1

Table of Contents

COMPUTED TOMOGRAPHY DATA ACQUISITION AND ANALYSIS.................................3

CT Data Acquisition....................................................................................................................3

CT Analysis..................................................................................................................................3

Statistical Methodology for Predictors of Hypoattenuated Leaflet Thickening (HALT) and Reduced Leaflet Motion (RLM)......................................................................................................5

PARTICIPATING SITES AND INVESTIGATORS.....................................................................6

STUDY ADMINISTRATION......................................................................................................11

INCLUSION AND EXCLUSION CRITERIA.............................................................................13

Inclusion Criteria........................................................................................................................13

Exclusion Criteria......................................................................................................................13

Supplementary Table 1: Baseline characteristics of patients who did not have a serial CT at 1 year and those who had a CT scan at 1 year but were not usable..................................................17

Supplementary Table 2: Anticoagulation status in patients with usable CTs at 30-days and/or 1-year after aortic valve replacement................................................................................................19

Supplemental Table 3: Details on hypoattenuating leaflet thickening, echocardiographic gradients and clinical presentation of patients receiving valve-related anticoagulation...............20

Supplemental Table 4: Incidence of hypoattenuated leaflet thickening in patients on anticoagulation at the time of CT..................................................................................................21

Supplemental Table 5: Distribution of anticoagulation at different time points in patients with hypoattenuated leaflet thickening..................................................................................................22

Supplemental Table 6: Distribution of anticoagulation at different time points in patients with reduced leaflet motion...................................................................................................................23

Supplemental Table 7: Baseline characteristics of patients with or without hypoattenuated leaflet thickening at 30 days.....................................................................................................................24

Supplemental Table 8: Incidence of hypoattenuated leaflet thickening stratified according to the valve size.......................................................................................................................................25

Supplemental Table 9: Incidence of reduced leaflet motion stratified according to valve size....26

Supplemental Table 10: Echocardiographic characteristics of patients with hypoattenuated leaflet thickening......................................................................................................................................27

Supplemental Table 11: Echocardiographic characteristics of patients with reduced leaflet motion............................................................................................................................................28

Supplemental Table 12: Impact of hypoattenuated leaflet thickening on clinical outcomes in patients undergoing transcatheter aortic valve replacement..........................................................29

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Supplemental Table 13: Impact of hypoattenuated leaflet thickening on clinical outcomes in patients undergoing surgical aortic valve replacement..................................................................30

Supplemental Table 14: Details on hypoattenuating leaflet thickening, echocardiographic gradients and clinical presentation of patients with clinical valve thrombosis.............................31

Supplemental Table 15: Details on hypoattenuated leaflet thickening, echocardiographic gradients and clinical presentation of patients with thromboembolic complications (stroke, transient ischemic attack or retinal artery embolism)....................................................................32

Supplemental Table 16: Impact of hypoattenuated leaflet thickening at any time point (30-day or 1-year computed tomograms) on clinical outcomes in patients undergoing transcatheter or surgical aortic valve replacement..................................................................................................34

Supplemental Table 17: Predictors of hypoattenuated leaflet thickening and reduced leaflet motion............................................................................................................................................35

Supplemental Figure 1: Study flow and treatment group assignment...........................................36

Supplemental Figure 2: Natural history of reduced leaflet motion...............................................37

Supplemental Figure 3: Relationship between hypoattenuating leaflet thickening (HALT) and valve hemodynamics.....................................................................................................................38

Supplemental Figure 4: Impact of hypoattenuated leaflet thickening on quality of life as assessed by the KCCQ questionnaire...........................................................................................................39

Supplemental Figure 5: Impact of hypoattenuated leaflet thickening on NYHA class.................40

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COMPUTED TOMOGRAPHY DATA ACQUISITION AND ANALYSIS

CT Data AcquisitionSites were instructed to perform CT imaging prioritizing latest generation single source scanners

with wide detector coverage or dual-source systems. ECG-synchronized CT data of the aortic

root was acquired using retrospective ECG-gating when employing systems with limited detector

coverage, or ECG-gated volume acquisition for systems with wide detector coverage. Coverage

of the entire cardiac cycle was recommended while limiting dose-modulation in order to achieve

diagnostic image quality in systole and diastole. Further acquisition settings as well contrast

administration settings were left to the site’s discretion. Thin-sliced (≤0.625 mm) multiphasic CT

images were reconstructed with either relative reconstruction in increments of 10% or less, or

absolute reconstruction with increments of 50 msec or less. To optimize image quality, sites were

instructed to use heart rate control with either oral or intravenous beta-blockade with a target HR

of <65 beats/min. The CT core laboratory provided feedback to sites in the event of insufficient

image quality.

CT AnalysisCT images were transferred to an independent core laboratory (St. Paul’s Hospital, University of

British Columbia, Vancouver) for analysis. Image data was reviewed by 2 independent reviewers

(PB and JL) using dedicated post-processing workstations equipped with CVI42 (Circle

Cardiovascular Imaging, Calgary, AB). Using multiplanar reformats aligned with short- and

long-axis dimensions of the THVs or SHVs, leaflets were evaluated for the presence of

hypoattenuated leaflet thickening. In case of disagreement, a third reader arbitrated (HJ).

Hypoattenuated leaflet thickening was defined as visually identified increased leaflet thickness

with typical meniscal appearance on long-axis views. Extent of leaflet thickening was

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semiquantitatively graded by the primary reviewer on long-axis views carefully aligned with the

leaflet center in regard to involvement along the curvilinear leaflet beginning at the base, using a

4-tier grading scale: None, <25%, >25%–50%, >50%–75%, and >75%. In the event of observed

leaflet thickening, the presence of leaflet restriction (incomplete opening in systole) was

evaluated, using a similar grading scale.

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Statistical Methodology for Predictors of Hypoattenuated Leaflet Thickening (HALT) and Reduced Leaflet Motion (RLM)

Univariate logistic regression for the following baseline variables was performed for 30-day and

1-year HALT and RLM: Treatment group (TAVR vs. surgery), age, sex, nonwhite race/ethnicity,

body mass index (BMI), valve size, Society of Thoracic Surgery (STS) score, New York Heart

Association (NYHA) class III/IV, history of coronary artery disease, coronary artery bypass

grafting, stroke/transient ischemic attack, peripheral vascular disease, diabetes, chronic

obstructive pulmonary disease, pulmonary hypertension, atrial fibrillation, pacemaker, presence

of left bundle/right bundle branch block, baseline aortic valve mean gradient and left ventricular

ejection fraction, and percent oversizing, calculated as (area based on valve size – annular area

from CT) / (annular area from CT). Additionally, for the TAVR only subgroup, we included

post-dilation during TAVR procedure as a potential covariate. All analyses were done using the

AT population. The variables with p value < 0.15 are included in the multivariate logistic

regression. All statistical analyses were performed with the use of SAS software, version 9.4

(SAS Institute).

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PARTICIPATING SITES AND INVESTIGATORS

Full Name Institution Name Role City State/Province

Stephen Bailey Allegheny—Singer Research Institute PI Pittsburgh PA

John Brown Atlantic Health System Hospital Corp PI Morristown NJ

Robert Kipperman Atlantic Health System Hospital Corp Co-PI Morristown NJ

Mark Webster Auckland City Hospital PI Auckland New Zealand

Frank Zidar Austin Heart, PLLC PI Austin TX

Faraz Kerendi Austin Heart, PLLC Co-PI Austin TX

Ashish Pershad Banner University Medical Center Phoenix PI Phoenix AZ

Kenith Fang Banner University Medical Center Phoenix Co-PI Phoenix AZ

H. Jr. Garrett Baptist Memorial Hospital Memphis PI Memphis TN

Basil Paulus Baptist Memorial Hospital Memphis Co-PI Memphis TN

Bassem Chehab Cardiovascular Research Institute of Kansas PI Wichita KS

Brett Grizzell Cardiovascular Research Institute of Kansas Co-PI Wichita KS

Michael Rinaldi Carolina's Health System PI Charlotte NC

Eric Skipper Carolina's Health System Co-PI Charlotte NC

Raj Makkar Cedars-Sinai Medical Center PI Los Angeles CA

Alfredo Trento Cedars-Sinai Medical Center Co-PI Los Angeles CA

Susheel Kodali Columbia University Medical Center New York PI New York NY

Isaac George Columbia University Medical Center New York Co-PI New York NY

Tamim Nazif Columbia University Medical Center New York Co-PI New York NY

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Shing Chiu Wong Cornell University New York PI New York NY

Arash Salemi Cornell University New York Co-PI New York NY

Robert Guyton Emory University Atlanta PI Atlanta GA

Vasilis Babaliaros Emory University Atlanta Co-PI Atlanta GA

Vinod Thourani Emory University Atlanta Co-PI Atlanta GA

Ajay Sinhal Flinders Medical Centre PI Bedford Park SA

Raymond McKay Hartford Hospital PI Hartford CT

Robert Hagberg Hartford Hospital Co-PI Hartford CT

William O'Neill Henry Ford Hospital Detroit PI Detroit MIDimitrios Apostolou Henry Ford Hospital Detroit Co-PI Detroit MI

Gaetano Paone Henry Ford Hospital Detroit Co-PI Detroit MI

Shahram Yazdani Inova Heart and Vascular Institute (Fairfax Inova) PI Falls Church VA

Eric Sarin Inova Heart and Vascular Institute (Fairfax Inova) Co-PI Falls Church VA

Brian Whisenant Intermountain Medical Center Salt Lake City PI Murray UT

Kent Jones Intermountain Medical Center Salt Lake City Co-PI Murray UT

Marcos Nores JFK Medical Center PI Atlantis FL

Mark Rothenberg JFK Medical Center Co-PI Atlantis FL

David Holmes Mayo Clinic Rochester PI Rochester MN

Juan Crestanello Mayo Clinic Rochester Co-PI Rochester MN

Kevin Greason Mayo Clinic Rochester Co-PI Rochester MN

Noah Jones Mount Carmel Health System PI Columbus OH

Patrick Wells Mount Carmel Health System Co-PI Columbus OH

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Willis Wu NC Heart and Vascular (Rex Hospital) PI Raleigh NC

Curtis Anderson NC Heart and Vascular (Rex Hospital) Co-PI Raleigh NC

Mathew Williams New York University Langone Medical Center PI New York NY

Mark Russo Newark Beth Israel Medical Center PI Newark NJ

Bruce Haik Newark Beth Israel Medical Center Co-PI Newark NJLeonard Lee Newark Beth Israel Medical Center Co-PI Newark NJ

Justin Levisay NorthShore University HealthSystem Research Institute Evanston PI Evanston IL

Ted Feldman NorthShore University HealthSystem Research Institute Evanston PI Evanston IL

Hyde Russell NorthShore University HealthSystem Research Institute Evanston Co-PI Evanston IL

Paul Pearson NorthShore University HealthSystem Research Institute Evanston Co-PI Evanston IL

Chris Malaisrie Northwestern University Chicago PI Chicago IL

Charles Davidson Northwestern University Chicago Co-PI Chicago IL

Mark Bodenhamer Oklahoma Cardiovascular Research Group Oklahoma City Co-PI Oklahoma

City OK

Mohammad Ghani Oklahoma Cardiovascular Research Group Oklahoma City Co-PI Oklahoma

City OK

Robert Hodson Providence Heart & Vascular Institute Portland PI Portland OR

Jeffrey Swanson Providence Heart & Vascular Institute Portland Co-PI Portland OR

Joseph Montarello Royal Adelaide Hospital—Adelaide PI Adelaide Australia

Clifford Kavinsky Rush University Medical Center PI Chicago IL

Robert March Rush University Medical Center Co-PI Chicago IL

Evelio Rodriguez Saint Thomas Health PI Nashville TN

Andrew Morse Saint Thomas Health Co-PI Nashville TN

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Paul Mahoney Sentara Cardiovascular Research Institute, Norfolk PI Norfolk VA

Joseph Newton Sentara Cardiovascular Research Institute, Norfolk Co-PI Norfolk VA

John Webb St. Paul's Hospital Vancouver PI Vancouver BC

Craig Miller Stanford University Medical Center PI Stanford CA

Alan Yeung Stanford University Medical Center Co-PI Stanford CA

Dean Kereiakes The Christ Hospital Cincinnati PI Cincinnati OH

Geoffrey Answini The Christ Hospital Cincinnati Co-PI Cincinnati OH

Samir Kapadia The Cleveland Clinic Foundation PI Cleveland OH

David Brown The Heart Hospital Baylor Plano PI Plano TX

Michael Mack The Heart Hospital Baylor Plano Co-PI Plano TX

Richard Smalling The University of Texas Health Science Center at Houston PI Houston TX

Tuyen Tom Nguyen

The University of Texas Health Science Center at Houston Co-PI Houston TX

Brad Oldemeyer UC Health Northern Colorado (Medical Center of the Rockies) PI Loveland CO

Mark Guadagnoli UC Health Northern Colorado (Medical Center of the Rockies) Co-PI Loveland CO

Vijay Iyer University at Buffalo—Kaleida Health PI Buffalo NY

Gary Grosner University at Buffalo—Kaleida Health Co-PI Buffalo NY

Richard Shemin University of California Los Angeles PI Los Angeles CA

William Suh University of California Los Angeles Co-PI Los Angeles CA

Thomas Beaver University of Florida Gainesville PI Gainesville FL

Charles Klodell University of Florida Gainesville PI Gainesville FL

David Anderson University of Florida Gainesville Co-PI Gainesville FL

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Mohammad Bashir University of Iowa Hospitals and Clinics Iowa City PI Iowa City IA

Firas Zahr University of Iowa Hospitals and Clinics Iowa City Co-PI Iowa City IA

Gregory Helmer University of Minnesota Medical Center PI Minneapolis MN

Kenneth Liao University of Minnesota Medical Center Co-PI Minneapolis MN

Joseph Bavaria University of Pennsylvania Philadelphia PI Philadelphia PA

Howard Herrmann University of Pennsylvania Philadelphia Co-PI Philadelphia PA

Gorav Ailawadi University of Virginia Charlottesville PI Charlottesville VA

James McCabe University of Washington Seattle PI Seattle WA

Gabriel Aldea University of Washington Seattle Co-PI Seattle WA

Alan Zajarias Washington University/Barnes-Jewish Hospital Saint Louis PI St. Louis MO

Hersh Maniar Washington University/Barnes-Jewish Hospital Saint Louis Co-PI St. Louis MO

Richard Schwartz Winthrop-University Hospital Mineola PI Mineola NY

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STUDY ADMINISTRATION

National Principal Investigators

• Martin B. Leon, MD, Columbia University Medical Center, New York, NY

• Michael J. Mack, MD, The Heart Hospital Baylor Plano, Plano, TX

CT Substudy Principal Investigator

• Raj Makkar, MD, Cedars-Sinai Medical Center, Los Angeles, CA

Steering Committee

• Howard Herrmann, Samir Kapadia, Susheel Kodali, Martin B. Leon, Michael J.

Mack, Raj Makkar, Craig R. Smith (chair), Wilson Szeto, Vinod Thourani, John

Webb

Data & Safety Monitoring Board

• Cardiovascular Research Foundation, New York, NY; Joseph Carrozza, Jr., MD,

chair

Clinical Events Committee

• Cardiovascular Research Foundation, New York, NY; Steven O. Marx, MD, chair

CT Core Laboratory

• The University of British Columbia; Jonathon Leipsic, MD, chair; Philipp Blanke,

MD, chair

Echocardiographic Core Laboratory

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• Quebec Heart & Lung Institute (Laval University); Philippe Pibarot, DVM PhD,

chair

• Cardiovascular Research Foundation, New York, NY; Rebecca Hahn, MD, chair

Sponsor

• Edwards Lifesciences, Irvine, CA

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INCLUSION AND EXCLUSION CRITERIA

Inclusion Criteria All study participants must meet the following inclusion criteria:

1. Severe, calcific aortic stenosis meeting the following criteria:

AVA ≤ 1.0 cm2 or AVA index ≤ 0.6 cm2/m2

Jet velocity ≥ 4.0 m/s or mean gradient ≥ 40 mm Hg and

NYHA functional class ≥ 2; or

Exercise tolerance test that demonstrates a limited exercise capacity, abnormal BP

response, or arrhythmia; or

Asymptomatic with LVEF < 50%

Note: Qualifying echo must be within the 90 days prior to randomization.

2. Heart team agrees the patient has a low risk of operative mortality and an STS < 4

3. No pre-existing indication for anticoagulation

4. No contraindication to undergoing a CT scan with contrast

5. The study patient has been informed of the nature of the study, agrees to its provisions

and has provided written informed consent as approved by the Institutional Review Board

(IRB)/Ethics Committee (EC) of the respective clinical site.

Exclusion Criteria Candidates will be excluded from the study if any of the following conditions are present:

1. Native aortic annulus size unsuitable for sizes 20, 23, 26, or 29 mm THV based on 3D

imaging analysis

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2. Iliofemoral vessel characteristics that would preclude safe passage of the introducer

sheath

3. Evidence of an acute myocardial infarction ≤ 1 month (30 days) before randomization

4. Aortic valve is unicuspid, bicuspid, or noncalcified

5. Severe aortic regurgitation (>3+)

6. Severe mitral regurgitation (>3+) or ≥ moderate stenosis

7. Pre-existing mechanical or bioprosthetic valve in any position. (Note: mitral ring is not an

exclusion).

8. Complex coronary artery disease:

a. Unprotected left main coronary artery

b. Syntax score > 32 (in the absence of prior revascularization)

c. Heart Team assessment that optimal revascularization cannot be performed

9. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis

within 30 days of randomization

10. Leukopenia (WBC < 3000 cell/ml), anemia (Hgb < 9 g/dl), thrombocytopenia (Plt <

50,000 cell/ml), history of bleeding diathesis or coagulopathy, or hypercoagulable states

11. Hemodynamic or respiratory instability requiring inotropic support, mechanical

ventilation or mechanical heart assistance within 30 days of randomization

12. Hypertrophic cardiomyopathy with obstruction (HOCM)

13. Ventricular dysfunction with LVEF < 30%

14. Cardiac imaging (echo, CT, and/or MRI) evidence of intracardiac mass, thrombus or

vegetation

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15. Inability to tolerate, or condition precluding treatment with,

antithrombotic/anticoagulation therapy during or after the valve implant procedure

16. Stroke or transient ischemic attack (TIA) within 90 days of randomization

17. Renal insufficiency (eGFR < 30 ml/min per the Cockcroft-Gault formula) and/or renal

replacement therapy at the time of screening.

18. Active bacterial endocarditis within 180 days of randomization

19. Severe lung disease (FEV1 < 50% predicted) or currently on home oxygen

20. Severe pulmonary hypertension (e.g., PA systolic pressure ≥ 2/3 systemic pressure)

21. History of cirrhosis or any active liver disease

22. Significant frailty as determined by the Heart Team (after objective assessment of frailty

parameters)

23. Significant abdominal or thoracic aortic disease (such as porcelain aorta, aneurysm,

severe calcification, aortic coarctation, etc.) that would preclude safe passage of the

delivery system or cannulation and aortotomy for surgical AVR

24. Hostile chest or conditions or complications from prior surgery that would preclude safe

reoperation (i.e., mediastinitis, radiation damage, abnormal chest wall, adhesion of aorta

or IMA to sternum, etc.)

25. Patient refuses blood products

26. BMI > 50 kg/m2

27. Estimated life expectancy < 24 months

28. Absolute contraindications or allergy to iodinated contrast that cannot be adequately

treated with pre-medication

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29. Immobility that would prevent completion of study procedures (e.g., 6-minute walk tests,

etc.)

30. Patient is not a candidate for both arms of the study (not applicable to single-arm

registries)

31. Currently participating in an investigational drug or another device study. (Note: Trials

requiring extended follow-up for products that were investigational, but have since

become commercially available, are not considered investigational trials. Observational

studies are not considered exclusionary).

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Supplementary Table 1: Baseline characteristics of patients who did not have a serial CT at 1 year and those who had a CT scan at 1 year but were not usable

 

Patients With CT at 30-Days,

But Not at 1 Year

Patients With Nonusable CT

at 1 Year

Age, yrs 73.0 ± 5.72 68.1 ± 8.07

Male sex, no. (%) 31/51 (60.8%) 6/9 (66.7%)

Nonwhite race or ethnic group, no. (%)† 3/51 (5.9%) 2/9 (22.2%)

Body-mass index‡ 28.1 ± 4.24 33.6 ± 4.81

STS score§ 1.8 ± 0.75 1.5 ± 0.34

NYHA class III or IV, no. (%) 23/51 (45.1%) 4/9 (44.4%)

Coronary artery disease, no./total no. (%) 8/51 (15.7%) 2/9 (22.2%)

Previous CABG, no./total no. (%) 1/51 (2.0%) 0/9 (0.0%)

Previous stroke/TIA, no./total no. (%) 0/51 (0.0%) 0/9 (0.0%)

Peripheral vascular disease, no./total no. (%) 2/51 (3.9%) 0/9 (0.0%)

Diabetes, no./total no. (%) 11/51 (21.6%) 4/9 (44.4%)

COPD, no./total no. (%) 2/51 (3.9%) 0/9 (0.0%)

Pulmonary hypertension, no./total no. (%) 0/51 (0.0%) 1/9 (11.1%)

Creatinine > 2 mg/dl, no./total no. (%)‖ 0/51 (0.0%) 0/9 (0.0%)

Frailty (overall; > 2/4+), no./total no. (%)* 0/51 (0.0%) 0/9 (0.0%)

Atrial fibrillation, no./total no. (%) 6/51 (11.8%) 0/9 (0.0%)

Permanent pacemaker, no./total no. (%) 1/51 (2.0%) 1/9 (11.1%)

Left bundle branch block, no./total no. (%) 1/51 (2.0%) 1/9 (11.1%)

Right bundle branch block, no./total no. (%) 2/51 (3.9%) 0/9 (0.0%)

Plus-minus values are mean ± SD. STS denotes Society of Thoracic Surgery score, CABG coronary artery bypass grafting, TIA transient ischemic attack, and COPD chronic obstructive pulmonary disease.† Race or ethnic group was reported by the patient.‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.§ Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) scores range from 0% to 100%, with higher scores indicating a greater risk of death within 30 days after the procedure. STS-PROM uses an algorithm that is based on the presence of coexisting

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illnesses in order to predict 30-day operative mortality. The STS-PROM score equals the predicted mortality expressed as a percentage. Less than 5% of patients in the population on which the STS-PROM algorithm is based had a predicted operative mortality (score) of more than 10%.‖ To convert the values for creatinine to micromoles per liter, multiply by 88.4.* Overall frailty was defined as the presence of three or more of the following criteria: grip strength of less than 18 kg, 5-meter walk-test time of more than 6 seconds, serum albumin level of less than 3.5 g per deciliter, and Katz Activities of Daily Living total score of 4 or less (with scores ranging from 0 to 6 and higher scores indicating greater independence in performing activities of daily living).

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Supplementary Table 2: Anticoagulation status in patients with usable CTs at 30-days and/or 1-year after aortic valve replacement

  N = 372*Patients with no anticoagulation post-index procedure 297Patients who received valve-related anticoagulation† 7

Stroke 2Transient ischemic attack 1Site-reported presumed valve thrombosis 4

Patients who received non-valve related anticoagulation 68Atrial fibrillation/flutter 45Heparin-induced thrombocytopenia 1Pulmonary embolism 2Deep vein thrombosis 1Deep vein thrombosis prophylaxis 2Unblinding of CT with initiation of anticoagulation for HALT 7Bioprosthetic valve/site preference 7Unknown 3

* 372 patients had usable CTs for the assessment of HALT at 30-days and/or 1-year.

† Patients were considered to receive anticoagulation for valve-related reasons if anticoagulation was initiated by the treating investigators for thromboembolic event or presumed valve thrombosis without unblinding of the CT.

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Supplemental Table 3: Details on hypoattenuating leaflet thickening, echocardiographic gradients and clinical presentation of patients receiving valve-related anticoagulation

Timing of Event

Type of AC

TAVR or

Surgery30-Days 1-Year Details of Clinical Event That Triggered Anticoagulation

1-year visit Apixaban TAVR

HALT −ve HALT > 75% RETINAL ARTERY OCCLUSION AND ELEVATED GRADIENT: Patient had retinal artery embolism at day 358 (adjudicated as a stroke)15.8 mm Hg 35.5 mm Hg

30-day visit Warfarin TAVR

HALT>50% HALT > 50% ELEVATED GRADIENT: Patient had elevated gradient on 30-day echo; rehospitalized for bleeding on day 56—found to have subdural hematoma and supratherapeutic INR32 mm Hg 34.8 mm Hg

30-day visit Warfarin TAVR

HALT –ve HALT –ve PRESUMED VALVE THROMBOSIS: Patient had symptoms of dizziness and leaflet thickening on transesophageal echocardiogram at 30 days; was started on anticoagulation for presumed valve thrombosis13.7 mm Hg 10.1 mm Hg

Post-op day 10 Warfarin TAVR

HALT 50%–75% HALT > 75% STROKE: Prescribed aspirin post procedure and subject noncompliant. Admitted with

ischemic stroke on post-op day 10; Prescribed aspirin and clopidogrel. Started on warfarin on post-op day 3013.3 mm Hg 13.3 mm Hg

Post-op day 3 Warfarin TAVR

HALT −ve HALT −ve STROKE: Patient had embolic stroke on post-op day 3, was started on heparin. Embolectomy was performed on day 4 and anticoagulation initiated with warfarin; hemorrhagic stroke on post-op day 8 related to embolectomy. Warfarin was discontinued.9.3 mm Hg 5.7 mm Hg

Post-op day 17 Warfarin Surgery

HALT −ve HALT −ve TIA: Patient had visual impairment on post-op day 17—was adjudicated as a TIA and was started on anticoagulation15.6 mm Hg 13.2 mm Hg

5 days post-op Warfarin Surgery

HALT –ve HALT –veSTROKE: Patient had a stroke on post-op day 5 and was started on anticoagulation

11.8 mm Hg 18.9 mm Hg

AC denotes anticoagulation, TAVR transcatheter aortic valve replacement, HALT hypoattenuated leaflet thickening, and TIA transient ischemic attack

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Supplemental Table 4: Incidence of hypoattenuated leaflet thickening in patients on anticoagulation at the time of CT

  30-Day CT   1-year CT

Endpoint AC* No AC* Risk Ratio (95% CI)   AC* No AC* Risk Ratio (95%

CI)

HALT 2/45 (4.4%) 33/301 (11.0%) 0.41 (0.10–1.63) 5/33 (15.2%) 68/279 (24.4%) 0.62 (0.27–1.43)

No HALT 43/45 (95.6%) 268/301 (89.0%) 28/33 (84.8%) 211/279 (75.6%)

HALT > 25% 1/45 (2.2%) 23/301 (7.6%) 0.29 (0.04–2.10) 3/33 (9.1%) 37/279 (13.3%) 0.69 (0.22–2.10)

HALT ≤ 25% 44/45 (97.8%) 278/301 (92.4%) 30/33 (90.9%) 242/279 (86.7%)

HALT > 50% 1/45 (2.2%) 14/301 (4.7%) 0.48 (0.06–3.55) 2/33 (6.1%) 20/279 (7.2%) 0.85 (0.21–3.46)

HALT ≤ 50% 44/45 (97.8%) 287/301 (95.3%) 31/33 (93.9%) 259/279 (92.8%)

Reduced leaflet motion 2/43 (4.7%) 32/280 (11.4%) 0.41 (0.10–1.64) 5/31 (16.1%) 65/267 (24.3%) 0.66 (0.29–1.52)

Normal leaflet motion 41/43 (95.3%) 248/280 (88.6%)     26/31 (83.9%) 202/267 (75.7%)  

*Anticoagulation includes anticoagulation at the time of CT. HALT denotes hypoattenuated leaflet thickening, CT computed tomography, and AC anticoagulation

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Supplemental Table 5: Distribution of anticoagulation at different time points in patients with hypoattenuated leaflet thickening

ALL PATIENTS HALT at 30 Days or 1 Year   HALT at 30 Days and 1 Year

Status of anticoagulation

No Yes No YesN = 206 N = 95 N = 344 N = 13

Discharge 23/206 (11.2%) 6/95 (6.3%) 37/344 (10.8%) 0/13 (0.0%)30 Day 28/206 (13.6%) 6/95 (6.3%) 45/344 (13.1%) 0/13 (0.0%)1 Year 23/206 (11.2%) 8/95 (8.4%) 34/344 (9.9%) 2/13 (15.4%)SURGERY HALT at 30 Days or 1 Year   HALT at 30 Days and 1 Year

Status of anticoagulation

No Yes No YesN = 105 N = 34 N = 166 N = 1

Discharge 19/105 (18.1%) 5/34 (14.7%) 29/166 (17.5%) 0/1 (0%)30 Day 23/105 (21.9%) 5/34 (14.7%) 35/166 (21.1%) 0/1 (0%)1 Year 17/105 (16.2%) 2/34 (5.9%) 24/166 (14.5%) 0/1 (0%)TAVR HALT at 30 Days or 1 Year HALT at 30 Days and 1 Year

Status of anticoagulation

No Yes No YesN = 101 N = 61 N = 178 N = 12

Discharge 4/101 (4%) 1/61 (1.6%) 8/178 (4.5%) 0/12 (0%)30 Day 5/101 (5%) 1/61 (1.6%) 10/178 (5.6%) 0/12 (0%)1 Year 6/101 (5.9%) 6/61 (9.8%)   10/178 (5.6%) 2/12 (16.7%)HALT denotes hypoattenuated leaflet thickening; and TAVR denotes transcatheter aortic valve replacementData are presented as n/N (%)

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Supplemental Table 6: Distribution of anticoagulation at different time points in patients with reduced leaflet motion

ALL PATIENTS RELM at 30 Days or 1 Year   RELM at 30 Days and 1 Year

Status of anticoagulation

No Yes No YesN = 193 N = 82 N = 337 N = 11

Discharge 23/193 (11.9%) 4/82 (4.9%) 37/337 (11.0%) 0/11 (0.0%)30 Day 27/193 (14.0%) 5/82 (6.1%) 44/337 (13.1%) 0/11 (0.0%)1 Year 19/193 (9.8%) 7/82 (8.5%) 34/337 (10.1%) 2/11 (18.2%)SURGERY RELM at 30 Days or 1 Year   RELM at 30 Days and 1 Year

Status of anticoagulation

No Yes No YesN = 98 N = 29 N = 165 N = 1

Discharge 19/98 (19.4%) 3/29 (10.3%) 30/165 (18.2%) 0/1 (0%)30 Day 23/98 (23.5%) 4/29 (13.8%) 35/165 (21.2%) 0/1 (0%)1 Year 14/98 (14.3%) 1/29 (3.4%) 24/165 (14.5%) 0/1 (0%)TAVR RELM at 30 Days or 1 Year   RELM at 30 Days and 1 Year

Status of anticoagulation

No Yes No YesN = 95 N = 53 N = 172 N = 10

Discharge 4/95 (4.2%) 1/53 (1.9%) 7/172 (4.1%) 0/10 (0%)30 Day 4/95 (4.2%) 1/53 (1.9%) 9/172 (5.2%) 0/10 (0%)1 Year 5/95 (5.3%) 6/53 (11.3%)   10/172 (5.8%) 2/10 (20%)RELM denotes reduced leaflet motion; and TAVR denotes transcatheter aortic valve replacementData are presented as n/N (%)

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Supplemental Table 7: Baseline characteristics of patients with or without hypoattenuated leaflet thickening at 30 days

  HALT No HALT  (N = 28) (N = 256)

Age, yrs 73.2 ± 4.4 72.3 ± 6.1Male sex, no. (%) 20 (71.4) 175 (68.4)Nonwhite race or ethnic group, no. (%)† 5 (17.9) 29 (11.3)Body mass index‡ 28.8 ± 4.1 30.1 ± 4.7STS score§ 1.8 ± 0.7 1.8 ± 0.7NYHA class III or IV, no. (%) 18 (64.3) 104 (40.6)Coronary artery disease, no./total no. (%) 11/28 (39.3) 76/256 (29.7)Previous CABG, no./total no. (%) 2/28 (7.1) 7/254 (2.8)Previous stroke/TIA, no./total no. (%) 1/28 (3.6) 9/256 (3.5)Peripheral vascular disease, no./total no. (%) 0 (0) 11/256 (4.3)Diabetes, no./total no. (%) 4/28 (14.3) 84/255 (32.9)COPD, no./total no. (%) 2/28 (7.1) 12/256 (4.7)Pulmonary hypertension, no./total no. (%) 1/28 (3.6) 12/255 (4.7)Creatinine > 2 mg/dl, no./total no. (%)‖ 0 (0) 0 (0)Frailty (overall; > 2/4+), no./total no. (%)** 0 (0) 0 (0)Atrial fibrillation, no./total no. (%) 0 (0) 13/256 (4.7)Permanent pacemaker, no./total no. (%) 1/28 (3.6) 5/256 (2.0)Left bundle branch block, no./total no. (%) 1/28 (3.6) 7/256 (2.7)Right bundle branch block, no./total no. (%) 2/28 (7.1) 21/256 (8.2)

Plus-minus values are mean ± SD. There were no significant between-group differences in baseline characteristics, except for New York Heart Association (NYHA) class III or IV (P<0.05). STS denotes Society of Thoracic Surgery score, CABG coronary artery bypass grafting, TIA transient ischemic attack, and COPD chronic obstructive pulmonary disease.

† Race or ethnic group was reported by the patient.‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.§ Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) scores range from 0 to 100%, with higher scores indicating a greater risk of death within 30 days after the procedure. STS-PROM uses an algorithm that is based on the presence of coexisting illnesses in order to predict 30-day operative mortality. The STS-PROM score equals the predicted mortality expressed as a percentage. Less than 5% of patients in the population on which the STS-PROM algorithm is based had a predicted operative mortality (score) of more than 10%.‖ To convert the values for creatinine to micromoles per liter, multiply by 88.4.

** Overall frailty was defined as the presence of three or more of the following criteria: grip strength of less than 18 kg, 5-meter walk-test time of more than 6 seconds, serum albumin level of less than 3.5 g per deciliter, and Katz Activities of Daily Living total score of 4 or less (with scores ranging from 0 to 6 and higher scores indicating greater independence in performing activities of daily living).

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Supplemental Table 8: Incidence of hypoattenuated leaflet thickening stratified according to the valve size

30-Day CT 1-Year CT

Valve Size (mm) TAVR(N = 213)

SAVR(N = 195)

TAVR(N = 213)

SAVR(N = 195)

19 NA 0/1 (0.0%) NA 0/1 (0.0%)

20 0/3 (0.0%) NA 0/3 (0.0%) NA

21 NA 2/24 (8.3%) NA 2/21 (9.5%)

23 7/52 (13.5%) 0/59 (0.0%) 15/49 (30.6%) 12/58 (20.7%)

25 NA 4/59 (6.8%) NA 11/50 (22.0%)

26 14/102 (13.7%) NA 21/87 (24.1%) NA

27 NA 1/17 (5.9%) NA 2/12 (16.7%)

29 7/27 (25.9%) 0/2 (0.0%) 9/29 (31.0%) 1/2 (50.0%)

CT denoted computed tomography, TAVR denotes transcatheter aortic valve replacement, and SAVR denotes surgical aortic valve replacement. Data are presented as n /N (%).

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Supplemental Table 9: Incidence of reduced leaflet motion stratified according to valve size

30-Day CT 1-Year CT

Valve Size (mm) TAVR(N = 213)

SAVR(N = 195)

TAVR(N = 213)

SAVR(N = 195)

19 NA 0/1 (0.0%) NA 0/1 (0.0%)

20 0/3 (0.0%) NA 0/3 (0.0%) NA

21 NA 2/21 (9.5%) NA 2/20 (10.0%)

23 7/47 (14.9%) 0/59 (0.0%) 12/45 (26.7%) 11/57 (19.3%)

25 NA 2/55 (3.6%) NA 9/49 (18.4%)

26 13/95 (13.7%) NA 17/84 (20.2%) NA

27 NA 1/16 (6.3%) NA 2/10 (20.0%)

29 5/25 (20.0%) 0/2 (0.0%) 9/28 (32.1%) 1/2 (50.0%)

CT denoted computed tomography, TAVR denotes transcatheter aortic valve replacement, and SAVR denotes surgical aortic valve replacement. Data are presented as n /N (%).

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Supplemental Table 10: Echocardiographic characteristics of patients with hypoattenuated leaflet thickening

Endpoint HALT at 30-Days No HALT at 30-Days HALT at 1-Year No HALT at 1-Year

Central AR (Yes/No) 0/35 (0.0%) 0/302 (0.0%) 0/73 (0.0%) 0/232 (0.0%)

Moderate 0/35 (0.0%) 0/302 (0.0%) 0/73 (0.0%) 0/232 (0.0%)

Mod-Severe 0/35 (0.0%) 0/302 (0.0%) 0/73 (0.0%) 0/232 (0.0%)

Severe 0/35 (0.0%) 0/302 (0.0%) 0/73 (0.0%) 0/232 (0.0%)

VTI ratio* 0.4 ± 0.01 (34) 0.4 ± 0.00 (283) 0.4 ± 0.01 (65) 0.4 ± 0.00 (216)

Ejection fraction 68.1 ± 1.06 (33) 66.7 ± 0.48 (294) 65.4 ± 0.92 (72) 68.1 ± 0.49 (225)

HALT denotes hypoattenuated leaflet thickening and AR denotes aortic regurgitation.Categorical data are presented as n/N (%) and continuous data are presented as mean ± standard error.*VTI ratio was calculated as (left ventricular outflow tract VTI) / (aortic valve VTI).

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Supplemental Table 11: Echocardiographic characteristics of patients with reduced leaflet motion

Endpoint RLM at 30-Days No RLM at 30-Days RLM at 1-Year No RLM at 1-Year

Central AR (Yes/No) 0/30 (0.0%) 0/286 (0.0%) 0/63 (0.0%) 0/231 (0.0%)

Moderate 0/30 (0.0%) 0/286 (0.0%) 0/63 (0.0%) 0/231 (0.0%)

Mod-Severe 0/30 (0.0%) 0/286 (0.0%) 0/63 (0.0%) 0/231 (0.0%)

Severe 0/30 (0.0%) 0/286 (0.0%) 0/63 (0.0%) 0/231 (0.0%)

VTI ratio* 0.4 ± 0.01 (30) 0.4 ± 0.00 (267) 0.4 ± 0.01 (55) 0.4 ± 0.01 (215)

Ejection fraction 67.6 ± 1.12 (29) 66.7 ± 0.50 (277) 65.2 ± 0.96 (62) 67.9 ± 0.51 (223)

RLM denotes reduced leaflet motion and AR denotes aortic regurgitation.Categorical data are presented as n/N (%) and continuous data are presented as mean ± standard error.*VTI ratio was calculated as (left ventricular outflow tract VTI) / (aortic valve VTI).

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Supplemental Table 12: Impact of hypoattenuated leaflet thickening on clinical outcomes in patients undergoing transcatheter aortic valve replacement

  Days 7–365   Days 7–30   Days 31–365

HALT +ve

HALT −ve

Risk Ratio (95% CI)

HALT +ve

HALT −ve

Risk Ratio (95% CI)

HALT +ve

HALT −ve

Risk Ratio (95% CI)

  N = 28 N = 156     N = 28 N = 156     N = 28 N = 156  Death 0 2 NA 0 0 NA 0 2 NAHeart failure 0 1 NA 0 0 NA 0 1 NAAngina 0 6 NA 0 0 NA 0 6 NAMyocardial infarction 0 0 NA 0 0 NA 0 0 NA

Clinical valve thrombosis* 3 1 16.71 (1.80–155.00) 0 0 NA 3 1 16.71 (1.80–155.00)

Stroke 1 1 5.57 (0.36–86.50) 1 0 NA 0 1 NATIA 1 2 2.79 (0.26–29.70) 0 0 NA 1 2 2.79 (0.26–29.70)Retinal artery embolism 1 1 5.57 (0.36–86.50) 0 0 NA 1 1 5.57 (0.36–86.50)Death/stroke/myocardial infarction 1 3 1.86 (0.20–17.22) 1 0 NA 0 3 NAStroke/TIA 2 3 3.71 (0.65–21.23) 1 0 NA 1 3 1.86 (0.20–17.22)Stroke/TIA/retinal artery embolism 3 4 4.18 (0.99–17.67) 1 0 NA 2 4 2.79 (0.54–14.49)Death/Stroke/TIA/retinal artery embolism 3 6 2.79 (0.74–10.49)   1 0 NA   2 6 1.86 (0.39–8.74)HALT denotes hypoattenuated leaflet thickening, TIA transient ischemic attack, and CI confidence interval.* Clinical valve thrombosis was defined as any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment.

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Supplemental Table 13: Impact of hypoattenuated leaflet thickening on clinical outcomes in patients undergoing surgical aortic valve replacement

  Days 7–365   Days 7–30   Days 31–365

HALT +ve

HALT −ve

Risk Ratio (95% CI)

HALT +ve

HALT −ve

Risk Ratio (95% CI)

HALT +ve

HALT −ve

Risk Ratio (95% CI)

  N = 7 N = 155     N = 7 N = 155     N = 7 N = 155  Death 0 2 NA 0 0 NA 0 2 NAHeart failure 1 6 3.69 (0.51–26.65) 0 1 NA 1 5 4.43 (0.59–33.02)Angina 0 3 NA 0 0 NA 0 3 NAMyocardial infarction 0 3 NA 0 0 NA 0 3 NAClinical valve thrombosis* 0 0 NA 0 0 NA 0 0 NAStroke 0 0 NA 0 0 NA 0 0 NATIA 0 1 NA 0 1 NA 0 0 NARetinal artery embolism 0 0 NA 0 0 NA 0 0 NADeath/stroke/myocardial infarction 0 5 NA 0 0 NA 0 5 NAStroke/TIA 0 1 NA 0 1 NA 0 0 NAStroke/TIA/retinal artery embolism 0 1 NA 0 1 NA 0 0 NADeath/Stroke/TIA/retinal artery embolism 0 3 NA   0 1 NA   0 2 NAHALT denotes hypoattenuated leaflet thickening, TIA transient ischemic attack, and CI confidence interval* Clinical valve thrombosis was defined as any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment.

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Supplemental Table 14: Details on hypoattenuating leaflet thickening, echocardiographic gradients, and clinical presentation of patients with clinical valve thrombosis

Treatment Arm

Timing of

Event

HALT at 30 Days

HALT at 1 Year Mean Gradient Clinical Details

TAVR 30

25%–50% HALT,

unrestricted leaflets

No HALT/HAM

Baseline: 59.2 mm Hg

Patient received warfarin at 30-days for elevated gradient30-day: 21.0 mm Hg

1-year: 10.2 mm Hg

TAVR 4050%–75%

HALT, partially restricted leaflets

>75% HALT, partially restricted leaflets

Baseline: 69.1 mm Hg Patient had elevated gradient at 30 days that triggered unblinding of CT; patient was started on warfarin; rehospitalized for bleeding on day 56; patient had subdural hematoma and supratherapeutic INR

30-day: 32.0 mm Hg

1-year: 34.8 mm Hg

TAVR 3050%–75%

HALT, partially restricted leaflets

Not available

Baseline: 50.7 mm HgPatient had shortness of breath while walking uphill at 30 days and HALT with leaflet restriction on CT; warfarin started at day 190

30-day: 11.6 mm Hg

1-year: 7.4 mm Hg

TAVR 182 No HALT Not available

Baseline: 41.6 mm Hg Leaflet thickening was seen on 30-day echo + patient was symptomatic (dizziness) but CT did not show HALT or leaflet restriction. Adjudicated as clinical valve thrombosis according to VARC2 criteria

30-day: 13.7 mm Hg

1-year: 10.1 mm Hg

HALT denotes hypoattenuated leaflet thickening, TAVR transcatheter aortic valve replacement, CT computed tomography, INR international normalized ratio, and VARC Valve Academic Research Consortium.

Clinical valve thrombosis was defined as any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment.

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Supplemental Table 15: Details on hypoattenuated leaflet thickening, echocardiographic gradients, and clinical presentation of patients with thromboembolic complications (stroke, transient ischemic attack, or retinal artery embolism)

Treatment Arm

Timing of

Event

HALT at 30 Days

HALT at 1 Year Mean Gradient Clinical Details

TAVR 1050%–75%

HALT, largely immobile leaflets

>75% HALT, largely

immobile leaflets

Baseline: 91.1 mm HgSTROKE: Patient was prescribed aspirin post procedure; non-compliant. Admitted with ischemic stroke on post-op day 10; Prescribed aspirin and clopidogrel. Started on warfarin on post-op day 30

30-day: 13.3 mm Hg

1-year: 13.3 mm Hg

TAVR 358 No HALT

>75% HALT, largely

immobile leaflets

Baseline: 46.3 mm HgRETINAL ARTERY OCCLUSION/STROKE: Patient had retinal artery branch occlusion; adjudicated as a stroke. Seen at 1-year follow-up on post-op day 373. TEE revealed aortic valve moving well but elevated gradients

30-day: 15.3 mm Hg

1-year: 35.5 mm Hg

TAVR 57 No HALT

<25% HALT, partially restricted leaflets

Baseline: 51.6 mm HgTIA: Patient had a transient episode of diplopia; MRI revealed infarct but not in the region that would cause vision abnormality. Maintained on apixaban until approximately 1-year post index procedure

30-day: 10.2 mm Hg

1-year: 11.9 mm Hg

TAVR 114 No HALT No HALT

Baseline: 33.0 mm HgTIA: Patient diagnosed with a TIA. Echocardiogram and carotid ultrasound were negative; 4D CT was performed that revealed no HALT/thrombus and normal leaflet motion

30-day: 10.3 mm Hg

1-year: 13.8 mm Hg

TAVR 357 25%–50% HALT, partially restricted leaflets

<25% HALT, partially restricted leaflets

Baseline: 42.5 mm HgTIA: Patient had an episode of left arm numbness lasting 10–15 minutes; neurologic exam was unremarkable at 1 year visit30-day: 9.0 mm Hg

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1-year: 11.3 mm Hg

Surgery 17 No HALT No HALT

Baseline: 51.2 mm Hg

TIA: Patient had visual impairment shortly after index procedure– was adjudicated as a TIA30-day: 15.6 mm Hg

1-year: 13.2 mm Hg

TAVR 11825%–50%

HALT, partially restricted leaflets

25%–50% HALT

Baseline: 42.5 mm HgRETINAL ARTERY OCCLUSION: Patient developed visual changes in left eye on post op day 118 and was diagnosed with transient retinal artery occlusion; Carotid ultrasound and transthoracic echocardiogram were normal

30-day: 11.7 mm Hg

1-year: 11.9 mm Hg

TAVR 260 No HALT No HALT

Baseline: 46.6 mm HgRETINAL ARTERY OCCLUSION: Patient had symptoms of veil lowering over left eye, diagnosed with retinal artery occlusion. No anticoagulation was initiated.

30-day: 7.2 mm Hg

1-year: 9.2 mm Hg

HALT denotes hypoattenuated leaflet thickening, TAVR transcatheter aortic valve replacement, CT computed tomography, INR international normalized ratio, and TIA transient ischemic attack.

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Supplemental Table 16: Impact of hypoattenuated leaflet thickening at any time point (30-day or 1-year computed tomograms) on clinical outcomes in patients undergoing transcatheter or surgical aortic valve replacement

  Days 7–365   Days 7–30   Days 31–365HALT

at Any Time Point

No HALT at Any Time Point

Risk Ratio (95% CI)

HALT at Any Time Point

No HALT at Any Time Point

Risk Ratio (95% CI)

HALT at Any Time Point

No HALT at Any Time Point

Risk Ratio (95% CI)

  N = 95 N = 269     N = 95 N = 269     N = 95 N = 269  

Death 0 4 NA 0 0 NA 0 4 NA

Heart failure 1 7 0.4 (0.1–3.2) 0 1 NA 1 6 0.5 (0.1–3.9)

Angina 2 9 06 (0.1–2.9) 0 0 NA 2 8 0.7 (0.2–3.3)

Myocardial infarction 0 3 NA 0 0 NA 0 3 NA

Clinical valve thrombosis* 3 1 8.5 (0.9–80.7) 0 0 NA 3 1 8.5 (0.9–80.7)

Stroke 2 0 NA 1 0 NA 1 0 NA

TIA 2 2 28 (0.4–19.8) 0 1 NA 2 1 5.7 (0.5–61.7)

Retinal artery embolism 1 1 2.8 (0.2–44.8) 0 0 NA 1 1 2.8 (0.2–44.8)

Death/stroke/myocardial infarction 2 7 0.8 (0.2–3.8) 1 0 NA 1 7 0.4 (0.1–3.2)

Stroke/TIA 4 2 5.7 (1.4–30.4) 1 1 2.8 (0.2–44.8) 3 1 8.5 (0.9–80.7)

Stroke/TIA/retinal artery embolism 5 3 4.7 (1.5–19.4) 1 1 2.8 (0.2–44.8) 4 2 5.7 (1.1–30.4)

Death/Stroke/TIA/retinal artery embolism 5 7 2 (0.5–6.2)   1 1 2.8 (0.2–44.8)   4 6 1.9 (0.5–6.5)

HALT denotes hypoattenuated leaflet thickening, TIA transient ischemic attack, and CI confidence interval.* Clinical valve thrombosis was defined as any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment.

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Supplemental Table 17: Predictors of hypoattenuated leaflet thickening and reduced leaflet motion

Predictors of HALT at 30 DaysParameter Estimate ± SE p ValueTAVR 1.4 ± 0.55 0.0114BMI −0.1 ± 0.05 0.0457Diabetes −1.25 ± 0.57 0.0286Predictors of RLM at 30 DaysParameter Estimate ± SE p ValueTAVR 1.32 ± 0.57 0.0204Predictors of HALT at 1 YearParameter Estimate ± SE p ValueNo significant baseline predictorsPredictors of RLM at 1 YearParameter Estimate ± SE p ValuePercent Oversizing 2.61 ± 1.17 0.0256HALT denotes hypoattenuated leaflet thickening, SE denotes standard error, TAVR denotes transcatheter aortic valve replacement, BMI denotes body mass index, and RLM denotes reduced leaflet motion.*Baseline predictors with p-value <0.05 from the multivariate analysis.

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Supplemental Figure 1: Study flow and treatment group assignment

37

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Supplemental Figure 2: Natural history of reduced leaflet motion

Natural history of reduced leaflet motion based on patients with usable CTs at both 30 days and 1 year in the overall cohort (A), TAVR (B), and surgery (C).

RLM denotes reduced leaflet motion*None of the 11 patients experiencing spontaneous resolution of RLM from 30 days to 1 year received anticoagulation between the 2 CT scans.

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Supplemental Figure 3: Relationship between hypoattenuating leaflet thickening (HALT) and valve hemodynamics

(Figure 2A) The mean aortic gradients at 30 days and the presence and severity of HALT at 30 days. (Figure 2B) The mean aortic gradients at 1 year and the presence and severity of HALT at 1 year.

Figure 2A: HALT at 30 days and aortic valve gradients at 30 days

Figure 2B: HALT at 1 year and aortic valve gradients at 1 year

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Supplemental Figure 4: Impact of hypoattenuated leaflet thickening on quality of life as assessed by the KCCQ questionnaire

41

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Supplemental Figure 5: Impact of hypoattenuated leaflet thickening on NYHA class