Protection Against Cerebral Embolism During Transcatheter Aortic Valve Replacement

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, Hasan Jilaihawi, 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, James M. McCabe, MD, Lowell Satler, MD, Alan Zajarias, MD, Wilson Y. Szeto, MD, Lars Svensson, 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, Dwyer MG, Jilaihawi H, Virmani R, Anwaruddin S, Thourani VH, Nazif T, Mangner N, Woitek F, Krishnaswamy A, 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 During Transcatheter 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 to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement

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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

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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; p Claret Medical Inc, Santa Rosa, CA; qLeipzig Heart Institute, Leipzig, Germany Short Running Title: Embolic protection in TAVR

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Sources of Funding: The SENTINEL Trial was funded by Claret Medical, Inc.

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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

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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.

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Address for Correspondence: Samir Kapadia, MD Cleveland Clinic 9500 Euclid Avenue, Desk J2-3 Cleveland, OH 44195 Tel: 216-444-6697 Email: [email protected]

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Acknowledgements: The authors would like to thank Matthew T. Finn, MD (Columbia University Medical Center) for assistance with manuscript preparation.

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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.

Analysis of Variance Aortic Stenosis Diffusion-weighted Magnetic Resonance Imaging Fluid-attenuated Inversion Recovery Intention to Treat Major Adverse Cardiac and Cerebral Events Mini Mental State Exam Magnetic Resonance Imaging Modified Rankin Score Multi Slice Computed Tomography National Institutes of Health Stroke Scale Society of Thoracic Surgeons Transcatheter Aortic Valve Replacement Transcatheter Cerebral Embolic Protection

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Abbreviations ANOVA AS DW-MRI FLAIR ITT MACCE MMSE MRI mRS MSCT NIHSS STS TAVR TCEP

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Trial Registration: ClinicalTrials.gov #NCT02214277

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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

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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

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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

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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

Methods Patients

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efficacy in reducing the effects of cerebral embolization.

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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

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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

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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

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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

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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

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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

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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.

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Brain MRI Studies

Brain MRI using a 3 Tesla scanner was performed in both imaging arms (device and control) at

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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.

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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-

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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

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randomization assignment. Histopathologic Assessment of Debris

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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.

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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

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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

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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, 90day 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.

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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

scans relative to the pre-TAVR scans.

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was defined as the sum of all diffusion-positive new cerebral lesion volumes in post-procedural

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

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neurocognitive function changes, and histopathology evaluations. Statistical Analysis

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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

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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

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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-

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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

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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

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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

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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

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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

Supplementary Appendix.

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the effect of multivariable predictors on new lesion volume are described in Appendix 3,

Statistical analyses were performed on the intention-to-treat (ITT) population using SAS

Results

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version 9.3 (SAS Institute, Cary, NC).

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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 27 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

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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

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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

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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

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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,

groups.

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USA). TAVR systems were used with similar distribution across all three randomized treatment

Procedural Details and Clinical Outcomes

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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

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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 noninferiority) (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

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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).

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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

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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,

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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

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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

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(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

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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).

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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).

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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).

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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

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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

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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

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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

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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

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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

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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

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among TAVR. (9)

Historically, demonstration of clinical efficacy with embolic protection to reduce

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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.(18,19,3336) Early TAVR trials showing increased peri-procedural stroke frequency(1-3) and MRI

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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

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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

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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

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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

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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

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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

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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

systems.

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MRI results and the response to embolic protection appeared to differ with varying TAVR

At the time the Sentinel Trial was designed, only one device was commercially available

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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,

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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

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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

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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

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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

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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

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for clinical trials. There may be other factors that may explain these differences like use of predilatation or post-dilatation, operator experience, or patient selection for different valves. Although these variables did not reach statistical significance in multivariate modeling, limited

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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

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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

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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.

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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

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overly aggressive device manipulation within the aortic valvar complex should be avoided, whenever possible.

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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

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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

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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

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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 nondefinitive.

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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

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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

during randomization) cannot be overemphasized.

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volume and the need to adjust for differences in valve type (e.g. stratification of valve types

In conclusion, this randomized trial investigating the SentinelTM dual filter

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frequency of embolic debris capture.

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neuroprotection therapy provides reassuring evidence of device safety and confirms the high-

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replacement strategy and valve design on stroke after transcatheter aortic valve

replacement: a meta-analysis and systematic review of literature. J Am Coll Cardiol

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Replacement. J Am Coll Cardiol 2016;68:673-84.

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aortic valve replacement. J Thorac Cardiovasc Surg 2012;144:1539.

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transfemoral aortic valve implantation: a prospective pilot study with diffusionweighted magnetic resonance imaging. J Am Coll Cardiol 2010;55:1427-32.

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valve replacement: a comprehensive review. J Am Coll Cardiol 2014;64:1950-63. Van Mieghem NM, Schipper ME, Ladich E et al. Histopathology of embolic debris

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captured during transcatheter aortic valve replacement. Circulation 2013;127:2194201.

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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.

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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. Haussig S, Mangner N, Dwyer MG et al. Effect of a Cerebral Protection Device on

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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

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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

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aortic valve implantation and the preventive role of embolic protection devices: A systematic review and meta-analysis. Int J Cardiol 2016;221:97-106. Samim M, van der Worp B, Agostoni P et al. TriGuard HDH embolic deflection

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device for cerebral protection during transcatheter aortic valve replacement. Catheter Cardiovasc Interv 2016 doi: 10.1002/ccd.26566. [Epub ahead of print].

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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. Kappetein AP, Head SJ, Genereux P et al. Updated standardized endpoint definitions

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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

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embolic protection devices. J Vasc Surg 2014;59:359-367.e1. Paul TK, Lee JH, White CJ. Renal embolic protection devices improve blood flow after stenting for atherosclerotic renal artery stenosis. Catheter Cardiovasc Interv

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Roberts D, Niazi K, Miller W et al. Effective endovascular treatment of calcified

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femoropopliteal disease with directional atherectomy and distal embolic protection: final results of the DEFINITIVE Ca(+)(+) trial. Catheter Cardiovasc Interv 2014;84:236-44.

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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

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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

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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.

Ng JL, Chan MT, Gelb AW. Perioperative stroke in noncardiac, nonneurosurgical

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surgery. Anesthesiology 2011;115:879-90.

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FIGURE LEGENDS Figure 1: Sentinel Device Panel A shows the Sentinel device. Panel B shows the proximal filter is placed in the innominate

micron. Panel C shows fluoroscopic image of the device. Figure 2: Study Flow

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artery and the distal filter is placed in the left carotid artery. The pore size of the filters is 140

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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

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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.

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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-

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inferiority). MACCE in the control arm (9.9%) was not statistically different compared with the device and safety arms (p=0.405).

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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

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Study analyzed the particulate debris from filters. Panel A shows rate of debris capture by type

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Table 1. Baseline Characteristics and Procedural Details

Lesion Volume as calculated on FLAIR (mm3)

Safety Arm (N=123)

Total Randomized (N=363)

Pvalue1

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

51.3% (61/119)

47.9% (58/121)

44.7% (55/123)

47.9% (174/363)

0.6062

27.0 [23.8, 30.5] 6.6 [4.5, 8.6]

27.0 [23.7, 32.1] 5.6 [3.9, 8.0]

26.2 [22.7, 30.4] 5.8 [3.9, 8.0]

26.7 [23.4, 30.8] 6.0 [4.2, 8.1]

0.3103 0.0860

30.3% (36/119)

34.7% (42/121)

30.1% (37/123)

31.7% (115/363)

0.6932

15.1% (18/119) 55.5% (66/119) 21.0% (25/119) 16.8% (20/119)

14.0% (17/121) 50.4% (61/121) 18.2% (22/121) 17.4% (21/121)

16.3% (20/123) 53.7% (66/123) 14.6% (18/123) 15.4% (19/123)

15.2% (55/363) 53.2% (193/363) 17.9% (65/363) 16.5% (60/363)

0.9003 0.7341 0.4289 0.9367

37.8% (45/119)

40.5% (49/121)

26.8% (33/123)

35.0% (127/363)

0.0577

5.0% (6/119) 6.7% (8/119)

4.1% (5/121) 7.4% (9/121)

8.1% (10/123) 8.1% (10/123)

5.8% (21/363) 7.4% (27/363)

0.4376 0.9678

2.5% (3/119)

1.7% (2/121)

3.3% (4/123)

2.5% (9/363)

0.7791

82.8% (96/116)

84.9% (101/119)

81.7% (98/120)

83.1% (295/355)

0.8077

7916.7 [3865.4, 17315.3]

7377.5 [2562.9, 19181.5]

N/A

7847.9 [3243.2, 17854.5]

0.43063

0.7 ± 0.18 (122)

0.7 ± 0.18 (359)

0.6603

41.0 [31.9, 49.0]

41.0 [33.0, 49.0]

0.3334

Fluoroscopy Time TAVR Device Used Sapien XT Sapien 3 CoreValve CoreValve Evolut R

0.4918 95.0% (114/119) 4.2% (5/119)

93.2% (218/231) 5.6% (13/231)

92.0% (103/112)

96.6% (115/119)

94.4% (218/231)

0.1570

99.1% (111/112)

100.0% (119/119)

99.6% (230/231)

0.4848

68.0 [41.0, 96.0] 15.0 [9.0, 20.0]

83.5 [54.0, 118.0] 18.0 [12.0, 29.0]

78.0 [52.0, 101.0] 14.0 [10.0, 27.0]

74.0 [52.0, 106.0]

0.0050

15.0 [10.0, 26.0]

0.0402

16.9% (20/118) 53.4% (63/118) 5.9% (7/118)

17.5% (21/120) 55.8% (67/120) 2.5% (3/120)

19.0% (23/121) 47.9% (58/121) 3.3% (4/121)

17.8% (64/359) 52.4% (188/359) 3.9% (14/359)

23.7% (28/118)

24.2% (29/120)

29.8% (36/121)

25.9% (93/359)

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91.2%(104/112) 7.0% (8/112)

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0.7 ± 0.17 (119)

42.7 [33.6, 52.0]

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Echocardiographic Findings Valve Area (cm2) 0.7 ± 0.20 (118) Mean aortic valve 41.0 [33.0, 47.0] gradient (mmHg) Procedural Details Sentinel Device Access Radial N/A Brachial N/A Both Filters N/A Deployed At Least One Filter N/A Deployed

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Device Arm (N=121)

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Age Male BMI STS PROM Score History of Atrial Fibrillation History of PVD History of CAD Previous CABG Previous PCI History of Diabetes Previous Stroke2 Previous TIA Heavily Calcified Aorta NYHA Class III/IV

Control Arm (N=119)

0.7176

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.

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2

Defined as neurological deficit lasting >24 hours confirmed by imaging.

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Based on two-sided Wilcoxon test 4 Defined as time from first vascular access puncture to achievement of hemostasis at the TAVR access site.

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Table 2. Clinical Outcomes Control Arm

Safety + Device Arm

p-value

30-day Clinical Outcomes 0.40 0.65 0.25 1.00 0.22 1.00 1.00 0.53

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Any MACCE† 9.9% (11/111) 7.3% (17/234) Death (all-cause) 1.8% (2/111) 1.3% (3/234) Stroke 9.1% (10/110) 5.6% (13/231) Disabling 0.9% (1/109) 0.9% (2/231) Non-disabling 8.2% (9/110) 4.8% (11/231) AKI (Stage 3) 0% 0.4% (1/231) TIA 0% 0.4% (1/231) Major Vascular Complication 5.9% (7/119) 8.6% (21/244) 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)

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Table 3. Median total new lesion volume and number of new lesions (unadjusted analysis, Day 2-7) 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)

Median Number of New Lesions in Protected Territories

3 (1, 6)

2 (1, 6)

Median Number of New Lesions in All Territories

5 (2, 10)

3 (2, 10)

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-8.6 (-110.7, 68.6)

0.80761

0 (-1, 0)

0.89792

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Data are presented as median (IQR) 1 Based on Wilcoxon Test 2 Based on negative binomial regression model

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Control Arm n=98

-1 (-2, 1)

0.7667

2

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Table 4. Neurocognitive Assessments Control Arm Change from Baseline

Mean ± SD (min, max), n

Change from Baseline

P-value1

-0.17 ± 0.88 (117)

NA

-0.14 ± 0.96 (117)

NA

NA

2 to 7 Days PostTAVR

-0.28 ± 1.1 (65)

-0.01 ± 0.59 (65)

-0.5 ± 1.02 (65)

-0.32 ± 0.7 (65)

0.0334

30 Day FollowUp

0.03 ± 0.88 (92)

0.14 ± 0.51 (92)

-0.14 ± 0.93 (93)

0.03 ± 0.55 (93)

0.1778

90 Day FollowUp

0.11 ± 0.87 (76)

0.23 ± 0.55 (76)

0.06 ± 0.87 (77)

0.2 ± 0.49 (77)

0.6103

-1.36 ± 1.36 (117)

NA

-1.28 ± 1.3 (117)

NA

NA

2 to 7 Days PostTAVR

-1.36 ± 1.36 (63)

0 ± 1 (63)

-1.7 ± 1.55 (65)

-0.36 ± 1.19 (65)

0.0865

30 Day FollowUp

-0.99 ± 1.34 (91)

90 Day FollowUp

-0.79 ± 1.21 (76)

Baseline

-0.23 ± 0.95 (117)

2 to 7 Days PostTAVR

-0.47 ± 0.87 (63)

30 Day FollowUp

-0.01 ± 0.86 (90)

90 Day FollowUp

0.14 ± 0.81 (76)

Baseline

Processing Speed

0.25 ± 0.86 (91)

-1.2 ± 1.4 (93)

0.14 ± 0.86 (93)

0.4692

0.39 ± 0.86 (76)

-0.94 ± 1.16 (77)

0.32 ± 0.79 (77)

0.4585

NA

-0.24 ± 0.91 (117)

NA

NA

-0.05 ± 0.38 (63)

-0.51 ± 0.94 (65)

-0.06 ± 0.5 (65)

0.9698

0.12 ± 0.39 (90)

-0.11 ± 1 (92)

0.14 ± 0.43 (92)

0.5470

0.27 ± 0.43 (76)

-0.05 ± 0.86 (77)

0.21 ± 0.46 (77)

0.7272

-0.64 ± 1.07 (117)

NA

-0.85 ± 0.94 (117)

NA

NA

2 to 7 Days PostTAVR

-1.06 ± 1.06 (66)

-0.63 ± 0.79 (66)

-1.34 ± 1.3 (66)

-0.7 ± 1.03 (66)

0.8534

30 Day FollowUp

-0.88 ± 1.18 (91)

-0.32 ± 0.8 (91)

-1.09 ± 1.13 (93)

-0.28 ± 0.85 (93)

0.4644

90 Day FollowUp

-0.61 ± 1.11 (76)

-0.13 ± 0.78 (76)

-0.86 ± 1.05 (77)

-0.02 ± 0.78 (77)

0.2933

Baseline

-0.72 ± 0.96 (117)

NA

-0.83 ± 0.85 (115)

NA

NA

2 to 7 Days PostTAVR

-0.7 ± 1.01 (65)

0.06 ± 0.86 (65)

-0.87 ± 0.94 (66)

-0.19 ± 0.96 (65)

0.1340

30 Day FollowUp

-1.02 ± 1.03 (92)

-0.36 ± 0.79 (92)

-1.28 ± 0.94 (93)

-0.46 ± 0.91 (92)

0.4282

90 Day FollowUp

-0.53 ± 0.98 (76)

0.12 ± 0.81 (76)

-0.58 ± 0.98 (77)

0.17 ± 0.86 (77)

0.6942

Baseline

26.07 ± 3.32 (116)

NA

26.12 ± 2.95 (114)

NA

NA

Visual Memory

Mental Status2

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P-value1

2 to 7 Days PostTAVR

26.02 ± 2.81 (62)

-0.25 ± 2.47 (61)

25.41 ± 3.58 (64)

-0.73 ± 2.95 (63)

NA

30 Day FollowUp

26.82 ± 2.74 (89)

0.52 ± 2.55 (89)

26.24 ± 2.84 (92)

0.41 ± 2.67 (91)

NA

90 Day FollowUp

27.24 ± 2.47 (76)

0.96 ± 2.42 (76)

26.56 ± 2.6 (77)

0.3 ± 2.76 (76)

NA

Baseline

2.7 ± 2.28 (116)

NA

3.33 ± 2.62 (114)

NA

NA

2 to 7 Days PostTAVR

2.26 ± 2.53 (62)

-0.48 ± 1.41 (61)

2.77 ± 2.83 (64)

-0.57 ± 2.12 (63)

NA

30 Day FollowUp

2.07 ± 2.14 (89)

-0.73 ± 1.57 (89)

2.38 ± 2.43 (91)

-0.68 ± 2.02 (90)

NA

90 Day FollowUp

2.37 ± 2.75 (76)

-0.49 ± 2.16 (76)

2.53 ± 2.66 (77)

-0.75 ± 2.22 (76)

NA

NA

-0.66 ± 0.75 (117)

NA

NA

-0.16 ± 0.58 (66)

-1 ± 0.95 (66)

-0.33 ± 0.65 (66)

0.1894

-0.03 ± 0.37 (92)

-0.77 ± 0.82 (93)

-0.09 ± 0.44 (93)

0.4207

0.18 ± 0.35 (76)

-0.47 ± 0.76 (77)

0.18 ± 0.38 (77)

0.9409

Baseline

-0.63 ± 0.79 (117)

2 to 7 Days PostTAVR

-0.81 ± 0.93 (66)

30 Day FollowUp

-0.59 ± 0.79 (92)

90 Day FollowUp

-0.34 ± 0.72 (76)

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P-values based on model adjusted for education, baseline Geriatric Depression Score, and baseline Mini Mental State Score. Raw score provided for Mental State and Depression.

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Change from Baseline

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Mean ± SD (n)

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Online Supplemental Appendix Cerebral Embolic Protection During Transcatheter Aortic Valve Replacement

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Kapadia, Kodali, et al.

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List of Study Sites and Investigators

Appendix 1: Description of the MRI acquisition and analyses techniques

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Appendix 2: Description of the neurocognitive function domains and methods Appendix 3: Multivariable modeling methodology

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

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References

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Table 1:

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Emory University Hospital Midtown PI: Vinod Thourani Sub-I: Vasilis Babaliaros Sub-I: Chandan Devireddy Sub-I: Kreton Mavromatis Atlanta, GA United States

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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

Weill Cornell Medical Center PI: Shing-Chiu Wong Sub-I: Geoffrey Bergman Sub-I: Arash Salemi New York, NY United States

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Columbia University Medical Center PI: Susheel Kodali Sub-I: Tamin Nazif New York, NY United States

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The SENTINEL Trial Site and Investigator Listing Henry Ford Health System Cedars-Sinai Medical Center PI: Adam Greenbaum PI: Raj Makkar Sub-I: William O’Neill Sub-I: Hasanian Al-Jilaihawi Sub-I: Marvin Eng Los Angeles, CA Detroit, MI United States United States Cleveland Clinic PI: Samir Kapadia Morton Plant Hospital Sub-I: Amar Krishnaswamy PI: Joshua Rovin Sub-I: E. Murat Tuzcu Sub-I: Lang Lin Sub-I: Stephanie Mick Sub-I: Douglas Spriggs Cleveland, OH Clearwater, FL United States 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

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St. Thomas Hospital PI: Andrew Morse Sub-I: Mark Stankewicz Sub-I: Evelio Rodriguez Nashville, TN United States

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Sentara Norfolk General Hospital PI: Paul Mahoney Norfolk, VA United States

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Herzzentrum Leipzig GmbH -Universitätsklinik PI: Axel Linke Sub-I: Norman Mangner Sub-I: Felix Woitek Leipzig Germany

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Asklepios Klinik St. Georg PI: Christian Frerker Hamburg Germany

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St. Luke's Hospital PI: David Cohen Kansas City, MO United States

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Appendix 1: MRI acquisition and analysis methodology STUDY PROCEDURES Magnetic Resonance Imaging

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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

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(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

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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-

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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

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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

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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

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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.

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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

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were further standardized by applying a piecewise-linear histogram adjustment method to compensate for scan-toscan variability in absolute intensity.6 Finally, to facilitate direct longitudinal analysis, all within-subject scans were

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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

or persistent.

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operator viewed all images and change maps simultaneously to increase confidence, and also coded lesions as new

In addition to lesion counts and volumetry, vascular territory was also assessed using an atlas-based technique. For

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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

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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 coregistration 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.

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Appendix 2: Neurocognitive test battery

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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, wellvalidated 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.

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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

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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:

2. 3.

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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. Change in neurocognitive composite scores from baseline to 7-days and baseline to 90-days post-TAVR for each treatment group. 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. 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.

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Appendix 3. Multivariable model methodology

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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.

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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.

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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.

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Table S3-1: List of Baseline Characteristics used for Univariate analyses

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 Any Diabetes [Y/N]

Ethnicity

Race

General anesthesia used [Y/N]

Region[USA/Germany]

Heart Rate

Respiration

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Characteristic

Height (inches)

Baseline Geriatric Depression Score

History of Atrial Fibrillation [Y/N]

Sex [Female/Male]

Baseline Modified Rankin Scale

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Baseline Neurocognitive z Overall

History of Peripheral vascular disease [Y/N] lnz[baseline volumes]

BMI

lnz[HU_850Volume]

TAVR Access

BSA

Mean aortic valve area

Temperature

Center

Modified Allen Result [Normal/Abnormal]] Neurological Deficit [Y/N]

TIA [Y/N]

CT Result[Normal/Abnormal]

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Systole Blood Pressure

Weight (lbs)

NIH Stroke Scale

Currently Taking Medications [Y/N]

Peak Aortic Jet Velocity

Diastole Blood Pressure

Porcelin Aorta [Y/N]

Post Dilatation

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Dilatation[Yes/No]

Rosenhek2

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Coronary Artery Disease [Y/N]

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Any other clinically significant infections, allergies, diseases, or surgeries [Y/N] AVA Indexed

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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 (

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Table S3-2). The step wise regression model minimized the AIC and variables entered the model if they had a pvalue <=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

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Table S3-2. Only the LNZ[Baseline T2-FLAIR Volumes] was predictive of LNZ[New Volumes in Protected Territories].

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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) LNZ[Baseline Lesion Volume] LNZ[Baseline T2-FLAIR Lesion Number] LNZ[HU_850 Volume] Age Dilitation Post TAVR Procedure Temperatue BSA

<.0001

Weight (lbs)

0.0568 0.0594 0.0632

0.009 0.0155 0.034 0.0495 0.0517

0.0636 0.0643 0.071 0.078 0.0884

Parameter

DF Estimate Standard Error

Intercept

1

LNZ[Baseline T2-FLAIR Volumes]

1

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Peak Aortic Jet Velocity STS Risk score Rosenhek2 Neurocognitve Verbal Memory Score History of Percutaneous Coronary Intervention (Y/N)

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Table S3-3: Results of step wise regression model

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<.0001 Neurological Deficit [Y/N] 0.0024 Currently taking medications (Y/N)

t Value P-Value

0.88 1.041516

0.85

0.39.

0.44 0.116631

3.83

0.0002

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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).

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The covariate assessment was repeated for the new volumes in all territories with the same results.

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Figure S3-2: Post Procedure New Volumes in Protected Territories vs. Baseline T2-FLAIR Volumes

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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]

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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.

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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.

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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]

Numerator DF Denominator DF F Value P-value

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Effect

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

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BL T2-FLAIR Lesion Volume (High/Low)

Residual by Predicted Plot

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Figure S3 1: Diagnostic Plot for the Analysis of Variance for LNZ[New Volumes in Protected territories]

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2 0

-2 -4 4

6 Predicted

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Residual

4

8

10

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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.

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Supplemental Table 1. Baseline characteristics of the Safety Cohort – ITT, evaluable for MACCE Safety+Test (N=234)

Control (N=111)

Total (N=345)

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

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Previous TIA Heavily Calcified Aorta

5.6% (13/234)

1.8% (2/111)

4.3% (15/345)

0.1577

8.1% (19/234)

7.2% (8/111)

7.8% (27/345)

0.8336

2.1% (5/234)

1.8% (2/111)

2.0% (7/345)

1.0000

83.5% (192/230)

82.4% (89/108)

83.1% (281/338)

0.9077

0.7 ± 0.17 (231)

0.7 ± 0.20 (110)

0.7 ± 0.18 (341)

0.9542

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

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Previous Stroke2

P-value1

Echocardiographic Findings Valve Area (cm2)

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Mean aortic valve gradient (mmHg)

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.

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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)

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

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STS PROM Score

P-value1

SC

6.0 [4.4, 8.0] (189) 6.9 [3.8, 9.3] (51) 6.0 [4.2, 8.2] (240)

0.6404

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

7.4% (14/189)

5.9% (3/51)

7.1% (17/240)

1.0000

2.1% (4/189)

2.0% (1/51)

2.1% (5/240)

1.0000

83.7% (154/184)

84.3% (43/51)

83.8% (197/235)

0.2825

7783.6 [2982.1, 18224.4] (189)

10285.9 [4638.0, 17038.5] (39)

7847.9 [3243.2, 17854.5] (228)

0.3318

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

Previous TIA Heavily Calcified Aorta NYHA Class III/IV

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Echocardiographic Findings

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.

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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)

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) 0.2999

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P-value1

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

80.0% (76/95)

87.6% (78/89)

83.7% (154/184)

0.1696

7800.1 [3248.4, 17315.3]

7551.6 [2127.8, 19875.6]

7783.6 [2982.1, 18224.4]

0.5881

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Lesion Volume as calculated on FLAIR (mm3)

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NYHA Class III/IV

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History of Atrial Fibrillation

Echocardiographic Findings

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

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Valve Area (cm2)

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.

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Control Arm (N=92)

Device Arm (N=93)

Total (N=185)

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)

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)

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Supplemental Table 4. Baseline characteristics of patients with paired baseline and 30 day neurocognitive assessment

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

80.9% (72/89)

84.6% (77/91)

82.8% (149/180)

0.5574

0.7 ± 0.21 (91)

0.7 ± 0.17 (91)

0.7 ± 0.19 (182)

0.7162

40.8 [33.0, 47.0] (91)

41.5 [32.3, 53.0] (90)

41.0 [32.4, 49.0] (181)

0.4658

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NYHA Class III/IV

P-value1

0.1214

Echocardiographic Findings Valve Area (cm2)

EP

Mean aortic valve gradient (mmHg)

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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.

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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 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

324.3 (141.1, 1077.8), n=24

147.7 (18.5, 479.9), n=21

0.1185

CoreValve Evolut R 3

Median New Lesion Volume (mm ), All Territories

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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

807.2 (326.6, 1716.5), n=24

369.1 (63.3, 786.4), n=21

0.0465

CoreValve Evolut R

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Median New Lesion Number, Protected Territories

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SAPIEN XT

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

5.5 (2.5, 11.5), n=24

2 (1, 6), n=21

0.0189

CoreValve Evolut R

Median New Lesion Number, All Territories

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

8.5 (5.5, 15.5), n=24

3 (1, 12), n=21

0.0346

CoreValve Evolut R

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SAPIEN XT

Note: Medtronic CoreValve (which only contributed 7 patients with imaging follow-up) was excluded from this analysis.

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Lesion volume analyses based on Wilcoxon test; lesion number analyses based on negative binomial regression model

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1

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Supplemental Table 6. 30-day median total new lesion volume (unadjusted analysis)

Test Arm

Control Arm

(n=78)

(n=80)

0 (0, 52.7)

0 (0, 83.1)

0.0

0 (0, 0)

0.8255

0 (0, 73.8)

0 (0, 108.1)

0.0

0 (0, 0)

0.8507

3

ITT, mm

All Territories 3

SC

ITT, mm

Data are presented as median (IQR)

EP

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Based on Wilcoxon Test

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1

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Protected Territories

Observed Hodges-Lehmann Treatment Estimate of Difference Location Shift (test - control) (95% CI)

P-value1

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Supplemental Table 7. Significant Results of (A) Univariate Analysis and (B) Multivariable Analysis of Baseline Characteristics Predicting Transformed New Volumes in Protected Territories

Pr > F

Source

Pr > F

Baseline Volume Strata (High/Low) LNZ[Baseline Lesion Volume] LNZ[Baseline Lesion Number] LNZ[HU_850 Volume] Age Dilitation Post TAVR Procedure Temperatue BSA

<.0001 <.0001 0.0024 0.009 0.0155 0.034 0.0495 0.0517

Weight (lbs) Neurological Deficit [Y/N] Currently taking medications (Y/N) Peak Aortic Jet Velocity STS Risk score Rosenhek2 Neurocognitve Verbal Memory Score History of Percutaneous Coronary Intervention (Y/N)

0.0568 0.0594 0.0632 0.0636 0.0643 0.071 0.078 0.0884

DF Estimate Standard Error

t Value P-Value

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Parameter

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A. Univariate Analysis

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Source

Intercept

1

0.88 1.041516

0.85

0.39.

Baseline T2-FLAIR Volume

1

0.44 0.116631

3.83

0.0002

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B. Multivariable Analysis

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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 Mean Estimate (95% CI)

Effect

p-value

Control Arm

162.8 (107.9, 245.5)

Device Arm

83.3 (55.0, 126.1)

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Least Squares Mean new lesion volume (mm3), Protected territories

0.0248

SC

Least Squares Mean new lesion volume (mm3), all territories 311.1 (212.2, 456.3)

Device Arm

180.6 (122.7, 265.8)

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Control Arm

0.0500

Least Squares Mean new lesion volume (mm3), Protected territories 172.6

Evolut R (n=45)

(103.7, 287.2) 113.6

SAPIEN XT (n=29)

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SAPIEN 3 (n=108)

0.166

(81.8, 157.8) 80.5 (42.6, 152.0)

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Least Squares Mean new lesion volume (mm3), all territories 408.0

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Evolut R (n=45)

(253.9, 655.6) 228.2

SAPIEN 3 (n=108)

0.021 (168.0, 309.9) 143.1

SAPIEN XT (n=29)

(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.

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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 Device Arm Mean Estimate (95% CI)

p-value*

RI PT

Control Arm Mean Estimate (95% CI) Least Squares Mean new lesion volume (mm3), Protected territories 279.1 Evolut R (n=45) (139.2, 559.4) 162.7 SAPIEN XT (n=29) (65.3, 405.4) 95.0 SAPIEN 3 (n=108) (60.2, 149.9) Least Squares Mean new lesion volume (mm3), all territories 691.0 Evolut R (n=45) (361.6, 1320.4) 268.1 SAPIEN XT (n=29) (114.5, 627.7) 162.5 SAPIEN 3 (n=108) (106.2, 248.7)

106.7 (50.7, 224.7) 39.8 (16.5, 96.1) 135.8 (84.7, 217.9)

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Effect

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240.9 (120.4, 481.7) 76.3 (33.6, 173.4) 320.3 (206.3, 497.4)

0.0642 0.0296

0.2834

0.0297 0.0369 0.0299

AC C

EP

TE D

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.

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Supplemental Figure 1. Correlation between neurocognitive score and MRI lesions

RI PT

a. Protected territories

r = -0.2028

AC C

EP

TE D

M AN U

SC

p = 0.0109

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b. All territories

RI PT

r = -0.2356

AC C

EP

TE D

M AN U

SC

p = 0.003

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