A Prospective, Single-arm, Multicenter Study of the SAPIEN 3 Ultra System in Intermediate Risk Patients With Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement
Phase: NA
Conditions: Aortic Valve Stenosis
Sponsor: Edwards Lifesciences

PROPRIETARY DATA: This document and the information contained herein may not be reproduced, used 
or disclosed without written permission from Edwards Lifesciences LLC. 
Edwards Lifesciences, Edwards, the stylized logo, and SAPIEN XT are trademarks of Edwards Lifesciences 
Corporation 
 
 
 
 
A Prospective, Single-arm, Multicenter Study of the SAPIEN 3 
Ultra System in Intermediate Risk Patients with Severe, 
Calcific, Aortic Stenosis Requiring Aortic Valve Replacement 
 
 
NCT03471065 
 
 
 
June 2019 

PROPRIETARY DATA: This document and the information contained herein may not be reproduced, used or 
disclosed without written permission from Edwards Lifesciences LLC. 
Edwards, Edwards Lifesciences, the stylized E logo, Edwards SAPIEN, SAPIEN, Edwards SAPIEN XT, SAPIEN XT, 
Edwards SAPIEN 3, SAPIEN 3, Edwards SAPIEN 3 Ultra, SAPIEN 3 Ultra, Edwards Axela, Axela, Edwards eSheath, 
and eSheath are trademarks of Edwards Lifesciences Corporation. 
 
 
 
 
A Prospective, Single-arm, Multicenter Study of the SAPIEN 3 
Ultra System in Intermediate Risk Patients with Severe, Calcific, 
Aortic Stenosis Requiring Aortic Valve Replacement 
 
 
 
 
 
Clinical Protocol/Clinical Investigation Plan 
Study Number:  2018-03 
Version 4.0 
June 2019 
 
 
 
Study Sponsor: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, California  92614 
USA 
 
 

SAPIEN 3 Ultra System 
SAPIEN 3 Ultra Study 
 
Edwards Lifesciences LLC 
 
Protocol number:  2018-03 
CONFIDENTIAL 
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TABLE OF CONTENTS 
LIST OF TABLES ...................................................................................................................... 3 
PROTOCOL SYNOPSIS ........................................................................................................... 4 
INVESTIGATOR SIGNATURE PAGE ....................................................................................... 7 
 
INTRODUCTION ................................................................................................................ 8 
 
AORTIC STENOSIS ......................................................................................................... 8 
 
TREATMENT OF AS ........................................................................................................ 8 
 
STUDY OBJECTIVE .......................................................................................................... 9 
 
INTENDED USE .............................................................................................................. 9 
 
STUDY DESIGN ................................................................................................................. 9 
 
STUDY DEVICES ..............................................................................................................10 
 
EDWARDS SAPIEN 3 ULTRA THV .................................................................................10 
 
EDWARDS SAPIEN 3 THV............................................................................................10 
 
EDWARDS SAPIEN 3 ULTRA DELIVERY SYSTEM ............................................................10 
 
EDWARDS AXELA SHEATH ............................................................................................11 
 
EDWARDS ESHEATH INTRODUCER SET ..........................................................................11 
 
EDWARDS CRIMPER AND CRIMP STOPPER .....................................................................11 
 
EDWARDS TRANSFEMORAL BALLOON CATHETER, 25 MM ................................................11 
 
STUDY ENDPOINTS .........................................................................................................12 
 
PRIMARY ENDPOINT .....................................................................................................12 
 
SECONDARY ENDPOINTS ..............................................................................................12 
 
STUDY POPULATION ......................................................................................................12 
 
INCLUSION CRITERIA ....................................................................................................12 
 
EXCLUSION CRITERIA ...................................................................................................13 
 
STUDY PROCEDURES .....................................................................................................14 
 
INFORMED CONSENT ....................................................................................................14 
 
SCREENING .................................................................................................................14 
 
Case Review .......................................................................................................................... 16 
 
PROCEDURE ................................................................................................................16 
 
Antithrombotic Recommendations ......................................................................................... 17 
 
Antibiotic Prophylaxis ............................................................................................................. 18 
 
Contrast Media ....................................................................................................................... 18 
 
Radiation Precautions ............................................................................................................ 18 
 
POST-PROCEDURE .......................................................................................................18 
 
DISCHARGE .................................................................................................................18 
 
FOLLOW-UP .................................................................................................................19 
 
30 Days .................................................................................................................................. 19 
 
6 Months ................................................................................................................................ 19 
 
Years 1, 3 and 5 ..................................................................................................................... 20 
 
Years 2 and 4 ......................................................................................................................... 20 
 
IMAGING ASSESSMENTS ...............................................................................................20 
 
NEUROLOGICAL ASSESSMENTS .....................................................................................20 
 
SUBJECT DISPOSITION ..................................................................................................21 
 
ADVERSE EVENTS ..........................................................................................................24 
 
ADVERSE EVENT DEFINITIONS ......................................................................................24 

SAPIEN 3 Ultra System 
SAPIEN 3 Ultra Study 
 
Edwards Lifesciences LLC 
 
Protocol number:  2018-03 
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INVESTIGATOR ASSESSMENT OF AES ............................................................................25 
 
AE REPORTING REQUIREMENTS ...................................................................................26 
 
Events that do not require reporting to Edwards ................................................................... 27 
 
RISKS AND BENEFIT ANALYSIS ....................................................................................28 
 
POTENTIAL BENEFITS ...................................................................................................28 
 
POTENTIAL RISKS .........................................................................................................28 
 
Risk Minimization ................................................................................................................... 29 
 
STATISTICAL ANALYSIS .............................................................................................30 
 
ANALYSIS POPULATIONS ...............................................................................................30 
 
SAMPLE SIZE CONSIDERATIONS ....................................................................................30 
 
STATISTICAL ANALYSES ................................................................................................30 
 
STUDY ADMINISTRATION ...........................................................................................30 
 
GENERAL STUDY ORGANIZATION ..................................................................................30 
 
CASE REVIEW BOARD ...................................................................................................30 
 
ECHOCARDIOGRAPHIC CORE LAB ..................................................................................31 
 
IMAGE MANAGEMENT....................................................................................................31 
 
HISTOPATHOLOGY ........................................................................................................31 
 
STUDY SITE SELECTION ................................................................................................31 
 
SITE PERSONNEL TRAINING ..........................................................................................31 
 
DEVICE MANAGEMENT ..................................................................................................32 
 Investigational Device ............................................................................................................ 32 
 Device Storage ...................................................................................................................... 32 
 Device Accountability ............................................................................................................. 32 
 
DATA MANAGEMENT .....................................................................................................32 
 MONITORING PROCEDURES ..........................................................................................32 
 SITE DISCONTINUATION ................................................................................................33 
 AUDITING .....................................................................................................................33 
 PUBLICATION POLICY ....................................................................................................33 
 
ETHICAL AND REGULATORY CONSIDERATIONS ....................................................33 
 
APPLICABLE PRINCIPLES AND REGULATIONS ..................................................................33 
 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE.......................................................34 
 
INFORMED CONSENT ....................................................................................................34 
 
CONFIDENTIALITY .........................................................................................................34 
 
INVESTIGATOR RECORDS ..............................................................................................35 
 
PROTOCOL AMENDMENTS .............................................................................................35 
 
PROTOCOL DEVIATIONS ................................................................................................35 
APPENDIX A. 
ABBREVIATIONS ........................................................................................36 
APPENDIX B. 
DEFINITIONS ...............................................................................................38 
APPENDIX C. 
REFERENCES .............................................................................................51 
 
 
LIST OF TABLES 
Table 1: THV Sizing Dimensions ................................................................................................................ 10 
Table 2: Recommended Antithrombotic Regimen ...................................................................................... 17 
Table 3: Schedule of Assessments ............................................................................................................. 22 
 
 

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PROTOCOL SYNOPSIS 
Title 
A Prospective, Single-arm, Multicenter Study of the SAPIEN 3 Ultra 
System in Intermediate Risk Patients with Severe, Calcific, Aortic Stenosis 
Requiring Aortic Valve Replacement 
Objective 
To confirm the procedural safety and performance of the SAPIEN 3 Ultra 
System in subjects with severe, calcific aortic stenosis who are at 
intermediate operative risk for standard aortic valve replacement (AVR) 
Study Device 
SAPIEN 3 Ultra Delivery System with the SAPIEN 3 Ultra THV (20, 23 and 
26 mm) and SAPIEN 3 THV (29 mm) 
Study Design 
Prospective, single-arm, multicenter study 
Study 
Population 
Subjects with symptomatic, severe, calcific, aortic stenosis requiring AVR 
who are at intermediate operative risk and have appropriate iliofemoral 
anatomy for transfemoral access. 
Sample Size 
Up to 110 subjects who have the procedure started 
Study Sites 
Up to 8 actively enrolling sites 
Assessment 
Schedule 
Screening, procedure, post-procedure, discharge, 30 days, 6 months and 
annually through 5 years 
Primary 
Endpoint 
The primary endpoint is procedural success defined as freedom from all 
of the following at exit from the procedure room: 
• 
Mortality 
• 
Conversion to surgery 
• 
Moderate or severe paravalvular regurgitation 
Secondary 
Endpoints 
The following secondary endpoints will be evaluated: 
• 
Major vascular complications through discharge 
• 
Valve migration or embolization through discharge 
Inclusion 
Criteria 
Candidates must meet all of the following criteria to be included in the 
study: 
1. Severe, calcific aortic stenosis meeting the following transthoracic 
echocardiogram (TTE) criteria: 
• 
Aortic valve area (AVA) ≤ 1.0 cm2 OR AVA index ≤ 0.6 cm2/m2 
• 
Jet velocity ≥ 4.0 m/s OR mean gradient ≥ 40 mmHg 
2. New York Heart Association (NYHA) functional class ≥ II 
3. Judged by the Heart Team to be at intermediate risk for open surgical 
therapy (i.e., predicted risk of surgical mortality ≥ 3% and < 8% at 30 
days, based on the Society of Thoracic Surgeons (STS) risk score 
and other clinical co-morbidities unmeasured by the risk calculator) 
4. The subject 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/Ethics Committee of the respective 

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Protocol number:  2018-03 
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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 available THV sizes on 3D 
imaging analysis 
2. Aortic valve is unicuspid, bicuspid or non-calcified 
3. Pre-existing mechanical or bioprosthetic valve in any position.  (Of 
note, mitral ring is not an exclusion) 
4. Severe aortic regurgitation (> 3+) 
5. Severe mitral regurgitation (> 3+) or ≥ moderate stenosis 
6. Ventricular dysfunction with left ventricular ejection fraction (LVEF) < 
30% 
7. Cardiac imaging (echocardiography, computed tomography and/or 
magnetic resonance imaging) evidence of intracardiac mass, 
thrombus or vegetation 
8. Evidence of an acute myocardial infarction ≤ 30 days before the valve 
implant procedure 
9. Subjects with planned concomitant ablation for atrial fibrillation 
10. Hypertrophic cardiomyopathy with obstruction (HOCM) 
11. Coronary anatomy that increases the risk of coronary artery 
obstruction post-TAVR 
12. Complex coronary artery disease (CAD): 
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 
13. Iliofemoral vessel characteristics that would preclude safe placement 
of the introducer sheath 
14. Significant abdominal or thoracic aortic disease that would preclude 
safe passage of the delivery system 
15. Active bacterial endocarditis within 180 days of the valve implant 
procedure 
16. Stroke or transient ischemic attack within 90 days of the valve implant 
procedure 
17. Symptomatic carotid or vertebral artery disease or successful 
treatment of carotid stenosis within 30 days of the valve implant 
procedure 
18. Severe lung disease (Forced Ejection Volume 1 (FEV1) < 50% 
predicted) or currently on home oxygen 
19. Severe pulmonary hypertension (e.g., pulmonary artery systolic 
pressure ≥ 2/3 systemic pressure) 

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Edwards Lifesciences LLC 
 
Protocol number:  2018-03 
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20. Hemodynamic or respiratory instability requiring inotropic support, 
mechanical ventilation or mechanical heart assistance within 30 days 
of the valve implant procedure 
21. History of cirrhosis or any active liver disease 
22. Renal insufficiency (estimated glomerular filtration rate (eGFR) < 30 
mL/min per the Cockcroft-Gault formula) and/or renal replacement 
therapy at the time of screening 
23. 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 
24. Inability to tolerate or condition precluding treatment with 
antithrombotic therapy during or after the valve implant procedure 
25. Absolute contraindications or allergy to iodinated contrast that cannot 
be adequately treated with pre-medication 
26. Significant frailty as determined by the Heart Team (after objective 
assessment of frailty parameters) 
27. Subject refuses blood products 
28. Body mass index > 50 kg/m2 
29. Estimated life expectancy < 24 months 
30. Positive urine or serum pregnancy test in female subjects of 
childbearing potential 
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. 
Statistical 
Methods 
The success criterion for this study is procedural success of at least 90%.  
The primary statistical analysis for this study is to estimate the procedure 
success rate.  With sample size of at least 55 subjects, if the observed rate 
is at least 90%, the lower bound of the observed 95% CI (calculated from 
binomial distribution) will be at least 80%.  Descriptive summary statistics 
will be provided. 
Sponsor 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, California  92614 USA 
 
 

SAPIEN 3 Ultra System 
SAPIEN 3 Ultra Study 
 
Edwards Lifesciences LLC 
 
Protocol number:  2018-03 
CONFIDENTIAL 
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INVESTIGATOR SIGNATURE PAGE 
Protocol Title:  A Prospective, Single-arm, Multicenter Study of the SAPIEN 3 Ultra System in 
Intermediate Risk Patients with Severe, Calcific, Aortic Stenosis Requiring Aortic Valve 
Replacement 
 
 
 
I have read this protocol and agree to adhere to its requirements.  I will ensure that the study is 
conducted in compliance with the protocol, Good Clinical Practice, Declaration of Helsinki and all 
applicable regulatory requirements. 
 
 
 
_________________________________________________ 
Study Site Name 
 
 
 
_________________________________________________ 
Site Principal Investigator Name (print) 
 
 
 
 
______________________________ 
 
_____________ 
Site Principal Investigator Signature  
 
Date 
 
 

SAPIEN 3 Ultra System 
SAPIEN 3 Ultra Study 
 
Edwards Lifesciences LLC 
 
Protocol number:  2018-03 
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INTRODUCTION 
 
Aortic Stenosis 
Aortic stenosis (AS) is one of the most common valvular diseases in developed countries, 
affecting ~5% of adults above the age of 65, and its prevalence is projected to increase over the 
next decade with an aging population (1, 2).  AS is a progressive, debilitating and life-threatening 
disease if left untreated.  The pathology involves progressive calcification of the leaflets that 
results in stenosis which limits valve opening.  The consequences of valve obstruction include 
increased afterload, left ventricular hypertrophy, and a decrease in systemic and coronary blood 
flow.  Typically, patients with AS are free from cardiovascular symptoms (e.g. angina, syncope, 
and/or heart failure) until late in the course of the disease.  However, once symptoms manifest, 
the prognosis is poor without intervention.  Survival analyses have demonstrated that the interval 
from onset of symptoms to time of death is approximately two years in patients with heart failure, 
three years in those with syncope, and five years in those with angina (3). 
 
Treatment of AS 
Relief of aortic valve obstruction typically results in an improvement of symptoms, hemodynamic 
parameters, and global left ventricle systolic function, as well as reversal of left ventricular 
hypertrophy (4, 5).  Treatment options for patients with severe, symptomatic AS include medical 
management, percutaneous balloon aortic valvuloplasty (BAV) or aortic valve replacement (AVR). 
AVR is considered the gold standard for treatment of patients with severe, symptomatic AS (6).  
AVR may be performed surgically or percutaneously.  Outcomes after surgical AVR (SAVR) are 
excellent in patients who do not have a high procedural risk, resulting in an improvement in 
symptoms, and in most patients, an improvement in exercise tolerance (7-11). 
Transcatheter aortic valve replacement (TAVR) was originally developed as an alternative to 
SAVR in patients who were at high risk for surgical mortality or who were not suitable for surgical 
intervention, with the first successful TAVR procedure performed by Cribier and colleagues in 
2002 (12). 
The Placement of AoRtic TranNscathetER valve (PARTNER) study, Cohort B compared standard 
medical therapy (including BAV) to TAVR in patients with severe AS who were not candidates for 
surgical intervention.  Mortality rates at 1 year were significantly lower in the TAVR cohort 
compared to those who underwent medical therapy (30.7% vs. 50.7%, p<0.001) (13).  At 5-years, 
71.8% of TAVR patients had died compared to 93.6% of patients treated medically (p<0.0001) 
(14). 
Numerous studies have since been performed comparing TAVR to SAVR.  Studies comparing 
the two treatments in patients at high surgical risk have demonstrated the superiority of outcomes 
with TAVR compared to SAVR (15-17) 
In the PARTNER II study evaluating outcomes of TAVR with SAPIEN XT vs SAVR in intermediate 
risk patents, there was no difference between TAVR and SAVR for the primary endpoint of all-

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Protocol number:  2018-03 
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cause death or disabling stroke at 2 years (Hazard Ratio: 0.89; 95% Confidence Interval (CI): 
0.73 to 1.09; p=0.25).  All-cause mortality occurred in 16.7% of those randomized to TAVR with 
SAPIEN XT, compared with 18.0% of those treated with SAVR.  Disabling stroke occurred in 6.2% 
of patients treated with TAVR and 6.3% of patients treated with SAVR (18).  In a propensity score-
matched comparison of the SAPIEN 3 TAVR patients and PARTNER II Cohort A SAVR patients, 
TAVR demonstrator noninferiority and superiority to SAVR (propensity score pooled weighted 
proportion difference: –9.2%; 95% CI: –13.0 to –5.4; p<0.0001).  At 1 year, the rate of all-cause 
death was 7.4%, disabling stroke occurred in 2%, reintervention was required in 1%, and 
moderate or severe paravalvular leak (PVL) was seen in 2% (19). 
As a result of these and other findings, the American College of Cardiology (ACC)/American Heart 
Association (AHA) guideline committees have provided TAVR with a Class I and IIa 
recommendation for patients with severe AS with high/prohibitive and intermediate surgical risk, 
respectively (20).  And according to the 2017 European Society of Cardiology (ESC)/ European 
Association for Cardio-Thoracic Surgery (EACTS) guidelines on valvular heart diseases, TAVR 
is favored over SAVR in elderly patients with suitable transfemoral access and elevated surgical 
risk (21). 
This study will evaluate the SAPIEN 3 Ultra System.  The SAPIEN 3 Ultra THV design differs from 
the SAPIEN 3 design only with respect to the weave of the outer skirt and attachment of the skirt 
to the frame.  The SAPIEN 3 Ultra Delivery System allows the THV to be crimped directly onto 
the deployment balloon eliminating the need for valve alignment and reducing the number of 
procedural steps.   
 
STUDY OBJECTIVE 
The objective of this study is to confirm the procedural safety and performance of the SAPIEN 3 
Ultra System in subjects with severe, calcific AS who are at intermediate operative risk for 
standard AVR. 
 
Intended Use 
The Edwards SAPIEN 3 Ultra valve and the Edwards SAPIEN 3 with the Edwards SAPIEN 3 Ultra 
delivery system and accessories are indicated for use in patients with severe, symptomatic, 
calcific aortic valve stenosis who are judged by a Heart Team, to be at intermediate or greater 
risk for open surgical therapy (i.e., predicted risk of surgical mortality ≥ 3% at 30 days, based on 
the Society of Thoracic Surgeons (STS) risk score and other clinical comorbidities unmeasured 
by the STS risk calculator). 
 
STUDY DESIGN 
This is a prospective, single-arm, multicenter study.  Up to 110 subjects will undergo the 
procedure at up to 8 participating centers.  Subject follow-up will occur at 30 days, 6 months and 
annually through five years. 

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Protocol number:  2018-03 
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STUDY DEVICES 
The following devices and accessories will be used per the Instructions for Use (IFU) and after 
sufficient training has been provided by Edwards. 
 
Edwards SAPIEN 3 Ultra THV 
The Edwards SAPIEN 3 Ultra THV is comprised of a balloon-expandable, radiopaque, cobalt-
chromium frame, trileaflet bovine pericardial tissue valve, and polyethylene terephthalate (PET) 
inner and outer fabric skirts.  The leaflets are treated according to the Carpentier-Edwards 
ThermaFix process.  See Table 1 for THV sizing recommendations. 
 
Edwards SAPIEN 3 THV 
The Edwards SAPIEN 3 THV is comprised of a balloon-expandable, radiopaque, cobalt-chromium 
frame, trileaflet bovine pericardial tissue valve, and PET inner and outer fabric skirts.  The leaflets 
are treated according to the Carpentier-Edwards ThermaFix process.  See Table 1 for THV sizing 
recommendations. 
The THV is intended to be implanted in a native annulus size range associated with the three-
dimensional area of the aortic annulus measured at the basal ring during systole. 
Table 1: THV Sizing Dimensions 
Native Valve Annulus 
Size (TEE)* 
Native Valve Annulus Size (CT) 
 
Area 
Area Derived Diameter 
THV Size 
16 – 19 mm 
273 – 345 mm2 
18.6 – 21.0 mm 
20 mm 
18 – 22 mm 
338 – 430 mm2 
20.7 – 23.4 mm 
23 mm 
21 – 25 mm 
430 – 546 mm2 
23.4 – 26.4 mm 
26 mm 
24 – 28 mm 
540 – 683 mm2 
26.2 – 29.5 mm 
29 mm 
*Due to limitations in two-dimensional images, 2-D TEE imaging should be supplemented with 3-D area measurements. 
THV size recommendations are based on native valve annulus size, as measured by 
transesophageal echocardiography (TEE) or computed tomography (CT).  Patient anatomical 
factors and multiple imaging modalities should be considered during THV size selection.  Note: 
Risks associated with undersizing and oversizing should be considered to minimize the risk of 
paravalvular leak, migration and/or annular rupture. 
 
Edwards SAPIEN 3 Ultra Delivery System 
The Edwards SAPIEN 3 Ultra delivery system which is used for delivery of the Edwards SAPIEN 
3 Ultra THV and the Edwards SAPIEN 3 THV consists of a Flex Catheter to aid in tracking, and 
THV positioning.  The delivery system includes a tapered tip to facilitate crossing of the native 
valve.  The handle contains a Flex Wheel to control flexing of the Flex Catheter, and the Fine 
Adjustment Wheel to facilitate THV positioning within the native annulus.  A stylet is included 
within the guidewire lumen of the delivery system.  A radiopaque Positioning Marker in the balloon 
is provided to assist with THV positioning. 

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Protocol number:  2018-03 
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The Qualcrimp crimping accessory (packaged with the Edwards SAPIEN 3 Ultra delivery system) 
is used during THV crimping. 
The loader (packaged with the Edwards SAPIEN 3 Ultra delivery system) is used to aid insertion 
of the delivery system into the sheath. 
 
Edwards Axela Sheath 
The Edwards Axela sheath is intended for introduction and removal of devices used with the 
Edwards SAPIEN 3 Ultra THV System. 
The Edwards Axela Sheath contains: 
a) An expandable sheath with hydrophilic coating that provides access into the target 
vessel while maintaining hemostasis and temporarily enlarges its diameter to allow for 
passage of a device. 
b) Two dilators  with hydrophilic coating that can either be used to dilate the vessel to 
accommodate the Edwards Axela sheath and/or facilitate entry and trackability of the 
sheath into the vessel. 
 
 
Edwards eSheath Introducer Set 
The Edwards eSheath Introducer Set contains: 
a) An expandable sheath (eSheath) that provides access into the target vessel while 
maintaining hemostasis and temporarily enlarges its diameter to allow for passage of a 
device. 
b) Two dilators with hydrophilic coating that can either be used to dilate the vessel to 
accommodate the eSheath and/or facilitate entry and trackability of the eSheath into the 
vessel. 
The eSheath has been approved for use and is commercially available with the SAPIEN 3 THV. 
 
Edwards Crimper and Crimp Stopper 
The Edwards crimper reduces the diameter of the valve to mount it onto the delivery system.  The 
crimper is comprised of a housing and a compression mechanism that is closed with a handle 
located on the housing.  A 2-piece crimp stopper (packaged with the delivery system) is used to 
crimp the valve to its intended diameter. 
 
Edwards Transfemoral Balloon Catheter, 25 mm 
The Edwards Transfemoral Balloon Catheter, 25 mm size, consists of a shaft and balloon with 
two radiopaque marker bands that indicate the working length of the balloon.  The proximal end 
of the device has a “Y-connector” with a balloon inflation port labeled as “BALLOON” and a 
guidewire lumen port labeled as “WIRE”. 

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Protocol number:  2018-03 
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STUDY ENDPOINTS 
 
Primary Endpoint 
The primary endpoint is procedural success defined as freedom from all of the following at exit 
from the procedure room: 
• 
Mortality 
• 
Conversion to surgery 
• 
Moderate or severe paravalvular regurgitation 
 
 
Secondary Endpoints 
The following secondary endpoints will be evaluated: 
• 
Major vascular complications through discharge 
• 
Valve migration or embolization through discharge 
 
 
STUDY POPULATION 
The study population will be comprised of subjects with symptomatic, severe, calcific AS requiring 
AVR who are at intermediate operative risk and have appropriate iliofemoral anatomy for 
transfemoral access. 
 
Inclusion Criteria 
Candidates must meet all of the following criteria to be included in the study: 
1. Severe, calcific AS meeting the following transthoracic echocardiogram (TTE) criteria: 
• 
Aortic Valve Area (AVA) ≤ 1.0 cm2 OR AVA index ≤ 0.6 cm2/m2 
• 
Jet velocity ≥ 4.0 m/s OR mean gradient ≥ 40 mmHg 
2. New York Heart Association (NYHA) functional class ≥ II 
3. Judged by the Heart Team to be at intermediate risk for open surgical therapy (i.e., 
predicted risk of surgical mortality ≥ 3% and < 8% at 30 days, based on the STS risk score 
and other clinical co-morbidities unmeasured by the risk calculator) 
4. The subject 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. 
 

SAPIEN 3 Ultra System 
SAPIEN 3 Ultra Study 
 
Edwards Lifesciences LLC 
 
Protocol number:  2018-03 
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Exclusion Criteria 
Candidates will be excluded from the study if any of the following conditions are present: 
1. Native aortic annulus size unsuitable for available THV sizes based on 3D imaging analysis 
2. Aortic valve is unicuspid, bicuspid or non-calcified 
3. Pre-existing mechanical or bioprosthetic valve in any position.  (Of note, mitral ring is not an 
exclusion) 
4. Severe aortic regurgitation (> 3+) 
5. Severe mitral regurgitation (> 3+) or ≥ moderate stenosis 
6. Ventricular dysfunction with left ventricular ejection fraction (LVEF) < 30% 
7. Cardiac imaging (echocardiography, CT and/or magnetic resonance imaging (MRI)) 
evidence of intracardiac mass, thrombus or vegetation 
8. Evidence of an acute myocardial infarction (MI) ≤ 30 days before the valve implant 
procedure 
9. Subjects with planned concomitant ablation for atrial fibrillation 
10. Hypertrophic cardiomyopathy with obstruction (HOCM) 
11. Coronary anatomy that increases the risk of coronary artery obstruction post-TAVR 
12. Complex coronary artery disease (CAD): 
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 
13. Iliofemoral vessel characteristics that would preclude safe placement of the introducer 
sheath 
14. Significant abdominal or thoracic aortic disease that would preclude safe passage of the 
delivery system 
15. Active bacterial endocarditis within 180 days of the valve implant procedure 
16. Stroke or transient ischemic attack (TIA) within 90 days of the valve implant procedure 
17. Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis 
within 30 days of the valve implant procedure 
18. Severe lung disease (Forced Ejection Volume 1 (FEV1) < 50% predicted) or currently on 
home oxygen 
19. Severe pulmonary hypertension (e.g., pulmonary artery systolic pressure ≥ 2/3 systemic 
pressure) 
20. Hemodynamic or respiratory instability requiring inotropic support, mechanical ventilation or 

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Protocol number:  2018-03 
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mechanical heart assistance within 30 days of the valve implant procedure 
21. History of cirrhosis or any active liver disease 
22. Renal insufficiency (estimated glomerular filtration rate (eGFR) < 30 mL/min per the 
Cockcroft-Gault formula) and/or renal replacement therapy at the time of screening 
23. 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 
24. Inability to tolerate or condition precluding treatment with antithrombotic therapy during or 
after the valve implant procedure 
25. Absolute contraindications or allergy to iodinated contrast that cannot be adequately treated 
with pre-medication 
26. Significant frailty as determined by the Heart Team (after objective assessment of frailty 
parameters) 
27. Subject refuses blood products 
28. Body mass index (BMI) > 50 kg/m2 
29. Estimated life expectancy < 24 months 
30. Positive urine or serum pregnancy test in female subjects of childbearing potential 
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. 
 
 
STUDY PROCEDURES 
 
Informed Consent 
The study investigator(s) and support staff will approach subjects with symptomatic, severe 
calcific AS who meet general requirements to assess their interest in participating in the study by 
providing them an overview of the study including the background, risks, benefits and study 
procedures.  If subjects are interested in participating in the study, the subject will sign the IRB/EC-
approved informed consent form (ICF) prior to any study-specific procedures being performed.  
All subjects consented should be entered into the study’s Electronic Data Capture (EDC) system.  
Subjects will be considered enrolled once the subject signs and dates the ICF. 
 
Screening 
The screening assessments will be completed within 30 days prior to the valve implant procedure, 
unless otherwise noted.  Screening assessments will include the following: 
Systems: 
• 
Medical History 

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• 
Physical Assessment (height, weight, blood pressure and heart rate only) 
• 
Medications:  Antithrombotics (anticoagulants, antiplatelets, thrombolytics) only 
Risk: 
• 
STS Risk Score 
• 
EuroSCORE II 
Cardiopulmonary: 
• 
NYHA Functional Class 
• 
12-lead Electrocardiogram (ECG) 
• 
Transthoracic Echocardiogram (TTE) – Qualifying TTE must be performed within 90 
days prior to the valve implant procedure. 
• 
Cardiac CT Angiography (CTA) with 3D reconstruction to determine aortic annulus area.  
Qualifying cardiac imaging must be performed within 1 year prior to the valve implant 
procedure. 
• 
Iliofemoral CTA, including thoracic and abdominal scan with visualization of iliac and 
femoral arteries.  Iliofemoral CTA must be performed within 1 year prior to the valve 
implant procedure. 
• 
Assessment of severity of coronary artery disease (CAD) may be performed by CTA or 
coronary angiography.  If CTA shows evidence or high likelihood of obstructive CAD or if 
the CTA is non-diagnostic, coronary angiography must be performed to assess the need 
for intervention.  Qualifying CTA/coronary angiography must be performed within 1 year 
prior to the valve implant procedure. 
• 
Pulmonary Function Test – only for subjects with a history of lung disease 
• 
SYNTAX Score – only for subjects with significant native CAD 
Neurological: 
• 
Modified Rankin Scale (mRS) 
Clinical Laboratory Tests: 
• 
White blood cell count (WBC), Hemoglobin, Platelet count 
• 
Prothrombin Time (PT) or International Normalized Ratio (INR) 
• 
Creatine Kinase (CK) and/or Troponins ≤ 72 hours before the valve implant procedure 
• 
Creatinine (including calculation of eGFR per the Cockcroft-Gault formula) 
• 
Albumin (as part of Frailty Index), total bilirubin 
• 
Aspartame Aminotransferase (AST), Alanine Aminotransferase (ALT) – only for subjects 
with chronic liver disease 
• 
Pregnancy test (urine or serum) – only for female subjects of childbearing potential 

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Functional: 
• 
Frailty Index (5 Meter Walk Test, grip strength, Activities of Daily Living and serum 
Albumin) 
 
 
Case Review 
Before a case is submitted for review, study site personnel will screen the subject for general 
enrollment criteria and ensure that the subject has been entered into the EDC System.  It is 
required that at least one site surgeon Investigator personally examine the subject to determine 
operative risk.  Once fully screened and deemed an appropriate candidate, the site will submit 
the case for consideration by the Case Review Board.  If the case is approved, the subject may 
be scheduled for the valve implant procedure.  If the case is not approved, the subject’s status 
will be terminated. 
Edwards will maintain a record of the case presentation and case approval notes. 
 
Procedure 
The study devices will be used per the most current IFU for device sizing, preparation and 
recommended implant procedure.  Only physicians appropriately trained to the use of the device 
and identified on the Delegation of Authority (DoA) log on file with Edwards may perform the 
implant procedure in study subjects. 
The valve implant procedure will be considered to have started when the first interventional 
access-related puncture (arterial) is established.  It is strongly encouraged that the procedure be 
performed within 14 days of Case Review Board approval. 
Procedure assessments will include the following: 
Systems: 
• 
Medications:  Antithrombotics only 
• 
Adverse Events 
Cardiopulmonary: 
• 
Aortogram to assess valve placement 
• 
Assessment of PVL by either: 
o TEE, or 
o Limited TTE and Aortogram 
 
If the procedure is aborted (prior to or after the start of the valve implant procedure), the procedure 
may be re-scheduled if the subject continues to meet all eligibility criteria. 

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Antithrombotic Recommendations 
Table 2 outlines the recommended antithrombotic regimen. 
Table 2: Recommended Antithrombotic Regimen 
Pre-Valve 
Implant 
Procedure 
• Aspirin (ASA) 81-100 mg QD 
• Subjects with a bare metal stent (BMS) within one month or drug-eluting stent 
(DES) within 12 months should be continued on Clopidogrel/prasugrel prior to 
their implant procedure. 
• Subjects in atrial fibrillation on warfarin should be bridged with low molecular 
weight (LMW) or unfractionated (UF) heparin prior to the implant procedure. 
• Subjects with persistent or paroxysmal atrial fibrillation and not on anticoagulation 
will not be required to have a TEE to rule out left atrial (LA) thrombus prior to 
implant procedure.  If intra-procedural TEE during TAVR reveals thrombus, 
implant procedure will be aborted and delayed until subject has been on warfarin 
or dabigatran for 30 days.  Note: thrombus must be eliminated in order to proceed 
with TAVR. 
• In subjects undergoing concomitant TAVR/Percutaneous Coronary Intervention 
(PCI), Clopidogrel loading with either 300 mg or 600 mg prior to the implant 
procedure is recommended in addition to ASA. 
Intraprocedural 
• Heparin will be given to achieve/ maintain activated clotting time (ACT) ≥ 250 sec. 
Post-Valve 
Implant 
Procedure 
Category I for Stroke Risk:  No atrial fibrillation, no recent stents 
• ASA 81 mg QD 
• Clopidogrel 300 mg load within 6 hours of the implant procedure (either pre or 
post) 
• Clopidogrel 75 mg QD for at least one month post-implant procedure 
Category II for Stroke Risk:  No atrial fibrillation, recent stents 
• ASA 81 mg QD 
• Clopidogrel 75 mg QD should be continued after the implant procedure without 
interruption for at least one month post-BMS and 12 months post-DES 
Category III for Stroke Risk:  Atrial fibrillation, no recent stents 
• ASA 81 mg QD 
• Subjects should be started on warfarin or dabigatran 24 hours post-TAVR if 
clinically safe and this should be continued for at least one month or indefinitely, if 
possible.  If clinically safe, subjects started on warfarin should be bridged with UF 
or LMW heparin until INR therapeutic. 
• If subjects are not a candidate for warfarin or dagibatran, Clopidogrel 75 mg QD 
can be considered as an alternative. 
Category IV for Stroke Risk:  Atrial fibrillation, recent stents 
• ASA 81 mg QD 
• Clopidogrel 75 mg QD for at least one month post-BMS or 12 months post-DES 
• Subjects should be started on warfarin or dabigatran 24 hours post-TAVR if 
clinically safe and continued indefinitely.  If clinically safe, subject’s being started 
on warfarin should be bridged with UF or LMW heparin until INR therapeutic. 
Note: Any changes to antithrombotic regimen from study visit to study visit will be noted on the electronic Case Report 
Form (eCRF) including reason for change. 

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Antibiotic Prophylaxis 
Study subjects should be prophylactically treated to prevent endocarditis per the 
recommendations of the AHA (22). 
 
Contrast Media 
Careful management of contrast media is required.  Accurate measurement of the contrast used 
will be captured in the subject medical records. 
 
Radiation Precautions 
Radiation precautions will be adhered to per institutional standards.  If a radiation-induced skin 
injury is suspected, the Investigator must report an adverse event, and assess and treat the 
subject as medically necessary. 
 
Post-procedure 
The post-procedure time period is defined as the 48 hours after the subject exits the procedure 
room.  The following will be assessed during the post-procedure time period: 
Systems: 
• 
Medications:  Antithrombotics only 
• 
Adverse Events 
Cardiopulmonary: 
• 
12-lead ECG 
Clinical Laboratory Tests: 
• 
WBC, Hgb, and platelet count 
• 
PT or INR 
• 
Creatinine 
 
 
Discharge 
Discharge is the actual date and time the subject is discharged.  For subjects discharged within 
48 hours of exiting the procedure room, it is not required to repeat tests collected during the Post-
Procedure period that are also required for the discharge visit.  If the subject was discharged over 
a weekend or holiday, the discharge assessments may be completed on the last weekday prior 
to discharge. 
The following assessments will be conducted within 24 hours of the date and time of discharge. 
Systems: 
• 
Physical assessment (weight, blood pressure and heart rate only) 

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• 
Medications:  Antithrombotics only 
• 
Adverse Events 
Cardiopulmonary: 
• 
NYHA functional class 
• 
TTE 
Clinical Laboratory Tests: 
• 
WBC, Hgb, and platelet count 
• 
PT or INR 
• 
Creatinine 
 
 
Follow-up 
The day of the procedure is considered Day 0 and will be used to schedule all subsequent visits 
and calculate visit windows.  Six months is defined as 180 days; one year is defined as 365 days. 
 
30 Days 
The following assessments will be conducted at 30 days (+7 days): 
Systems: 
• 
Physical assessment (weight, blood pressure and heart rate only 
• 
Medications:  Antithrombotics only 
• 
Adverse Events 
Cardiopulmonary: 
• 
NYHA functional class 
• 
TTE 
 
 
6 Months 
The following assessments will be conducted by telephone or office visit at 6 months (+30 days): 
Systems: 
• 
Medications:  Antithrombotics only 
• 
Adverse Events 
 

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Years 1, 3 and 5 
The following assessments will be conducted at years 1, 3 and 5 (+ 45 days): 
Systems: 
• 
Physical assessment (weight, blood pressure and heart rate only) 
• 
Medications:  Antithrombotics only 
• 
Adverse Events 
Cardiopulmonary: 
• 
NYHA functional class 
 
 
Years 2 and 4 
The following assessments will be conducted by telephone or office visit at years 2 and 4 (+ 45 
days): 
Systems: 
• 
Medications:  Antithrombotics only 
• 
Adverse Events 
 
 
Imaging Assessments 
Imaging performed during the course of the study should follow the CT Reference Document and 
the Echo Manual of Operations, except for the limited TTE performed post-procedure, which is 
only performed to assess PVL. 
 
Neurological Assessments 
Every effort should be made to have a neurologist (or neurology fellow) perform the mRS 
assessment.  If it is not possible to have the neurologist/fellow perform the assessments within 
the protocol-specified visit window, a certified study team member may perform them. 
Following the procedure, all subjects should be assessed to determine if there is evidence of 
neurological impairment.  For all subjects diagnosed with a new stroke after the procedure start, 
a follow-up mRS assessment should be performed 90 days (± 30 days) after stroke onset to 
assess stroke disability (visit or phone assessment is acceptable).  If the 90-day post-stroke 
assessment is scheduled to occur within 30 days of a protocol-specified visit, the mRS does not 
need to be repeated. 
 
 

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Subject Disposition 
The following categories of subject disposition have been defined for this trial: 
Enrolled:  Subjects will be considered enrolled once the ICF is signed and dated. 
Discontinued:  Enrolled subjects will be considered discontinued when they exit the study prior 
to completing all required follow-up.  Potential reasons include but are not limited to: 
• 
Study Procedure Never Started:  Subjects considered enrolled that do not meet pre-
procedure eligibility criteria will be exited from the study. 
• 
Procedure Started but Study Device Never Implanted:  Subjects in whom the procedure 
was started but did not receive a study valve will be followed for 30 days or until 
resolution of any adverse events related to the valve implant procedure and then exited 
from the study. 
• 
Study Device Explanted:  Subjects who have a surgical reintervention where the study 
valve is explanted will be followed for 30 days post-reintervention or until resolution of 
any adverse events related to the procedure and then exited from the study. 
Subjects that have a valvuloplasty or valve-in-valve procedure will continue to be followed 
for the duration of the study. 
If a subject discontinues, all attempts should be made to have the subject come into the clinic 
for an exit visit.  An exit form indicating the reason for discontinuation will be completed.  
Subjects who discontinue will not be replaced. 
Completed:  Enrolled subjects will be considered to have completed the study when all required 
follow-up has been performed. 
 
 

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Table 3 summarizes the subject assessments at each time point. 
Table 3: Schedule of Assessments 
Screening 
Procedure 
Post-Procedure 
Discharge 
30 Days 
6 Months o,p 
1, 3 ,5 Years p 
2, 4 Years o,p 
Visit Window (days) 
- 30 a 
 
+ 2 n 
 
+ 7 
+ 30 
+ 45 
+ 45 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
Physical Assessment 
X 
 
 
X 
X 
 
X 
 
Medications: Antithrombotics 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
STS Risk Score 
X 
 
 
 
 
 
 
 
EuroSCORE II 
X 
 
 
 
 
 
 
 
NYHA Functional Class 
X 
 
 
X 
X 
 
X 
 
12-lead ECG 
X 
 
X 
 
 
 
 
 
TTE 
X b 
 
 
X 
X 
 
 
 
Cardiac CTA 
X c 
 
 
 
 
 
 
 
Iliofemoral CTA 
X c 
 
 
 
 
 
 
 
Assessment of CAD 
X c,d 
 
 
 
 
 
 
 
Assessment of valve placement 
 
X 
 
 
 
 
 
 
Assessment of PVL 
 
X m 
 
 
 
 
 
 
Pulmonary Function Test 
X e 
 
 
 
 
 
 
 
SYNTAX Score 
X f 
 
 
 
 
 
 
 
mRS g 
X 
 
 
 
 
 
 
 
WBC, Hgb, Platelet Count 
X 
 
X 
X 
 
 
 
 
PT or INR 
X 
 
X 
X 
 
 
 
 
CK and/or Troponins 
X h 
 
 
 
 
 
 
 
eGFR 
X 
 
 
 
 
 
 
 
Creatinine 
X 
 
X 
X 
 
 
 
 
Albumin, Total Bilirubin 
X 
 
 
 
 
 
 
 
AST/ALT 
X i 
 
 
 
 
 
 
 
Pregnancy test 
X j 
 
 
 
 
 
 
 
Frailty Index 
X k 
 
 
 
 
 
 
 
Case Review 
X l 
 
 
 
 
 
 
 
Valve Implant Procedure 
 
X 
 
 
 
 
 
 
 

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a. Screening assessments will be completed within 30 days prior to valve implant procedure, unless otherwise 
noted. 
b. Must be performed within 90 days prior to the valve implant procedure. 
c. Must be performed within 1 year prior to the valve implant procedure. 
d. Assessment of severity of CAD may be performed by CTA or coronary angiography.  If CTA shows evidence or 
high likelihood of obstructive CAD or if the CTA is non-diagnostic, coronary angiography must be performed to 
assess the need for intervention. 
e. Only for subjects with a history of lung disease. 
f. Only for subjects with significant native CAD. 
g. Every effort should be made to have a neurologist (or neurology fellow) perform the assessment.  If it is not 
possible to have the neurologist/fellow perform the assessments within the protocol-specified visit window, a 
certified study team member may perform them.  Following the procedure, all subjects should be assessed to 
determine if there is evidence of neurological impairment.  For all subjects diagnosed with a new stroke after the 
procedure start, a follow-up mRS assessment should be performed 90 days (± 30 days) after stroke onset to 
assess stroke disability (visit or phone assessment is acceptable). 
h. Required ≤ 72 hours before the valve implant procedure. 
i. 
Only required for subjects with chronic liver disease. 
j. 
Only for female subjects of childbearing potential (urine or serum) 
k. Includes activities of daily living, 5 meter walk test, grip strength and albumin. 
l. 
Case Review will be completed when all screening procedures have been completed, all inclusion/exclusion 
criteria have been fundamentally confirmed and the site is ready to present a case. 
m. By TEE or Limited TTE AND Aortogram 
n. Post-procedure time period is defined as the 48 hours after the subject exits the procedure room. 
o. Can be done by telephone or office visit. 
p. Six months is defined as 180 days; one year is defined as 365 days. 
 
 

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ADVERSE EVENTS 
 
Adverse Event Definitions 
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the study device.  For users or other persons, this definition is 
restricted to events related to the study device. 
AEs may be volunteered by subjects, elicited or collected via observation by the Investigator or 
designee, or discovered by review of clinical records by Edwards Safety team or Edwards 
Monitoring team.  Subjects will be instructed to contact the Investigator and/or study coordinator 
if any significant AEs occur between study visits. 
A Serious Adverse Event (SAE) is any adverse event that: 
• 
Led to death; 
• 
Led to serious deterioration in the health of the subject that either resulted in: 
o a life-threatening illness or injury; 
o a permanent impairment of a body structure or a body function; 
o in-patient or prolonged hospitalization; 
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to body structure or a body function; 
• 
Led to fetal distress, fetal death or congenital abnormality or birth defect; 
• 
Significant medical event:  Important medical events that do not meet the above criteria 
may still be considered an SAE if they seriously jeopardize the subject and require 
immediate medical or surgical intervention to prevent one of the aforementioned 
outcomes. 
 
NOTE 1:  Planned hospitalization for pre-existing condition, or a procedure required by the Clinical 
Investigation Plan, without a serious deterioration in health, is not considered a serious adverse event. 
NOTE 2:  Permanent impairment of a body structure or a body function - An AE, which results in a 
substantial disruption of a person‘s ability to conduct normal life functions.  This does not pertain to minor 
events, but to serious events which result in a significant, persistent or permanent change, impairment, 
damage or disruption in the subject‘s body function/structure, physical activities and/or quality of life. 
NOTE 3:  Life-threatening – an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe. 
Adverse Device Effects (ADE) and Serious Adverse Device Effects (SADE) are AEs related 
to the use of a medical device. 
NOTE 1: This includes any AE resulting from insufficiencies or inadequacies in the IFU, the deployment, 

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the implantation, the installation, the operation or any malfunction of the medical device. 
NOTE 2: This includes any event that is a result of a user error or intentional abnormal use of the medical 
device. 
Anticipated AE means an effect which by its nature, incidence, severity or outcome has been 
previously identified in the risk analysis report.  The potential AEs associated with the procedures 
involved and study devices are listed in the current IFU. 
Unanticipated Serious Adverse Device Effect (USADE) is defined as any SADE which by its 
nature, incidence, severity or outcome has not been identified in the current version of the risk 
analysis report or IFU. 
Device Deficiency is defined as an inadequacy of a medical device related to its identity, quality, 
durability, reliability, safety or performance.  This may include malfunctions, use error or 
inadequacy in the information supplied by the manufacturer. 
A malfunction or deterioration is defined as the failure of a device to perform in accordance with 
its intended purpose when used in accordance with the manufacturer´s instructions.  The intended 
performance of a device refers to the intended use for which the device is labeled or marketed. 
Reporting conventions for device deficiencies that could result in an SAE are the same as those 
for an actual SAE. 
 
Investigator Assessment of AEs 
For each AE, the Investigator will determine whether the event is related to the device and/or the 
implant procedure, whether it was anticipated or not anticipated (based on the list of potential 
risks provided in the IFU) and whether the event meets the definition of an SAE or USADE. 
The causal relationship of the event to the device and the implant procedure will be categorized 
as follows: 
1) Not related:  relationship to the device or procedures can be excluded when there is no 
temporal relationship, the event is not a known adverse effect of similar devices or procedures, 
it is not clinically plausible, or the event can be attributed to another cause. 
2) Unlikely:  the relationship with the use of the device seems not relevant and/or the event can 
be reasonably explained by another cause, but additional information may be obtained. 
3) Possible:  the relationship with the use of the device is weak but cannot be ruled out 
completely.  Alternative causes are also possible (e.g. an underlying or concurrent illness/ 
clinical condition or/and an effect of another device, drug or treatment).  Cases were 
relatedness cannot be assessed or no information has been obtained should also be classified 
as possible. 
4) Probable:  the relationship with the use of the device seems relevant and/or the event cannot 

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be reasonably explained by another cause, but additional information may be obtained. 
5) Causal relationship:  the event is associated with the device or with procedures beyond 
reasonable doubt when there is a temporal relationship, the event is a known adverse effect 
of similar devices or procedures, it is clinically plausible, or the event cannot be attributed to 
another cause. 
 
 
AE Reporting Requirements 
All AEs will be captured from the time of enrollment until subject participation has ended (i.e. 
completion of study or discontinuation).  See section 8.3.1 for events that are not required to be 
reported to Edwards. 
Pre-existing medical conditions or symptoms reported prior to subject enrollment will not be 
recorded as an AE.  In the event there is a worsening in the pre-existing medical condition or 
symptoms due to the device or study-related procedure, then an AE must be recorded. 
Death should not be recorded as an AE, but should be reflected as an outcome to another specific 
AE. 
If known, the diagnosis for an AE should be recorded, rather than listing individual signs and 
symptoms. 
All AEs will be reported in subject medical records, and the appropriate eCRF throughout the 
duration of the study, and will be followed until resolution, stabilization or study completion. 
All SAEs and Device Deficiencies that might have led to a SAE should be reported to Edwards  
immediately, but not later than 3 calendar days after site study personnel’s awareness of 
the event. 
Other AEs must be reported to Edwards as soon as practical but no later than 10 working days 
of awareness. 
Information must be entered into the electronic database or, when the electronic database is not 
available, reported directly to the Edwards Safety Officer.  In the event that the EDC system is 
not in service, a paper copy of the AE CRF must be e-mailed to EUTHVSafety@Edwards.com 
according to the timelines described above. 
At the time of initial AE notification, the following minimal information must be provided: 
• 
Subject ID 
• 
AE term/diagnosis 
• 
AE onset date 
 
For selected events, the site might be requested to provide to Edwards (or designee) a copy of 

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anonymized supporting documentation (such as hospital record, laboratory results, autopsy 
results). 
All AEs will be reviewed by the Edwards Safety Officer.  Each AE will be assessed as to its 
relationship to the study device and/or implant procedure, whether it was anticipated or not 
anticipated, and whether it qualifies as an SAE and USADE. 
Depending on the local requirements or following agreement between both parties, Edwards or 
the Principal Investigator will be responsible for performing safety reporting to the EC according 
to the relevant local regulatory requirements. 
Edwards will be responsible for reporting to the National Competent Authority according to 
national requirements and in line with MEDDEV 2.7/3 (Serious Adverse Event Reporting) and/or 
MEDDEV 2.12-1 (Medical Device Vigilance System), as applicable. 
 
Events that do not require reporting to Edwards 
For purposes of this study, the following events will not be required to be reported as AEs to 
Edwards, because they are normally expected to occur in conjunction with transcatheter valve 
implantation or are associated with customary, standard care of subjects undergoing THV 
implantation: 
• 
Post-operative pain. 
• 
Post-anesthesia emesis, nausea or headache (within 24 hours of procedure). 
• 
Electrolyte imbalance without clinical sequelae following procedure, even if requiring 
correction. 
• 
Low grade temperature increase (≤ 101°F or 38.5°C). 
• 
Elevated white blood count, outside the standard laboratory normal value, without signs 
and symptoms of infection. 
• 
Minor, localized tenderness, swelling, induration, oozing, etc. at incision / delivery 
system insertion site. 
• 
Systolic or diastolic blood pressure changes that do not require treatment or intervention. 
• 
Thrombocytopenia: does not become an AE until treatment is administered; Suspected 
heparin-induced thrombocytopenia should be reported. 
• 
Hyperglycemia – The use of insulin in the post-operative period does not constitute 
hyperglycemia if during the index hospitalization.  An elevated blood sugar of less than 
250 mg/dL during the first 48 hours post-operative does not constitute hyperglycemia. 
• 
Expected, non-clinically significant events such as non-significant lab variances. 
• 
Dizziness: imprecise term commonly used to describe various symptoms such as 
faintness, giddiness, imbalance, lightheadedness, unsteadiness or vertigo without signs 
of TIA or stroke. 

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Additionally, pre-planned future surgical procedures not associated with the study procedure or 
device do not need to be reported. 
 
RISKS AND BENEFIT ANALYSIS 
 
Potential Benefits 
There are no guaranteed benefits from participation in this study.  Information gained from this 
study may be of benefit to other people with the same medical condition in the future.  The long-
term results of using the SAPIEN 3 Ultra and SAPIEN 3 THVs are not known at the present time. 
Implantation of the SAPIEN 3 Ultra and SAPIEN 3 THVs may result in improved valvular function, 
acute alleviation of symptoms related to AS, and improved quality of life in patients with 
intermediate operative risk of mortality. 
 
Potential Risks 
The potential risks associated with this study can be grouped into two categories.  First, there are 
the potential risks related to the overall procedure (standard cardiac catheterization, BAV and use 
of anesthesia).  Second, there are the additional potential risks associated with the use of the 
SAPIEN 3 Ultra THV and SAPIEN 3 THV Systems. 
Potential risks associated with the overall procedure including access, cardiac catheterization, 
local and/or general anesthesia: 
• 
Allergic reaction to antithrombotic 
therapy or contrast medium or 
anesthesia 
• 
Anemia 
• 
Aneurysm 
• 
Angina 
• 
Arrhythmias including ventricular 
fibrillation (VF) and ventricular 
tachycardia (VT) 
• 
Arteriovenous fistula or 
pseudoaneurysm 
• 
Cardiogenic shock 
• 
Compartment syndrome 
• 
Death 
• 
Dissection: aortic or other vessels 
• 
Emboli, distal (air, tissue or 
thrombotic emboli) 
• 
Hematoma 
• 
Hypertension or hypotension 
• 
Inflammation 
• 
Myocardial ischemia or infarction 
• 
Pain or changes at the access site 
• 
Perforation or rupture of cardiac 
structures 
• 
Perforation or rupture of vessels 
• 
Pericardial effusion or cardiac 
tamponade 
• 
Peripheral ischemia or nerve injury 
• 
Pulmonary edema 
• 
Renal insufficiency or renal failure 
• 
Respiratory insufficiency or 
respiratory failure 
• 
Syncope 

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• 
Vasovagal response 
• 
Vessel spasm 
• 
Vessel thrombosis/occlusion 
• 
Vessel trauma requiring surgical 
repair or intervention 
 
 
Additional potential risks associated with the TAVR procedure, the bioprosthesis, and the use of 
its associated devices and accessories include: 
• 
Allergic/immunologic reaction to the 
implant 
• 
Atrial fibrillation/Atrial flutter 
• 
Bleeding requiring transfusion or 
intervention 
• 
Cardiac arrest 
• 
Cardiac failure or low cardiac output 
• 
Cardiogenic shock 
• 
Conduction system injury (defect) 
including atrioventricular block, 
which may require a permanent 
pacemaker 
• 
Coronary occlusion 
• 
Dissection, rupture, trauma of the 
aortic annulus and surrounding 
structures including ascending aorta, 
coronary ostia and ventricular 
septum 
• 
Emergency cardiac surgery 
• 
Hemolysis 
• 
Infection, fever, septicemia, 
abscess, endocarditis 
• 
 Injury to mitral valve 
• 
Mechanical failure of delivery 
system, and/or accessories, 
including balloon rupture and tip 
separation 
• 
Silent cerebral ischemia, stroke, 
transient ischemic attack, cognitive 
impairment 
• 
Structural valve deterioration (wear, 
fracture, calcification, stenosis) 
• 
Valve deployment in unintended 
location 
• 
Valve explants 
• 
Valve migration, malposition or 
embolization requiring intervention 
• 
Valve regurgitation, paravalvular or 
transvalvular  
• 
Valve thrombosis 
 
Risk Minimization 
Product handling and implant procedure guidance are provided in the IFU and training manual, 
which will be used for device training to minimize risks associated with device use.  All cases will 
be reviewed and approved prior to the procedure to confirm that the subject is an appropriate 
candidate for the investigational devices.  Edwards representative(s) will be present during all 
implant procedures to provide device-related guidance. 

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 STATISTICAL ANALYSIS 
 
Analysis Populations 
Enrolled subjects will consist of all subjects who sign and date the ICF. 
• 
The As Treated (AT) population is defined to include all enrolled subjects for whom the 
valve implant procedure was started. 
• 
The Valve Implant (VI) population is the subset of the AT population consisting of all 
subjects who receive and retain the study valve upon leaving the procedure room.  If it is 
necessary to implant more than one study valve (valve-in-valve), the subject will still be 
in the VI population.. 
 
 
Sample Size Considerations 
The success criterion for this study is procedural success of at least 90%.  The primary statistical 
analysis for this study is to estimate the procedure success rate.  With a sample size of at least 
55 subjects, if the observed rate is at least 90%, the lower bound of the observed 95% CI 
(calculated from binomial distribution) will be at least 80%. 
 
Statistical Analyses 
Descriptive statistics will include: number of subjects and frequencies in % for categorical 
variables and mean and standard deviation for continuous variables.  Kaplan-Meier estimates will 
be calculated for survival outcomes and where appropriate for adverse event outcomes. 
 STUDY ADMINISTRATION 
 
General Study Organization 
Edwards is the Study Sponsor and has the overall responsibility for the conduct of the study, 
including assurance that the study meets the regulatory requirements. 
Edwards will be responsible for obtaining appropriate approvals prior to study commencement, 
selecting investigators, ensuring that sites have IRB/EC approval prior to device shipment, and 
conducting clinical site monitoring to ensure that subjects are being properly consented and the 
study is being conducted according to the protocol.  Edwards will notify investigative sites of 
enrollment closure. 
Edwards will maintain copies of correspondence, data, shipment of devices, adverse device 
effects and other records related to the clinical study as appropriate. 
 
Case Review Board 
The Case Review Board is comprised of physicians experienced with Edwards THV products for 
treatment of AS in the intermediate risk population.  The role of the Case Review Board is to 
review submitted cases to determine if the subject is an appropriate candidate for the study, with 

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a focus on confirming subject operative risk, valve sizing, appropriate vascular access, valve 
morphology and any relevant clinical factors impacting enrollment eligibility. 
 
Echocardiographic Core Lab 
An independent echocardiographic core lab will review and analyze echocardiographic images.  
A standardized protocol for acquiring images and training will be provided to the clinical sites prior 
to study initiation. 
 
Image Management 
An image transfer vendor will receive, maintain and provide cardiac images (echocardiogram and 
CT) to the appropriate personnel for analysis. 
Instructions for image upload will be provided to study site personnel prior to study initiation.  
Study site personnel should make every reasonable effort to upload all images to the image 
transfer vendor within 5 business days of image acquisition.  Any unscheduled imaging performed 
related to the safety or performance of the device should also be uploaded. 
 
Histopathology 
Histopathology will be performed on all explanted valves.  Explants will be prepared, preserved 
and shipped to the Histopathology Core Lab per instructions provided by Edwards. 
 
Study Site Selection 
Site and investigator selection criteria will be established to ensure that the study personnel and 
their institutions are qualified to screen, perform and manage the study procedures as well as 
support the associated requirements for research. 
 
Site Personnel Training 
Training by Edwards or its designee is required for study site personnel in accordance with the 
roles outlined in the DoA log.  Training will include review of the device IFU, study protocol, case 
review process, identification of eligible subjects, instructions on data collection, standardized 
image acquisition, methods for soliciting data from alternative sources and regulatory 
requirements. 
Training may be provided in one of the following formats:  in-person training sessions, 
teleconference, online via WebEx/Skype, or read and review.  Retraining may be performed for 
sites who have demonstrated protocol or implant procedure compliance issues. 
Documentation of study site personnel qualifications and training will be maintained in the site’s 
study files with copies sent to Edwards. 

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Device Management 
 Investigational Device 
All investigational devices will be supplied by Edwards.  Unique identifiers associated with any 
device should be recorded in the subject’s medical file as well as on the implant card that is given 
to the subject. 
 Device Storage 
All investigational device components provided for the study should be stored in a secure location 
where only study personnel can access the device for use. 
 Device Accountability 
The study site will maintain detailed records of the receipt and disposition of all investigational 
devices.  Device disposition will be verified by the monitor periodically throughout the study.  The 
Investigator will return unused devices to Edwards along with the completed device accountability 
log at completion of enrollment.  Use of the investigational devices and accessories provided for 
use in this study is prohibited outside of this protocol. 
 
Data Management 
This study will use a secure, password protected EDC system accessible via the Internet.  A 
unique Subject ID will be assigned for each subject enrolled in the study.  All pertinent data will 
be entered by the study site and core lab personnel into eCRFs. 
Every reasonable effort should be made to complete data entry within 5 business days of data 
collection.  Data review by Edwards personnel will occur remotely as well as during on-site 
monitoring.  Data discrepancies will be queried and resolved through the EDC system. 
The site Principal Investigator or designee must ensure the accuracy and completeness of the 
recorded data and provide his/her electronic signature on the appropriate eCRFs at regular 
intervals during the study, as requested by Edwards.  If changes are made to data previously 
signed-off, a new electronic signature will be required to acknowledge/approve the changes. 
 Monitoring Procedures 
All study sites will be monitored periodically by Edwards or designee to ensure compliance with 
the protocol and the Investigator’s Agreement and that all study subjects have been properly 
consented.  The monitor will ensure that the completed eCRFs match the medical records and 
work with the site to resolve differences through electronically-generated queries or formal action 
items. 

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 Site Discontinuation 
Edwards has the right to discontinue an Investigator or study site for the following reasons: 
• 
Failure of the Investigator to enroll subjects into the study at an acceptable rate 
• 
Failure of the Investigator to comply with pertinent regulations of appropriate regulatory 
authorities 
• 
Insufficient adherence to protocol requirements 
• 
Submission of knowingly false information from the research facility to Edwards, the 
monitor, or any regulatory authority. 
If a study site is discontinued, subjects enrolled prior to discontinuation will continue to be followed 
per the protocol. 
 Auditing 
The study may be subject to a quality assurance audit by Edwards or a designee, as well as 
inspection by appropriate regulatory authorities.  It is important that the Investigator and relevant 
study site personnel are available during any audits and that sufficient time is devoted to the 
process.  In the event of an audit by regulatory authorities, the Investigator should contact 
Edwards as soon as possible. 
 Publication Policy 
Publication or presentation of the overall clinical study results and/or site-specific results requires 
prior written approval of Edwards.  If Edwards approves the publication or presentation of the 
overall clinical study results and/or site-specific results, then Institutions and Investigators will 
comply with the Publications and Public Disclosure Section of the Clinical Trial Agreement.  
Edwards will provide statistical support for the publication process. 
The study results will be made public within 24 months of the end of data collection and a full 
report of the outcomes will be made public no later than three (3) years after the end of data 
collection. 
 ETHICAL AND REGULATORY CONSIDERATIONS 
 
Applicable Principles and Regulations 
The study will be performed in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki (as updated in Fortaleza Brazil in 2013). 
The following regulations and guidelines will be followed: 
• 
ISO 14155: 2011 Clinical Investigation of Medical Devices for Human Subjects - Good 
Clinical Practice 
• 
MDD 93/42/EEC European Medical Device Directive 93/42/EEC (MDD) 

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• 
MEDDEV 2.7/3 revision 3 Clinical Investigations:  Serious Adverse Event Reporting 
under Directives 90/385/EEC AND 93/42/EEC 
• 
MEDDEV 2.12-1 revision 8:  Guidelines on a Medical Device Vigilance System 
• 
General Data Protection Regulation 2016/679 
• 
Specific country regulations will be fulfilled, as applicable 
 
 
Institutional Review Board/Ethics Committee 
This protocol, the proposed ICF, other written subject information and any proposed advertising 
material must be submitted to the IRB/EC for written approval.  A copy of the written IRB/EC 
approval of the protocol and ICF must be received by Edwards before recruitment of subjects into 
the study and shipment of investigational product. 
The Investigator must submit and, where necessary, obtain approval from the IRB/EC for all 
subsequent protocol amendments and changes to the ICF. 
The Investigator is responsible for obtaining annual IRB/EC approval and renewal throughout the 
duration of the study.  Copies of the Investigator’s reports and the IRB/EC continuance of approval 
must be sent to Edwards. 
 
Informed Consent 
Edwards will provide a sample ICF to the Investigator to prepare for use at his/her site.  The site-
specific ICF, and any subsequent modifications, must be in agreement with current regulations 
and guidelines and must be approved by Edwards prior to submission to the IRB/EC.  The 
reviewing IRB/EC must approve the ICF before use at the site. 
Before participating in the clinical study, each subject must give written Informed Consent after 
the context of the study has been fully explained in a language that is easily understood by the 
subject.  The subject must also be given the opportunity to ask questions and have those 
questions answered to his/her satisfaction. 
A copy of each subject’s signed and dated consent form must be maintained by each Investigator 
in a designated clinical study administrative file.  A signed copy of the consent form must be given 
to each subject.  The consent process must be documented in the subject’s medical chart; the 
documentation should include minimally that consent was obtained prior to participation in the 
research study, date consent was obtained, and confirmation that a copy of the consent was given 
to the subject. 
 
Confidentiality 
All data used in the analysis and reporting of this evaluation will be without identifiable reference 
to the subject.  Authorized personnel assigned by Edwards will have access to the confidential 
files and will have the right to inspect and copy all records pertinent to this study. 

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Investigator Records 
Records to be maintained by the Investigator include, but are not limited to, the following: 
• 
Clinical study protocol and all amendments 
• 
Signed Clinical Trial Agreement and any amendments 
• 
IRB/EC approval letters, including continuing reviews and all amendments/changes 
• 
IRB/EC approved informed consent documents 
• 
All correspondence with another Investigator, IRB/EC, Edwards or monitor 
• 
Records of receipt, use or disposition of a device 
 
The following records must be maintained for each subject enrolled in the study: 
• 
Signed ICF 
• 
All relevant source documentation for study visits and study-related procedures 
• 
Supporting documentation of any AEs 
 
All enrolling sites will maintain the study records for a period of two years after the latter of the 
following two dates:  The date on which the investigation is terminated or completed, or the date 
that the records are no longer required for purposes of supporting a premarket approval 
application. 
 
Protocol Amendments 
The protocol can be altered only by written amendments made by Edwards.  The amended 
protocol will be submitted to the EC and required regulatory agencies, as applicable, before being 
distributed to sites.  Each site must obtain IRB/EC approval, complete required training (if any, 
and as required by DoA role), and receive written approval from Edwards before implementing 
the amended protocol. 
 
Protocol Deviations 
An Investigator must not make any changes or deviate from this protocol, except to protect the 
life and physical well-being of a subject in an emergency.  Emergency changes to protect the life 
of the subject do not require prior approval, but must be reported to Edwards and the reviewing 
IRB/EC within 5 days of the incident. 
Each deviation from the protocol must be documented with the date and reason for the deviation 
and reported to Edwards as soon as possible, and to the IRB/EC per local guidelines and 
government regulations. 
 
 

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APPENDIX A. ABBREVIATIONS 
Abbreviation 
Full Term 
ACC 
American College of Cardiology 
ACT 
Activated Clotting Time 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AHA 
American Heart Association 
AKI 
Acute Kidney Injury 
ALT 
Alanine Aminotransferase 
AS 
Aortic Stenosis 
ASA 
Aspirin 
AST 
Aspartate Aminotransferase 
AT 
As Treated 
AVA 
Aortic Valve Area 
AVR 
Aortic Valve Replacement 
BAV 
Balloon Aortic Valvuloplasty 
BMI 
Body Mass Index 
BMS 
Bare Metal Stent 
CABG 
Coronary Artery Bypass Graft 
CAD 
Coronary Artery Disease 
CI 
Confidence Interval 
CK 
Creatine Kinase 
CKMB 
Creatine Kinase MB Isoenzyme 
CT 
Computed Tomography 
DES 
Drug Eluting Stent 
DoA 
Delegation of Authority 
EACTS 
European Association for Cardio-Thoracic Surgery 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
eGFR 
Estimated Glomerular Filtration Rate 
EOA 
Effective Orifice Area 
ESC 
European Society of Cardiology 
FEV1 
Forced Expiratory Volume in 1 Second 
Hgb 
Hemoglobin 
HOCM 
Hypertrophic Obstructive Cardiomyopathy 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
IFU 
Instructions For Use 
INR 
International Normalized Ratio 

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Abbreviation 
Full Term 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization; 
LA 
Left Atrial 
LMW 
Low Molecular Weight 
LVEF 
Left Ventricular Ejection Fraction 
MDD 
Medical Device Directive 
MI 
Myocardial Infarction 
MR/MRI 
Magnetic Resonance / Magnetic Resonance Imaging 
mRS 
Modified Rankin Scale 
NIHSS 
National Institutes of Health Stroke Scale 
NYHA 
New York Heart Association 
OPG 
Objective Performance Goal 
PARTNER 
Placement of AoRtic TranNscathetER 
PCI 
Percutaneous Coronary Intervention 
PET 
Polyethylene Terephthalate 
Plt 
Platelets 
PT 
Prothrombin Time 
PVL 
Paravalvular Leak 
QD 
Every Day / Daily 
SADE 
Serious Adverse Device Effect 
SAVR 
Surgical Aortic Valve Replacement 
SAE 
Serious Adverse Event 
STS 
Society of Thoracic Surgeons 
SVD 
Structural Valve Deterioration 
TAVR 
Transcatheter Aortic Valve Replacement 
TEE 
Transesophageal Echocardiogram 
THV 
Transcatheter Heart Valve 
TIA 
Transient Ischemic Attack 
TTE 
Transthoracic Echocardiogram 
USADE 
Unanticipated Serious Adverse Device Effect 
UF 
Unfractionated Heparin 
VF 
Ventricular Fibrillation 
VI 
Valve Implant 
VT 
Ventricular Tachycardia 
WBC 
White Blood Cell 
 
 

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APPENDIX B. DEFINITIONS 
Term 
Definition 
Reference/ 
Justification 
Access Site 
Any location (arterial or venous) traversed by a guidewire, a catheter 
or a sheath for TAVR 
VARC-1 (23) 
Access Site 
Related 
Complication 
Any adverse clinical consequence possibly associated with any of the 
access sites used during the procedure 
Planned repair of access site entry portals are not considered access 
site-related complications. 
VARC-1, 
VARC-2 (24) 
Acute Kidney 
Injury (AKI) 
AKI is defined by an abrupt decrease in kidney function 
• Reportable AKI is for any creatinine with an increase in serum 
creatinine to > 150% of baseline, OR 
• increase of ≥ 0.3 mg/dL compared to baseline within 48 hours of 
index procedure, OR 
• Urine output < 0.5 mL/kg per hour for > 6 but < 12 hours 
Patients receiving renal replacement therapy (dialysis, hemodialysis, 
peritoneal dialysis, hemofiltration, transplant therapy) are considered 
to meet Stage 3 AKI criteria. 
For AKI diagnosis beyond Index Procedure (or for subjects who do 
not get Index Procedure), the same criteria are to be used with a pre-
AKI diagnosis baseline. 
Note:  AKI stage will be determined per VARC-2 criteria. 
AKIN / 
KDIGO / 
VARC-2 / 
Sponsor 
Angina / 
Cardiac Chest 
Pain 
Chest pain due to myocardial ischemia caused by an imbalance 
between myocardial blood supply and oxygen demand. 
Sponsor 
Aortic 
Dissection 
Aortic dissection is defined as separation of the layers within the 
aortic wall.  Tears in the intimal layer could have blood entering 
intima-media space resulting in the propagation of dissection 
(proximally or distally). 
Sponsor 
Aortic 
Stenosis, 
Native 
Aortic stenosis is classified as “severe” when the following are 
present: 
• Jet velocity ≥ 4.0 m/s 
• Mean gradient ≥ 40 mmHg 
• Valve area ≤ 1.0 cm2 
• Valve area index ≤ 0.6 cm2/m2 
2014 
AHA/ACC 
Arrhythmia / 
Conduction 
System Injury 
(Defect) 
Arrhythmia: an increased heart rate (> 100 beats/min Tachycardia) or 
decreased heart rate (< 60 beats/min Bradycardia) or an irregular 
heart rate which could result in symptoms or require medical/surgical 
intervention. 
Conduction system defect:  an impairment of Sinoatrial node, 
Atrioventricular node or specialized muscular fibers that conduct 
impulses through the heart (Internodal fibers, Bundle of His, Bundle 
branches, Purkinje fibers). 
Sponsor 

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Term 
Definition 
Reference/ 
Justification 
Atrial 
Fibrillation 
Atrial fibrillation is rapid irregular heart rhythm characterized by rapid 
and irregular beating of atria with or without associated ventricular 
fibrillation and has ECG characteristics of atrial fibrillation and lasts 
sufficiently long to be recorded on a 12-lead ECG, or at least 30 
seconds on a rhythm strip. 
The type of atrial fibrillation includes: 
• Paroxysmal atrial fibrillation:  Atrial fibrillation that terminates 
spontaneously or with intervention within 7 days of onset.  
Episodes may recur with variable frequency. 
• Persistent atrial fibrillation:  Continuous atrial fibrillation that is 
sustained >7 days or requires medical (rate/rhythm control) or 
surgical intervention (Ex: ablation, cardioversion or Maze 
procedure). 
• Permanent AF:  Permanent AF is used when there has been an 
inability to restore and/or maintain sinus rhythm with medical 
and/or surgical intervention. 
Sponsor (25) 
Bicuspid 
Aortic Valve 
Bicuspid aortic valve is an inheritable condition where aortic valve 
appears on gross examination with only two cusps as a result of 
fusion during development.  This comprises a spectrum of deformed 
aortic valves presenting with two functional cusps forming a valve 
mechanism with less than three zones of parallel apposition between 
cusps. 
Type 1: valve with one raphe 
Type 2: valve with two raphes 
(26) 

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Term 
Definition 
Reference/ 
Justification 
Bleeding 
Overt bleeding is defined as clinically obvious (visible bleeding and 
bleeding identified by imaging only). 
Examples of overt bleeding include: 
• Pseudoaneurysm 
• Retroperitoneal hematoma seen on CAT scan 
• Visible access site hematoma 
Actionable Bleeding is more bleeding than expected for clinical 
circumstance needing increased level of care like 
• hospitalization 
• medical/surgical intervention 
• transfusions 
Thresholds for reporting procedural bleeding for SAVR procedure is 
bloody chest tube output > 600 mL within any 24-hour period and for 
TF-TAVR >100 mL total EBL (Estimated Blood Loss) from access 
site.  These are suggested as guidelines for Site reporting of 
Bleeding events and clinical judgement should be used in reporting 
bleeding events. 
All post-procedural overt bleeding events must be reported 
including hematuria, melena, hematemesis, occult gastrointestinal 
bleeds or drop in Hgb with overt source of bleeding detected 
requiring transfusions etc. 
If the reason for Hgb drop was other than due to the overt bleeding 
i.e. due to hemodilution, chronic iron deficiency anemia, this will not 
be considered as a bleeding event. 
Note:  Bleeding will be adjudicated per VARC-2 and BARC criteria. 
Sponsor 
CABG 
Coronary artery bypass graft surgery is a procedure performed to 
bypass partially or completely occluded coronary arteries with veins 
(commonly Great/Small Saphenous veins) and/or arteries (commonly 
Internal thoracic/Mammary artery) harvested from elsewhere in the 
body, thereby improving the blood supply to the coronary circulation 
supplying the myocardium (heart muscle). 
Sponsor/ 
2014 
ACC/AHA 
Key Data 
Elements 
and 
Definitions 
for 
Cardiovascu
lar Endpoint 
Events in 
Clinical 
Trials 
Cardiac Arrest 
Cardiopulmonary arrest or circulatory arrest is a sudden stop in 
effective blood circulation due to the failure of the heart to contract 
effectively or at all. 
Sponsor / 
STS 
Cardiac 
Tamponade 
Evidence of a new pericardial effusion associated with hemodynamic 
instability evident by: 
1. Echo showing pericardial fluid and signs of tamponade such as 
right heart compromise, or 
2. Systemic hypotension due to pericardial fluid compromising 
cardiac function 
VARC-2 / 
STS 

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Term 
Definition 
Reference/ 
Justification 
Cardiogenic 
Shock 
Sustained (> 30 min) episode of systolic BP < 90 mmHg and/or 
cardiac index < 2.2 L/min/m2 determined to be secondary to cardiac 
dysfunction, and/or the requirement for parenteral inotropic or 
vasopressor agents or mechanical support (e.g., intra-aortic balloon 
pump, extracorporeal circulatory support, ventricular assist device) to 
maintain BP and cardiac index above those specified levels 
2014 
ACC/AHA 
Key Data 
Elements 
and 
Definitions 
for 
Cardiovascul
ar Endpoint 
Events in 
Clinical Trials 
Cardiopulmon
ary Bypass 
(CPB) 
CPB is a form of extracorporeal circulation that temporarily takes over 
the function of the heart and lungs during surgery, maintaining the 
circulation and oxygen content of blood in the patient's body. 
Sponsor 
Cerebrovascul
ar Disease 
Cerebrovascular disease includes all disorders in which an area of 
the brain is temporarily or permanently affected by ischemia or 
bleeding and one or more of the cerebral blood vessels are involved 
in the pathological process.  It includes: 
• 
Stroke 
• 
TIA 
• 
Noninvasive or invasive arterial imaging test demonstrating 
>=50% stenosis of any of the major extracranial or intracranial 
vessels to the brain  
• 
Previous cervical or cerebral artery revascularization surgery or 
percutaneous intervention 
This does not include chronic (nonvascular) neurological diseases or 
other acute neurological insults such as metabolic and anoxic 
ischemic encephalopathy 
STS 
Congestive 
Heart Failure 
(CHF) 
Heart failure develops when the heart due to an abnormality of 
cardiac function (detectable or not), fails to pump blood at a rate 
commensurate with the requirements of the metabolizing tissues or is 
able to do so only with an elevated diastolic filling pressure. 
Diagnosis requires physician documentation or report of clinical signs 
and symptoms of heart failure like: 
• 
Exertional dyspnea or Dyspnea at rest 
• 
Orthopnea or Paroxysmal nocturnal dyspnea (PND) 
• 
Acute pulmonary edema  
• 
Fluid retention; or the description of rales, jugular venous 
distension  
• 
Pulmonary edema on physical exam, or pulmonary edema on 
chest x-ray presumed to be cardiac dysfunction 
A low ejection fraction alone, without clinical evidence of heart failure 
does not qualify as heart failure. 
An elevated BNP without other supporting documentation should not 
be reported as CHF 
STS 

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Term 
Definition 
Reference/ 
Justification 
Coronary 
Obstruction 
Angiographic or echocardiographic evidence of a new, partial or 
complete, obstruction of a coronary artery lumen or ostium, either by 
the valve prosthesis itself, the native leaflets, calcifications, or 
dissection, occurring during or after the TAVR procedure. 
Mechanical coronary artery obstruction following TAVR includes: 
• 
impingement of the coronary ostia by the valve support structure 
in the setting of suboptimal valve positioning and/or ‘small aortic 
root’ anatomy; OR 
• 
displacement of native aortic valve leaflets towards the coronary 
ostia during TAVR 
VARC-2/ 
STS/ 
Sponsor 
Device 
For the determination of device relationship, the study device 
consists of: 
• 
Edwards SAPIEN 3 Ultra THV 
• 
Edwards SAPIEN 3 THV 
• 
Edwards SAPIEN 3 Ultra Delivery System 
• 
Edwards Axela Sheath 
• 
Edwards eSheath Introducer Set 
Sponsor 
Device 
(Valve) 
Fracture 
The separation of any portion of the frame into two or more parts; as 
may be determined by radiography, computed tomography (CT), 
magnetic resonance imaging (MRI) or by direct examination. 
Sponsor 
Device 
Malfunction 
The failure of a device to meet any of its performance specifications 
or otherwise perform as intended.  Performance specifications 
include all claims made in the labeling of the device.  The intended 
performance of a device refers to the intended use for which the 
device is labeled. 
FDA, 21 CFR 
803.3(m) 
Device 
(Valve) 
Thrombosis 
Any thrombus attached to or near an implanted valve that is an 
incidental imaging finding (echocardiography or CT etc.) and is 
asymptomatic, occludes part of the blood flow path, interferes with 
valve function (immobility of one or more leaflets etc.), or is 
sufficiently large to warrant treatment. 
Prosthetic valve-associated thrombus identified at autopsy in a 
patient whose cause of death was not valve-related should not be 
reported as valve thrombosis 
VARC-2 
Endocarditis 
Endocarditis must meet at least one of the following: 
• 
Fulfilment of the Duke endocarditis criteria 
• 
Evidence of abscess, paravalvular leak, pus, or vegetation 
confirmed as secondary to infection by histological or 
bacteriological studies during a re-operation 
• 
Findings of abscess, pus, or vegetation involving a repaired or 
replaced valve during an autopsy 
VARC-2 
(27) 
EuroSCORE 
II 
http://www.euroscore.org/calc.html  
European 
System for 
Cardiac 
Operative 
Risk 
Evaluation 
Explant 
Removal of the investigational valve implant regardless of reason 
after the Index procedure is complete. 
Sponsor 

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Term 
Definition 
Reference/ 
Justification 
Hemolysis 
The presence of a paravalvular leak on transesophageal or 
transthoracic echocardiography plus anemia requiring transfusion 
plus acute decrease in haptoglobin levels and/or increase in Serum 
Lactate Dehydrogenase (LDH) levels and/or standard blood 
examinations supporting hemolysis (Complete Blood Count, 
Peripheral Smear, etc.) and diagnosis of hemolysis due to prosthetic 
valve confirmed by a hematologist. 
Sponsor 
Hospitalizatio
n (repeat) 
Repeat hospitalization is defined as admission to an inpatient unit or 
ward in the hospital or emergency department stay for ≥24 hours, for 
either diagnostic or therapeutic purpose. 
Hospitalization for the valve implant procedure (Index procedure) is 
not considered repeat hospitalization. 
Hospitalizations planned for pre-existing conditions are excluded 
unless there is worsening of the baseline condition. 
Sponsor 
Hospitalizatio
n (Valve-
related or 
Cardiovascula
r) 
Prosthetic Aortic Valve-related rehospitalization is repeat 
hospitalization for symptoms of prosthetic valve related 
decompensation due to an acute, subacute, or late valve prosthesis 
dysfunction such as valve stenosis, valve regurgitation, valve 
thrombosis, endocarditis or bleeding complications related to oral 
anticoagulation or antiplatelet therapy for valve-related 
thromboembolic event prevention. 
This diagnosis also requires these symptoms of valve disease not 
related to other diagnoses like: 
• 
documentation of anginal symptoms with no clinical evidence that 
angina was related to CAD or ACS 
• 
documented loss of consciousness which is not related to seizure 
or tachyarrhythmia 
 
Valve Procedure-related rehospitalization is repeat hospitalization 
for complications related to the index valve procedure such as 
bleeding and vascular complications, stroke/TIA, arrhythmias and 
AKI.  This does not include complications indirectly related to the 
procedure or related to the hospitalization such as UTI, dehydration, 
other hospital acquired infections, etc. 
 
Heart failure related hospitalization is defined as repeat 
hospitalization for clinical symptoms, objective signs and/or 
diagnostic evidence of worsening heart failure and necessitating a 
medical intervention like administration of intravenous (Ex: IV 
diuretics, Vasopressors etc.) or mechanical heart failure 
therapies(Ex: Intra-aortic balloon pump, Left ventricular assist 
devices and TAVR valve reintervention etc.). 
 

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Term 
Definition 
Reference/ 
Justification 
Hypertension 
Hypertension is defined as a systolic blood pressure (SBP) of 140 
mmHg or more, or a diastolic blood pressure (DBP) of 90 mmHg or 
more, or taking antihypertensive medication. 
Joint National 
Committee 
on 
Prevention, 
Detection, 
Evaluation, 
and 
Treatment of 
High Blood 
Pressure 
(JNC 7) 
Hypertrophic 
Cardiomyopat
hy (HOCM) 
Cardiomyopathy is a term applied to a wide spectrum of cardiac 
diseases in which the predominant feature is poor myocardial 
function in the absence of any anatomic abnormalities. 
Idiopathic hypertrophic subaortic stenosis (IHSS) is also known as 
hypertrophic obstructive cardiomyopathy (HOCM), and is 
characterized by a primary hypertrophy of the myocardium.  The 
obstructive forms involve different degrees of dynamic subvalvar 
aortic obstruction from a thickened ventricular wall and anterior 
motion of the mitral valve. 
Cardiomyopathies are into three entities: 
1. Dilated, characterized by ventricular dilatation and systolic 
dysfunction 
2. Hypertrophic, characterized by physiologically inappropriate 
hypertrophy of the left ventricle 
3. Restrictive, characterized by diastolic dysfunction, with a 
presentation often identical to constrictive pericarditis. 
STS 
Congenital 
Heart 
Surgery 
Database 
Data 
Specification
s 
Hypotension 
Hypotension is defined as a systolic blood pressure (SBP) lower than 
90 mmHg, or mean arterial pressure (MAP) lower than 60 mmHg 
Sponsor 
Index 
Hospitalizatio
n (Index 
Procedure 
Hospitalizatio
n) 
Index hospitalization is defined as the period of in-hospital stay for 
the prosthetic valve implant procedure.  The period of Index 
hospitalization begins with date and time of admission for valve 
implant procedure and continues till the date and time the patient is 
discharged from the hospital where Index procedure is done. 
Sponsor 
Lung Disease, 
Severe 
FEV1 < 50% predicted or currently on home oxygen 
Sponsor 

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Term 
Definition 
Reference/ 
Justification 
Modified 
Rankin Scale 
(mRS) 
A commonly used scale for measuring the degree of disability or 
dependence in the daily activities of people who have suffered a 
stroke, as follows: 
0 No symptoms at all 
1 No significant disability despite symptoms; able to carry out all 
usual duties and activities 
2 Slight disability; unable to carry out all previous activities, but able 
to look after own affairs without assistance 
3 Moderate disability; requiring some help, but able to walk without 
assistance 
4 Moderately severe disability; unable to walk without assistance 
and unable to attend to own bodily needs without assistance 
5 Severe disability; bedridden, incontinent and requiring constant 
nursing care and attention 
6 Dead 
(28) 
Mortality, All-
Cause 
Cardiovascular mortality 
Any of the following criteria: 
• 
Death due to proximate cardiac cause (e.g. myocardial infarction, 
cardiac tamponade, worsening heart failure) 
• 
Death caused by non-coronary vascular conditions such as 
neurological events, pulmonary embolism, ruptured aortic 
aneurysm, dissecting aneurysm, or other vascular disease 
• 
All procedure-related deaths, including those related to a 
complication of the procedure or treatment for a complication of 
the procedure 
• 
All valve-related deaths including structural or nonstructural valve 
dysfunction or other valve-related adverse events 
• 
Sudden or unwitnessed death 
• 
Death of unknown cause 
Non-cardiovascular mortality 
Any death in which the primary cause of death is clearly related to 
another condition (e.g. trauma, cancer, suicide). 
VARC-2 

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Term 
Definition 
Reference/ 
Justification 
Myocardial 
Infarction 
An acute ischemic event that is associated with documented and 
clinically significant myocardial necrosis  
Any one of the following criteria meets the diagnosis for MI: 
 
Periprocedural MI (≤ 72H after Index procedure)  
New signs or symptoms of ischemia. 
• 
Symptoms like chest pain or shortness of breath; 
• 
Ischemic signs like ECG changes indicative of new ischemia 
[new ST segment elevation/depression of ≥1mm in ≥2 contiguous 
leads or new persistent left bundle branch block (LBBB)] or 
• 
New pathological Q-waves in ≥2 contiguous leads or 
• 
Imaging evidence of a new loss of viable myocardium or new wall 
motion abnormality 
• 
AND Elevated cardiac biomarkers (Peak CK-MB rises post-
procedure exceeding 5× the upper reference limit for CK-MB OR 
Peak troponin rises post-procedure exceeding 15× as the upper 
reference limit for troponin) 
• 
If cardiac biomarkers are increased at baseline (>99th 
percentile), a further increase of at least 50% post-procedure is 
required AND the peak value must exceed the previously stated 
limit. 
STS 
 
Spontaneous MI (Before Index Procedure or > 72 hours after the 
index procedure) 
Detection of rise and/or fall of cardiac biomarkers (preferably 
Troponin) with at least one value above the 99th percentile URL 
together with at least one of the following: 
• 
Symptoms of ischemia like chest pain or shortness of breath; 
• 
ECG changes indicative of new ischemia (new ST-segment or T-
wave changes or new LBBB) or new pathologic Q-waves in ≥ 2 
contiguous leads 
• 
Imaging evidence of a new loss of viable myocardium or new wall 
motion abnormality 
MI associated with sudden, unexpected cardiac death 
Sudden cardiac death or cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, accompanied by presumably new 
ST-segment elevation or new LBBB, and/or evidence of fresh 
thrombus by coronary angiography and/or at autopsy, but death 
occurring before blood samples could be obtained, or at a time before 
the appearance of cardiac biomarkers in the blood 
 
Pathologic findings of an acute myocardial infarction 
National 
Institutes of 
Health Stroke 
Scale 
(NIHSS) 
The NIHSS is a method/tool developed by the National Institutes of 
Health used to gauge the severity of a stroke.  NIHSS is a tool to help 
physicians objectively determine the severity of a stroke, help predict 
clinical outcomes and help guide management. 
NIHSS/Spon
sor 

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Term 
Definition 
Reference/ 
Justification 
New York 
Heart 
Association 
Classification 
(NYHA) 
NYHA 
Class 
Functional Capacity 
I 
Patients with cardiac disease but without resulting limitation of 
physical activity.  Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea or anginal pain. 
II 
Patients with cardiac disease resulting in slight limitation of 
physical activity.  They are comfortable at rest.  Ordinary physical 
activity results in fatigue, palpitation, dyspnea or anginal pain. 
III 
Patients with cardiac disease resulting in marked limitation of 
physical activity.  They are comfortable at rest.  Less than 
ordinary activity causes fatigue, palpitation, dyspnea or anginal 
pain. 
IV 
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort.  Symptoms of heart failure or 
the anginal syndrome may be present even at rest.  If any 
physical activity is undertaken, discomfort is increased. 
(29) 
Paravalvular 
Leak (PVL) 
Paravalvular or paraprosthetic leak is a complication associated with 
the implantation of a prosthetic heart valve whether traditional 
(surgical) or a transcatheter (TAVR) approach. 
PVL refers to blood flowing through a channel between the structure 
of the implanted valve and cardiac tissue as a result of a lack of 
appropriate sealing 
ESC 
Peripheral 
Vascular 
Disease 
(PVD) 
Includes peripheral arterial disease of upper and lower extremity, 
renal, mesenteric, and abdominal aortic systems, as follows: 
• 
Claudication, either with exertion or at rest 
• 
Amputation for arterial vascular insufficiency 
• 
Vascular reconstruction, bypass surgery, or percutaneous 
intervention to the extremities (excluding dialysis fistulas and vein 
stripping) 
• 
Documented abdominal aortic aneurysm with or without repair 
• 
Positive noninvasive test (e.g., ankle brachial index =< 0.9, 
ultrasound, magnetic resonance or computed tomography 
imaging of > 50% diameter stenosis in any peripheral artery, i.e., 
renal, subclavian, femoral, iliac) or angiographic imaging 
Peripheral arterial disease excludes disease in the carotid, 
cerebrovascular arteries or thoracic aorta. 
PVD does not include DVT. 
STS 
Pulmonary 
Hypertension 
Pulmonary hypertension (PH), defined as a mean pulmonary arterial 
pressure ≥ 25 mmHg at rest in the presence of Left Atrial 
Pressure(LAP)/Wedge pressure ≤15 mmHg and is often 
characterized by a progressive and sustained increase in pulmonary 
vascular resistance that eventually may lead to right ventricular (RV) 
failure 
ACC/Sponso
r 
Pre-existing 
Condition 
A pre-existing condition is any chronic, recurring condition identified 
prior to enrollment in a clinical study, whether present at enrollment 
or not.  A preexisting condition is not an adverse event unless it 
worsens as a result of the study treatment. 
Sponsor 

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Term 
Definition 
Reference/ 
Justification 
Reintervention 
Any intervention that repairs, alters or replaces a previously 
implanted or operated  valve, which occurs after the completion of 
the valve implant procedure and the transfer to the procedure room.  
These interventions include: 
• 
Balloon aortic valvuloplasty 
• 
Surgical aortic valve replacement 
• 
Valve in valve 
• 
Paravalvular leak closure 
STS/AATS 
Stroke / 
Transient 
Ischemic 
Attack (TIA) 
Diagnostic Criteria 
Acute episode of a focal or global neurological deficit with at least 
one of the following: 
• 
change in level of consciousness 
• 
hemiplegia, hemiparesis, numbness or sensory loss affecting one 
side of the body 
• 
dysphasia or aphasia, hemianopia, amaurosis fugax, or other 
neurological signs or symptoms consistent with stroke 
AND 
No other readily identifiable nonstroke cause for the clinical 
presentation (e.g., brain tumor, trauma, infection, hypoglycemia, 
peripheral lesion, pharmacological influences)to be determined by or 
in conjunction with designated neurologist 
VARC-2 

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Term 
Definition 
Reference/ 
Justification 
Confirmation of the diagnosis by at least one of the following#: 
• 
Neurology or neurosurgical specialist 
• 
Neuroimaging procedure (MR or CT scan) 
• 
Clinical presentation alone 
 
Neurological event type classification: 
Stroke: duration of a focal or global neurological deficit ≥24 h OR 
<24 h if available neuroimaging documents a new intracranial or 
subarachnoid hemorrhage (hemorrhagic stroke) or central nervous 
system infarction (ischemic stroke) OR the neurological deficit results 
in death. 
TIA: duration of a focal or global neurological deficit <24 h and 
neuroimaging does not demonstrate a new hemorrhage or infarct 
 
Stroke etiological classification: 
1. Hemorrhagic: an acute episode of focal or global cerebral or 
spinal dysfunction caused by intraparenchymal, intraventricular, or 
subarachnoid hemorrhage. 
2. Ischemic: an acute episode of focal cerebral, spinal, or retinal 
dysfunction caused by an infarction of the central nervous system 
tissue 
3. Undetermined: stroke with insufficient information to allow 
categorization as ischemic or hemorrhagic. 
 
Stroke severity classification: 
1. Non-disabling: a mRS score of <2 at 90 days or the last available 
clinical visit with evaluable data or one that does not result in an 
increase of at least one mRS category from an individual’s pre-stroke 
baseline 
2. Disabling: a mRS score of ≥2 at 90 days or the last available 
clinical visit with evaluable data and an increase of at least one mRS 
category from an individual’s pre-stroke baseline 
Structural 
Valvular 
Deterioration 
(SVD) 
Structural deterioration includes dysfunction or deterioration due to 
changes intrinsic to the valve, such as wear, fracture, calcification, 
leaflet tear, leaflet retraction, suture line disruption of components, 
prosthetic valve thickening, stenosis as determined by reoperation, 
autopsy or clinical investigation 
SVD excludes infection/endocarditis or thrombosis 
(30) 
STS Adult 
Cardiac 
Surgery Risk 
Calculator 
The Society of Thoracic Surgeons’ risk models predict the risk of 
operative mortality and morbidity after adult cardiac surgery on the 
basis of subject demographic and clinical variables. 
http://riskcalc.sts.org/stswebriskcalc/#/  
STS 
Syncope 
A fainting spell or loss of consciousness 
STS 
SYNTAX 
Score 
An angiographic grading tool to determine the complexity of CAD. 
http://www.syntaxscore.com/ 
http://ir-nwr.ru/calculators/syntaxscore/frameset.htm 
 

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Term 
Definition 
Reference/ 
Justification 
THV-in-THV 
An additional valve prosthesis is implanted within a previously 
implanted prosthesis because of suboptimal device position and/or 
function, during or after the valve implant procedure 
VARC-2 
Transient 
Ischemic 
Attack (TIA) 
See “Stroke / Transient Ischemic Attack (TIA)” 
 
Valve Implant 
Procedure 
Placement of study device and/or additional procedures occurring in 
the procedure room which are completed prior to subject transfer to a 
post-procedure recovery unit (e.g. Recovery Room, ICU/CCU, etc. 
The valve implant procedure will be considered to have started when 
the first interventional access-related puncture (arterial) is 
established.  The end of valve implant procedure is defined as date 
and time of vascular closure post-eSheath removal. 
Performance of TEE does not by itself constitute start of procedure 
Sponsor 
Valve 
Malpositioning 
Valve migration 
• 
After initial correct positioning, the valve prosthesis moves 
upward or downward, within the aortic annulus from its initial 
position, with or without consequences 
Valve embolization 
• 
The valve prosthesis moves during or after deployment such that 
it loses contact with the aortic annulus 
Ectopic valve deployment 
• 
Permanent deployment of the valve prosthesis in a location other 
than the aortic root 
VARC-2 
Vascular 
Injury 
Injury to the vascular system that may be caused by the implanted 
valve or other accessories like guidewires, vascular sheaths, delivery 
catheters, or any balloons used for implanted valve dilatation etc.  
This includes arterial injuries like dissection, perforation, 
arteriovenous fistula, pseudoaneurysm formation, retroperitoneal 
hemorrhage, thromboembolism or incomplete arteriotomy closure 
and venous injuries like perforation, tears, or venous thrombosis 
including pulmonary embolism etc. and cardiac structural injuries like 
perforation or tearing of the major cardiac structures, 
pseudoaneurysm, cardiac tamponade or atrial septal defect etc. 
VARC-2 / 
Sponsor 
 
 
 

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Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Guyton RA, et al. 2014 
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Panchal HB, Ladia V, Desai S, Shah T, Ramu V. A meta-analysis of mortality and major 
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Thourani VH, Kodali S, Makkar RR, Herrmann HC, Williams M, Babaliaros V, et al. 
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Nishimura RA, Otto CM, Bonow RO, Carabello BA, Erwin JP, 3rd, Fleisher LA, et al. 2017 
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Kappetein AP, Head SJ, Genereux P, Piazza N, van Mieghem NM, Blackstone EH, et al. 
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thoracic Surgery. 2012;42(5):S45-60. 
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January CT, Wann LS, Alpert JS, Calkins H, Cleveland JC, Cigarroa JE, et al. 
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Sievers H-H, Schmidtke C. A classification system for the bicuspid aortic valve from 304 
surgical specimens. The Journal of Thoracic and Cardiovascular Surgery. 
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27. 
Durack DT, Lukes AS, Bright DK, Service DE. New criteria for diagnosis of infective 
endocarditis: utilization of specific echocardiographic findings. The American journal of 
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Van Swieten JC, Koudstaal PJ, Visser MC, Schouten HJA, Van Gijn J. Interobserver 
agreement for the assessment of handicap in stroke patients. Stroke. 1988;19(5):604-7. 
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Akins CW, Miller DC, Turina MI, Kouchoukos NT, Blackstone EH, Grunkemeier GL, et al. 
Guidelines for reporting mortality and morbidity after cardiac valve interventions. The 
Annals of thoracic surgery. 2008;85(4):1490-5.