in a blinded manner. MR images at each site
were acquired only on a 3 Tesla certified and validated system at 0, 2-7 and 30 days. Diffusion weighted images
(DWI) were acquired with a 2D echo planar sequence with one b=0 image and 3 orthogonal diffusion directions
with b=1000 s/mm1. Additional parameters were: repetition time (TR) = 13000ms, echo time (TE) = 100ms, slice
thickness = 3mm (no gap), acquisition matrix 204 x 156, final voxel size = 1.25mm x 1.25mm x 3.0mm. The DWI
images were required at baseline and 2-7 days post procedure on all evaluable imaging cohort patients. Fluid
attenuated inversion recovery (FLAIR) images were acquired with a 2D spin echo inversion recovery sequence with
an inversion time (TI) of 2580ms. Additional parameters were: TR = 9730ms, TE=92ms, slice thickness = 2mm (no
gap), acquisition matrix 256 x 186, final voxel size = 0.94mm x 1.17mm x 2.0mm. The FLAIR images were
required at baseline and 30 days post procedure on all evaluable imaging cohort patients. High resolution T1-
weighted images (hires-T1) were acquired with an MP-RAGE sequence. Additional parameters were: TR = 1690ms,
TE=2.57ms, flip angle (FA) = 12, TI=1100ms, slice thickness = 1.5mm (no gap), acquisition matrix 256 x 224, final
voxel size = 1.00mm x 1.00mm x 1.5mm. Finally, either a manufacturer-based dual-echo GRE sequence was used to
acquire B0 field maps (voxel size = 4.00mm x 4.00mm x 5.00mm.), or the DWI images were acquired with two
different phase encoding directions. Minor site-specific deviations were allowed to accommodate individual scanner
capabilities, provided they were approved by MR physicists at the reading center and were acquired consistently
within the site.
DWI acquisitions are subject to substantial artifacts, including eddy current distortions, susceptibility-induced
warping, and signal dropout. Although these do not have a substantial impact on clinical assessment of large lesions
associated with stroke or transient ischemic attack (TIA), they are quite large relative to the small embolic lesions
resulting from the TAVI procedure – distortions may easily be on the order of 1cm, while lesions may be as small as
a few mm. Therefore, a number of pre-processing steps were taken to improve image quality and subsequent
analysis. First, the raw DWI images were corrected for distortions using FMRIB’s FSL FDT library.2 This was
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
accomplished using either directly acquired fieldmaps or by inferring the field map from paired, phase-reversed
DWI acquisitions.3 Next, the diffusion b=0 (b0) and three corrected b=1000 diffusion-encoded raw images were
combined to create trace and apparent diffusivity coefficient (ADC) images.
Because the lesions are often so small, subtraction imaging was also employed to increase lesion salience.4 Baseline
DWI and FLAIR images were voxel-wise subtracted from follow-up images to produce direct change maps. To
facilitate this subtraction approach, additional pre-processing steps were performed. First, low-frequency spatial
intensity inhomogeneities on FLAIR images were corrected using N3.5 Corrected FLAIR and DWI trace images
were further standardized by applying a piecewise-linear histogram adjustment method to compensate for scan-to-
scan variability in absolute intensity.6 Finally, to facilitate direct longitudinal analysis, all within-subject scans were
co-registered to each subject’s baseline FLAIR image using FLIRT with 6 degrees of freedom.7
Lesions were delineated on corrected and aligned 2-7, and 30 day DWI trace images and 30 day FLAIR images
using a semi-automated contouring technique provided by the JIM software package, with simultaneous reference to
the ADC and subtraction images.8 Using this approach, a trained operator identified lesions individually, and for
each lesion an assistive algorithm delineated a highly reproducible iso-contour at the maximum local gradient. The
operator viewed all images and change maps simultaneously to increase confidence, and also coded lesions as new
or persistent.
In addition to lesion counts and volumetry, vascular territory was also assessed using an atlas-based technique. For
this purpose, a vascular territory atlas was manually created in the standard MNI 152 template space9 based on
existing literature,10 and including 28 separate regions. Individual hires-T1 images were used to non-linearly align
this atlas to individual lesion maps. First, individuals’ hires-T1 images were corrected for intensity inhomogeneity
using N3, then aligned to the MNI 152 template using a two-stage process consisting of an initial rigid-body co-
registration followed by composition with a warp field obtained from a non-linear warping technique.11 These
transforms were then inverted, and applied to the original atlas. Lesion number and volume within each vascular
territory were than assessed separately.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Appendix 2: Neurocognitive test battery The Stroke and Cerebrovascular Disease Division, Department of Neurology, Columbia University Medical Center designed a neurocognitive test battery tailored to the presumed mechanisms of cognitive impairment in the setting of transcatheter aortic-valve implantation (TAVI) and the deployment of this investigational cerebral protection device: perfusion failure in the cerebral circulation and microembolism to the brain. In the former case, cognitive dysfunction is global (bi-hemispheral) in nature, producing deficits in processing speed, executive function, and attention/concentration12. In the instance of microembolism, these particles are too small to cause the branch occlusions needed for focal neurocognitive syndromes, such as aphasia (left hemisphere) or visual neglect (right hemisphere).13 Rather, there is a diffuse impact that can be either bi-hemispheral or within a single hemisphere across a wide swath of brain territory in the MCA and ACA distribution territories.12 A weakness in prior studies examining the neurocognitive impact of TAVI is the lack of specificity and sensitivity in the tests used. Either measures are too brief (e.g. the Mini Mental State Exam, or MMSE)14, or have not been validated in the setting of diffuse vascular disease (e.g., RBANS)15, raising concern about Type II error. The battery employed in this study, and its variants, have been used in both NIH-funded (NHLBI, NINDS) and industry-sponsored studies, assessing neurocognitive sequelae in end-stage heart failure and LVAD support16, 17, carotid artery disease18-20, and recently piloted in the PARTNER 2 trial to establish feasibility in the target demographic. All tests are standardized, well-validated instruments in the literature21, and provide extensive normative data permitting baseline analysis and change over time, at 30 and 90 days post implantation. Both efficacy (improvement) and safety (worsening) can be derived from these measures. The MMSE was given only to establish comparability to prior work and to serve as a covariate for baseline mental status. Depression is also a covariate.
Neurocognitive Test Laterality Domain Trails A Bi-hemispheral Attention Trails B Bi-hemispheral Executive Function Digit Span Bi-hemispheral Attention Digit Symbol Bi-hemispheral Processing Speed Letter-Number Sequencing Bi-hemispheral Working Memory Controlled Oral Word Association Left Hemisphere Processing Speed Hopkins Verbal Learning Test Left Hemisphere Verbal Memory Rey Complex Figure (Copy) Right Hemisphere Executive Function Brief Visual Memory Test Right Hemisphere Visual Memory Mini Mental State Exam --- Mental Status Geriatric Depression Scale --- Depression Developed by Ronald M. Lazar, PhD, FAHA, FAAN, Professor and Marykay Pavol, PhD, ABCN, Assistant Professor, Doris & Stanley Tananbaum Stroke Center Neurological Institute of New York
Primary Neurocognitive Analysis: Comparison of the change in composite neurocognitive z-scores from Baseline to 30-days post-TAVR between the group in whom the Sentinel device was used and the group that did not receive distal protection, controlling for MMSE and the depression scores.
Composite Score Calculation: A z-score for each domain was calculated based on the normative means and standard deviations for each neurocognitive test supplied by the Neurocognitive Core Lab at Columbia. These norms were stratified by age and education (when possible). When there is more than one test for a given domain (e.g., Trails A and Digit Span for “Attention”), an average was computed from the z-scores comprising the tests for that domain. When there is more than one outcome for a given test (e.g., Total Recall, Delayed Recall and Recognition for “Verbal Memory”), a mean z-score was derived from these outcomes. The composite
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
neurocognitive z-score for each treatment group is the average z-score from all domains (Attention, Executive Function, Processing Speed, Verbal Memory, Visual Memory). Change scores were calculated (by domain) by subtracting post-surgical exam scores from the baseline scores.
Secondary Neurocognitive Analyses:
1. The interaction of the 30-day composite neurocognitive change score for each treatment group with lesion outcomes from post-TAVR DWI, 30-Day FLAIR, and Baseline FLAIR.
2. Change in neurocognitive composite scores from baseline to 7-days and baseline to 90-days post-TAVR for each treatment group.
3. Baseline composite neurocognitive scores for all study participants to characterize pre-TAVR cognitive function and correlations between these baseline composite scores and baseline FLAIR imaging variables.
4. Change in individual domain scores from Baseline to 7-days, 30-days and 90-days post-TAVR between the group in whom the Sentinel device was used and the group that did not receive distal protection, and the relationships among these domain scores to Baseline FLAIR, post-TAVR DWI and 30-Day FLAIR imaging variables.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Appendix 3. Multivariable model methodology
Introduction During the time of design and initiation of the Sentinel trial, only one TAVR device was commercially available in the U.S. However, several additional TAVR devices became available during the course of the trial and were not stratified in the randomization. In addition, given that this is a first-in-kind study and the data evidenced significant skew and large variance, it was possible that a key baseline that was not pre-identified. This supplement will describe the steps taken to address these concerns in a post-hoc analysis.
Analysis Population The ITT population used in this analysis are all randomized patients that have had a MRI follow-up post TAVR irrespective of whether the follow-up falls within the 2-7 day windows as specified by the protocol.
Normalizing the Outcome: New Volumes in Protected or All Territories Post TAVR Procedure A log transformation was required to normalize the skewed end point lesion volume data, baseline T2-FLAIR volumes, and baseline HU-850 aortic valve calcification measures. The high frequency of zero values required a correction to the logarithmic transformation. Zero values were set to 5 mm3, the midpoint of zero the MRI detection limit of 10 mm3. In the rest of this supplement, the prefix LNZ will indicate that the data has been transformed as described in this section. Figure S3-1 shows the distribution of the LNZ transformed lesion volumes in protected and all territories.
Figure S3-1: Histogram of New Volumes on the Log Base E scale where zero volumes are set to 5 mm3 on the arithmetic scale and Log Base E[5] on the log scale.
Identifying Key Baseline Covariates A comprehensive univariate analysis of all baseline characteristics (characteristics that existed before the TAVR procedure) was performed with the baseline characteristic as predictor and the transformed new volumes in protected territories as the outcome. Table S3-1 provides the list of baseline characteristics that were tested.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Table S3-1: List of Baseline Characteristics used for Univariate analyses
Characteristic Characteristic Characteristic
Acute Success [Y/N] Distal Vessel Diameter Pre-Dilation [Y/N]
Age Dual Antiplatelet Therapy [Y/N] Procedure Time
Antithrombotic Medications [Y/N] Education Proximal Vessel Diameter
Any Adverse Event(s) during the procedure
Ethnicity Race
Any Diabetes [Y/N] General anesthesia used [Y/N] Region[USA/Germany]
Any other clinically significant infections, allergies, diseases, or surgeries [Y/N]
Heart Rate Respiration
AVA Indexed Height (inches) Rosenhek2
Baseline Geriatric Depression Score History of Atrial Fibrillation [Y/N] Sex [Female/Male]
Baseline Modified Rankin Scale History of Peripheral vascular disease [Y/N]
STS
Baseline Neurocognitive z Overall lnz[baseline volumes] Systole Blood Pressure
BMI lnz[HU_850Volume] TAVR Access
BSA Mean aortic valve area Temperature
Center Modified Allen Result [Normal/Abnormal]]
TIA [Y/N]
Coronary Artery Disease [Y/N] Neurological Deficit [Y/N] Weight (lbs)
CT Result[Normal/Abnormal] NIH Stroke Scale
Currently Taking Medications [Y/N] Peak Aortic Jet Velocity
Diastole Blood Pressure Porcelin Aorta [Y/N]
Dilatation[Yes/No] Post Dilatation
Baseline T2-FLAIR and HU850 Volume measurements were transformed using the LNZ transformation previously described.
Any baseline characteristic with a p-value less than or equal to 0.1 (see Table S3-1 for a list of characteristics tested) were included in a step-wise multi-variable regression model (
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Table S3-2). The step wise regression model minimized the AIC and variables entered the model if they had a p-value <=0.1 and exited the model if the p-value was > 0.05. The results of the forward and backward stepwise regression model is shown in Table S3-3. Only LNZ[Baseline T2-FLAIR Volumes] was retained out of all the variables listed in
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Table S3-2. Only the LNZ[Baseline T2-FLAIR Volumes] was predictive of LNZ[New Volumes in Protected Territories].
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Table S3-2: Results of Univariate Analysis of Baseline Characteristics predicting transformed New Volumes in Protected Territories
Source Pr > F Source Pr > F Baseline T2-FLAIR Volume Strata (High/Low)
<.0001 Weight (lbs) 0.0568
LNZ[Baseline Lesion Volume] <.0001 Neurological Deficit [Y/N] 0.0594LNZ[Baseline T2-FLAIR Lesion Number]
0.0024 Currently taking medications (Y/N) 0.0632
LNZ[HU_850 Volume] 0.009 Peak Aortic Jet Velocity 0.0636Age 0.0155 STS Risk score 0.0643Dilitation Post TAVR Procedure 0.034 Rosenhek2 0.071Temperatue 0.0495 Neurocognitve Verbal Memory Score 0.078BSA 0.0517 History of Percutaneous Coronary Intervention (Y/N) 0.0884
Table S3-3: Results of step wise regression model
Parameter DF Estimate StandardError
t Value P-Value
Intercept 1 0.88 1.041516 0.85 0.39.
LNZ[Baseline T2-FLAIR Volumes] 1 0.44 0.116631 3.83 0.0002
Error! Reference source not found.3- 2 shows a scatter plot of Post Procedure New Volumes in Protected Territories vs. Baseline T2-FLAIR Volumes on a log base 10 scale (zero values are set to 1). There is a clear relationship between the two. However, there is a great deal of variability. Therefore, to reduce the additional variability that might be added to the model if one uses the continuous data, the baseline data was transformed into a binary variable, volumes above the median of the pooled baseline data (high) or below the median of the baseline data (low).
The covariate assessment was repeated for the new volumes in all territories with the same results.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Figure S3-2: Post Procedure New Volumes in Protected Territories vs. Baseline T2-FLAIR Volumes
Building the model to assess treatment effects In the previous sections, baseline T2-FLAIR volume was identified as the key baseline covariate. Further, the randomization was not stratified by TAVR device. Potential differences due to physician selection preferences or design differences may affect the outcome and are of scientific interest in the burgeoning TAVR market, therefore the TAVR Device was added to the model as described below.
~ + + +
Where Yijk is either the LNZ[New Volumes in Protected Territories] or LNZ[New Volumes in All Territories]
In order to get stable TAVR device estimates from the model, Medtronic CoreValve which only contributed 7 patients with imaging follow-up, were excluded from the analysis.
Results The p-values in reported in this section represent the adjusted p-values within each ANOVA. The results of the analysis of variance for LNZ[New Volumes in Protected Territories] are in Table S4 and Figure S3 1. Once the model is adjusted for baseline T2-FLAIR volumes, TAVR device and the interaction between TAVR device and treatment arm, treatment arm as a main effect is shown to be a significant predictor of the outcome (p=0.025).
It should be noted that there is a significant interaction effect between treatment arm and TAVR device. The overall treatment effect, after adjustment for TAVR Device, and the interaction between TAVR and Treatment, is a 42% reduction in post procedure new lesion volume in protected areas [see Supplemental Table 6 following this appendix). However, SAPIEN 3 generated the lowest post procedure new lesion volume (30% - 50% lower than the other TAVR devices; see Supplemental Table 6). Therefore, SAPIEN 3 derived the least benefit from the use of the Sentinel device resulting in little to no difference between the treatment arms. This is responsible for the significant interaction effect between the device and treatment. Unfortunately, since the randomization was not stratified by TAVR device, the low new lesion volumes in the S3 TAVR device could be due to a number of reasons including the influence of the use of clinician judgement when matching device to patient.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
This interaction effect may be due to unknown factors associated with clinician judgement as to which device to use at the time of the procedure. Therefore, while the impact of the treatment and its interaction with TAVR device on the outcome can be surmised from this model, the size of the treatment effect requires a more rigorous design that controls for baseline volume and randomizes the TAVR device to the patient.
Table S4-3: Results of Analysis of Variance Using LNZ[New Volumes in Protected Territories]
Effect Numerator DF Denominator DF F Value P-value
BL T2-FLAIR Lesion Volume (High/Low) 1 175 19.08 <.0001
Valve Type 2 175 1.81 0.1666
Arm 1 175 5.13 0.0248
Valve Type*Arm 2 175 4.24 0.0159
Figure S3 1: Diagnostic Plot for the Analysis of Variance for LNZ[New Volumes in Protected territories]
Residual by Predicted Plot
-
Sensitivity analyses The analysis of variance for both the LNZ[New Volumes in Protected Territories] and LNZ[New Volumes in All Territories] was repeated with using the LNZ[Baseline Volumes] as a continuous variable. The overall results were the same except the p-value for treatment arm increased to 0.041 and 0.078 for LNZ[New Volumes in Protected Territories] and LNZ[New Volumes in All Territories] respectively.
The analysis of variance was also repeated using the ranks of the New Volumes in Protected or All territories as outcome, essentially making the outcome a uniform distribution. The p-values for the treatment arm was the similar, 0.031 and .066 for LNZ[New Volumes in Protected Territories] and LNZ[New Volumes in All Territories] respectively.
-4
-2
0
2
4
2 4 6 8 10
Resid
ual
Predicted
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Table 1. Baseline characteristics of the Safety Cohort – ITT, evaluable for MACCE
Safety+Test
(N=234) Control (N=111)
Total (N=345) P-value1
Age - years 83.1 [77.2, 87.5] n=234
85.0 [78.5, 89.0] n=111
83.8 [78.0, 87.9] n=345
0.0896
Male 47.4% (111/234) 49.5% (55/111) 48.1% (166/345) 0.7305
BMI 26.4 [23.2, 30.9] n=231
27.1 [24.0, 30.6] n=109
26.9 [23.4, 30.8] n=340
0.6580
STS PROM Score 5.8 [4.0, 8.0] n=234
6.4 [4.5, 8.6] n=111
6.0 [4.2, 8.1] n=345
0.0565
History of Atrial Fibrillation
33.3% (78/234) 31.5% (35/111) 32.8% (113/345) 0.8063
History of PVD 15.4% (36/234) 14.4% (16/111) 15.1% (52/345) 0.8732
History of CAD 52.1% (122/234) 55.0% (61/111) 53.0% (183/345) 0.6456
Previous CABG 17.1% (40/234) 21.6% (24/111) 18.6% (64/345) 0.3737
Previous PCI 16.7% (39/234) 16.2% (18/111) 16.5% (57/345) 1.0000
History of Type II Diabetes
32.5% (76/234) 38.7% (43/111) 34.5% (119/345) 0.2761
Previous Stroke2 5.6% (13/234) 1.8% (2/111) 4.3% (15/345) 0.1577
Previous TIA 8.1% (19/234) 7.2% (8/111) 7.8% (27/345) 0.8336
Heavily Calcified Aorta 2.1% (5/234) 1.8% (2/111) 2.0% (7/345) 1.0000
NYHA Class III/IV 83.5% (192/230) 82.4% (89/108) 83.1% (281/338) 0.9077
Echocardiographic Findings
Valve Area (cm2) 0.7 ± 0.17 (231) 0.7 ± 0.20 (110) 0.7 ± 0.18 (341) 0.9542
Mean aortic valve gradient (mmHg)
41.5 [33.0, 50.0] n=229
41.0 [32.0, 47.0] n=110
41.0 [32.4, 49.0] n=339
0.3564
Note: Continuous data presented as Mean ± SD (n) or Median [IQR] (n). Categorical data presented using % (n/N). 1 P-values are testing for statistical differences across randomized arms. Continuous data are compared using ANOVA; categorical data are compared using Fisher's exact test. 2 Defined as neurological deficit lasting more than 24 hours confirmed by imaging.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Table 2. Baseline characteristics of patients with and without paired baseline and 2-7 day MRI
Observed MRI
(N=189) Missing MRI
(N=51) Total
(N=240) P-value1
Age - years 84.1 [78.5, 87.6] (189)
83.1 [75.4, 89.4] (51)
83.8 [78.1, 88.3] (240)
0.5216
Male 47.6% (90/189) 56.9% (29/51) 49.6% (119/240) 0.2712
BMI 27.0 [23.7, 30.8] (186)
27.7 [24.5, 32.1] (50)
27.0 [23.8, 31.0] (236)
0.2921
STS PROM Score 6.0 [4.4, 8.0] (189) 6.9 [3.8, 9.3] (51) 6.0 [4.2, 8.2] (240) 0.6404
History of Atrial Fibrillation
33.3% (63/189) 29.4% (15/51) 32.5% (78/240) 0.7364
History of PVD 14.8% (28/189) 13.7% (7/51) 14.6% (35/240) 1.0000
History of CAD 53.4% (101/189) 51.0% (26/51) 52.9% (127/240) 0.7550
Previous CABG 23.3% (44/189) 5.9% (3/51) 19.6% (47/240) 0.0048
Previous PCI 15.9% (30/189) 21.6% (11/51) 17.1% (41/240) 0.4012
History of Type II Diabetes
37.6% (71/189) 41.2% (21/51) 38.3% (92/240) 0.6309
Previous Stroke2 3.2% (6/189) 9.8% (5/51) 4.6% (11/240) 0.0590
Previous TIA 7.4% (14/189) 5.9% (3/51) 7.1% (17/240) 1.0000
Heavily Calcified Aorta 2.1% (4/189) 2.0% (1/51) 2.1% (5/240) 1.0000
NYHA Class III/IV 83.7% (154/184) 84.3% (43/51) 83.8% (197/235) 0.2825
Lesion Volume as calculated on FLAIR (mm3)
7783.6 [2982.1, 18224.4] (189)
10285.9 [4638.0, 17038.5] (39)
7847.9 [3243.2, 17854.5] (228)
0.3318
Echocardiographic Findings
Valve Area (cm2) 0.7 ± 0.18 (187) 0.7 ± 0.18 (50) 0.7 ± 0.18 (237) 0.2974
Mean aortic valve gradient (mmHg)
40.6 [32.0, 47.7] (186)
44.5 [40.0, 56.0] (50)
41.1 [33.5, 49.2] (236)
0.0029
Note: Continuous data presented as Mean ± SD (n) or Median [IQR] (n). Categorical data presented using % (n/N). 1 P-values are testing for statistical differences across randomized arms. Continuous data are compared using ANOVA for mean or two-sided Wilcoxon text for median; categorical data are compared using Fisher's exact test. 2 Defined as neurological deficit lasting more than 24 hours confirmed by imaging.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Table 3. Baseline and procedural characteristics of patients with paired baseline and 2-7 day MRI – ITT, complete case population
Control Arm
(N=98) Device Arm
(N=91) Total
(N=189) P-value1
Age 85.0 [79.7, 89.0] (98)
83.2 [77.8, 87.2] (91)
84.1 [78.5, 87.6] (189)
0.1397
Male 50.0% (49/98) 45.1% (41/91) 47.6% (90/189) 0.5605
BMI 27.0 [23.7, 30.6] (96)
26.8 [23.7, 31.8] (90)
27.0 [23.7, 30.8] (186)
0.5113
STS PROM Score 6.4 [4.6, 8.0] (98) 5.6 [4.2, 8.0] (91) 6.0 [4.4, 8.0] (189) 0.2999History of Atrial Fibrillation
32.7% (32/98) 34.1% (31/91) 33.3% (63/189) 0.8780
History of PVD 16.3% (16/98) 13.2% (12/91) 14.8% (28/189) 0.6826
History of CAD 55.1% (54/98) 51.6% (47/91) 53.4% (101/189) 0.6635
Previous CABG 22.0% (20/91) 24.5% (24/98) 23.3% (44/189) 0.7324
Previous PCI 16.5% (15/91) 15.3% (15/98) 15.9% (30/189) 0.8447
History of Diabetes 36.7% (36/98) 39.6% (36/91) 38.1% (72/189) 0.7647
Previous Stroke2 3.1% (3/98) 3.3% (3/91) 3.2% (6/189) 1.0000
Previous TIA 6.1% (6/98) 8.8% (8/91) 7.4% (14/189) 0.5827
Heavily Calcified Aorta 2.0% (2/98) 2.2% (2/91) 2.1% (4/189) 1.0000
NYHA Class III/IV 80.0% (76/95) 87.6% (78/89) 83.7% (154/184) 0.1696
Lesion Volume as calculated on FLAIR (mm3)
7800.1 [3248.4, 17315.3]
7551.6 [2127.8, 19875.6]
7783.6 [2982.1, 18224.4]
0.5881
Echocardiographic Findings
Valve Area (cm2) 0.7 ± 0.17 (89) 0.7 ± 0.20 (98) 0.7 ± 0.18 (187) 0.5969
Mean aortic valve gradient (mmHg)
40.0 [31.8, 46.5] (98)
41.0 [32.3, 50.2] (88)
40.6 [32.0, 47.7] (186)
0.2929
Note: Continuous data presented as Mean ± SD (n) or Median [IQR] (n). Categorical data presented using % (n/N). 1 P-values are testing for statistical differences across randomized arms. Continuous data are compared using ANOVA or two-sided Wilcoxon test; categorical data are compared using Fisher's exact test. 2 Defined as neurological deficit lasting more than 24 hours confirmed by imaging.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Table 4. Baseline characteristics of patients with paired baseline and 30 day neurocognitive assessment
Control Arm
(N=92) Device Arm
(N=93) Total
(N=185) P-value1
Age 84.8 [78.4, 89.0] (92)
83.1 [77.8, 87.2] (93)
83.8 [78.1, 88.3] (185)
0.2585
Male 50.0% (46/92) 49.5% (46/93) 49.7% (92/185) 1.0000
BMI 27.3 [24.5, 31.1] (90)
27.0 [23.7, 32.6] (92)
27.1 [24.1, 31.8] (182)
0.7377
STS PROM Score 6.4 [4.5, 8.5] (92) 5.3 [3.9, 7.9] (93) 6.0 [4.2, 8.0] (185) 0.1214 History of Atrial Fibrillation
31.5% (29/92) 31.2% (29/93) 31.4% (58/185) 1.0000
History of PVD 12.0% (11/92) 15.1% (14/93) 13.5% (25/185) 0.6679
History of CAD 55.4% (51/92) 50.5% (47/93) 53.0% (98/185) 0.5568
Previous CABG 22.8% (21/92) 19.4% (18/93) 21.1% (39/185) 0.5927
Previous PCI 12.0% (11/92) 21.5% (20/93) 16.8% (31/185) 0.1145
History of Diabetes 39.1% (36/92) 41.2% (39/93) 40.5% (75/185) 0.7651
Previous Stroke 1.1% (1/92) 3.2% (3/93) 2.2% (4/185) 0.6209
Previous TIA 5.4% (5/92) 8.6% (8/93) 7.0% (13/185) 0.5669
Heavily Calcified Aorta 1.1% (1/92) 1.1% (1/93) 1.1% (2/185) 1.0000
NYHA Class III/IV 80.9% (72/89) 84.6% (77/91) 82.8% (149/180) 0.5574
Echocardiographic Findings
Valve Area (cm2) 0.7 ± 0.21 (91) 0.7 ± 0.17 (91) 0.7 ± 0.19 (182) 0.7162
Mean aortic valve gradient (mmHg)
40.8 [33.0, 47.0] (91)
41.5 [32.3, 53.0] (90)
41.0 [32.4, 49.0] (181)
0.4658
Note: Continuous data presented as Mean ± SD (n) or median [IQR] (n). Categorical data presented using % (n/N). 1 P-values are testing for statistical differences across randomized arms. Continuous data are compared using ANOVA or two-sided Wilcoxon test; categorical data are compared using Fisher's exact test. 2 Defined as neurological deficit lasting more than 24 hours confirmed by imaging.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Table 5. DW-MRI Median new lesion volume and number of new lesions by TAVR device type (unadjusted analysis, Day 2-7)
Control Arm Device Arm P-value1
Median New Lesion Volume (mm3), Protected Territories
SAPIEN XT 322 (31, 785.7), n=14 55.4 (0, 181.9), n=15 0.0455
SAPIEN 3 143.4 (33, 233.3), n=56 104.7 (50.1, 384.3), n=52 0.4454
CoreValve Evolut R 324.3 (141.1, 1077.8), n=24 147.7 (18.5, 479.9), n=21 0.1185
Median New Lesion Volume (mm3), All Territories
SAPIEN XT 518.1 (134.5, 1170.7), n=14 114 (29, 321.7), n=15 0.0341
SAPIEN 3 193.5 (59.3, 464.1), n=56 265 (131.8, 962.1), n=52 0.0516
CoreValve Evolut R 807.2 (326.6, 1716.5), n=24 369.1 (63.3, 786.4), n=21 0.0465
Median New Lesion Number, Protected Territories
SAPIEN XT 3.5 (1, 9), n=14 2 (0, 3), n=15 0.0347
SAPIEN 3 2 (1, 4), n=56 2 (1, 6.5), n=52 0.0425
CoreValve Evolut R 5.5 (2.5, 11.5), n=24 2 (1, 6), n=21 0.0189
Median New Lesion Number, All Territories
SAPIEN XT 7 (1, 12), n=14 2 (1, 5), n=15 0.0300
SAPIEN 3 4 (1.5, 6), n=56 3 (2, 10), n=52 0.0124
CoreValve Evolut R 8.5 (5.5, 15.5), n=24 3 (1, 12), n=21 0.0346
Note: Medtronic CoreValve (which only contributed 7 patients with imaging follow-up) was excluded from this analysis. 1 Lesion volume analyses based on Wilcoxon test; lesion number analyses based on negative binomial regression model
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Table 6. 30-day median total new lesion volume (unadjusted analysis)
Test Arm
(n=78) Control Arm
(n=80)
Observed Treatment Difference
(test - control)
Hodges-Lehmann Estimate of
Location Shift (95% CI) P-value1
Protected Territories ITT, mm3
0 (0, 52.7) 0 (0, 83.1) 0.0 0 (0, 0) 0.8255
All Territories ITT, mm3
0 (0, 73.8) 0 (0, 108.1) 0.0 0 (0, 0) 0.8507
Data are presented as median (IQR) 1 Based on Wilcoxon Test
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Table 7. Significant Results of (A) Univariate Analysis and (B) Multivariable Analysis of Baseline Characteristics Predicting Transformed New Volumes in Protected Territories
Source Pr > F Source Pr > F Baseline Volume Strata (High/Low) <.0001 Weight (lbs) 0.0568LNZ[Baseline Lesion Volume] <.0001 Neurological Deficit [Y/N] 0.0594LNZ[Baseline Lesion Number] 0.0024 Currently taking medications (Y/N) 0.0632LNZ[HU_850 Volume] 0.009 Peak Aortic Jet Velocity 0.0636Age 0.0155 STS Risk score 0.0643Dilitation Post TAVR Procedure 0.034 Rosenhek2 0.071Temperatue 0.0495 Neurocognitve Verbal Memory Score 0.078BSA 0.0517 History of Percutaneous Coronary Intervention (Y/N) 0.0884A. Univariate Analysis
Parameter DF Estimate StandardError
t Value P-Value
Intercept 1 0.88 1.041516 0.85 0.39.
Baseline T2-FLAIR Volume 1 0.44 0.116631 3.83 0.0002B. Multivariable Analysis
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Table 8. Least Squares Means and Test of Main Effects (adjusted by Interaction of Valve Type and Treatment Arm, and High/Low BL Lesion Volume) – ITT Population
Effect Mean Estimate(95% CI) p-value
Least Squares Mean new lesion volume (mm3), Protected territories
Control Arm 162.8(107.9, 245.5)
0.0248
Device Arm 83.3(55.0, 126.1)
Least Squares Mean new lesion volume (mm3), all territories
Control Arm 311.1(212.2, 456.3)
0.0500
Device Arm 180.6(122.7, 265.8)
Least Squares Mean new lesion volume (mm3), Protected territories
Evolut R (n=45) 172.6
(103.7, 287.2)
0.166 SAPIEN 3 (n=108) 113.6
(81.8, 157.8)
SAPIEN XT (n=29) 80.5
(42.6, 152.0)
Least Squares Mean new lesion volume (mm3), all territories
Evolut R (n=45) 408.0
(253.9, 655.6)
0.021 SAPIEN 3 (n=108) 228.2
(168.0, 309.9)
SAPIEN XT (n=29) 143.1
(79.1, 258.7)
Note: In order to get stable TAVR device estimates from the model, Medtronic CoreValve (which only contributed 7 patients with imaging follow-up) was excluded from the analysis.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Table 9. Least Squares Means and Test of Interaction Effects (Arm within Valve Type adjusted by Treatment Arm, Valve Type and and High/Low BL Lesion Volume) – ITT, Lesion Volume
Effect Control Arm
Mean Estimate (95% CI)
Device Arm Mean Estimate
(95% CI) p-value*
Least Squares Mean new lesion volume (mm3), Protected territories
Evolut R (n=45) 279.1(139.2, 559.4)
106.7 (50.7, 224.7) 0.0642
SAPIEN XT (n=29) 162.7(65.3, 405.4)
39.8 (16.5, 96.1) 0.0296
SAPIEN 3 (n=108) 95.0(60.2, 149.9)
135.8 (84.7, 217.9) 0.2834
Least Squares Mean new lesion volume (mm3), all territories
Evolut R (n=45) 691.0(361.6, 1320.4)
240.9 (120.4, 481.7)
0.0297
SAPIEN XT (n=29) 268.1(114.5, 627.7)
76.3(33.6, 173.4)
0.0369
SAPIEN 3 (n=108) 162.5(106.2, 248.7)
320.3 (206.3, 497.4)
0.0299
Note: In order to get stable TAVR device estimates from the model, Medtronic CoreValve (which only contributed 7 patients with imaging follow-up) was excluded from the analysis. *No adjustment for multiple comparisons was made.
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
Supplemental Figure 1. Correlation between neurocognitive score and MRI lesions
a. Protected territories
r = -0.2028
p = 0.0109
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
b. All territories
r = -0.2356
p = 0.003
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
References
1. Smith, S., Jenkinson, M., & Woolrich, M. Advances in functional and structural MR image analysis and
implementation as FSL. Neuroimage. 2004
2. Jezzard, P., & Balaban, R. Correction for geometric distortion in echo planar images from B0 field variations.
Magnetic Resonance in Medicine. 1995;34(1), 65–73.
3. Andersson, J.L.R., Skare, S., Ashburner, J. How to correct susceptibility distortions in spin-echo echo-planar
images: application to diffusion tensor imaging. NeuroImage, 20(2):870-888, 2003.
4. Liguori, M., Meier, D. S., Hildenbrand, P., Healy, B. C., Chitnis, T., Baruch, N. F., Guttmann, C. R. G. (2011).
One year activity on subtraction MRI predicts subsequent 4 year activity and progression in multiple sclerosis.
Journal of Neurology, Neurosurgery, and Psychiatry. 2011;82(10), 1125–31. doi:10.1136/jnnp.2011.242115
5. Sled, J. G., Zijdenbos, A. P., & Evans, A. C. A nonparametric method for automatic correction of intensity
nonuniformity in MRI data. IEEE Transactions on Medical Imaging. 1998;17(1), 87–97. doi:10.1109/42.668698
6. Nyul, L., Udupa, J., & Zhang, X. New variants of a method of MRI scale standardization. Medical Imaging,
IEEE. 2000;19(2), 143–150.
7. Jenkinson, M., & Smith, S. A global optimisation method for robust affine registration of brain images. Medical
Image Analysis, 2001;5(2), 143–156.
8. Tavazzi, E., Dwyer, M. G., Weinstock-Guttman, B., Lema, J., Bastianello, S., Bergamaschi, R., Munschauer, F.
E. Quantitative diffusion weighted imaging measures in patients with multiple sclerosis. Neuroimage,
2007;36(3):746–54. doi:10.1016/j.neuroimage.2007.03.056
9. Grabner, G., Janke, A., & Budge, M. (2006). Symmetric atlasing and model based segmentation: an application to
the hippocampus in older adults. In Medical Image Computing and Computer-Assisted Intervention (pp. 58–66).
Berlin.
10. Möller, T. B., & Reif, E. (2007). Pocket Atlas of Sectional Anatomy: Head and neck (p. 264). Thieme.
11. Hartkamp, N. S., De Cocker, L. J., Helle, M., van Osch, M. J. P., Kappelle, L. J., Bokkers, R. P. H., &
Hendrikse, J. In vivo visualization of the PICA perfusion territory with super-selective pseudo-continuous arterial
spin labeling MRI. NeuroImage, 2013;83:58–65. doi:10.1016/j.neuroimage.2013.06.070
MANUSCRIP
T
ACCEPTED
ACCEPTED MANUSCRIPT
12. Marshall RS, Lazar RM. Pumps, aqueducts, and drought management: Vascular physiology in vascular cognitive impairment. Stroke; a journal of cerebral circulation. 2011;42:221-226
13. Mohr J, Lazar R, Marshall R. Middle cerebral artery disease. In: Mohr J, Wolf P, Grotta J, Moskowitz M, Maybert M, von Kummer R, eds. Stroke: Pathophysiology, diagnosis and management. New York: Elsevier; 2011:385-424.
14. Kahlert P, Knipp SC, Schlamann M, Thielmann M, Al-Rashid F, Weber M, et al. Silent and apparent cerebral ischemia after percutaneous transfemoral aortic valve implantation: A diffusion-weighted magnetic resonance imaging study. Circulation. 2010;121:870-878
15. Ghanem A, Kocurek J, Sinning JM, Wagner M, Becker BV, Vogel M, et al. Cognitive trajectory after transcatheter aortic valve implantation. Circulation. Cardiovascular interventions. 2013
16. Lietz K, Brown K, Ali SS, Colvin-Adams M, Boyle AJ, Anderson D…Lazar, RM. The role of cerebral hyperperfusion in postoperative neurologic dysfunction after left ventricular assist device implantation for end-stage heart failure. The Journal of thoracic and cardiovascular surgery. 2009;137:1012-1019
17. Festa JR, Jia X, Cheung K, Marchidann A, Schmidt M, Shapiro PA…Lazar, RM. Association of low ejection fraction with impaired verbal memory in older patients with heart failure. Archives of neurology. 2011;68:1021-1026
18. Lazar RM, Marshall RS, Pile-Spellman J, Young WL, Hacein-Bey L, Sloan RP, et al. Continuous time estimation as a behavioural index of human cerebral ischaemia during temporary occlusion of the internal carotid artery. Journal of neurology, neurosurgery, and psychiatry. 1996;60:559-563
19. Marshall RS, Festa JR, Cheung YK, Chen R, Pavol MA, Derdeyn CP…Lazar, RM. Cerebral hemodynamics and cognitive impairment: Baseline data from the recon trial. Neurology. 2012;78:250-255
20. Festa JR, Schwarz LR, Pliskin N, Cullum CM, Lacritz L, Charbel FT…Lazar, RM. Neurocognitive dysfunction in adult moyamoya disease. Journal of neurology. 2010;257:806-815
21. Lezak D, Howieson D, Loring D. Neuropsychological assessment. Oxford; 2004.