PARTNER 3 Trial - SAPIEN 3 Transcatheter Heart Valve Implantation in Patients With a Failing Mitral Bioprosthetic Valve
Phase: NA
Conditions: Mitral Valve Insufficiency, Mitral Valve Disease, Mitral Valve Regurgitation, Heart Failure
Sponsor: Edwards Lifesciences

 
 
 
 
 
PARTNER 3 Trial – Mitral Valve in Valve 
A Prospective, Single-Arm, Multicenter Study to Investigate the Safety and 
Effectiveness of SAPIEN 3 Transcatheter Heart Valve Implantation in Patients with a 
Failing Mitral Bioprosthetic Valve 
 
 
 
NCT03193801 
 
 
May 8, 2020 
 

The PARTNER 3 MVIV Trial 
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, Edwards Lifesciences, the stylized E logo, Certitude, Commander, Edwards Certitude, Edwards 
Commander, Edwards SAPIEN, Edwards SAPIEN 3, SAPIEN and SAPIEN 3 are trademarks of Edwards 
Lifesciences Corporation. 
Page 1 of 71 
 
 
 
 
 
PARTNER 3 Trial – Mitral Valve in Valve 
A Prospective, Single-Arm, Multicenter Study to Investigate the Safety and 
Effectiveness of SAPIEN 3 Transcatheter Heart Valve Implantation in Patients with a 
Failing Mitral Bioprosthetic Valve 
 
 
 
Protocol Study Number 
 
2015-08 MVIV 
 
Protocol Date & Version 
 
May 8, 2020 
 
Version 4.0 
 
Study Sponsor: 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 
USA 
 
 

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TABLE OF CONTENTS 
PROTOCOL SYNOPSIS ...................................................................................................... 5 
INVESTIGATOR SIGNATURE PAGE .................................................................................. 9 
1 
INTRODUCTION ......................................................................................................... 10 
2 
STUDY OBJECTIVE ................................................................................................... 13 
3 
STUDY DESIGN .......................................................................................................... 13 
4 
ENROLLMENT ............................................................................................................ 14 
5 
STUDY DEVICES ........................................................................................................ 14 
5.1 
DEVICE DESCRIPTIONS ..................................................................................... 14 
6 
STUDY ENDPOINTS ................................................................................................... 17 
6.1 
PRIMARY ENDPOINT ................................................................................................ 17 
6.2 
SECONDARY ENDPOINTS FOR LABELING .................................................................. 17 
6.3 
ADDITIONAL SECONDARY ENDPOINTS ...................................................................... 17 
7 
STUDY POPULATION / PROPOSED INDICATION FOR USE ................................... 18 
7.1 
INCLUSION CRITERIA ............................................................................................... 18 
7.2 
EXCLUSION CRITERIA ............................................................................................. 19 
8 
STUDY PROCEDURES ............................................................................................... 20 
8.1 
SCREENING PERIOD ............................................................................................... 20 
8.2 
ENROLLMENT ......................................................................................................... 23 
8.3 
PROCEDURE (DAY 0) .............................................................................................. 23 
8.4 
POST-PROCEDURE ................................................................................................. 26 
8.5 
DISCHARGE ............................................................................................................ 26 
8.6 
POST-PROCEDURE FOLLOW UP VISITS .................................................................... 27 
8.7 
ASSESSMENT FOR LEAFLET THROMBOSIS ................................................................ 30 
8.8 
NEUROLOGICAL ASSESSMENTS ............................................................................... 30 
8.9 
MISSED VISITS ....................................................................................................... 30 
8.10 
DISCONTINUATION AFTER ENTERING THE PROCEDURE ROOM ................................... 30 
8.11 
DEATH REGISTRIES ................................................................................................ 31 
9 
ADVERSE EVENTS .................................................................................................... 34 
9.1 
DEFINITIONS ........................................................................................................... 34 
9.2 
CAUSALITY OF AES ................................................................................................. 36 
9.3 
AE REPORTING REQUIREMENTS .............................................................................. 36 
9.4 
PRE-EXISTING CONDITIONS ..................................................................................... 38 
9.5 
SPONSOR ASSESSMENT OF AES ............................................................................. 39 
10 RISKS AND BENEFIT ANALYSIS .............................................................................. 39 
10.1 
POTENTIAL BENEFITS.............................................................................................. 39 
10.2 
POTENTIAL RISKS ................................................................................................... 40 
11 STATISTICAL ANALYSIS ........................................................................................... 42 

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11.1 
SAMPLE SIZE CALCULATIONS .................................................................................. 42 
11.2 
ANALYSIS POPULATIONS ......................................................................................... 42 
11.3 
TIMING ................................................................................................................... 42 
11.4 
PRIMARY ENDPOINT ANALYSIS ................................................................................ 42 
11.5 
SECONDARY ENDPOINTS ......................................................................................... 42 
11.6 
ADDITIONAL ANALYSES ........................................................................................... 43 
11.7 
GENERAL STATISTICAL METHODOLOGY ................................................................... 43 
12 STUDY ADMINISTRATION ......................................................................................... 45 
12.1 
GENERAL STUDY ORGANIZATION ............................................................................. 45 
12.2 
DATA SAFETY MONITORING BOARD (DSMB) ............................................................ 45 
12.3 
CLINICAL EVENT ADJUDICATION COMMITTEE (CEC) ................................................. 45 
12.4 
STUDY PROCEDURES.............................................................................................. 46 
12.5 
TRAINING ............................................................................................................... 47 
12.6 
DEVICE MANAGEMENT ............................................................................................ 47 
12.7 
DATA MANAGEMENT ............................................................................................... 48 
12.8 
MONITORING PROCEDURES .................................................................................... 48 
12.9 
AUDITING ............................................................................................................... 48 
12.10 RECORD RETENTION .............................................................................................. 49 
13 ETHICAL AND REGULATORY CONSIDERATIONS .................................................. 49 
13.1 
APPLICABLE PRINCIPLES AND REGULATIONS ............................................................ 49 
13.2 
INSTITUTIONAL REVIEW BOARD/ETHICS COMMITTEE ................................................. 49 
13.3 
PATIENT INFORMED CONSENT ................................................................................. 49 
13.4 
CONFIDENTIALITY ................................................................................................... 50 
13.5 
INVESTIGATOR RECORDS ........................................................................................ 50 
13.6 
INVESTIGATOR REPORTS ........................................................................................ 50 
13.7 
AMENDING THE PROTOCOL ..................................................................................... 51 
13.8 
PROTOCOL DEVIATIONS .......................................................................................... 51 
13.9 
PUBLICATION POLICY .............................................................................................. 51 
APPENDIX A ABBREVIATIONS ...................................................................................... 52 
APPENDIX B DEFINITIONS ............................................................................................. 55 
APPENDIX C REFERENCES ........................................................................................... 68 
 
 
 

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List of Tables 
Table 1.  Early Mortality in Reoperative Valve Surgery ..............................................................12 
Table 2.  Device Sizing for SAPIEN 3 THV in Surgical Bioprosthesis Procedures .....................14 
Table 3.  Recommended Anticoagulation/Antithrombotic Regimen ...........................................25 
Table 4.  Schedule of Procedures .............................................................................................32 
 
List of Figures 
Figure 1.  Edwards SAPIEN 3 Model 9600TFX .........................................................................14 
 
 
 

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PROTOCOL SYNOPSIS 
Title 
A prospective, single-arm, multicenter study to investigate the safety and 
effectiveness of SAPIEN 3 transcatheter heart valve (THV) implantation in 
patients with a failing mitral bioprosthetic valve 
Purpose 
To assess the safety and effectiveness of the SAPIEN 3 THV in patients with a 
failing mitral bioprosthetic valve 
Study Device 
Edwards SAPIEN 3 THV system with the associated delivery systems 
Control 
Not applicable 
Study Design 
Prospective, single-arm, multicenter study 
Patient Population 
Patients with symptomatic heart disease due to a failing bioprosthetic mitral 
valve (stenosed, insufficient, or combined) who are judged by a heart team, 
including a cardiac surgeon, 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 STS risk calculator). 
Sample Size 
A total of 50 patients who undergo the procedure 
Study Sites 
Up to 15 US sites and up to 5 sites outside the US will participate 
Visit Schedule 
Screening/Baseline, Procedure, Discharge, 30 days, 6 months, and annually 
through 10 years 
Primary Endpoint 
Safety and Effectiveness:  Non-hierarchical composite endpoint of all-cause 
mortality and stroke at 1-year post-procedure 
Secondary 
Endpoints for 
Labeling 
1. New York Heart Association (NYHA) Functional Class at 30 days 
2. Kansas City Cardiomyopathy Questionnaire (KCCQ) at 30 days 
3. Mitral regurgitation (MR) at 30 days 
4. Pulmonary artery systolic pressure at 30 days 
Additional 
Secondary 
Endpoints 
1. Procedure success defined as absence of procedural mortality AND correct 
positioning of a single prosthetic heart valve into the proper anatomical 
location 
2. Mortality (all cause & cardiovascular) at 30 days and 1 year 
3. Stroke (disabling and nondisabling) at 30 days and 1 year 
4. Vascular complications (major) at 30 days and 1 year 
5. Bleeding complications (life-threatening, disabling, or major) at 30 days and 
1 year 
6. Myocardial infarction requiring intervention at 30 days and 1 year 
7. Acute kidney injury (AKI) at 30 days 
8. Requirement for renal replacement therapy at 1 year 
9. New permanent pacemaker implantation resulting from new or worsened 
conduction disturbances at 30 days and 1 year 
10. NYHA Functional Class at 1 year 
11. Hemodynamic function: mean and peak gradient at 30 days, years 1 through 
5, year 7 and year 10 

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12. Mitral valvular regurgitation (paravalvular & central) at years 1 through 5, 
year 7 and year 10 
13. New onset atrial fibrillation at 30 days and 1 year 
14. Rehospitalization (valve-related or procedure related and including 
congestive heart failure [CHF]) at 30 days, 1 year, and annually 
15. Index hospitalization days, intensive care unit (ICU) days, and discharge 
location 
16. Structural valve deterioration (SVD) at years 1 through 5, year 7 and year 10 
17. Days alive and out of hospital at 1 year 
18. Six-minute walk test (6MWT) at 1 year 
19. Heath status as evaluated by Quality of Life (QoL) questionnaires 
a. KCCQ at 1 year 
b. EQ-5D-5L at 30 days and 1 year 
c. SF-36 at 30 days and 1 year 
Inclusion Criteria 
Patients for this study must meet all of the following inclusion criteria: 
1. Failing surgically implanted bioprosthetic valve in the mitral position 
demonstrating ≥ moderate stenosis and/or ≥ moderate insufficiency. 
2. Surgical bioprosthetic valve with a true internal diameter (True ID) of 16.5 
mm to 28.5 mm. 
3. NYHA Functional Class ≥ II. 
4. Heart Team agrees the patient is intermediate risk (i.e. STS score of ≥ 3 and 
<8).  The Heart Team evaluation should include risk calculators such as the 
STS as well as overall clinical status and comorbidities not fully addressed 
by the STS risk score (verified during the case review process). 
5. Heart Team agrees valve implantation will likely benefit the patient. 
6. The study patient has been informed of the nature of the study, agrees to its 
provisions and has provided written informed consent as approved by the 
Institutional Review Board (IRB) / Ethics Committee (EC) of the respective 
clinical site. 
Exclusion Criteria 
Patients will be excluded from the study if any of the following conditions are 
present: 
1. Index valve has ≥ mild paravalvular regurgitation where the surgical 
bioprosthesis is not securely fixed in the native annulus or is not structurally 
intact as determined by transesophageal echocardiography (TEE). 
2. Surgical or transcatheter aortic valve placed so that extension into left 
ventricular outflow tract (LVOT) may impinge on the mitral implant. 
3. Known residual mean gradient >10 mmHg at the end of the index procedure 
for implantation of the original surgical valve. 
4. Severe right ventricle (RV) dysfunction. 
5. Anatomical characteristics that would preclude safe access to the apex 
(transapical). 
6. Severe regurgitation or stenosis of any other valve. 
7. Severe lung disease (FEV1 < 50% predicted) or currently on home oxygen. 

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8. Severe pulmonary hypertension (e.g., PA systolic pressure ≥ 2/3 systemic 
pressure) 
9. Anatomical characteristics that would increase risk of LVOT obstruction (e.g., 
aortomitral angle, LVOT size, etc.) 
10. Evidence of an acute myocardial infarction ≤ 1 month (30 days) before 
enrollment. 
11. Any therapeutic invasive cardiac procedure resulting in a permanent implant 
that is performed within 30 days prior to the index procedure.  Implantation of 
a permanent pacemaker (PPM) or implantable cardioverter defibrillator (ICD) 
is not considered an exclusion. 
12. Patients with planned concomitant surgical or transcatheter ablation for atrial 
fibrillation. 
13. Leukopenia (white blood count < 3000 cell/mL), anemia (hemoglobin < 9 
g/dL), thrombocytopenia (blood platelet count < 50,000 cell/mL), history of 
bleeding diathesis or coagulopathy, or hypercoagulable states. 
14. Untreated clinically significant coronary artery disease requiring 
revascularization. 
15. Hemodynamic or respiratory instability requiring inotropic support, 
mechanical ventilation, or mechanical heart assistance within 30 days of 
enrollment. 
16. Emergency interventional/surgical procedures within one month (30 days) 
prior to the procedure. 
17. Any planned surgical, percutaneous coronary, or peripheral procedure to be 
performed within the 30-day follow-up from the procedure. 
18. Hypertrophic cardiomyopathy with obstruction (HOCM). 
19. Left ventricular ejection fraction (LVEF) < 30%. 
20. Cardiac imaging evidence of intracardiac mass, thrombus, or vegetation. 
21. Inability to tolerate or condition precluding treatment with 
antithrombotic/anticoagulation therapy during or after the valve implant 
procedure. 
22. Absolute contraindications or allergy to iodinated contrast that cannot be 
adequately treated with premedication. 
23. Stroke or transient ischemic attack (TIA) within 90 days of enrollment. 
24. Symptomatic carotid or vertebral artery disease or successful treatment of 
carotid stenosis within 30 days of enrollment. 
25. Renal insufficiency (eGFR < 30 ml/min per the Cockcroft-Gault formula) 
and/or renal replacement therapy at the time of screening. 
26. Active bacterial endocarditis within 6 months (180 days) of the procedure. 
27. Patient refuses blood products. 
28. Estimated life expectancy < 24 months. 
29. Currently participating in an investigational drug or another device study.  
Note: Clinical trials requiring extended follow-up for products that were 
investigational, but have since become commercially available, are not 
considered investigational trials. 

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30. Positive urine or serum pregnancy test in female subjects of childbearing 
potential. 
Statistical 
Analysis 
Statistical comparison against baseline will be performed for selected secondary 
endpoints.  All other data will be summarized descriptively. 
Principal 
Investigators 
Mayra Guerrero, MD 
Mayo Clinic Rochester 
Rochester, MN 55905 
S. Chris Malaisrie, MD 
Northwestern University Feinberg School of Medicine 
Chicago, IL 60611 
Alan Zajarias, MD 
Washington University School of Medicine 
St. Louis, MO 63110 
Sponsor 
Edwards Lifesciences LLC 
One Edwards Way 
Irvine, CA 92614 
 
 

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INVESTIGATOR SIGNATURE PAGE 
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. 
 
 
 
 
 
Investigative Site Name 
 
 
 
 
 
Site Principal Investigator Name (print) 
 
 
 
 
 
 
 
Site Principal Investigator Signature  
 
Date 
 
 
 

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1 INTRODUCTION 
Since the initial implantations in 2002, transcatheter heart valve (THV) replacement has evolved 
into a recognized alternative therapy to open heart surgery for inoperable and high risk patients 
with severe native aortic valve stenosis.  More recently, patients with a previously implanted failing 
aortic and mitral surgical bioprostheses have also been identified as additional patient populations 
that requires mediation of stenotic, regurgitant, or combined prosthetic lesions.  The ability to 
perform a reoperative valve replacement on the beating heart without the need for a full median 
sternotomy or use of the heart-lung machine is an equally desirable option for patients with a 
failing bioprosthesis in the mitral position and requires further study. 
Mitral valve disease requiring intervention is manifested by stenosis and/or regurgitation.  Mitral 
stenosis (MS) is most commonly associated with rheumatic heart disease resulting in progressive 
thickening and scarring of the mitral valve structures and narrowing of the mitral valve opening.  
The incidence of rheumatic fever has dropped dramatically in developed countries is rarely seen 
in the United States.  Most cases of MS are in patients who have emigrated from countries where 
rheumatic fever is still endemic.1  By nature of the disease, affected individuals are typically 
over the age of 65 years2, the majority of who are Medicare beneficiaries in the United States 
(US).  Mitral regurgitation (MR) can be caused by rheumatic disease or infections, mitral valve 
prolapse or myocardial ischemia and accounts for the majority of mitral valve interventions. 
For MS, the definitive treatments are balloon valvuloplasty or in severe cases, valve replacement.  
Mitral valve repair with an annuloplasty device is the treatment of choice for MR.  When this is not 
possible, a mitral valve replacement is performed with the preference for a bioprosthesis in the 
elderly.  Mitral valve replacement with a stented bioprosthesis instead of a mechanical prosthesis 
is often chosen for patients in normal sinus rhythm, but also in those with the need to avoid oral 
anticoagulation such as patients with a history of gastrointestinal bleeding, concomitant coronary 
artery disease, high-risk occupations or in females planning for children. 
Biological heart valve substitutes became available in the 1960s to replace severely stenotic 
native aortic and mitral valves and in contemporary clinical practice are the valves of choice for 
surgical therapy in the older patient population3.  Bioprostheses are recognized for their reduced 
risk of thromboembolic events, avoidance of anticoagulation and good hemodynamic 
performance.  The most commonly used biological prostheses are stented heterografts 
(xenografts) made of bovine pericardium or porcine aortic valves that are mounted on a metal 
alloy or polymer frame.  The cloth-covered frame includes a sewing ring to aide in fixation of the 
device to the annular remnant of the resected native aortic valve or atrial aspect mitral valve 
orifice. 
The last 60 years of bioprosthetic valve development and manufacturing have seen advances 
and improvements in tissue preservation and fixation, calcification mitigation processes and valve 
design that have streamlined procedures and extended the durability of these devices.  
Acceptable intermediate- (5 years), long-term (15 years) and very long-term results (25 years) 
have been observed and recently published in patients receiving a mitral xenograft at the age of 
68 years or older.  4,5,6  Between 1999 and 2002, the United States STS database reported an 

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increase in the implantation of bioprosthetic valves from 50% to 65%.7,8  Mitral valve repair 
procedures reportedly increased from 18.9% in 1998 to 45.8% in 2005.  During the same period 
however, mitral valve replacements decreased3. 
Over time various cellular mechanisms, such as lipid-mediated inflammation, immune response 
and dysfunctional phosphocalcific metabolism can contribute to calcification and intrinsic changes 
to the prosthetic tissue that result in leaflet dysfunction and deterioration.9 It has been shown that 
calcification begins in the areas of greatest stress to the leaflets mostly commonly at the 
commissures and in the basal areas of the leaflets.  Thrombus and vegetation’s related to 
endocarditis can also cause extrinsic calcification on the leaflets and progressive collagen 
deterioration of the tissue can result in design-related leaflet tearing requiring urgent reoperation. 
This primary tissue failure is also referred to as structural valve deterioration (SVD) and is seen 
in both stented and stentless pericardial and porcine devices in the aortic and mitral positions10.  
SVD is also the dominant complication in mitral valve bioprostheses with an onset that is often 
recognized earlier than with aortic devices.  This is thought to be due to the higher closing 
pressures during systole against the mitral leaflets when compared to lower diastolic pressures 
closing the aortic valve.   In mitral valve patients SVD changes may be seen as early as 4-5 years 
and by 10 years may average 30%.  By 15 years postoperatively, the actuarial freedom from 
mitral bioprosthetic primary tissue failure has ranged from 35 to 71%.11  Recent case studies 
report SVD requiring explant in 2 Perimount mitral bioprostheses after 16 and 22 years 
respectively12, 13.  As with aortic valves, deterioration is age related with SVD occurrence higher 
in younger patients. 
Treatment options for patients with a failing surgical bioprosthetic valve in the mitral position are 
similar to those for patients with native valve mitral stenosis with regurgitation including; 
percutaneous balloon valvuloplasty for temporary relief of stenosis, reoperative surgical 
replacement of the degenerated device, the implantation of a transcatheter valve within the 
surgical valve (VinSV) or palliative medical therapy without an obstruction-relieving procedure. 
Inoue published the first clinical report of using balloon valvuloplasty to manage mitral stenosis14.  
The use of balloon valvuloplasty in patients with failing aortic and mitral bioprosthetic devices was 
first described in the late 1980’s and by the early 1990´s was reported with varying degrees of 
success; although technically possible it has been associated with surgical valve tissue disruption 
resulting in severe aortic regurgitation15 and/or embolization of friable calcific deposits or 
thrombotic material16.  It is currently recommended as a palliative therapy in patients with failing 
bioprosthetic heart valves. 
When patients become symptomatic, a prosthetic valve replacement is necessary.  Chan and 
colleagues17 examined the need for reoperation according to age at implant in 3975 patients who 
had undergone a primary aortic valve replacement (AVR, n =3152) or mitral valve replacement 
(MVR, n=823) with a bioprosthetic valve between 1976 and 2010.  In MVR, 59% of patients 
received a Hancock II porcine valve and 29% an Ionescu-Shiley pericardial prosthesis.  A 
subsequent mitral valve reoperation was reported in 144 patients with 23 less than 40 years of 
age, 91 between 40 and 60 years and in 30 patients more than 60 years of age.  At 15 years the 

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freedom from reoperation was more than 80% for patients older than 65 years.  The time to MV 
reoperation was 8.1 years in patients less than 40 years and 10.1 years in patients between 40 
and 60 years.  In both the AVR and MVR group the median interval to reoperation was not reached 
in patients older than age 60 indicating that at no time point did 50% of these patients undergo 
reoperation.  Univariable risk factors for AVR and MVR reoperation with a contemporary 
bioprosthesis were age and concomitant CABG surgery.  The authors observed in the older 
patient population (>60 years) that the 15-year freedom from reoperation 62% for MVR. 
In patients requiring a conventional reoperation for a failing aortic or mitral bioprosthetic heart 
valve the primary goal is to minimize and avoid morbidity and mortality.  Reoperative procedures 
in these patients are technically possible but often challenging as many patients have not been 
under regular medical care and observation and are referred late, often presenting in advanced 
age and poor functional condition with congestive heart failure, compromised hemodynamics and 
multiple organ comorbidities.  The accompanying comorbidities can significantly affect the 
reoperative risk of mortality and has been reported as high as 20%18-20 .  Emergency reoperation 
carries an even higher mortality rate with reports between 22.6% and 44%21,22. 
Table 1 shows early mortality rates of reoperative valve surgery in biological valve series with 
more than 100 patients ranging from 6.5% to 13.8%. 
Table 1.  Early Mortality in Reoperative Valve Surgery 
Series 
Time Period 
Patients 
Valve Position 
Early 
Mortality 
Mazzucco et al, 1993 23 
1970-1990 
221 
Mitral 
10.4% 
Akins et al, 1998 24 
1985-1997 
400 
Aortic & Mitral 
7.8% 
Yamak et al, 1999 25 
1986-1996 
261 
Mitral 
7.7% 
Caus et al, 1999 26 
1978-1998 
524 
Aortic, Mitral & Tricuspid 
8.0% 
Dalrymple-Hay et al, 2002 27 
1980-1999 
259 
Aortic & Mitral 
6.5% 
Jamieson et al, 2003 28 
1975-1999 
463 
Mitral 
7.1% 
Balsam et al. 2010 29 
*Hospital mortality 
1992-2007 
363 
Aortic & Mitral 
13.8%* 
 
The” valve-in-surgical valve” concept (THV in SV) was first reported in failed conventional 
biological valves with the insertion of mechanical valve substitutes in the early 1990´s.30 33  The 
authors describe the challenges, difficulties and resulting complications associated with the 
removal of bioprosthetic devices that require replacement several years after initial implantation.  
The struts of mitral bioprostheses are often buried within the ventricular myocardium or, in the 
aortic position, are fused with the wall of the aortic root where there is also concern about adjacent 
structures such as the coronary ostia, underlying vessels, the His bundle and interventricular 
septum.  Already at that time, caution was expressed about having devices of the right diameter 
to fit into the retained sewing rings and not leave the patient with residual stenoses. 

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THV-in-SV procedures experimentally examined in animals at the Heart Center in Leipzig, 
Germany were published in 200734.  Wenaweser and colleagues35 in Switzerland reported the 
first human THV-in-SV in a degenerated Mitroflow pericardial valve (Sorin Group, Vancouver, BC, 
Canada) with a Medtronic CoreValve THV (Irvine, California USA) in 2007.  Walther and 
colleagues36 followed in 2008 with the first Edwards SAPIEN implant within an Edwards 
PERIMOUNT pericardial prosthesis. 
Paradis and colleagues reviewed 9 case series papers published between 2011 and 2015 and 
presented a state-of-the-art review of transcatheter valve treatment for aortic and mitral surgical 
valve dysfunction9.  Included in the review are 77 mitral valve-in-valve patients and 36 mitral valve-
in-ring patients.  The mean age of these patients was 72 years with very high mean surgical risk 
scores (STS = 13.8% and logistic EuroSCORE =40%).  A SAPIEN XT THV was used in 83% of 
cases and a Medtronic Melody device in 12% of cases.  The transapical approach was the 
preferred access route in 64% of cases and the transseptal approach in 36% of cases.  
Implantation success was 94.5% and the 30-day mortality rate was 8.2%.  No LVOT obstruction 
was reported in the valve-in-valve cohorts. 
Results from the VIVID registry presented at the 2015 EuroPCR in Paris, France were also 
available in the review and reported on 349 patients with a mitral valve-in-valve procedure and 88 
patients with a valve-in-ring implantation (mean age 72 years, 60% female, mean STS = 12.9%).  
The majority of these patients presented with regurgitation (45%) followed by stenosis (23%) and 
combined lesions (32%).  Transapical access was used in 78.9%, transseptal access in 18.5% 
and direct left atrial access in 2.5% of patients.  Transcatheter valve malpositioning was reported 
in 6.6% of patients and a LVOT obstruction in 2.6% of valve-in-valve cases.  All-cause death at 
30 days was reported in the valve-in-valve cohort at 7.7%, strokes were reported in 2.9% and 
mitral regurgitation was seen in 2.6% of patients.  There were limited reports of late results 
including 93 patients and a mortality rate of 20.5% was reported after a mean follow-up of 14 
months.  Thrombosis was reported in 4 valve-in-valve patients, a valve migration requiring a 
second transapical valve-in-valve procedure 2 months post-procedure was seen and no cases of 
structural valve deterioration requiring intervention were reported. 
The list of references is given in Appendix C. Abbreviations and definitions for the terms used in 
the protocol are given in Appendices A and B, respectively. 
2 STUDY OBJECTIVE 
To assess the safety and effectiveness of the SAPIEN 3 THV in patients with a failing mitral 
bioprosthetic valve. 
3 STUDY DESIGN 
This is a prospective, single-arm, multicenter study of SAPIEN 3 THV implantation in patients with 
a failing bioprosthetic mitral valve demonstrating stenosis and/or insufficiency. 

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4 ENROLLMENT 
A total of 50 patients will undergo the procedure at up to 15 US sites and up to 5 sites outside the 
US.  No site will be allowed to enroll more than 25% of patients. 
5 STUDY DEVICES 
The devices used in the study are commercially available devices and include the following: 
Edwards SAPIEN 3 System 
• 
Edwards SAPIEN 3 THV (20 mm, 23 mm, 26 mm and 29 mm sizes) 
• 
Edwards Commander Delivery System for transseptal delivery 
• 
Edwards Certitude Delivery System for transapical delivery 
• 
Edwards eSheath Introducer Sheath Set 
• 
Edwards Certitude Introducer Sheath Set 
• 
Edwards Crimper 
 
5.1 DEVICE DESCRIPTIONS 
5.1.1 Edwards SAPIEN 3 THV 
The SAPIEN 3 THV (Figure 1) is a catheter-delivered heart valve that combines a balloon 
expandable stent and bioprosthetic valve technology. 
The device is comprised of a balloon-expandable, radiopaque, cobalt-chromium alloy frame, a 
trileaflet bovine pericardial tissue valve, a PET internal fabric skirt, and a PET outer skirt.  The 
valve tissue is treated with Edwards ThermaFix process, packaged and terminally liquid sterilized 
in a buffered glutaraldehyde solution. 
Figure 1.  Edwards SAPIEN 3 Model 9600TFX 
 
The SAPIEN 3 is available in 4 sizes.  For SAPIEN 3 THV-in-surgical valve procedures, size 
recommendations for surgical bioprostheses with true internal diameters are shown in Table 2. 
Table 2.  Device Sizing for SAPIEN 3 THV in Surgical Bioprosthesis Procedures 
Surgical Valve True Internal Diameter1 
SAPIEN 3 Size 
16.5-19.0 mm 
20 mm 
18.5-22 mm 
23 mm 

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22-25 mm 
26 mm 
25-28.5 mm 
29 mm 
1 Bapat V, Attia R, Thomas M. Effect of Valve Design on the Stent Internal Diameter of a Bioprosthetic Valve: A Concept of True 
Internal Diameter and Its Implications for the Valve-in-Valve Procedure.  JACC: Cardiovascular Interventions.  Vol. 7, No. 2 2014: 
115-127. 
Note:  The dimensions of the failed bioprosthesis should be determined so that the appropriate 
THV size can be implanted; and is best determined by using computed tomography to perform 
the necessary measurements.  Surgical valve ‘True ID’ may be smaller than the labeled valve 
size. 
5.1.2 Edwards Delivery Systems 
The Commander and Certitude Delivery Systems include: 
• 
Loader 
• 
Qualcrimp Accessory 
• 
2-piece Crimp Stopper 
 
Commander Delivery System 
The Edwards Commander Delivery System consists of a Flex Catheter to aid in valve alignment 
to the balloon, tracking and positioning of the THV.  The delivery system includes a tapered tip to 
facilitate crossing of the aortic valve.  The handle contains a Flex Wheel to control flexing of the 
Flex Catheter, and a Balloon Lock and Fine Adjustment Wheel to facilitate valve alignment and 
positioning of the valve within the aortic annulus.  A stylet is included within the guidewire lumen 
of the delivery system.  The Balloon Catheter has radiopaque Valve Alignment Markers defining 
the working length of the balloon.  A radiopaque Center Marker in the balloon is provided to help 
with valve positioning.  A radiopaque Triple Marker proximal to the balloon indicates the Flex 
Catheter position during deployment. 
Certitude Delivery System 
The Edwards Certitude Delivery System includes a handle with a Flex Wheel for articulation of 
the Balloon Catheter and a Loader.  The loader allows for the delivery of the crimped THV through 
the hemostasis valves of the sheath.  Three radiopaque indicators on the catheter shaft define 
the position on the balloon where the THV should be crimped and also provide visualization of 
the balloon.  The THV is crimped between the two radiopaque shoulders on the distal and 
proximal ends of the balloon.  A radiopaque Center Marker in the balloon is provided to help with 
valve positioning.  An inflation and guidewire hub are housed in the handle assembly. 
Loader 
The loader is used to aid insertion of the delivery system into the sheath and may be removed to 
utilize the full working length of the inserted device. 

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Qualcrimp Accessory 
The Qualcrimp crimping accessory (packaged with the delivery systems) is used during crimping 
of the THV and is intended to protect the SAPIEN 3 leaflets. 
Crimper and 2-piece Crimp Stopper 
The crimper reduces the diameter of the THV to mount it onto its delivery system.  The crimper is 
comprised of a compression mechanism that is closed with a handle located on the housing.  A 
2-piece crimp stopper (packaged with the delivery systems) attaches to the crimper and is used 
to correctly crimp the THV. 
5.1.3 Edwards eSheath Introducer Set 
The Edwards eSheath introducer set contains two dilators and a sheath with hydrophilic coating, 
and a loader packaged with the Edwards Commander delivery system.  The Edwards eSheath 
introducer set is indicated for the introduction and removal of devices used with the Edwards 
SAPIEN 3 THV. 
5.1.4 Certitude Introducer Sheath Set 
The Edwards Certitude introducer sheath set is intended for use with the Edwards Certitude 
delivery system for delivery of the SAPIEN 3 THV via TA/TAo access.  The sheath contains a 
radiopaque maker for visualization of the sheath tip and non-radiopaque depth markings on the 
distal end of the body of the sheath.  The proximal end of the sheath includes a flush tube and 
three hemostasis valves.  An introducer is supplied with the sheath.  The entire introducer is 
radiopaque. 
The SAPIEN 3 THV, Commander Delivery System, Certitude Delivery System, and components 
will be used per their respective IFU and after training of physicians/site personnel has been 
achieved as determined by the study Sponsor.  Further descriptions of these devices are provided 
in the respective IFUs. 
 

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6 STUDY ENDPOINTS 
6.1 Primary Endpoint 
Non-hierarchical composite endpoint of all-cause mortality and stroke at 1-year post-procedure. 
6.2 Secondary Endpoints for Labeling 
1. New York Heart Association (NYHA) Functional Class at 30 days 
2. Kansas City Cardiomyopathy Questionnaire (KCCQ) at 30 days 
3. Mitral regurgitation (MR) at 30 days 
4. Pulmonary artery systolic pressure at 30 days 
 
6.3 Additional Secondary Endpoints 
1. Procedure success defined as absence of procedural mortality AND correct positioning of a 
single prosthetic heart valve into the proper anatomical location 
2. Mortality (all cause & cardiovascular) at 30 days and 1 year 
3. Stroke (disabling and nondisabling) at 30 days and 1 year 
4. Vascular complications (major) at 30 days and 1 year 
5. Bleeding complications (life-threatening, disabling, or major) at 30 days and 1 year 
6. Myocardial infarction requiring intervention at 30 days and 1 year 
7. Acute kidney injury (AKI) at 30 days 
8. Requirement for renal replacement therapy at 1 year 
9. New permanent pacemaker implantation resulting from new or worsened conduction 
disturbances at 30 days and 1 year 
10. NYHA Functional Class at 1 year 
11. Hemodynamic function: mean and peak gradient at 30 days, years 1 through 5, year 7 and 
year 10 
12. Valvular regurgitation (paravalvular & central) at years 1 through 5, year 7 and year 10  
13. New onset atrial fibrillation at 30 days and 1 year 
14. Rehospitalization (valve-related or procedure related and including congestive heart failure 
[CHF]) at 30 days, 1 year, and annually 
15. Index hospitalization days, intensive care unit (ICU) days, and discharge location 
16. Structural valve deterioration (SVD) at years 1 through 5, year 7 and year 10 
17. Days alive and out of hospital at 1 year 

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18. Six-minute walk test (6MWT) at 1 year 
19. Health status as evaluated by Quality of Life (QoL) questionnaires 
• 
KCCQ at 1 year 
• 
EQ-5D-5L at 30 days and 1 year 
• 
SF-36 at 30 days and 1 year 
 
7 STUDY POPULATION / PROPOSED INDICATION FOR USE 
The Edwards SAPIEN 3 THV, Edwards Commander and Certitude delivery systems and 
accessories are indicated for use in patients with symptomatic heart disease due to a failing 
bioprosthetic mitral valve (stenosed, insufficient, or combined) who are judged by a heart team, 
including a cardiac surgeon, 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 STS risk calculator). 
7.1 Inclusion Criteria 
Patients must meet the following inclusion criteria: 
1. Failing surgically implanted bioprosthetic valve in the mitral position demonstrating ≥ 
moderate stenosis and/or ≥ moderate insufficiency. 
2. Surgical bioprosthetic valve with a true internal diameter (True ID) of 16.5 mm to 28.5 
mm. 
3. NYHA Functional Class ≥ II. 
4. Heart Team agrees the patient is intermediate risk (i.e. STS score of ≥3 and < 8).  The 
Heart Team evaluation should include risk calculators such as the STS as well as overall 
clinical status and comorbidities not fully addressed by the STS risk score (verified 
during the case review process). 
5. Heart Team agrees valve implantation will likely benefit the patient. 
6. The study patient has been informed of the nature of the study, agrees to its provisions 
and has provided written informed consent as approved by the Institutional Review 
Board (IRB) / Ethics Committee (EC) of the respective clinical site. 
 
 
 

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7.2 Exclusion Criteria 
Patients will be excluded from the study if any of the following conditions are present: 
1. Index valve has ≥ mild paravalvular regurgitation where the surgical bioprosthesis is not 
securely fixed in the native annulus or is not structurally intact as determined by 
transesophageal echocardiography (TEE). 
2. Surgical or transcatheter aortic valve placed so that extension into left ventricular outflow 
tract (LVOT) that may impinge on the mitral implant. 
3. Known residual mean gradient >10 mmHg at the end of the index procedure for 
implantation of the original surgical valve. 
4. Severe right ventricle (RV) dysfunction. 
5. Anatomical characteristics that would preclude safe access to the apex (transapical). 
6. Severe regurgitation or stenosis of any other valve. 
7. Severe lung disease (FEV1 < 50% predicted) or currently on home oxygen  
8. Severe pulmonary hypertension (e.g., PA systolic pressure ≥ 2/3 systemic pressure) 
9. Anatomical characteristics that would increase risk of LVOT obstruction (e.g., aortomitral 
angle, LVOT size, etc.).  
10. Evidence of an acute myocardial infarction ≤ 1 month (30 days) before enrollment. 
11. Any therapeutic invasive cardiac procedure resulting in a permanent implant that is 
performed within 30 days prior to the index procedure.  Implantation of a permanent 
pacemaker (PPM) or implantable cardioverter defibrillator (ICD) is not considered an 
exclusion. 
12. Patients with planned concomitant surgical or transcatheter ablation for atrial fibrillation. 
13. Leukopenia (white blood count < 3000 cell/mL), anemia (hemoglobin < 9 g/dL), 
thrombocytopenia (blood platelet count < 50,000 cell/mL), history of bleeding diathesis 
or coagulopathy, or hypercoagulable states. 
14. Untreated clinically significant coronary artery disease requiring revascularization. 
15. Hemodynamic or respiratory instability requiring inotropic support, mechanical 
ventilation, or mechanical heart assistance within 30 days of enrollment. 
16. Emergency intervention/surgical procedures within one month (30 days) prior to the 
procedure. 
17. Any planned surgical, percutaneous coronary, or peripheral procedure to be performed 
within the 30-day follow-up from the procedure. 
18. Hypertrophic cardiomyopathy with obstruction (HOCM). 
19. Left ventricular ejection fraction (LVEF) < 30%. 
20. Cardiac imaging evidence of intracardiac mass, thrombus, or vegetation. 

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21. Inability to tolerate or condition precluding treatment with antithrombotic/anticoagulation 
therapy during or after the valve implant procedure. 
22. Absolute contraindications or allergy to iodinated contrast that cannot be adequately 
treated with premedication. 
23. Stroke or transient ischemic attack (TIA) within 90 days of enrollment. 
24. Symptomatic carotid or vertebral artery disease or successful treatment of carotid 
stenosis within 30 days of enrollment. 
25. Renal insufficiency (eGFR < 30 ml/min per the Cockcroft-Gault formula) and/or renal 
replacement therapy at the time of screening. 
26. Active bacterial endocarditis within 6 months (180 days) of the procedure. 
27. Patient refuses blood products. 
28. Estimated life expectancy < 24 months. 
29. Currently participating in an investigational drug or another device study.  Note: Clinical 
trials requiring extended follow-up for products that were investigational, but have since 
become commercially available, are not considered investigational trials. 
30. Positive urine or serum pregnancy test in female subjects of childbearing potential. 
 
8 STUDY PROCEDURES 
8.1 
Screening Period 
The screening period is designed to obtain patient consent, determine patient eligibility for the 
study, and to submit the presentation for case review.  The Screening Visit procedures will occur 
within the 30 days prior to the valve implant procedure, unless otherwise noted below.  All patients 
that sign an informed consent will be entered into the electronic database (EDC) and be assigned 
a Subject ID.  All assessments performed will be entered into EDC. 
Patients that have signed the informed consent and do not meet the inclusion/exclusion criteria 
in Sections 7.1 and 7.2 will be considered a Screen Failure (SF).  All assessments performed and 
the inclusion or exclusion criteria that was not met will be entered into EDC. 
The patient status will be considered ‘Discontinued’ if the following occur during the screening 
period: 
• 
The patient withdraws consent or expires prior to or after the Case Review 
• 
The patient completes all of the screening procedures, including Case Review call, and 
Case Review is not approved 
All assessments performed and the reason for patient discontinuation will be entered into EDC 
and the Exit form will be completed. 
The following information will be collected during the screening period: 

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Consent: 
• 
Patient informed consent completion (Section 8.1.1) 
Operability: 
• 
STS Risk Score 
Other Assessments: 
• 
Logistic EuroSCORE 
• 
EuroSCORE II 
Systems: 
• 
Medical history, demographics and physical assessment  
• 
Medications: anti-thrombotics/anticoagulants and HMG coA reductase inhibitors 
Cardiopulmonary: 
• 
Canadian Cardiovascular Society (CCS) status of angina 
• 
12-lead ECG 
• 
NYHA Class 
• 
Comprehensive transthoracic echocardiogram (TTE), including, but not limited to, 
assessment of mitral valve gradients (mean and peak), areas, indices, degree of 
regurgitation, left and/or right ventricle systolic function (global and segmental).  
Qualifying echocardiogram (echo) must be performed within 90 days prior to enrollment. 
• 
Cardiac imaging (CT) with 3D reconstruction to verify failing prosthesis dimensions and 
to assess aortomitral annular angle and risk of LVOT obstruction.  Qualifying cardiac 
imaging must be performed within 1 year prior to enrollment, unless clinically 
contraindicated. 
• 
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. 
• 
SYNTAX Score for significant native coronary artery disease (CAD) 
• 
Pulmonary Function Test for patients with a history of lung disease 
Neurological Assessments: 
• 
Mini Mental State Examination (MMSE) 
• 
National Institutes of Health Stroke Scale (NIHSS) 
• 
Modified Rankin Scale (mRS) 
Functional Assessments: 

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• 
Six Minute Walk Test (6MWT) 
• 
Frailty Index (5 Meter Walk Test [5MWT], grip strength, Activities of Daily Living (ADL), 
and Albumin laboratory) 
• 
Quality of Life Assessments 
o KCCQ 
o EQ-5D-5L 
o SF-36 
Clinical Laboratory Tests: 
• 
White Blood Count (WBC), Hemoglobin (Hgb), and platelet count 
• 
Prothrombin time (PT) or International Normalized Ratio (INR) 
• 
Creatinine 
• 
Estimated glomerular filtration rate (eGFR) 
• 
Albumin (as part of Frailty Index) 
• 
Total Bilirubin 
• 
Aspartate aminotransferase (AST)/Alanine aminotransaminase (ALT) (required for 
patients with chronic liver disease) 
• 
B-type natriuretic peptide (BNP) 
• 
Urine or serum pregnancy test for all females of childbearing potential 
Eligibility Review: 
• 
Case Review (Section 8.1.2) 
 
 
 

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8.1.1 Informed Consent 
The study investigator(s) and support staff will approach patients with a failing surgically implanted 
bioprosthetic valve demonstrating moderate mitral stenosis and/or ≥ moderate insufficiency 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 patients are interested in 
participating in the study, the study patient will sign the IRB/EC approved informed consent form 
prior to any study specific procedures are performed.  All patients consented should be entered 
into the study’s EDC system. 
8.1.2 Case Review 
The Case Review Board is a select review committee comprised of Investigators who are 
participating in the trial.  The role of the Case Review Board is to review submitted cases to 
determine if the patient is an appropriate candidate for the trial, with a focus on valve sizing, 
appropriate vascular access, and any relevant clinical factors impacting enrollment eligibility (e.g., 
risk of LVOT obstruction, etc.).  Before a case is submitted for review, the site Principal 
Investigator and Heart Team will screen the patient for fundamental enrollment criteria.  Once 
fully screened and deemed an appropriate candidate, the site will submit the case for review and 
approval consideration by the Case Review Board.  Once a case is approved by the Case Review 
Board, the patient will be eligible for the implant procedure.  The Sponsor will maintain a record 
of the case presentation and case approval notes. 
8.2 Enrollment 
Once all screening procedures have been completed, all inclusion/exclusion criteria have been 
confirmed and the Case Review has been completed and approved, the patient is considered to 
be enrolled in the study. 
If the patient has been enrolled and the patient withdraws consent prior to the procedure start, 
the patient will be considered discontinued.  All assessments performed and the reason for 
withdrawal will be entered into EDC and the Exit form will be completed. 
8.3 Procedure (Day 0) 
Every effort should be made to have the valve implant procedure performed within 14 days of 
enrollment.  The date of the valve implant procedure is considered Day 0. 
The valve implant procedure will be considered to have started when the first interventional 
access related puncture or skin incision occurs.  Performance of TEE does not by itself constitute 
start of procedure. 
Day 0 will be used to schedule all subsequent visits and calculate visit windows.  Patients who 
receive the THV implant will continue in the study and complete the study through year 5 
according to the visits and events described in Section 8.0 and Schedule of Procedures. 

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Day 0 valve implant procedure assessments will include the following: 
Systems: 
• 
Medications: anti-thrombotics/anticoagulants and HMG coA reductase inhibitors 
• 
Adverse event assessment 
Cardiopulmonary: 
• 
Ventriculogram, transthoracic echocardiogram (TTE), or transesophageal 
echocardiogram (TEE) (TEE is required for transseptal procedures) 
Procedural imaging (i.e., TEE and fluoroscopy) should be submitted to the Sponsor after the 
procedure. 
If the valve implant is aborted (prior to or after the start of the valve implant procedure), the Day 
0 visit may be re-scheduled if the patient continues to meet all inclusion/exclusion criteria. 
8.3.1 Device Preparation 
A detailed description of device preparation and required equipment is supplied in the IFU. 
8.3.2 Procedure Recommendations 
Table 3 outlines the recommended anticoagulation/antithrombotic regimen.  The categories were 
developed by The PARTNER II Trial Patient and Procedure Management Steering Committee.  
There are no current validated guidelines in this specific study population, however, the literature 
was surveyed and used as guidance for the following proposed guidelines.37 
NOTE: The CHAD score only applied to patients in AF and had not been validated in non-AF 
patient populations; therefore, the CHAD score reference was used as one among many 
guidelines to establish the risk stratification for intensity of anticoagulation regimen. 
 
 

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Table 3.  Recommended Anticoagulation/Antithrombotic Regimen 
Pre Valve Implant Procedure 
• Aspirin 81-100 mg QD 
• Patients with BMS within one month or DES within 12 months should be continued on 
Clopidogrel/prasugrel prior to their implant procedure 
• Patients in atrial fibrillation on warfarin should be bridged with LMW or UF heparin prior to the implant 
procedure 
• Patients with persistent or paroxysmal atrial fibrillation, not on anti-coagulation, will not be required to 
have a TEE to rule out LA thrombus prior to implant procedure.  If intra- procedural TEE during the 
implant reveals thrombus, the implant procedure will be aborted and delayed until the patient has been 
on warfarin or dabigatran for 30 days.  Note: thrombus must be eliminated in order to proceed with the 
implant procedure. 
• In patients undergoing an implant procedure, 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 ACT> 300 sec 
• The recommended dose of protamine after access closure is half of the full dose 
Post-Procedure* 
• Heparin use as a bridging agent to warfarin therapy is recommended until the INR stabilizes at 2 or 
greater, then continue with oral anticoagulants only 
• ASA 81 mg qd 
• In high risk patients, warfarin and Plavix is recommended when the INR ≥ 2; discontinue ASA 
• Warfarin for at least 6 months post-implant procedure (may be discontinued after 6 months if no AF) 
• Clopidogrel, 75 mg qd, if warfarin therapy has been discontinued 
*Dual antiplatelet therapy (e.g., clopidogrel and aspirin) is not widely recommended, but may be considered on an individual basis if 
indicated for a given patient.  The anticoagulant and antiplatelet regimen past the 6-month follow up visit will be determined at the 
Investigator’s discretion. 
AF=Atrial fibrillation. 
Note: Any changes to antithrombotic/anticoagulation regimen from study visit to study visit will be noted on the Case Report Form 
(CRF) including reason for change. 
8.3.3 Antibiotic Prophylaxis 
Study patients should be prophylactically treated for endocarditis per the recommendations of the 
American Heart Association. 
8.3.4 Contrast Media 
Careful management of contrast media is required.  Measurement of the contrast used will be 
captured in the CRF. 
8.3.5 Radiation Precautions 
Radiation precautions will be adhered to per institutional standards.  Total procedural radiation 
exposure will be documented on the CRFs in accordance with institutional measures (i.e. total 
procedural fluoroscopy time, dosage, etc.). 

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Radiation exposure of 6-15 mSv is estimated for the Screening CT38.  If a radiation induced skin 
injury is suspected, the Investigator should see the patient at an office visit and should arrange 
for appropriate follow-up care. 
8.4 Post-Procedure 
The post-implant procedure time period is defined as the 48 hours after the patient exits the cath 
lab/ operating room.  Study patients will be continuously monitored clinically, hemodynamically, 
and electrocardiographically during catheterization for all local, systemic side effects and 
complications.  After completion of the implant procedure, all study patients will be monitored per 
institution standard of care.  Subsequent monitoring will also be continued according to 
institutional standard of care. 
The following information will be collected during the Post-Procedure time period: 
Systems: 
• 
Medications: anti-thrombotics/anticoagulants and HMG coA reductase inhibitors 
• 
Adverse event (AE) assessment 
Cardiopulmonary: 
• 
12-lead ECG 
Clinical Laboratory Tests: 
• 
WBC, Hgb, and platelet count 
• 
PT or INR 
• 
Creatinine 
Neurological assessments: 
• 
NIHSS 
8.5 Discharge 
Discharge is the actual date and time the patient is discharged.  For patients discharged within 
48 hours of exiting the cath lab / operating room, it is not required to repeat tests collected during 
the Post-Procedure period that are also required for the discharge visit.  If the patient was 
discharged over a weekend or holiday, the discharge assessments may be completed on the last 
weekday prior to discharge. 
The following information will be collected for study patients within 24 hours of the date and time 
of discharge.  The location the patient will be discharged to should be documented in the EDC 
form. 
Systems: 
• 
Physical assessment including weight, blood pressure, and heart rate 

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• 
Medications: anti-thrombotics/anticoagulants and HMG CoA reductase inhibitors 
• 
AE assessment 
Cardiopulmonary: 
• 
NYHA Class 
• 
TTE (per echo protocol) 
Clinical Laboratory Tests: 
• 
WBC, Hgb, and platelet count 
• 
PT or INR 
• 
Creatinine 
• 
BNP 
Neurological Assessments: 
• 
NIHSS 
8.6 Post-Procedure Follow Up Visits 
8.6.1 30-Day Post-Procedure Visit 
The 30-day post-procedure visit window will be calculated from the Day 0 valve implant date.  The 
visit window is +7 days. 
The following data will be collected for all study patients 30 days post-implant procedure. 
Systems: 
• 
Physical assessment including weight, blood pressure, and heart rate 
• 
Medications: anti-thrombotics/anticoagulants and HMG CoA reductase inhibitors 
• 
AE assessment 
Cardiopulmonary: 
• 
12-lead ECG 
• 
NYHA Class  
• 
TTE (per echo protocol) 
Neurological Assessments: 
• 
MMSE 
• 
NIHSS 
• 
mRS 
Functional Assessments: 

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• 
6MWT 
• 
Quality of Life Questionnaires 
o KCCQ 
o EQ-5D-5L 
o SF-36 
Clinical Laboratory Tests: 
• 
WBC, Hgb, and platelet count 
• 
Creatinine 
• 
BNP 
 
8.6.2 6 -Month Post-Procedure Visit 
The 6-month post-implant procedure visit window will be calculated from the Day 0 visit date.  The 
visit window is +14 days. 
The following data will be collected for all study patients 6 months post-valve implant procedure. 
Systems: 
• 
Physical assessment including weight, blood pressure, and heart rate 
• 
Medications: anti-thrombotics/anticoagulants and HMG CoA reductase inhibitors 
• 
AE assessment 
Cardiopulmonary: 
• 
NYHA Class 
Functional Assessments: 
• 
Quality of Life Questionnaires 
o KCCQ 
o EQ-5D-5L 
o SF-36 
 
8.6.3 12-Month Post-Procedure Visit 
The 12-month post-implant procedure visit window will be calculated from the Day 0 valve implant 
date.  The visit window is +30 days. 
The following data will be collected for all study patients 12-month post-implant procedure. 
Systems: 

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• 
Physical assessment including weight and blood pressure 
• 
Medications: anti-thrombotics/anticoagulants and HMG CoA reductase inhibitors 
• 
AE assessment 
Cardiopulmonary: 
• 
12-lead ECG 
• 
NYHA Class  
• 
TTE (per echo protocol) 
Neurological Assessments: 
• 
MMSE 
Functional Assessments: 
• 
6MWT 
• 
Quality of Life Questionnaires 
o KCCQ 
o EQ-5D-5L 
o SF-36 
 
8.6.4 Years 2 through 10 Annual Post-Procedure Visit 
The yearly post-implant procedure visit window will be calculated from the Day 0 valve implant 
date.  The visit window is +45 days. 
The following data will be collected for all study patient’s years 2 through 10 annually post-
implant procedure visit. 
Systems: 
• 
Physical assessment including weight, blood pressure, and heart rate 
• 
Medications: anti-thrombotics/anticoagulants and HMG CoA reductase inhibitors 
• 
AE assessment 
Cardiopulmonary: 
• 
NYHA Class 
• 
TTE (years 2, 3, 4, 5, 7 and 10 only per echo protocol) 
Functional Assessments: 
• 
Quality of Life Questionnaire 
o KCCQ 

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o SF-36 
 
8.7 Assessment for Leaflet Thrombosis 
In the event that an increase in mean gradient of > 5mm Hg from post-procedure is identified 
OR the patient experiences any of the following AEs during the study, every effort should be 
made to obtain additional imaging (TEE or 4D CT, per local site practice) from the time of the 
event to determine the presence or absence of leaflet thrombosis.  If unable to be obtained at 
the time of the event, imaging should be obtained at the patient’s next scheduled follow up visit. 
• 
Stroke 
• 
TIA 
• 
Other potential embolic event 
• 
Worsening shortness of breath 
 
8.8 
Neurological Assessments 
Every effort should be made to have a neurologist (or neurology fellow) perform the NIHSS and 
mRS assessments.  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 the 
assessments. 
Following the procedure, all subjects should be assessed to determine if there is evidence of 
neurological impairment.  If symptoms of a stroke are suspected, the NIHSS should be performed.  
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 the next protocol-specified visit, the mRS does not need to be repeated. 
8.9 Missed Visits 
Site personnel should make all reasonable efforts to locate and communicate with the subject at 
each visit time point.  For each missed visit, multiple attempts to contact the subject should be 
made and details recorded in the source documentation. 
A patient is not considered lost to follow-up until the full 10 years of follow-up have elapsed. 
8.10 Discontinuation after Entering the Procedure Room 
Every patient should be encouraged to remain in the study until they have completed the protocol 
required follow-up period.  If the patient discontinues prematurely from the study, the reason for 
discontinuation must be documented.  All attempts should be made to have the patient come into 
the clinic for an Exit visit. 

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If the following situations occur, the patient status will be considered ’Discontinued’: 
• 
The patient has entered the cath lab or operating room (procedure room) and an 
inclusion or exclusion criteria failure has been found. 
• 
The patient has entered the procedure room and expires prior to the start of the valve 
implant procedure. 
• 
The patient expires after the procedure has started. 
• 
The patient withdraws consent after the valve implant procedure and prior to the final 
study visit. 
• 
The patient expires after the valve implant procedure and prior to the final study visit. 
If the patient has a THV other than the SAPIEN 3 implanted, the patient status will be considered 
discontinued and the patient will be monitored through Day 30 or until any AEs occurring are 
resolved. 
All assessments performed and the reason for discontinuation will be entered into EDC and Exit 
form completed. 
8.11 Death Registries 
In the event of a patient lost to follow-up or early withdrawal, Edwards may request the site to 
search the Social Security Death Index and/or other death registries.  If patient death is confirmed, 
Edwards may request the site to obtain the death certificate. 
 
 

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Table 4.  Schedule of Procedures 
 
Screening 
Procedure 
(Implant) 
Post-
Procedure 
Discharge 
30D 
6M 
12M 
2-10Y 
Visit Window (days) 
-30 d 
0 
 
 
+7 
+14 
+30 
+45 
Physical Assessment 
 
 
 
 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
 
Medical History & Demographics 
X 
 
 
 
 
 
 
 
Physical Assessment 
X 
 
 
X 
X 
X 
X 
X 
CCS Angina 
X 
 
 
 
 
 
 
 
NYHA Classification 
X 
 
 
X 
X 
X 
X 
X 
MMSE 
X 
 
 
 
X 
 
X 
 
STS Risk Score 
X 
 
 
 
 
 
 
 
Logistic EuroSCORE 
X 
 
 
 
 
 
 
 
EuroSCORE II 
X 
 
 
 
 
 
 
 
SYNTAX Score 
X 
 
 
 
 
 
 
 
Medications 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event Assessment 
 
X 
X 
X 
X 
X 
X 
X 
NIHSS a 
X 
 
X b 
X b 
X 
 
 
 
Modified Rankin Scale a,c 
X 
 
 
 
X 
 
 
 
6 Minute Walk Test 
X 
 
 
 
X 
 
X 
 
Frailty Index i 
X 
 
 
 
 
 
 
 
Laboratory Measurements 
 
 
 
 
 
 
 
 
WBC, Hgb, Platelet Count 
X 
 
X 
X 
X 
 
 
 
PT or INR 
X 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
eGFR 
X 
 
 
 
 
 
 
 
Creatinine 
X 
 
X 
X 
X 
 
 
 
Albumin, Total Bilirubin 
X 
 
 
 
 
 
 
 
AST/ALT j 
X 
 
 
 
 
 
 
 
BNP 
X 
 
 
X 
X 
 
 
 
Pregnancy test, if female of 
childbearing potential 
X 
 
 
 
 
 
 
 
Non-Invasive Tests 
 
 
 
 
 
 
 
 
Pulmonary Function Test (PFT) m 
X 
 
 
 
 
 
 
 
ECG 
X 
 
X 
 
X 
 
X 
 
Echocardiogram (TTE) 
X e 
X h 
 
X 
X 
 
X 
X l 
Final Eligibility Review 
 
 
 
 
 
 
 
 
Case Review g 
X 
 
 
 
 
 
 
 

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Screening 
Procedure 
(Implant) 
Post-
Procedure 
Discharge 
30D 
6M 
12M 
2-10Y 
Visit Window (days) 
-30 d 
0 
 
 
+7 
+14 
+30 
+45 
Invasive Tests 
 
 
 
 
 
 
 
 
3D Cardiac imaging (CT) 
X f 
 
 
 
 
 
 
 
TEE or 4D CT 
 
 
 
 
X k 
X k 
X k 
X k 
Valve implant procedure 
 
X 
 
 
 
 
 
 
Assessment of CAD n 
X 
 
 
 
 
 
 
 
Ventriculogram (mitral position) h 
 
X 
 
 
 
 
 
 
Quality-of-Life Assessments 
 
 
 
 
 
 
 
 
KCCQ 
X 
 
 
 
X 
X 
X 
X 
EQ-5D-5L 
X 
 
 
 
X 
X 
X 
 
SF-36 
X 
 
 
 
X 
X 
X 
X 
a. 
Every effort should be made to have a neurologist (or neurology fellow) perform the NIHSS and mRS assessments.  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 the assessments. 
b. 
Following the procedure, all subjects should be assessed to determine if there is evidence of neurological impairment.  If 
symptoms of a stroke are suspected, the NIHSS should be performed. 
c. 
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 the next protocol-specified visit, the mRS does not need to be 
repeated. 
d. 
Screening procedures will be completed within 30 days prior to the valve implant procedure unless otherwise noted.  
e. 
Qualifying echocardiogram must have been performed within the 90 days prior to enrollment. 
f. 
All patients will have cardiac imaging at the screening visit. 
g. 
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. 
h. 
Ventriculogram, TTE, or TEE on date of valve implant procedure.  TEE is required for transseptal procedures 
i. 
Frailty Index includes activities of daily living (ADLs), 5 meter walk test (5MWT), grip strength, and albumin laboratory. 
j. 
Only required for patients with chronic liver disease. 
k. 
To determine the presence of leaflet thrombosis if clinically indicated and TEE or 4D CT imaging is unable to be obtained at the 
time of the event. 
l. 
Echocardiograms to be obtained years 2, 3, 4, 5, 7 and 10. 
m. 
Only for patients with a history of lung disease 
n. 
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. 
 
 

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9 ADVERSE EVENTS 
9.1 Definitions 
Adverse Event 
An Adverse Event (AE) is any untoward medical occurrence, unintended disease or injury or 
untoward clinical signs (including abnormal laboratory findings) in patients, users or other 
persons, whether or not related to the investigational medical device. 
Adverse events may be volunteered by patients, elicited by the Investigator or designee, the CEC, 
safety team, monitoring team, or collected via observation by the Investigator.  All AEs will be 
assessed by the Investigator who will determine whether or not the event is related to the device 
and/or implant procedure, and whether or not the event meets seriousness criteria.  If it is 
determined that an AE has occurred, the investigator should obtain all the information required to 
complete the AE CRF. 
In addition, patients will be advised to contact the investigator, and/or study coordinator if any 
significant adverse events occur between study visits. 
All clinically significant AEs will be reported by the Investigator and reviewed by the Sponsor in 
compliance with applicable regulations as indicated below Section 9.2. 
Serious Adverse Event 
An Adverse Event is considered serious if the event: 
• 
Leads to death; 
• 
Leads to a serious deterioration in the health of the study patient that: 
o Results in life-threatening illness or injury; 
o Results in a permanent impairment of a body structure or a body function; 
o Requires inpatient hospitalization or prolongation of existing hospitalization; 
o Results in medical or surgical intervention to prevent 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 patient and require immediate medical or surgical intervention to 
prevent one of the aforementioned outcomes. 
Death should not be recorded as an adverse event but should only be reflected as an outcome to 
another specific AE. 

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Anticipated Adverse Event 
An anticipated adverse event is identified as a potential risk associated with the overall procedure 
or investigational device as stated in the IFU. 
Unanticipated Adverse Device Effect 
An Unanticipated Adverse Device Effect (UADE) is any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with a device, if that effect, 
problem, or death was not previously identified in nature, severity, or degree of incidence in the 
investigational plan or application (including a supplementary plan or application), or any other 
unanticipated serious problem associated with a device that  relates to the rights, safety or welfare 
of patients. 
The Investigator shall submit to the Sponsor and to the reviewing IRB/EC a report of any UADE 
occurring during an investigation as soon as possible, but in no event later than 10 days after the 
investigator first learns of the effect. 
All adverse events assessed as UADEs must be followed until resolution or until a stable clinical 
endpoint is reached.  All required treatments and outcomes of the UADE must be recorded. 
Edwards will notify FDA as well as all participating clinical investigators and IRBs/ECs of all 
UADEs that occur during this study within 10 working days after becoming aware of the event.  
Investigators are responsible for reviewing information received about UADEs. 
Device Malfunctions 
A device malfunction is defined as the failure of a device to meet its performance specifications 
or otherwise perform as intended.  Performance specifications include all claims made in the 
labeling for the device.  The intended performance of a device refers to the intended use for which 
the device is labeled or marketed. 
Adverse Device Effect 
An Adverse Device Effect (ADE) is an AE related to the use of a medical device. 
NOTE 1:  This includes any AE resulting from insufficiencies or inadequacies in the instructions for use, the 
deployment, 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 use error or intentional abnormal use of the medical 
device. 
Serious Adverse Device Effect 
A Serious Adverse Device Effect (SADE) is an ADE that has resulted in any of the consequences 
characteristic of a SAE. 

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Unanticipated Serious Adverse Device Effect 
An 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 
A 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. 
9.2 Causality of AEs 
For each AE, the Investigator will determine whether the event is related to the device and/or the 
implant procedure, and whether the event meets the definition of a SAE. 
The causal relationship of the event to the device and the implant procedure will be categorized 
as follows: 
• 
Not Related: There is no relationship between the event and the device or procedure 
• 
Unlikely Related: The relationship with the use of the device seems not relevant and/or 
the event can be reasonably explained by another cause 
• 
Possibly Related: There is a possibility of relationship between the event and the 
device or procedure (temporal sequence; no contradicting evidence) 
• 
Related: The event is related or most likely associated with the device or procedure 
(relevant temporal sequence; event abates upon device application completion/removal; 
no other reasonable explanation) 
 
9.3 AE Reporting Requirements 
All relevant AEs will be captured from the time of enrollment until the study patient’s participation 
has ended (i.e. completion of study or withdrawal of consent). 
Adverse events must be followed until resolution, stabilization or study completion.  The AE CRFs 
should be completed promptly: 

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US site reporting timelines:  All AEs should be reported within 7 business days of becoming 
aware of the event.  Device malfunctions should be reported within 10 days of the site becoming 
aware of the event. 
OUS site reporting timelines:  All SAEs and device deficiencies must be reported to Edwards 
immediately, but no later than 3 calendar days after site study personnel’s awareness of the event.  
Other AEs must be reported to Edwards as soon as possible. 
In the event that the EDC system is not in service, a paper copy of the AE Case Report Form 
(CRF) must be faxed or emailed to Sponsor THV Medical Safety at (949) 809-2933 or emailed 
to THV_Safety@edwards.com.  At the time of initial notification, the following minimal 
information must be provided: 
• 
Study site 
• 
Patient ID 
• 
Adverse event description 
• 
Causal relationship to device and implant procedure 
• 
Aware date 
The site must provide a copy of supporting documentation (example: admission H&P, implant 
procedure reports, anesthesia records, discharge summary, echocardiogram and ECG reports, 
laboratory results, etc.) for all SAEs and UADEs to Edwards Lifesciences (or designee).  Source 
documentation may be requested by the Edwards Medical Safety Officer for other AEs in order 
to verify that events are being assessed appropriately. 
Enrolling sites must provide to the Sponsor at a minimum an admission history and physical, index 
procedure report and discharge from index hospitalization along with relevant echocardiographic 
reports.  This will be done irrespective of subject having any AE/SAE.. 
All AEs and SAEs regardless of device/procedure relationship must be reported over the 12-
month period following the THV implant procedure.  Reportable AEs after year 1 through year 
10 or study exit include only the following events: 
• 
All study endpoint events regardless of time of onset (e.g., stroke at 3 years) 
• 
All AEs that are assessed or suspected to be device or implant procedure related 
• 
All AEs that meet the criteria for serious adverse event irrespective of device or implant 
procedure relationship 
• 
All AEs that result in emergency department/observation unit visit 
• 
All AEs considered to be an Unanticipated Adverse Device Effect 
The site Principal Investigator is responsible for informing the IRB/EC of SAEs, UADE and/or AEs 
as required.  A copy of this report should be provided to the Sponsor (or designee). 

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9.3.1 Events that do not Require Reporting to the Sponsor 
For purposes of this study, the following events will not be required to be reported as adverse 
events to the Sponsor (unless required by local regulations), because they are normally 
expected to occur in conjunction with transcatheter valve implantation or are associated with 
customary, standard care of patients 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). 
• 
Dizziness: Imprecise term commonly used to describe various symptoms such as 
faintness, giddiness, imbalance, lightheadedness, unsteadiness or vertigo without signs 
of TIA or stroke. 
• 
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 (HIT) 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. 
 
9.4 Pre-existing conditions 
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 of the pre-existing medical condition or 
symptoms due to the device, implant procedure, or study related procedures, then an AE must 
be recorded. 
 
 

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9.5 Sponsor Assessment of AEs 
All AEs will be reviewed by a Medical Safety Officer.  Each AE will be assessed for the 
following: 
• 
Relationship to the study device and/or implant procedure 
• 
Anticipated/Unanticipated (based on the list of potential risks provided in Section 10.2 of 
this protocol and the applicable IFU) 
• 
Seriousness (based on SAE criteria) 
 
10 RISKS AND BENEFIT ANALYSIS 
There are potential risks associated with transcatheter valve replacement.  There are risks related 
to the overall procedures (complications associated with standard cardiac catheterization, local 
and/or general anesthesia) as well as additional possible risks uniquely associated with the use 
of the study valve and its delivery systems. 
10.1 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 THV are not known at the present time.  Alternative treatments 
include surgical MVR and medical management. 
Implantation of the transcatheter heart valve may result in improved valvular function, acute 
alleviation of symptoms related to mitral stenosis, and improved quality of life in patients with a 
failing surgical bioprosthetic valve. 
 

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10.2 Potential Risks 
There are potential risks associated with THV implantation.  There are risks related to the overall 
procedures (complications associated with standard cardiac catheterization, balloon 
valvuloplasty, local and/or general anesthesia) as well as additional possible risks uniquely 
associated with the use of the study valve and its delivery systems. 
Potential risks associated with anesthesia and interventional procedures include but are not 
limited to: 
• 
Abnormal lab values (including 
electrolyte imbalance) 
• 
Allergic reaction to anesthesia, 
contrast media, or device materials 
• 
Anemia 
• 
Angina 
• 
Arrhythmia 
• 
AV fistula or pseudoaneurysm 
• 
Bleeding 
• 
Cardiovascular injury including 
perforation or damage of vessels, 
ventricle, atrium, myocardium or 
valvular structures that may require 
intervention 
• 
Conduction system defect which 
may require a permanent 
pacemaker 
• 
Death 
• 
Embolization including air, calcific 
valve material, or thrombus 
• 
Exercise intolerance or weakness 
• 
Fever 
• 
Heart failure 
• 
Heart murmur 
• 
Hematoma 
• 
Hemorrhage requiring transfusion or 
intervention 
• 
Hypertension or hypotension 
• 
Infection including septicemia and 
endocarditis 
• 
Inflammation 
• 
Ischemia or nerve injury 
• 
Myocardial infarction 
• 
Mediastinitis 
• 
Mediastinal bleeding 
• 
Pain or changes at the access site 
• 
Paralysis 
• 
Pericardial effusion or cardiac 
tamponade 
• 
Permanent disability 
• 
Pleural effusion 
• 
Pulmonary edema 
• 
Renal insufficiency or renal failure 
• 
Reoperation 
• 
Respiratory insufficiency or 
respiratory failure 
• 
Restenosis 
• 
Retroperitoneal bleed 
• 
Stroke/transient ischemic attack, 
clusters or neurological deficit 
• 
Syncope 

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In addition to the risks listed above, additional potential risks specifically associated with the use 
of the SAPIEN 3 THV, the delivery systems, and/or accessories include, but may not be limited 
to, the following: 
• 
Cardiac arrest 
• 
Cardiac failure or low cardiac output 
• 
Cardiogenic shock 
• 
Device degeneration 
• 
Device embolization 
• 
Device explants 
• 
Device migration or malposition 
requiring intervention 
• 
Device thrombosis requiring 
intervention 
• 
Emergency cardiac surgery 
• 
Hemolysis 
• 
Left ventricular outflow tract 
obstruction 
• 
Mechanical failure of delivery 
system, and/or accessories 
• 
Non-emergent reoperation 
• 
Nonstructural dysfunction 
• 
Paravalvular or transvalvular leak 
• 
Structural valve deterioration (wear, 
fracture, calcification, leaflet 
tear/tearing from the stent posts, 
leaflet retraction, suture line 
disruption of components of a 
prosthetic valve, thickening, 
stenosis) 
• 
Transvalvular flow disturbance 
• 
Valve deployment in unintended 
location 
• 
Valve regurgitation 
• 
Valve stenosis 
• 
Valve thrombosis 
 
10.2.1 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. 
Additionally, efforts will be made to minimize risks through site/investigator selection and 
management.  First, site and investigator selection criteria are 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.  Second, the trial management 
structure is designed to provide disciplined oversight of the trial activities including close 
monitoring of site and personnel performance and also support opportunities for investigators and 
study personnel to share best practices through investigator meetings, ongoing education and 
case reviews. 
The SAPIEN 3 THV represents a third generation THV for Edwards Lifesciences and was 
developed with the experience from the first and second generation SAPIEN THVs.  The SAPIEN 
3 System has undergone extensive clinical testing in the aortic position and is commercially 

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available for TAVR, including for use in high surgical risk patients with a failing surgical aortic or 
mitral bioprosthesis, in the US and countries that honor the CE mark. 
11 STATISTICAL ANALYSIS 
11.1 Sample Size Calculations 
The sample size for the study is determined empirically. 
11.2 Analysis Populations 
The All Treated (AT) population will be the primary population for trial endpoint analysis and will 
consist of all patients for whom the index procedure is begun, whether or not the index procedure 
is completed.  If multiple procedures are attempted for the study valve implant, the last procedure 
with the study valve successfully deployed will be considered the index procedure and the date 
of the index procedure will be used for determining all follow-up visits and related assessments.  
The Valve Implant (VI) population is a subset of the AT population consisting of all patients who 
receive and retain the intended valve during the index procedure. 
11.3 Timing 
• 
For AT analyses the index procedure date will be day 0. 
• 
Time to event will be computed by subtracting the event date minus the index procedure 
date (day 0).  For example, if the procedure occurs on January 1, and the patient dies on 
January 31, the death will be considered a 30-day death for analysis. 
• 
The timing for all visits will be based on the index procedure date.  If the patient never 
receives the procedure, the patient won’t be included in AT population and the 30-day 
visit will never be due; All visits for such patients will be based on the enrollment date. 
• 
In analysis of time-dependent variables, one year is defined as 365.25 days, and one 
month as 30.4375 (= 365.25/12) days. 
 
11.4 Primary Endpoint Analysis 
Non-hierarchical composite endpoint of all-cause mortality and stroke at 1-year post-procedure 
will be summarized using a Kaplan-Meier (KM) method.  All-cause mortality and stroke will be 
adjudicated by the CEC. 
11.5 Secondary Endpoints 
Each of the four secondary endpoints with statistical inference for labeling will be compared to 
baseline measurements.  To keep overall type I error of 0.05, a gatekeeping method39 will be 
applied for multiplicity adjustment.  The four secondary endpoints will be evaluated in the 
hierarchical order shown as in Section 6.  Each endpoint will be tested using a two-sided t-test at 
alpha = 0.05.  If any of the endpoints does not achieve statistical significance at alpha = 0.05, the 

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lower numbered endpoints in the list will not be considered for this purpose.  Descriptive summary 
will be provided for each endpoint regardless if the statistical test is significant or not. 
The rest of the secondary endpoints will be summarized descriptively, no statistical test will be 
performed.  For categorical variables, the descriptive statistics will include counts and 
percentages.  For the continuous endpoints, the descriptive statistics will include mean, standard 
deviation, medium, and range.  For time to event endpoints, descriptive statistics will include 
number of patients at risk, number of patients with events and KM rate. 
11.6 Additional Analyses 
• 
Baseline data will be reported by summary statistics separately. 
• 
The various procedural variables will be reported by summary statistics. 
• 
Visit compliance data will be presented. 
• 
A listing of the additional imaging (TEE or 4D CT, per local site practice) data which 
determines the presence or absence of leaflet thrombosis will be provided. 
 
11.7 General Statistical Methodology 
11.7.1 Time Dependent Variables 
Time-dependent variables will be analyzed using the Kaplan-Meier algorithm, with standard errors 
computed by Greenwood’s formula.  The number of patients-at-risk will be computed at exact 
time points specified, without reference to any nominal follow-up windows. 
11.7.2 Continuous and Ordinal Variables 
• 
For continuous variables, summary statistics will include means, standard deviations, 
medians and range. 
• 
For ordinal variables, summary statistics will include medians and quartiles; means of 
quantified ordered classes will also be presented when appropriate. 
• 
NYHA and regurgitation will be considered as ordinal variables.  Group counts and 
percentages will be presented for these variables. 
 
11.7.3 Categorical Variables 
• 
For categorical variables, summary statistics will include counts and percentages. 
 

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11.7.4 Missing Data 
• 
Missing variables will not be imputed for planned analyses, except where otherwise 
specified in the Statistical Analysis Plan (SAP) 
 
11.7.5 Adverse Event Analysis 
• 
Adverse event analysis will involve both site and CEC reporting. 
o Where events have been adjudicated by the CEC, those adjudications will be used in 
preference to site reports. 
o Where site events are analyzed, the MedDRA coding will also be used.  
• 
Adverse events to be analyzed include the composites involved in the primary and 
secondary endpoints, as well as all individual events contained in these composites.  All 
these events will be adjudicated by the CEC and used for analyses. 
• 
Adverse event tables will include counts of events, patients with event, and estimated 
event rates at the specific time point of interest. 
 
Adverse event data occurring past 30 days will be presented in the first clinical study 
report for the PMA as counts of events and patients with event.  No formal analyses will 
be performed for such data. 
 
11.7.6 Periodic Analyses 
Periodic analyses may be performed during the trial to the extent required by the appropriate 
regulatory authorities and the DSMB. 
Other than the required reports mentioned above, there will be no reporting of trial outcome data 
prior to the 30-day analysis close date. 
11.7.7 Quality of Life Questionnaires 
Quality of life questionnaires will be scored according to algorithms provided by the vendor.  The 
various summary scores produced by the algorithms will be analyzed as continuous variables. 
11.7.8 General Specifications 
• 
Whenever applicable, confidence limits will be two sided, using alpha = 0.05. 
• 
Unless otherwise specified, the precise form of each algorithm will be the default of SAS, 
using the latest release installed at Edwards at the time of analysis.  This will be version 
9.3 or later. 

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• 
Various CRFs will contain comment fields.  Data in these fields will not be analyzed, but 
listings will be provided for internal use on request. 
 
12 STUDY ADMINISTRATION 
12.1 General Study Organization 
Edwards Lifesciences is the Study Sponsor and has the overall responsibility for the conduct of 
the study, including assurance that the study meets the regulatory requirements of the appropriate 
regulatory bodies. 
Edwards Lifesciences will be responsible for obtaining IDE approval for the study, selecting 
investigators, ensuring that sites have IRB/EC approval prior to investigational device shipment, 
and conducting clinical site monitoring to ensure that patients are being properly consented and 
the study is being conducted according to the protocol. 
As appropriate, Edwards Lifesciences will submit changes in the Investigational Plan to the FDA 
and Investigators to obtain IRB/EC re-approval. 
Edwards Lifesciences will maintain copies of correspondence, data, shipment of devices, adverse 
device effects and other records related to the clinical trial as appropriate. 
Edwards Lifesciences will submit all reports required by the FDA as identified in 21 Code of 
Federal Regulations (CFR) 812.150(B).  This includes UADEs, withdrawal of IRB/EC approval, 
current investigators list, annual progress reports, recall information, final reports and protocol 
violations. 
12.2 Data Safety Monitoring Board (DSMB) 
A Data Safety Monitoring Board (DSMB) will monitor all AEs and SAEs to provide safety oversight.  
DSMB members will not be involved in the study and have no conflict of interest.  At least one 
member will be a cardiothoracic surgeon with specific expertise in mitral stenosis.  DSMB 
activities, including stopping rules for early termination, will be defined in the DSMB Charter. 
12.3 Clinical Event Adjudication Committee (CEC) 
The Clinical Events Committee (CEC) will adjudicate endpoint events and provide assessment of 
SAEs and device/procedure relatedness.  The CEC will include cardiologists and cardiothoracic 
surgeons with experience in the field of mitral stenosis who are not involved in the study and have 
no conflict of interest.  CEC activities will be defined in the CEC Charter. 

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12.4 Study Procedures 
12.4.1 Echocardiogram 
Study patients will receive an echocardiogram at the visits specified in Section 8.0.  A central 
imaging core lab will be established to independently review and analyze echocardiographic 
images.  A standardized protocol for acquiring images will be developed by the core lab and be 
provided to the clinical sites prior to study initiation.  Sites will be trained on acquiring images prior 
to study initiation. 
12.4.2 Computed Tomography (CT) 
All study patients will have a screening CT as referenced in Section 8.0.  Sites will be trained on 
acquiring images prior to study initiation.  In addition, all CTs will be independently analyzed by a 
CT/angiographic core lab. 
12.4.3 Quality of Life Questionnaires 
Investigational sites will be provided with paper QoL questionnaires (KCCQ, EQ-5D-5L, and the 
SF-36).  Patient questionnaires will be IRB/EC approved prior to patient administration. 
Investigational staff will administer patient questionnaires to study patients.  Patients will be 
instructed to complete each questionnaire at visits specified in Section 8.0.  The patient will be 
instructed by the investigational staff to sign and date the paper questionnaire once the 
questionnaire is completed.  Patients will be instructed by the investigational staff not to change 
questionnaire answers once the questionnaire has been completed.  Investigational sites should 
retain the completed questionnaire in the patients’ source documents.  Site staff will enter data 
collected from the completed patient questionnaire into the EDC. 
The patient level summary scores will be computed by the Edwards Biostatistics group, and these 
scores will be used in evaluating protocol endpoints. 
Quality of life will be measured through standard surveys: 
• 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is an assessment of disability 
and quality of life impairment due to congestive heart failure. 
• 
EQ-5D-5L is a standardized questionnaire for describing and valuing patients’ health-
related quality of life for clinical and economic appraisal. 
• 
The SF- 36 is a generic health status instrument and rating scale that allows mapping of 
health status to population-level utility weights.  This is an important metric for cost- 
effectiveness analysis. 
 

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12.4.4 Image Management 
A image transfer vendor will be established to receive, maintain, and provide cardiac images 
(echocardiogram, fluoroscopy and CT) to the appropriate core lab for analysis. 
Instructions for image upload will be provided to investigative staff prior to study initiation.  
Investigative staff should make every reasonable effort to upload procedural images to the image 
transfer vendor within 1 business day of acquisition.  All other images should be uploaded within 
5 business days of image acquisition.  Any unscheduled imaging performed related to the safety 
or performance of the device should also be uploaded. 
12.4.5 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. 
12.5 Training 
To ensure proper device usage, uniform data collection, and protocol compliance, training is 
required for relevant study site personnel in accordance to roles outlined in the Delegation of 
Authority (DoA). 
At the beginning of the study, Edwards Lifesciences will provide training to site personnel.  
Training will include review of the instructions for use of the device, study protocol, case review 
process, identification of eligible patients, instructions on in-hospital data collection, standardized 
data collection for core laboratory analysis, methods for soliciting data from alternative sources, 
and regulatory requirements. 
Documentation of site personnel qualification and training should be maintained in the site’s 
clinical trial files and copies collected and forwarded for the Sponsor site file. 
Ongoing training may be provided in one of the following formats by the Sponsor or its designee: 
live training sessions, teleconference, WebEx, online, or read and review.  The Sponsor reserves 
the right to enforce retraining for sites who have demonstrated study or implant procedure 
compliance issues. 
12.6 Device Management 
12.6.1 Study Device 
All SAPIEN 3 products will be supplied by Edwards Lifesciences.  Each SAPIEN 3 THV will have 
a unique identifier which should be recorded in the patient’s medical file as well as on the implant 
card that is given to the patient. 

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12.6.2 Device Storage 
All SAPIEN 3 System components provided for the study should be stored in a secure location 
where only study personnel can access the device for use.  Only physicians identified in the 
Investigator’s Delegation of Authority Log on file at Edwards Lifesciences may implant this device 
in study patients. 
12.6.3 Device Accountability 
The study site will maintain detailed records of the receipt and disposition of all investigational 
devices on the Device Accountability Log (DAL).  Device disposition will be verified by the clinical 
monitor periodically throughout the study.  The Investigator will return unused devices to Edwards 
along with the completed device disposition log at completion of the investigation.  Use of the 
SAPIEN 3 THV and accessories provided for use in the study is prohibited outside of this protocol. 
12.7 Data Management 
Edwards Lifesciences will provide data management through a secure, password protected EDC 
system accessible by sites via the Internet.  A unique Patient ID will be assigned for each patient 
enrolled in the study.  All pertinent data will be entered by the study site and core lab personnel 
into the electronic Case Report Forms (eCRFs). 
Every reasonable effort should be made to complete data entry within 5 business days of data 
collection.  Data review by Edwards Lifesciences 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 then provide his/her electronic signature on the appropriate eCRFs.  Changes 
to data previously submitted to the Sponsor will require a new electronic signature to 
acknowledge/approve the changes. 
12.8 Monitoring Procedures 
All clinical sites will be monitored periodically by Edwards Lifesciences or designee to ensure 
compliance with the protocol and the Investigator’s Agreement and that all study patients have 
been properly consented.  The monitor will ensure that the completed eCRFs match the source 
documents and work with the site to resolve differences through queries or formal action items. 
Edwards Lifesciences will evaluate circumstances where an investigator deviates from the clinical 
protocol and will retain the right to remove either the investigator or the investigational site from 
the study. 
12.9 Auditing 
The study may be subject to a quality assurance audit by Edwards Lifesciences or a designee, 
as well as inspection by appropriate regulatory authorities.  It is important that the Investigator 

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and relevant study 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 Lifesciences as soon as possible. 
12.10 
Record Retention 
All clinical sites will maintain study records for a minimum of two years after marketing for this 
patient population approval is obtained or after the site is notified by Edwards  
Lifesciences that the study has been terminated.  Record retention dates will be provided to all 
parties concerned by Edwards Lifesciences. 
13 ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 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) and in compliance with Title 21 
Code of Federal Regulations (CFR) Parts 11, 50, 54, 56, 812 and Good Clinical Practices.  
Specific country regulations will be fulfilled, as applicable. 
13.2 Institutional Review Board/Ethics Committee 
This protocol, the proposed Informed Consent Form (ICF), other written patient 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 Lifesciences 
before recruitment of patients 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 Lifesciences. 
13.3 Patient Informed Consent 
Edwards Lifesciences will provide a sample ICF to the Investigator to prepare for use at his/her 
site.  The site-specific ICF must be in agreement with current GCP guidelines. 
Edwards Lifesciences must approve the site-specific ICF prior to submission to the IRB/EC.  The 
reviewing IRB/EC must approve the ICF before use at that site. 
Before participating in the clinical trial, each patient must give written Informed Consent after the 
context of the study has been fully explained in a language that is easily understood by the patient.  
The subject must also be given the opportunity to ask questions and have those questions 
answered to his/her satisfaction. 

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A copy of each patient’s signed and self-dated consent form must be maintained by each 
Investigator in a designated clinical trial 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. 
Any modifications to the site-specific ICF must be approved by Edwards Lifesciences and the 
IRB/EC. 
13.4 Confidentiality 
All data used in the analysis and reporting of this evaluation will be without identifiable reference 
to the patient.  Authorized personnel assigned by Edwards Lifesciences will have access to the 
confidential files and will have the right to inspect and copy all records pertinent to this trial.  All 
data used in the analysis and reporting of this evaluation will be without identifiable reference to 
the subject. 
13.5 Investigator Records 
Records to be maintained by the Investigator include, but are not limited to, the following: 
• 
Clinical trial 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 
The following records must be maintained for each subject enrolled in the trial: 
• 
Signed patient informed consent 
• 
All relevant source documentation for study visits and study-related procedures 
• 
Supporting documentation of any adverse events 
 
13.6 Investigator Reports 
Adverse event reporting requirements are discussed in Section 9.2. 
Withdrawal of IRB/EC Approval.  Within 5 working days, the Principal Investigator will report to 
Edwards Lifesciences a withdrawal of approval by the reviewing IRB/EC of the investigator’s part 
of an investigation. 
Informed Consent.  If an investigator uses a device without obtaining informed consent, the 
investigator shall report such use to Edwards Lifesciences and the reviewing IRB/EC within 5 
working days after the use occurs. 
Progress Reports.  The Principal Investigator will submit progress reports on the investigation to 
Edwards Lifesciences and the IRB/EC at least yearly. 

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Final Report.  Upon completion or termination of this Trial, the Principal Investigator must submit 
a final written report to Edwards Lifesciences and the IRB/EC as required by the regulations.  The 
report must be submitted within 3 months of completion or termination of the trial. 
13.7 Amending the Protocol 
This protocol must be followed exactly.  It can be altered only by written amendments made by 
Edwards Lifesciences.  Following appropriate approval by Edwards Lifesciences, the amended 
protocol will be submitted to the required regulatory agencies before being distributed to all 
enrolling sites.  Each site must obtain IRB/EC approval and complete required training (if any, 
and as required by DoA role). 
13.8 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 patient do not require prior approval but must be reported to Edwards Lifesciences 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 Lifesciences as soon as possible, and to the IRB/EC per local guidelines 
and government regulations. 
13.9 Publication Policy 
Publication or presentation of the overall clinical study results and/or site-specific results requires 
prior written approval of Edwards Lifesciences.  If Edwards Lifesciences 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 Lifesciences will provide statistical support for the publication process. 
All corresponding publications will be in accordance with the International Committee of Medical 
Journal Editors Recommendations for the Conduct, Reporting, Editing, and Publication of 
Scholarly Work in Medical Journals (updated December 2015). 
Results from the clinical study will be made available to the public within 24 months after the end 
of data collection or if the study is terminated early. 
 
 

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Appendix A Abbreviations 
Abbreviation  
Full Term 
ACT 
Activated Clotting Time 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AF 
Atrial Fibrillation 
AKI 
Acute Kidney Injury 
ALT 
Alanine Aminotransaminase 
AR  
Aortic Regurgitation 
AS 
Aortic Stenosis 
ASA 
Aspirin 
AST 
Aspartate Aminotransaminase 
AT 
All Treated 
AV 
Atrioventricular 
AVR 
Aortic Valve Replacement 
BAV 
Balloon Aortic Valvuloplasty 
BMS 
Bare Metal Stent 
BNP 
B-Type Natriuretic Peptide 
CABG 
Coronary Artery Bypass Grafting 
CAD 
Coronary Artery Disease 
CBC 
Complete Blood Count 
CCS 
Canadian Cardiovascular Society 
CEC 
Clinical Events Committee 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CK-MB 
Creatine Kinase MB 
CT 
Computed Tomography 
CTA 
Clinical Trial Agreement 
CTA 
Computed Tomography Angiography 
CV 
Curriculum Vitae 
DAL 
Device Accountability Log 
DES 
Drug-Eluting Stent 
DoA 
Delegation of Authority 
DSMB 
Data Safety Monitoring Board 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
Echo 
Echocardiogram 

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Abbreviation  
Full Term 
eGFR 
Estimated Glomerular Filtration Rate 
EMEA 
Europe, Middle East, Africa 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
Hgb 
Hemoglobin 
HIT 
Heparin-induced Thrombocytopenia 
HOCM 
Hypertrophic Cardiomyopathy with Obstruction 
H&P 
History and Physical 
ICD 
Implantable Cardioverter Defibrillator 
ICF 
Informed Consent Form 
ICU 
Intensive Care Unit 
IDE 
Investigational Device Exemption 
IFU 
Instructions For Use 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
KM 
Kaplan Meier 
LMW Heparin 
Low Molecular Weight Heparin 
LVEF 
Left Ventricular Ejection Fraction 
LVOT 
Left Ventricular Outflow Tract 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI  
Myocardial Infarction 
MMSE 
Mini Mental State Examination 
MR/MRI  
Magnetic Resonance / Magnetic Resonance Imaging 
MR 
Mitral Regurgitation 
mRS 
Modified Rankin Scale 
MS 
Mitral Stenosis 
MV 
Mitral Valve 
MVR 
Mitral Valve Replacement 
NIHSS 
National Institutes of Health Stroke Scale 
NYHA  
New York Heart Association 
PCI 
Percutaneous Coronary Intervention 
PET  
Polyethylene Terephthalate 
PPM 
Prosthetic-Patient-Mismatch 
PT 
Prothrombin Time 
PVL 
Paravalvular Leak 
qd 
Once Daily 
QoL 
Quality of Life 
RV  
Right Ventricle 

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Abbreviation  
Full Term 
SAE  
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SF 
Screen Failure 
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 
UADE  
Unanticipated Adverse Device Effect 
UF Heparin 
Unfractionated Heparin 
US 
United States 
VARC  
Valve Academic Research Consortium 
VI  
Valve Implant 
VIV 
Valve-in-Valve 
WBC  
White Blood Cell 
5-MWT 
5-Meter Walk Test 
6MWT  
Six Minute Walk Test  
 
 
 

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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 TMVR 
VARC-1 
Access site 
related 
complication 
Any adverse clinical consequence possibly associated 
with any of the access sites used during the procedure 
VARC-1 
Acute kidney 
injury 
The increase in creatinine meeting at least Stage 1 must 
occur within 48 hours. 
Staging will be based on the worse stage that occurs 
within 7 days of the index procedure. 
Stage 1 
• 
Increase in serum creatinine to 150-199% (1.5-1.99 
× increase compared with baseline) OR increase of 
≥0.3 mg/dL (≥26.4 mmol/L) OR 
• 
Urine output <0.5 ml/kg per hour for >6 but <12 
hours 
Stage 2 
• 
Increase in serum creatinine to 200-299% (2.0-2.99 
× increase compared with baseline) OR 
• 
Urine output <0.5 ml/kg per hour for >12 but <24 
hours 
Stage 3 
• 
Increase in serum creatinine to ≥300% (>3 × 
increase compared with baseline) OR serum 
creatinine of ≥4.0 mg/dL (≥354 mmol/L) with an 
acute increase of at least 0.5 mg/dL (44 mmol/L) 
OR 
• 
Urine output <0.3 ml/kg per hour for ≥24 hours OR 
• 
Anuria for ≥12 hours 
 
Patients receiving renal replacement therapy (dialysis, 
hemodialysis, peritoneal dialysis, hemofiltration, 
transplant therapy) are considered to meet Stage 3 
criteria irrespective of other criteria 
VARC-2 
Anemia 
A condition in which the blood is deficient in red blood 
cells, in hemoglobin, or in total volume, without clear 
evidence of overt bleeding, that is actionable (e.g. 
requires medications, transfusion etc.) 
Sponsor 
Angina / Cardiac 
chest pain 
Chest pain due to an inadequate supply of oxygen to the 
heart muscle 
Sponsor 

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Term 
Definition 
Reference/ 
Justification 
Angina, grading 
scale 
Grade 
Description 
Grade I 
Ordinary physical activity, such as walking 
and climbing stairs, does not cause 
angina.  Angina occurs with strenuous, 
rapid, or prolonged exertion at work or 
during recreation 
Grade II 
Slight limitation of ordinary activity.  Angina 
occurs with walking or climbing stairs 
rapidly, walking uphill, walking or stair 
climbing after meals, walking in the cold, 
into the wind, while under emotional stress, 
or during the first hours after 
awakening.  Walking more than two blocks 
on the level and climbing more than one 
flight of ordinary stairs at a normal pace 
and in normal conditions, does not cause 
angina 
Grade III 
Marked limitation of ordinary physical 
activity.  Angina occurs with walking one to 
two blocks on the level and climbing one 
flight of stairs in normal conditions and at a 
normal pace 
Grade IV 
Inability to carry on any physical activity 
without discomfort.  Angina syndrome may 
be present at rest 
Canadian 
Cardiovascular 
Society 
Arrhythmia / 
Conduction 
System Injury 
(Defect) 
Arrhythmia: an irregular heart rate or abnormal rhythm 
resulting in symptoms or requiring medical intervention. 
 
Conduction system defect: an impairment of the 
electrical pathways and specialized muscular fibers that 
conduct impulses through the heart (ex. bundle branch 
block, heart block, etc.). 
Sponsor 
Atrial fibrillation 
Atrial fibrillation > 24 hours, requiring new drug treatment 
/ anticoagulation OR requiring chemical or electrical 
cardioversion 
Sponsor 
Atrial Septal 
Defect 
Clinically significant ASD as a result of the study 
procedure with or without significant shunting 
Sponsor 

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Term 
Definition 
Reference/ 
Justification 
Bleeding 
Any bleeding associated with transfusion, drop in Hgb of 
at least 3 g/dL from the baseline, or overt sign of blood 
loss.  For instance, the threshold to report bleeding for 
TF-TMVR is > 100 mL blood loss during procedure. 
 
Overt bleeding is defined as any clinically obvious source 
of bleeding or bleeding source identified after appropriate 
investigation and diagnostic testing (e.g. imaging).  Any 
procedural blood loss should be considered an overt 
bleeding. 
 
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. 
 
Examples of overt bleeding include pseudoaneurysm, 
retroperitoneal hematoma seen on CAT scan, visible 
access site hematoma, gross hematuria, gross GI 
bleeding including melena, hematemesis and 
hematochezia. 
Sponsor 
 
CABG 
Coronary artery bypass surgery 
Sponsor 
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 
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 
Cardiovascular 
Endpoint Events in 
Clinical Trials 
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 
Hypertrophic 
Cardiomyopathy 
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 
Specifications 
Cerebrovascular 
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 

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Term 
Definition 
Reference/ 
Justification 
Congestive Heart 
Failure (CHF) 
Diagnosis requires physician documentation or report of 
any of the following: 
• 
Unusual dyspnea on light exertion 
• 
Recurrent dyspnea occurring in the supine position 
• 
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 
Cardiopulmonary 
bypass (CPB) 
Bypass of the heart and lungs as in open heart surgery 
Sponsor 
Coronary vessel 
compression or 
obstruction 
Angiographic evidence of any reduction in coronary 
artery luminal diameter or coronary sinus diameter due 
to either external compression, thrombosis, embolism, 
dissection, or other cause 
MVARC 
Device 
For the determination of device relationship, the study 
device consists of: 
• 
The Edwards SAPIEN 3 valve 
• 
The Edwards Valve Delivery System 
• 
The Edwards Expandable Sheath 
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, magnetic resonance imaging 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. 
FDA., 21 CFR 
803.3(m) 
Device (Valve) 
thrombosis 
Any thrombus attached to or near an implanted valve 
that occludes part of the blood flow path, interferes with 
valve function, or is sufficiently large to warrant 
treatment.  Note that 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 

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Term 
Definition 
Reference/ 
Justification 
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 
Durack DT, Lukes 
AS, Bright DK.  New 
criteria for diagnosis 
of infective 
endocarditis 
utilization of specific 
echocardiographic 
findings.  Duke 
Endocarditis Service.  
Am J Med 
1994;96:200-9 
EuroSCORE II 
http://www.euroscore.org/calc.html  
European System for 
Cardiac Operative 
Risk Evaluation 
EuroSCORE, 
logistic 
http://www.euroscore.org/calcold.html 
European System for 
Cardiac Operative 
Risk Evaluation 
Explant 
Removal of the investigational valve implant for any 
reason 
Sponsor 
Hemolysis 
Evidence of RBC destruction best explained by 
hemolysis (LDH >350 u/L and decreased haptoglobin 
based on site lab normals) and no other explanation for 
the findings.  Microscopic evidence may be considered 
supportive 
Sponsor 
Hospitalization 
(repeat) 
Any admission to the hospital (including an emergency 
department visit ≥ 24 hours) for either a diagnostic or 
therapeutic purpose (e.g. diuretics, inotropes, 
chronotropes, oral or intra-venous therapy) following 
discharge from the index hospitalization 
Sponsor 
Hypertension 
Systolic pressure > 140 or a diastolic pressure > 90 
mmHg 
Sponsor 
Hypotension 
Systolic pressure < 90 or a diastolic pressure < 60 
mmHg 
Sponsor 
Index 
hospitalization 
The beginning of the Index Hospitalization is defined as 
the day the patient is admitted for valve implant 
procedure and continues until the patient is discharged 
from the hospital. 
Sponsor 
Infection 
Known infection requiring intravenous antibiotics for 
other than prophylaxis, and/or extended hospitalization 
Sponsor 
LVOT Obstruction 
Left ventricular outflow tract obstruction resulting in peak 
gradient increase >10 mm Hg from baseline (screening) 
MVARC 

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Term 
Definition 
Reference/ 
Justification 
Mini-mental state 
examination 
(MMSE) 
A questionnaire that is used extensively in clinical and 
research settings to measure cognitive impairment. 
Pangman, VC; Sloan, 
J; Guse, L. (2000).  
"An Examination of 
Psychometric 
Properties of the 
Mini-Mental State 
Examination and the 
Standardized Mini-
Mental State 
Examination: 
Implications for 
Clinical 
Practice". Applied 
Nursing 
Research 13 (4): 
209–213. 
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 
Van Swieten, J. C., et 
al. "Interobserver 
agreement for the 
assessment of 
handicap in stroke 
patients." Stroke 19.5 
(1988): 604-607. 

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Term 
Definition 
Reference/ 
Justification 
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 
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: 
• 
Detection of a rise and/or fall of cardiac biomarker 
values [preferably cardiac troponin (cTn)] with at least 
one value above the 99th percentile upper reference 
limit (URL) and with at least one of the following: 
- Symptoms of ischemia 
- New or presumed new significant ST-segment–T 
wave (ST–T) changes or new left bundle branch 
block (LBBB) 
- Development of pathological Q waves in the ECG 
- Imaging evidence of new loss of viable myocardium 
or new regional wall motion abnormality 
• 
Identification of an intracoronary thrombus by 
angiography 
STS 
National Institutes 
of Health Stroke 
Scale (NIHSS) 
The NIHSS can help physicians determine the severity of 
a stroke, predict clinical outcomes and can help guide 
management. 
NIHSS 

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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. 
The Criteria 
Committee of the 
New York Heart 
Association.  
(1994). Nomenclature 
and Criteria for 
Diagnosis of 
Diseases of the Heart 
and Great 
Vessels. (9th ed.).  
Boston: Little, Brown 
& Co. pp. 253–256. 
Paravalvular Leak 
PVL refers to blood flowing through a channel between 
the structure of the implanted valve and cardiac tissue or 
previously implanted valve as a result of a lack of 
appropriate sealing 
ESC / Sponsor 
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 

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Term 
Definition 
Reference/ 
Justification 
Pre-existing 
condition 
A pre-existing condition is one that is present at the start 
of study treatment.  A preexisting condition is not an 
adverse event unless it worsens as a result of the study 
treatment. 
Sponsor 
Prosthetic mitral 
valve stenosis 
Prosthetic valve stenosis defined by increase in mean 
mitral valve gradient > 5 mmHg from post-implant 30-day 
echo to most recent post-implant echo AND EOA < 1.5 
cm2. 
Sponsor 
Prosthetic mitral 
valve regurgitation 
Prosthetic valve regurgitation > moderate [2+] total 
regurgitation AND at least one grade (with 3-class 
scheme) or two grades (with 5-class scheme) increase in 
total MR from 30-days post-implant echo to post-implant 
echo being compared. 
Sponsor 
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 mitral valvuloplasty 
• 
Surgical mitral valve replacement 
• 
Valve in valve 
• 
Paravalvular leak closure 
STS/AATS/Sponsor 
Valve implant 
procedure 
Placement of study device and/or additional procedures 
occurring in the cath lab and/or operating 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 (venous or arterial) is established for TMVR. 
 
The end of the procedure will be considered once device 
(Edwards eSheath) removed 
Performance of TEE does not by itself constitute start of 
procedure 
Sponsor 

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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 
Duration of a focal or global neurological deficit >24 h; 
OR <24 h, if available neuroimaging documents a new 
hemorrhage or infarct; OR the neurological deficit results 
in death 
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* 
Confirmation of the diagnosis by at least one of the 
following#: 
 Neurology or neurosurgical specialist 
 Neuroimaging procedure (MR or CT scan) 
 Clinical presentation alone 
 
Stroke definitions†: 
 Non-disabling: a mRS score of less than 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 
 
 Disabling: a mRS score of 2 or more 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 
 
Stroke classification: 
 Hemorrhagic: an acute episode of focal or global 
cerebral or spinal dysfunction caused by 
intraparenchymal, intraventricular, or subarachnoid 
hemorrhage. 
 Ischemic: an acute symptomatic episode of focal 
cerebral, spinal, or retinal dysfunction caused by an 
infarction of the central nervous system tissue 
 Undetermined: stroke with insufficient information to 
allow categorization as ischemic or hemorrhagic. 
Transient Ischemic Attack (TIA) 
Duration of focal or global neurological deficit <24 h, any 
VARC-2 

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Term 
Definition 
Reference/ 
Justification 
variable neuroimaging does not demonstrate a new 
hemorrhage or infarct 
 
*Patients with non-focal global encephalopathy will not 
be reported as a stroke without unequivocal evidence 
based upon neuroimaging studies. 
#If a stroke is reported without evidence of confirmation 
of the diagnosis by one of these methods, the event may 
still be considered a stroke on the basis of the clinical 
presentation alone. 
†Modified Rankin score assessments should be made by 
qualified individuals according to a certification process. 
Structural Valvular 
Deterioration 
(SVD) 
Structural valve deterioration includes dysfunction or 
deterioration exclusive of infection or thrombosis as 
determined by reoperation, autopsy or clinical 
investigation.  The term structural deterioration refers to 
changes intrinsic to the valve, such as wear, fracture, 
calcification, leaflet tear, leaflet retraction, suture line 
disruption of components a prosthetic valve, thickening, 
stenosis 
Akins, Cary W., et al. 
"Guidelines for 
reporting mortality 
and morbidity after 
cardiac valve 
interventions." 
European Journal of 
Cardio-Thoracic 
Surgery 33.4 (2008): 
523-528. 
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 patient 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 coronary artery disease. 
http://www.syntaxscore.com/ 
http://ir-nwr.ru/calculators/syntaxscore/frameset.htm 
 
6 Minute Walk 
Test 
A performance-based measure of functional exercise 
capacity.  The test measures the distance an individual is 
able to walk over a total of six minutes on a hard, flat 
surface.  See more at: http://www.rheumatology.org/I-
Am-A/Rheumatologist/Research/Clinician-
Researchers/Six-Minute-Walk-Test-
SMWT#sthash.cFCDWfkn.dpuf 
ATS 
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)” 
 

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Term 
Definition 
Reference/ 
Justification 
Vascular injury 
Injury that may be caused by a guidewire, vascular 
sheath, delivery catheter, or any balloon used for mitral 
valve predilatation and can include arterial or venous 
dissection, perforation, arteriovenous fistula, 
pseudoaneurysm formation, retroperitoneal hemorrhage, 
or incomplete arteriotomy closure. 
Venous injuries can include perforation, tears and 
thromboembolism. 
Cardiac vascular injury can include perforation or tearing 
of the major cardiac structures that require repair. 
Sponsor 
Valve 
malpositioning 
Valve migration 
• 
After initial correct positioning, the device moves 
within its initial position but not leading to device 
embolization 
Valve embolization 
• 
The valve prosthesis moves during or after 
deployment such that it loses contact with its initial 
position 
Ectopic valve deployment 
• 
Permanent deployment of the valve prosthesis in a 
location other than intended 
MVARC 
 
 
 

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Appendix C References 
 
 
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2 Cheung A, Webb JG, Barbanti M, Freeman M, Binder RK, Thompson C, Wood DA, Ye J. 5-
year experience with transcatheter transapical mitral valve-in-valve implantation for 
bioprosthetic valve dysfunction. J Am Coll Cardiol. 2013. 30;61:1759-66 
 
3 Chaikof, E. The Development of Prosthetic Heart Valves- Lessons in Form and Function. 2007 
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4 Loor G, Schuster A, Cruz V et. al. The Carpentier-Edwards Perimount Magna mitral valve 
bioprosthesis: intermediate-term efficacy and durability.  J of Cardiothorac Surg. 2016; 11:20. 
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5 Grunkemeier GL, Furnary AP, Wu YX et al.  Durability of pericardial versus porcine 
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6 Bourgignon T, Bouquiaux-Stablo A-L, Loardi C, et al. Very late outcomes for mitral valve 
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cardiac valve interventions. J Thorac Cardiovasc Surg. 2008; 135:732-738. 
 
11 Cohn L, ed.  Cardiac Surgery in the Adult. Third Edition. New York: McGraw-Hill Companies, 
 
 

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2010.  
 
12 Kubota S, S Wakasa, T Ooka et al.  A case of Carpentier-Edwards pericardial bioprosthesis in 
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13 Ito H, K Sakata, T Haruiki et al.  Structural valve deterioration of a mitral Carpentier-Edwards 
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24Akins CW, Buckley MJ, Daggett WM, et al: Risk of reoperative valve replacement for failed 
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26Caus T, Albertini JN, Chi Y, et al.  Multiple valve replacement increases the risk of reoperation 
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30 Campanella C, Hider CF, Duncan AJ, et al. Must the mitral valve always be removed during 
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31 Raffa H, Al-Ibrahim K, Aniff Sorefan A, et al.  Superimposition of a Mechanical Valve on an 
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32 Stassano P, Losi MA, Golino A, et al.  Bioprosthesis replacement with mechanical valve 
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33 Paterson HS, Jacob C, Campanella C et al.  Retention of bioprosthetic valve annulus in mitral 
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34 Walther T, Falk V, Dewey T et al. Valve-in-a-valve concept for transcatheter minimally 
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35Wenaweser P,  Buellesfeld L, Gerlins U, et al. "Percutaneous aortic valve replacement for 
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the CoreValve Revalving system." Catheter Cardiovasc Interv 2007; 70(5): 760-764. 
 
36Walther T, Kempfert J, Borger MA et al.  Human minimally invasive off-pump valve-in-a-valve 
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37 Finsterer, J. and C. Stollberger, Strategies for primary and secondary stroke prevention in 
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38 Blanke P, Bulla S, Baumann T, et al, Thoracic Aorta: Prospective electrocardiographically 
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