Surgical Replacement and Transcatheter Aortic Valve Implantation (SURTAVI)
Phase: NA
Conditions: Severe Aortic Stenosis
Sponsor: Medtronic Cardiovascular

Protocol
This trial protocol has been provided by the authors to give readers additional information about their work.
Protocol for: Reardon MJ, Van Mieghem NM, Popma JJ, et al. Surgical or transcatheter aortic-valve replacement 
in intermediate-risk patients. N Engl J Med. DOI: 10.1056/NEJMoa1700456

This supplement contains the following items: 
1. First SURTAVI protocol implemented (V3)
 pg 2 
2. Last SURTAVI protocol (V12 – US and V12.1 – Canada and EU)
 pg 204 and 487 
3. Summary of protocol changes
 pg 764 
4. Original SAP
 pg 769 
5. Final SAP
 pg 796 
6. Summary of SAP changes
 pg 842 

 
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SURTAVI 
SUrgical Replacement and Transcatheter 
Aortic Valve Implantation 
 
 
Clinical Investigation Plan 
 
 
VERSION 3.0 
18 November 2011 
  
 
Sponsor: 
Medtronic, Inc. 
Clinical Research 
Mailstop: MVS66 
Mounds View South 
8200 Coral Sea St NE 
Mounds View, MN 55112 USA 
Medtronic Bakken Research Center 
CardioVascular Department 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 

 
 
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Contact Information Details* 
Study Chair 
Prof. Patrick W. Serruys, MD, PhD (Study Chair) 
Professor of Medicine 
Head of Interventional Cardiology 
Erasmus Medical Center 
Dept. of Interventional Cardiology, Thoraxcenter Room 
BD 381 
's Gravendijkwal 230 
3015 CE Rotterdam, The Netherlands 
Dr. Nicolas M. Van Mieghem, MD (Deputy Study Chair) 
Interventional Cardiologist 
Erasmus Medical Center 
Dept. of Interventional Cardiology, Thoraxcenter Room 
BD 171 
's Gravendijkwal 230 
3015 CE Rotterdam, The Netherlands 
Principal Investigators 
Prof. Stephan Windecker, MD, PhD 
Head of Interventional Cardiology 
Bern University Hospital 
Department of Cardiology 
Swiss Cardiovascular Center Bern  
Freiburgstrasse 4  
CH-3010 Bern, Switzerland 
Prof. A. Pieter Kappetein, MD, PhD 
Cardio-Thoracic Surgeon 
Erasmus Medical Center  
Dept. of Thoracic Surgery  
Room BD 569  
's Gravendijkwal 230 
3015 CE Rotterdam, The Netherlands 
 
Prof. Rüdiger Lange, MD, PhD 
Direktor der Klinik für Herz- und Gefäßchirurgie 
Deutsches Herzzentrum München 
Lazarettstr. 36 
80636 München, Germany  
 
Prof. Thomas Walther, MD, PhD 
Direktor der Abteilung Herzchirurgie 
Kerckhoff-Klinik 
Benekestr. 2-8 
61231 Bad Nauheim; Germany 
Dr. Jeffrey J. Popma, MD 
Director, Interventional Cardiology 
Beth Israel Deaconess Medical Center 
185 Pilgrim Rd.  
Boston, MA 02215 USA 
Dr. Michael J. Reardon, MD 
Professor, Cardiothoracic Surgey 
The Methodist Hospital 
6550 Fannin St., Suite 1401 
Houston, TX 77030  USA 
Dr. David H. Adams, MD 
Marie-Josée and Henry R. Kravis Professor and 
Chairman 
Deprtment of Cardiothoracic Surgery 
The Mount Sinai Medical Center 
1190 Fith Avenue 
New York, NY 10029  USA 
 

 
 
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Trial Oversight 
Will Prather 
Clinical Research Director 
Medtronic CardioVascular 
Phone: (763) 514.9897 
Email: william.c.prather@medtronic.com 
 
Francesca Barbieri – EU  
Clinical Research Director 
BRC – Cardiac Surgery Clinical 
Phone: (+31-43) 3566 824 
Email: francesca.barbieri@medtronic.com 
 
Sponsor 
 
 
Medtronic, Inc. 
Clinical Research 
Mailstop: MVS66 
Mounds View South 
8200 Coral Sea Street NE 
Mount View, MN 
55112 USA 
 
Medtronic Bakken Research Center  
CardioVascular Department 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
Randomization Telephone Number 
 
The Randomization telephone number (IXRS) will 
be provided in the investigator site file. 
 
*  Updated contact information will be provided as applicable.  Additional information regarding 
contacts listed above available upon request. 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL and PROPRIETARY 
This document contains confidential information and is solely the property of Medtronic, Inc.  Acceptance of 
this document constitutes an agreement by the recipient that no unpublished information contained herein will 
be published or disclosed without the prior written approval of Medtronic, Inc.  This document may be 
disclosed to the appropriate Institutional Review Board (IRB)/Ethics Committee (EC) with the stipulation that 
the IRB/EC treats the information contained herein as the confidential property of Medtronic, Inc. 

 
 
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TABLE OF CONTENTS 
A 
SYNOPSIS ......................................................................................................... 9 
B 
PURPOSE ........................................................................................................ 14 
B.1 
Background ........................................................................................................................ 14 
B.2 
Medtronic CoreValve® System and Intended Use ............................................................. 16 
B.2.1 Device Description .................................................................................................. 16 
B.2.2 Device Approval Status ........................................................................................... 17 
B.2.3 Intended Use of the Device ..................................................................................... 17 
B.3 
Study Objectives ................................................................................................................ 17 
B.3.1 Primary .................................................................................................................... 17 
B.3.2 Secondary ............................................................................................................... 17 
B.3.3 Exploratory .............................................................................................................. 17 
C 
TRIAL PROTOCOL .......................................................................................... 18 
C.1 
Ethics and Regulatory Compliance ................................................................................... 18 
C.1.1 Applicable Regulations ............................................................................................ 18 
C.1.2 Institutional Review Board (IRB)/Medical Ethics Committee (MEC) ....................... 18 
C.1.3 Regulatory Submission ........................................................................................... 18 
C.1.4 Ethical Conduct of the Trial ..................................................................................... 19 
C.2 
Trial Administration ............................................................................................................ 19 
C.2.1 Steering Committee ................................................................................................. 19 
C.2.2 Publication Committee ............................................................................................ 19 
C.3 
Methodology ...................................................................................................................... 20 
C.3.1 Purpose ................................................................................................................... 20 
C.3.2 Patient Population ................................................................................................... 20 
C.3.3 Design ..................................................................................................................... 20 
C.3.4 Investigational Centers ............................................................................................ 20 
C.3.5 Number of Subjects ................................................................................................. 21 
C.3.6 Inclusion/Exclusion Criteria ..................................................................................... 21 
C.3.6.1 
Inclusion Criteria ...................................................................................... 21 
C.3.6.2 
Exclusion Criteria ..................................................................................... 22 
C.3.7 Informed Consent .................................................................................................... 23 
C.3.8 Revisions in Patient Information and Informed Consent Form ............................... 24 
C.3.9 Enrollment Flowchart for Randomization to MCS TAVI or SAVR ........................... 24 
C.3.10 
Trial Training ....................................................................................................... 25 
C.4 
Trial Procedures ................................................................................................................ 25 
C.4.1 Screening Procedures ............................................................................................. 25 
C.4.2 Heart Team Procedures .......................................................................................... 26 
C.4.3 Enrollment and Randomization ............................................................................... 27 
C.4.4 Baseline Assessments ............................................................................................ 27 

 
 
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C.4.5 Medtronic CoreValve® System TAVI or Surgical Aortic Valve Replacement 
Procedure ................................................................................................................ 28 
C.4.5.1 
MCS TAVI ................................................................................................ 28 
C.4.5.2 
Surgical Aortic Valve Replacement ......................................................... 33 
C.4.6 Assessments done at discharge (both SAVR and TAVI) ........................................ 37 
C.4.7 Follow-Up Evaluations ............................................................................................. 38 
C.4.7.1 
30 Days .................................................................................................... 38 
C.4.7.2 
3 Months .................................................................................................. 38 
C.4.7.3 
6 Months .................................................................................................. 39 
C.4.7.4 
12 Months ................................................................................................ 39 
C.4.7.5 
18 Months ................................................................................................ 39 
C.4.7.6 
24 Months ................................................................................................ 40 
C.4.7.7 
3-5 Years ................................................................................................. 40 
C.4.8 Echo Assessment .................................................................................................... 40 
C.4.9 Neurologic Assessment ........................................................................................... 41 
C.4.10 
Angiographic and Computed Tomography Assessment .................................... 41 
C.4.11 
Data Collection .................................................................................................... 41 
C.4.12 
Unscheduled Follow-up Assessments ................................................................ 44 
C.4.13 
Missed Follow-up Visits ...................................................................................... 44 
C.4.14 
Investigational Product Accountability ................................................................ 44 
C.4.15 
Device Malfunction or Explant ............................................................................ 44 
C.4.16 
Protocol Deviations ............................................................................................. 45 
C.4.17 
Subject Withdrawal or Discontinuation ............................................................... 46 
C.4.18 
Termination or Discontinuation of Trial ............................................................... 46 
C.5 
Adverse Events.................................................................................................................. 46 
C.5.1 Definitions ................................................................................................................ 46 
C.5.1.1 
Adverse Event ......................................................................................... 46 
C.5.1.2 
Serious Adverse Event ............................................................................ 47 
C.5.1.3 
Major Adverse Cardiovascular and Cerebrovascular Events .................. 47 
C.5.1.4 
Major Adverse Event ............................................................................... 48 
C.5.1.5 
Adverse Device Effect (ADE) or Device-Related Adverse Event ............ 48 
C.5.1.6 
Unanticipated Adverse Device Effect (UADE) ......................................... 48 
C.5.1.7 
Device Deficiency .................................................................................... 48 
C.5.1.8 
Technical Observation ............................................................................. 48 
C.5.2 Reporting ................................................................................................................. 49 
C.5.2.1 
Serious Adverse Events (SAEs) .............................................................. 49 
C.5.2.2 
Unanticipated Adverse Device Effects .................................................... 49 
C.5.2.3 
Device Deficiencies and Technical Observations ................................... 50 
C.5.2.4 
All Other Adverse Events ........................................................................ 50 
C.5.2.5 
Anticipated Adverse Events ..................................................................... 50 

 
 
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C.5.2.6 
Deaths ..................................................................................................... 51 
C.5.3 Clinical Events Committee (CEC) ........................................................................... 51 
C.5.4 Data Safety Monitoring Board (DSMB) ................................................................... 52 
C.6 
Statistical Methods and Analysis ....................................................................................... 53 
C.6.1 Statistical considerations and analysis .................................................................... 53 
C.6.2 Reports .................................................................................................................... 53 
C.6.3 Description of Baseline Variables ........................................................................... 53 
C.6.4 Analysis Populations ............................................................................................... 53 
C.6.4.1 
Screening population ............................................................................... 53 
C.6.4.2 
Randomized population ........................................................................... 53 
C.6.5 Primary analysis ...................................................................................................... 54 
C.6.5.1 
Hypothesis of non-inferiority .................................................................... 54 
C.6.5.2 
Sample size and power calculation ......................................................... 54 
C.6.6 Description of performed analysis, per population .................................................. 55 
C.6.6.1 
Analysis of screening population ............................................................. 55 
C.6.6.2 
Analysis of – ITT population .................................................................... 55 
C.6.6.3 
Analysis of as treated population ............................................................. 56 
C.6.6.4 
Analysis of implanted population ............................................................. 56 
C.6.7 Statistical methods to be used ................................................................................ 56 
C.6.8 Procedure for accounting data, treatment for missing, unused or spurious data ... 56 
C.6.9 Interim analysis ....................................................................................................... 56 
C.6.10 
Pre-Defined Subgroups ...................................................................................... 57 
C.6.11 
Health-Related Quality of Life (HRQoL) and Treatment Costs ........................... 57 
C.6.11.1 
Quality of Life ......................................................................................... 57 
C.6.11.2 
Economic Outcomes/Cost-Effectiveness .............................................. 57 
C.6.12 
Secondary Endpoints .......................................................................................... 58 
C.7 
Data and Quality Management .......................................................................................... 62 
C.7.1 Electronic Data Capture .......................................................................................... 62 
C.7.2 Data Collection ........................................................................................................ 62 
C.7.3 Core Laboratories Procedures ................................................................................ 62 
C.7.4 Source Documents .................................................................................................. 62 
C.8 
Records and Reports ......................................................................................................... 63 
C.8.1 Responsibilities of the Sponsor ............................................................................... 63 
C.8.2 Responsibilities of the Investigator .......................................................................... 64 
D 
RISK / BENEFIT ANALYSIS ............................................................................ 66 
D.1 
Methods to Minimize Risk .................................................................................................. 67 
D.2 
Potential Benefits ............................................................................................................... 67 

 
 
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E 
DESCRIPTION OF MEDTRONIC® COREVALVE SYSTEM ............................ 68 
E.1 
Investigational Product Description ................................................................................... 68 
E.2 
Medtronic CoreValve Ordering, Storage, and Disposition................................................. 70 
F 
MONITORING AND AUDITING ....................................................................... 71 
F.1 
Monitoring .......................................................................................................................... 71 
F.2 
Auditing .............................................................................................................................. 71 
G 
LABELING ....................................................................................................... 72 
H 
CONSENT MATERIALS .................................................................................. 72 
I 
IRB/MEC INFORMATION ................................................................................ 72 
J 
OTHER INSTITUTIONS ................................................................................... 72 
K 
ADDITIONAL RECORDS AND REPORTS ...................................................... 72 
L 
REPORT OF PRIOR INVESTIGATIONS ......................................................... 72 
M 
PUBLICATION POLICY ................................................................................... 73 
N 
AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN ......................... 74 
O 
ABBREVIATIONS AND DEFINITIONS ............................................................ 75 
O.1 
List of Abbreviations .......................................................................................................... 75 
O.2 
Definitions of Terms ........................................................................................................... 78 
P 
STUDY MANAGEMENT ................................................................................... 93 
P.1 
Miscellaneous .................................................................................................................... 93 
P.1.1 Insurance ................................................................................................................. 93 
P.1.2 Reimbursement ....................................................................................................... 93 
P.1.3 Indemnification ........................................................................................................ 93 
P.1.4 Subject confidentiality .............................................................................................. 93 
Q 
REFERENCES ................................................................................................. 94 
 

 
 
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R 
APPENDIX ....................................................................................................... 98 
R.1 
Sample Informed Consents 
R.2 
Investigative Site and IRB Information 
R.3 
Other Institutions 
R.4 
Additional Records and Reports 
R.5 
Sample Case Report Forms 
R.6 
Aortogram Acquisition Guidelines 
R.7 
Echocardiography Acquisition Guidelines 
R.8 
Electrocardiogram (ECG) Submission 
R.9 
Computed Tomography (CT) Angiography Acquisition Guidelines 
R.10 Interactive Voice/Web Resaponse System (IXRS) Vendor Information 
R.11 Explanted Device/Pathology and Return Procedures 
R.12 Economic and Quality of Life Data Collection 
R.13 Pacing Guidelines 
R.14 Six Minute Walk Test Instructions 
R.15 National Institute of Health Stroke Scale (NIHSS) 
R.16 Modified Rankin Scale (mRS) Instructions 
R.17 Mini Mental State Exam (MMSE-2) 
R.18 Additional Neurological Assessments 
R.19 Medtronic CoreValve® Clinical Assessments 
R.20 Katz Index of Independence in Activities of Daily Living 
R.21 Investigator Brochure / Report of Prior Investigations for the Medtronic CoreValve® 
System 
R.22 SURTAVI Risk Model 
 

 
 
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A 
SYNOPSIS 
Title of Trial: 
Surgical Replacement And Transcatheter Aortic 
Valve Implantation (SURTAVI) 
Name of Product: 
Medtronic CoreValve® System 
Purpose: 
The purpose of this study is to investigate the safety 
and efficacy of transcatheter aortic valve implantation 
(TAVI) in patients with severe, symptomatic Aortic 
Stenosis (AS) at intermediate surgical risk by 
randomizing patients to either Surgical Aortic Valve 
Replacement (SAVR) or TAVI with the Medtronic 
CoreValve® System. The total trial duration is 
expected to be approximately seven years. 
Design: 
Subjects will be randomized on a 1:1 basis to either 
transcatheter aortic valve implant (TAVI) with the 
Medtronic CoreValve® System (MCS) or to surgical 
aortic valve replacement (SAVR) 
Primary Objective: 
The primary objective of this trial is to evaluate in a 
prospective randomized fashion whether TAVI is 
non-inferior to SAVR with respect to the event free 
survival of the combined endpoint of all-cause 
mortality and major stroke at 24 months in patients 
with symptomatic severe aortic stenosis and at 
intermediate surgical risk. 
Secondary Objective: 
The secondary objective of this trial is to assess 
differences in quality of life, clinical benefit (combined 
efficacy endpoint) and health economics in patients 
with symptomatic severe aortic stenosis and at 
intermediate risk treated with either Transcatheter 
Aortic Valve Implantation (TAVI) or Surgical Aortic 
Valve Replacement (SAVR). 
Exploratory Objective: 
An analysis will be conducted to determine if patients 
can be identified as intermediate risk for 
Transcatheter Aortic Valve Implantation (TAVI) 
based upon age and the presence of a defined list of 
co-morbidities commonly associated with patients 
undergoing TAVI procedures.   
Primary Endpoint: 
All-cause mortality or major stroke at 24 months 
Secondary Endpoints: 
The following secondary endpoints will be 
compared between MCS TAVI and SAVR subjects 
cohorts: 
1.  Major Adverse Cardiovascular and 
Cerebrovascular Events (MACCE)-free survival at 
30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years.  
MACCE is defined as a composite of: 
• All-cause death 
• Myocardial infarction (MI) 
• All stroke, and 
• Reintervention (defined as any cardiac surgery 
or percutaneous reintervention catheter 
procedure that repairs, otherwise alters or 
adjusts, or replaces a previously implanted 
valve) 

 
 
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2. The occurrence of individual MACCE components 
at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
3. Major Adverse Events (MAE) at 30 days, 6 
months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years. 
4. Conduction disturbance requiring permanent 
pacemaker implantation at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually 
thereafter up to 5 years. 
5. Change in NYHA class from baseline at 30 days, 6 
months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years. 
6. Change in distance walked during 6-minute walk 
test (6MWT) from baseline to 30 days, baseline to 
12 months, and baseline to 24 months. 
7. Ratio of days alive out of hospital versus total days 
alive assessed at 12 months and 24 months 
follow-up.  
8. Quality of Life (QoL) change from baseline at 30 
days, 3 months, 6 months, 12 months, 18 months, 
24 months, and annually thereafter up to 5 years. 
9. Echocardiographic assessment of prosthetic valve 
performance at discharge, 6 months, 12 months, 
24 months, and annually thereafter up to 5 years 
using the following measures: 
• transvalvular mean gradient 
• effective orifice area 
• degree of prosthetic aortic valve regurgitation 
(transvalvular and paravalvular). 
10. Aortic valve disease related hospitalizations.  
11. Cardiovascular deaths and valve-related deaths. 
12. Strokes and TIAs. 
13. Peri-procedural neurological injury. 
14. Index procedure related MAEs. 
15. Length of index procedure hospital stay. 
The following secondary endpoints will be 
assessed for the MCS TAVI cohort subjects only: 
16. Device success defined as follows: 
•  Successful vascular access, delivery and 
deployment of the device, and successful 
retrieval of the delivery system, 
•  Correct position of the device in the proper 
anatomical location (placement in the annulus 
with no impedance on device function), 
•  Intended performance of the prosthetic valve 
(aortic valve area > 1.2 cm2 (by 
echocardiography using the continuity 
equation) and mean aortic valve gradient < 20 
mmHg or peak velocity < 3 m/sec, without 
moderate or severe prosthetic valve AR) 
• Only one valve implanted in the proper 
anatomical location. 

 
 
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17. Procedural success, defined as device success 
and absence of in-hospital MACCE. 
18. Evidence of prosthetic valve dysfunction at 30 
days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
Trial Sites: 
Up to 50 sites globally 
Sample Size: 
1200 patients (600 MCS TAVI, 600 SAVR) 
Patient Population: 
Patients who have symptomatic severe Aortic 
Stenosis at intermediate surgical risk defined by a 
Society of Thoracic Surgeons’ (STS) mortality risk of 
≥3% and ≤8% will be presented to the Heart Team 
for inclusion in the trial.  In the United States, patients 
must have STS mortality risk of ≥4% and ≤8% to be 
presented to the Heart Team. 
Inclusion Criteria: 
1.   Subject must have STS mortality risk score ≥3% 
and ≤8% (in United States, STS mortality risk 
score ≥4% and ≤8%) 
2.   Heart Team consisting of at least one 
interventional cardiologist and one cardiac 
surgeon agree on indication, treatment proposal, 
and eligibility for randomization based on their 
clinical judgment (including anatomy assessment, 
risk factors, etc.); 
3.   Critical aortic valve area defined as an initial 
aortic valve area of ≤1.0 cm2 or aortic valve area 
index < 0.6 cm2/m2; 
4.   In presence of normal LV function: 
a) Mean gradient > 40mmHg OR Vmax > 4m/sec 
OR 
b)  In presence of low flow, low gradient severe 
AS, a dobutamine stress echo must be 
conducted that demonstrates presence of 
contractile reserve defined as follows ≥20% 
increase in stroke volume and mean gradient 
>40mmHg; 
5.   Subject is symptomatic from his/her aortic valve 
stenosis, as demonstrated by New York Heart 
Association (NYHA) Functional Class II or 
greater; 
6.   The subject and the treating physician agree that 
the subject will return for all required post-
procedure follow-up visits; 
7.   Subject meets the legal minimum age to provide 
informed consent based on local regulatory 
requirements. 

 
 
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Exclusion Criteria: 
1.   Hypersensitivity or contraindication to aspirin, 
heparin, ticlopidine, clopidogrel, coumadin, 
nitinol, or sensitivity to contrast media which 
cannot be adequately pre-medicated; 
2.   Blood dyscrasias as defined: leukopenia (WBC 
<1000mm3), thrombocytopenia (platelet count 
<50,000 cells/mm3), history of bleeding diathesis 
or coagulopathy; 
3.   Ongoing sepsis, including active endocarditis; 
4.   Any condition considered a contraindication to 
extracorporeal assistance; 
5.   Any percutaneous coronary or peripheral 
interventional procedure performed within 30 
days prior to randomization with bare metal 
stents and 6 months with drug eluting stents; 
6.   Symptomatic carotid or vertebral artery disease 
or successful treatment of carotid stenosis within 
six weeks of randomization;  
7.   Cardiogenic shock manifested by low cardiac 
output, vasopressor dependence, or mechanical 
hemodynamic support; 
8.   Recent (within 6 months of randomization) 
cerebrovascular accident (CVA) or transient 
ischemic attack (TIA); 
9.   Active gastrointestinal (GI) bleeding within the 
past 3 months; 
10. Subject refuses a blood transfusion; 
11. Severe dementia (resulting in either inability to 
provide informed consent for the trial/procedure, 
prevents independent lifestyle outside of a 
chronic care facility, or will fundamentally 
complicate rehabilitation from the procedure or 
compliance with follow-up visits); 
12. Multivessel coronary artery disease with a 
Syntax score >22; 
13. Estimated life expectancy of less than 24 
months due to associated non-cardiac co-
morbid conditions; 
14. Other medical, social, or psychological 
conditions that in the opinion of the Investigator 
precludes the subject from appropriate consent 
or adherence to the protocol required follow-ups 
exams; 
15. Currently participating in an investigational drug 
or another device trial (excluding registries); 
16. Evidence of an acute myocardial infarction ≤30 
days before the index procedure; 
17. Need for emergency surgery for any reason; 
18. True porcelain aorta; 
19. Extensive mediastinal radiation; 
20. Liver failure (Child-C); 

 
 
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21. Reduced ventricular function with left ventricular 
ejection fraction (LVEF) <20% as measured by 
resting echocardiogram; 
22. Uncontrolled atrial fibrillation; 
23. Pregnancy or intent to become pregnant prior to 
completion of all protocol follow-up 
requirements; 
24. End stage renal disease requiring chronic 
dialysis or creatinine clearance < 20 cc/min. 
Anatomical Exclusion Criteria 
25. Native aortic annulus size <20 mm or >29 mm 
per the baseline diagnostic imaging; 
26. Pre-existing prosthetic heart valve in any 
position; 
27.  Mixed aortic valve disease [aortic stenosis and 
aortic regurgitation with predominant aortic 
regurgitation (3-4+)]; 
28. Severe mitral or severe tricuspid regurgitation; 
29. Severe mitral stenosis; 
30.  Hypertrophic obstructive cardiomyopathy; 
31. Echocardiographic or Multislice Computed 
Tomography (MSCT) evidence of intracardiac 
mass, thrombus or vegetation; 
32. Ascending aorta diameter >43 mm unless the 
aortic annulus is 20-23 mm in which case the 
ascending aorta diameter >40 mm; 
33. Femoral and left subclavian/axillary access:  
a)  Aortic root angulation (angle between plane 
of aortic valve annulus and horizontal 
plane/vertebrae) > 70°;  
OR  
b)  Right subclavian/axillary access: Aortic root 
angulation > 30°; 
34. Congenital bicuspid or unicuspid valve verified 
by echocardiography. 
Vascular Exclusion Criteria 
35. Transarterial access not able to accommodate 
an 18Fr sheath. 
Enrollment Phase: 
20 months 
Follow-up Evaluations: 
Subjects will be followed through 5 years with 
assessments at 30 days, 3 months, 6 months, 12 
months, 18 months, 24 months, and 3, 4, and 5 
years post MCS TAVI or post SAVR. 
 

 
 
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B 
PURPOSE 
B.1 
Background 
Aortic valve stenosis (AS) is the most prevalent valve disorder in the adult population in 
developed countries affecting approximately 2% to 4% of people over 65 years of age (2, 3) . 
This corresponds to approximately 3 million people with AS in Europe alone. One in five will 
eventually progress to symptomatic AS representing 600,000 patients.  
2
E.U. Pop. >65 (y.o.)
77M
Prevalence Rate
4%
Cardiovascular Health 
Study, Analysis Group, 
STS Database
Prevalence
3M
Aortic valve 
replacement (%)
20%
L.E.K. Consulting,
STS Database, 
EW Analysis
Addressable
Patients Today
600,000
SAVR denied 
~ 200,000
Euro Heart Survey 
extrapolation
Prevalence of Aortic Stenosis
European Union 2008
 
Patients with severe AS face a grim prognosis once they become symptomatic. The landmark 
paper on symptomatic AS by Ross and Braunwald in 1968 highlighted this premise: median 
survival averages only 2, 3 and 5 years after symptom onset of angina, syncope and heart 
failure respectively(4). Furthermore mortality is already substantial in the months following the 
first symptoms (5). The dismal prognosis of patients with untreated severe, symptomatic aortic 
stenosis has been recently corroborated in the conservative treatment arm of the PARTNER B 
cohort. Both, the ESC and ACC/AHA cardiology societies have endorsed guidelines on valvular 
heart disease emphasizing the need for surgical aortic valve replacement (SAVR) once 
symptoms develop or in case of impaired LV function (Level of evidence grade 1)(6, 7).  
Despite these well-established guidelines, one in every three patients with symptomatic AS is 
considered at too high a risk for surgery mostly because of age, left ventricular dysfunction and 
co-morbidities(8). If we would assume that only two in every three patients with symptomatic 
AS would be referred for SAVR and there are 600,000 patients with symptomatic AS in Europe 
alone, this means that hypothetically about 200,000 patients would not be considered for 
intervention(9). This unmistakably underscores an unmet clinical need. Conversely relieving the 
AS would not clear the patients from his/her co-morbidities implicating not only a higher 
operative risk but also a more or less reserved life expectancy. Undoubtedly this reality and 
patients’ and physicians’ preferences for lesser invasive strategies have fuelled the ongoing 
interest in developing minimally invasive transcatheter therapies. 
Alain Cribier pioneered the transcatheter aortic valve implantation (TAVI) technology and 
reported the first in man experience of TAVI in a patient with symptomatic AS who was deemed 
inoperable in 2002(10). Subsequent feasibility studies validated the proof of concept (11, 12). 
The Edwards-SAPIEN valve (Edwards Lifesciences, Irvine, CA, USA) and the Medtronic-

 
 
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CoreValve system (Medtronic Corporation, Minneapolis, MN, USA) are the only two TAVI 
platforms with CE mark approval since 2007.  Numerous single-center and multi-center 
observational registries followed with dazzling speed suggesting the safety and efficacy of the 
TAVI technology (13-17). The TAVI technology comes with its own specific hurdles and 
complications (18), not necessarily overlapping with those of SAVR: vascular injury; stroke, 
cardiac injury such as heart block, coronary obstruction, and cardiac perforation; paravalvular 
leak; and valve misplacement. The non-uniformity in presenting respective data makes 
comparison of results from different centers hazardous and impractical (19, 20). The Valvular 
Academic Research Consortium (VARC), a FDA endorsed collaboration between academic 
research organizations and professional societies in the United States and Europe is an 
initiative to generate a consensus statement on TAVI related definitions aiming to create order 
and uniformity making data more prone to analysis and comparison (21, 22).  
Technical refinements and commercial entrepreneurship have made the technology accessible 
to many centers worldwide. This might pose future implications especially in the current era 
where randomized trials with TAVI are strikingly lacking.  
Grossly, there are three types of medical practices: the first is the institution with on-site 
interventional cardiologic and cardiothoracic surgical activity and with close inter-disciplinary 
collaboration where interventional cardiologists and cardiothoracic surgeons reach a consensus 
on which patients to select for a specific surgical or interventional treatment strategy (9). These 
centers would reasonably respect and adhere to the so-called CE mark labeling indications. 
Secondly there are centers where interventional cardiologists and cardiothoracic surgeons do 
not really convene and work as two separate departments. Finally there are practices running 
an interventional cardiology program without on-site cardiothoracic surgery, estimated to make 
up 37% of all PCI centers in the European Union. Expectedly, these kinds of organizations 
without intimate collaboration between cardiothoracic surgeons and interventional cardiologists 
will look to broaden their interventional activities with an attractive innovation like TAVI. 
Whether this kind of uncontrolled and widespread distribution of a new technology is 
appropriate and timely is debatable. The flipside would be a worldwide practice being less 
controllable, potentially clouding the safety and efficacy profile of the procedure. Needless to 
say that criticism by the medical community and health authorities could jeopardize future 
reimbursement policies (23, 24). The advent of randomized trial data is crucial and this next 
step in establishing a new treatment strategy should not be taken for granted as governmental 
authorities entitled to grant premarket approval to cardiovascular devices are under increased 
scrutiny and quality control (25). 
After nearly a decade of worldwide mounting TAVI experience, the Cohort –B from the much 
anticipated PARTNER (Placement of AoRTic TraNscathetER Valve Trial) trial representing the 
first randomized data set, reporting a dramatic 20% absolute reduction in mortality in favor of 
TAVI compared to medical therapy in patients who, as determined by surgeons could not 
undergo conventional surgical valve replacement (26).  
In the Cohort-A from the PARTNER trial, patients for whom a surgeon and cardiologist concur 
that the predicted risk of operative mortality is ≥15% and/or with a minimum STS score of 10, 
are randomized to TAVI or SAVR. The trial completed its randomization early 2009 and first 
data was presented at ACC, April 2011 reporting achievement of the primary endpoint (TAVR 
was non-inferior to AVR for all-cause mortality at 1 year). 
At the PCR London Valves meeting in October 2010 was reported that over 22000 patients 
have been treated with TAVI worldwide. More specifically, over 12000 Medtronic CoreValve 
System have been implanted worldwide (data on file provided by Medtronic). Inevitably, with 
increased operator experience and access to the device, physicians will shift their attention to 
younger patients with a less pronounced operative risk. Similar to the coronary 
revascularization arena (27), the blending of surgical and interventional expertise has created 
unique interdisciplinary dynamics paving the way for a randomized trial comparing TAVI with 
SAVR in a surgical intermediate risk patient population.  
It is in this spirit that the SURTAVI trial (SURgical and Transcatheter Aortic Valve Implantation) 
was conceived. The interdisciplinary approach and consensus of the so-called Heart Team (the 
cardiothoracic surgeon, interventional cardiologist and other treating physicians if necessary) is 
crucial. This aspect of decision making cannot be over-emphasized and is essential for the 
quality of current medical practice in general and any planned randomized trial of TAVI versus 

 
 
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SAVR in particular. The VARC publication (21, 22) on TAVI definitions and the accumulating 
TAVI expertise in Europe has created a unique momentum for such a European based 
randomized initiative complementary to the US pivotal IDE randomized trial in AS patients with 
high operative risk.  
For a new technology to be accepted as a new asset in the armamentarium for treating 
symptomatic AS several essential questions need to be answered: is the technology effective? 
Which patients are likely to benefit (patient selection)? How does this new strategy compare 
with the alternatives? And what’s the cost of the intervention? The proof of concept has been 
validated. The innovative less invasive transcatheter strategy should be at least as effective 
and safe than conventional SAVR or have proof of superiority for both safety and efficacy 
compared to medical therapy.  
Theoretical benefits of this transcatheter approach in a beating heart by avoiding the need of 
musculoskeletal incisions, cardioplegic arrest, aortic cross clamping, aortotomy, full 
cardiopulmonary bypass seem evident. Ultimately the cost-effectiveness will determine whether 
the new treatment strategy is a valid option to be considered for reimbursement by 
governmental health institutions.  
B.2 
Medtronic CoreValve® System and Intended Use 
B.2.1 Device Description 
The Medtronic CoreValve System consists of the following product elements: 
 
Percutaneous Aortic Valve Bioprosthesis (PAV): consisting of a multi-level self-
expanding frame with porcine pericardial bioprosthesis.  The bioprosthesis is 
processed with an antimineralization treatment of alpha-amino oleic acid (AOA) a 
compound derived from oleic acid, a naturally occurring long-chain fatty acid. 
 
Delivery Catheter System (DCS): designed to house the tissue valve prosthesis in the 
collapsed position for percutaneous delivery to the patient’s aortic annulus. 
 
Compression Loading System (CLS): facilitates consistent and trauma-free manual 
loading of the PAV into the DCS. 
The models to be used are:   
 
Percutaneous Aortic Valve Prosthesis (PAV) - Model MCS-P3-26-AOA (26mm) and 
MCS-P3-29-AOA (29mm) and MCS-P3-31-AOA (31mm) (CE mark application 
pending) 
 
Delivery Catheter System (DCS) – DCS-C4-18Fr AccuTrak® Delivery System (CE 
marked in July 2010) 
 
Compression Loading System (CLS) - Model CLS-3000-18Fr (CE marked in 2007) 
In addition, any future approved models may be used in the study. 
The PAV is adapted to a range of aortic annulus and ascending aorta diameters as shown in 
Table 1. 
Table 1:  Patient Anatomical Diameters  
MCS-PAV and patient’s Characteristics 
REF# 
Aortic Annulus Diameter 
(range in mm) 
Aortic Diameter @ Sino-tubular 
Junction (range in mm) 
MCS-P3-26-AOA 
20-23 
≤40 
MCS-P3-29-AOA 
23-27 
≤43 
MCS-P3-31-AOA 
26-29 
≤43 
 

 
 
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B.2.2 Device Approval Status 
The Notified Body NSAI granted an approval for CE Marking for the 18Fr CoreValve 
ReValving™ System (renamed to ―Medtronic CoreValve System‖ after acquisition from 
CoreValve Inc. by Medtronic Inc. on 9 April 2009) effective March 1, 2007. Model MCS-P3-640 
(26mm) and MCS-P3-943 (29mm) received CE mark effective 2006) and MCS-P3-943 (31mm) 
received CE marked in July 2011.  The models to be used in this trial, listed in Table 1, are 
identical to the CE marked device with exception of the addition of antimineralization treatment 
of alpha-amino oleic acid AOA to the device.  
A new Delivery Catheter System (DCS) with AccuTrak® Stability Layer was designed to 
optimize the valve positioning and will be used in this trial. CE mark approval was received on 
July 2010. The DCS and CLS components used for this trial are the CE marked product.  
Medtronic submitted an Original IDE (G100012) to seek approval to initiate an Investigational 
Device Exemption for the Medtronic CoreValve System. This study is intended for use in 
subjects with severe symptomatic Aortic Stenosis (AS) necessitating aortic valve replacement 
in Extreme Risk and High Risk Patient Populations. This IDE was conditionally approved on 
October 13, 2010 and received full approval on November 10, 2011.   
B.2.3 Intended Use of the Device 
The Medtronic CoreValve® System is intended for use in patients who have symptomatic 
severe aortic stenosis (AS) necessitating valve replacement and who are at intermediate 
surgical risk defined by a Society of Thoracic Surgeons’ (STS) mortality risk of ≥3% and ≤8% 
and presenting with anatomical dimensions as described in Table 1. 
B.3 
Study Objectives 
B.3.1 Primary 
The primary objective of this trial is to evaluate in a prospective randomized fashion whether 
TAVI is non-inferior to SAVR with respect to the event free survival of the combined endpoint of 
all-cause mortality and major stroke at 24 months in patients with symptomatic severe aortic 
stenosis and at intermediate surgical risk.  
B.3.2 Secondary 
The secondary objective of this trial is to assess differences in quality of life, clinical benefit 
(combined efficacy endpoint) and health economics in patients with symptomatic severe aortic 
stenosis and at intermediate risk treated with either Transcatheter Aortic Valve Implantation 
(TAVI) or Surgical Aortic Valve Replacement (SAVR). 
B.3.3 Exploratory 
An analysis will be conducted to determine if patients can be identified as intermediate risk for 
Transcatheter Aortic Valve Implantation (TAVI) based upon age and the presence of a defined 
list of co-morbidities commonly associated with patients undergoing TAVI procedures.  A 
complete discussion of this exploratory objective can be found in Appendix R.22. 
 

 
 
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C 
TRIAL PROTOCOL 
C.1 
Ethics and Regulatory Compliance 
C.1.1 Applicable Regulations 
This trial will be conducted in compliance with the protocol, the Sponsor’s standard operating 
procedures and/or guidelines, the United States Food and Drug Administration (FDA) and local 
regulations where applicable, the International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines, ISO14155 (2011), and the Declaration of Helsinki. 
C.1.2 Institutional Review Board (IRB)/Medical Ethics Committee (MEC) 
The trial will be conducted in accordance with 21 CFR 56 Institutional Review Boards.  The trial 
protocol and consent must be approved by the responsible Institutional Review Board (IRB) or 
Medical Ethics Committee (MEC) at each investigational site.  Trial activities must not 
commence prior to receipt of documentation of IRB/MEC approval by the site and Medtronic.  
The Investigator and trial staff must comply with the requirements of their IRB/MEC. 
Prior to enrolling subjects in this study, each investigation site’s IRB/MEC will be required to 
approve the current study clinical investigation plan, the Patient Information and Informed 
Consent form, and any other written information to be provided to the subjects. The approved 
consent form should clearly reflect the IRB/MEC approval date. In the US, Investigator must 
also utilize IRB approved Health Insurance Portability and Accountability Act (HIPAA) 
Authorization.  
IRB/MEC approval of the clinical study must be received in the form of a letter and provided to 
Medtronic before commencement of the study at an investigation site. The approval letter must 
contain enough information to identify the version or date of the documents approved. In 
addition the approval letter needs to be accompanied by an IRB/MEC roster or letter of 
compliance, to allow verification that the investigator, other center study staff, and/or Medtronic 
personnel are not members of the IRB/MEC. If they are members of the IRB/MEC, written 
documentation is required stating that he/she did not participate in the approval process. 
Investigators must inform Medtronic of any change in status of IRB/MEC approval once the 
investigation site has started enrolment. 
C.1.3 Regulatory Submission 
Prior to enrolling any patients in the study, all local regulatory requirements must be fulfilled. 
Each study site must have written documentation of site/investigator readiness, including but 
not limited to IRB/MEC approval of the current version of the Investigational Plan, Informed 
Consent form, a signed Investigator’s Agreement, current investigator curriculum vitae, and 
documentation of training.  The coordinating and principal investigators shall agree to this 
investigational plan and any amendments and indicate their approval by signing and dating the 
Investigator’s Agreement. 
Approval from the Regulatory Authorities, if applicable, is required prior to the first patient 
enrollment in a particular center. Medtronic will obtain a copy of the approval letter, directly from 
the Regulatory Authorities. 
If any action is taken by an IRB/MEC with respect to the investigation, that information will be 
forwarded to Medtronic by the respective investigator. 
Other documents that are referred to in this Clinical Investigation Plan are listed below and will 
be made available upon request: 
 
Monitoring Plan 
 
Data Management Plan 
 
Statistical Analysis Plan 
 
Patient Information and Informed Consent Form 
 
Case Report Forms 
 

 
 
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C.1.4 Ethical Conduct of the Trial 
The trial will be conducted in accordance with the design and specific provisions of this 
protocol, in accordance with the ethical principles that have their origin in the Declaration of 
Helsinki, and that are consistent with Good Clinical Practice (GCP) and the applicable 
regulatory requirements. 
The principles of the Declaration of Helsinki have all been implemented in this study by means 
of the patient informed consent process, IRB/MEC approval, study training, clinical trial 
registration, preclinical testing, risk benefit assessment, and publication policy. 
C.2 
Trial Administration 
C.2.1 Steering Committee 
The Steering Committee will be an advisory body to Medtronic.  Their roles and responsibilities 
may include, but are not limited to the following: 
 
Overall conduct of the study with regard to  
o 
Protocol development and implementation 
o 
Study progress 
o 
Patient safety 
o 
Data quality and integrity 
 
Quality performance at individual sites 
o 
The Steering Committee will support site investigators in resolving any clinical 
or procedural issues that may impact patient well-being or integrity of the study 
o 
Any site placed on probation for any reason may be terminated from the study 
after an appropriate review by the Steering Committee 
 
Review of all Data Safety Monitoring Board (DSMB) recommendations 
 
Assess requests for sub-studies 
 
Assist with Publication efforts by disseminating study information through appropriate 
scientific sessions and publications 
o 
All requests for abstract and manuscript preparation and submission require 
Steering Committee review and approval. All final decisions will be made by 
Medtronic; however, the recommendations made by the Steering Committee 
will be highly considered 
 
Participate in Investigator Meetings (and other study related meetings) 
 
Serve as a contact for other study investigators (providing peer consultation) 
Prior to the onset of the trial, the Steering Committee will establish a charter.  The Steering 
Committee charter will be approved by Medtronic and the Steering Committee members. 
C.2.2 Publication Committee 
The Publication Committee will review and approve publication ideas and facilitate 
submissions, including abstracts and manuscripts.  The Publication Committee will consist of 
SURTAVI trial investigators (interventional cardiologists and cardiac surgeons) and Medtronic 
representatives. 
The Publication Committee will be responsible for: 
 
Defining and refining the publication strategy 
 
Overseeing the development of manuscripts, abstracts, and presentations 
 
Identifying and appointing the manuscript/abstract first author(s)/writer(s)/presenters(s) 
 
Reviewing the publication 
Prior to the onset of the trial, the Publication Committee will establish a plan.  The Publication 
Committee plan will be approved by Medtronic and the Publication Committee members. 

 
 
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C.3 
Methodology 
C.3.1 Purpose 
The purpose of this study is to investigate the safety and efficacy of transcatheter aortic valve 
implantation (TAVI) in patients with severe, symptomatic Aortic Stenosis (AS) at intermediate 
surgical risk by randomizing patients to either Surgical Aortic Valve Replacement (SAVR) or 
TAVI with the Medtronic CoreValve® System. The total trial duration is expected to be 
approximately seven years. 
Data from this trial will be used to support regulatory applications in seeking approval for the 
Medtronic CoreValve System in the intermediate surgical risk population. 
C.3.2 Patient Population 
Patients who have symptomatic severe Aortic Stenosis at intermediate surgical risk defined by 
a Society of Thoracic Surgeons’ (STS) mortality risk of ≥3% and ≤8% will be presented to the 
Heart Team for inclusion in the trial.  In the United States, patients must have STS mortality risk 
of ≥4% and ≤8% to be presented to the Heart Team.  While results for the entire population of 
randomized patients with STS mortality risk of ≥3% and ≤8% will be used for publication 
purposes, the subgroup of patients with STS mortality risk of ≥4% and ≤8% will be analyzed for 
the purpose of obtaining FDA approval. 
C.3.3 Design 
This study is designed as a prospective, multi-center, multi-national, randomized, interventional 
study trial to investigate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in 
patients with severe, symptomatic Aortic Stenosis (AS) at intermediate surgical. 
Approximately, 1200 subjects will be recruited in up to 50 investigational centers located in the 
United States and Europe.  The study may be expanded to include additional geographies based on 
enrolment rates and identification of qualified centers. 
Subjects will be randomized on a 1:1 basis to either transcatheter aortic valve implant (TAVI) 
with the Medtronic CoreValve® System (MCS) or to surgical aortic valve replacement (SAVR). 
To avoid bias in the study population the following measures have been taken: 
 
All sponsor and external study personnel will be trained on the Clinical Investigation 
Plan (CIP) and related study materials; and 
 
Subjects will be screened to confirm study eligibility with defined inclusion/exclusion 
criteria prior to enrollment. 
C.3.4 Investigational Centers 
The trial will be a multicenter, multinational trial conducted at up to 50 investigational centers.   
For this study, the following investigator/center selection minimum criteria are considered: 
 
Center must have sufficient patient population  
 
Each participating CoreValve implanter must have completed at least 30 cumulative 
TAVI procedures  
 
There will be no other study ongoing during this study duration, which is in conflict with 
the SURTAVI study 
 
Investigator should have adequate staff that is accessible and has time to manage the 
study for 7 days per week, 24 hours per day 
 
Investigator, co-investigators, and study staff must be willing to provide his/her 
Curriculum Vitae 
 
Investigator and co-investigators must be willing to sign and comply with the protocol-
specific Investigator Agreement 
 
Center must be willing to comply with the Clinical Investigation Plan and data 
requirements, including reporting Adverse Events 

 
 
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 
Center has demonstrated experience with conducting clinical (device) trials that comply 
with applicable regulatory standards 
 
Center is willing to participate in follow-up of patients for 5 years 
 
Center has an internet connection with sufficient speed of data transfer 
All investigators will be appropriately qualified practitioners legally entitled to practice, and 
experienced in the diagnosis and treatment of patients requiring an aortic valve treatment with a 
TAVI or SAVR.  
For the purposes of the SURTAVI study, it is imperative that Medtronic leverages highly 
qualified surgeons for the surgical aortic valve replacements (SAVR) that will occur as a part of 
the trial. The following minimum criteria will be used for all cardiac surgeons performing SAVRs 
in the SURTAVI study:    
 
At least 5 years of experience post-residency 
 
At least 100 career aortic valve replacements post-residency 
 
At least 75 valve procedures in the last 3 years 
 
At least 35 surgical aortic valve replacements in the last 3 years 
 
At least 15 aortic valve replacements in the last year 
C.3.5 Number of Subjects 
1,200 subjects will be randomized [600 MCS TAVI: 600 Surgical Aortic Valve Replacement 
(SAVR)]. The anticipated enrollment rate is 60 subjects per month with total enrollment phase 
of approximately 20 months. 
Enrollments shall not exceed 20% (240) of total randomized subjects at any individual site. 
Enrollment is competitive; therefore there is no set minimum number of subjects to be enrolled 
per site. 
C.3.6 Inclusion/Exclusion Criteria 
C.3.6.1 
Inclusion Criteria 
To participate in this trial, the subject must meet ALL of the following inclusion criteria.  
1. Subject must have Society of Thoracic Surgeon (STS) mortality risk score ≥3% and 
≤8% (in United States, STS mortality risk score ≥4% and ≤8%); 
2. Heart Team consisting of at least one interventional cardiologist and one cardiac 
surgeon agree on indication, treatment proposal, and eligibility for randomization based 
on their clinical judgment (including anatomy assessment, risk factors, etc.,); 
3. Critical aortic valve area defined as an initial aortic valve area of ≤1.0 cm2 or aortic 
valve area index < 0.6 cm2/m2; 
4. In presence of normal left ventricular (LV) function: 
a) Mean gradient > 40mmHg OR Vmax > 4m/sec 
OR 
b) In presence of low flow, low gradient severe AS, a dobutamine stress echo must be 
conducted that demonstrates presence of contractile reserve defined as follows 
≥20% increase in stroke volume and mean gradient >40mmHg; 
5. Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New 
York Heart Association (NYHA) Functional Class II or greater; 
6. The subject and the treating physician agree that the subject will return for all required 
post-procedure follow-up visits; 
7. Patient meets the legal minimum age to provide informed consent based on local 
regulatory requirements. 

 
 
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C.3.6.2 
Exclusion Criteria 
Subjects are NOT eligible for trial participation if they meet ANY of the following exclusion 
criteria: 
1. Hypersensitivity or contraindication to aspirin, heparin, ticlopidine, clopidogrel, 
coumadin, nitinol, or sensitivity to contrast media which cannot be adequately pre-
medicated; 
2. Blood dyscrasias as defined: leukopenia (WBC <1000mm3), thrombocytopenia (platelet 
count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy; 
3. Ongoing sepsis, including active endocarditis; 
4. Any condition considered a contraindication to extracorporeal assistance; 
5. Any percutaneous coronary or peripheral interventional procedure performed within 30 
days prior to randomization with bare metal stents and 6 months with drug eluting 
stents; 
6. Symptomatic carotid or vertebral artery disease or successful treatment of carotid 
stenosis within six weeks of randomization;  
7. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or 
mechanical hemodynamic support; 
8. Recent (within 6 months of randomization) cerebrovascular accident (CVA) or transient 
ischemic attack (TIA); 
9. Active gastrointestinal (GI) bleeding within the past 3 months; 
10. Subject refuses a blood transfusion; 
11. Severe dementia (resulting in either inability to provide informed consent for the 
trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will 
fundamentally complicate rehabilitation from the procedure or compliance with follow-
up visits); 
12. Multivessel coronary artery disease with a Syntax score >22; 
13. Estimated life expectancy of less than 24 months due to associated non-cardiac co-
morbid conditions; 
14. Other medical, social, or psychological conditions that in the opinion of the Investigator 
precludes the subject from appropriate consent or adherence to the protocol required 
follow-ups exams; 
15. Currently participating in an investigational drug or another device trial (excluding 
registries); 
16. Evidence of an acute myocardial infarction ≤30 days before the index procedure; 
17. Need for emergency surgery for any reason; 
18. True porcelain aorta; 
19. Extensive mediastinal radiation; 
20. Liver failure (Child-C); 
21. Reduced ventricular function with left ventricular ejection fraction (LVEF) <20% as 
measured by resting echocardiogram; 
22. Uncontrolled atrial fibrillation; 
23. Pregnancy or intent to become pregnant prior to completion of all protocol follow-up 
requirements; 
24. End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min. 

 
 
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Anatomical exclusion criteria 
25. Native aortic annulus size <20 mm or >29 mm per the baseline diagnostic imaging; 
26. Pre-existing prosthetic heart valve in any position; 
27. Mixed aortic valve disease [aortic stenosis and aortic regurgitation with predominant 
aortic regurgitation (3-4+)]; 
28. Severe mitral or severe tricuspid regurgitation; 
29. Severe mitral stenosis; 
30. Hypertrophic obstructive cardiomyopathy; 
31. Echocardiographic or Multislice Computed Tomography (MSCT) evidence of 
intracardiac mass, thrombus or vegetation; 
32. Ascending aorta diameter >43 mm unless the aortic annulus is 20-23 mm in which 
case the ascending aorta diameter >40 mm; 
33. Femoral and left subclavian/axillary access:  
a) Aortic root angulation (angle between plane of aortic valve annulus and horizontal 
plane/vertebrae) > 70°  
OR 
 
b) Right subclavian/axillary access: Aortic root angulation > 30°; 
34. Congenital bicuspid or unicuspid valve verified by echocardiography. 
Vascular Exclusion Criteria 
35. Transarterial access not able to accommodate an 18Fr sheath. 
C.3.7 Informed Consent 
The investigator must obtain written informed consent prior to subjecting the subject to any 
study related activity.  
Well in advance of the consent discussion, the subject should receive the MEC/IRB approved 
Patient Information and Informed Consent Form (ICF). During the consent discussion the 
investigator or his/her designee must fully inform the subject of all pertinent aspects of the study 
including the approval of the MEC/IRB of the written Patient Information. If a subject is illiterate, 
an impartial witness must be present during the entire informed consent discussion. All items 
discussed in the Patient Information and the ICF must be explained. The language used shall 
be in the subject’s native language, as non-technical as possible and must be understandable 
to the subject and the impartial witness, where applicable.  
The subject must have ample time and opportunity to inquire about details of the study, and to 
decide whether or not to participate in the clinical study. All questions about the study should be 
answered to the satisfaction of the subject. 
Neither the investigator, nor the investigation site staff shall coerce or unduly influence a 
subject to participate or to continue to participate in the clinical study. The informed consent 
process shall not appear to waive the subject’s rights. 
When the subject decides to participate in the clinical study, the ICF must be signed and 
personally dated by the subject and investigator. If applicable, the witness shall also sign and 
personally date the consent form to attest that the information in the Patient Information and 
Informed Consent Form was accurately explained and clearly understood by the subject, and 
that informed consent was freely given.  
Signing the ICF serves to document the written and verbal information that the Investigator or 
authorized delegate provides to the patient or legal representative, the patient or legal 
representative’s understanding of the information, and their agreement to participate.  The 
Investigator or authorized delegate must document in the patient’s medical records that the 
patient was consented and the date on which the consent was obtained.  The original signed 
consent form will be retained in the patient’s trial records.  A copy of the informed consent will 

 
 
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be provided to the patient or legal representative and a copy placed in the patient’s medical 
record. 
Data relating to the trial might be made available to third parties (for example in case of an audit 
performed by regulatory authorities), provided the data are treated as confidential and that the 
subject’s privacy is guaranteed.  In the United States, ―Protected Health Information‖ will be 
maintained in compliance with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). 
C.3.8 Revisions in Patient Information and Informed Consent Form 
Medtronic will inform the investigators whenever information becomes available that may be 
relevant to the subject’s continued participation in the study. The investigator or his/her 
designee should inform the subject in a timely manner.  Medtronic will revise the written ICF 
whenever new information becomes available that may be relevant to the subject’s continued 
participation in the study. The revised information will be sent to the investigator for approval by 
the IRB/MEC. After approval by the IRB/MEC, a copy of this information must be provided to 
the participating subjects, and the informed consent process as described above needs to be 
repeated.  
C.3.9 
Enrollment Flowchart for Randomization to MCS TAVI or SAVR 
Table 2: Enrollment Flowchart 
 
 
If the patient meets all of the inclusion criteria and none of the exclusion and Heart Team 
determines the patient is eligible for randomization in the SURTAVI trial, subjects will be 
randomized on a 1:1 basis to either TAVI or SAVR.  Randomization will be stratified by the 
need for coronary revascularization. In case of required coronary revascularization, 
concomitant percutaneous coronary intervention (PCI) and TAVI is encouraged; however 
staging is left at the discretion of the operator. Coronary artery bypass graft (CABG) should be 
conducted during the index procedure. 
A total of 1200 patients will be enrolled in the randomized trial (600 TAVI, 600 SAVR).  

 
 
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C.3.10 Trial Training 
Prior to investigational site activation or subsequent involvement in study activities, Medtronic 
(or designee) will provide study training relevant and pertinent to the involvement of personnel 
conducting study activities, including investigator responsibilities, adverse event reporting as 
well as device training (if necessary, usage and handling of device under investigation). 
Training may be conducted via Site Initiation Visits, Investigator and Coordinator Meetings, 
and/or other media sessions. The sponsor will maintain documentation of attendance at each of 
these training opportunities, as applicable.  
Additionally, Medtronic representative(s) may be present at each site’s MCS TAVI procedures 
as part of the ongoing training process. 
C.4 
Trial Procedures 
C.4.1 Screening Procedures 
Prior to any trial-specific tests or procedures, written informed consent must be obtained from 
the subject. Failure to obtain a signed and hand dated informed consent prior to the procedure 
constitutes a protocol violation, which is reportable to the IRB/MEC, the Food and Drug 
Administration (FDA), and other regulatory authorities as applicable. 
All potential subjects for trial entry must be screened for eligibility. All patients with symptomatic 
severe AS that provide informed consent will be entered into the Electronic Data Capture (EDC) 
system and total number of patients screened will be counted.  The reasons why a patient did 
not enter the Heart Team meeting will be collected [e.g. patient does not have STS mortality 
risk score ≥3% and ≤8% (in United States ≥4% and ≤8%)] and, age, STS score, and co-
morbidities.  
Data readily available in the patient’s medical record may be utilized to fulfill screening 
requirements and do not need to be repeated. If not previously completed, the following tests 
and procedures must be performed prior to randomization to verify eligibility. The 
recommended timeframe for these tests and procedures is within30 days prior to submission to 
the Heart Team, unless otherwise specified. 
 
Demographics and Medical History 
 
Clinical Assessments and Physical Examination including:  vital signs and all major 
systems findings, weight, height, and body surface area (BSA); BSA will be calculated 
from height and weight by use of the formula by Dubois and Dubois (BSA = 0.007184 × 
weight [kg]0.425 × height [m]0.725)] 
 
NYHA classification 
 
STS Risk Score, Logistic EuroSCORE, SYNTAX Score, Katz Index of Independence in 
Activities of Daily Living 
 
Co-morbidities 
 
Routine Laboratory Tests: 
o 
Complete Blood Count: 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance  
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio, if applicable  
o 
Activated Partial Thromboplastin Time  
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
o 
Albumin Sodium  
o 
Potassium 

 
 
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 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic two-dimensional (2D) echocardiogram (TTE). 
The TTE must be performed within 45 days prior to review by the Heart Team. 
[Note: if patient recently underwent balloon aortic valvuloplasty (BAV), a TTE 
should be obtained post-BAV; within 45 days prior to review by the Heart 
Team].  Echocardiograms will be performed according to the Echocardiography 
Procedures found in Appendix R.7.  All echocardiograms for randomized 
subjects will be independently analyzed by the Echocardiographic Core Lab. 
 
Multi-Slice Computed Tomography (MSCT) Angiogram 
o 
Multi-Slice Computed Tomography (MSCT) angiograms with complete 
visualization of both iliacs, femorals and aorta (and subclavian/axillaries, if 
applicable), up to and including the aortic annulus.  In the situation where 
subjects have compromised renal function that precludes contrast media, 
Magnetic Resonance (MR) imaging may be used as an alternative.  MSCT 
angiograms will be performed according to the Computed Topography (CT) 
Angiography Acquisition Guidelines found in Appendix R.9. If the MSCT 
angiogram was conducted in the last 365 days and subject has not had a 
peripheral vascular intervention since the time of the image, a more recent 
exam is not required as long as visualization of both iliacs and femorals (and 
subclavian/axillaries, if applicable) to the aorta can be viewed.  However, if the 
subject had a peripheral vascular intervention, the exam must be repeated 
after the intervention and within 90 days of review by the Heart Team. 
 
Coronary Arteriogram 
o 
Selective coronary arteriography to assess the presence and severity of 
coronary artery disease which should include angiograms of both coronary 
arteries and all bypass grafts (if applicable). If the coronary arteriogram has 
been performed within the last 365 days and the subject qualifies for the study 
(no significant coronary artery disease), a more recent exam is not required.  
However, if the subject had evidence of significant coronary artery disease 
and/or received a coronary intervention, the exam must be repeated after the 
intervention and within 90 days of review by the Heart Team. 
 
12-lead Electrocardiogram (ECG) 
C.4.2 Heart Team Procedures 
Each center will utilize a Heart Team consisting of at least one interventional cardiologist and 
one cardiac surgeon to make final determination regarding eligibility of the prospective subject 
to be randomized in the SURTAVI trial.  In order for a subject to be presented to the Heart 
Team, they must have an STS mortality risk score of ≥3% and ≤8%.  In the United States, 
patients must have STS mortality risk score of ≥4% and ≤8%. 
Prior to determining if a patient is eligible for randomization the Heart Team will review each 
patient’s screening data and confirm the following: 
 
STS risk calculation was properly performed 
 
Any additional risk factors not accounted for in the STS risk calculator (e.g. frailty) that 
may increase the level of surgical risk: 
o 
Are properly documented  
o 
Confirm there is no incremental risk that would exclude the patient (i.e. increase 
relative surgical risk to greater than intermediate risk) 
 
All inclusion criteria are met and none of the exclusion criteria 
The final decision of the local Heart Team will be documented in a co-signed decision form. 

 
 
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C.4.3 Enrollment and Randomization 
Prior to randomization and enrollment of a subject, the following must occur: 
 
Confirm signed informed consent 
 
Confirm patient meets all of the inclusion and none of the exclusion criteria, including 
approval by the Heart Team 
Subjects will be considered enrolled into the trial at the time of randomization1 (i.e. time of 
treatment assignment).  Randomization will occur only if the patient meets all inclusion criteria 
and does not meet any exclusion criteria and has been assessed by the Heart Team as being 
an appropriate candidate for randomization in the SURTAVI trial.   
Due to the inclusion/exclusion criteria, not all patients that consent to the trial will be enrolled.  
All sites will be required to maintain a record of patients screened for the trial meeting general 
inclusion criteria who have signed the approved informed consent document.  For subjects that 
do not meet trial criteria, the reason for not continuing in the trial must be documented and 
recorded in the EDC system.  Patients consented but not randomized will be considered screen 
failures and no further study-related follow-up will be required. 
Subjects must have their MCS TAVI or SAVR procedure no later than 30 days post-
randomization.  
Trial randomization will not be blinded.  Once randomization is complete and a treatment arm is 
assigned, crossover from SAVR to TAVI treatment is not permitted.  The sponsor will strictly 
monitor device dispensation to ensure that only those subjects randomized to the MCS TAVI 
treatment arm receive the Medtronic CoreValve® PAV. 
Distribution of the subjects within the trial groups will be controlled at the implanting sites by 
means of central randomization using interactive voice/web randomization service (IXRS).  The 
randomization scheme will be securely stored at the IXRS provider. 
Randomization with an assignment to the treatment arm or control arm (MCS TAVI or SAVR) 
will be executed in a 1:1 ratio. Stratified randomization by investigational site and by the need 
for coronary revascularization will be used to ensure subjects will be allocated to each 
comparison group proportionately. Additionally, a blocked randomization scheme with random 
block sizes will be used within each stratum. 
Subjects outside the United States with STS mortality risk score of ≥3% and <4% will be limited 
to a total of 300 subjects. 
C.4.4 Baseline Assessments 
The following baseline assessments should occur within 14 days prior to the index procedure. 
 
Clinical Assessment and Physical examination 
 
NYHA classification 
 
Concomitant medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Routine Laboratory Tests: 
o 
Complete Blood Count 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio, if applicable  
                                                     
 
1   Based on protocol design, the time of enrollment will be the same as randomization which is a deviation from ISO 
14155 (2011) 

 
 
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o 
Activated Partial Thromboplastin Time (aPTT) 
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
Neurological Assessments: 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Modified Rankin Score (mRS) – for subjects with history of stroke only 
o 
Mini-Mental State Exam (MMSE-2)Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
12-lead Electrocardiogram (ECG) 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event Review 
C.4.5 Medtronic CoreValve® System TAVI or Surgical Aortic Valve Replacement 
Procedure 
C.4.5.1 
MCS TAVI 
General Procedural Considerations  
Transcatheter Aortic Valve Implantation (TAVI) requires meticulous preparation and typically a 
multi-disciplinary team approach involving among others, interventional cardiologists, cardiac 
imaging specialists, cardio-thoracic surgeons and anesthesiologists.  
In case of significant coronary artery disease that requires revascularization, the heart team will 
assess the feasibility of performing PCI simultaneously with the TAVI procedure based on the 
coronary lesion characteristics. When it is anticipated PCI can be performed in timely fashion 
with only a limited amount of additional contrast medium it is encouraged to perform PCI 
concomitant with the TAVI. When PCI is deemed challenging requiring relatively more time and 
contrast medium, staged PCI is recommended: TAVI will then be performed at least 7 days 
after PCI.  
The implantation procedure itself takes place either in a catheterization laboratory with 
adequate hygiene precautions or ideally in a hybrid operating room equipped for state-of-the-art 
transcatheter and/or surgical procedures.  
The execution of the TAVI involves an operating team typically consisting of 1 or 2 operators, 
an anesthesia team and at least 2 nurses/technicians.  
Both the dedicated ―valve team‖ and the operators should have the expertise to select the 
appropriate access route and device size on a patient-per-patient basis. 
All patients undergoing TAVI should be treated using the ilio-femoral access route by default 
(first treatment strategy). Additional non-ilio-femoral access routes will only be used in case ilio-
femoral access is not feasible. 
The use of an embolic protection device during the TAVI procedure is not permitted. 

 
 
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Pre-Procedure 
 
If the patient is currently on warfarin therapy, or local equivalent, prior to the procedure: 
o 
Discontinue warfarin therapy 3 days prior to the procedure 
o 
Confirm that the INR < 1.8 prior to the procedure 
o 
Administer antiplatelet therapy: 
 
Aspirin (75- 325 mg) daily or  
 
Clopidogrel (75 mg) daily (or ticlopidine if clopidogrel is contraindicated) for 3 
days prior to the procedure 
 
If the patient is currently not on warfarin therapy prior to the procedure: 
o 
Aspirin (75-325 mg) on the day of the procedure and 
o 
Clopidogrel (300 mg)  
 
Consider adjunctive proton pump inhibitors, H2 antagonists or antacids 
 
Routine Laboratory Tests: 
o 
Complete Blood Count 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
 
If the GFR < 60 cc/min, consider: 
 Fluid hydration on the day prior to the procedure 
 Discontinuation of NSAIDs and ACE inhibitors 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio, if applicable  
o 
Activated Partial Thromboplastin Time  
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
12-lead Electrocardiogram (ECG) 
MCS TAVI Procedure 
 
Medications 
One hour prior to the procedure, prophylactic antibiotic therapy of the Investigator’s choice 
should be initiated: 
o 
Cefuroxime 750mg intravenous (IV) 1 hour pre-procedure, then 6 hours and 12 hours 
post-procedure 
o 
If allergic to Penicillin, prescribe Vancomycin 1g IV  
o 
Consider holding anti-hypertensives 
 
Anesthesia and Procedural Set Up 
o 
Establish a central venous line  
o 
Administer general anesthesia or conscious sedation per hospital protocol 
o 
Prior to beginning the Medtronic CoreValve® System implant, place a temporary 4-5 
Fr. balloon-tip pacing wire in a stable location within the right ventricular (a screw-tip 
wire may be used for more secure placement for subjects at high-risk for 
dislodgement, if necessary) 
o 
Whenever possible, use the upper torso venous system (e.g., jugular, subclavian) for 
temporary pacing wire access 
o 
Use fluoroscopy to guide wire placement and stability 
o 
Confirm sensing and capture 
o 
Program the backup pacing rate to minimize ventricular pacing (e.g. 30-40 bpm). If 
heart block develops, adjust the rate accordingly 

 
 
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o 
Record ECG and angiogram during the procedure 
 
Vascular Access 
o 
The primary access artery will be used to introduce the CoreValve device and the 
balloon catheter; the secondary access artery will be used to introduce the reference 
pigtail 
o 
Insert a 6Fr introducer sheath into the secondary access artery 
o 
Insert 18Fr introducer sheath into the primary access artery using hospital protocol 
(either percutaneously or surgical cut down) 
o 
Administer anticoagulant therapy according to hospital protocol. If heparin is 
administered as an anticoagulant, check activated clotting time (ACT) at five minutes 
and monitor every 30-60 minutes after initial bolus of heparin  
o 
Maintain ACT ≥ 250 seconds 
o 
Anticoagulant may be administered at any time prior to this point, but avoid delaying 
beyond this point 
 
Crossing the native valve 
o 
Advance the graduated pigtail catheter to the ascending aorta and position the distal 
tip in the noncoronary cusp of the native aortic valve 
o 
Identify the ideal annular viewing plane using contrast injections at various 
angiographic angles, preferably in the left anterior oblique (LAO) projection 
o 
Insert an angiographic catheter over a standard, J-tip guidewire into the primary 
access sheath and advance to the ascending aorta 
o 
Exchange the J-tip guidewire for a 0.035-in (0.889-mm) straight-tip guidewire. 
Advance the straight-tip guidewire across the native aortic valve into the left ventricle 
o 
After crossing the native aortic valve with the guidewire, advance the angiographic 
catheter into the left ventricle 
o 
Exchange the straight-tip guidewires for an exchange-length J-tip guidewire 
o 
Exchange the angiographic catheter for a 6Fr pigtail catheter 
o 
Remove the guidewire and connect the catheter to the transducer. Using both 
catheters, record the aortic pressure gradient 
o 
Using a right anterior oblique (RAO) projection, advance previously pigtail-shaped, 
0.035-in (0.889-mm) high-support guidewire through the pigtail catheter and position 
in the apex of the left ventricle 
o 
Remove the pigtail catheter while maintaining guidewire position in the left ventricle 
 
Rapid Pacing and Pre-dilatation of the Implant site 
o 
Insert the valvuloplasty balloon through the 18Fr introducer sheath and advance it to 
the ascending aorta 
o 
Perform a rapid pacing test. A successful test is defined as 1-to-1 pacing capture with 
an immediate drop in pressure and elimination of the systolic-diastolic waveform 
o 
Reposition the angiographic equipment to the ideal viewing plane as previously 
described. Position the valvuloplasty balloon across the native valve, while 
maintaining strict fluoroscopic surveillance of the distal tip of the guidewire in the left 
ventricle (LV) 
o 
Perform BAV per hospital protocol and remove the valvuloplasty balloon while 
maintaining guidewire position across the native aortic valve 
o 
Balloon sizing directed to 1:1 sizing of the minimal annular diameter by computerized 
tomographic angiography (CTA) or echocardiogram with maximum 25 mm balloon 
o 
Perform full balloon expansion 
 
Medtronic CoreValve® Implantation 
o 
Insert the device over the 0.035-in (0.889-mm) guidewire and advance it, while 
maintaining strict fluoroscopic surveillance of the guidewire in the LV 
o 
When crossing the aortic arch, control the guidewire preventing it from moving 
forward 
o 
Advance the device through the native valve. Perform an angiogram to confirm that 
the graduated pigtail catheter is in position within the noncoronary cusp of the aortic 
root, preferably in the shallow LAO projection 

 
 
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o 
Use Fluoroscopy to identify the appropriate landmarks 
o 
Place the bioprosthesis within the aortic annulus.  Optimal placement of the 
bioprosthesis is 4 mm - 6 mm below the annulus. The annulus is defined as the 
angiographic floor of the aortic root 
o 
After attaining optimal catheter position, slowly turn the micro knob and begin to 
deploy the bioprosthesis. As the inflow aspect of the bioprosthesis starts to flare 
outward, monitor bioprosthesis position under fluoroscopy 
o 
Caution: During implantation, if resistance to deployment is encountered (for 
example, the micro knob starts clicking or is tight or stuck), apply mild upward 
pressure to the macro slider while turning the micro knob. If the bioprosthesis still 
does not deploy, remove it from the patient and use another system 
o 
Perform an angiogram. Once annular contact is made, the bioprosthesis should not 
be advanced into a lower position 
o 
Continue deploying rapidly to the 2/3 deployment point; stop turning the micro knob 
o 
Perform an angiogram to assess the location of the bioprosthesis.  
o 
If the bioprosthesis is positioned low, carefully pull the DCS to reposition the 
bioprosthesis 
o 
Evaluate the valve position and valve function using hemodynamic, aortography, and 
possible echocardiography  
o 
When satisfactory position is achieved, continue to turn the micro knob until both 
frame loops disengage 
o 
Use orthogonal views under fluoroscopy to confirm that the frame loops have 
detached from the catheter tabs. If a frame loop is still attached to a catheter tab, 
under fluoroscopy, advance the catheter slightly and, if necessary, gently rotate the 
handle clockwise (<180°) and counterclockwise (<180°) to disengage the loop from 
the catheter tab 
o 
Withdraw the DCS carefully to the aorta avoiding contact with the inflow portion of the 
frame while maintaining guidewire position 
 
Post Deployment 
o 
Close the DCS capsule and remove the DCS through the 18Fr introducer sheath 
o 
Advance a 6Fr pigtail catheter over the guidewire into the left ventricle 
o 
Remove the guidewire and connect the pigtail catheter to the transducer 
o 
Using both pigtail catheters, record aortic pressure gradient 
o 
Withdraw 6Fr pigtail 
o 
Perform postimplant aortogram with the reference pigtail to assure coronary patency 
and assess aortic regurgitations.  Aortogram Acquisition Guidelines are located in 
Appendix R.6 
o 
Remove the 18Fr introducer sheath and complete the puncture site closure per 
hospital protocol 
o 
Perform contrast angiography of the primary vessels to verify the absence of any 
vascular complications with the reference pigtail 
o 
Remove the reference pigtail catheter over a standard guidewire 
o 
Remove the 6Fr introducer and close the access site per hospital protocol 
Ballooning as needed during the implant procedure is standard practice and should not be 
considered a reintervention. 

 
 
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Immediate Post-Procedure  
The procedure is considered complete after final angiography has been performed, and the 
introducer sheath has been removed from the subject.  Thereafter, if an introducer sheath is re-
introduced, this is considered a repeat intervention, which must be documented on the 
reintervention Electronic Case Report Form (eCRF).  
 
Coronary Arteriogram 
 
Following the current recommendation all patients with prosthetic heart valves need 
endocarditis prophylaxis 
 
All patients should receive Deep Vein Thrombosis (DVT) prophylaxis with Heparin/Low 
Weight Molecular Heparin (LMWH) starting approximately 6 hours after TAVI if bleeding 
permits 
 
Anticoagulants should be discontinued per hospital standard 
 
Activated clotting time (ACT) should be monitored per hospital standards but 
recommendation is >250 seconds 
 
Cardiac Enzymes: CK within 8-12 hours post procedure and at any time when a clinical 
ischemic event is suspected. CK-MB is required if CK is elevated >2X the laboratory 
upper limit of normal. If a clinical event is confirmed, a total of 3 draws of cardiac enzymes 
within the first 24 hours (drawn approximately every 8 hours) following the clinical event 
should be obtained 
 
12-lead Electrocardiogram (ECG) to be performed within 48 hours of procedure 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) to be completed with 24 hours of 
procedure 
 
Transesophageal Echocardiogram (TTE) 
o 
Comprehensive transthoracic 2D echocardiogram (TTE) should be performed 
within 24-48 hours of procedure to assess device success.  Echocardiograms will 
be performed according to Echocardiography Procedures found in Appendix R.7  
 
It is recommended that subjects are treated for a minimum of three months with dual anti-
platelet medication 
o 
If the patient is on warfarin therapy post-procedure it is recommended that subjects 
are prescribed either daily: 
 
Aspirin (75 to 325 mg) or  
 
Clopidogrel (75 mg) (or ticlopidine, if clopidogrel is contraindicated) for at 
least three months following the procedure 
o 
If the patient will not be on warfarin therapy post-procedure it is recommended that 
subjects are prescribed daily: 
 
Aspirin (75to 325 mg) and  
 
Clopidogrel (75 mg) (or ticlopidine, if clopidogrel is contraindicated) for at 
least three months following the procedure 
 
Concomitant medications 
 
Documentation of all adverse events/serious adverse events from enrollment to discharge 
including all unanticipated adverse device effects (UADE), technical observations, 
reinterventions or repeat admissions to the catheterization suite and deaths 
o 
Any patient with evidence of a new neurological event should have a neurology 
consult and subsequently an imaging study if deemed necessary by the neurologist 
or stroke specialist 

 
 
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Post-Procedure Pacing Guidelines 
 
All patients should stay on telemetry until discharge 
 
Maintain temporary pacing until at least 48 hours post-implant in Cardiovascular Intensive 
Care Unit (CV-ICU) or local equivalent 
 
After 48 hours, obtain Electrocardiogram (ECG) and assess patient rhythm and 
conduction 
 
Based on assessment, and with the consult of an electrophysiologist as needed, take one 
of the following actions: 
o 
Discontinue temporary pacing 
o 
Continue temporary pacing for another 24 hours (longer if needed) to make further 
assessments 
o 
Place a permanent pacemaker according to ACC/AHA/HRS Guidelines for Device-
Based Therapy of Cardiac Rhythm Abnormalities (Class I or IIb for Acquired 
Atrioventricular Block in Adults or Permanent Pacing in Chronic Bifascicular Block) 
o 
Prior to the permanent pacemaker implantation, document the reason for the 
placement of the permanent pacemaker via a 12-lead ECG 
o 
For complete heart block, review patient medications 
o 
Consider withholding some medications to assess for patient’s intrinsic rate and 
conduction 
o 
If heart block persists off medications, a permanent pacemaker should be 
considered 
o 
If a permanent pacemaker is required, a dual chamber system is recommended to 
optimize patient hemodynamics 
o 
If a permanent pacemaker is implanted, perform a device interrogation and an 
assessment of AV conduction post insertion and prior to hospital discharge as well 
as at every follow-up visit to evaluate device utilization (Refer to the Pacing 
Guidelines in Appendix R.13  
C.4.5.2 
Surgical Aortic Valve Replacement 
Minimum Standards for Surgical Aortic Valve Replacement  
Subjects randomized to SAVR should be treated according to the surgeon and hospital’s 
standard practices. The surgeon or co-surgeon performing the SAVR must be a trial 
investigator for the site. The choice of surgical valve is left to the discretion of the investigator. 
However, the use of a bioprosthetic valve is required. 
General Procedural Considerations 
One of the key requirements for good surgical outcome is an excellent collaboration of the 
dedicated multidisciplinary teams consisting of typically two cardiac surgeons with SAVR 
experience, a cardiac anesthesia team, an experienced cardio technician as well as at least two 
operation theater nurses.  
 
Operation Theater 
Surgical aortic valve replacement is to be performed in an operative theater with state-of-the-art 
technical equipment with certified sterility standards, adequate illumination, laminar flow, 
dedicated scrub nurses, and on site full technical support.  
 
Perfusion 
A dedicated, experienced perfusion team with greater than 75 Extracorporeal Circulation (ECC) 
runs per cardio technician per year who can perform all current cardioplegia strategies and is 
familiar with deep hypothermic circulatory arrest (DHCA) is recommended.  The perfusion team 
should be capable of covering the full heart surgical spectrum including CABG, heart valve 
defect (HVD), Heart failure and assist devices, extracorporeal membrane oxygenation (ECMO) 
support, intra-aortic balloon pump (IABP), and cardiac transplant.   

 
 
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Pre-Procedure 
 
If the patient is currently on warfarin therapy, or local equivalent, prior to the procedure 
o 
Discontinue warfarin therapy 3 days prior to the procedure 
o 
Confirm that the INR < 1.8 prior to the procedure 
o 
Administer antiplatelet therapy: 
 
Aspirin (75- 325 mg) or  
 
Clopidogrel (75 mg) daily or ticlopidine if clopidogrel is contraindicated) for 3 
days prior to the procedure 
 
If the patient is currently not on warfarin therapy prior to the procedure: 
o 
Aspirin (75-325 mg) on the day of the procedure and  
o 
Clopidogrel, 300 mg  
 
Consider adjunctive proton pump inhibitors, H2 receptor antagonists or antacids 
 
Routine Laboratory Tests: 
o 
Complete Blood Count 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
 
If the GFR < 60 cc/min, consider: 
 Discontinuation of NSAIDs and ACE inhibitors 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio, if applicable  
o 
Activated Partial Thromboplastin Time  
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
12-Lead Electrocardiogram 
 
One hour prior to the procedure, prophylactic antibiotic therapy of the Investigator’s 
choice should be initiated: 
o 
Cefuroxime 750mg IV 1 hour pre-procedure, then 6 hours and 12 hours post-
procedure 
o 
If allergic to Penicillin, prescribe Vancomycin 1g IV  
o 
Consider holding anti-hypertensives 
Surgical Considerations  
Surgical aortic valve replacement is typically performed with cardio-pulmonary bypass (CPB) on 
an arrested heart with a clamped aorta. Local practice and surgical standards should govern 
type of cardioplegia and the temperature/flow/pressure perfusion strategy as well as the 
activated clotting time used at either institution for safe CPB. Typically a minimum of 2 
liters/m²/minute with a systemic arterial blood pressure of 60mmHg during CPB should be 
maintained and possibly increased in the elderly patients.  
 
Cannulation for isolated SAVR CPB should be ascending aorta for arterial return unless there is 
ascending aortic arteriosclerosis or dilatation (>4cm in diameter), and right atrial for venous 
drainage. Embolic devices are not routinely used in SAVR. 
 

 
 
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Typical surgical workflow 
 
Procedural set-up and Anatomic Evaluation: 
o 
The patient is prepared and draped 
o 
IV antibiotics should be administered following the local standard of care  
o 
Following the presternal skin incision the sternum is split 
o 
Prepare the mediastinum and open the pericardium  
o 
Inspect the ascending aorta for calcifications (including epiaortic scan if necessary) 
o 
Complete heparin application and arterial and venous cannulation 
o 
Initiate CPB, and at surgeons discretion, left heart venting via right upper pulmonary 
vein or pulmonary artery  
o 
Cross clamp the aorta and initiate cardioplegic arrest  
o 
Perform an aortotomy  
o 
Complete annular decalcification (the surgeon should take all possible means to 
prevent embolization of debris)  
 
 
Prosthesis Specific Sizing: 
o 
If the aortic annulus does not permit valve replacement with a patient matched valve 
diameter, the aortic annulus should be enlarged at the surgeon’s discretion  
 
 
Valve Preparation and Implantation: 
o 
The valve prosthesis should be prepared following the manufacturer 
recommendations  
o 
After rinsing bioprosthetic valves should be kept wet throughout the procedure 
o 
Anchoring of the prosthesis with, for example, interrupted Teflon reinforced Tycron 
sutures or an equivalent technique is recommended 
o 
De-air and close the aortotomy 
o 
Insert temporary ventricular and atrial pacing wires and chest tubes  
o 
Wean from ECC hemostasis  
o 
Complete sternal wiring and layered closure 
 
 
Additional Procedural Considerations: 
o 
In case of concomitant significant subvalvular left ventricular outflow tract occlusion 
(LVOTO) then resection is recommended 
o 
If there is a significant patent foramen ovale (PFO) closure is recommended in cases 
of substantial right to left flow 
o 
It might be recommendable to apply CO2 surgical field flooding to ease de-airing  
 
Intraoperative Aortic Assessment     
Transesophageal echo (TEE) should be used in all cases to additionally assess for aortic 
calcifications before manipulating the aorta. In case of doubt an Epiaortic scan might further 
help for surgical decision making. Additionally the TEE should be used to assess for 
subvalvular LVOTO and persistent foramen ovale. 
 
Before Termination of Surgery Repeat Intraoperative TEE 
It is mandatory that TEE is used to assess the postoperative SAVR result in all patients.  
Assessment should include aortic valve function, central or paravalvular leakage, valve 
gradient, exclude remaining LVOTO from subvalvular stenosis as well as ventricular function 
with special emphasis on new segmental wall function abnormalities. 
 
Any regurgitation of more than trace should be critically evaluated and at surgeons discretion 
the valve re-inspected and if necessary changed. 
 

 
 
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Immediate Post-Procedure  
The procedure is considered complete at the time of skin closure. Immediately post-procedure 
the following tests and procedures must be performed and data collected: 
 
Cardiac Enzymes: CK within 8-12 hours post procedure and at any time when a clinical 
ischemic event is suspected. CK-MB is required if CK is elevated >2X the laboratory 
upper limit of normal. If a clinical event is confirmed, a total of 3 draws of cardiac enzymes 
within the first 24 hours (drawn approximately every 8 hours) following the clinical event 
should be obtained 
 
Concomitant Medications 
 
12-lead Electrocardiogram (ECG) to be performed within 48 hours of procedure 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) to be completed within 24 
hours of procedure 
 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic 2D echocardiogram (TTE) should be performed 
within 24-48 hours.  Echocardiograms will be performed according to 
Echocardiography Procedures found in Appendix R.7  
 
Adverse Event review 
 
Post-Procedural Medication 
 
It is recommended that subjects are treated with aspirin (75 -325mg daily) for a minimum 
of three months  
 
If warfarin therapy is indicated (e.g. A-fib): maintain therapeutic anticoagulation with 
Heparin or Low Molecular Weight Heparin until INR between 2 and 3 is reached after 
loading with warfarin 
 
The preoperative antibiotic therapy may be repeated within the next 6 to 12 hours 
 
All patients should receive DVT prophylaxis with Heparin/LMWH starting approximately 6 
hours after SAVR if bleeding permits 
 
Following the current recommendation all patients with prosthetic heart valves need 
endocarditis prophylaxis 
 
Post-Procedure Pacing Guidelines 
 
All patients should stay on telemetry until discharge 
 
Maintain temporary pacing until at least 48 hours post-implant in CV-ICU or local 
equivalent 
 
After 48 hours, obtain Electrocardiogram (ECG) and assess patient rhythm and 
conduction 
 
Based on assessment, and with the consult of an electrophysiologist as needed, take one 
of the following actions: 
o 
Discontinue temporary pacing 
o 
Continue temporary pacing for another 24 hours (longer if needed) to make 
further assessments 
o 
Place a permanent pacemaker according to ACC/AHA/HRS Guidelines for 
Device-Based Therapy of Cardiac Rhythm Abnormalities (Class I or IIb for 
Acquired Atrioventricular Block in Adults or Permanent Pacing in Chronic 
Bifascicular Block) 
o 
Prior to the permanent pacemaker implantation, document the reason for the 
placement of the permanent pacemaker via a 12-lead ECG 
o 
For complete heart block, review patient medications 
o 
Consider withholding some medications to assess for patient’s intrinsic rate and 
conduction 
o 
If heart block persists off medications, a permanent pacemaker should be 
considered 
o 
If a permanent pacemaker is required, a dual chamber system is recommended 
to optimize patient hemodynamics 

 
 
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o 
If a permanent pacemaker is implanted, perform a device interrogation and an 
assessment of AV conduction post insertion and prior to hospital discharge as 
well as at every follow-up visit to evaluate device utilization (Refer to the Pacing 
Guidelines in Appendix R.13 
C.4.6 Assessments done at discharge (both SAVR and TAVI) 
Prior to hospital discharge (or within 7 days post-MCS TAVI, whichever occurs first) the 
following tests and procedures must be performed and data collected: 
 
Clinical Assessment and Physical Examination 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets)   
 
Routine Laboratory Tests: 
o 
Complete Blood Count: 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio, if applicable  
o 
Activated Partial Thromboplastin Time  
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
Neurological Assessments 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic 2D echocardiogram (TTE) should be performed 
as close to discharge (or 7 days, whichever comes first) as possible.  
Echocardiograms will be performed according to Echocardiography 
Procedures found in Appendix R.7 
 
12-lead Electrocardiogram 
 
Adverse Event review 

 
 
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C.4.7 Follow-Up Evaluations 
All randomized subjects will undergo in-clinic follow-up evaluations at the following time points 
post implant.   
(All follow-up periods are defined as the number of days after the randomization date, except 
for the 30 days period, which is defined as the number of days since the date of procedure) 
Note Day 0 = day of randomization: 
 
30 days (- 7 days and + 14 days) 
 
3 months (90 ± 14 days) 
 
6 months (180 ± 30 days) 
 
12 months (365 ± 30 days) 
 
18 months (545 ± 60 days) 
 
24 months (730 ± 60 days) 
 
3 years (1080 ± 60 days) 
 
4 years(1440 ± 60 days) 
 
5 years (1800 ± 60 days) 
All randomized subjects will complete long-term follow-up through 5 years.  Upon completion of 
the final protocol visit (5 year visit or discontinuation) subject participation will be considered 
complete and the patient should then be followed per the local standard of care for their 
condition. 
C.4.7.1 
30 Days 
The following assessments will be conducted at the 30 day visit.   
 
Clinical Assessment and Physical examination 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Routine Laboratory Tests: 
o 
Hemoglobin 
o 
Creatinine and Creatinine Clearance 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
12-lead Electrocardiogram 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event review 
C.4.7.2 
3 Months 
The following assessments will be conducted via telephone at the 3 Month visit.   
 
Quality of Life Questionnaire 
o 
EQ-5D only 

 
 
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C.4.7.3 
6 Months 
The following assessments will be conducted at the 6 Month visit.   
 
Clinical Assessment and Physical examination 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
Quality of Life Questionnaires 
 
Adverse Event Review 
C.4.7.4 
12 Months 
The following assessments will be conducted at the 12 Month visit.   
 
Clinical Assessment and Physical examination 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Neurological Assessments 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Mini-Mental State Exam (MMSE-2) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event review 
C.4.7.5 
18 Months 
The following assessments will be conducted at the 18 Month visit.   
 
Clinical Assessment and Physical examination 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
12-lead Electrocardiogram 
 
Quality of Life Questionnaires 
 
Adverse Event review 

 
 
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C.4.7.6 
24 Months 
The following assessments will be conducted at the 24 Month visit.   
 
Clinical Assessment and Physical examination 
 
NYHA classification 
 
Concomitant medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Neurological Assessments 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event review 
C.4.7.7 
3-5 Years 
The following assessments will be conducted at the 3, 4, and 5 year visits.   
 
Clinical Assessment and Physical examination 
 
NYHA classification 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
Quality of Life Questionnaires 
 
Adverse Event review – refer to C.5.2 Reporting for AE reporting requirements post-24 
Months 
C.4.8 Echo Assessment 
Echocardiography is the cornerstone of baseline and follow-up imaging. A comprehensive 
trans-thoracic echocardiogram (TTE) to assess the morphology and function of the respective 
heart chambers and valves is mandatory prior to implant. Calculation of the left ventricular 
Ejection Fraction (EF) by visual assessment, measurement of left ventricular end-diastolic 
volume and diameter and inter-ventricular septal thickness to characterize the left ventricle and 
transaortic jet velocity, mean transaortic gradient and aortic valve area by the continuity 
equation to illustrate AS severity are essential(1).  
Echo assessment for all time periods will be conducted by a core laboratory. 
Sites should make every effort to utilize the same echo machine for all subjects at all required 
interval throughout the duration of the protocol.  Additionally, sites should perform regular 
maintenance and calibration of echo machines per local standards and ensure proper 
documentation is available for audit, as applicable. 

 
 
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C.4.9 Neurologic Assessment 
The incidence of new clinically detectable neurological events or deficits, or any comparative 
change in indices of higher cognitive function following implantation of the Medtronic 
CoreValve® System in the treatment of patients with symptomatic severe aortic stenosis is an 
important clinical endpoint. Therefore, a baseline neurological examination by a qualified study-
trained neurologist or stroke specialist is mandatory and as outlined in section C.4.7 Follow-Up 
Evaluations. 
In case of a new neurological event, the diagnosis of stroke should be supported by 
complementary findings on neuro-imaging examination. The need for additional imaging is up 
to discretion of the Neurologist or Stroke Physician. Both diffusion-weighted Magnetic 
Resonance imaging and multi-slice Computed Tomography are valid neuro-imaging modalities 
(however CTA or MRA is preferred to CT or MRI), the selection of which will be left per 
institution’s standard of care.  
In addition to the neurological assessments at specified time periods, additional evaluations 
should be conducted as follows during the course of the trial: 
 
NIHSS:   
o 
For subjects with a new neurological event (stroke, TIA, or encephalopathy), 
additional NIHSS exams are to be performed at 30 days, and 3 months post-
event 
o 
NIHSS also to be done within 24 hours of any aortic valve or ascending aortic 
intervention 
 
Any patient with evidence of a new neurological event should have a 
neurology consult and an imaging study if deemed necessary 
 
Modified Rankin Scale 
o 
For subjects with new neurological event, assessment to be performed at 7 
days or discharge (whichever occurs first), 30 days, and 3 months post-stroke 
 
Mini Mental State Exam (MMSE-2) 
o 
For subjects with a new neurological event assessments are to be performed 
at 30 days and 3 months post-stroke 
Refer to the Appendix R.18 for a description of the Additional Neurological Testing. 
C.4.10 
Angiographic and Computed Tomography Assessment 
Complete angiographic (invasive or MSCT) assessment of the aortic bifurcation and ilio-
femoral-arterial tree is mandatory prior to the Heart team Conference. 
An additional benefit of Multislice CT scan in the TAVI cohort is to obtain a thorough 
assessment of the anatomy of the left ventricular outflow tract (LVOT) up to the common 
femoral arteries. MSCT also provides information on coronary and carotid anatomy, and might 
identify occult malignancy which is also valuable information in SAVR cohort.   
The aortic valve calcification is evaluated using the Agatston score and a qualitative gradation 
(grade 1—no calcification; grade 2—mildly calcified (small isolated spots); grade 3—moderately 
calcified (multiple larger spots); grade 4 — heavily calcified (extensive calcification of all 
cusps)(53). With respect to the elliptical shape of the virtual aortic annulus, the axial plane 
where the 3 basal aortic leaflet attachments can be identified simultaneously is used for 
measuring the maximum and minimum annular diameter (most often corresponding to 2 
orthogonal sagittal and coronal planes)(54). Additionally the maximum diameters of the LVOT, 
sinuses of Valsalva and sinotubular junction are obtained. Maximum diameter, calcification and 
tortuosity of the ascending and descending thoracic aorta are evaluated. As for the iliofemoral 
tree, the minimal luminal diameter, plaque and calcification burden and tortuosity are assessed 
in order to judge transfemoral accessibility for the Medtronic CoreValve® System. 
C.4.11 
Data Collection 
All scheduled testing and procedures to be conducted during the baseline, index procedure, 
and follow-up assessments are summarized in Table 3. 

 
 
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Table 3:  Schedule of Assessments 
 
Parameter 
Screening 
RANDOMIZATION = DAY 0 
Baseline 
(within 14 days of 
procedure) 
Procedure 
Discharge 
30 days 
3 Months 
6  Month 
12 Month 
18 Month 
24 Month 
3 – 5  years 
Informed consent (and in US HIPAA 
Authorization) 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
 
 
 
 
 
 
 
 
 
 
 
Demographics and Medical history 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment and Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
NYHA Class 
 
 
 
 
 
 
 
 
 
 
 
STS Risk Score, Logistic EuroScore, SYNTAX 
Score, Katz Index 
 
 
 
 
 
 
 
 
 
 
 
Co-morbidities 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications12 
 
 
 
 
 
 
 
 
 
 
 
Routine Laboratory Tests 
 
 
1,2 
 
3 
 
 
 
 
 
 
Neurological Assessments7 (NIHSS, MMSE 
and Additional Neurological Assessments)10 
 
9 
 
 
 
 
 
 
 
 
 
Abbreviated Neurological Assessment     
(NIHSS only) 
 
 
8 
 
 
 
 
 
 
 
 
Transthoracic Echocardiogram (TTE) 
 
 
5 
 
 
 
 
 
 
 
 
Transesophageal Echocardiogram (TEE) 
 
 
 
 
 
 
 
 
 
 
 
Computed Tomography (CT) Angiogram 
(MSCT required at screening)6 
 
 
 
 
 
 
 
 
 
 
 
Coronary Arteriogram 
 
 
() 
 
 
 
 
 
 
 
 
12-lead Electrocardiogram 
 
 
4 
 
 
 
 
 
 
 
 
6 Minute Walk Test 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life Questionnaires (EQ-5D, KCCQ, 
and SF-12) 
 
13 
 
 
 
 
 
 
 
 
 
Quality of Life Questionnaire (EQ-5D only)14  
 
 
 
 
 
 
 
 
 
 
 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
11 

 
 
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(•) MCS TAVI subjects only (SAVR subjects will not have these assessments) 
1  Laboratory test results must be performed pre-procedure and CK to be obtained within 8-12 
hours post-procedure  
2   Pre-procedure 
3  Post-discharge and subsequent follow-up visits require only hemoglobin, creatinine and 
creatinine clearance are required to be collected 
4  Electrocardiogram within 48 hours of procedure 
5  TTE to be completed within 24-48 hours of procedure to assess device success 
6  All subjects should have screening thoracic and abdominal CT angiograms with complete 
visualization of both iliacs, femorals, and aorta (and subclavian/axillaries, if applicable), up to 
and including the aortic annulus 
7  In addition to the protocol required assessment (NIHSS and MMSE); for subjects with 
neurological event or stroke, additional NIHSS and MMSE exams are to be performed at 30 
days and 90 days post-event. mRS should be completed at 7 days post-event or discharge 
(whichever occurs first), 30 days, and 90 days post-event. NIHSS is also to be done within 
24 hours of any aortic valve or ascending aortic intervention 
8  NIHSS to be done within 24 hours of the procedure 
9  Modified Rankin to be performed at baseline for patients with a previous history of stroke 
only 
10  Additional Neurological Assessments include:  Visual Fields Testing, Gait Assessment, Hand 
Function, Writing Evaluation, and Drawing Assessment 
11  SAE, MAE, cardiovascular events, device-related events, including device-related technical 
observations, UADEs, all stroke (CVAs), and death reports 
12 Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, beta-blockers, 
statins and anti-platelets)   
13   Quality of Life Questionnaires should be completed prior to informing the subject of 
randomization assignment   
14   Quality of Life Questionnaire – EQ-5D to be administered via telephone 
 

 
 
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C.4.12 
Unscheduled Follow-up Assessments 
If a subject returns to the institution between their scheduled follow-up visits the visit will be 
treated as an unscheduled visit and the assessments completed at this visit will be done at the 
discretion of the investigator. eCRFs are provided for unscheduled visits.   
C.4.13 
Missed Follow-up Visits 
Every effort should be made to ensure subjects return to the clinic for all protocol required 
follow-up.  If the subject is unable to return for an in-person clinic visit, the Investigator, or 
designee, must document in the patient record the reason the subject was unable to complete 
the visit and, if applicable, follow the requirements for deviation reporting as outlined in section 
C.4.16 Protocol Deviations. 
The Investigator should also make every effort to contact the subject or subject’s legal 
representative, within the visit window, to collect the subject’s vital status as well as information 
related to potential adverse events, safety data, and hospitalizations. 
C.4.14 
Investigational Product Accountability 
The Investigator is responsible for maintenance of the Shipment/Device Disposition Log. The 
log must detail the product and lot numbers as well as the location and status of all 
investigational devices (including DCS and CLS components, where applicable) received by the 
hospital and/or Investigator. At the end of the clinical trial the Principal Investigator must sign 
the original log. 
This clinical trial will be conducted in some geographies where the Medtronic CoreValve® 
System is commercially available.  In these geographies the device will be used outside the 
current approved indication, therefore the PAV will be labeled as investigational.  Note, the 
DCS and CLS components are identical to the CE marked CoreValve System and will be 
supplied within the approved commercial CE marked labeling. The Investigator must provide 
full accountability for each PAV from the time of receipt through disposition and/or return.  
Accountability for the each DCS and CLS must include all disposition within the clinical trial. 
In geographies where the device is not currently approved the PAV, DCS and CLS components 
will be labeled as investigational.  The Investigator must provide full accountability for each 
PAV, DCS and CLS from the time of receipt through disposition. 
At the end of the study enrollment period, all remaining investigational product must be returned 
to Medtronic.  
C.4.15 
Device Malfunction or Explant 
In the event of a device malfunction of the Medtronic CoreValve® System (MCS) prior to 
implant or in the event that a Medtronic CoreValve® PAV is explanted after implant (due to 
reintervention or autopsy), the PAV and/or affected MCS components should be returned to 
Medtronic to the following:   
 
Medtronic, Inc.  
Attn: Explant Lab [PE#] 
1851 E. Deere Avenue 
Santa Ana, CA  92705-5720 
 
 
Additional details surrounding the device return process are contained within the Medtronic 
explant kit and in Appendix R.11. 

 
 
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C.4.16 
Protocol Deviations 
A protocol deviation is defined as an event where the clinical investigator or site personnel did 
not conduct the trial according to the protocol or the Investigator agreement.  Deviations will be 
reported regardless of whether medically justifiable, pre-approved by Medtronic, or taken to 
protect the patient in an emergency. 
A protocol deviation form is to be completed for each trial protocol deviation, including, but not 
limited to: 
 
Failure to obtain informed consent 
 
Incorrect version of consent provided to patient 
 
Failure to obtain IRB/MEC protocol review and approval before starting the trial 
 
Enrollment of patient during an IRB/MEC approval lapse 
 
Clinical investigator exceeding enrollment limits specified by sponsor 
 
Patient did not meet inclusion/exclusion criteria 
 
Incorrectly performed testing 
 
Protocol-required testing and/or measurements not done or performed outside of 
window 
 
Source data permanently missing 
 
UADE not reported in the required timeframe 
FDA regulations [21 CFR 812.140] require that the Investigator maintain accurate, complete, 
and current records, including documents showing the dates of and reasons for each deviation 
from the protocol.  Relevant information for each deviation will be documented on a deviation 
form completed by site personnel and reviewed by the Investigator. 
Federal regulations  [21 CFR 812.150], ISO 14155, and local regulatory authorities (where 
applicable), require Investigators to obtain prior approval from the sponsor before initiating 
changes in or deviations from the protocol, except when necessary to protect the life or physical 
well being of a patient in an emergency.   
Prior approval by the sponsor is expected in those situations in which the Investigator 
anticipates, contemplates or makes a conscious decision to depart from procedures specified in 
the protocol.  Prior approval is generally not expected in situations where unforeseen 
circumstances are beyond the Investigator’s control, but is still considered a deviation (e.g. a 
trial subject who fails to attend a scheduled follow-up visit, a trial subject too ill to perform a 
protocol-required test).  To obtain approval, the Investigator must call or email and discuss the 
potential deviation with the Medtronic trial manager or designee prior to initiating any changes.  
If approval is granted, the Medtronic trial manager or designee will provide the applicable 
documentation to be maintained in the site files. 
FDA regulations require the Investigator to notify the sponsor and the reviewing IRB/MEC 
within 5 working days of the following deviations [21 CFR 812.150]: 
 
a deviation from protocol to protect the life or physical wellbeing of a patient in an 
emergency 
 
failure to obtain an informed consent   
Investigators or an authorized designee must notify Medtronic as soon as possible by calling 
the trial manager or designee and completing the protocol deviation form. 
The Investigator is required to adhere to local IRB/MEC procedures for reporting deviations. 
The DSMB may review protocol deviations to ensure compliance and overall study integrity. 

 
 
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C.4.17 
Subject Withdrawal or Discontinuation 
All subjects will be encouraged to remain in the trial through the last follow-up visit at month 60.  
Subjects who discontinue participation prematurely after randomization will be included in the 
analysis of results (as appropriate) but they will not be replaced in the enrollment of total trial 
subjects. If a trial subject is discontinued from the trial early, the reason for discontinuation 
should be documented in the patient file and a Study Exit eCRF must be completed.   
The trial site and Sponsor will make every effort to have all subjects complete the follow up visit 
schedule.  A subject will not be considered lost-to-follow-up unless all efforts to obtain 
compliance are unsuccessful. At a minimum, the effort to obtain follow-up information must 
include three attempts to make contact via telephone and if contact via phone is not successful, 
a traceable letter from the Investigator must be sent to the subject’s last known address.  
Should both telephone and mail efforts to contact the subject be unsuccessful, the subject’s 
primary physician should be contacted.  Subjects will then be deemed lost to follow up.  All 
contact efforts to obtain follow-up must be documented in both the subject’s medical records 
and in the trial eCRFs. 
If a patient officially withdraws from the study but is willing to allow either regular vital status 
determinations for the study or a one-time vital status determination, these are to be conducted 
per the follow-up visit schedule or only at the last planned follow-up visit, respectively, and may 
be conducted via telephone. 
If a patient discontinues the trial at any time, is withdrawn from the study early, or completes all 
protocol required follow-up they should then be followed per the local standard of care for their 
condition. 
C.4.18 Termination or Discontinuation of Trial 
Medtronic may decide to suspend or prematurely terminate the study.  If the study is terminated 
prematurely or suspended, Medtronic shall promptly inform the clinical investigators of the 
termination or suspension and the reason(s) for this. The investigator shall then promptly inform 
the reviewing MEC/IRB. 
Possible reasons for early trial termination include: 
 
Unanticipated Adverse Device Effect (UADE) presents an unreasonable risk to 
patients 
 
Recommendation from DSMB 
If the trial is terminated early, the Sponsor will, as soon as possible, provide a written statement 
to the Investigators to enable prompt notification of the IRB/MECs.  The Sponsor will also 
inform the FDA.  If the trial enrollment is terminated early, the follow-up visits will continue for all 
enrolled subjects. 
C.5 
Adverse Events 
C.5.1 Definitions 
The definitions presented in this section allow for a clear understanding of adverse event data 
collection and subsequent analysis.  
C.5.1.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device.   
NOTE 1:  This definition includes events related to the investigational medical device or the comparator. 
NOTE 2:  This definition includes events related to the procedures involved. 
NOTE 3:  For users or other persons, this definition is restricted to events related to investigational medical devices. 
The following events in Table 4 are expected to occur with any surgical implant and therefore 
should not be reported as AEs, unless they occur outside of the stated timeframe: 

 
 
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Table 4:  Expected Events 
Description of the Event 
Timeframe (hours) from Procedure 
Anesthesia-related nausea and/or vomiting 
24 
Low-grade fever (<100oF or <37.8oC) 
48 
Back pain related to laying on the procedure 
table 
72 
Incisional pain (pain at access site) 
72 
Sleep problems or insomnia 
72 
Mild to moderate bruising or ecchymosis 
168 
C.5.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is an event that: 
 
Led to death 
 
Led to serious deterioration in the health of the subject, that either resulted in: 
o a life threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o inpatient or prolonged hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure of a body function  
 
Led to fetal distress, fetal death or a  congenital anomaly or birth defect 
NOTE:  Planned hospitalization for a pre-exiting condition, or a procedure required by the CIP, without serious 
deterioration in health, is not considered a serious adverse event. 
In addition to above standard definition of SAE, the following events will also be defined as 
serious in the SURTAVI trial, including events that do not meet the above criteria for SAE. 
 
Stage 2 and 3 acute renal injuries 
 
Moderate or severe aortic regurgitation (AR) 
 
Moderate or severe aortic stenosis (AS) 
 
Life-threatening and Major bleeding events 
 
Any new or worsening LBBB or RBBB that requires the placement of a permanent 
pacemaker and/or surgical or invasive intervention 
 
Moderate or severe mitral stenosis (MS) 
 
All myocardial infarctions 
 
All moderate or severe paravalvular leaks 
 
Major strokes 
 
Major vascular complications 
Events that do not meet these criteria are considered non-serious. 
C.5.1.3 
Major Adverse Cardiovascular and Cerebrovascular Events 
Major adverse cardiovascular and cerebrovascular events (MACCE) is defined as a composite 
of: 
 
All-cause death 
 
Myocardial infarction (MI)  
 
All stroke, and 
 
Reintervention (defined as any cardiac surgery or percutaneous reintervention catheter 
procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted 
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C.5.1.4 
Major Adverse Event 
Major adverse event (MAE) includes: 
 
MACCE 
 
Acute kidney Injury  
 
Cardiac tamponade 
 
Prosthetic valve dysfunction  
 
Cardiogenic shock 
 
Valve endocarditis 
 
Valve embolism 
 
Life-threatening, disabling or major bleeding  
 
Major vascular complication 
 
Cardiac perforation 
 
Device migration 
C.5.1.5 
Adverse Device Effect (ADE) or Device-Related Adverse Event 
An ADE is an adverse event related to the use of an investigational medical device.  During this 
clinical investigation an event should be considered related to the device when it is the result of 
the Medtronic CoreValve® System (MCS): 
 
The percutaneous aortic valve (PAV) 
 
The delivery catheter system (DCS) 
 
The compression loading system (CLS) 
 
The implant procedure 
 
An event should be considered not related to the device when it is the result of: 
 
A pre-existing medical condition 
 
A new illness, injury or condition 
 
Medication 
NOTE 1:  This definition includes adverse events resulting from insufficient or inadequate instructions for use 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 
NOTE 2:  This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device. 
C.5.1.6 
Unanticipated Adverse Device Effect (UADE) 
An unanticipated adverse device effect or UADE is defined as ―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 protocol or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with the device that relates 
to the rights, safety, or welfare of subjects‖ [21 CFR 812.3 (s)]. 
Those known adverse events related to the device, procedure or therapy are listed in Section 
C.5.2.5 and in the Risk/Benefit Analysis section (Section D) of this document.  
C.5.1.7 
Device Deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance 
 
NOTE:  Device deficiencies include malfunctions, use errors, and inadequate labeling. 
C.5.1.8 
Technical Observation 
A technical observation is a defect, malfunction, or failure of any part of the Medtronic 
CoreValve® System.  This may pertain to the device or system not functioning according to its 
design intent. Each technical observation (whether or not associated with any untoward medical 
occurrence in a subject) will be reported on the Adverse Event (AE) eCRF and tabulated as an 
AE.   

 
 
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C.5.2 
Reporting 
Investigators are required to keep records on ―all relevant observations, including records 
concerning adverse device effects (whether anticipated or unanticipated)‖ [21 CFR 812.140].  
Adverse event collection will begin from the point of study enrollment to study closure.   All new 
or worsening (from baseline) adverse events and technical observations will be captured on the 
AE eCRF through the 24month follow-up visit. It is the responsibility of the Investigator to 
assess the subject for adverse events and capture the required adverse event information on 
the AE eCRF.   
Once a subject has completed their 24-month scheduled follow-up visit only serious adverse 
events, major adverse events, cardiovascular events, device-related adverse events, including 
device related technical observations, unanticipated adverse device effects (UADE), all strokes 
(CVAs) and deaths will be required to be reported. Reference section C.5.1 Adverse Events for 
event definitions and criteria. Medtronic representatives or their designees will conduct 
monitoring visits to review source documentation and verify the complete and accurate 
capturing of adverse events. 
The Investigator must also notify the responsible IRB/MEC regarding new and significant safety 
information and any event identified by Medtronic that requires expedited FDA, and/or local 
regulatory agency, reporting as serious, unexpected, and related to the investigational device. It 
is the responsibility of the investigator to ensure site specific IRB/MEC safety reporting 
requirements are met. 
Medtronic Clinical will ensure all device-related adverse events and all procedure-related SAEs 
are processed according to internal policies and procedures. When necessary, Medtronic Field 
Assurance will respond to sites in writing with the findings related to the product experiences.  
The general procedure for investigators reporting any adverse event is as follows: 
 
Report the event to Medtronic as soon as possible but no later than the timeframes 
outlined below.  (At the time of Site Initiation, sites will be provided with the contact 
information of the appropriate Medtronic designee). 
 
Complete all sections of the Adverse Event eCRF. 
 
Each unique event/diagnosis must be documented separately. 
 
Documented pre-existing conditions are not considered to be reportable AEs unless 
there is a change in the nature or severity of the condition. 
 
The Adverse Event eCRF must be reviewed by the Investigator.  
Reporting guidelines related to specific types of adverse events are outlined below. 
C.5.2.1 
Serious Adverse Events (SAEs) 
Medtronic requests that the Investigator notify the sponsor immediately but not later than within 
3 working days of first learning of any SAE using the EDC system.  If necessary, the 
Investigator may be requested to provide copies of source documentation regarding the event 
(e.g., physician/nurse notes or summaries). The Investigator should also notify their IRB/MEC 
and, if applicable, local regulatory agencies, per their requirements. 
Medtronic will conduct an evaluation of the event and if it is determined by Medtronic to be a 
UADE, it will be reported as described in the following sections. 
C.5.2.2 
Unanticipated Adverse Device Effects 
Investigators must report any (potential) unanticipated adverse device effects to Medtronic and 
their IRB/MEC immediately but no later than 10 working days after the Investigator first learns 
of the event [21 CFR 812.150].  UADEs should be reported immediately to Medtronic via 
telephone as well as on an eCRF. The Investigator should also notify their IRB/MEC and, if 
applicable, local regulatory agencies, per their requirements. 
The Investigator should consider the device labeling and the Risk/Benefit Analysis section of 
this document (Section D) when determining whether an event is unanticipated or not. 
If an event is determined by Medtronic to be a UADE, Medtronic will report the event to all 
investigators to enable reporting to their respective IRB/MECs.  Medtronic will provide this 

 
 
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notification within 10 working days after Medtronic first receives notice of the effect.  [21 CFR 
812.150] 
If Medtronic and the DSMB determine that the event presents an unreasonable risk to the 
participating subjects, Medtronic must terminate all investigations or parts of investigations 
presenting the risk in the clinical trial 5 working days after making that determination and not 
later than 15 working days after Medtronic first receives notice of the effect.  [21 CFR 812.46]  
Follow-up visits for enrolled subjects will continue according the schedule of assessments. 
C.5.2.3 
Device Deficiencies and Technical Observations 
Device Deficiency information and Technical Observations will be collected throughout the 
study and reported to Medtronic. 
Device Deficiencies and Technical Observations should be reported on an Adverse Event 
eCRF. 
Device deficiencies that did not lead to an Adverse Event but could have led to an SADE 
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate, 
require immediate reporting (see Table 8). Initial reporting may be done on the eCRF 
completing as much information as is available. The original completed eCRF must be 
submitted to Medtronic as soon as possible. 
C.5.2.4 
All Other Adverse Events 
Medtronic requests that the Investigator notify the sponsor within 10 working days of first 
learning of any other AE using the EDC system.  If necessary, the Investigator may be 
requested to provide copies of source documentation regarding the event (e.g., physician/nurse 
notes or summaries). 
C.5.2.5 
Anticipated Adverse Events 
Potential risks associated with MCS TAVI may include, but are not limited to, the following: 
 
Death 
 
Acute myocardial infarction  
 
Stroke  
 
Urgent need for surgery 
o 
Coronary artery bypass  
o 
Heart valve replacement  
o 
Valve explant  
 
Urgent need for balloon valvuloplasty (note that BAV during implantation is expected) 
 
Urgent need for Percutaneous Coronary Intervention (PCI)  
 
Cardiogenic shock  
 
Perforation of the myocardium or vessel  
 
Cardiac Tamponade  
 
Ascending aorta trauma 
 
Myocardial ischemia  
 
Acute coronary artery occlusion 
 
Disturbances in the electrical system of the heart that may result in the permanent 
placement of a device (pacemaker)  
o 
Atrio-ventricular node block  
o 
Bundle branch block  
o 
Asystole  
 
Ventricular arrhythmias  
 
Valve or distal embolization 
 
Thrombosis (including valve thrombosis) 
 
Hemorrhage requiring transfusion  

 
 
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 
Arteriovenous fistula  
 
Vessel dissection or spasm  
 
Valve migration  
 
Prosthetic valve dysfunction including but not limited to: 
o 
Fracture  
o 
Bending (out-of-round configuration) of the valve frame 
o 
Under-expansion of the valve frame 
o 
Calcification  
o 
Pannus 
o 
Wear, tear, prolapse, or retraction in the valve leaflet 
o 
Poor valve coaptation 
o 
Suture breaks or disruption 
o 
Leak 
o 
Mal-sizing (prosthesis-patient mismatch) 
o 
Malposition (either too high or too low) 
o 
Regurgitation 
o 
Stenosis  
 
Mitral valve regurgitation  
 
Hypotension or hypertension  
 
Acute renal injury 
 
Allergic reaction to antiplatelet agents or contrast medium  
 
Infection (including endocarditis) 
 
Bowel ischemia  
 
Vascular access site or access related complications, including but not limited to: 
o 
pain 
o 
bleeding 
o 
hematoma  
o 
pseudoaneurysm 
o 
irreversible nerve injury 
o 
compartment syndrome 
o 
stenosis 
C.5.2.6 
Deaths 
The Investigator should notify Medtronic and his/her IRB/MEC immediately but not later than 
within 3 working days of learning of a subject’s death, whether or not the death is related to the 
investigational device.  The Investigator should also notify local regulatory agencies, if 
applicable, per their requirements. The Investigator should also attempt to determine, as 
conclusively as possible, whether such deaths are related to the Medtronic CoreValve® System.  
When an autopsy is conducted, a copy of the report should be provided to Medtronic.  
Medtronic will evaluate the event and if device-related and unexpected, the event will be 
reported as a UADE. 
Any subject death will be reported on the Study Exit eCRF and accompanied by an Adverse 
Event eCRF identifying the cause of death. 
C.5.3 
Clinical Events Committee (CEC) 
An independent Clinical Events Committee (CEC) will review and adjudicate, at a minimum, all 
deaths and endpoint related adverse events. The CEC will consist of interventional 
cardiologists, cardiologists, and cardiovascular surgeons, including a chairperson, who are not 
participants in the trial.  Additional specialist, such as neurologists, may also be selected as part 
of the CEC. 
The purpose of the CEC is to conduct a medical review and classify/adjudicate, at a minimum, 
all deaths and/or clinical endpoints collected in the trial according to definitions and processes 
outlined in the Medtronic CoreValve® SURTAVI Trial protocol and the CEC charter, which will 
be developed and approved by Medtronic and the CEC members. 
Events will be reviewed and adjudicated by a minimum of three CEC members, who will meet 
at regular intervals, via teleconference or in person, as deemed necessary. All other events will 

 
 
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be reviewed and adjudicated by qualified internal Medtronic safety individual(s) to ensure they 
should not be adjudicated by the full CEC and that the events are appropriately classified by the 
investigator. 
Prior to the onset of the trial, the CEC will establish explicit rules outlining the minimum amount 
of data required and the algorithm followed in order to classify/adjudicate a trial endpoint related 
clinical event. CEC decisions will be documented in meeting minutes, which will be maintained 
in the trial file. 
C.5.4 Data Safety Monitoring Board (DSMB) 
An independent, unblinded DSMB will be established and will be comprised of at least 3 
experts, including a chairperson.  The DSMB will have a minimum of one cardiac surgeon, one 
interventional cardiologist and one statistician, and will be independent of Medtronic and the 
trial investigators.  Investigators participating in the trial may participate in the meetings to offer 
clarification surrounding events, but will not have voting privileges.  Medtronic personnel may 
facilitate the DSMB meeting but will not have voting privileges.  The DSMB will meet (via 
teleconference or in person) prior to the first subject enrollment to establish procedures for 
DSMB review, chairman appointment and guidelines for trial recommendations.  The full DSMB 
will meet on a periodic basis to perform a comprehensive data review and will meet more 
frequently when needed.  Primary and safety-related secondary endpoints may also be 
reviewed at these meetings. Meetings will consist of both open and closed sessions. 
The DSMB will also perform a supplemental review of, at a minimum, all serious adverse 
events and deaths and any other data requested by the DSMB on a more frequent periodic 
basis to ensure patient safety.  DSMB members will review the report, and when necessary 
provide recommendations about the conduct of the study and/or request a full DSMB meeting.  
A DSMB charter will be developed and approved by Medtronic and the DSMB members. The 
committee will outline the criteria for both the full DSMB meeting and supplemental DSMB 
reviews within the DSMB charter. 
Following each full DSMB meeting, the board will report to Medtronic in writing and may 
recommend changes in the conduct of the trial.  These DSMB recommendations may include 
recommendations on trial status such as continuing the trial without modifications, continuing 
the trial with modifications, stopping the enrollment in the trial or a specific trial arm, or 
recommendations about trial conduct including recommendations around enrollment or protocol 
deviations.  
In the case of UADEs, if Medtronic and the DSMB determine that the event presents an 
unreasonable risk to the participating subjects, Medtronic must terminate the clinical trial within 
5 working days after making that determination and not later than 15 working days after 
Medtronic first receives notice of the effect. [21 CFR 812.46]. All clinical sites will be notified of 
this action.  
The DSMB may call additional meetings if, at any time, there is concern about any aspect of the 
trial.  All data presented at the meetings will be considered confidential and returned to the trial 
statistician at the closure of the DSMB meeting. 
Additional details about the DSMB are outlined in the DSMB charter. 

 
 
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C.6 
Statistical Methods and Analysis 
Any deviations from this section and/or the Statistical Analysis Plan will be described and 
justified in the Final Report, as appropriate or justified in the CIP. 
C.6.1 Statistical considerations and analysis 
This section describes the statistical considerations and analysis plans for the SURTAVI trial.  
The statistical analysis will be performed by the statistics department of Medtronic. As primary 
analysis all randomized subjects will be analyzed following the intention to treat (ITT) approach, 
i.e. according to the randomized assignment, regardless of what therapy was actually received.  
All follow-up periods are defined as the number of days after the randomization date, except for 
the 30 days period, which is defined as the number of days since the procedure date. 
C.6.2 Reports 
Medtronic is responsible for the reports cited in Table 7 (Sponsor Reporting Responsibilities).  
These reports are subject to regulatory retention and inspection requirements.  In addition to 
the reports listed in Table 7, FDA, Competent Authorities, or the reviewing IRB/MEC may 
request reports pertaining to any aspect of the clinical trial. 
C.6.3 Description of Baseline Variables 
Baseline demographic and clinical variables will be summarized for each of the treatment 
groups for the intent-to-treat, as treated, and per implanted populations. All continuous 
variables will be summarized as means, medians, standard deviations and interquartile ranges 
and compared between treatment groups using a two-sample t-test or the non-parametric 
Wilcoxon rank-sum test.  Categorical variables will be summarized as frequencies and 
percentages and compared between treatment groups using Pearson’s 2 test or Fisher’s exact 
test, as appropriate.  Ordinal variables will be compared using Cochran-Mantel-Haenszel test 
with row mean scores. 
C.6.4 Analysis Populations 
C.6.4.1 
Screening population 
All patients with symptomatic severe AS  that provide informed consent will be considered 
screened and all available data will be entered into the EDC system.  
C.6.4.2 
Randomized population 
If the patient signs informed consent, meets all inclusion and none of the exclusion criteria, and 
Heart Team determines the patient is suitable for randomization in the trial, the patient is added 
to the randomized population once the treatment assignment is made. Within the randomized 
population three populations are distinguished: 
 
The intention to treat (ITT) population, - Patients are reported according to the 
randomized assignment, SAVR or TAVI, regardless of what, if any, therapy was 
actually received  
 
The ―as treated‖ population - This population includes the randomized patients on 
whom the assigned procedure was attempted, whether or not the procedure was 
accomplished and/or successful.  A procedure attempt is defined as when the subject 
is brought into the procedure room and any of the following have occurred: anesthesia 
administered, vascular line placed, TEE placed or any monitoring line placed  
 
The implanted population: This population includes the ―as treated‖ patients who are 
actually implanted with either the CoreValve device or a surgical valve 

 
 
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C.6.5 Primary analysis 
The primary endpoint of all-cause mortality or major stroke at 24 months will be evaluated using 
the difference between the SAVR survival rate and the TAVI survival rate for all-cause mortality 
or major stroke during a fixed follow-up of 24 months’ time, as resulting from the Kaplan-Meier 
analysis. The hypothesis test is designed to show non-inferiority of TAVI to SAVR for the 
primary endpoint.  
The primary endpoint will be evaluated using the test statistic as suggested by Com-Nougue et 
al.2 
)
ˆ
(ˆ
)
ˆ
(ˆ
)
ˆ
1(
)
ˆ
1(
2
1
0
2
1
S
V
S
V
S
S
z






 
where 
0
 is the non-inferiority margin, 
1ˆS  and 
2ˆS  are the Kaplan-Meier survival estimates at 
24-months for TAVI and SAVR respectively, and 
)
ˆ
(ˆ
1S
V
 and 
)
ˆ
(ˆ
2
S
V
 are the corresponding 
Greenwood variance estimates. The Greenwood variance is calculated as shown in Cantor3. 
C.6.5.1 
Hypothesis of non-inferiority 
The hypothesis test is designed to show non-inferiority of TAVI to SAVR for the primary 
endpoint with a one-sided alpha of 0.05.  The null (H0) and alternative (HA) hypotheses are: 
H0: MCS TAVI ≥ SAVR + 7.5% 
HA: MCS TAVI < SAVR + 7.5% 
In the above expression MCS TAVI and 
 denote rates of all-cause mortality or major stroke 
during a fixed follow-up of 24 months, for a population with an STS score in the range 3-8. 
A 90% large sample confidence interval for the difference in rates will be calculated as: 

)
ˆ
1(
)
ˆ
1(
2
1
S
S



)
ˆ
(ˆ
)
ˆ
(ˆ
2
1
2
/
S
V
S
V
z



 
If the upper limit of the interval does not exceed 7.5% TAVI will be declared non-inferior to 
SAVR. 
If non-inferiority is met, then a superiority test will be performed with a two-sided alpha of 0.05. 
C.6.5.2 
Sample size and power calculation 
For the sample size and power calculation the population value of MCS TAVI and 
are both assumed to be 25%. In the PARTNER Cohort A results, as presented at the ACC on 
April 3, 2011, the KM estimate at one-year follow-up for SAVR was 28.0%. This trial however 
had a higher-risk population than SURTAVI. The PARTNER rate is adjusted therefore 
downwards and a two-year follow-up period instead of a one-year follow-up period is used. The 
resulting 25% should be a conservative estimation of the 2Y SURTAVI rate. 
Assumptions: 
 
1:1 treatment allocation ratio 
 
One-sided alpha = 0.05  
 
Combined endpoint of mortality or major stroke follows a piecewise exponential 
distribution with 1-month, 12-month, and 24-month rates of 6%, 16%, and 25%, 
respectively, for both MCS TAVI and SAVR. 
 
Non-inferiority margin of 7.5% 
                                                     
 
2  Com-Nougue, C., Rodary, C., Patte, C., 1993. How to establish equivalence when data are censored: a randomized 
trial of treatments for B non-Hodgkin lymphoma. Statist. Med. 12, 1353–1364. 
3  Alan B. Cantor, 2001. Projecting the standard error of the Kaplan-Meier estimator, Statist. Med. 20 2091-2097 

 
 
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 
Patients are lost to follow-up at a rate of 3% per year, following an exponential 
distribution. 
 
The analysis will take place when the time since implant is at least 24 months for all 
subjects.   
 
Subject enrollment is assumed to follow the rates presented in Table 5. 
Table 5:  Projected Monthly Enrollment Rates 
Month 
1 
2-3 
4 
5 
6 
7 
8-12 
13+ 
Monthly 
Enrollment Rate  
10 
20 
30 
40 
45 
50 
55 
60 
Thus the expected enrollment rate is 490 patients during the first 12 months and 720 during the 
next 12 months. 
The above test statistic does not have a closed form solution for the calculation of sample size 
or power.  Instead, the tables below present power estimates for two sample sizes.  For each 
estimate, 10,000 simulations were run, resulting in a Monte Carlo standard error of about 
±0.5%.  Sample sizes combine both MCS TAVI and SAVR.  Estimates are also presented for 
the maximum observed difference in 24-month event rates that would still result in statistical 
significance (i.e., concluding non-inferiority).  
Table 6:  Estimated Power and Maximum Difference Resulting in Statistical Significance 
 
Power 
Maximum Difference in Event 
Rates Resulting in Non-
Inferiority 
Sample Size 
900 
82.0% 
3.0% 
1200 
90.8% 
3.5% 
By using a sample size of 1200 patients (600 MCS TAVI, 600 SAVR) in the range of STS 3-8 
more than 90% power is achieved. If in the trial the difference between the KM estimates for the 
rates of all-cause mortality or major stroke for MCS TAVI and SAVR does not exceed 3.5%, 
MCS TAVI is considered non-inferior to SAVR. 
The subgroup for purpose of obtaining FDA approval is the STS 4-8 group. Assuming less than 
25% of the 3-8 population has an STS-value of 3-4, more than 900 of the patients will fall in the 
STS 4-8 group. This group has therefore more than 80% power. 
C.6.6 Description of performed analysis, per population 
C.6.6.1 
Analysis of screening population 
For the screening population only descriptive statistical analysis will be performed, on variables 
that are captured in the EDC system. 
C.6.6.2 
Analysis of – ITT population 
For the patients in the randomized population the primary analysis of the primary endpoint and 
inferential statistics for the following secondary endpoints will be performed on ITT basis: 
 
Major adverse cardiovascular and cerebrovascular events (MACCE) 
 
Individual MACCE components 
 
Major adverse events (MAE)  
 
Conduction disturbance requiring permanent pacemaker implantation 
 
NYHA 
 
Six-minute walk test 
 
Ratio of days alive out of hospital versus total days alive 
 
Quality of life 
 
Echocardiographic assessment of valve performance  

 
 
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 
Aortic valve disease-related hospitalizations 
 
Cardiovascular deaths and valve-related deaths 
 
Strokes and TIAs. 
C.6.6.3 
Analysis of as treated population 
The ―as treated‖ population will be used for a secondary, supportive analysis of the primary 
endpoint.  This result should be consistent with the result of the ITT analysis in order to 
demonstrate non-inferiority.  The as treated population will also be used for analyzing the 
following secondary endpoints: 
 
Index procedure-related MAEs 
 
Length of index procedure hospital stay 
 
Device success 
 
Procedure success 
C.6.6.4 
Analysis of implanted population 
The implanted population will be used for analyzing the secondary endpoint of prosthetic valve 
dysfunction.  An additional analysis of the primary endpoint and of the secondary endpoint of 
echocardiographic assessment of valve performance will also be performed on the implanted 
population. 
C.6.7 Statistical methods to be used 
In general, binary variables will be summarized using counts, percentages, and exact 95% 
confidence intervals.  For continuous variables, percentiles, means, standard deviations, and 
95% confidence intervals for the mean using the Gaussian approximation will be calculated. 
Time-to-event data will be summarized using Kaplan-Meier estimates and 95% confidence 
intervals.  
C.6.8 Procedure for accounting data, treatment for missing, unused or spurious 
data  
Every effort will be undertaken to minimize missing data. In time-to-event outcomes the patient 
will be censored from the moment of (a) discontinuation of the study, (b) the first occurrence of 
the specific event, (c) the latest time information is available on the occurrence of the event, 
whichever comes first; consistent with the Kaplan-Meier approach.  
No statistical techniques will be used to impute missing data for categorical or continuous 
outcomes. 
To assess the potential impact of missing data for the primary endpoint, a sensitivity analysis 
will be conducted which will include a complete case, a best-case (assume missing MCS TAVI 
subjects are alive and event-free and SAVR subjects have died), a worst-case (assume missing 
MCS TAVI subjects have died and SAVR subjects are alive and event-free), and a tipping point 
analysis. 
C.6.9 Interim analysis 
No formal interim analysis will take place. However, data from the MCS TAVI arm may be 
utilized to seek CE Mark approval for the Intermediate Risk indication prior to study completion.  
This analysis will not impact the Type I error rate as there will not be an early analysis of 
randomized data. 
Additionally, safety monitoring will be performed by an independent DSMB at regular intervals. 

 
 
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C.6.10 Pre-Defined Subgroups 
While results for primary and secondary endpoints for the entire population of randomized 
patients with STS mortality risk of ≥3% and ≤8% will be used for publication purposes, the 
subgroup of patients with STS mortality risk of ≥4% and ≤8% will be analyzed for all primary 
and secondary endpoints for the purpose of obtaining FDA approval. 
 
Diabetes Mellitus (yes, no) 
 
Age (<70 years of age, 70-74 years of age, 75-79 years of age and >=80 years of age) 
 
Sex (male, female) 
 
Presence of co-morbidities 
 
Need for coronary revascularization 
A test for interaction between the treatment effect (SAVR versus TAVI) and the subgroup 
variable will be performed. 
These comparisons are not powered, and will be for exploratory purposes only, not to be used 
to support labeling claims.  
C.6.11 Health-Related Quality of Life (HRQoL) and Treatment Costs 
Health-related quality of life (HRQoL) and treatment costs will be assessed alongside the core 
clinical trial to evaluate the impact of the TAVI and SAVR strategies on a range of relevant 
quality of life (QoL) domains and also to evaluate the cost-effectiveness of the two treatment 
strategies. 
C.6.11.1 Quality of Life 
Health Related Quality of Life (HRQoL) and functional status will be assessed using a 
combination of generic and disease-specific measures selected to cover a broad range of 
health domains that may be affected by severe aortic stenosis disease, its treatment, and its 
complications: the Medical Outcomes Study 12-item Short Form (SF-12),4 the Kansas City 
Cardiomyopathy Questionnaire (KCCQ), and the EuroQoL (EQ-5D). All patients will complete 
standardized, written questionnaires at baseline (prior to subject being informed of 
randomization), 30 days, 6 months, 12 months, 18 months, 24 months and annually thereafter 
up to 5 years.  At 3 months subjects will also be contacted via telephone to complete the EQ-
5D. 
C.6.11.2 Economic Outcomes/Cost-Effectiveness 
Data on resource utilization will be collected for the index hospitalization and through long-term 
follow-up for all enrolled subjects.  These resource items will include number and duration in-
patient stays in hospital by type of unit (e.g. intensive care, high-dependency care and standard 
ward care); number of clinic visits (by type of physician); and details of the main procedure 
undertaken.  As part of the trial analysis, resource use estimates will be presented by 
randomized group (e.g. mean per patient plus standard deviation).  These dates, together with 
the EQ-5D data will provide an important input into cost effectiveness analysis.  However, as 
such analysis is likely to be based on a modeling framework, to include evidence from a 
number of sources (e.g. a meta-analysis of other TAVI trials) and to vary according to the 
jurisdiction of interest, it is appropriate to detail the methods in separate protocols and analysis 
plans.  
                                                     
 
4  Ware JE, Kosinski M, Keller SD. A 12-item short-form health survey (SF-12): construction of scales and preliminary 
tests of reliability and validity. Medical Care 1996;32:220-33. 

 
 
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C.6.12 
Secondary Endpoints 
The following secondary endpoints will be compared between MCS TAVI and SAVR subject 
cohorts: 
1. Major Adverse Cardiovascular and Cerebrovascular Events (MACCE)-free survival at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  
MACCE is defined as a composite of: 
 
All-cause death 
 
Myocardial infarction (MI) 
 
All stroke, and 
 
Reintervention (defined as any cardiac surgery or percutaneous reintervention 
catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously 
implanted valve) 
MACCE-free survival estimates will be provided for the randomized groups at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  All 
randomized subjects will be included in the analysis.  
The endpoint will be evaluated using Kaplan-Meier survival analysis and the log-rank test.     
2. The occurrence of individual MACCE components at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
 
MACCE components will be summarized and MACCE component event-free rates will be 
provided at 30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter 
up to 5 years.  All randomized subjects will be included in the analysis.   
 
The endpoint will be evaluated using Kaplan-Meier survival analysis and the log-rank test. 
3. Major Adverse Events (MAE) at 30 days, 6 months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years. 
 
MAE events will be summarized and MAE event-free rates will be provided at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.    All 
randomized subjects will be included in the analysis. 
 
The endpoint will be evaluated using Kaplan-Meier survival analysis and the log-rank test. 
4. Conduction disturbance requiring permanent pacemaker implantation at 30 days, 6 months, 
12 months, 18 months, 24 months, and annually thereafter up to 5 years. 
 
The incidence of conduction disturbance requiring permanent pacemaker implantation will 
be provided at 30 days, 6 months, 12 months, 18 months, 24 months, and annually 
thereafter up to 5 years, separately for new onset and pre-existing conduction disturbance.  
All randomized subjects will be included in the analysis.    
The endpoint will be evaluated using Kaplan-Meier survival analysis and the log-rank test. 
5. Change in NYHA class from baseline at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
 
For each subject with paired data, the number of classes changed from baseline (-2, -1, 0, 
1, 2, or 3) will be calculated at 30 days, 6 months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years.   
 
The endpoint will be evaluated using a two-sample t-test or Wilcoxon rank- sum test as 
appropriate.  

 
 
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6. Change in distance walked during 6-minute walk test (6MWT) from baseline to 30 days, 
baseline to 12 months, and baseline to 24 months. 
 
All subjects who are able to perform the six-minute walk evaluation; and those subjects who 
are unable to perform the walk evaluation due to heart failure symptoms at the time of the 
follow-up visit will be included in the analysis. 
 
The six-minute walk evaluation will be evaluated at 30 days, 12 months, and at 24 months 
using a two-sample t-test or Wilcoxon rank-sum test as appropriate.   
7. Ratio of days alive out of hospital versus total days alive assessed at 12 months and 24 
months follow-up.  
 
The proportion of post randomization days alive out of hospital against total days alive will 
be compared between groups at 12 and 24 months.  The numerator will be the number of 
days alive out of hospital, and the denominator will be the number of days alive as of the 
follow-up visit date.  All hospitalizations will be included in this analysis, including 
hospitalization for device implant.  All randomized subjects will be included in the analysis. 
 
The endpoint will be evaluated using continuous data analyses such as a two-sample t-test 
or Wilcoxon rank-sum test. 
8. Quality of Life (QoL) change from baseline at 30 days, 3 months, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
 
The Kansas City Cardiomyopathy Questionnaire (KCCQ), SF-12, and EuroQoL will be 
assessed at baseline, 30 days, 6 months, 12 months, 18 months, 24 months, and annually 
thereafter up to 5 years.  All subjects completing the questionnaires will be evaluated and 
the reasons for missing data will be provided. 
 
The changes in QoL scores will be evaluated using a two-sample t-test or Wilcoxon rank-
sum test as appropriate. 
9. Echocardiographic assessment of prosthetic valve performance at discharge, 6 months, 12 
months, 24 months, and annually thereafter up to 5 years using the following measures: 
 
transvalvular mean gradient 
 
effective orifice area 
 
degree of prosthetic aortic valve regurgitation (transvalvular and paravalvular) 
 
The four echocardiographic measurements will be evaluated at discharge, 6 months, 12 
months, 24 months, and annually thereafter up to 5 years.  All randomized subjects 
undergoing echocardiography procedures will be evaluated.   
 
All measures will be evaluated using a two-sample t-test or the Wilcoxon rank-sum test for 
continuous variables, and the Mantel-Haenszel test for categorical variables, as 
appropriate.   
10. Aortic valve disease related hospitalizations  
 
The number of subjects re-hospitalized after the initial index procedure will be compared at 
30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 
years.  All randomized subjects will be included in the analysis.    
 
Hospitalization-free rates will be provided at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years.  All randomized subjects will be included in 
the analysis.  The endpoint will be evaluated using Kaplan-Meier survival analysis and the 
log-rank test.   
11. Cardiovascular deaths and valve-related deaths 
The number of cardiovascular deaths and valve-related deaths at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years.  All randomized 
subjects will be included in the analysis.   
  
 The endpoint will be evaluated using Kaplan-Meier survival analysis and the log-rank test. 

 
 
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12. Strokes and TIAs 
The number of subjects with strokes (of any severity) and TIAs at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years. A separate analysis 
will be performed for each of the following: 
 
a composite of all strokes and TIAs 
 
major strokes only 
 
minor strokes only 
 
TIAs only  
Each endpoint will be evaluated using Kaplan-Meier survival analysis and the log-rank text. 
13. Peri-procedural Neurological Injury (Stroke, TIA, Encephalopathy) 
For each treatment group, the proportion of subjects with a neurologic injury (stroke, TIA, or 
encephalopathy) at discharge or at 7 days post-index procedure (whichever occurs first) will 
be calculated. The numerator will be the number of subjects with a neurologic injury (stroke, 
TIA, or encephalopathy) at discharge or at 7 days post-index procedure (whichever occurs 
first), and the denominator will be the number of subjects in that treatment group. Results 
will also be presented separately for major stroke, minor stroke, TIA, and encephalopathy.  
Proportions will be compared between groups using the pooled z-test without correction for 
continuity. 
14. Index procedure related MAEs 
 
Index procedure-related MAE events will be summarized and event rates will be provided at 
30 days.  The numerator will be the number of procedure-related MAE events experienced 
by the end of the follow-up visit, and the denominator will be the number of subjects 
evaluated at the follow-up visit plus the number of subjects not evaluated but who 
experienced a procedure-related MAE event prior to the end of the follow-up visit window. 
 
The endpoint is descriptive and no statistical hypothesis test will be performed. 
15.  Length of index procedure hospital stay 
 
The length of TAVI or SAVR hospital stay will be summarized for all subjects. 
 
Descriptive statistics will be provided.  The endpoint is descriptive and no statistical 
hypothesis test will be performed. 
 
The following secondary endpoints will be assessed for the MCS TAVI cohort subjects only: 
16. Device success defined as follows: 
 
successful vascular access, delivery and deployment of the device, and successful 
retrieval of the delivery system, 
 
correct position of the device in the proper anatomical location (placement in the 
annulus with no impedance on device function), 
 
Intended performance of the prosthetic valve1 (aortic valve area > 1.2 cm2 (by 
echocardiography using the continuity equation) and mean aortic valve gradient < 20 
mmHg or peak velocity < 3 m/sec, without moderate or severe prosthetic valve AR) 
 
Only one valve implanted in the proper anatomical location 
1  assessed acutely in a resting state, either within 24-48 hours after the index procedure or before hospital 
discharge 
Device success, as defined above, will be calculated for all subjects undergoing the TAVI 
procedure.   
The endpoint is descriptive and no statistical hypothesis test will be performed. 

 
 
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17. Procedural success, defined as device success and absence of in-hospital MACCE. 
 
Procedure success, as defined above, will be calculated for all randomized subjects 
undergoing the TAVI procedure.   
 
The endpoint is descriptive and no statistical hypothesis test will be performed. 
18. Evidence of prosthetic valve dysfunction at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
 
The number of subjects with evidence of prosthetic valve dysfunction will be evaluated at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  
All subjects will be included in the analysis. 
 
A Kaplan-Meier survival analysis will be performed.  The endpoint is descriptive and no 
statistical hypothesis test will be performed. 

 
 
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C.7 
Data and Quality Management 
C.7.1 Electronic Data Capture 
Medtronic will use the Oracle Clinical Remote Data Capture database system for data 
collection. 
Oracle is a secure, password-protected, Part 11 compliant database which is backed up 
regularly (at a minimum once daily). 
C.7.2 Data Collection 
The investigator must ensure accuracy, completeness and timeliness of the data reported in the 
EDC system and in all other required reports. Data reported on the eCRFs which are derived 
from source documents must be consistent with the source documents or the discrepancies 
need to be justified in a documented rationale, signed and dated by the (principal) investigator, 
to be filed in the subject file. 
Required data will be recorded on the eCRFs by authorized site personnel as indicated on the 
Delegation of Authority Log. The eCRFs must be completed and/or updated to reflect the latest 
observations on the subjects participating in the trial. 
The investigator (or approved sub-investigator) will electronically sign the appropriate pages of 
each eCRF. 
The EDC system maintains an audit trail on entries, changes or corrections in CRFs. If a 
person only authorized to complete CRFs makes changes to an already signed CRF, the 
investigator shall re-sign this CRF. 
The sponsor and/or assigned designee will be responsible for the processing and quality 
control of the data. All trial-related documents must be retained for a period of at least 2 years 
after the last approval of a marketing application and until there are no pending or contemplated 
marketing applications in an ICH region, or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational device. Medtronic will inform the 
investigator/institution when these documents are no longer required to be retained. 
No trial document or image should be destroyed without prior written agreement between the 
Sponsor and the investigator. Should the investigator wish to assign the trial records to another 
party or move them to another location, advance written notice should be given to the Sponsor. 
Copies of the eCRFs to be used are included in Appendix R.5. 
C.7.3 Core Laboratories Procedures 
Data from the core lab will be transferred to Medtronic and stored in the Oracle Clinical Remote 
Data Capture system as described in the Medtronic CoreValve® SURTAVI Trial Data 
Management Plan. 
C.7.4 Source Documents 
Source documentation is defined as the first time the data appear and may include all clinical 
records, hospital records, surgery reports, autopsy reports, and any other material that contains 
original information used for trial data collection or adverse event reporting.  No eCRFs may 
serve as source documents. 
Source documentation may vary from site to site. 
The source documents must be retained by the investigational site for a period of 2 years after 
trial conclusion and made available for monitoring or auditing by the sponsor’s representative or 
representatives of the FDA and other applicable regulatory agencies.  The Investigator must 
ensure the availability of source documents from which the information on the eCRFs was 
derived. 

 
 
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C.8 
Records and Reports 
C.8.1 Responsibilities of the Sponsor 
The Sponsor must maintain the following records, at a minimum: 
 
All essential correspondence related to the clinical trial 
 
Signed Investigator Agreement 
 
Curriculum vitae for each Investigator 
 
Records of device shipment and disposition (shipping receipts, material destruction 
records, etc.) 
 
Adverse event information  
 
Complaint documentation 
 
All data forms, prepared and signed by the Investigators and received source 
documentation and core lab reports 
 
Protocol and report of prior investigations 
 
Site monitoring reports 
 
Financial disclosure information 
The Sponsor is responsible for the preparation of, the accuracy of the data contained in, the 
review of and the submission of the reports listed in Table 7. 
Table 7:  Sponsor Reporting Responsibilities 
Report 
Submit to 
Description 
Unanticipated Adverse 
Device Effects (UADE) 
IRB/MEC, 
Investigators, FDA, 
and local regulatory 
agencies, where 
applicable 
Medtronic will report on any confirmed 
unanticipated adverse device effect 
evaluation as soon as possible but no later 
than within 10 working days after first 
receiving notice of the effect. (21 CFR 
812.150) and in compliance with local 
regulatory requirements, as applicable. 
Withdrawal of IRB/MEC 
approval 
IRB/MEC, 
Investigators, FDA, 
and local regulatory 
agencies, where 
applicable 
Notification, when appropriate, will be made 
within 5 working days after Medtronic 
receives notice of withdrawal of IRB/MEC 
approval. 
Withdrawal of FDA  
approval 
IRB/MEC, 
Investigators 
Notification will be made within 5 working 
days after Medtronic receives notice of 
withdrawal of FDA approval. 
Current Investigator List 
FDA and local 
regulatory agencies, 
where applicable 
Medtronic will submit a current list of the 
names and addresses of all participating 
Investigators at six-month intervals, 
beginning six months after FDA approval of 
IDE. 
Progress Report 
IRB/MEC, 
Investigators, FDA 
A progress report will be submitted at least 
yearly. 
Recall and Device 
Disposition 
IRB/MEC, 
Investigators, FDA, 
and local regulatory 
agencies, where 
applicable 
Notification will be made within 30 working 
days of Medtronic’s request that an 
Investigator return, repair or otherwise 
dispose of any devices.  Such notification will 
state why the request was made. 

 
 
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Report 
Submit to 
Description 
Final Report 
IRB/MEC, 
Investigators, FDA 
Notification will be made within 30 working 
days of the completion or termination of the 
investigation.  A final report will be submitted 
within six months after trial completion or 
termination. 
Failure to obtain Informed 
Consent 
FDA 
Notification will be made within 5 working 
days after Medtronic’s receipt of such 
notification indicating Informed Consent was 
not obtained. 
Emergency Deviations from 
Investigational Plan 
FDA and local 
regulatory agencies, 
where applicable 
Notification will be made within 5 working 
days after Medtronic learns of an emergency 
deviation from the Investigational Plan where 
the deviation was made to protect the life or 
physical wellbeing of a subject. 
C.8.2 Responsibilities of the Investigator 
The Investigator is responsible for the preparation, review, signature, and retention of the 
records listed below: 
 
All essential correspondence that pertains to the investigation 
 
Device use/disposition records 
 
Records of each subject’s case history and exposure to the device.  Case histories 
include the CRFs and supporting data (source documentation), including, for example: 
o 
Signed and dated consent forms 
o 
Medical records, including, for example, progress notes of the physicians, the 
subject’s hospital chart(s) and the nurses’ notes 
o 
All adverse event information  
o 
A record of the exposure of each subject to the investigational device (e.g., 
date of implant procedure and follow-up assessment dates) 
o 
Documentation of any deviation from the protocol, including the date and the 
rationale for such deviation 
 
Screening Logs, Enrollment Logs and Patient Identification Logs 
 
Signed Investigator Agreement, curriculum vitae and training records 
 
Protocol and any amendments 
 
IRB/MEC approval documentation, and where applicable, other local regulatory 
approvals 
The Investigator may withdraw from responsibility to maintain records by transferring custody to 
another person, who will accept responsibility for record and report maintenance. 
The Investigator is responsible for the preparation, review, signature, and submission of the 
reports listed below in.  These are also subject to inspection by government agencies and must 
be retained as specified above.   

 
 
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Table 8:  Investigator Reporting Responsibilities 
Report 
Submitted to 
Description 
Unanticipated Adverse 
Device Effects (UADE) 
Sponsor, IRB/MEC, 
and local regulatory 
agencies, where 
applicable 
UADEs should be reported immediately via 
telephone as well as on an eCRF. UADEs must 
be submitted as soon as possible, but in no event 
later than10 working days after the Investigator 
first learns of the effect. (21 CFR 812.150) 
Serious Adverse 
Events and Deaths 
Sponsor,  and local 
regulatory agencies, 
where applicable 
Medtronic requests that the Investigator’s report 
on all serious adverse events and deaths be 
submitted immediately but not later than within 3 
working days after the Investigator first learns of 
the event. 
Withdrawal of IRB/MEC 
approval 
Sponsor 
The Investigator must report a withdrawal of the 
reviewing IRB/MEC, approval within 5 working 
days. 
Progress Report 
Sponsor, IRB/MEC 
The Investigator must submit a progress report on 
an annual basis if the trial lasts longer than one 
year. 
Failure to obtain 
Informed Consent 
Sponsor, IRB/MEC 
The Investigator must make notification within 5 
working days after device implant. 
Final Report 
Sponsor, IRB/MEC 
This report must be submitted within 3 months 
after termination or completion of the 
investigation. 
Deviations from Investigational Plan (CFR 812.150) 
Emergency Use 
Sponsor, IRB/MEC 
Notification must be made within 5 working days 
of the occurrence of an emergency deviation 
made to protect the life or physical well-being of a 
subject. 
Planned deviation 
Sponsor, IRB/MEC, 
FDA 
If the deviation affects scientific soundness of the 
trial or the rights, safety, or welfare of the subject 
and is not an emergency, prior approval must be 
obtained from Medtronic, the reviewing IRB/MEC, 
and FDA. 
Other Deviations 
Sponsor 
Deviations that are beyond the control of the 
investigator (such as patient who fails to return to 
follow-up visit) or deviations that do not affect the 
scientific soundness of the trial or the rights, 
safety, or welfare of the subject and are not an 
emergency, should be submitted as they are 
identified by the site or Medtronic staff 

 
 
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D 
RISK / BENEFIT ANALYSIS 
There are risks for participants in this trial.  However, it should be noted that most of the risks of 
trial participation are not materially different than those entailed by an individual who undergoes 
the same treatment outside of the context of this trial. 
Known adverse events that may result from TAVI include but may not be limited to:  
 
Death 
 
Acute myocardial infarction  
 
Stroke  
 
Urgent need for surgery 
o 
Coronary artery bypass  
o 
Heart valve replacement  
o 
Valve explant  
 
Urgent need for balloon valvuloplasty (note that BAV during implantation is expected) 
 
Urgent need for Percutaneous Coronary Intervention (PCI)  
 
Cardiogenic shock  
 
Perforation of the myocardium or vessel  
 
Cardiac Tamponade  
 
Ascending aorta trauma 
 
Myocardial ischemia  
 
Acute coronary artery occlusion 
 
Disturbances in the electrical system of the heart that may result in the permanent 
placement of a device (pacemaker)  
o 
Atrio-ventricular node block  
o 
Bundle branch block  
o 
Asystole  
 
Ventricular arrhythmias  
 
Valve  or distal embolization 
 
Thrombosis (including valve thrombosis) 
 
Hemorrhage requiring transfusion  
 
Arteriovenous fistula  
 
Vessel dissection or spasm  
 
Valve migration  
 
Prosthetic valve dysfunction including but not limited to: 
o 
Fracture  
o 
Bending (out-of-round configuration) of the valve frame 
o 
Under-expansion of the valve frame 
o 
Calcification  
o 
Pannus 
o 
Wear, tear, prolapse or retraction in the valve leaflet 
o 
Poor valve coaptation 
o 
Suture breaks or disruption 
o 
Leak 
o 
Mal-sizing (prosthesis-patient mismatch) 
o 
Malposition (either too high or too low) 
o 
Regurgitation 
o 
Stenosis  
 
Mitral valve regurgitation  
 
Hypotension or hypertension  
 
Acute renal injury 
 
Allergic reaction to antiplatelet agents or contrast medium  
 
Infection (including endocarditis)  
 
Bowel ischemia  

 
 
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 
Vascular access site or access related complications, including but not limited to: 
o 
pain 
o 
bleeding 
o 
hematoma  
o 
pseudoaneurysm 
o 
irreversible nerve injury 
o 
compartment syndrome 
o 
stenosis 
Additional information regarding risk analysis is located in the Investigator Brochure (Appendix 
R.21). 
D.1 
Methods to Minimize Risk 
The investigational plan is specifically designed to manage and minimize risks through careful 
patient selection, thorough training of investigators, adherence to the pre-determined time 
points to assess subject clinical status and regular clinical monitoring visits by Sponsor 
appointed monitoring personnel.  
In addition, an independent Data Safety Monitoring Board will monitor safety of the subjects 
throughout the trial. 
D.2 
Potential Benefits 
Patients treated with the Medtronic CoreValve® System may experience improvement in 
quality of life, morbidity and mortality compared to traditional open-heart aortic valve 
replacement. Potential benefits include, but are not limited to, absence of open-heart 
surgery-related risks, reduced procedure time, reduced anesthesia procedure time, shorter 
hospital stay and earlier return to normal activities than after open-heart aortic valve 
replacement. 
There is no direct benefit associated to participation in this study, but the information obtained 
during this study will be used scientifically. The results of this study can help physicians 
understand the implications of percutaneous treatment of patients with intermediate risk for 
surgery using the Medtronic CoreValve® System. 

 
 
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DESCRIPTION OF MEDTRONIC® COREVALVE SYSTEM 
E.1 
Investigational Product Description 
The Medtronic CoreValve® System (MCS) consists of 3 components: the Percutaneous Aortic 
Valve Bioprosthesis (PAV) in Figure 1below, the Delivery Catheter System (DCS) in Figure 2, 
and the Compression Loading System (CLS) in Figure 3. 
 
Percutaneous Aortic Valve Bioprosthesis 
 
Figure 1:  Percutaneous Aortic Valve (PAV) 
 
 
The PAV is manufactured by suturing valve leaflets and a skirt, made from a single layer of 
porcine pericardium, into a tri-leaflet configuration. The PAV is designed to replace the native 
aortic heart valve without open heart surgery and without concomitant surgical removal of the 
failed native valve. 
The bioprosthesis is processed with an antimineralization treatment of alpha-amino oleic acid 
(AOA) a compound derived from oleic acid, a naturally occurring long-chain fatty acid. 
The self-expanding multi-level frame is made of Nitinol and is radiopaque. 
The PAV is available for a range of aortic annulus and ascending aortic diameters as shown in 
Table 9 below. 
Table 9:  Patient Anatomical Diameters 
Model 
Size (mm) 
Aortic Annulus 
Diameter 
(range in mm) 
Ascending Aortic 
Diameter (mm) 
MCS-P3-26-AOA 
26 
20-23 
≤40 
MCS-P3-29-AOA 
29 
23-27 
≤43 
MCS-P3-31-AOA 
31 
26-29  
≤43 
 

 
 
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Delivery Catheter System 
The AccuTrak® DCS (DCS-C4-18FR) is compatible with a 0.889-mm (0.035-in) guidewire. The 
working length of the AccuTrak® DCS is 112.5 cm. It incorporates a protective deployment 
sheath that houses and deploys the PAV. The AccuTrak® DCS can be used to house and 
deliver all commercially available sizes of the PAV (26mm,29mm, and 31mm PAV). The outer 
diameter of the DCS is 12Fr, the stability layer is 15Fr and the outer diameter of the valve 
capsule is 18 Fr. 
Figure 2:  Delivery Catheter System (DCS) 
 
The AccuTrak® DCS features an integrated handle designed to provide the user with accurate 
and controlled deployment.  After the DCS is placed in the vicinity of the aortic annulus, the 
user retracts the deployment sheath, thereby deploying the PAV to the desired location.  In use, 
the deployment sheath can be partially pulled back to evaluate the PAV location prior to fully 
releasing the PAV. In this way, the user can make slight adjustments to the PAV location if 
needed prior to release.  
Compression Loading System (Model CLS-3000-18 FR) 
Figure 3:  Compression Loading System (CLS) 
 
 
The CLS (Model CLS-3000-18FR) compresses the PAV into the DCS. The CLS is comprised of 
the following elements: 
 
inflow cone 
 
inflow tube (straight tube) 
 
outflow cap 
 
outflow cone 
 
outflow tube (tube with flared ends) 
Medtronic may incorporate additional devices into this clinical study providing they receive 
regulatory approval and the scientific soundness of the study is not adversely affected.   
Additional information regarding the Medtronic CoreValve® System (MCS) is available in the 
Investigator Brochure (Appendix R.21).  Note the Instructions For Use are also located in 
Appendix R.21. 

 
 
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E.2 
Medtronic CoreValve Ordering, Storage, and Disposition 
The Medtronic CoreValve and all required delivery components will be ordered through 
Medtronic. Medtronic will only allow shipment of investigational devices to the hospital or 
investigator when the Clinical Research Specialist has declared the investigation site ready to 
start the study.   
Devices will be shipped to sites as needed based on subject enrollment/randomization and 
procedures scheduled.  Only one device should be used per patient, unless in case of device 
malfunctions or in case of complications. Sites will be supplied with sufficient device stock to 
complete scheduled procedures.  Upon completion of scheduled procedures all unused devices 
must be returned to Medtronic.  Instructions for device return are outlined on the 
Shipment/Device Disposition Log.  
Investigational devices must be stored in a secured area. The method of storage shall prevent 
the use of investigational devices outside the applications as mentioned in this Clinical 
Investigation Plan. In addition, all information for the use, storage and handling of the 
investigational device as indicated in the Investigator’s Brochure, must be taken into account. 
Instructions for Use and storage recommendations are outlined in Appendix R.21. 

 
 
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F 
MONITORING AND AUDITING 
F.1 
Monitoring 
The investigational site will be monitored to ensure compliance with the trial protocol, 
adherence to applicable regulations, and accuracy of trial data.  Monitoring visits will be 
conducted primarily to ensure the safety and wellbeing of the subjects is preserved.  Monitoring 
visits will also be used to verify that trial data submitted on case report forms are complete and 
accurate with respect to the subject records and to verify device accountability.   
Site personnel will complete eCRFs following each subject visit.  Trial data submitted will be 
reviewed against patient charts and other sources containing original records of patient data.  
Source document verification will be conducted via a risk based approach as outlined in the 
Monitoring Plan. 
The responsible individual for this trial is included on the title page of the CIP. 
The progress of the trial will be monitored by: 
 
On-site review, as deemed appropriate by the sponsor 
 
Telephone communications between the site personnel (e.g., Investigator, Trial 
Coordinator) and trial monitors 
 
Review of eCRFs and the associated clinical records 
 
Review of regulatory documents 
Upon study completion Site Closeout Visits will be conducted, as outlined in the Monitoring 
Plan. 
Monitoring and monitoring oversight will be provided by Medtronic CardioVascular (Mounds 
View, MN, USA, and Maastricht, the Netherlands).  Representatives of Medtronic (i.e. 
contractors and designees) may also act as the trial monitors to the site. 
Prior to the first site activation a monitoring plan will be established outlining the above 
activities, as well as study materials to be supplied to sites, the process for corrective and 
preventive actions and Investigator disqualification procedures. 
F.2 
Auditing 
Medtronic may conduct audits at participating clinical sites. The purpose of an audit is to verify 
the performance of the monitoring process and the trial conduct, independently of the personnel 
directly involved in the trial. Regulatory bodies, such as the Food and Drug Administration, may 
also perform inspections at participating sites. The investigator and/or institution shall permit 
Medtronic and regulatory bodies direct access to source data and documents. 

 
 
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LABELING 
In Europe, the CoreValve PAV component labeling will not carry the CE mark and the labeling 
with state for ―clinical study purposes only‖ in accordance with ISO14155. The Investigational 
Instructions for Use (IFU) is supplied in English with the PAV component and this will also not 
carry the CE mark.  The DCS and CLS components are identical to the CE marked CoreValve 
System and will be supplied with the approved commercial CE marked labeling. 
In the United States and other geographies, where CoreValve is not currently approved, the 
PAV, DCS and CLS will be labeled as Investigational. 
Instructions for Use and additional labeling are attached in Appendix R.21. 
H 
CONSENT MATERIALS 
The template consents for the trial are attached in Appendix R.1. 
I 
IRB/MEC INFORMATION 
IRB/MEC information is attached in Appendix R.2. 
J 
OTHER INSTITUTIONS 
Information regarding other institutions involved in this trial is located in Appendix R.3. 
K 
ADDITIONAL RECORDS AND REPORTS 
Information regarding additional Records and Reports can be in found in Appendix R.4. 
L 
REPORT OF PRIOR INVESTIGATIONS 
The Report of Prior Investigations (RPI) is attached in the Investigator Brochure in Appendix 
R.21. 

 
 
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M 
PUBLICATION POLICY 
Medtronic, as the Sponsor of this trial, recognizing the seminal importance of this investigation, 
is committed to the widespread dissemination of all primary and secondary endpoint results.  A 
publication plan will be implemented and followed.  At the conclusion of the trial, a multisite 
abstract reporting the primary results will be prepared by the Principal Investigators (in 
collaboration with others including but not limited to the Steering Committee, directors of the 
core laboratories, CEC, and Lead Investigators from high enrolling sites) and presented at an 
annual scientific meeting (e.g., Transcatheter Cardiovascular Therapeutics, EuroPCR, the 
American Heart Association, or the American College of Cardiology).  A multisite publication will 
similarly be prepared for publication in a reputable scientific journal.  The publication of the 
principal results from any single site experience within the trial is not allowed until both the 
preparation and publication of the multisite results, and then only with written permission from 
Medtronic.  
Following analysis and presentation of the primary endpoint results, active participation of all 
committee members, Investigators from high enrolling sites, and core laboratory personnel will 
be solicited for data analysis and abstract and manuscript preparation.  Submission of all 
abstracts and publications regarding the primary endpoint and secondary endpoints from the 
trial requires approval by the Principal Investigators after review by the Operations Committee. 
A separate publication plan will provide detailed information about the publication committee, 
authorship, publication proposals, and requests for data. 

 
 
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N 
AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN 
All amendments to the CIP shall be agreed between the sponsor and the clinical investigator(s).  
Amendments will be recorded with a justification for the amendments in Table 10 below: 
 
Table 10:  Clinical Investigation Plan Change History 
Version 
Description of Change 
Rationale for Change 
 
 
 
 

 
 
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ABBREVIATIONS AND DEFINITIONS 
O.1 
List of Abbreviations 
Please refer to Table 11 below for a list of abbreviations for use in the SURTAVI trial. 
Table 11:  List of Abbreviations 
Abbreviation 
Term 
2D 
Two Dimensional 
6MWT 
Six Minute Walk Test 
AE 
Adverse Event 
ACT 
Active Clotting Time 
ADE 
Adverse Device Effect 
AF 
Atrial Fibrillation 
AOA 
Alpha-amino Oleic Acid 
AR 
Aortic Regurgitation 
AS 
Aortic Stenosis 
AVR 
Aortic Valve Replacement 
BAV 
Balloon Aortic Valvuloplasty 
BSA 
Body Surface Area 
BNP 
B-type Natriuretic Peptide 
BP 
Blood Pressure 
BSA 
Body Surface Area 
CA 
Competent Authority 
CE 
European Conformity 
CEC 
Clinical Events Committee 
CFR 
U.S. Code of Federal Regulations 
CIP 
Clinical Investigation Plan 
CLS 
Compression Loading System 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTA 
Computerized tomographic angiography 
CVA 
Cerebrovascular Accident 
CV-ICU 
Cardiovascular Intensive Care Unit 
DCS 
Delivery Catheter System 
DHCA 
Deep Hypothermic Circulatory Arrest 
DSMB 
Data Safety Monitoring Board 
DVT 
Deep Vein Thrombosis 

 
 
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Abbreviation 
Term 
ECC 
Extracorporeal Circulation 
ECG 
Electrocardiogram 
ECMD 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EF 
Ejection Fraction 
EuroSCORE 
European System for Cardiac Operative Risk Evaluation 
FDA 
U.S. Food and Drug Administration 
Fr 
French 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HVD 
Heart Valve Dysfunction 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
IABP 
Intra-Aortic Balloon Pump 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IRB/MEC 
Institutional Review Board 
IFU 
Instructions for use 
ITT 
Intent-to-treat 
IV 
Intravenous 
IXRS 
Interactive Voice/Web Response System 
LA 
Left Atrial/Atrium 
LAO 
Left Anterior Oblique 
LBBB 
Left Bundle Branch Block 
LVEF 
Left Ventricular Ejection Fraction 
LVOT 
Left Ventricular Outflow Tract 
LVOTO 
Left Ventricular Outflow Tract Occlusion 
LWMH 
Low Weight Molecular Heparin 
MACCE 
Major Adverse Cardiovascular and Cerebrovascular Event 
MAE 
Major Adverse Event 
MCS 
Medtronic CoreValve® System 
MEC 
Medical Ethics Committee 
MI 
Myocardial Infarction 
MMSE-2 
Mini Mental State Exam 
NIHSS 
National Institute of Health Stroke Scale 
mRS 
Modified Rankin Score 

 
 
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Abbreviation 
Term 
NYHA 
New York Heart Association 
PAV 
Percutaneous Aortic Valve 
PCI 
Percutaneous Coronary Intervention 
PPM 
Patient Prosthesis Mismatch 
TAVI 
Transcatheter aortic valve implant 
QoL 
Quality of Life 
RAO 
Right Anterior Oblique 
RBBB 
Right Bundle Branch Block 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SAVR 
Surgical Aortic Valve Replacement 
SOP 
Standard Operating Procedures 
STS 
Society of Thoracic Surgeons 
TEE 
Transesophageal Echocardiography 
TIA 
Transient Ischemic Attack 
TTE 
Transthoracic Echocardiography 
UADE 
Unanticipated Adverse Device Effect 
 

 
 
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O.2 
Definitions of Terms 
ACUTE KIDNEY INJURY 
 Acute Kidney Injury will be defined according to the definition proposed by the Valve Academic Research Consortium 
(VARC) Consensus Report for Transcatheter Aortic Valve Implantation (TAVI); 2010-12-05. 
Acute Kidney Injury: Modified RIFLE Classification  
Stages 
Change in Serum Creatinine (up to 72 hours) compared to Baseline 
Stage 1 
Increase in serum creatinine to 150-200% (1.5-2.0 x increase compared with 
baseline) or increase of ≥ 0.3 mg/dl (≥26.4 µmol/L)  
Stage 2* 
Increase in serum creatinine to 200-300% (> 2-3 x increase compared with 
baseline) or increase between >0.3 mg/dl (>26.4 µmol/L) and <4.0 mg/dl 
(<354 µmol/L) 
Stage 3*/** 
Increase in serum creatinine to ≥300% (> 3 x increase compared with 
baseline) or serum creatinine of ≥ 4.0 mg/d (≥354 µmol/L) with an acute 
increase of at least 0.5 mg/dl (44 µmol/L) 
*  Stage 2 and 3 acute renal injuries will be considered to be serious adverse events. 
** Patients receiving renal replacement therapy are considered to meet Stage 3 criteria 
irrespective of other criteria 
ACUTE VESSEL OCCLUSION  
 The state of complete luminal obstruction with no antegrade blood flow. 
 ADVERSE EVENT (AE)  
An adverse event is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device.  
NOTE 1: This definition includes events related to the investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to investigational medical devices. 
 ADVERSE DEVICE EFFECT (ADE)  
Adverse event related to the use of an investigational medical device 
 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device 
 AORTIC DISSECTION 
Intimal tear resulting in blood splitting the aortic media and producing a false lumen that can 
progress in an antegrade or retrograde direction. Aortic dissection is further classified using 
Stanford classification (Types A and B) depending on whether ascending or descending aorta 
involved) or DeBakey classification (Types I, II and III) as shown below.  
 

 
 
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AORTIC REGURGITATION (AR) 
Aortic valve incompetence resulting in backward flow of blood.   
Aortic Valve Regurgitation will be defined according to the definition proposed by the Valve Academic Research 
Consortium (VARC) Consensus Report for Transcatheter Aortic Valve Implantation (TAVI); 2010-12-05. 
Prosthetic Aortic Valve Regurgitation Criteria (Central and Paravalvular) 
Parameter 
Mild 
Moderate  
Severe 
Valve Structure and Motion 
 
Mechanical or bioprosthetic 
Usually normal 
Usually abnormal 
Usually abnormal 
Structural parameters 
 
Left ventricular size 
Normal 
Normal/mildly dilated 
Dilated 
Doppler parameters (qualitative or semiquantitative) 
 
Jet width in central jets (% LVO diameter): color* 
 
Jet density: CW Doppler 
 
Jet deceleration rate (PHT, ms): CW Doppler** 
 
LV outflow vs. pulmonary flow: PW Doppler 
 
  
Diastolic: flow reversal in the descending aorta 
PW Doppler 
 
 
Circumferential extent of paraprosthetic AR (%) 
 
Narrow (≤25%) 
Incomplete or faint 
Slow (>500) 
Slightly increased 
 
 
Absent or brief 
early diastolic 
<10 
 
Intermediate (26-64%) 
Dense 
Variable (200-500) 
Intermediate 
 
 
Intermediate 
 
10-20 
 
Large (≥65%) 
Dense 
Steep (<200) 
Greatly Increased 
 
 
Prominent, 
Holodiastolic 
>20 
Doppler parameters (quantitative) 
 
Regurgitant volume (mL/beat) 
 
Regurgitant fraction (%) 
 
<30 
<30 
 
30-59 
30-50 
 
>60 
>50 
*Parameter applicable to central jets and is less accurate in eccentric jets 
** Influenced by left ventricular compliance 
AR=aortic regurgitation; CW= continuous wave; LVO= left ventricular outflow; PW= pulsed wave 
 
2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
 
Classification of the Severity of Valve Disease in Adults 
Aortic Regurgitation 
 
Mild 
Moderate  
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+ 
2+ 
3-4+ 
Color Doppler jet width 
Central jet, width less 
25% of LVOT 
Greater than mild but 
no signs of AR 
Central jet, width greater 
than 65% LVOT 
Doppler vena contracta width 
(cm) 
< 0.3 
0.3-0.6 
> 0.6 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per 
beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.10 
0.10-0.29 
≥ 0.30 
Additional essential criteria 
Left ventricular size 
 
 
 
 
 
Increased 
Moderate or severe aortic regurgitation (AR) will be considered a serious adverse event. 

 
 
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AORTIC STENOSIS (AS)  
A narrowing, stiffening or stricture of the aortic valve.  
2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
 
Aortic Stenosis 
Indicator 
Mild  
Moderate 
Severe 
Jet velocity (m/s) 
Less than 3.0 
3.0-4.0 
Greater than 4.0 
Mean gradient (mmHg) 
Less than 25 
25-40 
Greater than 40 
Valve area (cm2) 
Greater than 1.5 
1.0-1.5 
Less than 1.0 
Valve area index (cm2/m2) 
 
 
Less than 0.6 
 Moderate or severe AS will be considered a serious adverse event. 
 
ARRHYTHMIA 
Any variation from the normal rhythm of the heartbeat, including sinus arrhythmia, premature 
beat, heart block, atrial fibrillation, atrial flutter and tachycardia.  
 Major Arrhythmias: Complete heart block, ventricular tachycardia and ventricular 
fibrillation 
 Serious Arrhythmias: Any arrhythmia requiring surgical or invasive intervention or DC 
cardioversion 
BLEEDING EVENT 
Bleeding event will be defined according to the definition proposed by the Valve Academic Research Consortium 
(VARC) Consensus Report for Transcatheter Aortic Valve Implantation (TAVI);  2010-12-05. 
Life-threatening or Disabling Bleeding 
 Fatal bleeding OR 
 Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, or 
pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome  
OR  
 Bleeding causing hypovolemic shock or severe hypotension requiring 
   vasopressors or surgery OR 
 Overt source of bleeding with drop in hemoglobin of ≥5 g/dL or whole blood or 
   packed red blood cells (RBC) transfusion ≥4 units*  
Major Bleeding 
 Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0g/dL or 
requiring transfusion of 2-3 units of whole blood/RBC AND  
 Does not meet criteria of life-threatening or disabling bleeding  
Minor Bleeding 
 Any bleeding worthy of clinical mention (e.g. access site hematoma) that does not qualify as 
life-threatening, disabling or major  
*  Given one unit of packed RBC typically will raise blood hemoglobin concentration by 1g/dL, 
an estimated decrease in hemoglobin will be calculated. 
 
Life-threatening and Major bleeding events are considered to be serious. 

 
 
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BUNDLE BRANCH BLOCK 
ACC/AHA/HRS 2006 Key Data Elements and Definitions for Electrophysiological Studies and Procedures; A Report of 
the American College of Cardiology/ American Heart Association Task Force on Clinical Data Standards 
(ACC/AHA/HRS Writing Committee to Develop Data Standards on Electrophysiology), JACC, Vol. 48, No. 11, 2006. 
Left Bundle Branch Block (LBBB) 
 
QRS duration 120 ms or longer 
 
Delayed onset of intrinsicoid deflection in 1, V5, and V6 _60 ms 
 
Broad and notched or slurred R waves in I, aVL, V5, and V6 
 
rS or QS complexes in right precordial leads 
 
ST-segment and T waves in opposite polarity to the major QRS deflection 
Right Bundle Branch Block (RBBB) 
 
QRS duration _120 ms 
 
rsR= or rSR= complexes in V1 and V2 
 
Delayed onset of intrinsicoid deflection in V1 and V2 _50 ms 
 
Broad, slurred S wave in 1, V5, 
Any new or worsening LBBB or RBBB that requires the placement of a permanent pacemaker 
and/or other surgical or invasive intervention will be considered to be serious. 
CARDIAC TAMPONADE 
Clinical syndrome caused by the accumulation of fluid in the pericardial space, resulting in 
reduced ventricular filling and subsequent hemodynamic compromise. 
CARDIOGENIC SHOCK 
Patient was, at the time of procedure, in a clinical state of hypoperfusion sustained for greater 
than 30 minutes, according to either of the following criteria:  
1. Systolic BP < 80 and/or Cardiac Index < 1.8 despite maximal treatment; or 
2. IV inotropes and/or IABP necessary to maintain Systolic BP > 80 and/or CI > 1.8 
 
CHRONIC RENAL INSUFFICIENCY 
Kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for or ≥3 months.  
Kidney damage is defined as pathologic abnormalities or markers of damage, including 
abnormalities in blood or urine test or imaging studies. 
CONDUCTION DISTURBANCE REQUIRING PERMANENT PACEMAKER IMPLANTATION 
ACC/AHA 2006 Guidelines for the Management of Patients with Valvular Heart Disease (published in the August 1, 
2006, issues of Journal of the American College of Cardiology and Circulation) 
Any disturbance in the cardiac electrical conduction system that meets the American College of 
Cardiology (ACC)/American Heart Association (AHA)/ Heart Rhythm Society (HRS) Class I or 
IIa Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities for Acquired 
Atrioventricular Block in Adults or Permanent Pacing in Chronic Bifascicular Block. 

 
 
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DEATH  
A serious adverse event that is classified by the following: 
All-cause death: All deaths from any cause after a valve intervention. This includes all 
cardiovascular and non-cardiovascular deaths.  
 Cardiovascular Death:  
(Cardiovascular death will be defined according to the definition proposed by the Valve Academic Research Consortium 
(VARC) Consensus Report for Transcatheter Aortic Valve Implantation (TAVI); 2010-12-05) 
Any one of the following criteria: 
 Any death due to proximate cardiac cause (e.g. MI, cardiac tamponade, worsening heart 
failure) 
 Unwitnessed death and death of unknown cause 
 All procedure-related deaths, including those related to a complication of the procedure or 
treatment for a complication of the procedure 
 Death caused by non-coronary vascular conditions such as cerebrovascular disease, 
pulmonary embolism, ruptured aortic aneurysm, dissecting aneurysm, or other vascular 
disease  
NOTE: All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established.  Specifically, 
any unexpected death even in subjects with coexisting potentially fatal non-cardiac disease (e.g. cancer, 
infection) should be classified as cardiac. 
Non-cardiovascular death:  Any death not covered by the above definitions, such as death 
caused by infection, malignancy, sepsis, pulmonary causes, accident, suicide, or trauma.  
Valve-related death:  
 Any death caused by prosthetic valve dysfunction, valve thrombosis, embolism, bleeding 
event, or implanted valve endocarditis; 
 Death related to reintervention on the operated valve 
DEVICE DEFICIENCY 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance 
  
NOTE:  Device deficiencies include malfunctions, use errors, and inadequate labeling. 
DEVICE MIGRATION 
Obvious movement of the Medtronic CoreValve® PAV from its documented original implant 
position, after access site closure, as confirmed by X-ray, echocardiography, CT scan or direct 
assessment during open heart surgery or autopsy. 
DEVICE MALPLACEMENT 
Placement of the Medtronic CoreValve® PAV in a non-therapeutic location, either inadvertently, 
or possibly intentionally due to unintended problems during the Medtronic CoreValve® System 
(MCS) delivery or procedure that necessitates placement in the non-therapeutic location.   
DEVICE RELATED  
Events that occur as the direct result of the Medtronic CoreValve® System (MCS) as it relates to 
delivery, placement, efficacy or durability; these may involve the implanted device or the 
delivery system components. 
DEVICE RELATED COMPLICATIONS 
Complications associated with the device as it relates to delivery, placement, efficacy or 
durability; these may involve the implanted device or the delivery system.   

 
 
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DEVICE SUCCESS 
 Device success is defined as follows: 
 successful vascular access, delivery and deployment of the device, and successful 
retrieval of the delivery system, 
 correct position of the device in the proper anatomical location (placement in the annulus 
with no impedance on device function), 
 Intended performance of the prosthetic valve1 (aortic valve area > 1.2 cm2 (by 
echocardiography using the continuity equation) and mean aortic valve gradient < 20 
mmHg or peak velocity < 3 m/sec, without moderate or severe prosthetic valve AR) 
 Only one valve implanted in the proper anatomical location 
 
1  
assessed acutely in a resting state, either within 24-48 hours after the index procedure or before hospital 
discharge 
EMBOLISM 
Free flowing blood clot or lesion material that is located in the systemic or pulmonary circulation 
that occurs in the absence of infection after the immediate perioperative period. Embolism may 
be manifested by a neurological event or a noncerebral embolic event.  
ENCEPHALOPATHY 
Altered mental state (e.g., seizures, delirium, confusion, hallucinations, dementia, coma, 
psychiatric episode, etc.).  
ENDOCARDITIS 
Implanted valve endocarditis: Any infection involving an implanted valve. The diagnosis of 
operated valvular endocarditis is based on one of the following criteria:  
 re-operation with evidence of abscess, paravalvular leak, pus, or vegetation confirmed as 
secondary to infection by histological or bacteriologic studies;  
 autopsy findings of abscess, pus, or vegetation involving a replaced valve; or  
 in the absence of reoperation or autopsy, meeting of the Duke Criteria for endocarditis. 
Infective endocarditis is diagnosed based on Duke Criteria and necessitates 2 major criteria, 
or 1 major and 3 minor criteria, or 5 minor criteria 
Major criteria 1: Positive blood culture for infective endocarditis  
Typical microorganism consistent with infective endocarditis from 2 separate blood 
cultures, as noted below: 
 Viridans streptococci, Streptococcus bovis, or HACEK group (Haemophilus. 
Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, 
Kingella or  
 Community-acquired Staphylococcus aureus or enterococci, in the absence of a 
primary focus  
-OR- 
Microorganisms consistent with infective endocarditis from persistently positive blood 
cultures defined as: 
 Two positive cultures of blood samples drawn >12 hours apart, or  
 All of 3 or a majority of 4 separate cultures of blood (with first and last sample drawn 1 
hour apart)  

 
 
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Major criteria 2: Evidence of endocardial involvement 
Positive echocardiogram for infective endocarditis defined as: 
 oscillating intracardiac mass on valve or supporting structures, in the path of 
regurgitant jets, or on implanted material in the absence of an alternative anatomic 
explanation, or  
 abscess, or  
 new partial dehiscence of prosthetic valve  
-OR- 
 New valvular regurgitation (worsening or changing of pre-existing murmur not 
sufficient) 
Minor criteria 1: Predisposition: predisposing heart condition or intravenous drug use 
Minor criteria 2: Fever: temperature > 38.0° C (100.4° F) 
Minor criteria 3: Vascular phenomena: major arterial emboli, septic pulmonary infarcts, 
mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions 
Minor criteria 4: Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth spots, 
and rheumatoid factor 
Minor criteria 5: Microbiological evidence: positive blood culture but does not meet a major 
criterion as noted above or serological evidence of active infection with organism consistent 
with infective endocarditis 
Minor criteria 6: Echocardiographic findings: consistent with infective endocarditis but do 
not meet a major criterion as noted above  
EXPLANT 
 Removal of the investigational valve implant for any reason, including post-mortem. 
HEMOLYSIS 
A plasma free hemoglobin value > 40 mg/dL is considered to be hemolysis and a reportable 
adverse event. 
 Major hemolysis: A plasma free hemoglobin value > 40 mg/dL that requires intervention 
(i.e. iron replacement, blood transfusion, folic acid administration, corticosteroids, 
Intravenous immunoglobulin G (IVIG) and/or surgery).  Major hemolysis events will be 
considered to be serious adverse events. 
 Minor hemolysis:  A plasma free hemoglobin value > 40 mg/dL that does not require 
intervention. 

 
 
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HOSPITALIZATION FOR SIGNS AND SYMPTOMS RELATED TO AORTIC VALVE DISEASE 
Aortic valve disease hospitalizations are defined as a non-elective hospital admission for signs 
and symptoms related to aortic valve disease (as described below) that results in at least a two-
night stay (i.e., where the admission date and the discharge date differ by at least two calendar 
days).  For the purpose of the protocol, overnight stays at nursing home facilities or extended 
care facilities do not meet the protocol definition of hospitalization.  This does include the 
administration or augmentation of intravenous heart failure therapy (e.g., inotropes, diuretics, 
and/or vasodilators).   
Patients with signs and symptoms related to aortic valve disease (as described below) who are 
hospitalized for less than two days or who are treated and released from the emergency 
department or an outpatient clinic (including treatment for intravenous heart failure therapy 
(e.g., inotropes, diuretics, and/or vasodilators)), will not be counted as aortic valve disease 
hospitalizations.   
Aortic valve disease will be evaluated using documented evidence of the following signs and 
symptoms.  An independent Clinical Events Committee (CEC) will review all available source 
documentation for all hospitalizations to determine if they are aortic valve disease 
hospitalizations.  The CEC adjudication will be used for final analysis. 
Signs and Symptoms of Aortic Valve Disease 
Sign/Symtpom 
Definition 
Aortic Valve Dysfunction 
 
Shortness of breath/dyspnea  
A feeling of difficult or labored breathing that is out of proportion to 
the patient’s level of physical activity 
Exercise intolerance  
A condition where the patient is unable to do physical exercise at 
the level or for the duration that would be expected of someone in 
his/her general physical condition, or experiences unusually 
severe post-exercise pain, fatigue, or other negative effects 
Dizziness/syncope  
Lightheadness or unsteadiness of gait or a partial or complete 
loss of consciousness with interruption of awareness of oneself 
and ones surroundings 
Chest pain  
Discomfort and soreness in and around the chest 
Worsening Heart Failure 
Volume Overload 
 
Orthopnea 
Dyspnea in which the person can breathe comfortably only when 
standing or sitting erect  
Paroxysmal nocturnal dyspnea 
Acute dyspnea caused by the lung congestion and edema that 
results from partial heart failure and occurring suddenly at night, 
usually an hour or two after the individual has fallen asleep.  
Jugular venous distension 
With the patient is positioned under 45°, and the filling level of the 
jugular vein determined. An abnormal response is more than 3 
centimeters above the sternal angle.  
Hepatomegaly 
Palpation of the edge of the liver below the edge of the ribs 
without inspiration  
Peripheral edema 
Swelling of tissues, usually in the lower limbs, due to the 
accumulation of fluids.  
Pulmonary rales 
Small clicking, bubbling, or rattling sounds in the lung associated 
with inspiration  
Abdominal-jugular reflux 
An elevation of venous pressure visible in the jugular veins and 
measurable in the veins of the arm, produced in active or 
impending congestive heart failure by firm pressure with the flat 
hand over the abdomen.  
Radiographic evidence of 
pulmonary edema 
NA 
Elevated B-type natriuretic peptide 
level   
NA 
Hypoperfusion 
 
Narrow pulse pressure  
Pulse pressure < 30 mmHg  
Hypotension 
Systolic BP < 90 systolic 
Renal or hepatic dysfunction 
 
Rise in baseline creatinine by 25%  
 
Increase in LFT (SGOT, SGPT) > 2 times normal  
Low serum sodium concentration  
Serum sodium < 130 mEq/dL 

 
 
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INFECTION 
Elevated body temperature (fever), and White Blood Count (WBC) > 12,000/ml, and Significant 
leftward shift on Differential. 
MAJOR ADVERSE CARDIOVASCULAR AND CEREBROVASCULAR EVENTS (MACCE)  
Defined as a composite rate of  
 all-cause death  
 myocardial infarction (MI)   
 all stroke, and 
 reintervention (defined as any cardiac surgery or percutaneous reintervention catheter 
procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted 
valve) 
MAJOR ADVERSE EVENT (MAE) 
Major Adverse events include the following: 
 MACCE 
 Acute kidney Injury 
 Cardiac tamponade 
 Prosthetic valve dysfunction  
 Cardiogenic shock 
 Valve endocarditis 
 Valve embolism 
 Life-threatening, disabling or major bleeding  
 Major vascular complication 
 Cardiac Perforation 
 Device Migration 
MITRAL REGURGITATION 
Mitral valve incompetence resulting in backward flow of blood.   
 
2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
 
Classification of the Severity of Valve Disease in Adults 
Mitral Regurgitation 
 
Mild 
Moderate  
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+ 
2+ 
3-4+ 
Color Doppler jet area 
Small, central jet, < 
4cm2  or <20% LA 
area) 
Signs of > mild 
present but no criteria 
for severe MR 
Vena contracta with > 
0.7cm with large central 
MR jet (area >40% of LA 
area) or with a wall-
impinging jet of any size, 
swirling in LA 
Doppler vena contracta width 
(cm) 
< 0.3 
0.3-0.69 
≥ 0.70 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per 
beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.20 
0.29 – 0.39 
≥ 0.40 
Additional essential criteria 
Left atrial size 
Left ventricular size 
 
 
 
 
 
Enlarged 
Enlarged 
 

 
 
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MITRAL STENOSIS 
A narrowing, stiffening or stricture of the mitral valve.  
2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
 
Mitral Stenosis 
 
Mild 
Moderate 
Severe 
Mean Gradient (mmHg) 
Less than 5 
5-10 
Greater than 10 
Pulmonary artery systolic 
pressure (mmHg) 
Less than 30 
30-50 
Greater than 50 
Valve area (cm2) 
Greater than 1.5 
1.0-1.5 
Less than 1.0 
Moderate or severe AS will be considered a serious adverse event. 
MYOCARDIAL INFARCTION (MI) 
Myocardial infarction will be defined according to the definition proposed by the Valve Academic Research Consortium 
(VARC) Consensus Report for Transcatheter Aortic Valve Implantation (TAVI); 2010-12-05. 
Peri-Procedural MI 
(≤ 72 hours after the index procedure) 
1. New ischemic symptoms (e.g. chest pain or shortness of breath), or new 
ischemic signs (e.g. ventricular arrhythmias, new or worsening heart failure, 
new ST-segment changes, hemodynamic instability, or imaging evidence of 
new loss of viable myocardium or new wall motion abnormality) AND 
2. Elevated cardiac biomarkers (preferably CK-MB) within 72 hours after the index 
procedure, consisting of two or more post-procedure samples that are ≥ 6-8 
hours apart with a 20% increase in the second sample and a peak value 
exceeding 10x the 99th percentile upper reference limit (URL) or a peak value 
exceeding 5x the 99th percentile URL and with new pathological Q waves in at 
least 2 contiguous leads. 
 
Spontaneous MI 
(> 72 hours after the index procedure) 
Any one of the following criteria: 
1. Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least 
one value above the 99th percentile URL, together with evidence of myocardial 
ischemia with at least one of the following: 
 
ECG changes indicative of new ischemia (new ST-T changes or new left 
bundle branch block [LBBB]); 
 
New pathological Q waves in at least 2 contiguous leads; 
 
Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality 
2. Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST 
elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography 
and/or at autopsy, but death occurring before blood samples could be obtained, or at 
a time before the appearance of cardiac biomarkers in the blood. 
3. Pathological findings of an acute myocardial infarction. 
All myocardial infarctions will be considered serious adverse events. 

 
 
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NEUROLOGICAL EVENT  
Any central, new neurological deficit, whether temporary or permanent and whether focal or 
global, that occurs after the subject emerges from anesthesia. 
NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) 
Classification system for defining cardiac disease and related functional limitations into four 
broad categorizations: 
Class I 
Subject with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
Class II 
Subjects 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. 
Class III 
Subjects with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV 
Subjects with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
PARAVALVULAR AORTIC REGURGITATION 
Leakage due to a separation of the prosthetic valve from the annulus. Diagnosis of paravalvular 
leak may be obtained from echocardiogram; however definitive diagnosis is obtained at 
reoperation, explant, or autopsy.  
 All moderate or severe paravalvular leaks will be classified as Serious Adverse Events. 
 (Refer to the definition of Aortic Regurgitation for additional paravalvular leak severity criteria)   
PATIENT PROSTHESIS MISMATCH (PPM) 
Patient Prosthesis Mismatch will be defined according to the definition from Urso et al, Interact Cardiovasc Thorac Surg. 
2009 Sep; 9(3):510-8. Epub 2009 Jun 4. 
 Severe PPM will be defined as an EOA ≤ 0.65 cm2 /m2 BSA 
 Moderate PPM defined as a patient with an EOA ≤ 0.85 cm2 /m2 BSA   
PERMANENT PACEMAKER IMPLANTATION  
Implantation of permanent pacemaker after the index procedure due to occurrence of 
conduction disturbances.  
 Procedure-related: Permanent Pacemaker is implanted in subjects with new onset 
conduction disturbances or worsening of existing conduction disturbances 
 Not related to procedure: Permanent Pacemaker is implanted in subjects with known 
conduction disturbances that did not advance after the index procedure. 
PROCEDURE RELATED COMPLICATIONS 
Complications associated with any part of the vascular access procedure, associated 
treatments or necessary secondary interventions that do not necessarily involve the device.  
This includes morbidity associated with either pre-medication, or anesthesia, or other adjunct to 
the surgical procedure.  Other technical errors including inappropriate patient selection, 
inappropriate operator techniques, measurements, or judgment that do not involve the device 
itself are also included.   

 
 
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PROCEDURAL SUCCESS 
 Defined as device success without occurrence of in-hospital MACCE. 
PROCEDURE-RELATED EVENTS 
Events occurring during or as a direct result of the index procedure. Events that occur before 
extubation and before access site closure are classified as procedural. 
PROSTHETIC VALVE DYSFUNCTION 
Prosthetic Valve Dysfunction will be defined according to the definition proposed by the Valve Academic Research 
Consortium (VARC) Consensus Report for Transcatheter Aortic Valve Implantation (TAVI); 2010-12-05 
 
Failure modes of prosthetic valve dysfunction include, but are not limited to, the following: 
 
Aortic Stenosis 
o 
Stent creep 
o 
Pannus 
o 
Calcification 
o 
Support structure deformation (out-of-round configuration), under-expansion, 
fracture, or trauma (cardio-pulmonary resuscitation, blunt chest trauma) 
o 
Mal-sizing [prosthesis-patient mismatch(PPM)]  
o 
Endocarditis 
o 
Prosthetic valve thrombosis 
o 
Native leaflet prolapse impeding prosthetic leaflet motion 
 
Aortic Regurgitation 
o 
Pannus 
o 
Calcification 
o 
Support structure deformation (out-of-round configuration), recoil, under-expansion, 
fracture, insufficient radial strength, or trauma (cardio-pulmonary resuscitation, 
blunt chest trauma) 
o 
Endocarditis 
o 
Prosthetic valve thrombosis 
o 
Mal-position (too high, too low) 
o 
Acute mal-coaptation 
o 
Leaflet wear, tear/perforation, prolapse or retraction 
o 
Suture breakage or disruption 
o 
Native leaflet prolapse impeding prosthetic leaflet motion 
Prosthetic valve dysfunction will be considered serious when it meets the definition of a serious 
adverse event (SAE). 
REINTERVENTION 
Any surgical or percutaneous interventional catheter procedure that repairs, otherwise alters or 
adjusts, or replaces a previously implanted valve. In addition to surgical reoperations, balloon 
dilatation, interventional manipulation, repositioning, or retrieval, and other catheter-based 
interventions for valve-related complications are also considered reinterventions. Reintervention 
is further subdivided into surgical and percutaneous. 
RESPIRATORY INSUFFICIENCY 
Post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) 
ratio [FEV1/FVC] less than 70%. 
Post-bronchodilator FEV1 less than 80% predicted, with or without chronic symptoms (i.e., 
cough or sputum production). 
RESPIRATORY FAILURE 
The need for ventilatory support for > 72 hours associated with an inability to wean from the 
respirator for any reason. 

 
 
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RIGHT VENTRICULAR INSUFFICIENCY 
Defined as sequelae of right ventricular failure including the following: 
 Significantly decreased right ventricular systolic and/or diastolic function 
 Tricuspid valvular regurgitation secondary to elevated pressure 
Clinical symptoms to include: 
o 
Hepatic congestion 
o 
Ascites 
o 
Anasarca 
o 
Presence of ―hepato-jugular reflux‖ 
o 
Edema 
SERIOUS ADVERSE DEVICE EFFECT (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event 
SERIOUS ADVERSE EVENT (SAE) 
A serious adverse event (SAE) is an event that: 
 Led to death, 
 Led to serious deterioration in health of the subject, that either resulted in: 
o 
a life threatening illness or injury, or 
o 
a permanent impairment of a body structure or a body function, or 
o 
in-patient or prolonged hospitalization, or 
o 
medical or surgical intervention to prevent a life-threatening illness or injury or 
permanent impairment to a body structure or a body function  
 Led to fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE: Planned hospitalization for pre-existing condition, or a procedure required by per protocol, without serious 
deterioration in health, is not considered a serious adverse event.  
Events that do not meet these criteria are considered non-serious. 
STROKE (CVA)  
Stroke and TIA will be defined according to the definition proposed by the Valve Academic Research Consortium 
(VARC) Consensus Report for Transcatheter Aortic Valve Implantation (TAVI); 2010-12-05 and the FDA’s Current 
Thinking Regarding Neurological Assessments for Transcatheter Valve Trials (July 25, 2011). 
Stroke Diagnostic Criteria 
 
Rapid onset 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 hours; OR < 24 hours, if therapeutic 
intervention(s) were performed (e.g. thrombolytic therapy or intracranial angioplasty); OR 
available neuroimaging documents a new hemorrhage or infarct; OR the neurologic deficit results 
in death 
 
No other readily identifiable non-stroke cause for the clinical presentations (e.g. brain tumor, 
trauma, infection, hypoglycemia, peripheral lesion, pharmacological influences)* 
 
Confirmation of the diagnosis by at least one of the following: 
o 
Neurology or neurosurgical specialist 
o 
Neuroimaging procedure (MR or CT scan or cerebral angiography) 
o 
Lumbar puncture (i.e. spinal fluid analysis diagnostic of intracranial hemorrhage) 
Stroke Definitions 
 
Transient Ischemic Attack 
o New focal neurologic deficit with rapid symptom resolution (usually 1-2 hours), always within 24 hours 
o Neuroimaging without tissue injury 
 
Stroke: (diagnosis as above, preferably with positive neuroimaging study)+ 
o Minor (non-clinically important disability) - modified Rankin score < 2 at 30-dayand 90-days+,** 
o Major (clinically important disability) - modified Rankin score ≥ 2 at 30-dayand 90 days**  
*   Patients with non-focal global encephalopathy will not be reported as a stroke without unequivocal evidence based upon 
neuroimaging studies 
+  Modified Rankin score assessments should be made by qualified individuals according to certification process. If there is discordance 
between modified Rankin and NIHSS determination of major versus minor stroke, a final determination of major versus minor stroke 
will be adjudicated by the neurology member of the clinical events committee. 

 
 
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** For the purposes of this protocol, the Modified Rankin Score at 90 days will be used to classify minor versus 
major stroke (<2 will be classified as minor and ≥ 2 will be classified as major). 
 
Modified Rankin Scale 
SCORE 
DESCRIPTION 
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 
Clinically important disabilities (major strokes) will be considered to be serious adverse events. 
 Strokes will be further categorized to the following: 
 Ischemic stroke is defined as an acute symptomatic episode of focal cerebral, spinal, or 
retinal dysfunction caused by an infarction of central nervous system tissue. 
 Hemorrhagic stroke is defined as an acute symptomatic episode of focal or global cerebral or 
spinal dysfunction caused by a nontraumatic intraparenchymal, intraventricular, or 
subarachnoid hemorrhage. 
 Undetermined stroke is defined as a stroke with insufficient information to allow 
categorization as A or B. 
TECHNICAL OBSERVATION 
A defect, malfunction, or failure of any part of the Medtronic CoreValve® System. This may 
pertain to the device or delivery and/or loading system not functioning according to its design 
intent.  
TRANSIENT ISCHEMIC ATTACK (TIA) 
 (Refer to the definition of TIA under stroke above) 
 New focal neurologic deficit with rapid symptom resolution (usually 1-2 hours), always within 
24 hours 
 Neuroimaging without tissue injury 

 
 
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TRICUSPID REGURGITATION 
2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
Severe tricuspid regurgitation: vena contracta width greater than 0.7cm and systolic reversal 
in hepatic veins.  
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report 
NOTE:   Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity or 
outcome has been identified in the risk analysis report. 
VALVE THROMBOSIS 
Any thrombus not caused by infection attached to or near the trial valve that occludes part of the 
blood flow path, interferes with valve function, or is sufficiently large to warrant treatment. Valve 
thrombus found at autopsy in a subject whose cause of death was not valve-related or found at 
operation for an unrelated indication should also be counted as valve thrombosis. 
VASCULAR COMPLICATIONS 
Vascular Complications will be defined according to the definition proposed by the Valve Academic Research 
Consortium (VARC) Consensus Report for Transcatheter Aortic Valve Implantation (TAVI); 2010-12-05. 
Vascular Access Site and Access Related Complications 
Major Vascular Complications  
1.  Any thoracic aortic dissection  
2.  Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve injury, 
or compartment syndrome) leading to either death, need for significant blood 
transfusions (≥4 units), unplanned percutaneous or surgical intervention, or 
irreversible end-organ damage (e.g. hypogastric artery occlusion causing visceral 
ischemia or spinal artery injury causing neurologic impairment)  
3.  Distal embolization (non-cerebral) from a vascular source requiring surgery or 
resulting in amputation or irreversible end-organ damage  
Minor Vascular Complications 
1.  Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula or pseudoaneurysm requiring compression or thrombin 
injection therapy, or hematomas requiring transfusion of ≥ 2 but < 4 units) not 
requiring unplanned percutaneous or surgical intervention and not resulting in 
irreversible end-organ damage  
2.  Distal embolization treated with embolectomy and/or thrombectomy and not resulting 
in amputation or irreversible end-organ damage  
3.  Failure of percutaneous access site closure that did not result in an interventional or 
surgical correction and is not associated with death, need for significant blood 
transfusions (≥4 units), or irreversible end-organ damage. 
Major vascular complications will be considered to be serious adverse events. 
 

 
 
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P 
STUDY MANAGEMENT 
P.1 
Miscellaneous 
P.1.1 Insurance 
The Medtronic Bakken Research Center B.V. is a wholly owned subsidiary of Medtronic Inc., 
which as the parent company of such entity maintains appropriate clinical study liability 
insurance coverage as required under applicable laws and regulations and will comply with 
applicable law and custom concerning specific insurance coverage. If required, a Clinical Trial 
Insurance statement/certificate will be provided to the IRB/MEC. 
P.1.2 
Reimbursement 
Study reimbursement is outlined in the Clinical Trial Agreement. 
P.1.3 
Indemnification 
Indemnification will be done according to local laws. 
P.1.4 Subject confidentiality 
At all times throughout the study confidentiality shall be observed by all parties involved. All 
information and data sent to parties involved in study conduct concerning patients or their 
participation in this study will be considered confidential. The patient identification number is to 
be recorded on all study documents and will link the study documents to the patient's name and 
medical record at the investigator's site. To maintain confidentiality, the patient's name or any 
other personal identifiers should not be recorded on any study document other than the 
informed consent form. 

 
 
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Q 
REFERENCES 
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29. Ong AT, Serruys PW, Mohr FW, Morice MC, Kappetein AP, Holmes DR, Jr., Mack MJ, van den Brand 
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surgery. Ann Thorac Surg 2009; 88(1 Suppl):S43-62. 

 
 
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45. Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J, Ponikowski P, Priori SG, 
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Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, 
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Swedberg K, Camm AJ. 2010 Focused Update of ESC Guidelines on device therapy in heart failure: 
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46. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, DeGraba TJ, 
Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL. Primary 
prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke 
Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease 
Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; 
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J, Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Schwamm LH, Tomsick 
T. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a 
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113(10):e409-449. 
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Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Sacco RL, Schwamm LH. 
Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and 
transient ischemic attack. Stroke 2008; 39(5):1647-1652. 
49. O'Brien SM, Shahian DM, Filardo G, Ferraris VA, Haan CK, Rich JB, Normand SL, DeLong ER, 
Shewan CM, Dokholyan RS, Peterson ED, Edwards FH, Anderson RP. The Society of Thoracic 
Surgeons 2008 cardiac surgery risk models: part 2--isolated valve surgery. Ann Thorac Surg 2009; 
88(1 Suppl):S23-42. 
50. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, 
management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative 
for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001; 
163(5):1256-1276. 
51. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW, Hogg RJ, Perrone RD, Lau J, Eknoyan 
G. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, 
classification, and stratification. Ann Intern Med 2003; 139(2):137-147. 
52. Zoghbi WA, Chambers JB, Dumesnil JG, Foster E, Gottdiener JS, Grayburn PA, Khandheria BK, 
Levine RA, Marx GR, Miller FA, Jr., Nakatani S, Quinones MA, Rakowski H, Rodriguez LL, 
Swaminathan M, Waggoner AD, Weissman NJ, Zabalgoitia M. Recommendations for evaluation of 
prosthetic valves with echocardiography and doppler ultrasound: a report From the American Society 
of Echocardiography's Guidelines and Standards Committee and the Task Force on Prosthetic 
Valves, developed in conjunction with the American College of Cardiology Cardiovascular Imaging 
Committee, Cardiac Imaging Committee of the American Heart Association, the European Association 
of Echocardiography, a registered branch of the European Society of Cardiology, the Japanese 
Society of Echocardiography and the Canadian Society of Echocardiography, endorsed by the 
American College of Cardiology Foundation, American Heart Association, European Association of 
Echocardiography, a registered branch of the European Society of Cardiology, the Japanese Society 
of Echocardiography, and Canadian Society of Echocardiography. J Am Soc Echocardiogr 2009; 
22(9):975-1014; quiz 1082-1014. 
53. Delgado V, Ng AC, van de Veire NR, van der Kley F, Schuijf JD, Tops LF, de Weger A, Tavilla G, de 
Roos A, Kroft LJ, Schalij MJ, Bax JJ. Transcatheter aortic valve implantation: role of multi-detector 
row computed tomography to evaluate prosthesis positioning and deployment in relation to valve 
function. Eur Heart J; 31(9):1114-1123. 
54. Schultz CJ, Moelker A, Piazza N, Tzikas A, Otten A, Nuis RJ, Neefjes LA, van Geuns RJ, de Feyter P, 
Krestin G, Serruys PW, de Jaegere PP. Three dimensional evaluation of the aortic annulus using 
multislice computer tomography: are manufacturer's guidelines for sizing for percutaneous aortic valve 
replacement helpful? Eur Heart J; 31(7):849-856. 
 
 

 
 
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SURTAVI 
SUrgical Replacement and Transcatheter 
Aortic Valve Implantation 
 
 
Appendix 
 
 
VERSION 3.0 
18 November 2011 
  
 
Sponsor: 
Medtronic, Inc. 
Clinical Research 
Mailstop: MVS66 
Mounds View South 
8200 Coral Sea St NE 
Mounds View, MN 55112 USA 
Medtronic Bakken Research Center 
CardioVascular Department 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
 

 
 
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TABLE OF CONTENTS 
R 
APPENDICES ................................................................................................ 100 
R.1 
Sample Informed Consent ............................................................................................... 100 
R.2 
List of Participating Investigational Centers .................................................................... 125 
R.3 
Other Institutions.............................................................................................................. 126 
R.4 
Additional Records and Reports ...................................................................................... 127 
R.5 
Sample Case Report Forms ............................................................................................ 128 
R.6 
Aortogram Acquisition Guidelines ................................................................................... 129 
R.7 
Echocardiography Acquisition Guidelines ....................................................................... 131 
R.8 
Electrocardiogram (ECG) Submission............................................................................. 150 
R.9 
Computed Tomography (CT) Angiography Acquisition Guidelines ................................. 151 
R.10 Interactive Voice/Web Response System (IXRS) ........................................................... 163 
R.11 Explanted Device/Pathology and Return Procedures ..................................................... 164 
R.12 Economic and Quality of Life Data Collection ................................................................. 166 
R.13 Pacing Guidelines ............................................................................................................ 167 
R.14 Six Minute Walk Test Instructions ................................................................................... 171 
R.15 National Institute of Health Stroke Scale (NIHSS) .......................................................... 184 
R.16 Modified Rankin Scale (mRS) Instructions ...................................................................... 188 
R.17 Mini Mental State Exam (MMSE-2) ................................................................................. 189 
R.18 Additional Neurological Assessments ............................................................................. 190 
R.19 Medtronic CoreValve® Clinical Assessment Guidelines .................................................. 192 
R.20 Katz Index of Independence in Activities of Daily Living ................................................. 193 
R.21 Investigator Brochure / Report of Prior Investigations for the Medtronic CoreValve® 
System ............................................................................................................................. 194 
R.22 SURTAVI Risk Model ...................................................................................................... 195 
R.22.1 
 SURTAVI Risk Model Rationale ...................................................................... 195 
R.22.2 
 SURTAVI co-morbidity list ............................................................................... 198 

 
 
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APPENDICES 
R.1 
Sample Informed Consent  
Attached are the informed consent form templates: 
 US 
 OUS 
 

 
 
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INFORMED CONSENT FORM 
US Template 
Medtronic CoreValve® SURTAVI Trial 
 
You are being asked to read this form so that you understand this research study and how you 
might take part in it. By signing this form, you will show that you understand and that you agree 
to take part in this research study. Your signature on this form is required before you can take 
part in this research study. 
BACKGROUND 
You are being asked to take part in a research study entitled “Medtronic CoreValve® SURTAVI 
Trial” because you have a disease of your aortic valve.  This disease if called aortic stenosis. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the left 
ventricle (main pumping chamber of the heart) into the aorta (main artery delivering blood to the 
body). If the valve becomes abnormally narrow through a process of thickening and stiffening 
(aortic stenosis) the heart must work harder to pump the same amount of blood with each beat. 
As the heart works harder, the heart muscle thickens (hypertrophy), and the heart chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve 
is the standard treatment. 
As an alternative to open heart surgery, the Medtronic CoreValve® System has been developed 
to replace a diseased aortic heart valve without the need for open heart surgery. This system 
allows the percutaneous aortic valve (study valve) to be implanted (inserted) through a long, 
thin flexible tube that is inserted through an incision in the skin and threaded through the 
bloodstream (percutaneous). 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This Web site will not include information that can identify you. At most, the Web site 
will include a summary of the results. You can search the Web site at any time. 
You are being asked to participate in this study because doctors have determined your aortic 
valve is no longer working properly. However, your doctors have also decided that your risk of 
experiencing major problems while undergoing open-heart surgery is moderate due to medical 
reasons or anatomical reasons (relating to how and where your heart, aortic valve and blood 
vessels are placed within your body). This means that you doctor believes your health is 
acceptable for open-heart surgery, but there are still a risk of potential problems. 
PURPOSE OF THE STUDY 
The purpose of this clinical  study is to determine if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions 
as you. 
The study valve is considered an “investigational device”, which means that clinical studies are 
required to determine if it is safe and provides clinical benefit. Medtronic, Inc. is sponsoring this 
study to obtain data on the safety and performance of the Medtronic CoreValve® System. The 
Medtronic CoreValve® System includes the valve described below and two parts that help load 
and deliver the valve correctly.  
This study will involve up to 1200 subjects at up to 50 hospitals in the United States and around 
the world, and is anticipated to take approximately 7 years to complete. Your participation in this 
study is expected to last approximately five years from the day you are enrolled in the study. 

 
 
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STUDY DEVICE 
The study valve is made from animal tissue 
attached to a metal frame.  
The study valve is designed to be implanted 
(inserted) using a delivery system catheter 
(long, thin flexible tube) to replace your 
diseased aortic heart valve without open-
heart surgery. 
Although the Medtronic CoreValve system is 
not approved by the US Food & Drug 
Administration (FDA) it has been approved in 
other parts of the world since 2006 and has 
been implanted in over 10,000 patients. 
 
PROCEDURES TO BE FOLLOWED 
If you agree to be in this study, data such as your age, gender, medical history and medication 
use will be recorded. You will undergo the following tests: 
• 
Physical examination 
 
 
• 
Computed tomography (CT) - a scan performed using an x-ray machine, which is linked 
to a computer to take pictures of your body. Sometimes a CT will require the use of a type 
of dye that makes the kidneys work harder and may be harmful to the kidneys. You may 
have an MRI in place of a CT scan if your doctor believes your kidneys are not working 
well enough for you to have a CT scan. MRI stands for magnetic resonance imaging and 
is a test that uses a strong magnet and a complex computer system to produce detailed 
images of your internal organs and soft body tissues. 
• 
Blood tests (about 2 tablespoons) 
• 
Echocardiography (transthoracic echocardiogram (TTE)) - a test that uses sound waves 
to take pictures of your heart and measure the degree of narrowing of your aortic valve; a 
probe with gel is placed on the outside of your chest to take pictures of your heart 
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches 
are placed on the outside of your chest 
• 
Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
If you are of child-bearing potential, we will ask you to take a pregnancy test. If you are 
pregnant, you will not be able to participate in this study. 
These procedures and tests are standard procedures and are not experimental. If you have 
already had any of these tests performed before, they may to be used for the study if your study 
doctor determines they don‟t need to be repeated for study purposes. The results from your 
exams and tests will be reviewed by your doctors who will determine if you are eligible to be in 
the study.   
Your study doctors may determine after reviewing your test results that you are not eligible to 
be in the study and/or it will not be possible to implant the study valve. If so, you will not be 
allowed to participate in the study. 
If your doctors decide you are eligible to be in the study your treatment will be determined in a 
way similar to flipping a coin, called randomization. You will be assigned to one of two groups. 
One group will receive a transcatheter aortic valve implant (TAVI), the other group will open-
heart surgical aortic valve replacement (SAVR). On average, one out of every two participants 
will receive TAVI. The other participants will receive SAVR. You will not be able to choose your 
treatment assignment. 

 
 
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Your enrollment in the study will begin once you are assigned to your treatment group. 
If you are enrolled in the study, you will be required to have the following additional tests 
completed within 14 days prior to the procedure (TAVI or SAVR): 
• 
Physical exam, including a determination of neurological (brain) status where you will be 
asked to answer a series of questions and perform a series of tasks such as writing and 
drawing 
• 
Blood tests (about 2 tablespoons) 
• 
Walking test – a test that records your breathing, heart rate, and how you feel after 6 
minutes of walking 
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches 
are placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life Questionnaires (QOL). 
Your personal physician will be informed about your participation in this clinical study. 
If you are assigned to the TAVI group: 
TAVI is an experimental procedure. 
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor.  You may be advised to continue these medications for 
at least three months following your procedure.  
Before the procedure you will be given an antibiotic (a medicine that kills bacteria or germs) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic 
that he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about 2 tablespoons) and an ECG before the procedure.   
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you 
of this need before the procedure. Additionally, if your study doctor decides that it is necessary 
during the procedure, you will be put under general anesthesia at that time. 
Your study doctor will decide what sites are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary. Additionally, your study 
doctor will decide if performing a surgical incision to any of the site(s) is necessary. 
During the procedure you may have a transesophageal echocardiogram which is also called a 
TEE. This test uses sound waves to take a closer look at the inside structures of the heart. To 
perform the test you will swallow a thin flexible tube with a special tip. This tube sits in the 
esophagus (the tube that connects the mouth to the stomach). The special tip of the tube sends 
out sound waves (ultrasound) that echo within the chest wall. The esophagus is located behind 
the heart so these echoes are picked up and create a picture of the heart that is displayed on a 
video monitor. The pictures will allow your study doctor to take a closer look at your valve. 
You will have a temporary pacemaker put in place during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins and threaded 
through your vein into the right side of your heart. The wire is attached to a battery operated 
device outside of your body. This temporary pacemaker will help keep your heart rate (speed) 
and rhythm steady. This temporary pacemaker will not be removed for at least 48 hours after 
your TAVI procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. Balloon valvuloplasty is a procedure used to widen a stiff or narrowed heart valve. A 
wire and a thin tube are guided by x-rays through the heart and positioned through the diseased 
heart valve. A balloon is placed over the wire and inflated, enlarging the opening through the 
diseased valve allowing the study valve to be placed. 

 
 
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Your doctor will then implant (insert) the study valve through the long, thin flexible tube that is 
inserted through an incision in the skin and threaded through the bloodstream. TAVI is 
performed using x-ray machines which will allow your doctor to see the study valve, your blood 
vessels and heart. The study valve will be guided through your blood vessels to your existing 
aortic valve and then the study valve will be placed over your existing valve. 
During the TAVI procedure, your doctor will perform angiography (x-ray pictures) and ECGs 
(recordings of the electrical impulses of your heart through patches placed on the chest) to 
observe your heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your 
study doctor with the procedure. Medtronic staff may assist the physician in the loading of the 
study valve. 
If you are assigned to the SAVR group: 
Open heart surgery, surgical repair and/or replacement of your aortic valve, are not 
experimental procedures. 
If you are assigned to the SAVR group, your doctors will replace your diseased aortic valve 
through open heart surgery. During surgery, you are asleep under general anesthesia. SAVR 
often requires a median sternotomy, where the bone in the center of the chest (sternum) is split 
down the middle. The chest is then opened to provide your doctor with access to the heart and 
chest cavity, in order to replace your aortic valve. Your surgery is performed while the function 
of your heart is taken over by a heart lung machine (called CPB for cardiopulmonary bypass). 
You may have a TEE (a thin tube sits in the esophagus and sends out sounds waves to create 
a picture of your heart) and a temporary pacemaker (thin wire threaded through your vein to 
right side of heart to keep your heart rate and rhythm steady) during the procedure. 
Your doctor may remove any tissue and calcium deposits that are interfering with the normal 
function of the valve. Your damaged valve may be completely removed. The new valve will be 
sewn into the space where your own valve used to be. After your doctor makes sure your valve 
is working properly, blood flow will be restored to your heart and the incisions will be closed. 
You will also have blood drawn for testing before and after the procedure. 
If your doctor is unable to implant (insert) the study valve in you during the TAVI or SAVR 
procedure, you will still be considered enrolled in the study and will need to return to the clinic 
for the required follow-up visits as described in the “Follow-up Visits after TAVI and SAVR” 
section. 
After TAVI and SAVR Procedure: 
After the TAVI and SAVR procedure, your study doctors will continue to monitor your progress 
and recovery. 
You will have the following tests performed within the two days following the procedure and 
before you are discharged from the hospital: 
•  
Determination of neurological (brain) status where you will be asked to answer a series 
of questions and perform a series of tasks 
•  
Blood tests (about 2 tablespoons) 
•  
Echocardiogram (TTE) 
•  
ECG 

 
 
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Follow-up Visits after TAVI and SAVR: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months 
(1 year), 18 months, 24 months (2 years), and 3, 4, and 5 years after the procedure. Most of the 
follow-up tests and examinations are routine, not experimental. Each visit will take about 1 ½ to 
2 hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
• 
Physical examination, including a determination of neurological (brain) status where 
you will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Blood tests (about 2 tablespoons) – 30 day visit only 
• 
Walking test – 30 day visit only 
• 
Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12 months, 24 months, and 3, 4, 5 years will include: 
• 
Physical examination, including a determination of neurological (brain) status where 
you will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last clinic visit 
• 
Blood tests (about 2 tablespoons) 
• 
Echocardiogram (TTE) 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Walking test – 12 and 24 months visits only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted via phone to 
complete a Quality of Life Questionnaire. 
If you have additional heart surgeries or cath lab procedures to work on or replace your aortic 
valve or study valve, you will be asked to answer questions and perform activities that will help 
the study doctors and nurses to determine your neurological (brain) status within 24 hours after 
each additional procedure. 
If you have a stroke, have been inform by a doctor that you experienced a stroke, or experience  
any of the following symptoms, notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as 
possible: sudden numbness, tingling, loss of movement (especially on 1 side of the body), 
vision changes, confusion or trouble understanding simple statements, severe headaches, or 
seizures.  Any of these symptoms could indicate that you are having problems with your 
neurological (brain) function.  If a doctor confirms that you had a stroke, you will have tests 
performed to determine your neurological (brain) status where you will be asked to answer a 
series of questions and perform a series of tasks. These tests will be performed at 7 days, 30 
days and 3 months after you have any of these symptoms. 
If you have any other problems or complications, seen by any other doctors, or are hospitalized 
during your participation in this study you should immediately notify Dr. Principal Investigator at 
xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis.  Your study doctor will determine if you will need to have another valve 
implanted.   
In the event of your death, we will request an autopsy. We will also request that either the whole 
heart and valve or just the valve are removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the investigational valve. 
Your family and your "legally authorized representatives", have the right to refuse the autopsy 
and refuse the request to remove the heart and/or valve even if you sign this consent form. 

 
 
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TAVI 
Potential risks associated with the implantation of the study valve may include, but are not 
limited to, the following: 
•  
Death 
•  
Acute myocardial infarction - heart attack; decrease blood flow to the heart causing 
death of an area of the heart muscle 
•  
Stroke - decreased blood flow to the brain causing death of brain cells 
•  
Urgent need for surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to place 
new vessels around the existing blocked vessels of the heart to improve blood 
supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
•  
Urgent need for balloon valvuloplasty (balloon valvuloplasty during the TAVI 
procedure is expected) – a procedure through the vessels inside the body and heart in 
which a narrowed heart valve is stretched open by a balloon 
•  
Urgent need for Percutaneous Coronary Intervention (PCI) – a procedure through 
the vessels inside the body and heart used to treat or open narrowed vessels of the 
heart 
•  
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
•   Perforation of the myocardium or vessel – a hole in the heart muscle or a blood 
vessel 
•   Cardiac Tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
•  
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
•  
Myocardial ischemia – reduced blood supply to the heart 
•  
Acute coronary artery occlusion – blockage or closure of an artery that supplies the 
heart with blood 
•  
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical impulses to 
the heart to help your heart beat normally. 
o 
Atrio-ventricular node block – a block in the electrical path from the top part of 
the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom part 
of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
•  
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part of the 
heart (ventricles) 
• 
Embolism – an abnormal particle (air, blood clots) floating in the blood stream or 
attached to an object, including the valve 
•  
Thrombosis (including valve thrombosis) - blood clot, including a blood clot on the 
valve 
•  
Hemorrhage requiring transfusion – bleeding requiring blood to be put back into the 
body 
• 
Arteriovenous fistula – abnormal connection between an artery vessel that takes 
blood away from the heart and a vein vessel that takes blood to the heart 
• 
Vessel dissection or spasm – the separation of the walls of a vessel or a sudden 
narrowing of the vessel) 
•  
Valve migration – upward or downward movement of the device from where it was 
originally placed 
•  
Valve dysfunctions of the CoreValve® including but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
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o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 
•  
Mitral valve regurgitation – a leaking valve between the left upper (left atrium) and left 
lower (left ventricle) parts of the heart where blood flows backward through the valve 
•  
Hypotension or hypertension - low or high blood pressure 
•  
Acute renal injury - failure of the kidneys to work correctly 
•  
Allergic reaction (unfavorable reaction by the body) to: 
o 
Antiplatelet agents - drugs that keep blood clots from forming 
o 
Contrast medium - a substance used to increase the visualization of body 
structures such as x-ray dye 
•  
Infection including infection of the heart or heart valves (endocarditis) – an 
abnormal growth of germs in the body or body part 
•  
Bowel ischemia – decrease blood supply to the intestines 
•  
Complications at the area where the doctor opened the skin or related to opening 
the skin, including but not limited to: 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed space 
that could cause muscle or nerve damage 
o 
Stenosis – narrowing of a vessel (artery) 
SAVR 
Although SAVR is not experimental there are potential risks associated with the procedure. 
These risks are the same even if you undergo the SAVR procedure and you decide not to 
participate in this study.  Some of these risks include, but may not be limited to the following: 
 
Obstruction of blood flow to the heart (angina) resulting in damage to the heart tissue 
 
(myocardial infarction/heart attack) 
 
Abnormal heart beat (cardiac arrhythmia and dysrhythmia) 
 
Blood leaking around the outside of the prosthetic valve (paravalvular leak) or any 
 
Problem with the valve that causes leaking of blood after the valve has closed 
(transvavular leak). 
 
Damage to red blood cells (hemolysis) that can result in anemia (decreased red blood 
cells) 
 
Death 
 
Inflammation of the lining of the heart (endocarditis) 
 
Heart failure 
 
Any problem with the prosthetic valve that causes narrowing of the valve opening 
(stenosis) 
 
Blood clots that develop in the heart of on the replacement valve. These clots may 
break loose and travel through the bloodstream (thromboembolism). This problem may 
cause 
 
Stroke (decrease blood flow to the brain causing damage to the brain) or heart attack. 
 
Failure of the valve to open and close properly 

 
 
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If you become pregnant there maybe risks, discomforts, or side effects to you and the 
embryo/fetus that are not yet known.  Please notify your study doctor as soon as possible to 
discuss any of these potential risks. 
POSSIBLE BENEFITS 
The possible benefits you may receive from participating in this research are that you may be 
able to receive a new heart valve without having open-heart surgery. Another possible benefit is 
that your new valve may work better than the way your diseased valve currently works. This 
may improve how you feel and may improve your daily activity. 
Your participation in this research may improve procedures that may guide the future treatment 
of heart surgery, by using procedures that are less invasive, meaning less cutting, entering or 
breaking through the body, which may benefit others in the future. However, there is no 
guarantee that you will benefit from being in this research. 
ALTERNATIVE TREATMENTS 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other 
treatment options include percutaneous (through an artery in the groin) aortic valve 
implantation, or medical management to relieve symptoms, which may include balloon 
valvuloplasty.  Ask your study doctor about other treatment options you may have. 
IF PROBLEMS DEVELOP 
If you believe that you have been injured as a result of your participation in the study, you 
should notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible or in serious cases, 
go to the emergency room.  
If you are assigned to the TAVI group  
For those patients receiving the Medtronic CoreValve System and the TAVI procedure, 
Medtronic has agreed to pay back [name of institutions that are parties to the CTA] for the costs 
of medical or surgical care they provide for any serious and unanticipated illness or injury under 
the following conditions: 
 
The illness or injury must be related to a defect or malfunction of the Medtronic 
CoreValve System or in the TAVI procedure as described in the Protocol, and not related to 
procedures that are routine standard of care. 
 
The illness or injury cannot be caused by (a) the negligence or intentional misconduct 
of the study staff or [name of institutions that are parties to the CTA]; (b) because the 
study staff or [name of institution(s)] that are parties to the CTA] did not follow the 
protocol for the study; or (c) the natural progression of your illness. 
 
The illness or injury must have happened before the study closes (last patient is seen 
for the 5 year follow-up visit) at this [Name of institution(s)]. 
 
[Name of institution(s) that are parties to the CTA] must notify Medtronic within one year 
of the date the study closes at all study sites or before the study closes at this site, 
whichever is earlier. 
Subject to the above conditions, Medtronic will pay back the costs that are not covered by your 
health insurance or Medicare. The amount Medtronic will pay back is the amount Medicare 
pays [name of institution(s) that are parties to the CTA] plus 10%. 
If you are assigned to the SAVR group  
In the event of physical injury or physical illness related to a procedure required for the SAVR 
group, no monetary compensation or subsidized (paid) will be provided. Medical treatment will 
be routinely provided to you by any person involved in this study including the study doctors, the 

 
 
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hospital, or the study sponsor. Any immediate medical treatment, however, that may be 
necessary will be provided. 
By agreeing to the above, you do not waive any of your legal rights which you otherwise would 
have as a research subject, nor do you release the study sponsor (Medtronic, Inc.), study 
doctors, or the hospital from liability for negligence. 
PAYMENT FOR PARTICIPATION IN THE STUDY 
You will not be paid to take part in the study. However, you may be reimbursed for local mileage 
and parking expenses directly related to any study related visits. Your study doctor or research 
coordinator will tell you how to get reimbursement.  
There is no monetary advantage to the study doctor for participation in this study. 
MEDICAL EXPENSES 
Your private or public health insurance company (for example Medicare) will be billed for the 
valve procedure and the cardiac catheterization and other procedures that are required by the 
study and you will be responsible for paying for any co-payment, co-insurance or deductible. It 
is possible that your private or public health insurance will not pay for some or all of the 
procedures, including the valve procedure or the cardiac catheterization procedure because you 
are participating in this study. Any costs not covered by your public or private insurance will be 
your responsibility. You should discuss the estimate of these costs with your study doctor. You 
will not be charged for the cost of collecting the data for this study and other clinic visits and 
diagnostic tests done solely for the purposes of this study. 
BASIS OF PARTICIPATION 
Your participation in this study is voluntary. If you refuse to be in this study there will be no 
penalty or loss of benefits to which you are otherwise entitled. You may withdraw from the study 
at any time and will not lose your benefits or be treated any differently as a result of withdrawing 
from the study. Any new findings (decisions or conclusions) that may influence your willingness 
to participate will be provided to you.  If you decide to leave the study before it is finished, 
please tell one of the persons listed in the section below “Obtaining Additional Information”. It 
may be requested that, if you withdraw, you return to your study doctor for a final visit. 
The study doctor may end your participation in the study at any time if: 
 
He or she determines it is not in the best interest of your health 
 
The study doctor loses contact with you and you do not return for your study visits as 
scheduled 
 
You refuse to allow the use of private health information during the course of the study 
The study doctor will make the decision and let you know if it is not possible for you to continue 
in the study. 
You may be removed from the study without your consent if the sponsor (Medtronic, Inc.) ends 
the study.  If this happens, you will be notified and the reasons will be explained to you.  Your 
physician will continue to provide the appropriate medical therapy. 
PERMISSION FOR ACCESS TO AND USE OF HEALTH INFORMATION 
This section governs how your health information will be used and shared by the study doctors 
during and after the study. The health information that may be used and shared includes all 
information collected during the study and any health information in your medical records that is 
relevant to the study. 

 
 
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1. PROVIDERS’ DISCLOSURE OF HEALTH INFORMATION IN YOUR RECORDS 
You agree to permit [hospital and/or clinic], your doctors, and your other health care providers 
(“Providers”) to share health information in your medical records with [investigator(s)] and 
[his/her/his/her/its] staff (“Researchers”). You agree to permit Providers to share your health 
information: 
 
With the Researchers; 
 
With the study sponsor, Medtronic, Inc. and its agents and contractors (together 
“Medtronic”); 
 
As required by law; 
o 
With government organizations and review boards required to watch over the 
safety and effectiveness of medical products and therapies and the conduct of 
research; and 
o 
With other persons who are required to watch over the safety and effectiveness 
of medical products and therapies and the conduct of research. 
2. RESEARCHER’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
You agree to permit the Researchers to use and share your health information: 
 
Among themselves to conduct the study; 
 
With other researchers in the study to conduct the study; 
 
With Medtronic; 
 
With government organizations and review boards required to watch over the safety 
and effectiveness of medical products and therapies and the conduct of research; and 
 
With other persons who are required to watch over the safety and effectiveness of 
medical products and therapies and the conduct of research. 
Once Providers or Researchers have shared your health information with a third party, the 
information may be subject to further sharing by the third party. Federal privacy laws may no 
longer protect it from further sharing. 
While the study is in progress, you will not be allowed to see your health information that is 
created or collected for the study. After the study is finished, you may see this information as 
described in the [hospital/clinical trial site]‟s Notice of Information practices. 
This permission to share your health information does not have an ending date. You do not 
have to give this permission, but if you do not, you will not be allowed to be in the study. You 
may change your mind and take back this permission to use your health information at any 
time. To take back this permission, you must write to [name and contact information]. If you take 
back this permission, you cannot continue in the study. Even if you take back this permission, 
Medtronic and Researchers may continue to use and share the health information already 
received as described in this informed consent 
Economic Study 
This study contains a health economics review that will be done to compare the in-hospital,  
12 month and 24 month follow-up medical care resource utilization and cost for patients in each 
of the treatment groups. As part of this study, you will be asked to sign a Medical Billing 
Release Form. This form will be used by a third party to collect hospital bills from the patient 
accounting department at any hospital to which you are admitted, from the time of your 
enrollment in Medtronic CoreValve® SURTAVI Trial through the study follow-up period. You 
may also be asked to sign a document that gives us your permission to review your billing 
information sent directly from the Medicare system in order to evaluate medical cost data. This 
information will be kept strictly confidential and be used solely to assess the medical expenses 
which occur as a direct result of participating in the Medtronic CoreValve® SURTAVI Trial. 

 
 
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Quality of Life Questionnaire 
Medtronic CoreValve® SURTAVI Trial will also contain a quality of life study. As part of this 
study, your research coordinator will have you or your legal representative complete a 
questionnaire called a Quality of Life Questionnaire.  You will need to complete this 
questionnaire when you are enrolled in the study and 1 month, 3 months, 6 months, 12 months, 
18 months, 2 years, 3 years, 4 years and 5 years after your study procedure. 
OBTAINING ADDITIONAL INFORMATION 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. The study doctor will inform you of any new significant information, 
when it becomes available, which may affect your willingness to continue to participate in this 
study. If you have any questions about this study or if you experience any health problems, you 
should contact Dr. Principal Investigator at xxx-xxx-xxxx. 
If you have questions about your rights as a participant in this study, you should contact the 
chairman of the Institutional Review Board at xxx-xxx-xxxx. 
MEDTRONIC’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
This section describes what Medtronic will do with the study data, including your health 
information received during the study. 
Medtronic will keep your health information confidential in keeping with all applicable laws and 
regulations. Medtronic may use your health information to conduct this study. Medtronic may 
use your health information for other purposes, such as: 
 
Watch over and improve the performance of its device; 
 
New medical research; 
 
Proposals for making new medical products or procedures; and 
 
Other business purposes. 
Any reports or publications about the study or any other research will not include your name or 
a description of you. Any records identifying you will not be made publically available.  
Information received during the study will not be used to market to you; your name will not be 
placed on any mailing lists or sold to anyone for marketing purposes. 
The US Food and Drug Administration‟s regulations, as well as other applicable laws, control 
Medtronic‟s work in developing and assuring the safety and quality performance of its medical 
devices. Medtronic may disclose your health information to the FDA, as well as to other US and 
foreign government authorities responsible for assuring the safety of medical devices. 
Medtronic also may disclose your health information to institutional review boards and other 
persons who are required to watch over the safety and effectiveness of medical products and 
therapies and the conduct of research. You agree to allow Medtronic to use study data in these 
ways. You also agree to allow FDA and other governmental authorities to inspect your health 
information. 

 
 
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CONSENT 
I confirm that: 
 
I have read the informed consent form of this study and my physician has answered all 
my questions regarding the study.  
 
I had sufficient time to consider my participation into this study, I am aware that 
participation into this study is completely voluntary, and I agree to follow the 
instructions from the investigator. 
 
I realize that I may decide to refuse participation or stop participation at any time 
without penalty and without affecting the quality of my health care or the relationship 
with my physician.  
 
I understand and agree that personal information about me will be collected from my 
medical records, used and processed (manually and by computer) by the manufacturer 
of a medical device used in my treatment or any other designated party that is involved 
in the study (e.g. hospital, physician, regulatory authorities, ethics committees).  
 
I understand and agree that representatives from Medtronic, regulatory authorities and 
the Institutional Review Board will be granted direct access to my medical records.  
 
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigational. 
 
I fully understand there is limited experience with this device in humans and that its 
safety and effectiveness have not been established and there are risks of serious 
complications associated with this study. 
 
I also understand that the doctors might determine after I give consent that it is not 
possible to implant the study valve. 
 
I hereby give my consent to participate in the “Medtronic CoreValve® SURTAVI Trial”. I have 
been given a copy of this consent form, and am also aware that the investigator will keep a 
copy in his or her files. 
 
 
__________________________________________ 
Patient Name or Legal Representative (please print) 
 
 
__________________________________  
 
_______________ 
Patient or Legal Representative Signature Date  
   
(MM/DD/YYYY) 
 
 
Statement from Person Obtaining Consent 
I certify that I have explained the nature of the device and the study to the above-named 
person. 
I have also explained the contents of this informed consent form to the above-named person. I 
have asked whether or not there are any questions. I have answered any questions that were 
raised by this person. 
 
 
______________________________________ 
Person Obtaining Consent Name (please print) 
 
 
__________________________________  
 
_______________ 
Signature of Person Obtaining Consent Date  
 
(MM/DD/YYYY) 

 
 
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PATIENT INFORMED CONSENT FORM - INFORMATION SHEET 
OUS Template 
Medtronic CoreValve® SURTAVI Trial 
You are being asked to read this form so that you understand this clinical study and how you 
might take part in it.  By signing this form, you will show that you understand and that you agree 
to take part in this clinical study.  Your signature on this form is required before you can take 
part in this clinical study. 
Background 
You are being asked to take part in a clinical study entitled “The Medtronic CoreValve® 
SURTAVI Trial” because you have a disease of your aortic valve. This disease is called aortic 
stenosis. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the 
lower chamber of the heart (ventricle) into the main artery delivering blood to the body (aorta).  
If the valve becomes abnormally narrow through a process of thickening and stiffening (aortic 
stenosis), then the heart must work harder to pump the same amount of blood with each beat.  
As the heart works harder, the heart muscle thickens (hypertrophy), and the lower chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve 
is the standard treatment. For some patients, the risk of experiencing major problems during 
open-heart surgery is greater because of other health problems.  
As an alternative to open-heart surgery, the Medtronic CoreValve® System has been 
developed to replace a diseased aortic heart valve without the need for open-heart surgery. 
This system allows the percutaneous aortic valve (study valve) to be implanted (inserted) 
through a long, thin flexible tube that is inserted through an incision in the skin and threaded 
through the bloodstream (percutaneous). 
You are being asked to participate in this study because doctors have determined your aortic 
valve is no longer working properly.  However, your doctors have also decided that your risk of 
experiencing major problems while undergoing open-heart surgery is moderate due to medical 
reasons or anatomical reasons (relating to how and where your heart, aortic valve and blood 
vessels are placed within your body). This means that your doctor believes your health is 
acceptable for open-heart surgery, but there is still a risk of potential problems. 
Purpose of the Study 
The purpose of this clinical study is to determine if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical 
conditions as you. 
The Medtronic CoreValve® System is considered an “investigational device” by the United 
States Food and Drug Administration (FDA) which means that clinical studies are required to 
determine if it is safe and provides clinical benefit.  Medtronic, Inc. is sponsoring this study to 
obtain data on the safety and performance of CoreValve® and its delivery system to gain FDA 
approval.   
The study will involve up to 1200 patients, and is being conducted at up to 50 hospitals in 
Europe, the United States and around the world. It is anticipated to take approximately seven 
years to complete.  Your participation in this study is expected to last approximately five years 
from the day you are enrolled.  
As a participant in the study, you have certain responsibilities. You have the responsibility to be 
truthful regarding your health and medication history. 
You are expected to return to your study doctor‟s office for the study visits. The evaluations 
performed at these visits are a component of the study.  They are important for data collection 
and for monitoring that the Medtronic CoreValve® System is working properly.  These 
evaluations will take place at baseline, implant procedure, discharge, and follow-up visits (30 

 
 
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days, 6, 12, 18, 24, 36, 48, and 60 months). You should not take part in this study if you will not 
be available for the study visits.   
You also have the responsibility to report any injuries, hospitalizations, emergency room visits 
or other medical visits, symptoms or complaints to the study doctor or study nurse as soon as 
possible.  
Medtronic CoreValve® System Description 
The study valve is made from animal tissue 
attached to a metal frame. The study valve is 
designed to be implanted (inserted) using a 
delivery system catheter (long, thin flexible 
tube) to replace your diseased aortic heart 
valve without open-heart surgery.  
The Medtronic CoreValve® system was CE 
marked in 2006 and has been implanted in 
over 10,000 patients. 
Once it is implanted, CoreValve® acts in the 
same method of the native valve. 
 
 
Procedures to Be Followed 
 
If you agree to be in this study, data such as your age, gender, ethnic origin, medical 
history and medication use will be recorded.  You will undergo the following tests to 
determine if you are suitable for receiving the CoreValve®: 
 
Transthoracic echocardiography (TTE): a test that uses sound waves to take pictures of 
your heart and measure the degree of narrowing of your aortic valve; a probe is placed on 
the outside of your chest to take pictures of your heart 
 
Computed Tomography (CT): a scan performed using an x-ray machine, which is linked 
to a computer to take pictures of your heart and aortic valve 
 
If your doctor decides it is unsafe for you to have a CT scan, you will have a Magnetic 
Resonance Imaging (MRI) test.  MRI is a scan that uses the magnetic properties of your 
tissues to take pictures of your heart.  For the MRI test, you will lie on a special exam 
table while the pictures are taken. 
 
Blood tests: about two tablespoons 
 
An electrocardiogram (ECG): a test that records electrical impulses of your heart; patches 
are placed on the outside of your chest 
 
A physical examination 
 
Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into:the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
If you are of child-bearing potential, we will ask you to take a pregnancy test. If you are 
pregnant, you will not be able to participate in this study. 
All of these procedures and tests are standard procedures for patients with aortic valve 
disease, and are not experimental.  If you have already had any of these tests performed 
before, they may to be used for the study if your study doctor determines they do not need to 
be repeated for study purposes. 

 
 
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If your doctors decide you are eligible to be in the study, your treatment will be determined in a 
way similar to flipping a coin, called randomization. You will be assigned to one of two groups. 
One group will receive a transcatheter aortic valve implant (TAVI), the other group will have an 
open-heart surgical aortic valve replacement (SAVR). One out of every two participants will 
receive TAVI. The other participants will receive SAVR. You will not be able to choose your 
treatment assignment. 
Your enrollment in the study will begin once you are assigned to your treatment group.  If you 
are enrolled in the study; you will be required to have the following additional tests completed 
within 14 days prior to the procedure (TAVI or SAVR): 
• 
Physical exam, including a determination of neurological (brain) status where you will be 
asked to answer a series of questions and perform a series of tasks 
• 
Blood tests (about two tablespoons) 
• 
Six-Minute walking test – a test that records your breathing, heart rate, and how you feel  
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches 
are placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life (QOL) Questionnaires. 
If you are assigned to the TAVI group: 
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications l will be 
described to you by your study doctor. You may be advised to continue taking blood thinning 
medications for at least three months following your procedure.  
Before the procedure you will be given a medicine that kills bacteria or germs) (antibiotic) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic 
that he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about two tablespoons) and an ECG before the procedure. 
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you 
of this need before the procedure. Additionally, if your study doctor decides that it is necessary 
during the procedure, you will be put under general anesthesia at that time. 
Your study doctor will decide what areas are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary. Additionally, your study 
doctor will decide if performing a surgical incision to any of the area(s) is necessary. 
During the procedure, you may have a transesophageal echocardiogram which is also called a 
TEE. This test uses sound waves to take a closer look at the inside structures of the heart. To 
perform the test, you will swallow a thin flexible tube with a special tip. This tube sits in the the 
tube that connects the mouth to the stomach (esophagus). The special tip of the tube sends out 
sound waves (ultrasound) that echo within the chest wall. The esophagus is located behind the 
heart so these echoes are picked up and create a picture of the heart that is displayed on a 
video monitor. The pictures will allow your study doctor to take a closer look at your valve. 
You will have a temporary pacemaker put in place during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins. It is then 
threaded through your vein into the right side of your heart. The wire is attached to a battery-
operated device that is outside of your body. This temporary pacemaker will help keep your 
heart rate and beat steady. This temporary pacemaker will not be removed for at least 48 hours 
after your TAVI procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. This is a procedure used to widen a hard or thin heart valve. A wire and a thin tube 
are guided by x-rays through the heart and positioned through the diseased heart valve. A 
balloon is placed over the wire and inflated, enlarging the opening through the diseased valve 
allowing the study valve to be placed. 

 
 
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Your doctor will then insert the study valve through the long, thin flexible tube that is inserted 
through an incision in the skin and threaded through the bloodstream. TAVI is performed using 
x-ray machines which will allow your doctor to see the study valve, your blood vessels and 
heart. The study valve will be guided through your blood vessels to your existing aortic valve 
and then the study valve will be placed over your existing valve. 
During the TAVI procedure, your doctor will perform x-ray pictures (angiogram) and recordings 
of the electrical impulses of your heart through patches placed on the chest (ECG) to observe 
your heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your 
study doctor with the procedure. Medtronic staff may assist the physician in the loading of the 
study valve. 
If you are assigned to the SAVR group: 
If you are assigned to the SAVR group, your doctors will replace your diseased aortic valve 
through open-heart surgery. During surgery, you are asleep under general anesthesia. SAVR 
often requires a median sternotomy, where the bone in the center of the chest (sternum) is split 
down the middle. The chest is then opened to provide your doctor with access to the heart and 
chest cavity, in order to replace your aortic valve. Your surgery is performed while the function 
of your heart is taken over by a heart lung machine (called CPB for cardiopulmonary bypass). 
You may have a TEE (a thin tube sits in the esophagus and sends out sounds waves to create 
a picture of your heart) and a temporary pacemaker (thin wire threaded through your vein to 
right side of heart to keep your heart rate and rhythm steady) during the procedure. 
Your doctor may remove any tissue and calcium deposits that are interfering with the normal 
function of the valve. Your damaged valve may be completely removed. The new valve will be 
sewn into the space where your own valve used to be. After your doctor makes sure your valve 
is working properly, blood flow will be restored to your heart and the incisions will be closed. 
You will also have blood drawn for testing before and after the procedure. 
After TAVI and SAVR Procedure: 
After your TAVI and SAVR procedure, your study doctors will continue to monitor your progress 
and recovery. 
You will have the following tests performed within the two days following your TAVI procedure 
and before you leave the hospital: 
•  
Determination of neurological (brain) status where you will be asked to answer a series of 
questions and perform a series of tasks 
•  
Blood tests (about two tablespoons) 
•  
Echocardiogram (TTE) 
•  
ECG 
Follow-up Visits after TAVI and SAVR: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 
months, 18 months, 24 months (3 years) and 3, 4, and 5 years after the procedure. The follow-
up tests and examinations are not experimental and most are performed on a routine basis. 
Each visit will take about 1 ½ to 2 hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
•  
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
•  
Blood tests (about two tablespoons) – 30 day visit only 
 
Quality of Life (QoL) Questionnaires 
 
ECG 
• 
Six-Minute walking test – 30 day visit only 
• 
Echocardiogram (TTE) – 6 month visit only 

 
 
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Your evaluation at 12, 24, 36, 48 and 60 months will include: 
•  
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
•  
Echocardiogram (TTE) 
•  
QoL Questionnaires 
•  
ECG 
 
Six-Minute walking test – 12 and 24 months visit only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted via phone to 
complete a Quality of Life Questionnaire. 
If the study doctor is unable to implant the study valve, you will still be followed for safety and 
will need to return to the clinic for the required follow-up visits as described above. 
If you have additional heart surgeries or cath lab procedures to work on or replace your aortic 
valve or study valve, you will be asked to answer questions and perform activities that will help 
the study doctors and nurses to determine your neurological (brain) status within 24 hours after 
each additional procedure. 
If you have a stroke, have been informed by a doctor that you experienced a stroke, experience 
any of the following symptoms, notify your study doctor at xxx-xxx-xxxx as soon as possible: 
sudden numbness, tingling on, loss of movement (occurring on one side of the body), sudden 
vision changes, confusion or trouble understanding simple statements, unable to speak, severe 
headaches, or seizures. Any of these symptoms could indicate that you are having problems 
with your neurological (brain) function. You will have tests performed to determine your 
neurological (brain) status where you will be asked to answer a series of questions and perform 
a series of tasks. These tests will be performed at 7 days, 30 days and 3 months after you have 
any of these symptoms. 
If you have any other problems or complications, seen by any other doctors, or are hospitalized 
during your participation in this study you should immediately notify Dr. Principal Investigator at 
xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis. The study doctor will determine if you will need to have another valve 
implanted.  
In the event of your death and an autopsy is performed, the study doctor will ask your family or 
"legally authorized representatives" for either the whole heart and valve or just the valve are 
removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the investigational valve. 
Your family and your "legally authorized representatives", have the right to refuse the autopsy 
and refuse the request to remove the heart and/or valve even if you sign this consent form. 

 
 
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POSSIBLE RISKS AND DISCOMFORTS 
TAVI 
Potential risks associated with the implantation of the study valve may include, but are not 
limited to, the following: 
•  
Death 
•  
Acute myocardial infarction - heart attack; decrease blood flow to the heart causing 
death of an area of the heart muscle 
•  
Stroke - decreased blood flow to the brain causing death of brain cells 
•  
Urgent need for surgery 
o Coronary artery bypass – (CABG) a surgery where the chest is opened to place new 
vessels around the existing blocked vessels of the heart to improve blood supply to 
the heart. 
o Heart valve replacement – replacing the existing heart valve with a new heart valve 
o Valve explant – the removal of the existing valve 
•  
Urgent need for balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure 
is expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
•  
Urgent need for Percutaneous Coronary Intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
•  
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
•   Perforation of the myocardium or vessel – a hole in the heart muscle or a blood vessel 
•   Cardiac Tamponade – the constriction or inability of the heart to pump due to buildup of 
blood or fluid around the lining of the heart 
•  
Ascending aorta trauma – injury to the large blood vessel leading blood away from the 
heart 
•  
Myocardial ischemia – reduced blood supply to the heart 
•  
Acute coronary artery occlusion – blockage or closure of an artery that supplies the 
heart with blood 
•  
Disturbances in the electrical system of the heart that may result in the permanent 
placement of a device (pacemaker) that delivers electrical impulses to the heart to 
help your heart beat normally. 
o  Atrio-ventricular node block – a block in the electrical path from the top part of the 
heart (atria) to the bottom part of the heart (ventricle) 
o  Bundle branch block – a delay or block in the electrical path in the bottom part of the 
heart (ventricle) 
o  Asystole – when the heart stops beating 
•  
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part of the 
heart (ventricles) 
• 
Embolism – an abnormal particle (air, blood clots) floating in the blood stream or 
attached to an object, including the valve 
•  
Thrombosis (including valve thrombosis) - blood clot, including a blood clot on the 
valve 
•  
Hemorrhage requiring transfusion – bleeding requiring blood to be put back into the 
body 
• 
Arteriovenous fistula – abnormal connection between an artery vessel that takes blood 
away from the heart and a vein vessel that takes blood to the heart 
• 
Vessel dissection or spasm – the separation of the walls of a vessel or a sudden 
narrowing of the vessel) 

 
 
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•  
Valve migration – upward or downward movement of the device from where it was 
originally placed 
•  
Valve dysfunctions of the CoreValve® including but not limited to: 
o  Fracture (break) in the valve frame 
o  Bending of the valve frame 
o  The valve frame does not open (expand) all the way 
o  Calcification (build-up of calcium on the valve) 
o  Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o  Wear, tear or movement forward (prolapse) or backward (retraction) from the normal 
position of the valve leaflets 
o  The valve leaflets do not close together 
o  A break in the stitches (sutures) of the valve frame or leaflets 
o  Leakage through or around the valve or valve frame 
o  Incorrect size of the valve implanted 
o  Incorrect position of the valve, either too high or too low 
o  Regurgitation – backward flow of blood through the valve 
o  Stenosis – narrowing of the opening of the valve 
•  
Mitral valve regurgitation – a leaking valve between the left upper (left atrium) and left 
lower (left ventricle) parts of the heart where blood flows backward through the valve 
•  
Hypotension or hypertension - low or high blood pressure 
•  
Acute renal injury - failure of the kidneys to work correctly 
•  
Allergic reaction (unfavorable reaction by the body) to: 
o  antiplatelet agents - drugs that keep blood clots from forming 
o  contrast medium - a substance used to increase the visualization of body structures 
such as x-ray dye 
•  
Infection including infection of the heart or heart valves (endocarditis) – an 
abnormal growth of germs in the body or body part 
•  
Bowel ischemia – decrease blood supply to the intestines 
•  
Complications at the area where the doctor opened the skin or related to opening 
the skin, including but not limited to: 
o  pain 
o  bleeding 
o  hematoma –blood collecting under the skin 
o  pseudoaneurysm - blood collecting on the outside of a vessel wall causing a balloon-
like widening 
o  irreversible nerve damage – permanent damage to nerves 
o  compartment syndrome – squeezing of nerves and muscles in a closed space that 
could cause muscle or nerve damage 
o  stenosis – narrowing of a vessel (artery) 
SAVR 
Although SAVR is not experimental there are potential risks associated with the procedure. 
These risks are the same even if you undergo the SAVR procedure and you decide not to 
participate in this study.  Some of these risks include, but may not be limited to the following: 
 
Obstruction of blood flow to the heart (angina) resulting in damage to the heart tissue 
(myocardial infarction/heart attack) 
 
Abnormal heart beat (cardiac arrhythmia and dysrhythmia) 
 
Blood leaking around the outside of the prosthetic valve (paravalvular leak) or any 
problem with the valve that causes leaking of blood after the valve has closed 
(transvavular leak). 
 
Damage to red blood cells (hemolysis) that can result in anemia (decreased red blood 
cells) 
 
Death 

 
 
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 
Inflammation of the lining of the heart (endocarditis) 
 
Heart failure 
 
Any problem with the prosthetic valve that causes narrowing of the valve opening 
(stenosis) 
 
Blood clots that develop in the heart of on the replacement valve. These clots may break 
loose and travel through the bloodstream (thromboembolism). This problem may cause 
 
Stroke (decrease blood flow to the brain causing damage to the brain) or heart attack. 
 
Failure of the valve to open and close properly 
If you are or you become pregnant, there may be risks, discomforts or side effects to you and 
your unborn child that are not yet known.  
Some possible inconveniences may include, but is not limited to the following: 
 
Transportation to and from the clinic for follow-up visits 
 
Parking 
 
Follow-up visit scheduling 
There may be other discomforts and risks related to the device and/or this study that are not 
foreseen at this time.  
CT Angiogram 
• 
Risks associated with heavy sedation, if used 
• 
Allergic reaction to contrast 
• 
Risk of cancer from radiation 
Potential Benefits for You 
The possible benefits you may receive from participating in this clinical study are that you may 
be able to receive a new heart valve without having open-heart surgery.  Another possible 
benefit is that your new study valve may work better than the way your diseased valve currently 
works.  This may improve how you feel and may improve your daily activity.  However, there is 
no guarantee that you will benefit from being in this clinical study. 
Potential Benefits for Other Patients 
Your participation in this clinical study may improve procedures that may guide the future 
treatment of aortic stenosis, by using procedures that are less invasive (meaning less cutting, 
entering or breaking through the body), which may benefit others in the future. 
Alternative Therapy 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other 
treatment options include percutaneous (through an artery in the groin) aortic valve 
implantation, or medical management to relieve symptoms, which may include balloon 
valvuloplasty.  Ask your study doctor about other treatment options you may have. 
Compensation for Illness or Injury 
If you are physically injured as a result of your participation in this study, reasonable and 
appropriate medical treatment will be provided to you free of charge by the study sponsor, if 
such treatment is not already covered by your medical insurance. 
Medtronic maintains appropriate clinical trial liability insurance coverage as required under 
applicable laws and regulations and will comply with applicable local law and custom 
concerning specific insurance coverage.  If required, a Clinical Trial insurance 
statement/certificate will be provided to your Medtronic Institution‟s Ethics Committee.  

 
 
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Compensation and Additional Costs 
You will not receive any compensation for your participation in this clinical investigation 
(including follow up).  There is no monetary advantage to the study doctor for participation in 
this study. 
You may request for reimbursement for costs associated with travel expenses for the purpose 
of the follow-up visits. 
To ensure your safety while participating in the study, all necessary precautions are taken. In 
addition, a patient insurance is in place to compensate for a financial loss as a result of study-
related health damage.  
Role of the Sponsor’s Representative 
Your study doctor will delegate study activities not only to other study personnel (both doctors 
and study nurses), but also sponsor representatives. These study activities may include support 
during the procedure and supporting during data collection throughout the study.  These 
activities are performed under supervision and responsibility of the investigator and will not bias 
the data integrity in any way.  
Use of Personal Data/Confidentiality 
Your participation in this study is entirely confidential.  
While participating in this study, personal information, including medical and health data, will be 
collected from your medical records. Such information may include data on ethnic origin. These 
data will be used and processed manually and by computer by Medtronic (meaning the 
Medtronic, Inc. group of companies). Other designated parties that are involved in the study, 
including third party data processors, the institution in which you are treated, your physician(s), 
regulatory authorities and ethics committees, may receive and also be granted access to your 
personal information in order to comply with legal and regulatory requirements. Your data may 
be communicated to the above-mentioned parties located in the country in which you are 
treated, the European Economic Area and in other countries, such as the United States of 
America, where the European Directive on Data Protection does not apply. 
Your personal data are collected for medical research purposes, to gather information on the 
device and its performance during and after this study and may be used for obtaining 
assessments for approvals for the device, additional scientific research, educational purposes 
and publications as well as for future health studies.  
Your confidential personal information will be made anonymous and key-coded, unless it may 
be impossible to make it anonymous it, for instance, where your name cannot be removed from 
the data carrier, such as: x-ray, angiogram or echocardiography.  
Study results may be published without disclosing your name or any other identifying 
characteristics. In all cases, your personal information will be handled at all times in accordance 
with appropriate confidentiality standards and all applicable data protection and privacy laws. 
You are entitled to access the personal information collected about you and to have 
inaccuracies corrected. 
Your personal physician will be informed about your participation in the clinical investigation. 
Voluntary Participation 
Your participation in this study is entirely voluntary. You are free to refuse participation and you 
are free to discontinue participation in the study at any time without fear of penalty or loss of 
medical care. In addition, you will be notified of any significant new findings that may develop 
during the course of the study, which may relate to your willingness to continue your 
participation.  

 
 
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Your physician or the sponsor may decide to terminate your participation in the study at any 
time without your prior consent. If this happens you will be notified and the reasons explained to 
you. 
Medtronic can also suspend or terminate the study at any time without your prior consent. If this 
happens, you will be notified and the reasons will be explained to you.  Your physician will 
continue to provide the appropriate medical treatment.  
Questions 
In case of any question, you can contact one of the following people: 
Questions about the clinical investigation: ………………………………… 
Questions in the event of illness or injury: …………………………………. 
Questions about patient rights : ………………………………………….  

 
 
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PATIENT INFORMED CONSENT FORM - SIGNATURE SHEET 
Medtronic CoreValve® SURTAVI Trial 
I have read the patient information of this study and my physician has answered all my 
questions regarding the study.  
I had sufficient time to consider my participation into this study, I am aware that participation 
into this study is completely voluntary, and I agree to follow the instructions from the 
investigator. 
I realize that I may decide to refuse participation or stop participation at any time without 
penalty and without affecting the quality of my health care or the relationship with my physician.  
I understand and agree that personal information about me will be collected from my medical 
records, used and processed (manually and by computer) by the manufacturer of a medical 
device used in my treatment or any other designated party that is involved in the study (e.g. 
hospital, physician, regulatory authorities, ethics committees).  
I understand and agree that representatives from Medtronic, regulatory authorities and the 
Ethics Committee will be granted direct access to my medical records.  
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigation. 
I understand that I am entitled to access the personal information collected about me and to 
have inaccuracies corrected. 
I have received a copy of the Patient Information and hereby I agree to participate voluntarily in 
and comply with this study. 
I agree to participate in this study and I have consented before the initiation of any study 
specific procedures. 
Patient: 
           __________________________  
  ___________________    
 ____________________  
 
 
Name 
 
 
 
Signature 
 
 
Date (dd MMM yyyy) 
 
 
 
 
         Must be written by patient                     Must be written by patient 
Legal Representative if patient is unable to give consent: 
__________________________            ___________________    
  ___________________   
Name  
 
         Signature 
 
 Date (dd MMM yyyy) 
 
 
 
         Must be written by  
 
    Must be written by 
 
 
 
         Legal Representative  
    Legal Representative 
  
 
 
 
 

 
 
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 Only persons officially trained and 
authorized on the delegated task list 
are allowed to sign off 
 
 
 
 
Investigator or designated person by investigator: 
I have conducted the informed consent discussion. 
 
__________________________   ___________________   
 ___________________   
 Name  
 
 
 
Signature 
    
 Date (dd MMM yyyy) 
 
If patient, or patient‟s legally acceptable representative, is unable to read: 
I have attended the entire informed consent discussion. I attest that the information in 
the consent form and any other written information was accurately explained to, and 
apparently understood by, the patient or the patient‟s legally acceptable representative. 
Informed consent was freely given by the patient or the patient‟s legally acceptable 
representative. 
Impartial Witness: 
 
_________________________  _____________________  
________________   
 Name  
 
 
 
 Signature 
  
 Date (dd MMM yyyy) 
 
Section should be filled in by impartial witness 
 
  
 
 

 
 
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R.2 
List of Participating Investigational Centers 
The list of participating Investigational Centers will be provided under separate cover. 
 
 

 
 
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R.3 
Other Institutions 
The following institutions/organizations will participate in the Medtronic CoreValve® SURTAVI 
Trial. An updated list of “Other Institutions” will be provided in progress reports and/or upon 
request. 
Clinical Events Committee (CEC) / Data Safety Monitoring Committee (DSMB): 
Cardilysis 
Westblaak 92 
3012 KM Rotterdam 
The Netherlands 
Explanted Device/Pathology Core Lab: 
CVPath Institute, Inc. 
 19 Firstfield Road 
 Gaithersburg, MD 20878 
Imaging Core Lab (CT, Echocardiography, and Electrocardiogram) 
Cardilysis 
Westblaak 92 
3012 KM Rotterdam 
The Netherlands 
InteleGRIDTM (imaging sharing network)  
Intelemage, LLC 
5400 Kennedy Ave 
Cincinnati, OH 45213  
Interactive Voice Response System (IXRS):  
 
United BioSource Corporation (UBC) 
 
303 2nd Street, Suite 700 
 
7th Floor South Tower 
 
San Francisco, CA 94107 
 

 
 
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R.4 
Additional Records and Reports 
No additional records and/or reports, other than those previously described in this 
investigational plan or required by FDA, will be maintained for this clinical investigation. 
 
 

 
 
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R.5 
Sample Case Report Forms 
Sample Case Report Forms (CRFs) will be provided under separate cover. 
 
 
 

 
 
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R.6 
Aortogram Acquisition Guidelines 
The purpose of the acquisition guidelines is to increase consistency and effectiveness in 
adjudicating the procedural aortograms. 
1. Required aortogram:  
 
Index Procedure – MCS TAVI 
2. Required cine runs: 
 
Pre-procedure aortogram in a projection with 3 aortic cusps aligned (for comparison 
of final aortogram with pre-procedure aortogram) 
 
Aortogram after deployment of the MCS and removal of the delivery catheter. 
This cine run is used to obtain the time of deployment/implantation 
 
Final aortogram at least 10 minutes after MCS implantation in the exact same 
projection as the pre-procedure aortogram (in order to measure depth of 
implantation and assess grade of aortic regurgitation) 
NOTE:  If the apex is not clearly visible in the final projection and in case of adequate renal 
function, in order to assess grade of AR, perform an additional final aortogram in RAO 
30° with visualization of the left ventricle in long axis, including the apex. 
3. Guidelines on how final aortogram after deployment of the valve should be 
performed: 
 
Use at least 20 ml of contrast, with an injection rate of 20 ml/sec 
 
Position the pigtail catheter in the upper third part of the frame 
 
Preferably use non-diluted contrast. 50%-diluted contrast is acceptable in case of 
renal insufficiency 
 
Use the angiographic projection with the three aortic cusps aligned in 1 plane: 
o 
Whenever available this optimal projection can be suggested by baseline 
MSCT exam 
o 
Pragmatic approach might be to use a shallow LAO or RAO projection, and 
adjust in a cranial or caudal position respectively to approach the optimal 
projection 
 
Confirm visualization of the left ventricular apex on the final aortogram 
 
Perform the final aortogram at least 10 minutes after deployment of the MCS; 
include a time indication on the aortogram 
 
Use marker pigtail or provide the French-size of the pigtail catheter for calibration 
purpose 
4. General imaging and recording procedures: 
 
Use a fixed table system and biplane x-ray equipment, if available 
 
Recommended resolution: 1024 x 1024 pixels 
 
All cine runs should be ECG-gated 
 
Preferred acquisition speed: 25 frames/second 
 
One single cine run should have a duration of at least 5 heart beats 
 
The digital clock should be activated 
 
The maximum magnification factor should be applied during cine run without losing 
the image of the entire frame 
 
There should be no overlap of the frame with other catheters or electrodes 

 
 
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 
Foreshortening of the frame should be avoided as much as possible 
 
Store all images on CDROM (DICOM format) and label the CDROM with: 
o 
hospital name 
o 
study name (i.e. SURTAVI) 
o 
patient ID 
o 
acquisition/procedure date 
5. Core lab analysis: 
The procedural aortograms will be analyzed for: 
 
Grade of aortic regurgitation 
 
Depth of implantation 
 
 
 
 
Figure 1: Example of depth of implantation measurement. 
 
 

 
 
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Echocardiography Acquisition Guidelines 
1. Scope of the document 
These guidelines aim to increase consistency and effectiveness in adjudicating the 
echocardiography data of selected candidates for the SURTAVI study. Optimal image 
acquisition, storage, and transmission will be described. 
2. Protocol required echocardiograms 
Transthoracic echocardiography is required at the following intervals: 
Screening 
- 45 days of Heart Team review 
Post Procedure 
Between 24 and 48 hours post procedure 
Discharge 
Prior to hospital discharge 
Six months 
± 30 days 
One year 
± 30 days 
At 2,3,4,5 years afterwards 
± 60 days 
3. Four general rules for echocardiography recordings 
3.1 Rule #1 for overall recordings: adhere STRICTLY to the PROTOCOL regarding: 
 
number of recordings (40 to 52) 
 
order of recordings (start with item # 1 and finish with # 46 see section 5 table 1) 
 
do NOT perform measurements on the echo recordings  
 
at end of echo exam, export the required recordings in DICOM3 format to a DVD. 
 
fill in the TRANSMITTAL form and send it to Cardialysis along with the echo DVD. 
 
only one echographer (+ 1 replacement) is allowed to participate in the study, he/she 
should print his/her name, fill in contact details and sign the transmittal form 
3.2 Rule #2 for Doppler recordings: 
 
Unless stated otherwise, all pulsed-wave and continuous-wave Doppler signals should 
be recorded at a sweep speed of 50-100 mm/sec (recording must contains three 
heartbeats) with optimized gain and filter setting, baseline position, and velocity range. 
3.3 Rule #3 for apical 2D views (4-, 5-, 2-, and 3-Chamber views)  
 
pay attention to ultrasound sector depth and gain settings 
 
the aortic valve should be out of scan plane in the 4-CH view  
 
exclude patient or transducer motion 
 
make sure the whole LV is in the scan sector in particular at end-diastole 
3.4 Rule #4 for EF calculation (apical 4- , 2-, and 3-Chamber views focused on LV) 
 
Record 3 runs (run 1: 3 beats, run 2: 3 beats, run 3: 10 beats) 
 
Refer to the accompanying MS PowerPoint file “SURTAVI_echo_acq.ppt” The file provides a 
demo of the echocardiography recordings needed for the SURTAVI study 
 

 
 
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4. 
Data requirements 
Participating centers in the SURTAVI study should obtain the appropriate Doppler and 
echocardiography recordings to document the following variables. 
 
Aortic annulus long-axis diameter in mid-systole (screening/baseline only) 
 
LVOT long axis diameter in mid-systole 
 
Sinus of Valsalva diameter (SOV) at end diastole (screening/baseline only) 
 
Sino-tubular junction diameter (STJ) at end diastole (screening/baseline only) 
 
Sinus of Valsalva height (SOVH) at end-diastole (screening/baseline only) 
 
Max aortic valve velocity (V2) by CW Doppler 
 
Velocity time integral (VTI) across aortic valve by CW Doppler 
 
Mean gradient across aortic valve (MGV2) by CW Doppler 
 
Peak LVOT velocity (V1) by PW Doppler 
 
Velocity time integral (VTI) of LVOT velocity by PW Doppler 
 
Mean LVOT gradient (MGV1) by PW Doppler 
 
Grade of aortic transvalvular regurgitation 
 
Grade of aortic paravalvular regurgitation 
 
Grade of mitral regurgitation 
 
PISA for MR (optional) 
 
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
 
Left ventricular (LV) end-diastolic diameter (LVEDD) 
 
Left ventricular (LV) end-systolic diameter (LVESD) 
 
Interventricular septal thickness at end diastole 
 
Left ventricular posterior wall thickness at end diastole 
 
Left atrial diameter (AP linear dimension) at systole 
 
Left ventricular ejection fraction by visual estimate 
 
Heart rate 
 
Mitral inflow “A” velocity 
 
Mitral inflow “E” velocity 
 
Mitral inflow deceleration time 
 
Mitral annular tissue Doppler systolic velocity (septal and lateral) 
 
Mitral annular tissue Doppler early diastolic velocity (septal and lateral) 
 
Mitral annular tissue Doppler late diastolic velocity (septal and lateral) 
Procedures for acquiring aortic root measurements and key hemodynamic variables are 
described in the following sections. For Doppler velocities, the values reported should represent 
the average of measurements from at least three cardiac cycles for patients in sinus rhythm, 
and the average of measurements from five cardiac cycles for patients not in sinus rhythm. For 
aortic valve, TR jet, and tissue Doppler velocities, the reported values should represent the 
average of the highest velocities obtained from the same transducer position. 
 

 
 
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5. 
Table 1. list of echo recordings 
Fifty-two (minimum 40) echo recordings (frozen images and cine loops) are required in the following order: 
 
A: From parasternal long-axis window 
1. 
Gray scale standard view displaying the left ventricle (LV), left atrium, LV outflow tract, aortic root and right ventricle 
2. 
Colour Doppler of mitral regurgitation 
3. 
Colour Doppler of aortic (or prosthetic) regurgitation  
4. 
Only if aortic regurgitation is present: repeat #3 with ZOOM & narrow sector with focus on vena contracta of 
regurgitant jet  
5. 
Gray scale ZOOM LV outflow tract 
6. 
Gray scale ZOOM at an intercostal space higher (aortic root / aortic prosthesis)  
B: From parasternal short-axis window 
7. 
Gray scale LV at mitral valve level 
8. 
Gray scale LV at papillary muscle level (use same depth setting as #7) 
9. 
Repeat #8 gray scale with M-mode (LV dimensions and anteroseptal / inferolateral wall thickness) 
10. Gray scale LV at apical level: lower your transducer position by 1 or 2 intercostal spaces and record the LV as 
circular as possible, just proximal to the level with end-systolic LV luminal obliteration  (use same depth setting as #7) 
11. Gray scale at the aortic valve level (post TAVI the native annulus is usually identified by maximal calcification) 
12. Repeat #11 gray scale with M-mode (left atrial & aortic dimensions)  
13. Repeat #11 colour Doppler: for central and paravalvular regurgitation: in post-TAVI start scanning from highest 
position and record first visible aortic regurgitation jet, scan more downwards and try to pick up additional jets 
14. Gray scale at the aortic level focussed on RV outflow tract 
15. Pulsed-wave Doppler of RV outflow tract velocity (5 to 10mm below the pulmonic valve) (frozen image) 
C: From special parasternal long-axis window (RV inflow) 
16. Colour Doppler of tricuspid regurgitation  
17. Only if tricuspid regurgitation is present in #16, continuous-wave Doppler of tricuspid regurgitation (frozen image)) 
D: From the apical 4-Chamber window 
18. Gray scale standard view displaying in the middle of the sector the LV and left atrium 
19. Colour Doppler of mitral regurgitation 
20. Only if mitral regurgitation is present in #19, colour Doppler ZOOM & narrow sector, shift Nyquist 35-40 for PISA 
measurements  
21. Only if mitral regurgitation is present in #19, record continuous-wave Doppler of mitral regurgitation (frozen image)  
22. Colour Doppler of tricuspid regurgitation  
23. Only if tricuspid regurgitation (TR) is present in #22, record continuous-wave Doppler of TR (frozen image) 
24. Pulsed-wave Doppler of transmitral flow at mitral valve tips at a sweep speed of 50-100 mm/s (frozen image)  
25. Tissue Doppler of the septal mitral annulus (frozen image and annotate “MED”) 
26. Tissue Doppler of the lateral mitral annulus (frozen image and annotate “LAT”) 
27. 3 x Gray scale focussed on LV with decreased depth (3 recordings; run 1: 3 beats, run 2: 3 beats, run 3: 10 beats) 
E: Apical 5-chamber window 
28. Gray scale standard view displaying in the middle of the sector the LV and left atrium 
29. Colour Doppler of aortic regurgitation 
30. Only if aortic regurgitation is present continuous-wave Doppler of aortic regurgitation (frozen image) 
31. Continuous-wave Doppler of aortic forward flow (frozen image) 
32. Pulsed-wave Doppler of LV outflow tract flow velocity (5 to 10mm below the aortic valve or in case of TAVI below the 
zone of flow acceleration) (frozen image) 
F: Apical 2-Chamber window 
33. Gray scale standard view displaying in the middle of the sector the LV and left atrium 
34. 3 x Gray scale focussed on LV with decreased depth (3 recordings; run 1: 3 beats, run 2: 3 beats, run 3: 10 beats) 
G: Apical 3-chamber window 
35. Gray scale standard view displaying in the middle of the sector the LV and left atrium 
36. Colour Doppler of mitral regurgitation 
37. Only if mitral regurgitation is present in #36, colour Doppler ZOOM & narrow sector, shift Nyquist 35-40 for PISA  
38. Only if mitral regurgitation is present in #36, record continuous-wave Doppler of mitral regurgitation (frozen image)  
39. Colour Doppler of aortic regurgitation 
40. Only if aortic regurgitation is present continuous-wave Doppler of aortic regurgitation (frozen image) 
41. Continuous-wave Doppler of aortic forward flow (frozen image) 
42. Pulsed-wave Doppler of LV outflow tract flow velocity (5 to 10mm below the aortic valve or in case of TAVI below the 
zone of flow acceleration) (frozen image)) 
43. 3 x Gray scale focussed on LV with decreased depth (3 recordings; run 1: 3 beats, run 2: 3 beats, run 3: 10 beats) 
H: special recordings 
44. Only if aortic regurgitation is present, suprasternal pulsed-wave Doppler of descending aorta diastolic flow (frozen 
image) 
45. Only if aortic regurgitation is present, subcostal pulsed-wave Doppler of abdominal aortic diastolic flow (frozen image) 
46. Only at baseline continuous-wave Doppler right parasternal aortic flow (frozen image) 

 
 
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6. 
Detailed instructions for acquisition of SURTAVI echocardiography recordings 
6.1 Quality control of the investigational site (initial site validation) 
 
Before starting the study, participating centers will have to send a test echo 
examination to assess the quality of the recording and the transmission and most 
importantly the ADHERENCE to the PROTOCOL.  
 
Each centre will have to wait for the validation (feedback letter) of the Echo Core Lab 
Office before starting to select any patient. The Echo Core Lab Office will complete the 
validation procedure within 72 hours after receipt of the echocardiography material. 
6.2 Guidelines for study object confidentiality 
 
Site-Patient identification: study subjects are to be identified by a specific study 
identification number as supplied by the sponsor.  
 
The following items will be entered in the patient identification section of ultrasound 
system and should be clearly shown on all digital cine loops or still frames. 
 Site-patient ID (XXXXX-YYY), date of exam and study interval  
 
To ensure adherence to the HIPAA (Health Insurance Portability and Accountability Act 
of 1996) guidelines for study subject confidentiality, no study subject names or other 
Protected Health Information (date of birth, hospital record number, etc) should be 
displayed. 
6.3 Echocardiography data storage and submission of material 
 
Echocardiograms of SURTAVI study participants at all time intervals should be 
recorded on DVD in a DICOM-3 format.  
 
Each echocardiogram, per patient and per visit, should be recorded on a separate 
DVD. Do not archive echocardiograms from multiple patients or multiple 
echocardiograms from one patient on the same disc. The paths in the DICOM directory 
should point to the correct files. Delete all unnecessary recordings from your echo 
machine before burning the DVD (limit the number of thumbnails on digital DVD grid to 
the ones needed, as described in the protocol).  
6.4 Submission 
 
Participating site should submit the DVD to the Core Laboratory immediately post-
acquisition for processing, analysis, and blinded reading. To avoid data loss and/or 
damage from shipping, the investigational sites should retain a digital copy of the 
echocardiogram prior to sending the original to the Core Laboratory. The original DVD 
will be stored at the Core Laboratory until completion of the study. The Core Laboratory 
will not return submitted material, will not provide a clinical report of the 
echocardiogram, and will not notify the investigational sites of any abnormal findings on 
the echocardiograms. It is the responsibility of each site to perform a local interpretation 
of the study and to manage the subject according to the local interpretation. 
6.5 Labelling and identification 
 
Each site will be supplied with labels to attach to the DVD. Before sending the DVD to 
the Core Laboratory, the label should be completed with the required information. Stick 
the completed label on the box of the DVD; never stick the labels on the DVD. Write the 
same information on the DVD with a marker intended for writing on DVD. The following 
information should be documented on the DVD box (Site-Patient ID, Exam date and 
Study interval) 
6.6 Further inquiries:  
 
For any questions, contact your monitor or Cardialysis via phone at  
+31 10 206 282. 

 
 
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7. 
Technical guidelines: how to optimize the echocardiography images 
7.1 ECG gating. 
 
All cine-loops and still frames must clearly display a single lead electrocardiographic 
recording in which P-, QRS-, and T-waves (but in particular the R wave) are clearly 
identifiable 
7.2 Number of recorded heart cycles.  
 
In sinus rhythm, record 3 continuous beats, unless indicated otherwise. In atrial 
fibrillation, record 5 continuous beats, unless indicated otherwise. Try to exclude 
premature beats 
7.3 Effects of respiration and timing of recordings.  
 
During all recordings, respiration should be quiet. Tissue Doppler measurements 
should be recorded after non-forced end-expiration 
7.4 Two-dimensional echocardiography general settings 
 
Use harmonic-imaging mode with maximized (mechanical index >1) power output 
 
Gain (and time-gain compensation) settings should be adjusted to eliminate 
background noise and to allow for a clear blood-tissue border. An optimal gain setting 
consists of a left ventricular cavity with minimal (but not completely absent) noise 
 
The gray scale / dynamic range should be adjusted to provide an image with marked 
contrast between light and dark areas 
 
The focus point should be set at the middle of the region of interest 
 
Depth settings should be minimized (do not display structures outside the region of 
interest) 
7.5 (Tissue) Doppler settings 
 
Use a display speed of 50 to 100 mm/sec and a sample volume length of 3-4 mm (in 
extremely low heart rates use a speed of 150 mm/sec). For mitral E-wave deceleration, 
time one recording is needed at a sweep speed of 150 mm/s 
 
Adjust gain, filter settings, position and velocity range to maximize the velocity 
excursion 
 
Minimize the angle between the direction of motion of the investigated structure or flow 
and the Doppler beam 
 
Transmitral flow should be assessed at the tips of the mitral valve 
 
Annotate the tissue Doppler recordings  
7.6 Colour Doppler settings 
 
 
7.7 Parasternal long-axis view 
 
Minimize the angle between the left ventricle and aorta (the inferolateral wall should be 
as perpendicular as possible to the transducer) the anteroseptal wall is visualized at the 
same distance from the transducer as the anterior wall of the ascending aorta 
7.8 Apical two and four-chamber view 
 
The left ventricular apex should be visible in the top of the sector  
 
The aortic valve should be out of the image plane 
 
Maximize the internal long-axis of the left ventricle (avoid foreshortening) by looking for 
a window one intercostal space lower (in particular when the left ventricle does not 
appear ellipsoid) 

 
 
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 
To ensure that the proper rotation has been made for a two-chamber view, the 
transducer is angled posteriorly to intersect both papillary muscles symmetrically. Then 
the transducer is angled slightly anteriorly so that neither papillary muscle is seen in its 
long axis in this view 
7.9 Special considerations for aortic regurgitation by colour flow imaging1-3 
In addition to the abovementioned recommendations: 
 
Standardize the machine settings for all examinations 
 
Colour gain should be set step by step just below the appearance of colour noise 
artefacts 
 
For Vena contracta: use a parasternal long-axis view in ZOOM mode with minimal 
colour sector size and imaging depth to maximize lateral and temporal resolution 
7.10 Subcostal window 
In order to provide optimal image acquisition from subcostal window, the following steps are 
required:  
 
The knee-flexed position relaxes the upper abdominal muscles and thereby improves 
visualization 
 
From the subcostal four-chamber view, anti-clockwise rotation of the transducer permits 
visualization and pulsed Doppler examination of the upper abdominal aorta 

 
 
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8. 
Measurements of aortic root geometry4 
The following measurements of the aortic root are obtained from the parasternal long-axis view 
(screening/baseline exams only): 
 
Aortic annulus long axis diameter. The aortic annulus long axis diameter is 
measured perpendicular to the long axis of the root, measured between the endothelial 
point that trisects the posterior aortic wall, non-coronary cusp hinge and anterior mitral 
leaflet hinge (posterior hinge point), and the point that bisects the septal endocardium 
and the right coronary cusp hinge (anterior hinge point). Measurements should be 
made at mid-systole and inclusive of cusp calcifications (Figure 1). To accurately 
incorporate cusp calcification for aortic annulus sizing, measure from the white-black 
interfaces of the posterior and anterior aortic cusp hinge points and add 2 mm to the 
measurement. 
 
Sinus of Valsalva diameter (SoV). The SoV diameter is perpendicular to the long axis 
of the root and typically parallel to the aortic valve annulus. It is the widest intra-luminal 
distance within the sinuses (measured at end-diastole from inner edge to inner edge, 
Figure 2, A). 
 
Sino-tubular junction diameter (STJ). The STJ diameter is the intra-luminal diameter 
parallel to the SoV diameter, where the sinuses narrow and join the ascending aorta 
(measured at end-diastole from inner edge to inner edge, Figure 2, B). 
 
Sinus of Valsalva height (SoVH). The SoVH is the distance between the STJ and the 
aortic annulus long-annulus diameter (measured at end-diastole, Figure 3). 
 
 
Figure 1. Examples of measurement of the aortic annulus long axis diameter 
 

 
 
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Figure 2. Example of measurement of the Sinus of Valsalva (A) and Sino-Tubular Junction (B) diameters. 
 
Figure 3. Example of measurement of the Sinus of Valsalva Height (C) 

 
 
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9. 
Measurement of Left Ventricular Outflow Tract (LVOT) Diameter 
The LVOT long axis diameter is measured in the parasternal long-axis view at early to mid 
systole. The optimal imaging plane is through the long axis of the aorta; therefore, the anterior 
and posterior walls of the aortic root should be parallel with the maximal aortic diameter. 
For native aortic valves, the LVOT long axis diameter is measured from the white-black 
interface of the septal endocardium to the anterior mitral leaflet, parallel to the aortic valve plane 
and within 0.5 cm - 1 cm of the valve orifice (Figure 4)1. Following implantation of the CoreValve 
device, the LVOT diameters and the LVOT area are measured immediately proximal to the 
inflow aspect of the stent (Figure 5). 
 
 
Figure 4. TTE mid-systolic frame showing measurement of 
the LVOT diameter for derivation of native aortic valve area. 
 
 
Figure 5. Cursor placement for measurement of LVOT diameter for derivation of prosthetic effective orifice area. 

 
 
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10. 
Measurement of LVOT Velocity5 
LVOT velocity is recorded with PW Doppler from the apical transducer position, either in the 
apical long-axis view or in the anteriorly angulated four-chamber view or “five-chamber view.” 
The PW sample volume is positioned just proximal to the aortic valve, with care to avoid the 
zone of pre-valve acceleration. The recommended procedure is to initially place the sample 
volume within the aortic valve leaflets (prosthetic or native), and then gradually move it apically 
until a clear spectral waveform is observed with a well-defined peak and minimal spectral 
broadening (Figure 6). The optimal sample volume placement is usually between 0.5 and 1.0 
cm upstream from the valve annulus.2 Post implantation, the sample volume should be placed 
at the entrance of the inlet of the CoreValve prosthesis. 
11. 
Measurement of Aortic Valve Velocity5 
The aortic valve velocity and VTI should be interrogated with CW Doppler from all transducer 
positions (apical, right parasternal, suprasternal notch, left supraclavicular, subcostal). The 
position that provides the highest velocity is used for measurements. A smooth velocity curve 
with a clear outer edge and maximal velocity should be recorded. The maximal velocity is 
measured at the outer edge of the dark signal; fine linear signals at the peak should not be 
included in measurements. The outer edge of the dark “envelope” of the velocity curve is traced 
to provide both the VTI for the continuity equation and the mean gradient (Figure 7).1 
             
 
Figure 6. An optimal LVOT signal shows a                          
Figure 7. CW Doppler of severe AS jet showing  
smooth velocity curve with a narrow velocity                       
measurement of maximal velocity and tracing of the 
range at each time point.                                                     
Velocity curve to calculate mean gradient. 
 

 
 
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12. 
Assessment of Aortic Regurgitation6, 7 
An integrated exam approach using colour flow, pulsed-wave (PW), and continuous-wave (CW) 
Doppler is used to assess the severity of transvalvular and paravalvular regurgitation. Colour 
flow Doppler imaging should be performed from the parasternal long and short-axis views, and 
the apical long-axis and/or 5-chamber views. A recording of the aortic regurgitant signal should 
be obtained with CW Doppler. If the degree of aortic regurgitation appears more than mild by 
visual estimate, the velocity in the proximal descending aorta and the abdominal aorta should 
be recorded with PW Doppler. 
The degree of transvalvular and paravalvular regurgitation will be graded as none, trace, mild, 
moderate, and severe based on the synthesis of the Doppler parameters shown in Table 2.3,4   
The category of “trace” is used in cases where regurgitation is barely detectable by colour 
Doppler. Regurgitant signals observed to originate within the stent will be considered 
transvalvular, and regurgitant signals observed to originate outside the stent will be considered 
paravalvular.  
Paravalvular regurgitant jets will be characterized by the extent of the aortic regurgitant jet 
relative to the short axis circumference of the aortic valve (Table 2- Valve Academic Research 
Consortium (VARC) Consensus Report for Transcatheter Aortic Valve Implantation (TAVI) or 
any update that will be available before start of analysis; and Table 3a and b -2008 Focused 
Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With 
Valvular Heart Disease (published in the October 2008 issues of Journal of the American 
College of Cardiology and Circulation). 
 
Table 2. Parameters for evaluation of the severity of aortic regurgitation1, 6, 8. 
Prosthetic Aortic Valve Regurgitation Criteria (Central and Paravalvular) 
Parameter 
Mild 
Moderate  
Severe 
Valve Structure and Motion 
 
Mechanical or bioprosethic 
Usually normal 
Usually abnormal† 
Usually abnormal† 
Structural parameters 
 
Left ventricular size 
Normal ‡ 
Normal/ 
mildly dilated ‡ 
Dilated 
Doppler parameters (qualitative or semi 
quantitative) 
 
Jet width in central jets (% LVO diameter): 
color* 
 
Jet density: CW Doppler 
 
Jet deceleration rate (PHT┼, ms): CW 
Doppler** 
 
LV outflow vs. pulmonary flow: PW Doppler 
Diastolic: flow reversal in the descending 
aorta 
PW Doppler 
 
 
Circumferential extent of paraprosthetic AR 
(%) 
 
 
 
Narrow (≤25%) 
Incomplete or faint 
 
Slow (>500) 
Slightly increased 
 
 
Absent or brief 
early diastolic 
 
<10 
 
 
 
Intermediate (26-64%) 
Dense 
 
Variable (200-500) 
Intermediate 
 
 
Intermediate 
 
 
10-20 
 
 
 
Large (≥65%) 
Dense 
 
Steep (<200) 
Greatly Increased 
 
 
Prominent, 
Holodiastolic 
 
>20 
Doppler parameters (quantitative) 
 
Regurgitant volume (mL/beat) 
 
Regurgitant fraction (%) 
 
<30 
<30 
 
30-59 
30-50 
 
>60 
>50 
 
* 
Parameter applicable to central jets and is less accurate in eccentric jets 
**  Influenced by left ventricular compliance 
AR=aortic regurgitation; CW= continuous wave; LVO= left ventricular outflow; PW= pulsed wave 
┼ 
PHT is shortened with increasing LV diastolic pressure and vasodilator therapy, and may be lengthened in chronic 
adaptation to severe aortic regurgitation. As such, PH, in contrast to the other parameters, does not reflect the volumetric 
severity of aortic regurgitation, but rather its hemodynamic impact. Therefore, in the setting of acute paravalvular or 
transvalvular leaks, intermediate values between 200 and 500 ms should not be used to classify the degree of 
regurgitation. 
† 
Abnormal mechanical valves, for example, immobile occluder (valvular regurgitation), dehiscence or rocking (paravalvular 
regurgitation); abnormal biologic valves, for example, leaflet thickening or prolapse (valvular), dehiscence or rocking 
(paravalvular regurgitation). 
‡ 
Applies to chronic, late postoperative AR in the absence of other etiologies. 

 
 
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Table 3a. Parameters for evaluation of the severity of aortic regurgitation 
Classification of the Severity of Valve Disease in Adults with 
Aortic Regurgitation 
 
Mild 
Moderate  
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+ 
2+ 
3-4+ 
Color Doppler jet width 
Central jet, width less 
25% of LVOT 
Greater than mild but 
no signs of AR 
Central jet, width greater 
than 65% LVOT 
Doppler vena contracta width 
(cm) 
Less than 0.3 
0.3-0.6 
Greater than 0.6 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per 
beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.10 
0.10-0.29 
≥ 0.30 
Additional essential criteria 
Left ventricular size 
 
 
 
 
 
Increased 
 
13. 
Assessment of Mitral Regurgitation2, 8 
Colour flow Doppler imaging of the left atrium should be performed from the parasternal long-
axis view, and from the apical four, two, and long axis views. Mitral regurgitant signals should 
be recorded with CW Doppler using a velocity scale that allows assessment of the density, 
shape, duration, and peak velocity of the mitral regurgitant signal. If the severity appears 
moderate or greater by visual assessment, pulmonary vein velocities should be recorded with 
PW Doppler to assess for the presence of systolic flow reversal. Grading of the severity of mitral 
regurgitation should be integrative using the parameters in Table 3.4 
Table 3b. Classification of the Severity of Valve Disease in Adults Mitral Regurgitation 
Classification of the Severity of Valve Disease in Adults 
Mitral Regurgitation 
 
Mild 
Moderate  
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+ 
2+ 
3-4+ 
Color Doppler jet area 
Small, central jet, < 
4cm2  or <20% LA 
area) 
Signs of > mild 
present but no criteria 
for severe MR 
Vena contracta with > 
0.7cm with large central 
MR jet (area >40% of LA 
area) or with a wall-
impinging jet of any size, 
swirling in LA 
Doppler vena contracta width 
(cm) 
< 0.3 
0.3-0.69 
≥ 0.70 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per 
beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.20 
0.29 – 0.39 
≥ 0.40 
Additional essential criteria 
Left atrial size 
Left ventricular size 
 
 
 
 
 
Enlarged 
Enlarged 
14. 
Assessment of Left Ventricular Function and Left Atrial Size9 
M-mode recordings of the left ventricle and left atrium should be obtained using 2-D guided 
beam alignment (Figures 7 and 8). Left ventricular chamber dimensions and wall thicknesses 
will be measured from 2D parasternal long axis views and should be utilized preferentially if M-
mode images are suboptimal. Chamber dimensions are measured using the American Society 
of Echocardiography (ASE) measurement convention.5 In addition, standard 2-D views of the 
left ventricle should be obtained from parasternal and apical transducer positions for visual 
estimation and quantitative assessment of left ventricular ejection fraction by visual estimate.   
 

 
 
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Figure 7. Measurement of left ventricular end-diastolic diameter (EDD) 
and end-systolic (ESD) from 2-D guided m-mode to optimize 
medial-lateral beam orientation. 
 
 
 
Figure 8. Measurement of left atrial diameter (LAD) by 2-D guided m-mode. 

 
 
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15. 
Acquisition of Mitral Inflow Velocities 
A spectral Doppler recording of mitral inflow velocities should be obtained with PW Doppler in 
the apical 4-chamber view, using a 1 to 3 mm sample volume placed between the mitral leaflet 
tips during diastole (Figure 9). The spectral gain and wall filter settings should be optimized to 
clearly display the onset and cessation of left ventricular inflow.6  
  
\
 
 Figure 9. Positioning of the sample volume for recording of mitral inflow velocities. 
16. 
Acquisition of Mitral Annular Tissue Doppler Velocities 
Mitral annular velocities should be obtained from the lateral and septal aspects of the mitral 
annulus using PW tissue Doppler performed in the apical 4-chamber view. The sample volume 
should be positioned at or 1 cm within the septal and lateral insertion sites of the mitral leaflets 
and adjusted as necessary (usually 5 to 10 mm) to cover the longitudinal excursion of the mitral 
annulus in both systole and diastole. Minimal angulations (<20 degrees) should be present 
between the ultrasound beam and the plane of cardiac motion.6 The Doppler gain should be 
minimized to prevent “blooming” of the signal to facilitate accurate measurement of the annular 
velocities. 

 
 
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17. 
Assessment of Device Migration 
CoreValve device placement site and migration will be assessed from the parasternal long axis 
view at each follow up point and compared to the initial post-procedural echo. A zoomed image 
of the left ventricular outflow tract including the anterior mitral leaflet and the anterior aortic wall 
should be included at each follow up echo. The location of the device will be determined by 
measurement of the distance from the proximal edge of the left ventricular outflow tract 
anteriorly, to the edge of the CoreValve device (Figure 10). Optimal placement of the valve 
should be within the left ventricular outflow tract just below the aortic annulus (Figure 11). 
 
Figure 10. Zoomed view of the left ventricular outflow tract (panel A) and schematic (panel B). Measurement of the 
distance from the proximal edge of the anterior aspect of the left ventricular outflow tract to the edge of the CoreValve 
device (arrows).  
 
 
Figure 11. Zoomed view of the left ventricular outflow tract. Panel A. Optimal device placement of the CoreValve device 
within the left ventricular outflow tract with the proximal edge of the device just below the aortic annulus. Panel B. Low 
placement of the CoreValve device extends beyond the left ventricular outflow tract into the left ventricular chamber, 
encroaching on anterior mitral valve leaflet. 
 

 
 
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18. 
Echo Core Lab Analysis5, 7 
Data generated by the Echo Core Lab will be the primary data used for analysis and reporting. 
Qualitative assessment of valvular regurgitation will be performed using the criteria previously 
described in sections 8 and 9 of this Appendix. The Echo Core Lab will report the following 
variables: 
 
Aortic annulus long-axis diameter in mid-systole (screening/baseline only) 
 
LVOT long axis diameter in mid-systole 
 
Sinus of Valsalva diameter (SOV) at end diastole (screening/baseline only) 
 
Sino-tubular junction diameter (STJ) at end diastole (screening/baseline only) 
 
Sinus of Valsalva height (SOVH) at end-diastole (screening/baseline only) 
 
Device location and migration 
 
Max aortic valve velocity (V2) by CW Doppler 
 
Velocity time integral (VTI) across aortic valve by CW Doppler 
 
Mean gradient across aortic valve (MGV2) by CW Doppler 
 
Peak LVOT velocity (V1) by PW Doppler 
 
Velocity time integral (VTI) of LVOT velocity by PW Doppler 
 
Mean LVOT gradient (MGV1) by PW Doppler 
 
Grade of aortic transvalvular regurgitation 
 
Grade of aortic paravalvular regurgitation 
 
Grade of mitral regurgitation 
 
ERO for MR (if available) 
 
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
 
Left ventricular (LV) end-diastolic diameter (LVEDD) 
 
Left ventricular (LV) end-systolic diameter (LVESD) 
 
Interventricular septal thickness at end diastole 
 
Left ventricular posterior wall thickness at end diastole 
 
Left atrial diameter (AP linear dimension) at systole 
 
Left ventricular ejection fraction by visual estimate 
 
Heart rate 
 
Mitral inflow “A” velocity 
 
Mitral inflow “E” velocity 
 
Mitral inflow deceleration time 
 
Mitral annular tissue Doppler systolic (s) velocity (septal and lateral) 
 
Mitral annular tissue Doppler early diastolic (e´) velocity (septal and lateral) 
 
Mitral annular tissue Doppler late diastolic (a´) velocity (septal and lateral) 

 
 
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In addition, the following variables will be derived by the central database from the appropriate 
measurements reported by the Echo Core Lab5: 
 
Mean Transvalvular Gradient (Mean  P) Across the Prosthetic Valve in mmHg 
 
Mean  P = MGV2 - MGV1 
 
Where: MGV2 is the mean pressure gradient across the prosthesis in mmHg, and MGV1 
is the mean pressure gradient from the left ventricular outflow tract in mmHg 
 
Peak Pressure Gradient (Peak  P) Across the Aortic Prosthetic Valve in mmHg 
 
Peak  P = 4 x (V2
2 - V1
2) 
 
Where: V2 is the peak velocity across the prosthesis in m/sec, and V1 is the peak 
velocity from the left ventricular outflow tract in m/sec 
 
Effective Orifice Area (EOA) in cm2 
 
EOA = LVOT Long Axis diameter2 x 0.785 x (VTIV1/VTIV2) 
 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and 
VTIV2 is the velocity time integral of the aortic prosthesis in cm. Alternatively, using 
velocity instead of VTI for simplification: 
 
AVA = π(radius of LVOT)2 × VLVOT/ Vmax  
 
Where Vmax is the maximum flow velocity across aortic valve, VLVOT is the maximum 
velocity across the LVOT. 
 
Effective Orifice Area Index (EOAI) in cm2/m2 
 
EOAI = EOA/BSA 
 
Where: EOA is the effective orifice area in cm2, and BSA is the body surface area in m2 
 
Velocity Time Integral Ratio (VTI Ratio) 
 
VTI Ratio = VTIV1/VTIV2 
 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and 
VTIV2 is the time velocity integral of the prosthetic aortic valve in cm 
 
Stroke Volume (SV) in ml/beat 
 
SV = LVOT long axis diameter2 x 0.785 x VTIV1 
Where:VTIV1 is the velocity time integral from the left ventricular outflow tract in cm 
 
Cardiac Output (CO) in l/min 
 
CO = (SV x HR)/1000 
Where: SV is the stroke volume in ml/beat, and HR is the heart rate in beats per minute 
 
Left Ventricular Mass (LVM) in grams 
LVM = 0.83 x [(LVEDD + LVPW + IVS)3 - (LVEDD)3] +0.6 
Where: LVEDD is the left ventricular end-diastolic diameter in cm, LVPW is the left 
ventricular posterior wall thickness at end diastole in cm, and IVS is the interventricular 
wall thickness at end diastole in cm. 
 
Left Ventricular Mass Index (LVMI) in g/m2 body surface area  
LVMI = LVM/BSA 
Where: LVM is left ventricular mass in g, and BSA is body surface area in m2 
 
Fractional Shortening (FS) in %  
FS = [(LVEDD - LVESD)/LVEDD] x 100 
Where: LVEDD is left ventricular end-diastolic diameter in cm, and LVESD is left 
ventricular end-systolic diameter in cm 

 
 
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 
Estimated Right Ventricular Systolic Pressure (RVSP) in mmHg 
RVSP = (4 x MVTR jet
2) + 10 
Where: MV TR jet is the max velocity of the tricuspid regurgitant jet, and 10 = the 
assumed mean right atrial pressure in mmHg 
 
Aortic Regurgitant volume (ml/beat) and fraction (%)  
The regurgitant volume across the aortic valve may be calculated as the difference 
between the LVOT volume and the transmitral volume, assuming there is no significant 
mitral regurgitation  
RV = Total stroke volume – forward stroke volume  
RV = SVAV – SVMV  
RF = [RV/SV] x 100 
SVAV = 0.785 x (LVOT)2 x VTILVOT (by Pulsed-wave Doppler) 
SVMV = 0.785 x (DMV)2 x VTIMV (by Pulsed-wave Doppler) 
Where: SV is stroke volume in mL, AV is aortic valve and MV is mitral valve 
 
Regurgitant Orifice Area (EROA) 
The regurgitant orifice area or EROA represents the average size of the defect in the 
aortic valve during diastole and is proportional to regurgitant severity.  
The regurgitant orifice area may be calculated as the regurgitant volume multiplied by 
the VTI of the continuous wave Doppler jet 
EROAAV = RV / VTIAR jet (by Continuous-wave Doppler) 

 
 
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19. 
Echocardiography References 
1. 
Zoghbi WA, Chambers JB, Dumesnil JG, Foster E, Gottdiener JS, Grayburn PA, Khandheria BK, 
Levine RA, Marx GR, Miller FA, Jr., Nakatani S, Quinones MA, Rakowski H, Rodriguez LL, 
Swaminathan M, Waggoner AD, Weissman NJ, Zabalgoitia M. Recommendations for evaluation of 
prosthetic valves with echocardiography and doppler ultrasound: A report from the american society 
of echocardiography's guidelines and standards committee and the task force on prosthetic valves, 
developed in conjunction with the american college of cardiology cardiovascular imaging committee, 
cardiac imaging committee of the american heart association, the european association of 
echocardiography, a registered branch of the european society of cardiology, the japanese society of 
echocardiography and the canadian society of echocardiography, endorsed by the american college 
of cardiology foundation, american heart association, european association of echocardiography, a 
registered branch of the european society of cardiology, the japanese society of echocardiography, 
and canadian society of echocardiography. J Am Soc Echocardiogr. 2009;22:975-1014; quiz 1082-
1014 
2. 
Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C, Hagendorff A, Monin JL, 
Badano L, Zamorano JL. European association of echocardiography recommendations for the 
assessment of valvular regurgitation. Part 2: Mitral and tricuspid regurgitation (native valve disease). 
Eur J Echocardiogr. 2010;11:307-332 
3. 
Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E, Monin JL, Pierard LA, 
Badano L, Zamorano JL. European association of echocardiography recommendations for the 
assessment of valvular regurgitation. Part 1: Aortic and pulmonary regurgitation (native valve 
disease). Eur J Echocardiogr. 2010;11:223-244 
4. 
Evangelista A, Flachskampf FA, Erbel R, Antonini-Canterin F, Vlachopoulos C, Rocchi G, Sicari R, 
Nihoyannopoulos P, Zamorano J, Pepi M, Breithardt OA, Plonska-Gosciniak E. Echocardiography in 
aortic diseases: Eae recommendations for clinical practice. Eur J Echocardiogr. 2010;11:645-658 
5. 
Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, 
Pellikka PA, Quinones M. Echocardiographic assessment of valve stenosis: Eae/ase 
recommendations for clinical practice. J Am Soc Echocardiogr. 2009;22:1-23; quiz 101-102 
6. 
Zoghbi WA. New recommendations for evaluation of prosthetic valves with echocardiography and 
doppler ultrasound. Methodist Debakey Cardiovasc J. 2010;6:20-26 
7. 
Chambers J, Shah PM. Recommendations for the echocardiographic assessment of replacement 
heart values. J Heart Valve Dis. 1995;4:9-13 
8. 
Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, 
Mehran R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, 
Vranckx P, Webb JG, Windecker S, Serruys PW. Standardized endpoint definitions for transcatheter 
aortic valve implantation clinical trials: A consensus report from the valve academic research 
consortium. Eur Heart J. 2011;32:205-217 
9. 
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, 
Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for 
chamber quantification: A report from the american society of echocardiography's guidelines and 
standards committee and the chamber quantification writing group, developed in conjunction with the 
european association of echocardiography, a branch of the european society of cardiology. J Am Soc 
Echocardiogr. 2005;18:1440-1463 
 
 

 
 
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R.8 
Electrocardiogram (ECG) Submission 
The standard 12 lead ECG will be utilized as a diagnostic and prognostic tool in patients 
participating in this study.  All ECGs are analyzed by cardiologists/electrophysiologist utilizing 
both qualitative and quantitative methodology.  The accuracy of these interpretations depends 
critically upon the quality of the ECG tracings.  The qualitative reading of ECGs will include 
analysis of rhythm, rate, conduction abnormalities, Q waves and major/minor ST and T wave 
changes. 
Acquisition: 
1. Standard 12-lead ECGs must be obtained (with the exception of implant procedure) 
2. ECG should be conducted with the subject at rest 
3. ECGs should be provided on a single page printout (i.e. lead strips are not acceptable) 
using standard amplification of 1mV/cm and paper speed of 25mm/sec (50mm/sec is 
strongly discouraged) 
4. Visible lead annotation 
5. More than 1 normal beat per lead. No average ECGs 
6. ECG without Pace-Maker beats is preferred 
Labeling: 
7. Protect subject confidentiality.  Effectively block out any subject confidential information 
recorded on the ECG  
8. ECG labels are to be placed on top of the tracing, being careful not to obstruct any of the 
lead recordings 
9. Labels with Study name will be provided by Medtronic and shall be filled out completely, 
including 
a) Site number 
b) Subject identification number 
c) ECG date and time  
d) Applicable visit/interval (i.e. screening, Discharge) 
10. Incomplete labeling will result in the generation of a data clarification query and untimely 
interpretation of the tracing 
Submission: 
11. Original ECGs are strongly encouraged but high quality photocopies with good visible 
gridline are accepted 
12. Submission of all ECGs within appropriate timeframe is imperative 
13. Send complete packets collectively for each patient (i.e. Index ECGs: Screening-Baseline 
and Discharge) 
 

 
 
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Computed Tomography (CT) Angiography Acquisition 
Guidelines 
Background 
Cardiac Multislice Computed Tomographic Angiography (Cardiac MSCT Angiography) is 
intended to evaluate aortic valve anatomy, aortic root dimensions for device sizing, and 
assessment of peripheral vessel dimensions and anatomy.  This appendix is meant as a 
guideline to help with the proper acquisition of the images necessary for assessment of the 
above mentioned items.  The primary objective should be to acquire the highest resolution 
images and perform the correct measurements, as specified below, by tailoring the acquisition 
to your particular hardware and experience.   
Equipment Requirements 
 
Multi-detector CT scanner (64-slice minimum) with ECG-gating capability 
o 
The scans acquired and submitted for analysis of the aortic root MUST be ECG-
gated 
o 
Non-gated scans in areas with cardiac motion lead to measurement inaccuracy 
and therefore incomplete information for device selection 
o 
Peripheral vessel image acquisition may be non-gated 
 
Ability to electronically transfer the imaging data via secure network (InteleGRID) 
Scans Acquired 
 
Chest Topogram 
 
ECG-gated contrast enhanced aortic root* 
 
Non ECG-gated contrast enhanced peripheral vessels* 
*Sub-millimeter slice thickness is required 
Scanning Procedures 
The scan protocol is similar to a CT coronary angiogram. The aim is to get adequate contrast in 
the region of interest which includes: endo-luminal surface for visualization of left heart, aorta, 
and peripheral access vessels (i.e., femorals and subclavians, when necessary). Temporal 
resolution should be optimized to reduce motion artifact. Spatial resolution should be as high as 
possible (goal is smallest isotropic voxel size). 
Step 1: Patient preparation 
 
Administer medication per institution standard practice for CT scanning (suggest avoid 
sublingual nitrate, avoid or caution with B-blockers) 
 
Attach ECG electrodes for gating of scan (suggest:  avoiding large respiratory muscles as 
these may introduce ECG-artifact). Verify quality and stability of ECG tracing on scanner 
console during an inspiratory breath hold 
 
Prepare large intravenous line (i.e., 18 or 20 gauge) for administration of contrast media 
 
Instruct patient to lie still during scan, even if they experience warmth or tingling due to 
the injection of contrast 
 
Instruct patient in practice breath-hold at end-inspiration for 10-15 seconds (duration 
required will depend on specific scanner performance). Assess heart rate variability 
during breath-hold. If heart rate is >65 bpm or unstable, consider cautious titration of 
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Step 2: Chest Topogram 
 
Acquire a chest topogram for use in planning the following imaging protocol 
 
Figure CTA-1:  Example image of chest topogram 
Step 3: ECG-gated contrast enhanced scan of aortic root 
The aim of this scan is to assess the aortic root and valve anatomy. Ensure the required scan 
parameters are used; these are listed below in Table 1. The following parameters are crucial to 
the optimum required scan: 
 
The recommended coverage area is from superior to the aortic arch to inferior to the 
cardiac apex. The minimum required coverage area is from 50mm above the aortic 
annulus to the inferior border of the heart.  Coverage less than this will not allow for 
proper assessment of the patients anatomic suitability 
 
The scan requires dynamic 4D acquisition using retrospective ECG-gating 
 
The required detector collimation is 0.4-0.625mm 
 
The required slice thickness is ≤ 0.8mm 
 
The recommended slice overlap is 0.4mm 
Contrast Enhanced Scan Execution 
 
Prepare iodinated contrast injection apparatus (recommendations in scan parameters 
are provided in Table 1) 
 
Set up scan parameters per the table below  
 
Instruct patient to lie still during scan, even if they experience warmth or tingling due to 
the injection of contrast 
 
Initiate contrast injection 
 
When contrast reaches threshold at bolus-tracking location, instruct patient to hold 
breath at end-inspiration, then initiate main scan protocol 
 
At completion of scan verify scan is of adequate quality 
 
Record amount of contrast given.  Note: this is not on the CRF, but is recommended in 
this patient population 
 
Record heart rate average and range.  Note: this is not on the CRF, but is 
recommended for explanation of image quality issues 

 
 
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Post-processing 
 
Verify heart rate ECG triggers are at consistent place in cardiac cycle, edit if necessary. 
Additional editing/removal of arrhythmias may be performed 
 
Reconstruct at multiple phases (10 increments of 10%), with ≤0.8mm slice thickness.  If 
the system has the capability, also reconstruct a “best systolic” and “best diastolic” 
phase. If image quality of the aortic root is not good in the end systolic phase the phase 
with the best image quality may be selected instead 
Table 1. Recommended Scan Parameters 
 
Recommended Parameters 
IV injection with iodine 
contrast 
80-100 (320mg/ml or higher), modify per patient as appropriate 
Injection rate 
4-6 mL/sec 
Bolus tracking, delay 
Delay time calculated using protocol for current scanner (bolus tracking or 
similar) with peak of contrast concentration in the ascending aorta during 
acquisition.  Bolus tracking is the preferred method.   
ECG Leads 
Required 
ECG-gating 
Retrospective (Prospective may be used in centers with much experience of 
the technique and in patients with stable heart rate) 
Scan direction 
Cranial-caudal 
Scan coverage 
From above the aortic arch to past the cardiac apex 
Detector collimation 
0.4 – 0.625 mm 
Pitch 
0.2–0.43 adapted to the heart rate 
Dose modulation 
Modulation and full current between 30 and 80% of the cardiac cycle (or no 
modulation i.e. full dose throughout) 
Slice thickness 
0.8mm 
Slice overlap 
0.4mm 
Reconstruction kernel 
Medium Smooth 
Post-processing 
Use single segmental reconstruction algorithm that minimizes motion artifact. 
Reconstruct at multiple phases (10 minimum, 20 preferred, increments of 5-
10%).  Reconstructed slice thickness  0.75-1mm. 
 

 
 
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Step 4: Non ECG-gated contrast enhanced scan of vessels  
The aim of this scan is to assess the peripheral access vessels and abdominal aorta for 
suitability for the procedure. 
 
 
Standard radiology CT angiography protocol should be used. 
 
Can be non ECG-gated 
 
Contrast Volume: 40-50 cc, Injection rate: 4 cc/sec.  Modify per patient as necessary to 
acquire good quality images 
 
Delay time calculated using protocol for current scanner (bolus tracking, etc) with peak 
of contrast concentration in the abdominal aorta and iliac arteries 
 
Suggested coverage areas:  
o 
Femoral access only screening: abdominal aorta above celiac artery and down to 
the femoral head.  Use this option there if you are confident that femoral access 
will be suitable for this patient 
o 
Subclavian access only screening: above the subclavian arteries and down to 
mid-thorax.  Use this option if prior information (i.e., CT scan) exists which 
demonstrates that femoral access will not be possible in this patient 
o 
Combined access screening: above the subclavian arteries and down to the 
femoral head.  This is the recommended option.  An additional option for 
subclavian screening is to include the subclavian vessels in the ECG-gated 
portion and use femoral only screening for the rest of the vessels 
 
Source data reconstructed using sub-millimeter slice thickness 
Aortic Root and Peripheral Vessel Measurements 
CT measurements are conducted in different parts of the cardiac cycle to correlate most closely 
with corresponding echo measurements 
 
Systole for aortic annulus measurements 
 
Diastole for sinus of Valsalva diameters, sinus of Valsalva heights, maximum ascending 
aorta diameter, and aortic root angulation 
 
Table 2: Required CT Measurements 
•
Aortic annulus measurements (Systole)
–
Major aortic annulus diameter.
–
Orthogonal minor aortic annulus diameter.
–
Annulus perimeter.
•
Additional aortic root measurements (Diastole)
–
Maximum ascending aorta diameter at 40mm above 
annulus. 
–
Sinus of Valsalva diameters.
–
Sinus of Valsalva heights.
–
Aortic root angulation.
Measured on 
ECG-gated 
images of the 
chest.
Measured on 
Non ECG-
gated images 
of the 
vasculature.
•
Vessel measurements
–
Minimum and perpendicular abdominal aorta diameter.
–
Right and left common and external illiac artery min and 
perpendicular diameter at minimum diameter along path.
–
Right and left femoral artery min and perpendicular 
diameter at minimum diameter along path.
–
If non-iliofemoral access is planned: right and left 
subclavian artery min and perpendicular diameter at 
minimum diameter along path.
 

 
 
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Proper Aortic Annulus Measurements 
The aortic annulus is not co-planar with the planes of the body (i.e., axial, sagittal, or coronal). 
Therefore, multi-planar reformatting of the CT images to create a double-oblique axial image is 
required for annulus measurements. This reformatting is critical; if the plane is not correctly 
aligned, it may be going through the sinuses or the LVOT.  This can lead to improper device 
selection. 
The methods described here for measurement of the aortic annulus (virtual basal ring) are 
similar to those reported in Schultz et al. EuroIntervention Supplement (2010) Volume 6 
(Supplement G) G6-G13.   
Step 1: Reformatting of Images 
 
Center image cross-hairs on aortic root in all windows where it is visible.  Lock cross-
hairs so they remain orthogonal for all steps 
 
In the coronal window, rotate cross-hairs (horizontal line) counter-clockwise to align 
with virtual basal plane, as shown in Figure CTA-2 (upper left panel) 
 
In the sagittal window, the horizontal line has to be rotated clockwise or counter-
clockwise to align with virtual basal plane, as shown in Figure CTA-2 (lower left panel) 
 
On the newly defined double-oblique axial image, scroll up and down through the aortic 
root until the most caudal attachment points of the three native leaflets come into view 
(indicated by arrowheads in Figure CTA-3 below). If one of the leaflets comes into view 
at a more cranial or caudal slice, adjust the coronal or sagittal cross-hairs until all three 
leaflets come into view on the same axial slice 
 
 
Figure CTA-2:  Example images in original orientation (axial, coronal and sagittal).  Red curved arrow and line 
indicate adjustment of coronal and sagittal planes to align with aortic basal annulus. 
 
Sagittal 
Coronal 
Axial 

 
 
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Figure CTA-3:  Example images of reformatted oblique coronal (upper left), oblique sagittal (lower left), double 
oblique axial (upper right) and 3D reconstruction lower right. Yellow arrowheads indicate most caudal attachment of 
three leaflets of aortic valve. 
 
 
For confirmation of the correct aortic annulus plane, scroll through the double oblique 
axial images starting in the mid sinus and ending at the level of the aortic annulus.  The 
sinuses should appear to be relatively the same size at the level of the mid-sinus and 
the leaflets should all disappear equally at the level of the annulus 
Step 2: Aortic Root Measurements 
Aortic Annulus Measurements 
 
Choose the cleanest systolic images for the aortic annulus measurements 
 
Aortic annulus measurements should be completed on the properly reformatted double-
oblique axial image at aortic annulus level 
 
Trace the perimeter of the basal annulus (Figure CTA-4, left).  Place cross-hairs at 
center of basal annulus, create major diameter through the center, create minor 
diameter defined as perpendicular to major and through center (Figure CTA-4, right).  
Record perimeter, major and minor diameter measurements on the screening 
worksheet 
    
Figure CTA-4:  Example of perimeter measurement (left) and major and minor diameter measurements (right). 
Oblique 
Coronal 
Oblique 
Sagittal 
Double-oblique axial 

 
 
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Additional Aortic Root Measurements 
 
Choose the best diastolic images for measurement of sinus of Valsalva diameters, 
sinus of Valsalva heights, maximum ascending aorta diameter (40 mm from annulus), 
and aortic root angulation.  Sinus of Valsalva diameters, heights, and maximum 
ascending aorta diameter should be completed on reformatted images using the same 
reformatting technique as used for the aortic annulus measurements 
Sinus of Valsalva Diameters 
 
Select the double oblique axial image where the widest portion of the three sinuses is 
visible 
 
Measure a diameter from each commissure through the center of the root to the 
opposite sinus.  Complete for all three sinuses (Figure CTA-5 
 
Figure CTA-5:  Example of sinus of Valsalva diameters. 
 

 
 
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Sinus of Valsalva Heights 
 
The sinotubular junction is typically not co-planar with the aortic annulus.  Therefore, a 
sinus of Valsalva height must be measured for each of the three sinuses.  This height is 
defined as the distance between the aortic annular plane and the tallest point in the 
sinus 
 
Choose the double oblique axial image so that it is located at the level of the aortic 
annulus.  The reformatting line representing the double oblique axial image should now 
be visible in the oblique coronal and oblique sagittal images at the level of the aortic 
annulus 
 
For the left coronary and non-coronary heights, use the oblique coronal image.  For the 
right coronary height, use the oblique sagittal image 
 
To complete the measurement, scroll through the oblique coronal or sagittal image 
(depending on which sinus you are measuring) and locate the heights location of the 
sinotubular junction.  On that image, measure the distance along the path of the aortic 
root from the aortic annular plane, marked by the reformatting line, to the sinotubular 
junction (Figure CTA-6).\ 
 
Left coronary height
Non coronary height
Right coronary height
 
Figure CTA-6:  Example of sinus of Valsalva heights. 
 

 
 
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Maximum Ascending Aorta Diameter 
 
Choose the double oblique axial image so that it is located at the level of the aortic 
annulus.  The reformatting line representing the double oblique axial image should now 
be visible in the oblique coronal and oblique sagittal images at the level of the aortic 
annulus 
 
Choose the oblique coronal image that is in the center of the aortic root 
 
Measure a distance of 40mm from the line representing the aortic annular plane 
 
Center the images at this level, and reformat the images so that the double oblique is 
perpendicular to the ascending aorta at this level (Figure CTA-7) 
 
Measure the maximum diameter at this level (Figure CTA-7) 
 
 
 
Figure CTA-7:  Oblique coronal with measurement of 40mm above the aortic annulus (left) and double-oblique 
reformatted to be perpendicular to that location (right).   
 

 
 
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Aortic Root Angulation 
 
The aortic root angle measured in this study is the angle between the aortic annulus 
and the true axial plane of the patient 
 
To measure, use the standard coronal diastolic image, before any reformatting 
 
Scroll to the middle of the aortic root in these images (Figure CTA-8) 
 
Use the angle tool to draw a line first across the aortic annulus and second horizontal to 
the coronal image, which represents the axial plane of the patient.  Start the angle 
measurement in the upper left of the patient, so that the angle is to the lower right of the 
patient (Figure CTA-8) 
 
1
2
3
 
Figure CTA-8:  Aortic root angulation measurement on the standard coronal image.  Use the angle tool beginning 
at point 1, with point 2 on the lower right of the patient, and the final point on the lower left of the patient.  The first 
line, between points 1 and 2 should be along the aortic annulus.  The second line, between points 2 and 3, should 
be horizontal in the coronal image, which represents the axial plane of the patient. 

 
 
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Step 3:  Access Vessel Measurements 
Peripheral vessel measurements are made on non-gated CT and measured on images 
perpendicular to the vessel.  The intent of these measurements is to determine the minimum 
diameters for the potential access routes.  All vessel measurements should be completed on 
images that are perpendicular to the vessels of interest.  
Minimum Abdominal Aortic Diameter 
 
Use a stretched vessel view to locate the minimum luminal abdominal aortic diameter 
 
Measure the minimum lumen diameter and a perpendicular diameter on the image 
orthogonal to the vessel at the minimum location (Figure CTA-9) 
 
Figure CTA-9:  Example of minimum abdominal aortic diameter.  Stretched vessel (left), with the pink line at the 
location of the minimum luminal abdominal diameter.  Orthogonal image (right), showing the minimum luminal 
diameter and the perpendicular diameter. 
Peripheral Vessel Measurements 
 
These techniques are to be used for measurements on the following arteries: 
o 
Right and left femorals 
o 
Right and left common and external iliacs 
o 
If non-femoral access is planned – right and left subclavians 
 
Use a stretched vessel view to locate the minimum luminal diameter 
 
Measure the minimum lumen diameter and a perpendicular diameter on the image 
orthogonal to the vessel at the minimum location (Figure CTA-10) 
 
Figure CTA-10:  Example of the peripheral vessels and measurements for the right (left) and left (right) iliac arteries. 

 
 
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Additional CT Measurements 
 
In the case of a thoracic aortic aneurysm, measure the maximum diameter in the 
aneurysm. 
 
To determine the maximum location, use similar methods to the other vessel 
measurements (stretched vessel view) 
 
Complete the measurement on the orthogonal images and report the maximum 
diameter 
Prepare data for submission  
 
Data should be stored in DICOM 3.0 format 
 
If possible, de-identify all images prior to uploading 
 
Burn images to DICOM DVD/CD or upload to internal electronic records system 
 
Ensure all required images are included on DVD/CD or internal electronic records 
system for upload: 
o 
ECG-gated contrast enhanced aortic root.  Upload on 4 time-points: 30% & 40% 
(systole) and 60% & 70% (diastole).  If the system has “best-systolic” and “best-
diastolic,” only upload those 2 phases.   
o 
Non ECG-gated contrast enhanced peripheral vessels – upload entire set. 
o 
Screenshots of all measurements 
 
Upload all images to InteleGRID (secure electronic system used for transferring 
images) 
 
 

 
 
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Interactive Voice/Web Response System (IXRS) 
Medtronic will utilize an Interactive Voice/Web Response (IXRS) System to manage subject 
screen failures and randomization into the Medtronic CoreValve® SURTAVI Trial. 
The IXRS system will assign patients a Screening ID to be used for all patients that sign the 
Informed Consent Form and are considered for possible enrollment by the Heart Team. If a 
patient is screened and does not meet eligibility criteria, the IXRS system will capture the 
reason for screen failure and disposition of the patient (if known). 
Upon meeting eligibility criteria, the IXRS system will randomize the patient and assign a 
Subject ID to be used in the Oracle Clinical Database upon enrollment.   
The IXRS system will assign subjects within one of four groups:  
 
TAVI with planned PCI 
 
TAVI without planned PCI 
 
SAVR with planned CABG 
 
SAVR without planned CABG 
 
Users can sign in to the Medtronic CoreValve® SURTAVI Trial study web site by using the URL 
below and use the sign in box labeled "IVRS Login": 
 
www.unitedbiosource.com/login.aspx 
 
The first time a user accesses the study web site, they will be prompted to update their 
password. The password must be at least 8 characters in length and contain at least 1 capital 
letter and 1 number or symbol. 
Remember that the User ID and Password are private and should not be shared with other 
individuals. 
For technical questions, contact UBC Technical Support at 888-794-0122 or at 
support@unitedbiosource.com 
 
 

 
 
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Explanted Device/Pathology and Return Procedures 
In the event of a device malfunction of the Medtronic CoreValve® System (MCS) prior to or 
during implant, or in the event that a Medtronic CoreValve® PAV is explanted after implant (due 
to reintervention or autopsy), the PAV and/or affected MCS components should be returned to 
Medtronic. 
SHIPPING INSTRUCTIONS 
System Malfunction (CoreValve Device, Delivery Catheter System (DCS) and/or 
Compression Loading System (CLS) Before or During Procedure 
1. Always retain original product packaging until the procedure is completed. 
2. Place product back into original packaging if it was not clinically used (i.e. in contact 
with blood or body fluids) 
3. If clinically used, use heart valve return kit to ship the valve or CLS. Use a DCS return 
kit for the DCS, if applicable. 
Explant of CoreValve at Reoperation 
1. Photograph the PAV in situ (if possible). 
2. If possible, indicate with a suture on the frame, the relation of the CoreValve to the 
midpoint of the mitral valve. 
3. Following explantation, rinse blood from the lumen with a physiologic solution (e.g. 
Ringer‟s lactate solution). 
4. Do not disturb or alter the valve leaflets in any way (as possible). 
5. Remove all packaging material and forms from kit. Temperature indicator should 
remain in box unless it has been activated. If it has been activated, discard noting that 
the kit is still usable. 
6. Immerse the PAV and any surrounding tissue in the solution provided in the explant kit. 
7. Place the jar into the yellow absorbent pouch and close, then into the zip lock bag and 
seal. 
Explant of CoreValve at Autopsy 
1. Remove all packaging material and forms from kit.  
2. If possible, leave aortic root intact with an ample margin between the valve and 
descending aorta. 
3. Whole hearts should be immersion fixed in formalin in the local autopsy suite or 
pathology lab for at least 24-48 hours prior to shipping. Note: hospitals or contract 
pathology labs should have formalin available for use. 
4. Use the plastic container provided in the return kit for fixing the heart. 
5. Before shipping, remove most of the formalin from the container and wrap the heart in 
the cloth specimen bag that is provided, which has been thoroughly soaked in formalin.  
Place the heart and specimen bag back into the container. 
6. Label the outside of the container (lid and container) with the CoreValve device serial 
number, patient ID, center name and study name.   
7. Seal the container tightly and wrap the container-lid interface with parafilm (if available). 
 

 
 
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All Explants/Returns 
1. Complete the Product Experience Report (PER) form and email a copy to 
rs.structuralheartfieldassurance@medtronic.com to receive a PE number. 
a. If an adverse event form has already been reported for this event and a PE 
number has already been issued via the AE, use the PE number from the AE 
correspondence.  In this instance, sending the PER to field assurance to receive 
a PCR number is not required. 
2. Note the PE number on the Product Experience Report and place the completed form 
and autopsy heart in the box.  
3. Using the pre-paid/pre-printed form, ship by Federal Express or other overnight carrier 
if a form is not provided for your convenience. For further assistance, call the number 
below.  
If a return kit is required, contact Customer Service: 
1-800-556-4247 
All return product should be sent to:  
Medtronic, Inc. 
Attn: Explant Lab/ [PE #] 
1851 E. Deere Ave. 
Santa Ana, CA 92705 
USA 
1-800-854-3570 
 

 
 
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Economic and Quality of Life Data Collection 
Throughout this trial, resource utilization data will be collected by the research coordinator 
along with clinical data using case report forms.   
Prior to enrollment in the study, patients will be asked to provide the information and permission 
to obtain such billing records for the length of their follow-up period.  All related data will be kept 
in a secure and confidential database.  
The QOL questionnaire will be administered to all subjects in languages where translation is 
available. It is not a deviation if a subject does not complete a Quality of Life Questionnaire 
because a translation is not available in the subject‟s language. 
All QOL assessments will be by written, self-administered questionnaires.  
QOL assessments will be performed by personnel at the study site.  It is recommended that the 
assessment is performed prior to informing the subject of their randomization.  
Ample, uninterrupted time should be provided for the subject to complete the questionnaire. 
Every effort should be made to have the subject complete the questionnaire him or herself.  
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a validated self-administered 23-
item questionnaire that quantifies physical limitations, symptoms, self-efficacy, social 
interference and quality of life.  
SF-12 
QualityMetric‟s SF-12v2® Health Survey is a shorter version of the SF-36v2® Health Survey 
that uses 12 questions to measure functional health and well-being from the patient‟s point of 
view. 
EuroQoL EQ-5D 
The EQ-5D is a measure of self-reported health outcomes that is applicable to a wide range of 
health conditions and treatments. It consists of two parts: a descriptive system (Part I) and a 
visual analogue scale (VAS) (Part II). Part I of the scale consists of 5 single-item dimensions 
including: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each 
dimension has a 3 point response scale designed to indicate the level of the problem. Part II 
uses a vertical graduated VAS (thermometer) to measure health status, ranging from worst 
imaginable health state to best imaginable health state. 
 

 
 
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Pacing Guidelines 
Recommendations for pacing pre-, peri- and post-operatively are provided below (see also 
Medtronic CoreValve® System Instructions For Use).  These are recommendations, however, 
and final decisions should be made via clinical presentation and physician discretion.  
Programmed settings for temporary and permanent pacing are per patient condition and 
physician discretion.   
Pre-operative Recommendations 
 
Ensure subject is informed about the placement of temporary pacing wires during the 
procedure and any additional associated risks. 
 
Ensure subject is informed about the potential for the placement of a permanent 
pacemaker and any additional associated risks. 
 
Obtain a baseline 12-lead ECG and assess for patient‟s conduction status 
 
Subjects with a pre-existing permanent pacemaker only: Conduct a full interrogation 
and AV conduction assessment. Print a copy of the interrogation and save the data on a 
diskette.  Label the diskette with labels provided by Medtronic, including center name, 
patient ID, date and time of visit/interrogation and type of visit. Retain the printout and 
diskette in the subject‟s file for source verification.   
o Recommended AV conduction assessment:   
 
Conduct an atrial threshold test with a long AV delay (e.g. 350ms) in DDD mode. 
 
If the subject‟s ventricular rhythm doesn't come through within the 350 ms, the 
subject would be considered dependent on ventricular pacing. 
Peri-operative Recommendations 
 
Prior to beginning the Medtronic CoreValve® System implant, place a temporary 4-5 Fr. 
balloon-tip pacing wire in a stable location within the right ventricular (a screw-tip wire 
may be used for more secure placement for subjects at high-risk for dislodgement, if 
necessary and experienced with implantation technique).   
o Whenever possible, use the upper torso venous system (e.g., jugular, sub-clavian) for 
temporary pacing wire access due to the recommendation to leave this system in for 
at least 48 hours post-procedure. 
o Use fluoroscopy to guide wire placement and stability. 
o Confirm sensing and capture 
o Program the backup pacing rate to minimize ventricular pacing (e.g. 30-40 bpm).  If 
heart block develops, adjustment the rate accordingly. 
 
Rapid pacing during balloon valvuloplasty 
o Conduct a rapid pacing test prior to balloon valvuloplasty.   
 
Successful test is defined as 1-to-1 pacing capture with an immediate drop in 
pressure and elimination of the systolic-diastolic waveform. 
Post-operative Recommendations 
 
All patients should stay on telemetry until discharge 
 
Maintain temporary pacing until at least 48 hours post-implant 
o Ensure a clean, sterile environment is maintained 
 
After 48 hours, obtain ECG and assess patient rhythm and conduction 
o Based on assessment, and with the consult of an electrophysiologist as needed, take 
one of the following actions: 
 
Discontinue temporary pacing 

 
 
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 
Continue temporary pacing for another 24 hours (longer if needed) to make 
further assessments 
 
Place a permanent pacemaker according to ACC/AHA/HRS Guidelines for 
Device-Based Therapy of Cardiac Rhythm Abnormalities1(Class I or IIa for 
Acquired Atrioventricular Block in Adults or Permanent Pacing in Chronic 
Bifascicular Block) 
 Prior to the permanent pacemaker implantation, document the reason for 
the placement of the permanent pacemaker via a 12-lead ECG. 
 
For complete heart block, review patient medications.  Consider withholding some 
medications to assess for patient‟s instrinsic rate and conduction.  If heart block persists 
off medications, a permanent pacemaker should be considered. 
 
If a permanent pacemaker is required, a dual chamber system is recommended to 
optimize patient hemodynamics. 
 
If a permanent pacemaker is implanted, perform a device interrogation and AV 
conduction assessment post insertion and prior to hospital discharge as well as at every 
follow-up visit to evaluate device utilization. Print a copy of the interrogation and save the 
data on a diskette. Label the diskette with labels provided by Medtronic, including center 
name, patient ID, date and time of visit/interrogation and type of visit.  Retain the printout 
and diskette in the subject‟s file for source verification.   
o Recommended AV conduction assessment:   
 
Conduct an atrial threshold test with a long AV delay 350ms) in DDD mode.   
 
If the subject‟s ventricular rhythm doesn't come through within the 350 ms, the 
subject would be considered dependent on ventricular pacing. 
                                                     
 
1  ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: J Am Coll Cardiol 2008; 51:2085–
105; Circulation 2008;117:2820–40
 

 
 
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ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities 
Recommendations for Acquired Atrioventricular Block in Adults 
Class I Permanent pacemaker implantation is indicated for: 
 
Third-degree and advanced second-degree atrioventricular (AV) block at any anatomic 
level associated with bradycardia with symptoms (including heart failure) or ventricular 
arrhythmias presumed to be due to AV block. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level associated 
with arrhythmias and other medical conditions that require drug therapy that results in 
symptomatic bradycardia. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level in awake, 
symptom-free patients in sinus rhythm, with documented periods of asystole greater than 
or equal to 3.0 seconds or any escape rate less than 40 bpm, or with an escape rhythm 
that is below the AV node. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level in awake, 
symptom-free patients with atrial fibrillation and bradycardia with 1 or more pauses of at 
least 5 seconds or longer. (LOE: C)  
 
Third-degree and advanced second-degree AV block at any anatomic level after catheter 
ablation of the AV junction. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level associated 
with postoperative AV block that is not expected to resolve after cardiac surgery. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level associated 
with neuromuscular diseases with AV block, such as myotonic muscular dystrophy, 
Kearns-Sayre syndrome, Erb dystrophy (limb-girdle muscular dystrophy), and peroneal 
muscular atrophy, with or without symptoms. (LOE: B) 
 
Second-degree AV block with associated symptomatic bradycardia regardless of type or 
site of block. (LOE: B) 
 
Asymptomatic persistent third-degree AV block at any anatomic site with average awake 
ventricular rates of 40 bpm or faster if cardiomegaly or left ventricular (LV) dysfunction is 
present or if the site of block is below the AV node. (LOE: B) 
 
Second- or third-degree AV block during exercise in the absence of myocardial ischemia. 
(LOE: C)  
Class IIa Permanent pacemaker implantation is reasonable for: 
 
Persistent third-degree AV block with an escape rate greater than 40 bpm in 
asymptomatic adult patients without cardiomegaly. (LOE: C) 
 
Asymptomatic second-degree AV block at intra or infra-His levels found at 
electrophysiological study. (LOE: B) 
 
First- or second-degree AV block with symptoms similar to those of pacemaker syndrome 
or hemodynamic compromise. (LOE: B) 
 
Asymptomatic type II second-degree AV block with a narrow QRS. When type II second-
degree AV block occurs with a wide QRS, including isolated right bundle-branch block, 
pacing becomes a Class I recommendation (see Section 2.1.3, “Chronic Bifascicular 
Block,” in the full-text guidelines). (LOE: B) 
 

 
 
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Recommendations for Permanent Pacing in Chronic Bifascicular Block 
Class I Permanent pacemaker implantation is indicated for: 
Advanced second-degree AV block or intermittent third-degree AV block. (LOE: B) 
Type II second-degree AV block. (LOE: B) 
Alternating bundle-branch block. (LOE: C) 
 
Class IIa Permanent pacemaker implantation is reasonable for: 
 
Syncope not demonstrated to be due to AV block when other likely causes have been 
excluded, specifically ventricular tachycardia (VT). (LOE: B) 
 
Incidental finding at electrophysiological study of a markedly prolonged HV interval 
(greater than or equal to 100 milliseconds) in asymptomatic patients. (LOE: B) 
 
Incidental finding at electrophysiological study of pacing-induced infra-His block that is not 
physiological. (LOE: B) 
 
 

 
 
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R.14 
Six Minute Walk Test Instructions 
American Thoracic Society
ATS Statement: Guidelines for the Six-Minute Walk Test  
THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY WAS APPROVED 
BY THE ATS BOARD OF DIRECTORS MARCH 2002  
CONTENTS  
Purpose and Scope  
Background  
Indications and Limitations  
Contraindications  
Safety Issues  
Technical Aspects of the 6-Minute Walk Test  
Required Equipment  
Patient Preparation  
Measurements  
Quality Assurance  
Interpretation  
References  
PURPOSE AND SCOPE  
This statement provides practical guidelines for the 6-minute walk test (6MWT). Specifically, it 
reviews indications, details factors that influence results, presents a brief step-by-step protocol, 
outlines safety measures, describes proper patient preparation and procedures, and offers 
guidelines for clinical interpretation of results. These recommendations are not intended to limit 
the use of alternative protocols for research studies. We do not discuss the general topic of 
clinical exercise testing.  
As with other American Thoracic Society statements on pulmonary function testing, these 
guidelines come out of a consensus conference. Drafts were prepared by two members (P.L.E. 
and R.J.Z.) and were based on a comprehensive Medline literature search from 1970 through 
2001, augmented by suggestions from other committee members. Each draft responded to 
comments from the working committee. The guidelines follow previously published methods as 
closely as possible and provide a rationale for each specific recommendation. The final 
recommendations represent a consensus of the committee. The committee recommends that 
these guidelines be reviewed in five years and in the meantime encourages further research in 
areas of controversy.  
BACKGROUND  
There are several modalities available for the objective evaluation of functional exercise 
capacity. Some provide a very complete assessment of all systems involved in exercise 
performance (high tech), whereas others provide basic information but are low tech and are 
simpler to perform. The modality used should be chosen based on the clinical question to be 
addressed and on available resources. The most popular clinical exercise tests in order of 
increasing complexity are stair climbing, a 6MWT, a shuttle-walk test, detection of exercise-
induced asthma, a cardiac stress test (e.g., Bruce protocol), and a cardiopulmonary exercise 
test (1, 2). Other professional organizations have published standards for cardiac stress testing 
(3, 4).  
Assessment of functional capacity has traditionally been done by merely asking patients the 
following: "How many flights of stairs can you climb or how many blocks can you walk?" 
However, patients vary in their recollection and may report overestimations or underestimations 
of their true functional capacity. Objective measurements are usually better than self-reports. In 
the early 1960s, Balke developed a simple test to evaluate the functional capacity by measuring 
the distance walked during a defined period of time (5). A 12-minute field performance test was 
then developed to evaluate the level of physical fitness of healthy individuals (6). The walking 
test was also adapted to assess disability in patients with chronic bronchitis (7). In an attempt to 
accommodate patients with respiratory disease for whom walking 12 minutes was too 

 
 
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exhausting, a 6-minute walk was found to perform as well as the 12-minute walk (8). A recent 
review of functional walking tests concluded that "the 6MWT is easy to administer, better 
tolerated, and more reflective of activities of daily living than the other walk tests" (9).  
The 6MWT is a practical simple test that requires a 100-ft hallway but no exercise equipment or 
advanced training for technicians. Walking is an activity performed daily by all but the most 
severely impaired patients. This test measures the distance that a patient can quickly walk on a 
flat, hard surface in a period of 6 minutes (the 6MWD). It evaluates the global and integrated 
responses of all the systems involved during exercise, including the pulmonary and 
cardiovascular systems, systemic circulation, peripheral circulation, blood, neuromuscular units, 
and muscle metabolism. It does not provide specific information on the function of each of the 
different organs and systems involved in exercise or the mechanism of exercise limitation, as is 
possible with maximal cardiopulmonary exercise testing. The self-paced 6MWT assesses the 
submaximal level of functional capacity. Most patients do not achieve maximal exercise 
capacity during the 6MWT; instead, they choose their own intensity of exercise and are allowed 
to stop and rest during the test. However, because most activities of daily living are performed 
at submaximal levels of exertion, the 6MWD may better reflect the functional exercise level for 
daily physical activities.  
INDICATIONS AND LIMITATIONS  
The strongest indication for the 6MWT is for measuring the response to medical interventions in 
patients with moderate to severe heart or lung disease. The 6MWT has also been used as a 
one-time measure of functional status of patients, as well as a predictor of morbidity and 
mortality (see Table 1 for a list of these indications). The fact that investigators have used the 
6MWT in these settings does not prove that the test is clinically useful (or the best test) for 
determining functional capacity or changes in functional capacity due to an intervention in 
patients with these diseases. Further studies are necessary to determine the utility of the 6MWT 
in various clinical situations.  
TABLE 1. Indications for the Six-Minute Walk Test  
Pretreatment and post treatment comparisons 
Lung transplantation (9, 10) 
Lung resection (11) 
Lung volume reduction surgery (12, 13) 
Pulmonary rehabilitation (14, 15) 
COPD (16–18) 
Pulmonary hypertension 
Heart failure (19, 20) 
Functional status (single measurement) 
COPD (21, 22) 
Cystic fibrosis (23, 24) 
Heart failure (25–27) 
Peripheral vascular disease (28, 29) 
Fibromyalgia (30) 
Older patients (31) 
Predictor of morbidity and mortality 
Heart failure (32, 33) 
COPD (34, 35) 
Primary pulmonary hypertension (10, 36) 
Definition of abbreviation: COPD = chronic obstructive pulmonary disease. 
Formal cardiopulmonary exercise testing provides a global assessment of the exercise 
response, an objective determination of functional capacity and impairment, determination of 
the appropriate intensity needed to perform prolonged exercise, quantification of factors limiting 
exercise, and a definition of the underlying pathophysiologic mechanisms such as the 
contribution of different organ systems involved in exercise. The 6MWT does not determine 
peak oxygen uptake, diagnose the cause of dyspnea on exertion, or evaluate the causes or 
mechanisms of exercise limitation (1, 2). The information provided by a 6MWT should be 
considered complementary to cardiopulmonary exercise testing, not a replacement for it. 

 
 
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Despite the difference between these two functional tests, some good correlations between 
them have been reported. For example, a significant correlation (r = 0.73) between 6MWD and 
peak oxygen uptake has been reported for patients with end-stage lung diseases (36).  
In some clinical situations, the 6MWT provides information that may be a better index of the 
patient's ability to perform daily activities than is peak oxygen uptake; for example, 6MWD 
correlates better with formal measures of quality of life (37). Changes in 6MWD after therapeutic 
interventions correlate with subjective improvement in dyspnea (38, 39). The reproducibility of 
the 6MWD (with a coefficient of variation of approximately 8%) appears to be better than the 
reproducibility of 1-second forced expiratory volume in patients with chronic obstructive 
pulmonary disease (COPD) (8, 39–42). Questionnaire indices of functional status have a larger 
short-term variability (22–33%) than does the 6MWD (37).  
The shuttle-walking test is similar to the 6MWT, but it uses an audio signal from a tape cassette 
to direct the walking pace of the patient back and forth on a 10-m course (43–45). The walking 
speed is increased every minute, and the test ends when the patient cannot reach the 
turnaround point within the required time. The exercise performed is similar to a symptom-
limited, maximal, incremental treadmill test. An advantage of the shuttle walking test is that it 
has a better correlation with peak oxygen uptake than the 6MWD (46, 47). Disadvantages 
include less validation, less widespread use, and more potential for cardiovascular problems.  
CONTRAINDICATIONS  
Absolute contraindications for the 6MWT include the following: unstable angina during the 
previous month and myocardial infarction during the previous month. Relative contraindications 
include a resting heart rate of more than 120, a systolic blood pressure of more than 180 mm 
Hg, and a diastolic blood pressure of more than 100 mm Hg.  
Patients with any of these findings should be referred to the physician ordering or supervising 
the test for individual clinical assessment and a decision about the conduct of the test. The 
results from a resting electrocardiogram done during the previous 6 months should also be 
reviewed before testing. Stable exertional angina is not an absolute contraindication for a 
6MWT, but patients with these symptoms should perform the test after using their antiangina 
medication, and rescue nitrate medication should be readily available.  
Rationale 
Patients with the previously mentioned risk factors may be at increased risk for arrhythmias 
or cardiovascular collapse during testing. However, each patient determines the intensity of 
their exercise, and the test (without electrocardiogram monitoring) has been performed in 
thousands of older persons (31, 48) and thousands of patients with heart failure or 
cardiomyopathy (32, 49, 50) without serious adverse events. The contraindications listed 
previously here were used by study investigators based on their impressions of the general 
safety of the 6MWT and their desire to be prudent, but it is unknown whether adverse 
events would occur if such patients performed a 6MWT; they are, therefore, listed as 
relative contraindications.  
SAFETY ISSUES  
1. Testing should be performed in a location where a rapid, appropriate response to an 
emergency is possible. The appropriate location of a crash cart should be determined by 
the physician supervising the facility.  
2. Supplies that must be available include oxygen, sublingual nitroglycerine, aspirin, and 
albuterol (metered dose inhaler or nebulizer). A telephone or other means should be in 
place to enable a call for help.  
3. The technician should be certified in cardiopulmonary resuscitation with a minimum of 
Basic Life Support by an American Health Association–approved cardiopulmonary 
resuscitation course. Advanced cardiac life support certification is desirable. Training, 
experience, and certification in related health care fields (registered nurse, registered 
respiratory therapist, certified pulmonary function technician, etc.) are also desirable. A 
certified individual should be readily available to respond if needed.  

 
 
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4. Physicians are not required to be present during all tests. The physician ordering the test 
or a supervising laboratory physician may decide whether physician attendance at a 
specific test is required.  
5. If a patient is on chronic oxygen therapy, oxygen should be given at their standard rate or 
as directed by a physician or a protocol.  
Reasons for immediately stopping a 6MWT include the following: (1) chest pain, (2) intolerable 
dyspnea, (3) leg cramps, (4) staggering, (5) diaphoresis, and (6) pale or ashen appearance.  
Technicians must be trained to recognize these problems and the appropriate responses. If a 
test is stopped for any of these reasons, the patient should sit or lie supine as appropriate 
depending on the severity or the event and the technician's assessment of the severity of the 
event and the risk of syncope. The following should be obtained based on the judgment of the 
technician: blood pressure, pulse rate, oxygen saturation, and a physician evaluation. Oxygen 
should be administered as appropriate.  
TECHNICAL ASPECTS OF THE 6MWT  
Location 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a 
hard surface that is seldom traveled. If the weather is comfortable, the test may be performed 
outdoors. The walking course must be 30 m in length. A 100-ft hallway is, therefore, required. 
The length of the corridor should be marked every 3 m. The turnaround points should be 
marked with a cone (such as an orange traffic cone). A starting line, which marks the beginning 
and end of each 60-m lap, should be marked on the floor using brightly colored tape.  
Rationale 
A shorter corridor requires patients to take more time to reverse directions more often, 
reducing the 6MWD. Most studies have used a 30-m corridor (51), but some have used 20- 
or 50-m corridors (52, 53). A recent multicenter study found no significant effect of the 
length of straight courses ranging from 50 to 164 ft, but patients walked farther on 
continuous (oval) tracks (mean 92 ft farther) (54).  
The use of a treadmill to determine the 6MWD might save space and allow constant 
monitoring during the exercise, but the use of a treadmill for 6-minute walk testing is not 
recommended. Patients are unable to pace themselves on a treadmill. In one study of 
patients with severe lung disease, the mean distance walked on the treadmill during 6 
minutes (with the speed adjusted by the patients) was shorter by a mean of 14% when 
compared with the standard 6MWD using a 100-ft hallway (55). The range of differences 
was wide, with patients walking between 400–1,300 ft on the treadmill who walked 1,200 ft 
in the hallway. Treadmill test results, therefore, are not interchangeable with corridor tests.  
REQUIRED EQUIPMENT  
1. Countdown timer (or stopwatch)  
2. Mechanical lap counter  
3. Two small cones to mark the turnaround points  
4. A chair that can be easily moved along the walking course  
5. Worksheets on a clipboard  
6. A source of oxygen  
7. Sphygmomanometer  
8. Telephone  
9. Automated electronic defibrillator  

 
 
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PATIENT PREPARATION  
1. Comfortable clothing should be worn.  
2. Appropriate shoes for walking should be worn.  
3. Patients should use their usual walking aids during the test (cane, walker, etc.).  
4. The patient's usual medical regimen should be continued.  
5. A light meal is acceptable before early morning or early afternoon tests.  
6. Patients should not have exercised vigorously within 2 hours of beginning the test.  
MEASUREMENTS  
1. Repeat testing should be performed about the same time of day to minimize intraday 
variability.  
2. A "warm-up" period before the test should not be performed.  
3. The patient should sit at rest in a chair, located near the starting position, for at least 10 
minutes before the test starts. During this time, check for contraindications, measure 
pulse and blood pressure, and make sure that clothing and shoes are appropriate. 
Complete the first portion of the worksheet (see the APPENDIX).  
4. Pulse oximetry is optional. If it is performed, measure and record baseline heart rate and 
oxygen saturation (SpO2) and follow manufacturer's instructions to maximize the signal 
and to minimize motion artifact (56). Make sure the readings are stable before recording. 
Note pulse regularity and whether the oximeter signal quality is acceptable.  
The rationale for measuring oxygen saturation is that although the distance is the 
primary outcome measure, improvement during serial evaluations may be manifest 
either by an increased distance or by reduced symptoms with the same distance walked 
(38). The SpO2 should not be used for constant monitoring during the exercise. The 
technician must not walk with the patient to observe the SpO2. If worn during the walk, 
the pulse oximeter must be lightweight (less than 2 pounds), battery powered, and held 
in place (perhaps by a "fanny pack") so that the patient does not have to hold or 
stabilize it and so that stride is not affected. Many pulse oximeters have considerable 
motion artifact that prevents accurate readings during the walk (57).  
5. Have the patient stand and rate their baseline dyspnea and overall fatigue using the Borg 
scale (see Table 2 for the Borg scale and instructions [58]).  
6. Set the lap counter to zero and the timer to 6 minutes. Assemble all necessary equipment 
(lap counter, timer, clipboard, Borg Scale, worksheet) and move to the starting point.  
7. Instruct the patient as follows:  
"The object of this test is to walk as far as possible for 6 minutes. You will walk back 
and forth in this hallway. Six minutes is a long time to walk, so you will be exerting 
yourself. You will probably get out of breath or become exhausted. You are 
permitted to slow down, to stop, and to rest as necessary. You may lean against the 
wall while resting, but resume walking as soon as you are able.  
You will be walking back and forth around the cones. You should pivot briskly around 
the cones and continue back the other way without hesitation. Now I'm going to show 
you. Please watch the way I turn without hesitation."  
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly.  
"Are you ready to do that? I am going to use this counter to keep track of the number of 
laps you complete. I will click it each time you turn around at this starting line. 
Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run 
or jog.  
Start now, or whenever you are ready."  

 
 
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TABLE 2. The Borg scale 
0 
Nothing at all 
0.5 
Very, very slight (just noticeable) 
1 
Very slight 
2 
Slight (light) 
3 
Moderate 
4 
Somewhat severe 
5 
Severe (heavy) 
6 
 
7 
Very severe 
8 
 
9 
 
10 
Very, very severe (maximal) 
 
This Borg scale should be printed on heavy paper (11 inches high and perhaps laminated) 
in 20-point type size. At the beginning of the 6-minute exercise, show the scale to the 
patient and ask the patient this: "Please grade your level of shortness of breath using this 
scale." Then ask this: "Please grade your level of fatigue using this scale." 
At the end of the exercise, remind the patient of the breathing number that they chose 
before the exercise and ask the patient to grade their breathing level again. Then ask the 
patient to grade their level of fatigue, after reminding them of their grade before the 
exercise. 
8. Position the patient at the starting line. You should also stand near the starting line 
during the test. Do not walk with the patient. As soon as the patient starts to walk, start 
the timer  
9. Do not talk to anyone during the walk. Use an even tone of voice when using the 
standard phrases of encouragement. Watch the patient. Do not get distracted and lose 
count of the laps. Each time the participant returns to the starting line, click the lap 
counter once (or mark the lap on the worksheet). Let the participant see you do it. 
Exaggerate the click using body language, like using a stopwatch at a race.  
After the first minute, tell the patient the following (in even tones): "You are doing well. 
You have 5 minutes to go."  
When the timer shows 4 minutes remaining, tell the patient the following: "Keep up the 
good work. You have 4 minutes to go."  
When the timer shows 3 minutes remaining, tell the patient the following: "You are doing 
well. You are halfway done."  
When the timer shows 2 minutes remaining, tell the patient the following: "Keep up the 
good work. You have only 2 minutes left."  
When the timer shows only 1 minute remaining, tell the patient: "You are doing well. 
You have only 1 minute to go."  
Do not use other words of encouragement (or body language to speed up).  
If the patient stops walking during the test and needs a rest, say this: "You can lean 
against the wall if you would like; then continue walking whenever you feel able." Do not 
stop the timer. If the patient stops before the 6 minutes are up and refuses to continue 
(or you decide that they should not continue), wheel the chair over for the patient to sit 
on, discontinue the walk, and note on the worksheet the distance, the time stopped, and 
the reason for stopping prematurely.  
When the timer is 15 seconds from completion, say this: "In a moment I'm going to tell 
you to stop. When I do, just stop right where you are and I will come to you."  
When the timer rings (or buzzes), say this: "Stop!" Walk over to the patient. Consider 
taking the chair if they look exhausted. Mark the spot where they stopped by placing a 
bean bag or a piece of tape on the floor.  
10. Post-test: Record the postwalk Borg dyspnea and fatigue levels and ask this: "What, if 
anything, kept you from walking farther?"  

 
 
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11. If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and then 
remove the sensor.  
12. Record the number of laps from the counter (or tick marks on the worksheet).  
13. Record the additional distance covered (the number of meters in the final partial lap) 
using the markers on the wall as distance guides. Calculate the total distance walked, 
rounding to the nearest meter, and record it on the worksheet.  
14. Congratulate the patient on good effort and offer a drink of water.  
QUALITY ASSURANCE  
Sources of Variability 
There are many sources of 6MWD variability (see Table 3). The sources of variability caused by 
the test procedure itself should be controlled as much as possible. This is done by following the 
standards found in this document and by using a quality-assurance program.  
TABLE 3. 6MWD Sources of Variability  
Factors reducing the 6MWD 
Shorter height 
Older age 
Higher body weight 
Female sex 
Impaired cognition 
A shorter corridor (more turns) 
Pulmonary disease (COPD, asthma, cystic fibrosis, interstitial lung disease) 
Cardiovascular disease (angina, MI, CHF, stroke, TIA, PVD, AAI) 
Musculoskeletal disorders (arthritis, ankle, knee, or hip injuries, muscle wasting, etc.) 
Factors increasing the 6MWD 
Taller height (longer legs) 
Male sex 
High motivation 
A patient who was previously performed the test 
Medication for a disabling disease taken just before the test 
Oxygen supplementation in patients with exercise induced hypoxemia 
 Definition of abbreviations: COPD = chronic obstructive pulmonary disease; 6MWD = 6-minute walking distance.  
 
Practice Tests 
A practice test is not needed in most clinical settings but should be considered. If a practice test 
is done, wait for at least 1 hour before the second test and report the highest 6MWD as the 
patient's 6MWD baseline.  
Rationale 
The 6MWD is only slightly higher for a second 6MWT performed a day later. The mean 
reported increase ranges from 0 to 17% (23, 27, 40, 41, 54, 59). A multicenter study of 470 
highly motivated patients with severe COPD performed two 6MWTs 1 day apart, and on 
average, the 6MWD was only 66 ft (5.8%) higher on the second day (54).  
Performance (without an intervention) usually reaches a plateau after two tests done within 
a week (8, 60). The training effect may be due to improved coordination, finding optimal 
stride length, and overcoming anxiety. The possibility of a practice or training effect from 
tests repeated after more than a month has not been studied or reported; however, it is 
likely that the effect of training wears off (does not persist) after a few weeks.  

 
 
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Technician Training and Experience 
Technicians who perform 6MWTs should be trained using the standard protocol and then 
supervised for several tests before performing them alone. They should also have completed 
cardiopulmonary resuscitation training.  
Rationale 
One multicenter study of older people found that after correction for many other factors, two 
of the technicians had mean 6MWDs that were approximately 7% lower than the other two 
sites (31).  
Encouragement 
Only the standardized phrases for encouragement (as specified previously here) must be used 
during the test.  
Rationale 
Encouragement significantly increases the distance walked (42). Reproducibility for tests 
with and without encouragement is similar. Some studies have used encouragement every 
30 seconds, every minute, or every 2 minutes. We have chosen every minute and standard 
phrases. Some studies (53) have instructed patients to walk as fast as possible. Although 
larger mean 6MWDs may be obtained thereby, we recommend that such phrases not be 
used, as they emphasize initial speed at the expense of earlier fatigue and possible 
excessive cardiac stress in some patients with heart disease.  
Supplemental Oxygen 
If oxygen supplementation is needed during the walks and serial tests are planned (after an 
intervention other than oxygen therapy), then during all walks by that patient oxygen should be 
delivered in the same way with the same flow. If the flow must be increased during subsequent 
visits due to worsening gas exchange, this should be noted on the worksheet and considered 
during interpretation of the change noted in 6MWD. The type of oxygen delivery device should 
also be noted on the report: for instance, the patient carried liquid oxygen or pushed or pulled 
an oxygen tank, the delivery was pulsed or continuous, or a technician walked behind the 
patient with the oxygen source (not recommended). Measurements of pulse and SpO2 should 
be made after waiting at least 10 minutes after any change in oxygen delivery.  
Rationale 
For patients with COPD or interstitial lung disease, oxygen supplementation increases the 
6MWD (17, 59, 61). Carrying a portable gas container (but not using it for supplemental 
oxygen) reduced the mean 6MWD by 14% in one study of patients with severe respiratory 
disability, but using the container to deliver supplemental oxygen during the exercise 
increased the mean 6MWD by 20–36% (59).  
Medications 
The type of medication, dose, and number of hours taken before the test should be noted.  
Rationale 
Significant improvement in the distance walked, or the dyspnea scale, after administration 
of bronchodilators has been demonstrated in patients with COPD (62, 63), as well as 
cardiovascular medications in patients with heart failure (19).  
INTERPRETATION  
Most 6MWTs will be done before and after intervention, and the primary question to be 
answered after both tests have been completed is whether the patient has experienced a 
clinically significant improvement. With a good quality-assurance program, with patients tested 
by the same technician, and after one or two practice tests, short-term reproducibility of the 
6MWD is excellent (36). It is not known whether it is best for clinical purposes to express 
change in 6MWD as (1) an absolute value, (2) a percentage change, or (3) a change in the 
percentage of predicted value. Until further research is available, we recommend that change in 
6MWD be expressed as an absolute value (e.g., the patient walked 50 m farther).  
A statistically significant mean increase in 6MWD in a group of study participants is often much 
less than a clinically significant increase in an individual patient. In one study of 112 patients 
(half of them women) with stable, severe COPD, the smallest difference in 6MWD that was 
associated with a noticeable clinical difference in the patients' perception of exercise 

 
 
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performance was a mean of 54 m (95% confidence interval, 37–71 m) (64). This study suggests 
that for individual patients with COPD, an improvement of more than 70 m in the 6MWD after an 
intervention is necessary to be 95% confident that the improvement was significant. In an 
observational study of 45 older patients with heart failure, the smallest difference in 6MWD that 
was associated with a noticeable difference in their global rating of worsening was a mean of 43 
m (20). The 6MWD was more responsive to deterioration than to improvement in heart failure 
symptoms.  
Reported Mean Changes in 6MWD After Interventions 
Supplemental oxygen (6 L/min) during exercise in patients with COPD or interstitial lung 
disease increased mean 6MWD by approximately 83 m (36%) in one study (59). Patients taking 
an inhaled corticosteroid experienced a mean 33 m (8%) increase in 6MWD in an international 
COPD study (16). Patients with COPD in a study of the effects of exercise and diaphragmatic 
strength training experienced a mean increase in 6MWD of 50 m (20%) (65). Lung volume 
reduction surgery in patients with very severe COPD has been reported to increase 6MWD by a 
mean of 55 m (20%) (13).  
Cardiac rehabilitation in patients referred with various heart diseases increased 6MWD by a 
mean of 170 m (15%) in a recent study (66). In 25 older patients with heart failure, an 
angiotensin-converting enzyme inhibitor medication (50 mg captopril per day) improved 6MWD 
a mean of 64 m (39%) compared with a mean increase of only 8% in those receiving a placebo 
(19).  
Interpreting Single Measurements of Functional Status 
Optimal reference equations from healthy population-based samples using standardized 6MWT 
methods are not yet available. In one study, the median 6MWD was approximately 580 m for 
117 healthy men and 500 m for 173 healthy women (48). A mean 6MWD of 630 m was reported 
by another study of 51 healthy older adults (53). Differences in the population sampled, type 
and frequency of encouragement, corridor length, and number of practice tests may account for 
reported differences in mean 6MWD in healthy persons. Age, height, weight, and sex 
independently affect the 6MWD in healthy adults; therefore, these factors should be taken into 
consideration when interpreting the results of single measurements made to determine 
functional status. We encourage investigators to publish reference equations for healthy 
persons using the previously mentioned standardized procedures.  
A low 6MWD is nonspecific and nondiagnostic. When the 6MWD is reduced, a thorough search 
for the cause of the impairment is warranted. The following tests may then be helpful: 
pulmonary function, cardiac function, ankle–arm index, muscle strength, nutritional status, 
orthopedic function, and cognitive function.  
Conclusions 
The 6MWT is a useful measure of functional capacity targeted at people with at least 
moderately severe impairment. The test has been widely used for preoperative and 
postoperative evaluation and for measuring the response to therapeutic interventions for 
pulmonary and cardiac disease. These guidelines provide a standardized approach to 
performing the 6MWT. The committee hopes that these guidelines will encourage further 
research into the 6MWT and allow direct comparisons among different studies.  
 
 

 
 
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APPENDIX  
The following elements should be present on the 6MWT worksheet and report: 
Lap counter:  __ __ __ __ __  __ __ __ __ __  __ __ __ __ __  
Patient name: ____________________      Patient ID# ___________  
Walk # ______    Tech ID: _________ Date: __________  
Gender: M F  Age: ____  Race: ____  Height: ___ft ____in, ____ meters  
Weight: ______ lbs, _____kg      Blood pressure: _____ / _____  
Medications taken before the test (dose and time): __________________  
Supplemental oxygen during the test: No  Yes, flow ______ L/min, type _____ 
Baseline 
End of Test 
Time 
___:___ 
___:___ 
Heart Rate 
_____ 
_____ 
Dyspnea 
_____ 
_____ (Borg scale) 
Fatigue 
_____ 
_____ (Borg scale) 
SpO2 
_____ % 
_____ % 
Stopped or paused before 6 minutes? No  Yes, reason: _______________  
Other symptoms at end of exercise: angina  dizziness  hip, leg, or calf pain  
Number of laps: ____ (x60 meters) + final partial lap: _____ meters =  
Total distance walked in 6 minutes: ______ meters  
Predicted distance: _____ meters    Percent predicted: _____%  
Tech comments:  
Interpretation (including comparison with a preintervention 6MWD): 
 

 
 
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Acknowledgments  
This statement was developed by the ATS Committee on Proficiency Standards for Clinical 
Pulmonary Function Laboratories.  
Members of the committee are:  
ROBERT O. CRAPO, M.D., Chair *  
RICHARD CASABURI, PH.D, M.D.  
ALLAN L. COATES, M.D.  
PAUL L. ENRIGHT, M.D.*  
NEIL R. MACINTYRE, M.D.  
ROY T. MCKAY, PH.D.  
DOUGLAS JOHNSON, M.D.  
JACK S. WANGER, M.S.  
R. JORGE ZEBALLOS, M.D.*  
Ad Hoc Committee members are:  
VERA BITTNER, M.D.  
CARL MOTTRAM, R.R.T.  
*Writing Committee Members  
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R.15 
National Institute of Health Stroke Scale (NIHSS) 
Administer stroke scale items in the order listed. Record performance in each category after 
each subscale exam. Do not go back and change scores. Follow directions provided for each 
exam technique. Scores should reflect what the patient does, not what the clinician thinks the 
patient can do. The clinician should record answers while administering the exam and work 
quickly. Except where indicated, the patient should not be coached (i.e., repeated requests to 
patient to make a special effort). 
 
 Instructions  
Scale Definition  
Score  
1a. Level of Consciousness: The investigator 
must choose a response if a full evaluation is 
prevented by such obstacles as an endotracheal 
tube, 
language 
barrier, 
orotracheal 
trauma/bandages. A 3 is scored only if the 
patient makes no movement (other than reflexive 
posturing) in response to noxious stimulation.  
0 = Alert; keenly responsive.  
1 = Not alert; but arousable by minor 
stimulation to obey, answer, or 
respond.  
2 = Not alert; requires repeated 
stimulation to attend, or is obtunded 
and requires strong or painful 
stimulation to make movements (not 
stereotyped).  
3 = Responds only with reflex motor or 
autonomic effects or totally 
unresponsive, flaccid, and areflexic.  
______  
1b. LOC Questions: The patient is asked the 
month and his/her age. The answer must be 
correct - there is no partial credit for being close. 
Aphasic and stuporous patients who do not 
comprehend the questions will score 2. Patients 
unable to speak because of endotracheal 
intubation, orotracheal trauma, severe dysarthria 
from any cause, language barrier, or any other 
problem not secondary to aphasia are given a 1. 
It is important that only the initial answer be 
graded and that the examiner not "help" the 
patient with verbal or non-verbal cues.  
0 = Answers both questions correctly.  
1 = Answers one question correctly.  
2 = Answers neither question correctly.  
______  
1c. LOC Commands: The patient is asked to 
open and close the eyes and then to grip and 
release the non-paretic hand. Substitute another 
one step command if the hands cannot be used. 
Credit is given if an unequivocal attempt is made 
but not completed due to weakness. If the patient 
does not respond to command, the task should 
be demonstrated to him or her (pantomime), and 
the result scored (i.e., follows none, one or two 
commands). Patients with trauma, amputation, or 
other physical impediments should be given 
suitable one-step commands. Only the first 
attempt is scored.  
0 = Performs both tasks correctly.  
1 = Performs one task correctly.  
2 = Performs neither task correctly.  
______  

 
 
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2. Best Gaze: Only horizontal eye movements 
will 
be 
tested. 
Voluntary 
or 
reflexive 
(oculocephalic) eye movements will be scored, 
but caloric testing is not done. If the patient has a 
conjugate deviation of the eyes that can be 
overcome by voluntary or reflexive activity, the 
score will be 1. If a patient has an isolated 
peripheral nerve paresis (CN III, IV or VI), score 
a 1. Gaze is testable in all aphasic patients. 
Patients with ocular trauma, bandages, pre-
existing blindness, or other disorder of visual 
acuity or fields should be tested with reflexive 
movements, and a choice made by the 
investigator. Establishing eye contact and then 
moving about the patient from side to side will 
occasionally clarify the presence of a partial gaze 
palsy.  
0 = Normal.  
1 = Partial gaze palsy; gaze is abnormal 
in one or both eyes, but forced 
deviation or total gaze paresis is not 
present.  
2 = Forced deviation, or total gaze 
paresis not overcome by the 
oculocephalic maneuver.  
______  
3. Visual: Visual fields (upper and lower 
quadrants) are tested by confrontation, using 
finger counting or visual threat, as appropriate. 
Patients may be encouraged, but if they look at 
the side of the moving fingers appropriately, this 
can be scored as normal. If there is unilateral 
blindness or enucleation, visual fields in the 
remaining eye are scored. Score 1 only if a clear-
cut asymmetry, including quadrantanopia, is 
found. If patient is blind from any cause, score 3. 
Double simultaneous stimulation is performed at 
this point. If there is extinction, patient receives a 
1, and the results are used to respond to item 11.  
0 = No visual loss.  
1 = Partial hemianopia.  
2 = Complete hemianopia.  
3 = Bilateral hemianopia (blind including 
cortical blindness).  
______  
4. Facial Palsy: Ask – or use pantomime to 
encourage – the patient to show teeth or raise 
eyebrows and close eyes. Score symmetry of 
grimace in response to noxious stimuli in the 
poorly responsive or non-comprehending patient. 
If facial trauma/bandages, orotracheal tube, tape 
or other physical barriers obscure the face, these 
should be removed to the extent possible.  
0 = Normal symmetrical movements.  
1 = Minor paralysis (flattened nasolabial 
fold, asymmetry on smiling).  
2 = Partial paralysis (total or near-total 
paralysis of lower face).  
3 = Complete paralysis of one or both 
sides (absence of facial movement in 
the upper and lower face).  
______  
5. Motor Arm: The limb is placed in the 
appropriate position: extend the arms (palms 
down) 90 degrees (if sitting) or 45 degrees (if 
supine). Drift is scored if the arm falls before 10 
seconds. The aphasic patient is encouraged 
using urgency in the voice and pantomime, but 
not noxious stimulation. Each limb is tested in 
turn, beginning with the non-paretic arm. Only in 
the case of amputation or joint fusion at the 
shoulder, the examiner should record the score 
as untestable (UN), and clearly write the 
explanation for this choice.  
0 = No drift; limb holds 90 (or 45) 
degrees for full 10 seconds.  
1 = Drift; limb holds 90 (or 45) degrees, 
but drifts down before full 10 seconds; 
does not hit bed or other support.  
2 = Some effort against gravity; limb 
cannot get to or maintain (if cued) 90 
(or 45) degrees, drifts down to bed, 
but has some effort against gravity.  
3 = No effort against gravity; limb falls.  
4 = No movement.  
UN = Amputation or joint fusion, explain: 
_____________________  
5a. Left Arm  
5b. Right Arm  
______  
______  

 
 
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6. Motor Leg: The limb is placed in the 
appropriate position: hold the leg at 30 degrees 
(always tested supine). Drift is scored if the leg 
falls before 5 seconds. The aphasic patient is 
encouraged using urgency in the voice and 
pantomime, but not noxious stimulation. Each 
limb is tested in turn, beginning with the non-
paretic leg. Only in the case of amputation or 
joint fusion at the hip, the examiner should record 
the score as untestable (UN), and clearly write 
the explanation for this choice.  
0 = No drift; leg holds 30-degree 
position for full 5 seconds.  
1 = Drift; leg falls by the end of the 5-
second period but does not hit bed.  
2 = Some effort against gravity; leg 
falls to bed by 5 seconds, but has 
some effort against gravity.  
3 = No effort against gravity; leg falls to 
bed immediately.  
4 = No movement.  
UN = Amputation or joint fusion, explain: 
________________  
6a. Left Leg  
6b. Right 
______  
______  
7. Limb Ataxia: This item is aimed at finding 
evidence of a unilateral cerebellar lesion. Test 
with eyes open. In case of visual defect, ensure 
testing is done in intact visual field. The finger-
nose-finger and heel-shin tests are performed on 
both sides, and ataxia is scored only if present 
out of proportion to weakness. Ataxia is absent in 
the patient who cannot understand or is 
paralyzed. Only in the case of amputation or joint 
fusion, the examiner should record the score as 
untestable (UN), and clearly write the explanation 
for this choice. In case of blindness, test by 
having the patient touch nose from extended arm 
position.  
0 = Absent.  
1 = Present in one limb.  
2 = Present in two limbs.  
UN = Amputation or joint fusion, explain: 
________________  
______  
8. Sensory: Sensation or grimace to pinprick 
when tested, or withdrawal from noxious stimulus 
in the obtunded or aphasic patient. Only sensory 
loss attributed to stroke is scored as abnormal 
and the examiner should test as many body 
areas (arms [not hands], legs, trunk, face) as 
needed to accurately check for hemisensory loss. 
A score of 2, “severe or total sensory loss,” 
should only be given when a severe or total loss 
of sensation can be clearly demonstrated. 
Stuporous and aphasic patients will, therefore, 
probably score 1 or 0. The patient with brainstem 
stroke who has bilateral loss of sensation is 
scored 2. If the patient does not respond and is 
quadriplegic, score 2. Patients in a coma (item 
1a=3) are automatically given a 2 on this item.  
0 = Normal; no sensory loss.  
1 = Mild-to-moderate sensory loss; 
patient feels pinprick is less sharp or is 
dull on the affected side; or there is a 
loss of superficial pain with pinprick, 
but patient is aware of being touched.  
2 = Severe to total sensory loss; patient 
is not aware of being touched in the 
face, arm, and leg.  
______  

 
 
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9. Best Language: A great deal of information 
about comprehension will be obtained during the 
preceding sections of the examination. For this 
scale item, the patient is asked to describe what 
is happening in the attached picture, to name the 
items on the attached naming sheet and to read 
from 
the 
attached 
list 
of 
sentences. 
Comprehension is judged from responses here, 
as well as to all of the commands in the 
preceding general neurological exam. If visual 
loss interferes with the tests, ask the patient to 
identify objects placed in the hand, repeat, and 
produce speech. The intubated patient should be 
asked to write. The patient in a coma (item 1a=3) 
will automatically score 3 on this item. The 
examiner must choose a score for the patient 
with stupor or limited cooperation, but a score of 
3 should be used only if the patient is mute and 
follows no one-step commands.  
0 = No aphasia; normal.  
1 = Mild-to-moderate aphasia; some 
obvious loss of fluency or facility of 
comprehension, without significant 
limitation on ideas expressed or form 
of expression. Reduction of speech 
and/or comprehension, however, 
makes conversation about provided 
materials difficult or impossible. For 
example, in conversation about 
provided materials, examiner can 
identify picture or naming card content 
from patient‟s response.  
2 = Severe aphasia; all communication is 
through fragmentary expression; great 
need for inference, questioning, and 
guessing by the listener. Range of 
information that can be exchanged is 
limited; listener carries burden of 
communication. Examiner cannot 
identify materials provided from 
patient response.  
3 = Mute, global aphasia; no usable 
speech or auditory comprehension.  
______  
10. Dysarthria: If patient is thought to be normal, 
an adequate sample of speech must be obtained 
by asking patient to read or repeat words from 
the attached list. If the patient has severe 
aphasia, the clarity of articulation of spontaneous 
speech can be rated. Only if the patient is 
intubated or has other physical barriers to 
producing speech, the examiner should record 
the score as untestable (UN), and clearly write an 
explanation for this choice. Do not tell the patient 
why he or she is being tested.  
0 = Normal.  
1 = Mild-to-moderate dysarthria; patient 
slurs at least some words and, at 
worst, can be understood with some 
difficulty.  
2 = Severe dysarthria; patient's speech 
is so slurred as to be unintelligible in 
the absence of or out of proportion to 
any dysphasia, or is mute/anarthric.  
UN = Intubated or other physical barrier, 
explain:________________________  
______  
11. 
Extinction 
and 
Inattention 
(formerly 
Neglect): 
Sufficient 
information 
to 
identify 
neglect may be obtained during the prior testing. 
If the patient has a severe visual loss preventing 
visual double simultaneous stimulation, and the 
cutaneous stimuli are normal, the score is 
normal. If the patient has aphasia but does 
appear to attend to both sides, the score is 
normal. The presence of visual spatial neglect or 
anosagnosia may also be taken as evidence of 
abnormality. Since the abnormality is scored only 
if present, the item is never untestable.  
0 = No abnormality.  
1 = Visual, tactile, auditory, spatial, or 
personal inattention or extinction to 
bilateral simultaneous stimulation in 
one of the sensory modalities.  
2 = Profound hemi-inattention or 
extinction to more than one 
modality; does not recognize own 
hand or orients to only one side of 
space.  
______  
 
 
 

 
 
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Modified Rankin Scale (mRS) Instructions  
Instructions:  
 
The mRS is to be determined after the NIHSS and Barthel Index have been determined 
and graded and by the same rater.  
 
The determination of the scale should be made from 5 to 0, i.e., the order presented.  
 
The purpose of the mRS is to record whether the patient is dead, severely, moderately, 
or slightly disabled and if not dead or disabled, whether the patient is performing all 
usual activities without symptoms or not. Because subjects and family members may 
understate the severity of disability, it is important for the rating clinician to understand 
that the mRS is a clinical scale and not a patient-reported outcome. The rater may ask 
questions but must assess the disability whether or not in agreement with the subject or 
family.  
 
5 Severe disability; someone needs to be available at all times; care may be provided by 
either a trained or an untrained caregiver.  
Question: Does the person require constant care?  
4 Moderately severe disability; need for assistance with some basic ADL, but not requiring 
constant care.  
Question: Is assistance essential for eating, using the toilet, daily hygiene, or walking?  
3 Moderate disability; need for assistance with some instrumental ADL but not basic ADL.  
Question: Is assistance essential for preparing a simple meal, doing household chores, 
looking after money, shopping, or traveling locally?  
2 Slight disability; limitations in participation in usual social roles, but independent for ADL.  
Questions:  
 
Has there been a change in the person‟s ability to work or look after others if these 
were roles before stroke?  
 
Has there been a change in the person‟s ability to participate in previous social and 
leisure activities?  
 
Has the person had problems with relationships or become isolated?  
 
Do any of the following interfere with the subject's ability to perform all usual activities: 
difficulty reading or writing, difficulty speaking or finding the right word, problems with 
balance or coordination, visual problems, numbness (face, arms, legs, hands, feet), 
loss of movement (face, arms, legs, hands, feet), difficulty with swallowing, or other 
symptom resulting from stroke?  
1 No significant disability; symptoms present but not other limitations.  
Question: Does the subject have any symptoms that do not interfere with the performance of 
all usual activities?  
0 No symptoms at all; no limitations and no symptoms.  
Note:  The above questions are a modification of the questions from Wilson, et. al, Stroke. 2002:33:2243-2246 and 
are modified here for the use in percutaneous heart valve trials for the FDA Division of CV Devices.  
 

 
 
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Mini Mental State Exam (MMSE-2) 
Mini Mental Status Exam1:  The MMSE-2 Standard Version should be used.    
 
Procedure: 
Administer the MMSE-2 exam utilizing the standardized worksheets provided. 
 
http://www.minimental.com/ 

 
 
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Additional Neurological Assessments 
Visual Field Testing 
Visual fields, (upper and lower quadrants) are tested by confrontation, using finger counting or 
visual threat as appropriate. 
Visual fields may be impaired by lesions anywhere in the neural visual pathways, from the optic 
nerves to the occipital lobes. 
• 
Individual eyes: 
In direct confrontation, examiner should sit directly in front of the patient, at the same level 
and approximately one meter apart. Ask the patient to cover one eye and maintain a fixed 
gaze on the examiners eye or nose. The examiner brings a small target (e.g. a match or a 
finger) from the periphery of the patient‟s visual field into each of the 4 visual quadrants 
and requests that the patient indicate when they first visualize the object. Wiggling the 
target assists in the patients separating and defining it.  
Repeat the testing for the other eye.  
Any abnormalities in target detection should prompt detailed testing with more precise 
instruments.  
• 
Bilateral eyes:  
In the same position, and with the patients fixed gaze on the examiners nose or eyes, use 
finger counting or visual threat to identify any asymmetry in the visual field.  
 
Gait Assessment 
Not tested as part of the NIH Stroke Scale.  
Ask the patient to walk down a straight hallway under observation, if ambulatory.  
Note any apparent abnormalities of gait. (Ataxic, lateralized hemi-paretic, „shuffling‟ or „small-
step‟ or other abnormality).  
 
Hand Function 
• 
Motor assessment  
The extensors are weaker than the flexors in the upper extremities. Consequently, 
following a neurological event, the arm eventually assumes a flexed position. Therefore 
the biceps will be stronger than the triceps, the wrist and finger flexors stronger than the 
extensors. For this reason it is not a good idea to monitor for stroke progression by testing 
grip strength. Test finger extensor strength instead. 
 
Muscle power is classically graded on a scale of 0 – 5, with 0 being no power and 5 being 
normal power. For the purposes of documenting subtleties in potential deficits, power in 
finger muscle groups should be documented on a 0 – 10 scale as follows.  
Grade 0 
 
No muscle contraction  
Grade 2 
 
Muscle contraction without joint movement 
Grade 4 
 
Partial movement with gravity eliminated 
Grade 6 
 
Movement against gravity 
Grade 8 
 
Movement against some resistance 
Grade 10   
Normal strength 
(Use odd numbers to document when physical findings fall between grades).  

 
 
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• 
Finger Abductors 
Instruct the patient to “Spread your fingers apart, push your index finger towards the other 
hand. Don‟t let me push it back”.  Push on the finger at the Proximal Interphalangeal  
(PIP) joint level.  
• 
Finger Adductors 
Ask patient to „grip a sheet of paper‟ between their fingers. Try to pull the sheet away from 
them.  
• 
Finger Extensors 
Instruct the patient to “Keep your fingers out straight, and don‟t let me bend them”. This is 
a test of extension at the metacarpophalangeal (MCP) joints. It is important to support the 
palm and apply pressure to the PIP joints, testing extension at only one set of joints, 
because extension at the PIP joints is performed by the small hand muscles.  
• 
Sensory Assessment 
In a seated position, ask the patient to place both hands on their lap with palms facing 
down. Instruct them to close their eyes, and using their index finger point to the position 
touched by the examiner on fingers of the opposite hand. Repeat for both hands. 
This should be documented as: „normal sensation‟ or „can feel but unable to localize‟ or 
„no sensation‟ for each hand. 
 
Writing Evaluation 
Ask the patient to write two sentences about a particular subject. (e.g. their hometown). There 
is no time limit, and patient can be given time prior to neurological examination as necessary.  
Note the patient‟s „use of paper‟, including the position of writing. Also, note whether the written 
subject is appropriate to that asked, and the correctness of the grammar, spelling and syntax 
used.  
Document as „fail‟ or „pass‟ or „subject unable to attempt test‟ if patient is unable.  
 
Drawing Assessment 
The „clock-drawing‟ test is used for screening for cognitive impairment and dementia, and as a 
measure of spatial dysfunction and neglect. Doing the test requires verbal understanding, 
memory and spatially coded knowledge in addition to constructive skills.  
Constructional apraxia may occur with lesions in either the left or right parietal lobe, although it 
is more frequent after right parietal damage (visually dominant).  
Clock drawing has been used as a diagnostic measure of unilateral spatial neglect, with neglect 
patients omitting numbers on one half, with or without transposition of the numbers from the 
neglect side to the other, or demonstrating inattention to parts of the spatial layout of numbers.  
The test has a high correlation with the MMSE and other tests of cognitive dysfunction.  
 
Ask patient to draw the face of a clock and put the numbers in the correct position.  
 
Then ask patient to draw in the hands at a particular time (e.g., "twenty minutes after 
eight").  
 
There is no time limit. 
One point will be assigned for each of the following items completed (draws closed circle, 
includes all 12 correct numbers, places numbers in correct positions, places hands in correct 
positions) for a total of four points. 
 

 
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Medtronic CoreValve® Clinical Assessment Guidelines 
Clinical Assessments will be collected to help assess the overall heath and frailty1 of study 
participants at the time of screening. These assessments include measures of nutrition, 
strength and balance, independence in average daily living, mental status, and medical 
comorbidities.   
The following are guidelines provided for administering the strength examination. 
 
Grip strength test2: The grip strength test is used to determine the strength in each of the 
participant‟s hands. 
Procedure: 
1. Equipment: Hand Dynamometer 
2. Illustrate the use of the instrument to the participant prior to testing. 
3. The participant should be in a seated position. 
4. Ask the participant to squeeze the dynamometer with as much force as possible, being 
careful to squeeze only once for each measurement. 
5. Three trials should be made for the right hand followed by three trials for left hand with a 
pause of about 10-20 seconds between each trial to avoid the effects of muscle fatigue. 
6. The highest reading for each hand should be reported on the case report form. 
 
 
1 
 Fried LP et al, (2001). Frailty in older adults: Evidence for a phenotype. Journal of Gerontology: Medical Science , 
56A (3), M146-M156. 
2 
 Luna-Heredia E, Martin-Pena G, Ruiz-Galiana J. Handgrip dynamometry in healthy adults. Clinical Nutrition 2005; 
24:250-258 
 

 
 
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Katz Index of Independence in Activities of Daily Living 
 
Activities 
Points (1 or 0) 
Independence 
(1 POINT) 
NO supervision, direction or 
personal assistance 
 
Dependence 
(0 Points) 
WITH supervision, direction, 
personal assistance or total 
assistance 
BATHING 
 
 
 
Points: __________ 
(1 POINT) Bathes self 
completely or needs help in 
bathing only a single part of 
the body such as the back, 
genital area or disabled 
extremity. 
(0 POINTS) Needs help with 
bathing more than one part of 
the body, getting in or out of 
the tub or shower. Requires 
total bathing. 
DRESSING 
 
 
 
Points: __________ 
(1 POINT) Gets clothes from 
closets and drawers and puts 
on clothes and outer garments 
complete with fasteners. May 
have help tying shoes. 
0 POINTS) Needs help with 
dressing self or needs to be 
completely dressed. 
TOILETING 
 
 
Points: ___________ 
(1 POINT) Goes to toilet, gets 
on and off, arranges clothes, 
cleans genital area without 
help 
(0 POINTS) Needs help 
transferring to the toilet, 
cleaning self or uses bedpan 
or commode. 
TRANSFERRING 
 
 
Points: ___________ 
(1 POINT) Moves in and out of 
bed or chair unassisted. 
Mechanical transferring aides 
are acceptable. 
(0 POINTS) Needs help in 
moving from bed to chair or 
requires a complete transfer. 
CONTINENCE 
 
Points: ___________ 
(1 POINT) Exercises complete 
self-control over urination and 
defecation. 
(0 POINTS) Is partially or 
totally incontinent of bowel or 
bladder. 
FEEDING 
 
 
Points: ____________ 
(1 POINT) Gets food from 
plate into mouth without help. 
Preparation of food may be 
done by another person. 
(0 POINTS) Needs partial or 
total help with feeding or 
requires parenteral feeding. 
 
 
TOTAL POINTS = _________    
6 = High (patient independent) 
0 = Low (patient very dependent) 
 
Slightly adapted from Katz S., Down, T.D., Cash, H.R. et al. (1970) 
Progress in the Development of the Index of ADL. Gerontologist 
10:20-30. Copyright The Gerontological Society of America 
 

 
 
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Investigator Brochure / Report of Prior Investigations for the 
Medtronic CoreValve® System 
The geography-specific Instructions for Use and Investigator Brochure will be provided 
separately, as applicable. 
 

 
 
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SURTAVI Risk Model 
Risk assessment is essential in the strategy to approach patients with valvular heart disease in 
general and AS in particular. Various risk models primarily focusing on short-term mortality 
have been validated for AS patients (30-38). Some were initially derived from a broader patient 
population undergoing any type of cardiac surgery, others were more explicitly tailored to 
patients with AS. Most notably, contemporary scoring models tend to be consistent in lower risk 
patients but diverge with increasing risk profile. This can be partly explained by the fact that 
these models were extracted from large databases where the average patient risk is fairly low. 
Therefore such models are less well validated for higher risk patients and expectedly perform 
less well in the “outlier” population currently considered for TAVI (39).  
An in-depth reappraisal of existing scoring models reveals some concordant risk factors  (e.g. 
age, gender) but also established risk factors that are clearly missing (e.g. mediastinal 
radiation, porcelain aorta and frailty) (40-42). Furthermore definitions of individual components 
are not uniform and do not correspond to current suggested guidelines/definitions by respective 
professional societies.  
R.22.1  
SURTAVI Risk Model Rationale 
1.   Joint database 
Following the initial report by the Bern, Rotterdam collaboration (28) including 1122 patients 
with severe AS, four academic institutions in Bern, Rotterdam, Bad Nauheim and Munich 
have created a joint database on all consecutive patients with severe AS treated with either 
TAVI or SAVR between January 2006 and December 2009. 
Preliminary analysis on 3688 patients has been performed, including 789 TAVI and 2899 
SAVR patients.  
The pre-specified primary outcome was all cause mortality at 1 year. Patients were actively 
followed up after the index procedure and their vital status confirmed by outpatient clinic 
visit, telephone contact, review of medical records or national civil registries. 
2.   Statistical methods 
The propensity scores of SAVR patients were estimated using a probit model with all 
baseline characteristics as described above as independent variables. The propensity score 
is the probability that a patient would have been treated with SAVR given that patient's 
observed baseline characteristics. To ensure the quality of the matching using propensity 
scores the common support assumption was applied, using the Epanechnikov kernel 
probability density estimates. The IPT weighted multivariable analysis was used. The IPT 
weighted analyses used the inverse of the propensity score as weights in SAVR patients 
and the inverse of 1 minus the propensity score in TAVI patients. All analyses were based 
on logistic regression models on the 1 year mortality and were performed in the overall 
dataset and stratified according to presence or absence of sufficient overlap of propensity 
scores (propensity score <0.675 versus ≥0.675). 
3.   Type of patient (patient selection) 
Preliminary analysis demonstrated a pre-dominance of patients with age >80 years old, and 
a logistic EuroSCORE <20% in the TAVI cohort (figure “scatterplot”). However, the majority 
of patients in the entire study population are between 65-and 83-years-old (figure “age 
distribution”). See also appendix L.2 
 

 
 
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Survival curves of the general Dutch 
population 
(derived 
from 
death 
register); and patients undergoing an 
AVR 
(derived 
from 
meta-analysis 
data), or an AVR with the additional 
risk 
factor 
of 
coronary 
sclerosis 
(derived from meta-analysis data). 
 
The range of both the EuroSCORE and STS 
score in a patient with 2 risk factors. The lower 
boundary indicates a score with risk factors that 
have little influence on the score, while the upper 
boundary indicates a score with risk factors that 
influence the score significantly 
 
 
 
 
 
 
 
 
 
 
 
 
As it is well-known that both the STS score and EuroSCORE are suboptimal in operative risk 
assessment, these models are only used for descriptive purposes (39). Age is the predominant 
predictor of mortality in general, and after valve surgery in particular. Furthermore, the impact of 
other risk factors appears to be accentuated in an older age population.  
 
 
The distribution of age in patients treated for 
aortic stenosis. The color indicates the 
percentage of patients treated with TAVI in the 
corresponding age group 
A scatterplot showing the age and corresponding 
EuroSCORE of patients treated for aortic stenosis. 
Indicated by colours are the treatment arms surgical 
aortic valve replacement and transcatheter aortic 
valve implantation. A previous commonly used 
EuroSCORE cut-off value of 20% is indicated in the 
graphic to show that many patients with lower scores 
are already treated by TAVI, but in lower ages this 
treatment 
remains 
limited 
due 
to 
the 
low 
EuroSCORE. 

 
 
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Therefore, we opt for a risk assessment based on age in combination with encoded co-
morbidities selected from a pre-specified listing. Patients at intermediate risk are defined as age 
70-74 years with 2 or 3 co-morbidities (cohort 1); age 75-79 years with 1 or 2 co-morbidities 
(cohort 2); and patients ≥80 years of age with ≤1 co-morbidities (cohort 3). 
In-depth analysis and translation of the risk profile mentioned above to the STS score (table 
STS below):  
 
Cohort 1: range of 0.9% to 10.2% in males, and 1.4% to 14.8% in females 
 
Cohort 2: range of 1.2% to 8.5% in males, and 1.8% to 12.4% in females 
 
Cohort 3*: range of 1.7% to 8.9% in males, and 2.6% to 12.7% in females 
 
 
STS score: ranges of scores are displayed as: score with least influential risk factors – score with most influential risk 
factors. *Upper age limit 91 years old 
 
In-depth analysis and translation of the risk profile mentioned above to the logistic EuroSCORE 
(Table EuroSCORE below):  
 
Cohort 1: range of 9.1% to 42.3% in males, and 12.2% to 50.5% in females 
 
Cohort 2: range of 7.2% to 32.1% in males, and 9.8% to 39.6% in females 
 
Cohort 3*: range of 6.6% to 27.8% in males, and 9.0% to 34.9% in females 
 
 
Euroscore: ranges of scores are displayed as: score with least influential risk factors – score with most influential risk 
factors. *Upper age limit 91 years old 
 
4.   Comparative patient outcome 
One-year mortality amounts to 30% in the overall high-risk matched population with a 
logistic EuroSCORE of 15.8%. The hazard ratio of propensity matched patients between 
SAVR and TAVI is 0.97. This suggests equipoise for both treatment strategies and is the 
legitimation for a randomized trial in this intermediate risk AS population. 
 

 
 
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R.22.2  
SURTAVI co-morbidity list  
 
Methodology for identifying enlisted co-morbidities: 
We first identified those components recurring in the previously published scoring models and 
looked for updated definitions by international professional societies. We then added missing 
risk factors, identified in the literature, which we felt, were essential. In addition, there exists an 
„open box‟ to capture less prevalent and unanticipated risk factors (e.g. liver failure, mediastinal 
radiation, porcelain aorta, etc.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The above risk factors will guide the Heart Team in the selection of the treatment options but 
will not dictate patient allocation. The final decision treatment will be done by the local Heart 
Team.   
1. Significant concomitant Coronary Artery Disease: defined as ≥70% stenosis by invasive 
coronary angiography because the combination of revascularization and aortic valve 
replacement reduces the rates of perioperative MI, perioperative mortality, late mortality 
and morbidity when compared with patients not undergoing simultaneous 
revascularization (ACC/AHA/ESC class IC recommendation)(6, 43, 44). Previous CABG 
or PCI is not considered to have considerable impact on short term outcome.  
2. Frailty: in the absence of a generally accepted consensus definition Frailty is defined as 
suggested by Lee and co-workers by the presence of any 1 of the following(40):  
a. 
Katz score(independence in Activities of Daily Living);  
b. 
Ambulation (walking aid/assist?);  
c. 
Diagnosis of (pre-)dementia. 
3. Left Ventricular dysfunction: defined as EF < 35%, with respect to the pivotal position of 
this particular threshold in the heart failure population (45). 
4. Neurological dysfunction: Cerebro-Vascular Disease, documented by any one of the 
following: CVA (symptoms lasting >24 hours or imaging of an acute clinically relevant 
brain lesion in patients with rapidly vanishing symptoms); TIA (brief episode of 
neurological dysfunction caused by a focal disturbance of brain or retinal ischemia, with 
clinical symptoms with recovery within 24 hrs and without evidence of infarction); Non-
invasive carotid test with > 60% diameter occlusion or prior carotid surgery or 
symptomatic carotid stenosis > 50%(46-49). Does not include neurological disease 
processes such as metabolic and/or anoxic ischemic encephalopathy. 
70 yrs of age 
and 2 or 3 risk factors 
75 yrs of age 
and 1 or 2 risk factors 
80 yrs of age 
And 0 or 1 risk factors 
Risk factors: 
 
 
Coronary artery disease requiring revascularization 
 
Frailty  
 
Left Ventricular dysfunction (EF <35%) 
 
Neurological dysfunction (with functional impairment) 
 
Pulmonary disease (Gold stage II)  
 
Peripheral vascular disease  
 
Renal disease (KDOQI Stage III) 
 
Redo cardiac surgery 
 
Pulmonary hypertension (syst PAP 60 mmHg at most recent measurement) 
 
Diabetes (R/ oral meds or insulin) 
 
„Open Box‟ capturing less prevalent risk factors (e.g. liver failure, mediastinal 
radiation, porcelain aorta, etc.) 

 
 
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5. Pulmonary disease: COPD Gold Stage II: moderate COPD with worsening airflow 
limitation (FEV1/FVC <70%; 50% ≥ FEV1 <80% predicted), with shortness of breath 
typically developing on exertion(50). 
6. Peripheral vascular disease: adapted from the STS risk model: Claudication, either with 
exertion or at rest; Amputation for arterial vascular insufficiency; Vascular reconstruction, 
bypass surgery, or percutaneous intervention to the extremities; Documented aortic 
aneurysm with or without repair; Positive non-invasive 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) 
7.  Renal disease: at least moderate chronic kidney disease with GFR < 60 mL/min 
according to the National Kidney Foundation kidney disease outcome quality initiative 
advisory board(51). 
8. Redo cardiac surgery 
9. Pulmonary hypertension (> 60mmHg at most recent measurement) 
10. Diabetes Mellitus on oral or insulin therapy. 
11. OPEN BOX: e.g., extensive mediastinal radiation, chest wall deformity, Liver Failure 
Child-C 
 
 
 

 
 
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Patients available for screening 
 
All patients 
0
1
2
3
4
≥5
Total cases
<60
107
85
17
11
1
1
222
60-64
47
37
15
8
0
0
107
65-69
57
53
24
10
5
0
149
70-74
60
66
47
10
5
4
192
75-79
64
89
38
20
5
2
218
≥80
46
53
43
35
6
11
194
1082
SAVR
668/1082 61.7%
Random --> TAVI / SAVR
283/1082 26.2%
Too high risk
131/1082 12.1%
Comorbidities (n)
Age (yrs)
 
 
 
SAVR patients 
 
0
1
2
3
4
≥5
Total cases
<60
106
84
17
11
0
0
218
60-64
47
37
14
6
0
0
104
65-69
57
52
23
8
3
0
143
70-74
59
65
44
5
4
0
177
75-79
60
83
33
14
1
0
191
≥80
36
32
15
3
0
0
86
919
SAVR
649/919 70.6%
Random --> TAVI / SAVR
233/919 25.4%
Too high risk
37/919
4.0%
Comorbidities (n)
Age (yrs)

 
 
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TAVI patients 
 
0
1
2
3
4
≥5
Total Cases
≤ 60
1
1
0
0
1
1
4
60-64
0
0
1
2
0
0
3
65-69
0
1
1
2
2
0
6
70-74
1
1
3
5
1
4
15
75-79
4
6
5
6
4
2
27
≥ 80
10
21
28
32
6
11
108
163
SAVR
19/163 
11.7%
Random --> TAVI / SAVR
50/163
30.7%
Too high risk
94/163 
57.7%
Age (yrs)
Comorbidities (n)
 
 
 
 
 
 
Distribution of age and comorbidities in patients with severe aortic stenosis in the Rotterdam practice. In each age 
group, patients are divided by the total number of comorbidities as previously defined. 
Indicated in green are the patients that are too low risk for randomization (62%). Indicated by orange are patients 
that will be randomized in SURTAVI (26%). In blue are patients too high risk for randomization (12%). Therefore, it 
is estimated that every 1 in 4 patients meets the inclusion criteria for screening. 

 
 
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STS versus Euro Score 
This table illustrates the relative impact of common co-morbidities in STS score (vertical axis) 
and Euroscore (horizontal axis) risk model. This present panel relates specifically of a male 
patient of 70 years old with 0, 1 or 2 risk factors.  
The black line separates the score values of the two respective models: below the line relates 
to STS score, above to Euroscore. 
The empty boxes indicate that the specific risk factor is not accounted for in the risk model, e.g. 
diabetes in Euroscore. 
If this patient has no co-morbidity he would have an STS score of 0.9 and a Euroscore of 3 (see 
first square in upper left corner). 
If this patient has a poor LVEF combined with peripheral vascular disease he would have a 
STS score of 1.5 and Euroscore of 15.5 
Redo surgery is displayed as “first reoperation / second reoperation”, and COPD as “moderate / 
severe”. Values indicated as “score - score” correspond to the range of scores possible when 
combining all 4 risk factors (for instance „moderate COPD + 1st redo‟ - „severe COPD + 2nd 
redo‟) 
DM = diabetes mellitus; PVD = peripheral vascular disease; CVD = cerebrovascular disease; 
LVEF = left ventricular ejection fraction; CAD = coronary artery disease; NYHA = New York 
Heart Association; COPD = chronic obstructive pulmonary disease; PH = pulmonary 
hypertension 
 
 
EUROSCORE 
  
None 
DM 
PVD 
CVD 
Poor 
LVEF 
CAD  
NYHA    
III / IV 
Redo 
Surgery 
Renal 
Failure 
COPD 
Dialysis 
PH 
Neurologic 
Dysfunction 
None 
0.9↓  3.0→ 
… 
5.8 
… 
8.7 
… 
… 
8.0 
5.8 
5.0 
… 
6.4 
6.9 
DM 
1.2 
  
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
PVD 
1.2 
1.5 
  
… 
15.5 
… 
… 
14.3 
10.5 
9.1 
… 
11.7 
12.5 
CVD 
0.9 
1.2 
1.2 
  
… 
… 
… 
… 
… 
… 
… 
… 
… 
Poor LVEF 
1.2 
1.5 
1.5 
1.2 
  
… 
… 
20.6 
15.4 
13.5 
… 
17.0 
18.1 
CAD 
0.9 
1.2 
1.2 
0.9 
1.2 
  
… 
… 
… 
… 
… 
… 
… 
NYHA III / IV 
0.9 / 1.3 
1.2 / 1.7 1.2 / 1.6 0.9 / 1.3 1.2 / 1.7 0.9 / 1.3 
  
… 
… 
… 
… 
… 
… 
Redo Surgery 
1.5 / 1.8 
1.9 / 2.2 1.9 / 2.2 1.5 / 1.8 2.0 / 2.3 1.5 / 1.8 1.5 - 2.5 
  
14.3 
12.4 
… 
15.7 
16.8 
Renal Failure 
1.8 
2.3 
2.2 
1.8 
2.3 
1.8 
1.8 / 2.5 2.9 / 3.4 
  
9.1 
… 
11.6 
12.4 
COPD 
1.5 / 1.9 
1.9 / 2.4 1.9 / 2.4 1.5 / 1.9 2.0 / 2.5 1.5 / 1.9 1.5 - 2.7 2.9 / 3.6 2.9 / 3.6 
  
… 
10.1 
10.8 
Dialysis 
2.9 
3.6 
3.5 
2.9 
3.7 
2.9 
2.9 / 4.0 4.6 / 5.3 
2.9 
4.5 / 5.7 
  
… 
… 
PH 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
  
13.7 
STS SCORE 
Neurologic Dysfunction 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
… 
  
 
 

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SURTAVI 
SUrgical Replacement and Transcatheter Aortic 
Valve Implantation 
 
 
Clinical Investigation Plan 
 
 
VERSION 12.0  
31 May 2016 
  
 
Sponsor: 
Medtronic, Inc. 
Clinical Research 
Mailstop: MVS66 
Mounds View South 
8200 Coral Sea St NE 
Mounds View, MN 55112 USA 
Medtronic Bakken Research Center 
Coronary and Structural Heart Department
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
 
 

 
 
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Contact Information Details* 
Study Chair 
Prof. Patrick W. Serruys, MD, PhD (Study Chair) 
Professor of Medicine 
Erasmus Medical Center 
Dept. of Interventional Cardiology, Thoraxcenter P.O. 
Box 21253000 CC Rotterdam, The Netherlands 
Dr. Nicolas M. Van Mieghem, MD, PhD (Deputy Study 
Chair) 
Interventional Cardiologist 
Erasmus Medical Center 
Dept. of Interventional Cardiology, Thoraxcenter Room 
BD 171 
's Gravendijkwal 230 
3015 CE Rotterdam, The Netherlands 
Principal Investigators 
Prof. Stephan Windecker, MD, PhD 
Head of Interventional Cardiology 
Bern University Hospital 
Department of Cardiology 
Swiss Cardiovascular Center Bern  
Freiburgstrasse 4  
CH-3010 Bern, Switzerland 
Prof. A. Pieter Kappetein, MD, PhD 
Cardio-Thoracic Surgeon 
Erasmus Medical Center  
Dept. of Thoracic Surgery  
Room BD 569  
's Gravendijkwal 230 
3015 CE Rotterdam, The Netherlands 
 
Prof. Rüdiger Lange, MD, PhD 
Direktor der Klinik für Herz- und Gefäßchirurgie 
Deutsches Herzzentrum München 
Lazarettstr. 36 
80636 München, Germany  
 
Prof. Thomas Walther, MD, PhD 
Direktor der Abteilung Herzchirurgie 
Kerckhoff-Klinik 
Benekestr. 2-8 
61231 Bad Nauheim; Germany 
Dr. Jeffrey J. Popma, MD 
Director, Interventional Cardiology 
Beth Israel Deaconess Medical Center 
185 Pilgrim Rd.  
Boston, MA 02215 USA 
Dr. Michael J. Reardon, MD 
Professor, Cardiothoracic Surgery 
The Methodist Hospital 
6550 Fannin St., Suite 1401 
Houston, TX 77030  USA 
Dr. David H. Adams, MD 
Marie-Josée and Henry R. Kravis Professor and 
Chairman 
Department of Cardiothoracic Surgery 
The Mount Sinai Medical Center 
1190 Fifth Avenue 
New York, NY 10029  USA 
 
 
 

 
 
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Trial Oversight 
Mike Boulware 
Clinical Research Manager 
Medtronic Coronary and Structural Heart 
Phone: (763) 514.9826 
Email: mike.j.boulware@medtronic.com 
 
Maarten Hollander – EU  
Clinical Research Manager 
Medtronic Bakken Research Center 
Phone: (+31-43) 3566864 
Email: maarten.hollander@medtronic.com 
 
Sponsor 
 
 
 
Medtronic, Inc. 
Clinical Research 
Mailstop: MVS66 
Mounds View South 
8200 Coral Sea Street NE 
Mounds View, MN 
55112 USA 
 
Medtronic Bakken Research Center  
Coronary and Structural Heart Department 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
Randomization System 
 
Randomization (IXRS) information will be provided 
in the investigator site file 
 
* Updated contact information will be provided as applicable.  Additional information regarding 
contacts listed above available upon request. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL and PROPRIETARY 
This document contains confidential information and is solely the property of Medtronic, Inc.  Acceptance of 
this document constitutes an agreement by the recipient that no unpublished information contained herein will 
be published or disclosed without the prior written approval of Medtronic, Inc.  This document may be 
disclosed to the appropriate Institutional Review Board (IRB)/Ethics Committee (EC) with the stipulation that 
the IRB/EC treats the information contained herein as the confidential property of Medtronic, Inc. 

 
 
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TABLE OF CONTENTS 
A 
SYNOPSIS ........................................................................................................... 8 
B 
PURPOSE .......................................................................................................... 15 
B.1 
Background ..................................................................................................................... 15 
B.2 
Investigational Devices and Intended Use ....................................................................... 17 
  Device Description ................................................................................................ 17 
B.2.1
B.2.1.1 
Medtronic CoreValve™ System .............................................................. 17 
B.2.1.2 
Medtronic CoreValve™ Evolut R™ System ........................................... 17 
  Device Approval Status ......................................................................................... 19 
B.2.2
B.2.2.1 
European Union ..................................................................................... 19 
B.2.2.2 
United States ......................................................................................... 20 
B.2.2.3 
Canada .................................................................................................. 20 
  Intended Use of the Device / Indications for Use ................................................... 20 
B.2.3
B.3 
Trial Objectives ............................................................................................................... 21 
  Primary .................................................................................................................. 21 
B.3.1
  Secondary ............................................................................................................. 21 
B.3.2
  Exploratory ............................................................................................................ 21 
B.3.3
C 
TRIAL PROTOCOL ............................................................................................ 22 
C.1 
Ethics and Regulatory Compliance ................................................................................. 22 
  Applicable Regulations .......................................................................................... 22 
C.1.1
  Institutional Review Board (IRB)/Medical Ethics Committee (MEC) ...................... 22 
C.1.2
  Regulatory Submission ......................................................................................... 22 
C.1.3
  Ethical Conduct of the Trial ................................................................................... 23 
C.1.4
C.2 
Trial Administration .......................................................................................................... 23 
  Steering Committee .............................................................................................. 23 
C.2.1
  Publication Committee .......................................................................................... 23 
C.2.2
C.3 
Methodology .................................................................................................................... 24 
  Purpose ................................................................................................................. 24 
C.3.1
  Patient Population ................................................................................................. 24 
C.3.2
  Design ................................................................................................................... 24 
C.3.3
  Investigational Centers .......................................................................................... 24 
C.3.4
  Number of Subjects ............................................................................................... 25 
C.3.5
  Inclusion/Exclusion Criteria ................................................................................... 25 
C.3.6
C.3.6.1 
Inclusion Criteria .................................................................................... 25 
C.3.6.2 
Exclusion Criteria ................................................................................... 25 
  Informed Consent .................................................................................................. 28 
C.3.7
  Revisions in Patient Information and Informed Consent Form ............................... 28 
C.3.8
  Enrollment Flowchart for Randomization to TAVI or SAVR ................................... 29 
C.3.9
 
Trial Training ..................................................................................................... 29 
C.3.10
C.4 
Trial Procedures .............................................................................................................. 30 
  Screening Procedures ........................................................................................... 30 
C.4.1
  Heart Team Procedures ........................................................................................ 32 
C.4.2
C.4.2.1 
Heart Team Composition ....................................................................... 32 
C.4.2.2 
Heart Team Review and Decision .......................................................... 32 
  Screening Committee ............................................................................................ 33 
C.4.3
  Roll-in Subjects ..................................................................................................... 33 
C.4.4
  Enrollment and Randomization ............................................................................. 33 
C.4.5
  Baseline Assessments .......................................................................................... 35 
C.4.6

 
 
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  Transcatheter Aortic Valve Implant or Surgical Aortic Valve Replacement 
C.4.7
Procedure ............................................................................................................. 36 
C.4.7.1 
TAVI ....................................................................................................... 36 
C.4.7.2 
Surgical Aortic Valve Replacement ........................................................ 43 
  Assessments done at discharge (both SAVR and TAVI) ....................................... 47 
C.4.8
  Follow-Up Evaluations ........................................................................................... 48 
C.4.9
C.4.9.1 
30 Days ................................................................................................. 48 
C.4.9.2 
3 Months ................................................................................................ 49 
C.4.9.3 
6 Months ................................................................................................ 49 
C.4.9.4 
12 Months .............................................................................................. 49 
C.4.9.5 
18 Months .............................................................................................. 50 
C.4.9.6 
24 Months .............................................................................................. 50 
C.4.9.7 
3-5 Years ............................................................................................... 50 
 
Echo Assessment ............................................................................................. 51 
C.4.10
 
Neurologic Assessment .................................................................................... 51 
C.4.11
 
Angiographic and Computed Tomography Assessment ................................... 52 
C.4.12
 
Data Collection ................................................................................................. 53 
C.4.13
 
Unscheduled Follow-up Assessments .............................................................. 55 
C.4.14
 
Missed Follow-up Visits .................................................................................... 55 
C.4.15
 
Investigational Product Accountability ............................................................... 55 
C.4.16
 
Device Malfunction or Explant ........................................................................... 55 
C.4.17
 
Protocol Deviations ........................................................................................... 56 
C.4.18
 
Subject Withdrawal or Discontinuation .............................................................. 57 
C.4.19
 
Termination or Discontinuation of Trial .............................................................. 57 
C.4.20
C.5 
Adverse Events ............................................................................................................... 58 
  Definitions ............................................................................................................. 58 
C.5.1
C.5.1.1 
Adverse Event ....................................................................................... 58 
C.5.1.2 
Serious Adverse Event .......................................................................... 58 
C.5.1.3 
Major Adverse Cardiovascular and Cerebrovascular Events ................. 58 
C.5.1.4 
Major Adverse Event .............................................................................. 59 
C.5.1.5 
Adverse Device Effect (ADE) or Device-Related Adverse Event ............ 59 
C.5.1.6 
Serious Adverse Device Effects (SADEs) .............................................. 59 
C.5.1.7 
Unanticipated Adverse Device Effect (UADE) ........................................ 59 
C.5.1.8 
Unanticipated Serious Adverse Device Effect (USADE) ........................ 60 
C.5.1.9 
Device Deficiency .................................................................................. 60 
C.5.1.10 
Technical Observation ......................................................................... 60 
  Reporting .............................................................................................................. 60 
C.5.2
C.5.2.1 
Serious Adverse Events (SAEs) ............................................................ 60 
C.5.2.2 
Serious Adverse Device Effects ............................................................. 61 
C.5.2.3 
Unanticipated Adverse Device Effects (UADE or USADE) ..................... 61 
C.5.2.4 
Device Deficiencies and Technical Observations ................................... 61 
C.5.2.5 
All Other Adverse Events ....................................................................... 61 
C.5.2.6 
Anticipated Adverse Events ................................................................... 61 
C.5.2.7 
Deaths ................................................................................................... 63 
C.5.2.8 
Vigilance Reporting ................................................................................ 63 
  Clinical Events Committee (CEC) .......................................................................... 63 
C.5.3
  Data Safety Monitoring Board (DSMB) .................................................................. 63 
C.5.4
C.6 
Statistical Methods and Analysis ..................................................................................... 65 
  Statistical Considerations and Analysis ................................................................. 65 
C.6.1
  Reports ................................................................................................................. 65 
C.6.2

 
 
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  Description of Baseline Variables .......................................................................... 65 
C.6.3
  Analysis Populations ............................................................................................. 65 
C.6.4
C.6.4.1 
Screening Population ............................................................................. 65 
C.6.4.2 
Randomized Population ......................................................................... 65 
  Primary Analysis ................................................................................................... 66 
C.6.5
C.6.5.1 
Hypothesis of Non-inferiority .................................................................. 66 
C.6.5.2 
Randomization, Sample Size and Analysis Plan .................................... 66 
  Missing Data and Planned Sensitivity Analyses (Primary Objective) ..................... 67 
C.6.6
  Description of Performed Analysis, per population ................................................ 67 
C.6.7
C.6.7.1 
Analysis of Screening Population ........................................................... 67 
C.6.7.2 
Analysis of ITT and mITT Populations ................................................... 67 
C.6.7.3 
Analysis of Implanted Population ........................................................... 68 
  Secondary Endpoints ............................................................................................ 69 
C.6.8
C.6.8.1 
Secondary Endpoints Compared Between TAVI and SAVR .................. 69 
C.6.8.2 
Secondary Endpoints Assessed for TAVI Only ...................................... 73 
  Rationale for Selection of Trial Endpoints .............................................................. 73 
C.6.9
 
Multiplicity Considerations ................................................................................. 73 
C.6.10
C.6.10.1 
Secondary Endpoints Tested to Support Labeling Claims ................... 74 
 
Heterogeneity/Poolability .................................................................................. 77 
C.6.11
 
Additional Analysis ............................................................................................ 77 
C.6.12
C.6.12.1 
Pre-Defined Subgroups ....................................................................... 77 
C.6.12.2 
Analysis of VARC Endpoints and Definitions ....................................... 77 
 
Health-Related Quality of Life (HRQoL) and Treatment Costs .......................... 78 
C.6.13
C.6.13.1 
Quality of Life ....................................................................................... 78 
C.6.13.2 
Economic Outcomes/Cost-Effectiveness ............................................. 78 
 
Use of Data for CE Mark ................................................................................... 78 
C.6.14
C.7 
Data and Quality Management ........................................................................................ 79 
  Electronic Data Capture ........................................................................................ 79 
C.7.1
  Data Collection ...................................................................................................... 79 
C.7.2
  Core Laboratories Procedures .............................................................................. 79 
C.7.3
  Source Documents ................................................................................................ 79 
C.7.4
  Maintenance and Calibration ................................................................................. 79 
C.7.5
C.8 
Records and Reports ...................................................................................................... 80 
  Responsibilities of the Sponsor ............................................................................. 80 
C.8.1
  Responsibilities of the Investigator ........................................................................ 81 
C.8.2
D 
RISK / BENEFIT ANALYSIS ............................................................................. 83 
D.1 
Methods to Minimize Risk ............................................................................................... 84 
D.2 
Potential Benefits ............................................................................................................ 84 
E 
DESCRIPTION OF MEDTRONIC COREVALVE™ SYSTEMS .......................... 85 
E.1 
Investigational Product Description ................................................................................. 85 
  Medtronic CoreValve System ................................................................................ 85 
E.1.1
  Medtronic CoreValve Evolut R System ................................................................. 88 
E.1.2
E.2 
Investigational Device Ordering, Storage, and Disposition .............................................. 91 
F 
MONITORING AND AUDITING ......................................................................... 92 
F.1 
Monitoring ....................................................................................................................... 92 
F.2 
Auditing ........................................................................................................................... 92 
G 
LABELING ......................................................................................................... 93 
H 
CONSENT MATERIALS .................................................................................... 93 
I 
IRB/MEC INFORMATION .................................................................................. 93 

 
 
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J 
OTHER INSTITUTIONS ..................................................................................... 93 
K 
ADDITIONAL RECORDS AND REPORTS ....................................................... 93 
L 
REPORT OF PRIOR INVESTIGATIONS ........................................................... 93 
M 
PUBLICATION POLICY ..................................................................................... 94 
N 
AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN ......................... 95 
O 
ABBREVIATIONS AND DEFINITIONS ............................................................. 97 
O.1 
List of Abbreviations ........................................................................................................ 97 
O.2 
Definitions of Terms ...................................................................................................... 100 
P 
TRIAL MANAGEMENT .................................................................................... 117 
P.1 
Miscellaneous ............................................................................................................... 117 
  Insurance ............................................................................................................ 117 
P.1.1
  Reimbursement ................................................................................................... 117 
P.1.2
  Indemnification .................................................................................................... 117 
P.1.3
  Subject confidentiality.......................................................................................... 117 
P.1.4
Q 
REFERENCES ................................................................................................. 118 
R 
APPENDICIES ................................................................................................. 122 
  
R.1 
Sample Informed Consent 
R.2 
List of Participating Investigational Centers 
R.3 
Other Institutions 
R.4 
Additional Records and Reports 
R.5 
Sample Case Report Forms 
R.6 
Aortogram Acquisition Guidelines 
R.7 
Echocardiography Acquisition Guidelines 
R.8 
Electrocardiogram (ECG) Submission 
R.9 
Computed Tomography (CT) Angiography Acquisition Guidelines 
R.10 Interactive Voice/Web Response System (IXRS)  
R.11 Explanted Device/Pathology and Return Procedures 
R.12 Economic and Quality of Life Data Collection 
R.13 Pacing Guidelines 
R.14 Six Minute Walk Test Instructions 
R.15 National Institute of Health Stroke Scale (NIHSS) 
R.16 Modified Rankin Scale (mRS) Instructions 
R.17 Mini Mental State Exam (MMSE-2:SV) 
R.18 Additional Neurological Assessments 
R.19 Medtronic CoreValve™ Clinical Assessment Guidelines 
R.20 Katz Index of Independence in Activities of Daily Living 
R.21 Investigator Brochure / Report of Prior Investigations 
R.22 Instuctions For Use 
R.23 Radiation Exposure and Data Collection 
R.24 SURTAVI Risk Model 
R.25 CMS Requirements for Coverage and Reimbursement – US ONLY 
 
 

 
 
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A SYNOPSIS 
Title of Trial: 
Surgical Replacement and Transcatheter Aortic Valve 
Implantation (SURTAVI) 
Name of Product: 
Medtronic CoreValve™ System and CoreValve™ 
Evolut™ R System 
Purpose: 
The purpose of this trial is to investigate the safety and 
efficacy of transcatheter aortic valve implantation 
(TAVI) in patients with severe, symptomatic Aortic 
Stenosis (AS) at intermediate surgical risk by 
randomizing patients to either Surgical Aortic Valve 
Replacement (SAVR) or TAVI.  
Design: 
Subjects will be randomized on a 1:1 basis to either 
transcatheter aortic valve implant (TAVI)or to surgical 
aortic valve replacement (SAVR) 
Primary Objective: 
The primary objective of this trial is to evaluate in a 
prospective randomized fashion whether TAVI is non-
inferior to SAVR with respect to composite endpoint of 
all-cause mortality and disabling stroke at 24 months in 
patients with symptomatic severe aortic stenosis and at 
intermediate surgical risk. 
Secondary Objective: 
The secondary objective of this trial is to assess 
differences in quality of life, clinical benefit (efficacy 
endpoints) and health economics in patients with 
symptomatic severe aortic stenosis and at intermediate 
risk treated with either Transcatheter Aortic Valve 
Implantation (TAVI) or Surgical Aortic Valve 
Replacement (SAVR). 
Exploratory Objective: 
An analysis will be conducted to determine if patients 
can be identified as intermediate risk for Transcatheter 
Aortic Valve Implantation (TAVI) based upon age and 
the presence of a defined list of co-morbidities 
commonly associated with patients undergoing TAVI 
procedures.   
Primary Endpoint: 
All-cause mortality or disabling stroke at 24 months 
Secondary Endpoints: 
The following secondary endpoints will be 
compared between TAVI and SAVR subjects 
cohorts: 
1. Incidence of Major Adverse Cardiovascular and 
Cerebrovascular Events (MACCE)- at 30 days, 6 
months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years.  MACCE is 
defined as a composite of: 
 All-cause death 
 Myocardial infarction (MI) 
 All stroke, and 
 Reintervention (defined as any cardiac surgery 
or percutaneous reintervention catheter 
procedure that repairs, otherwise alters or 
adjusts, or replaces a previously implanted 
valve) 
2. The occurrence of individual MACCE components 
at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
3. Major Adverse Events (MAE) and individual 
components at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 

 
 
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years. 
4. Incidence of Early safety at 30 days defined as a 
composite of: 
 All-cause mortality 
 All stroke (disabling and non-disabling) 
 Life-threatening bleeding 
 Acute kidney injury—Stage 2 or 3 (including 
renal replacement therapy)  
 Coronary artery obstruction requiring 
intervention 
 Major vascular complication 
 Valve-related dysfunction requiring repeat 
procedure (BAV, TAVI, or SAVR) 
 All-cause death 
Early safety composite endpoint-incidence 
estimates will be provided for the two treatment 
groups at 30 days. 
5. Incidence of Clinical Efficacy (after 30 days) at 6 
months, 12 months, 18 months, 24 months and 
annually thereafter up to 5 years. Clinical efficacy 
defined as a composite of: 
 All-cause mortality 
 All stroke (disabling and non-disabling) 
 Requiring hospitalizations for valve-related 
symptoms or worsening congestive heart failure 
 NYHA class III or IV 
 Valve-related dysfunction (mean aortic valve 
gradient ≥20 mmHg, effective orifice area (EOA) 
≤ 0.9-1.1 cm2 and/or doppler velocity index 
(DVI) < 0.35 m/s, AND/OR moderate or severe 
prosthetic valve regurgitation) 
Clinical efficacy estimates will be provided for the 
two treatment groups at 6 months, 12 months, 18 
months, 24 months and annually thereafter up to 5 
years. 
6. Incidence of Time-Related Safety at 30 days, 6 
months, 12 months, 18 months, 24 months and 
annually thereafter up to 5 years. Time-Related 
Safety defined as a composite of: 
 Structural valve deterioration: 
o Valve-related dysfunction (mean aortic valve 
gradient ≥20 mmHg, EOA ≤ 0.9-1.1 cm2 
and/or DVI < 0.35 m/s, AND/OR moderate or 
severe prosthetic valve regurgitation) 
o Requiring repeat procedure (TAVI or SAVR) 
 Prosthetic valve endocarditis 
 Prosthetic valve thrombosis 
 Thromboembolic events (eg. stroke) 
 VARC bleeding, unless clearly unrelated to 
valve therapy (eg. trauma) 
Time related safety composite endpoint-incidence 
estimates will be provided for the two treatment 
groups at 30 days, 6 months, 12 months, 18 
months, 24 months and annually thereafter up to 5 
years. 
7. Conduction disturbance requiring permanent 
pacemaker implantation at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually 
thereafter up to 5 years. 
8. Change in NYHA class from baseline at 30 days, 6 

 
 
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months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years. 
9. Change in distance walked during 6-minute walk 
test (6MWT) from baseline to 30 days, baseline to 
12 months, and baseline to 24 months. 
10. Ratio of days alive out of hospital versus total days 
alive assessed at 12 months and 24 months follow-
up.  
11. Quality of Life (QoL) change from baseline at 30 
days, 3 months, 6 months, 12 months, 18 months, 
24 months, and annually thereafter up to 5 years. 
12. Echocardiographic assessment of prosthetic valve 
performance at discharge, 6 months, 12 months, 
24 months, and annually thereafter up to 5 years 
using the following measures: 
 Transvalvular mean gradient 
 Effective orifice area 
 Degree of prosthetic aortic valve regurgitation 
(transvalvular and paravalvular). 
13. Aortic valve disease related hospitalizations.  
14. Cardiovascular deaths and valve-related deaths. 
15. Strokes and TIAs. 
16. Peri-procedural neurological injury. 
17. Index procedure related MAEs. 
18. Length of index procedure hospital stay. 
19. Presence of atrial fibrillation at post-procedure, 
discharge, 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 
years. 
The following secondary endpoints will be 
assessed for the TAVI cohort subjects only: 
20. Device success defined as follows: 
 Absence of procedural mortality AND 
 Correct positioning of a single prosthetic heart 
valve into the proper anatomical location AND 
 Intended performance of the prosthetic heart 
valve (no prosthesis-patient mismatch and 
mean aortic valve gradient <20 mmHg or peak 
velocity <3 m/s, AND no moderate or severe 
prosthetic valve regurgitation) 
o Assessed acutely in resting state, either 
within 24-48 hours after the index procedure 
or before hospital discharge 
21. Procedural success, defined as device success 
and absence of in-hospital MACCE. 
22. Evidence of prosthetic valve dysfunction at 30 
days, 6 months, 12 months, 24 months, and 
annually thereafter up to 5 years. 
23. Resheath and recapture success (Evolut R only). 
 
 
 

 
 
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Trial Sites: 
Up to 115 sites globally 
Sample Size: 
Approximately 1600 patients  
Patient Population: 
Patients who have symptomatic severe Aortic Stenosis 
who are determined by the Heart Team to be at 
intermediate surgical risk. 
Inclusion Criteria: 
1. Subject must have co-morbidities such that Heart 
Team agrees predicted risk of operative mortality is 
≥3% and <15% at 30 days (Intermediate Clinical 
Risk classification). Heart team evaluation of 
clinical surgical mortality risk for each patient 
includes the  calculated STS score for predicted 
risk of surgical mortality augmented by 
consideration of the overall clinical status and co-
morbidities unmeasured by the STS risk 
calculation; 
2. Heart Team unanimously agree on treatment 
proposal and eligibility for randomization based on 
their clinical judgment (including anatomy 
assessment, risk factors, etc.); 
3. Subject has severe aortic valve stenosis presenting 
with 
a) Critical aortic valve area defined as an initial 
aortic valve area of ≤1.0 cm2 or aortic valve 
area index < 0.6 cm2/m2  
AND 
b) Mean gradient > 40mmHg or Vmax > 4m/sec 
by resting echocardiogram or simultaneous 
pressure recordings at cardiac catheterization 
[or with dobutamine stress, if subject has a left 
ventricular ejection fraction (LVEF) <55%] or 
velocity ratio < 0.25; 
4. Subject is symptomatic from his/her aortic valve 
stenosis, as demonstrated by New York Heart 
Association (NYHA) Functional Class II or greater; 
5. Subject and the treating physician agree that the 
subject will return for all required post-procedure 
follow-up visits; 
6. Subject meets the legal minimum age to provide 
informed consent based on local regulatory 
requirements. 
 
 
 

 
 
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Exclusion Criteria: 
1. Subject has refused surgical aortic valve 
replacement (SAVR) as a treatment option; 
2. Any condition considered a contraindication for 
placement of a bioprosthetic valve (i.e. subject 
requires a mechanical valve); 
3. A known hypersensitivity or contraindication to all 
anticoagulation/antiplatelet regimens (including 
inability to be anticoagulated for the index 
procedure), nitinol, or sensitivity to contrast media 
which cannot be adequately pre-medicated; 
4. Blood dyscrasias as defined: leukopenia (WBC 
<1000mm3), thrombocytopenia (platelet count 
<50,000 cells/mm3), history of bleeding diathesis 
or coagulopathy; 
5. Ongoing sepsis, including active endocarditis; 
6. Any condition considered a contraindication to 
extracorporeal assistance; 
7. Any percutaneous coronary or peripheral 
interventional procedure performed within 30 days 
prior to randomization (Subjects with recent 
placement of drug eluting stent(s) should be 
assessed for ability to safely proceed with SAVR 
within the protocol timeframe); 
8. Symptomatic carotid or vertebral artery disease or 
successful treatment of carotid stenosis within six 
weeks of randomization;  
9. Cardiogenic shock manifested by low cardiac 
output, vasopressor dependence, or mechanical 
hemodynamic support; 
10. Recent (within 6 months of randomization) 
cerebrovascular accident (CVA) or transient 
ischemic attack (TIA); 
11. Active gastrointestinal (GI) bleeding that would 
preclude anticoagulation; 
12. Subject refuses a blood transfusion; 
13. Severe dementia (resulting in either inability to 
provide informed consent for the trial/procedure, 
prevents independent lifestyle outside of a chronic 
care facility, or will fundamentally complicate 
rehabilitation from the procedure or compliance 
with follow-up visits); 
14. Multivessel coronary artery disease with a Syntax 
score >22 and/or unprotected left main coronary 
artery (Syntax score calculation is not required for 
patients with history of previous revascularization 
if repeat revascularization is not planned); 
15. Estimated life expectancy of less than 24 months 
due to associated non-cardiac co-morbid 
conditions; 
16. Other medical, social, or psychological conditions 
that in the opinion of the Investigator precludes 
the subject from appropriate consent or 
adherence to the protocol required follow-up 
exams; 
17. Currently participating in an investigational drug or 
another device trial (excluding registries); 

 
 
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18. Evidence of an acute myocardial infarction ≤30 
days before the index procedure; 
19. Need for emergency surgery for any reason; 
20. True porcelain aorta (i.e. Heart Team agrees the 
aorta is not clampable for SAVR); 
21. Extensive mediastinal radiation; 
22. Liver failure (Child-C); 
23. Reduced ventricular function with left ventricular 
ejection fraction (LVEF) <20% as measured by 
resting echocardiogram; 
24. Uncontrolled atrial fibrillation (eg. resting heart rate 
> 120bpm); 
25. Pregnancy or intent to become pregnant prior to 
completion of all protocol follow-up requirements; 
26. End stage renal disease requiring chronic dialysis 
or creatinine clearance < 20 cc/min; 
27. Pulmonary Hypertension (systolic pressure> 
80mmHg); 
28. Severe Chronic Obstructive Pulmonary Disease 
(COPD) demonstrated by Forced Expiratory 
Volume (FEV1) < 750cc; 
29. Frailty assessments identify: 
 Subject is < 80 years of age and three or more 
of the following apply 
 Subject is ≥ 80 years of age and two or more of 
the following apply 
o Wheelchair bound 
o Resides in an institutional care facility (eg. 
nursing home, skilled care center) 
o Body Mass Index <20kg/m2 
o Grip strength <16kg 
o Katz Index score ≤4 
o Albumin <3.5 g/dL. 
30. Marfan syndrome or other known connective 
tissue disease that would necessitate aortic root 
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Anatomical Exclusion Criteria 
31. Native aortic annulus size <18 mm or >29 mm per 
the baseline diagnostic imaging; 
32. Pre-existing prosthetic heart valve in any position; 
33. Mixed aortic valve disease [aortic stenosis and 
aortic regurgitation with predominant aortic 
regurgitation (3-4+)]; 
34. Severe mitral or severe tricuspid regurgitation; 
35. Severe mitral stenosis; 
36. Hypertrophic obstructive cardiomyopathy; 
37. Echocardiographic or Multislice Computed 
Tomography (MSCT) evidence of new or 
untreated intracardiac mass, thrombus or 
vegetation; 
38. Ascending aorta diameter greater than maximum 
diameter relative to the native aortic annulus size: 
 
Aortic Annulus 
Diameter 
Ascending Aorta 
Diameter 
18 mm – 20 mm 
>34 mm 
20 mm – 23 mm 
>40 mm 
23 mm – 29 mm 
>43 mm 
39. Aortic root angulation (angle between plane of 
aortic valve annulus and horizontal 
plane/vertebrae)  
a) Femoral and left subclavian/axillary access > 
70°  
OR  
b)  Right subclavian/axillary access: Aortic root 
angulation > 30°; 
40. Congenital bicuspid or unicuspid valve verified by 
echocardiography; 
41. Sinus of Valsalva anatomy that would prevent 
adequate coronary perfusion. 
Vascular Exclusion Criteria 
42. Transarterial access not able to accommodate an 
18Fr sheath. 
Enrollment Phase: 
36 months 
Follow-up Evaluations: 
Subjects will be followed through 5 years with 
assessments at 30 days, 3 months, 6 months, 12 
months, 18 months, 24 months, and 3, 4, and 5 years 
post TAVI or post SAVR. The total trial duration is 
expected to be approximately 7 years. 
 
 
 

 
 
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B PURPOSE 
B.1 
Background 
Aortic valve stenosis (AS) is the most prevalent valve disorder in the adult population in 
developed countries affecting approximately 2% to 4% of people over 65 years of age (2, 3) . 
This corresponds to approximately 3 million people with AS in Europe and approximately 1.5 
million in the United States. One in five will eventually progress to symptomatic AS representing 
more than 900,000 patients in these two geographies.  
Patients with severe AS face a grim prognosis once they become symptomatic. The landmark 
paper on symptomatic AS by Ross and Braunwald in 1968 highlighted this premise: median 
survival averages only 2, 3 and 5 years after symptom onset of angina, syncope and heart 
failure respectively(4). Furthermore mortality is already substantial in the months following the 
first symptoms (5). The dismal prognosis of patients with untreated severe, symptomatic aortic 
stenosis has been recently corroborated in the conservative treatment arm of the PARTNER B 
cohort. Both, the ESC and ACC/AHA cardiology societies have endorsed guidelines on valvular 
heart disease emphasizing the need for surgical aortic valve replacement (SAVR) once 
symptoms develop or in case of impaired LV function (Level of evidence grade 1)(6, 7, 8).  
Physicians’ preferences for lesser invasive strategies have fuelled the ongoing interest in 
developing minimally invasive transcatheter therapies. Alain Cribier pioneered the transcatheter 
aortic valve implantation (TAVI) technology and reported the first-in-man experience of TAVI in a 
patient with symptomatic AS who was deemed inoperable in 2002(10). Subsequent feasibility 
studies validated the proof of concept (11, 12). The Edwards-SAPIEN valve (Edwards 
Lifesciences, Irvine, CA, USA) and the Medtronic CoreValve system (Medtronic Corporation, 
Minneapolis, MN, USA) were the first two TAVI platforms with CE mark approval, followed by 
the Symetis Acurate (Symetis, Ecublens, Switzerland) and JenaValve (JenaValve, Munich, 
Germany).  Numerous single-center and multi-center observational registries followed 
suggesting the safety and performance of the TAVI technology (13-17). The TAVI technology 
comes with its own specific complications (18), not necessarily overlapping with those of SAVR: 
vascular injury; stroke, cardiac injury such as heart block, coronary obstruction, and cardiac 
perforation; paravalvular leak; and valve misplacement. The non-uniformity in presenting 
respective data makes a comparison of results from different centers challenging (19, 20). The 
Valvular Academic Research Consortium (VARC), a FDA-endorsed collaboration between 
academic research organizations and professional societies in the United States and Europe is 
an initiative to generate a consensus statement on TAVI related definitions aiming to create 
order and uniformity making data more prone to analysis and comparison (21, 22).  
Technical refinements and commercial entrepreneurship have made the technology accessible 
to many centers worldwide. This might pose future implications since few randomized trials with 
TAVI have been performed.  
There are three types of medical practices.  The first is the institution with on-site interventional 
cardiologic and cardiothoracic surgical activity and with close inter-disciplinary collaboration, 
where interventional cardiologists and cardiothoracic surgeons reach a consensus on which 
patients to select for a specific surgical or interventional treatment strategy (9). These centers 
would reasonably respect and adhere to CE mark labeling indications. Second, there are 
centers where interventional cardiologists and cardiothoracic surgeons do not often convene, 
and usually work as two separate departments. Finally, there are practices with an interventional 
cardiology program but without on-site cardiothoracic surgery, estimated to make up 37% of all 
PCI centers in the European Union. Expectedly, these kinds of organizations without intimate 
collaboration between cardiothoracic surgeons and interventional cardiologists will look to 
broaden their interventional activities with an attractive innovation like TAVI. A worldwide 
practice that is less controlled would potentially cloud the safety and efficacy profile of the 
procedure. This criticism by the medical community and health authorities could jeopardize 
future reimbursement policies (23, 24). The advent of randomized trial data is crucial and this 
next step in establishing a new treatment strategy should not be taken for granted as 
governmental authorities entitled to grant premarket approval to cardiovascular devices are 
under increased scrutiny and quality control (25). 
After nearly a decade of worldwide mounting TAVI experience, the Cohort B arm of the much-
anticipated PARTNER (Placement of AoRTic TraNscathetER Valve Trial) trial representing the 
first randomized data set, reported a dramatic 20% absolute reduction in mortality in favor of 

 
 
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TAVI compared to medical therapy in patients who, as determined by surgeons could not 
undergo conventional surgical valve replacement (26).  
In the Cohort A of the PARTNER trial, patients for whom a surgeon and cardiologist concurred 
that the predicted risk of operative mortality was ≥15% and/or with a minimum STS score of 10 
were randomized to TAVI or SAVR. The trial completed its randomization in early 2009 and first 
data were presented at ACC in April 2011, reporting successful achievement of the primary 
endpoint (TAVR was non-inferior to AVR for all-cause mortality at 1 year). 
At the PCR London Valves meeting in October 2010, it was reported that over 22000 patients 
had been treated with TAVI worldwide. To date over 45,000 Medtronic CoreValve System have 
been implanted worldwide (data on file with Medtronic). Inevitably, with increased operator 
experience and access to the device, physicians will shift their attention to younger patients with 
a less pronounced operative risk due to the decreased invasiveness of the TAVI procedure as 
compared with SAVR, coupled with the safety and performance observed in the PARTNER trial 
and other literature reports in the extreme and high risk populations. Similar to the coronary 
revascularization arena (27), the blending of surgical and interventional expertise has created 
unique interdisciplinary dynamics paving the way for a randomized trial comparing TAVI with 
SAVR in a surgical intermediate risk patient population.  
It is in this spirit that the SURTAVI trial (SURgical and Transcatheter Aortic Valve Implantation) 
was conceived. The interdisciplinary approach and consensus of the Heart Team (the 
cardiothoracic surgeon, interventional cardiologist and other treating physicians if necessary) is 
crucial. This aspect of decision making cannot be over-emphasized and is essential for the 
quality of current medical practice in general and any planned randomized trial of TAVI versus 
SAVR in particular. The VARC publication (21, 22) on TAVI definitions and the accumulating 
TAVI expertise in Europe has created a unique momentum for such a randomized initiative 
complementary to the US Pivotal IDE randomized trial in AS patients with high operative risk.  
For a new technology to be accepted as a new asset for treating symptomatic AS several 
essential questions need to be answered: is the technology effective? Which patients are likely 
to benefit (patient selection)? How does this new strategy compare with the alternatives? And 
what is the cost of the intervention relative to alternatives? The proof of concept has been 
validated. The innovative and less invasive transcatheter approach should be at least as 
effective and safe as conventional SAVR or have proof of superiority for both safety and efficacy 
compared to medical therapy.  
The theoretical benefits of this transcatheter approach seem evident by avoiding the need of 
musculoskeletal incisions, cardioplegic arrest, aortic cross clamping, aortotomy, and full 
cardiopulmonary bypass. Ultimately the cost-effectiveness will determine whether the new 
treatment strategy is a valid option to be considered for reimbursement by governmental health 
institutions.  
 
 

 
 
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B.2 
Investigational Devices and Intended Use 
 
Device Description 
B.2.1
B.2.1.1 
Medtronic CoreValve™ System 
The Medtronic CoreValve™ System consists of the following product elements: 
 
Transcatheter Aortic Valve Bioprosthesis (TAV): consisting of a multi-level self-
expanding frame with porcine pericardial bioprosthesis.  The bioprosthesis is processed 
with an anti-mineralization treatment of alpha-amino oleic acid (AOA) a compound 
derived from oleic acid, a naturally occurring long-chain fatty acid. 
 
Delivery Catheter System (DCS): designed to house the tissue valve prosthesis in the 
collapsed position for transcatheter delivery to the patient’s aortic annulus. 
 
Compression Loading System (CLS): facilitates consistent and trauma-free manual 
loading of the TAV into the DCS. 
The models to be used are:   
 
Transcatheter Aortic Valve Prosthesis (TAV) - Models MCS-P4-23-AOA, MCS-P4-23-
AOA-US (23mm), MCS-P3-26-AOA, MCS-P3-26-AOA-US (26mm), MCS-P3-29-AOA,  
MCS-P3-29-AOA-US (29mm), and MCS-P3-31-AOA, MCS-P3-31-AOA-US (31mm)  
 
Delivery Catheter System (DCS) – AccuTrak®:  DCS-C4-18FR, DCS-C4-18F-US, DCS-
C4-18FR-23MM, DCS-C4-18FR-23US (US), and DCS-C4-18FR-23 (OUS) 
 
Compression Loading System (CLS) - Model CLS-3000-18FR, CLS4-18F, CLS-3000-
18FR-US, and CLS4-18F-23 
B.2.1.2 
Medtronic CoreValve™ Evolut R™ System 
In addition, the CoreValve Evolut R System will be used in this trial.  The system is comprised of 
the following product elements: 
 
Evolut R Transcatheter Aortic Valve (TAV): comprised of three leaflets and a sealing 
skirt constructed from glutaraldehyde-fixated porcine pericardium, sewn to a 
compressible and self-expandable Nitinol support frame. The TAV is processed with an 
anti-mineralization treatment of alpha-amino oleic acid (AOA), a compound derived from 
oleic acid, a naturally occurring long-chain fatty acid. 
 
EnVeo R Delivery Catheter System (DCS) with EnVeo R Inline Sheath: facilitates the 
placement of the TAV within the annulus of the aortic valve.  
 
EnVeo R Loading System (LS): facilitates manual loading of the TAV into the 
deployment sheath capsule of the DCS by gradually reducing the diameter of the 
bioprosthesis radially to an optimal diameter. 
The models to be used for the CoreValve Evolut R System are: 
 
Evolut R Transcatheter Aortic Valve (TAV): EVOLUTR-23-C, EVOLUTR-23-US (23mm), 
EVOLUTR-26-C, EVOLUTR-26-US (26mm), and EVOLUTR-29-C, EVOLUTR-29-US 
(29mm) 
 
EnVeo R Delivery Catheter System (DCS) with EnVeo R Inline Sheath: ENVEOR –L, 
ENVEOR-L-C, ENVEOR-US 
 
EnVeo R Loading System (LS): LS-ENVEOR-23, LS-ENVEOR-23-C, LS-ENVEOR-23-
US (23mm) and LS-ENVEOR-2629, LS-ENVEOR-2629-C,LS-ENVEOR-2629-US 
(26mm and 29mm) 
 
In the US, commercial devices, as referenced in the sections above and in Table 1, are 
approved for use in the clinical trial, as necessary, in the event that an investigational device is 
not available.  
Also, any future approved (i.e. CE marked) models or device iterations may be used in the trial. 
The TAV is adapted to a range of aortic annulus and ascending aorta diameters as shown in 
Table 1. 

 
 
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Table 1:  Patient Anatomical Diameters  
CoreValve™ Evolut™ Bioprosthesis 
Model 
Aortic Annulus Diameter 
(range in mm) 
Aortic Diameter at the 
Sino-tubular Junction 
(range in mm) 
MCS-P4-23-AOA 
MCS-P4-23-AOA-US 
18-20 
≤34 
CoreValve™ Bioprosthesis 
Model 
Aortic Annulus Diameter 
(range in mm) 
Aortic Diameter at the 
Sino-tubular Junction 
(range in mm) 
MCS-P3-26-AOA 
MCS-P3-26-AOA-US 
20-23 
≤40 
MCS-P3-29-AOA 
MCS-P3-29-AOA-US 
23-27 
≤43 
MCS-P3-31-AOA 
MCS-P3-31-AOA-US 
26-29 
≤43 
CoreValve™ Evolut™ R Bioprosthesis 
Model 
Aortic Annulus Diameter 
(range in mm) 
Aortic Diameter at the 
Sino-tubular Junction 
(range in mm) 
EVOLUTR-23-C 
EVOLUTR-23-US 
18 – 20 
NA 
EVOLUTR-26-C 
EVOLUTR-26-US 
20 – 23 
NA 
EVOLUTR-29-C 
EVOLUTR-29-US 
23 – 26 
NA 
 
 

 
 
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Device Approval Status 
B.2.2
The approval statuses of the Medtronic CoreValve™ System and CoreValve™ Evolut™ R System 
are outlined in Table 2 below. This table presents the current approval status for the respective 
CoreValve Systems where the clinical trial is conducted. 
Table 2: Device Approval Status 
Device Approval 
Status 
United States 
European Union 
Canada 
Medtronic CoreValve™ System 
TAV  
Market Released 
Market Released 
26mm, 29mm, and 
31mm - Market 
Released  
23mm - Investigational 
DCS 
Market Released 
Market Released 
Market Released 
CLS 
Market Released 
Market Released 
Market Released 
Medtronic CoreValve™ Evolut™ R System 
TAV 
Market Released 
Market Released 
Investigational 
DCS 
Market Released 
Market Released 
Investigational 
LS 
Market Released 
Market Released  
Investigational 
B.2.2.1 
European Union 
CoreValve 
The notified body granted an approval for CE Marking for the 18Fr CoreValve ReValving™ 
System (renamed to “Medtronic CoreValve System” after acquisition from CoreValve Inc. by 
Medtronic Inc. on 9 April 2009) effective March 1, 2007. Model MCS-P3-640 (26mm) and MCS-
P3-943 (29mm) received CE mark effective 2006) and MCS-P3-943 (31mm) received CE 
marked in July 2011.  AOA treated valves (26mm, 29mm, and 31mm) received CE mark in 
March 2012. The AOA treated 23mm valve (MCS-P4-23-AOA) received CE mark in May 2012 
(marketed as CoreValve™ Evolut™).  The models to be used in this trial, listed in Table 1, are 
identical to the CE marked devices.  The devices used in this trial will be used outside the 
current approved indication. The Medtronic CoreValve System is still under investigation for the 
intermediate risk indication. 
The Delivery Catheter System (DCS) with AccuTrak® Stability Layer was designed to optimize 
the valve positioning and will be used in this trial. CE mark approval was received in July 2010. 
The Delivery System for 23mm TAV (DCS-C4-18FR-23) has a shortened capsule and plunger 
to house and deliver the 23 mm TAV.   The DCS and CLS components used for this trial are the 
CE marked product.  
 
CoreValve Evolut R 
The notified body granted CE Mark approval for Model EVOLUTR-23 (23mm) of the CoreValve 
Evolut R System effective August 12, 2014. This included the TAV EVOLUTR-23 (23mm), 
EnVeo R DCS with EnVeo R Inline Sheath (ENVEOR-L) and EnVeo R LS [LS-ENVEOR-23 
(23mm)].  CE Mark approval was granted on January 30, 2015 for Model Evolut R-26 (26mm) 
and Model Evolut R-29 (29mm).  This included the TAV EVOLUTR-26 (26mm) and EVOLUTR-
29 (29mm), EnVeo R DCS with EnVeo R Inline Sheath (ENVEOR-L) and EnVeo R LS [LS-
ENVEOR-2629 (26mm and 29mm)]. The CoreValve Evolut R System will not be made available 
for use in SURTAVI at any investigational sites in Canada (ie, regulatory approval for Evolut R 
usage within the trial will not be sought). The Medtronic CoreValve Evolut R System is still under 
investigation for the intermediate risk indication.  The DCS and CLS components used for this 
trial are the CE marked product. 
 

 
 
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B.2.2.2 
United States 
CoreValve 
Medtronic submitted an Original IDE (G100012) to seek approval to initiate an Investigational 
Device Exemption for the Medtronic CoreValve System (size 26mm and 29mm). This trial was 
intended for use in subjects with severe symptomatic Aortic Stenosis (AS) necessitating aortic 
valve replacement in Extreme Risk and High Risk Patient Populations. This IDE was 
conditionally approved on October 13, 2010 and received full approval on November 10, 2011.  
Medtronic added an additional 31mm TAV size to the IDE via G100012/S24 followed by 23mm 
TAV via G100012/S31.  
The FDA granted marketing approval of CoreValve for Extreme Risk patients on January 17, 
2014 and High Risk patients on June 12, 2014. The devices used in this trial will be used 
outside the current approved indication.  The models to be used in this trial, listed in Table 1, 
are identical to the FDA approved devices.  FDA granted approval for the use of commercially 
labeled devices in the trial on August 6, 2014. The devices used in this trial will be used outside 
the current approved indication.  The Medtronic CoreValve System is still under investigation for 
the intermediate risk indication.  
 
CoreValve Evolut R 
Medtronic submitted an Original IDE (G140059) to seek approval to initiate an Investigational 
Device Exemption for the Medtronic CoreValve Evolut R System. This study was intended for 
use in subjects with severe symptomatic Aortic Stenosis (AS) necessitating aortic valve 
replacement in Extreme Risk and High Risk Patient Populations. This IDE was conditionally 
approved on May 2, 2014 and received full approval on September 29, 2014.  The FDA granted 
marketing approval of CoreValve Evolut R for Extreme Risk and High Risk on June 22, 2015.  
The models to be used in this trial, listed in Table 1, are identical to the FDA approved devices.  
FDA granted approval for the use of commercially labeled devices in the trial on July 15, 2015. 
All components to the CoreValve Evolut R System are still under investigation for the 
intermediate risk indication.  
B.2.2.3 
Canada 
CoreValve 
The commercial application for the Medtronic CoreValve System (26mm and 29mm) was 
approved by Health Canada on August 2, 2012 and the 31mm on February 7, 2014. Medtronic 
CoreValve System 23mm is available only via Special Access, which is considered 
investigational and may be used upon special access granted by Health Canada.  The models 
to be used in this trial, listed in Table 1, are identical to the Health Canada approved and 
Special Access devices.  The devices used in this trial will be used outside the current approved 
indication. The Medtronic CoreValve System is still under investigation for the intermediate risk 
indication. 
 
CoreValve Evolut R 
The CoreValve Evolut R System will not be made available for use in SURTAVI at any 
investigational sites in Canada (ie, regulatory approval for Evolut R usage within the trial will not 
be sought).All components to the CoreValve Evolut R System are still under investigation for all 
risk classifications.  
 
 
Intended Use of the Device / Indications for Use 
B.2.3
The Medtronic CoreValve™ System and CoreValve™ Evolut R System are intended/indicated for use 
in patients who have symptomatic severe aortic stenosis (AS) necessitating valve replacement and 
who are at intermediate surgical risk and presenting with anatomical dimensions as described in Table 
1. 
 

 
 
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B.3 Trial Objectives 
 
Primary 
B.3.1
The primary objective of this trial is to evaluate in a prospective randomized fashion whether 
Transcatheter Aortic Valve Implantation (TAVI) is non-inferior to Surgical Aortic Valve 
Replacement (SAVR) with respect to the composite endpoint of all-cause mortality and disabling 
stroke at 24 months in patients with symptomatic severe aortic stenosis and at intermediate 
surgical risk.  
 
Secondary 
B.3.2
The secondary objective of this trial is to assess differences in quality of life, clinical benefit 
(efficacy endpoints) and health economics in patients with symptomatic severe aortic stenosis 
and at intermediate risk treated with either Transcatheter Aortic Valve Implantation (TAVI) or 
Surgical Aortic Valve Replacement (SAVR). 
 
Exploratory 
B.3.3
An analysis will be conducted to determine if patients can be identified as intermediate risk for 
Transcatheter Aortic Valve Implantation (TAVI) based upon age and the presence of a defined 
list of co-morbidities commonly associated with patients undergoing TAVI procedures.  A 
complete discussion of this exploratory objective can be found in Appendix R.24. 
 

 
 
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C TRIAL PROTOCOL 
C.1 
Ethics and Regulatory Compliance 
 
Applicable Regulations 
C.1.1
This trial will be conducted in compliance with the protocol, the Sponsor’s standard operating 
procedures and/or guidelines, the United States Food and Drug Administration (FDA) and local 
regulations where applicable, the International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines, ISO14155 (2011), and the Declaration of Helsinki (2008 and 
subsequent versions).  Additionally, the Medical Device Directive (MEDDEV 2.7/3) will be 
followed for Investigator reporting of Serious Adverse Events (SAEs) to the sponsor. 
 
Institutional Review Board (IRB)/Medical Ethics Committee (MEC) 
C.1.2
The trial will be conducted in accordance with 21 CFR 56 Institutional Review Boards and/or 
local regulations for Medical Ethics Committee (MEC).  The trial protocol and consent must be 
approved by the responsible Institutional Review Board (IRB) or MEC at each investigational 
site.  Trial activities must not commence prior to receipt of documentation of IRB/MEC approval 
by the site and Medtronic.  The Investigator and trial staff must comply with the requirements of 
their IRB/MEC. 
Prior to enrolling subjects in this trial, each investigation site’s IRB/MEC will be required to 
approve the current trial clinical investigation plan, the Patient Information and Informed Consent 
form, and any other written information to be provided to the subjects. In the US, Investigator 
must also utilize IRB approved Health Insurance Portability and Accountability Act (HIPAA) 
Authorization.  
IRB/MEC approval of the clinical trial must be received in the form of a letter and provided to 
Medtronic before commencement of the trial at an investigation site. The approval letter must 
contain enough information to identify the version or date of the documents approved. In 
addition the approval letter needs to be accompanied by an IRB/MEC roster or letter of 
compliance, to allow verification that the investigator, other center trial staff, and/or Medtronic 
personnel are not members of the IRB/MEC. If they are members of the IRB/MEC, written 
documentation is required stating that he/she did not participate in the approval process. 
Investigators must inform Medtronic of any change in status of IRB/MEC approval once the 
investigation site has started enrolment. 
 
Regulatory Submission 
C.1.3
Prior to enrolling any patients in the trial, all local regulatory requirements must be fulfilled. Each 
trial site must have written documentation of site/investigator readiness, including but not limited 
to IRB/MEC approval of the current version of the Investigational Plan, Informed Consent form, 
a signed Investigator’s Agreement, current investigator curriculum vitae, and documentation of 
training.  The coordinating and principal investigators shall agree to this investigational plan and 
any amendments and indicate their approval by signing and dating the Investigator’s 
Agreement. 
Approval from the Regulatory Authorities, if applicable, is required prior to the first patient 
enrollment in a particular center. Medtronic will obtain a copy of the approval letter, directly from 
the Regulatory Authorities. 
If any action is taken by an IRB/MEC with respect to the investigation, that information will be 
forwarded to Medtronic by the respective investigator. 
Other documents that are referred to in this Clinical Investigation Plan are listed below and will 
be made available upon request: 
 
Monitoring Plan 
 
Data Management Plan 
 
Statistical Analysis Plan 
 
Patient Information and Informed Consent Form 
 
Case Report Forms 
 

 
 
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Ethical Conduct of the Trial 
C.1.4
The trial will be conducted in accordance with the design and specific provisions of this protocol, 
in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and 
that are consistent with Good Clinical Practice (GCP) and the applicable regulatory 
requirements. 
The principles of the Declaration of Helsinki have all been implemented in this trial by means of 
the patient informed consent process, IRB/MEC approval, trial training, clinical trial registration, 
preclinical testing, risk benefit assessment, and publication policy.  
The sponsor will avoid improper influence on, or inducement of the subject, monitor, and 
investigator(s) or other parties participating in, or contributing to, the clinical investigation by 
implementing the patient informed consent process, clinical investigation agreements, and 
IRB/MEC review and approval. 
C.2 Trial Administration 
 
Steering Committee 
C.2.1
The Steering Committee will be an advisory body to Medtronic.  Their roles and responsibilities 
may include, but are not limited to the following: 
 
Overall conduct of the study with regard to  
o 
Protocol development and implementation 
o 
Study progress 
o 
Patient safety 
o 
Data quality and integrity 
 
Quality performance at individual sites 
o 
The Steering Committee will support site investigators in resolving any clinical 
or procedural issues that may impact patient well-being or integrity of the study 
o 
Any site placed on probation for any reason may be terminated from the study 
after an appropriate review by the Steering Committee 
 
Review of all Data Safety Monitoring Board (DSMB) recommendations 
 
Assess requests for sub-studies 
 
Assist with Publication efforts by disseminating study information through appropriate 
scientific sessions and publications 
o 
All requests for abstract and manuscript preparation and submission require 
Steering Committee review and approval. All final decisions will be made by 
Medtronic; however, the recommendations made by the Steering Committee 
will be highly considered 
 
Participate in Investigator Meetings (and other study related meetings) 
 
Serve as a contact for other study investigators (providing peer consultation) 
Prior to the onset of the trial, the Steering Committee will establish a charter.  The Steering 
Committee charter will be approved by Medtronic and the Steering Committee members. 
 
Publication Committee 
C.2.2
The Publication Committee will review and approve publication ideas and facilitate submissions, 
including abstracts and manuscripts.  The Publication Committee will consist of SURTAVI trial 
investigators (interventional cardiologists and cardiac surgeons) and Medtronic representatives. 
The Publication Committee will be responsible for: 
 
Defining and refining the publication strategy 
 
Overseeing the development of manuscripts, abstracts, and presentations 
 
Identifying and appointing the manuscript/abstract first author(s)/writer(s)/presenters(s) 
 
Reviewing the publication 
 

 
 
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C.3 Methodology 
 
Purpose 
C.3.1
The purpose of this trial is to investigate the safety and efficacy of transcatheter aortic valve 
implantation (TAVI) in patients with severe, symptomatic Aortic Stenosis (AS) at intermediate 
surgical risk by randomizing patients to either Surgical Aortic Valve Replacement (SAVR) or 
TAVI. Data from this trial will be used to support regulatory applications in seeking approval for 
the Medtronic CoreValve System and/or CoreValve Evolut R System in the intermediate surgical 
risk population. 
 
Patient Population 
C.3.2
Patients who have symptomatic severe Aortic Stenosis who are determined by the Heart Team 
to be at intermediate surgical risk. 
 
Design 
C.3.3
This trial is designed as a prospective, multi-center, multi-national, randomized, interventional 
trial to investigate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in 
patients with severe, symptomatic Aortic Stenosis (AS) at intermediate surgical risk. 
Approximately 1600 subjects will be recruited in up to 115 investigational centers located in the 
United States, Canada and Europe.  The trial may be expanded to include additional 
geographies based on enrollment rates and identification of qualified centers. 
Subjects will be randomized on a 1:1 basis to either transcatheter aortic valve implant (TAVI) or 
to surgical aortic valve replacement (SAVR). 
To avoid bias in the trial population the following measures have been taken: 
 
All sponsor and external trial personnel will be trained on the Clinical Investigation Plan 
(CIP) and related trial materials; and 
 
Subjects will be screened to confirm trial eligibility with defined inclusion/exclusion 
criteria prior to enrollment. 
The total trial duration is expected to be approximately eight years. 
 
Investigational Centers 
C.3.4
Site distribution is anticipated to include up to 75 centers in the United States, 10 in Canada and 
30 in Europe. 
For this study, the following investigator/center selection minimum criteria are considered: 
 
Center must have sufficient patient population  
 
Each center’s Implant Team (i.e. 1st and 2nd operators) must have completed at least 30 
cumulative TAVI procedures  
 
There will be no other study ongoing during this study duration, which would prevent the 
center from meeting enrollment goals for SURTAVI or provide adequate staffing 
 
Investigator should have adequate staff that is accessible and has time to manage the 
study for 7 days per week, 24 hours per day 
 
Investigator, co-investigators, and study staff must be willing to provide his/her 
Curriculum Vitae 
 
Investigator and co-investigators must be willing to sign and comply with the protocol-
specific Investigator Agreement 
 
Center must be willing to comply with the Clinical Investigation Plan and data 
requirements, including reporting Adverse Events 
 
Center has demonstrated experience with conducting clinical (device) trials that comply 
with applicable regulatory standards 
 
Center is willing to participate in follow-up of patients for 5 years 
 
Center has an internet connection with sufficient speed of data transfer 
All investigators will be appropriately qualified practitioners legally entitled to practice, and 
experienced in the diagnosis and treatment of patients requiring an aortic valve treatment with a 
TAVI or SAVR.  

 
 
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For the purposes of the SURTAVI trial, it is imperative that Medtronic leverages highly qualified 
surgeons for the surgical aortic valve replacements (SAVR) that will occur as a part of the trial. 
The following minimum criteria will be used for all cardiac surgeons performing SAVRs in the 
SURTAVI trial:    
 
At least 5 years of experience post-residency 
 
At least 100 career aortic valve replacements post-residency 
 
At least 75 valve procedures in the last 3 years 
 
At least 35 surgical aortic valve replacements in the last 3 years 
 
At least 15 aortic valve replacements in the last year 
 
Number of Subjects 
C.3.5
Up to 2000 subjects will be randomized [1:1, TAVI: Surgical Aortic Valve Replacement (SAVR)]. 
The enrollment phase is anticipated to be approximately 36 months. Subjects will be followed 
through 5 years for assessment of long-term safety and efficacy endpoints.  The total trial 
duration is expected to be approximately 8 years. 
Enrollments shall not exceed 20% (approximately 400) of total randomized subjects at any 
individual site. Enrollment is competitive; therefore there is no set minimum number of subjects 
to be enrolled per site. Appropriate measures will be taken to monitor enrollment across 
geographies to ensure at least 40% of the total patient population is enrolled within the United 
States. 
 
 Inclusion/Exclusion Criteria 
C.3.6
C.3.6.1 
Inclusion Criteria 
To participate in this trial, the subject must meet ALL of the following inclusion criteria.  
1. 
Subject must have co-morbidities such that Heart Team agrees predicted risk of 
operative mortality is ≥3% and <15% at 30 days (Intermediate Clinical Risk 
classification). Heart team evaluation of clinical surgical mortality risk for each patient 
includes the  calculated STS score for predicted risk of surgical mortality augmented by 
consideration of the overall clinical status and co-morbidities unmeasured by the STS 
risk calculation; 
2. 
Heart Team unanimously agree on treatment proposal and eligibility for randomization 
based on their clinical judgment (including anatomy assessment, risk factors, etc.); 
3. 
Subject has severe aortic stenosis presenting with: 
a) Critical aortic valve area defined as an initial aortic valve area of ≤1.0 cm2 or 
aortic valve area index < 0.6 cm2/m2 
 
AND 
b) Mean gradient > 40mmHg or Vmax > 4m/sec by resting echocardiogram or 
simultaneous pressure recordings at cardiac catheterization [or with dobutamine 
stress, if subject has a left ventricular ejection fraction (LVEF) <55%] or velocity 
ratio < 0.25; 
4. 
Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New 
York Heart Association (NYHA) Functional Class II or greater; 
5. 
Subject and the treating physician agree that the subject will return for all required post-
procedure follow-up visits; 
6. 
Subject meets the legal minimum age to provide informed consent based on local 
regulatory requirements. 
C.3.6.2 
Exclusion Criteria 
Subjects are NOT eligible for trial participation if they meet ANY of the following exclusion 
criteria: 
1. Subject has refused surgical aortic valve replacement (SAVR) as a treatment option; 
2. Any condition considered a contraindication for placement of a bioprosthetic valve (i.e. 
subject requires a mechanical valve); 

 
 
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3. A known hypersensitivity or contraindication to all anticoagulation/antiplatelet regimens 
(or inability to be anticoagulated for the index procedure), nitinol, or sensitivity to 
contrast media which cannot be adequately pre-medicated; 
4. Blood dyscrasias as defined: leukopenia (WBC <1000mm3), thrombocytopenia (platelet 
count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy; 
5. Ongoing sepsis, including active endocarditis; 
6. Any condition considered a contraindication to extracorporeal assistance; 
7. Any percutaneous coronary or peripheral interventional procedure performed within 30 
days prior to randomization (Subjects with recent placement of drug eluting stent(s) 
should be assessed for ability to safely proceed with SAVR within the protocol 
timeframe); 
8. Symptomatic carotid or vertebral artery disease or successful treatment of carotid 
stenosis within six weeks of randomization;  
9. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or 
mechanical hemodynamic support; 
10. Recent (within 6 months of randomization) cerebrovascular accident (CVA) or transient 
ischemic attack (TIA); 
11. Active gastrointestinal (GI) bleeding that would preclude anticoagulation; 
12. Subject refuses a blood transfusion; 
13. Severe dementia (resulting in either inability to provide informed consent for the 
trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will 
fundamentally complicate rehabilitation from the procedure or compliance with follow-up 
visits); 
14. Multivessel coronary artery disease with a Syntax score >22 and/or unprotected left 
main coronary artery (Syntax score calculation is not required for patients with history of 
previous revascularization if repeat revascularization is not planned); 
15. Estimated life expectancy of less than 24 months due to associated non-cardiac co-
morbid conditions; 
16. Other medical, social, or psychological conditions that in the opinion of the Investigator 
precludes the subject from appropriate consent or adherence to the protocol required 
follow-up exams; 
17. Currently participating in an investigational drug or another device trial (excluding 
registries); 
18. Evidence of an acute myocardial infarction ≤30 days before the index procedure; 
19. Need for emergency surgery for any reason; 
20. True porcelain aorta (i.e. Heart Team agrees the aorta is not clampable for SAVR); 
21. Extensive mediastinal radiation; 
22. Liver failure (Child-C); 
23. Reduced ventricular function with left ventricular ejection fraction (LVEF) <20% as 
measured by resting echocardiogram; 
24. Uncontrolled atrial fibrillation (eg. resting heart rate >120bpm); 
25. Pregnancy or intent to become pregnant prior to completion of all protocol follow-up 
requirements; 
26. End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min; 
27. Pulmonary Hypertension (systolic pressure> 80mmHg); 
28. Severe Chronic Obstructive Pulmonary Disease (COPD) demonstrated by Forced 
Expiratory Volume (FEV1) < 750cc; 
29. Frailty assessments identify: 
 Subject is < 80 years of age and three or more of the following apply 
 Subject is ≥ 80 years of age and two or more of the following apply 
o Wheelchair bound 
o Resides in an institutional care facility (eg. nursing home, skilled care center) 
o Body Mass Index < 20 kg/m2 
o Grip strength <16 kg 
o Katz Index score ≤ 4 

 
 
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o Albumin < 3.5 g/dL; 
30. Marfan syndrome or other known connective tissue disease that would necessitate 
aortic root replacement/intervention. 
Anatomical Exclusion Criteria 
31. Native aortic annulus size <18 mm or >29 mm per the baseline diagnostic imaging; 
32. Pre-existing prosthetic heart valve in any position; 
33. Mixed aortic valve disease [aortic stenosis and aortic regurgitation with predominant 
aortic regurgitation (3-4+)]; 
34. Severe mitral or severe tricuspid regurgitation; 
35. Severe mitral stenosis; 
36. Hypertrophic obstructive cardiomyopathy; 
37. Echocardiographic or Multislice Computed Tomography (MSCT) evidence of new or 
untreated intracardiac mass, thrombus or vegetation; 
38. Ascending aorta diameter greater than maximum diameter relative to the native aortic 
annulus size: 
 
Aortic Annulus Diameter
Ascending Aorta Diameter
18 mm – 20 mm
>34 mm
20 mm – 23 mm 
>40 mm 
23 mm – 29 mm 
>43 mm 
 
39. Aortic root angulation (angle between plane of aortic valve annulus and horizontal 
plane/vertebrae): 
a) Femoral and left subclavian/axillary access > 70°  
OR 
 
b) Right subclavian/axillary access: Aortic root angulation > 30°; 
40. Congenital bicuspid or unicuspid valve verified by echocardiography; 
41. Sinus of Valsalva anatomy that would prevent adequate coronary perfusion. 
Vascular Exclusion Criteria 
42. Transarterial access not able to accommodate an 18Fr sheath. 

 
 
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Informed Consent 
C.3.7
The investigator must obtain written informed consent prior to subjecting the subject to any trial 
related activity.  
Well in advance of the consent discussion, the subject should receive the MEC/IRB approved 
Patient Information and Informed Consent Form (ICF). During the consent discussion the 
investigator or his/her designee must fully inform the subject of all pertinent aspects of the trial 
including the approval of the MEC/IRB of the written Patient Information. If a subject is illiterate, 
an impartial witness must be present during the entire informed consent discussion. All items 
discussed in the Patient Information and the ICF must be explained. The language used shall be 
in the subject’s native language, as non-technical as possible and must be understandable to 
the subject and the impartial witness, where applicable.  
The subject must have ample time and opportunity to inquire about details of the trial, and to 
decide whether or not to participate in the clinical trial. All questions about the trial should be 
answered to the satisfaction of the subject. 
Neither the investigator, nor the investigation site staff shall coerce or unduly influence a subject 
to participate or to continue to participate in the clinical trial. The informed consent process shall 
not appear to waive the subject’s rights. 
When the subject decides to participate in the clinical trial, the ICF must be signed and 
personally dated by the subject and investigator. If applicable, the witness shall also sign and 
personally date the consent form to attest that the information in the Patient Information and 
Informed Consent Form was accurately explained and clearly understood by the subject, and 
that informed consent was freely given.  
Signing the ICF serves to document the written and verbal information that the Investigator or 
authorized delegate provides to the patient, the patient understanding of the information, and 
their agreement to participate.  The Investigator or authorized delegate must document in the 
patient’s medical records that the patient was consented and the date on which the consent was 
obtained.  The original signed consent form will be retained in the patient’s trial records.  A copy 
of the informed consent will be provided to the patient and a copy placed in the patient’s medical 
record. 
Data relating to the trial might be made available to third parties (for example in case of an audit 
performed by regulatory authorities), provided the data are treated as confidential and that the 
subject’s privacy is guaranteed.  In the United States, “Protected Health Information” will be 
maintained in compliance with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). 
 
Revisions in Patient Information and Informed Consent Form 
C.3.8
Medtronic will inform the investigators whenever information becomes available that may be 
relevant to the subject’s continued participation in the trial. The revised information will be sent 
to the investigator for approval by the IRB/MEC. After approval by the IRB/MEC, a copy of this 
information must be provided to the participating subjects, and the informed consent process as 
described above needs to be repeated. The investigator or his/her designee should inform the 
subject in a timely manner. 
 

 
 
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Enrollment Flowchart for Randomization to TAVI or SAVR 
C.3.9
 
Figure 1: Enrollment Flowchart 
 
 
 
  
If the patient meets all of the inclusion criteria and none of the exclusion and Heart Team 
determines the patient is eligible for randomization in the SURTAVI trial, subjects will be 
randomized on a 1:1 basis to either TAVI or SAVR.  Randomization will be stratified by the need 
for coronary revascularization. In case of required coronary revascularization, concomitant 
percutaneous coronary intervention (PCI) and TAVI is encouraged; however staging is left at the 
discretion of the operator. Coronary artery bypass graft (CABG) should be conducted during the 
index procedure. 
 Trial Training 
C.3.10
Prior to investigational site activation or subsequent involvement in trial activities, Medtronic (or 
designee) will provide trial training relevant and pertinent to the involvement of personnel 
conducting trial activities, including investigator responsibilities, adverse event reporting as well 
as device training (if necessary, usage and handling of device under investigation). Training may 
be conducted via Site Initiation Visits, Investigator and Coordinator Meetings, and/or other 

 
 
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media sessions. The sponsor will maintain documentation of attendance at each of these 
training opportunities, as applicable.  
Additionally, Medtronic representative(s) may be present at each site’s TAVI procedures as part 
of the ongoing training process. 
 
C.4 Trial Procedures 
 
Screening Procedures 
C.4.1
Prior to any trial-specific tests or procedures, written informed consent must be obtained from 
the subject. Failure to obtain a signed and hand dated informed consent prior to the procedure 
constitutes a protocol violation, which is reportable to the IRB/MEC, the Food and Drug 
Administration (FDA), and other regulatory authorities as applicable. 
All potential subjects for trial entry must be screened for eligibility. All patients with symptomatic 
severe AS that provide informed consent will be entered into the Electronic Data Capture (EDC) 
system and total number of patients screened will be counted.  The reasons why a patient did 
not enter the Heart Team meeting will be collected (eg. patient does not meet inclusion criteria 
or meets an exclusion criteria) and, age, STS score, and available screening data.  
Data readily available in the patient’s medical record may be utilized to fulfill screening 
requirements and do not need to be repeated. If not previously completed, the following tests 
and procedures must be performed prior to randomization to verify eligibility. The recommended 
timeframe for these tests and procedures is within 30 days prior to submission to the Heart 
Team, unless otherwise specified. 
 
Demographics and Medical History 
 
Clinical Assessments – Refer to Appendix R.19 
o 
5-Meter Gait Speed 
o 
Grip Strength 
 
Physical Examination including:   
o 
Vital signs, weight, height, and body surface area (BSA);  
 
BSA will be calculated from height and weight by use of the formula by 
Dubois and Dubois (BSA = 0.007184 × weight [kg]0.425 × height [m]0.725)] 
o 
Major systems findings 
 
NYHA Classification 
 
Risk Assessments: 
o 
STS Risk Score – Dataset Version 2.73 
o 
Logistic EuroSCORE 
o 
EuroSCORE II 
o 
SYNTAX Score 
o 
Katz Index of Independence in Activities of Daily Living 
 
Co-morbidities 
 
Routine Laboratory Tests: 
o 
Complete Blood Count: 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance  
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT)  
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
 

 
 
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 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic two-dimensional (2D) echocardiogram (TTE) is 
required within 365 days prior to review by the Heart Team to confirm diagnosis 
of severe aortic stenosis(AS) including: 
 
Aortic valve area / indexed aortic valve area 
 
Mean gradient / peak velocity / velocity ratio 
o 
If a historical TTE is used to confirm AS diagnosis a repeat TTE must be 
performed within 45 days prior to review by the Heart Team to: 
 
Assess: 
 
Aortic regurgitation 
 
Mitral and tricuspid valve status (stenosis and regurgitation)  
 
LVEF 
 
Rule out: 
 
New or recent MI 
 
New or untreated intracardiac mass, thrombus  or vegetation 
 
Congenital bicuspid or unicuspid valve 
o 
If the patient recently underwent balloon aortic valvuloplasty (BAV), a TTE 
should be obtained post-BAV; within 45 days prior to review by the Heart Team 
to reconfirm all inclusion/exclusion echocardiographic parameters 
o 
Protocol required echocardiograms should be performed according to the 
Echocardiography Procedures found in Appendix R.7. 
 
Multi-Slice Computed Tomography (MSCT) Angiogram 
o 
Multi-Slice Computed Tomography (MSCT) angiograms with complete 
visualization of both iliacs, femorals and aorta (and subclavian/axillaries, if 
applicable), up to and including the aortic annulus.  In the situation where 
subjects have compromised renal function that precludes contrast media, 
Magnetic Resonance (MR) imaging may be used as an alternative.  MSCT 
angiograms should be performed according to the Computed Topography (CT) 
Angiography Acquisition Guidelines found in Appendix R.9. If the MSCT 
angiogram was conducted in the last 365 days and subject has not had a 
peripheral vascular intervention since the time of the image, a more recent 
exam is not required as long as visualization of both iliacs and femorals (and 
subclavian/axillaries, if applicable) to the aorta can be viewed.  However, if the 
subject had a peripheral vascular intervention, the exam must be repeated after 
the intervention and within 90 days of review by the Heart Team. 
 
Coronary Arteriogram 
o 
Selective coronary arteriography to assess the presence and severity of 
coronary artery disease which should include angiograms of both coronary 
arteries and all bypass grafts (if applicable). If the coronary arteriogram has 
been performed within the last 365 days and the subject qualifies for the trial 
(no significant coronary artery disease), a more recent exam is not required.  
However, if the subject had evidence of significant coronary artery disease 
and/or received a coronary intervention, the exam must be repeated after the 
intervention and within 90 days of review by the Heart Team. 
 
12-lead Electrocardiogram (ECG) 
 
 

 
 
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Heart Team Procedures 
C.4.2
Each center will utilize a Heart Team to make determinations regarding eligibility of the 
prospective subject to be randomized in the SURTAVI trial. 
C.4.2.1 
Heart Team Composition 
Local Heart Teams must be comprised of a multidisciplinary team qualified by education and 
experience to determine appropriate patient treatment. 
Minimum Membership1  
 
Interventional Cardiologist - ≥ 1 representative is required 
 
Cardiac Surgeon - ≥ 1 representative is required 
Additional Membership Considerations  
Additional members of the Heart Team should be included based on current standard practices 
and patient specific consideration, including but not limited to: 
 
Echocardiographer 
 
Anesthesiologist 
 
Cardiologist (general or referring physician) 
 
Geriatrician 
 
Neurologist or stroke specialist 
 
Radiologist or imaging specialist 
 
Heart Failure specialist 
 
Intensivist 
 
Nurse(s) 
 
Social Worker 
C.4.2.2 
Heart Team Review and Decision 
Prior to determining if a patient is eligible for randomization the Heart Team will review each 
patient’s screening data and confirm the following: 
 
STS risk calculation was properly performed 
 
Any additional risk factors not accounted for in the STS risk calculator that may increase 
the level of surgical risk: 
o 
Heart Team should consider the following potential incremental risks: 
 
Age ≥ 75 
 
BNP ≥ 550pg/mL or NT proBNP ≥ 3200pg/mL 
 
Prior Stroke/TIA 
 
FEV1 750-1000cc 
 
Home / Supplemental oxygen 
 
Nocturnal Bi-level Positive Airway Pressure 
 
5-Meter Gait Speed ≥ 6 seconds 
 
Severe Diastolic Dysfunction (Grade III or IV) 
 
Liver Disease (Child A or B) 
 
Pulmonary Hypertension (systolic pressure 60-80mmHg) 
 
Frailty (eg. BMI <21 kg/m2, Albumin <3.5 g/dL, etc.) 
 
Other risks, as deemed applicable 
o 
Confirm the incremental risk, as determined by the Heart Team, does not 
result in a risk definition higher than intermediate risk 
 
 All inclusion criteria are met and none of the exclusion criteria 
 
Both the reviewing Interventional Cardiologist and Cardiac Surgeon(s) must unanimously agree 
the patient has a predicted risk of operative mortality ≥ 3% and < 15% and appropriate for trial 
enrollment.  The decision of the local Heart Team must be documented on the “Heart Team 
Decision” form and signed by the reviewing Interventional Cardiologist and Cardiac Surgeon(s). 
                                                    
 
1  US only - Protocol criteria for Heart Team approval may not meet the minimum requirements outlined by Centers for 
Medicare and Medicaid Services (CMS) for reimbursement.  Reference Appendix R.25 for additional information. 

 
 
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Screening Committee 
C.4.3
The Screening Committee will ensure appropriate and consistent patient selection across all 
sites.  Prior to the onset of the trial, a charter will be drafted to that outline roles and 
responsibilities as well as describe the Screening Committee process.   
Final decisions on patient eligibility will be made by the Screening Committee.  
 
Roll-in Subjects 
C.4.4
For participating centers who meet the requirement of 30 cumulative TAVI procedures but have 
no previous CoreValve experience (eg. Investigational centers where CoreValve is not 
commercially available and/or centers that did not participate in the US Pivotal Extreme/High 
Risk protocols) the first three successfully enrolled subjects will be considered “roll-in” subjects, 
will not be randomized, and will automatically be assigned to TAVI.  A maximum of three 
successful roll-in subjects are allowed per center.  
The purpose of the roll-in subjects is to provide investigators the time for training and 
familiarization with the investigational TAVI device. The Training and Education team will review 
recommendations made by Medtronic field support, Medtronic CoreValve Proctors and the 
Steering Committee for transition of sites from the roll-in phase to the randomization phase of 
enrollment after the first three subjects have been treated.   
A subject will be considered a treated roll-in subject once the TAVI delivery catheter system 
(DCS) is introduced into the subject. A site must have three treated roll-in subjects before they 
can be evaluated to move into the randomization phase. The Training and Education team or 
designee will review and document their decisions based on the technique of the investigators, 
as well as the frequency, severity and nature of events in the roll-in subjects. 
Roll-in subjects will complete in-clinic follow-up evaluations at the following time points post 
implant as subjects randomized to  TAVI.  However, the results for the roll-in population will be 
analyzed separately from the randomized population.   
 
Enrollment and Randomization 
C.4.5
Prior to randomization and enrollment of a subject, the following must occur: 
 
Confirm patient signed informed consent 
 
Confirm patient meets all of the inclusion and none of the exclusion criteria, including 
approval by the Heart Team 
Subjects will be considered enrolled into the trial at the time of randomization2 (i.e. time of 
treatment assignment).  Randomization will occur only if the patient meets all inclusion criteria 
and does not meet any exclusion criteria and has been assessed by the Heart Team as being 
an appropriate candidate for randomization in the SURTAVI trial.   
Due to the inclusion/exclusion criteria, not all patients that consent to the trial will be enrolled.  
All sites will be required to maintain a record of patients screened for the trial meeting general 
inclusion criteria who have signed the approved informed consent document.  For subjects that 
do not meet trial criteria, the reason for not continuing in the trial must be documented and 
recorded in the EDC system.  Patients consented but not randomized will be considered screen 
failures and no further trial-related follow-up will be required. 
Subjects must have their TAVI or SAVR procedure no later than 30 days post-randomization.  
Trial randomization will not be blinded.  Once randomization is complete and a treatment arm is 
assigned, crossover from SAVR to TAVI treatment is not permitted.  The sponsor will strictly 
monitor device dispensation to ensure that only those subjects randomized to the TAVI 
treatment arm receive the Medtronic CoreValve™ or CoreValve™ Evolut™ R TAV. 
Distribution of the subjects within the trial groups will be controlled at the implanting sites by 
means of central randomization using interactive voice/web randomization service (IXRS).  The 
randomization scheme will be securely stored at the IXRS provider. 
                                                    
 
2   Based on protocol design, the time of enrollment will be the same as randomization which is a deviation from ISO 
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Randomization with an assignment to the treatment arm or control arm (TAVI or SAVR) will be 
executed in a 1:1 ratio. Stratified randomization by investigational site and by the need for 
coronary revascularization will be used to ensure subjects will be allocated to each comparison 
group proportionately. Additionally, a blocked randomization scheme with random block sizes 
will be used within each stratum. 
 
 

 
 
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Baseline Assessments 
C.4.6
The following baseline assessments should occur within 14 days prior to the index procedure. 
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
o 
Skin assessment – refer to Radiation Exposure and Data Collection, Appendix 
R.23 
 
NYHA classification 
 
Concomitant medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Routine Laboratory Tests: 
o 
Complete Blood Count 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT) 
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
Neurological Assessments: 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Modified Rankin Score (mRS)  
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
12-lead Electrocardiogram (ECG) 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
o 
Questionnaires may be administered any time after the subject has provided 
informed consent but should be collected prior to informing the subject of their 
treatment assignment 
 
Adverse Event Review 
 
 

 
 
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Transcatheter Aortic Valve Implant or Surgical Aortic Valve Replacement 
C.4.7
Procedure 
C.4.7.1 
TAVI 
General Procedural Considerations  
Transcatheter Aortic Valve Implantation (TAVI) requires meticulous preparation and typically a 
multi-disciplinary team approach involving among others, interventional cardiologists, cardiac 
imaging specialists, cardio-thoracic surgeons and anesthesiologists.  
Within the United States, additional requirements apply for composition of the intra-
operative team for TAVI procedures.  Requirements are outlined in Appendix R.25. 
In case of significant coronary artery disease that requires revascularization, the Heart Team will 
assess the feasibility of performing PCI simultaneously with the TAVI procedure based on the 
coronary lesion characteristics. When it is anticipated PCI can be performed in timely fashion 
with only a limited amount of additional contrast medium it is encouraged to perform PCI 
concomitant with the TAVI. When PCI is deemed challenging requiring relatively more time and 
contrast medium, staged PCI is recommended: TAVI will then be performed at least 7 days after 
PCI.  
The implantation procedure itself takes place either in a catheterization laboratory with adequate 
hygiene precautions or ideally in a hybrid operating room equipped for state-of-the-art 
transcatheter and/or surgical procedures.  
The execution of the TAVI involves an operating team typically consisting of 1 or 2 operators, an 
anesthesia team and at least 2 nurses/technicians. Medtronic representative(s) (eg. Therapy 
Development Specialists, proctors, etc.) may be present during TAVI procedures for training 
process, to perform valve loading or to provide general case support. 
Both the dedicated “valve team” and the operators should have the expertise to select the 
appropriate access route and device size on a patient-per-patient basis. 
All patients undergoing TAVI should be treated using the iliofemoral access route by default (first 
treatment strategy). Additional non-iliofemoral access routes will only be used in case iliofemoral 
access is not feasible.  Alternative access is limited to subclavian and direct aortic. 
The use of an embolic protection device during the TAVI procedure is not permitted. 
 
 

 
 
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Pre-Procedure 
 
Pre-medication recommendations: 
o 
If the subject is currently on warfarin therapy, or local equivalent, prior to the 
procedure: 
 
Discontinue warfarin therapy 3 days prior to the procedure 
 
Confirm that the INR < 1.8 prior to the procedure 
 
Administer antiplatelet therapy: 
 
Aspirin (75- 325 mg) daily or  
 
Clopidogrel (75 mg) daily (or ticlopidine if clopidogrel is 
contraindicated) for 3 days prior to the procedure 
o 
If the subject is currently not on warfarin therapy prior to the procedure: 
 
Aspirin (75-325 mg) on the day of the procedure and 
 
Clopidogrel (300 mg)  
o 
Consider adjunctive proton pump inhibitors, H2 antagonists or antacids 
 
Routine Laboratory Tests: 
o 
Complete Blood Count 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
 
If the GFR < 60 cc/min, consider: 
 
Fluid hydration on the day prior to the procedure 
 
Discontinuation of NSAIDs and ACE inhibitors 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT) 
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
12-lead Electrocardiogram (ECG) 
TAVI Procedure 
 
Medications 
One hour prior to the procedure, prophylactic antibiotic therapy of the Investigator’s 
choice should be initiated: 
o 
Cefuroxime 750mg intravenous (IV) 1 hour pre-procedure, then 6 hours and 12 
hours post-procedure 
o 
If allergic to Penicillin, prescribe Vancomycin 1g IV  
o 
Consider holding anti-hypertensives 
 
Anesthesia and Procedural Set Up 
o 
Establish a central venous line  
o 
Administer general anesthesia or conscious sedation per hospital protocol 
o 
Prior to beginning the investigational TAVI device system implant, place a 
temporary 4-5 Fr. balloon-tip pacing wire in a stable location within the right 
ventricular (a screw-tip wire may be used for more secure placement for 
subjects at high-risk for dislodgement, if necessary) 
o 
Whenever possible, use the upper torso venous system (eg. jugular, subclavian) 
for temporary pacing wire access 
o 
Use fluoroscopy to guide wire placement and stability 
o 
Confirm sensing and capture 
o 
Program the backup pacing rate to minimize ventricular pacing (eg. 30-40 bpm). 
If heart block develops, adjust the rate accordingly 
o 
Record ECG and angiogram during the procedure 
 
Vascular Access 

 
 
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o 
The primary access artery will be used to introduce the CoreValve device and 
the balloon catheter; the secondary access artery will be used to introduce the 
reference pigtail 
o 
Insert a 6Fr introducer sheath into the secondary access artery 
o 
Insert 18Fr introducer sheath into the primary access artery using hospital 
protocol (either percutaneously or surgical cut down) 
o 
Administer anticoagulant therapy according to hospital protocol. If heparin is 
administered as an anticoagulant, check activated clotting time (ACT) at five 
minutes and monitor every 30-60 minutes after initial bolus of heparin  
o 
Maintain ACT ≥ 250 seconds 
o 
Anticoagulant may be administered at any time prior to this point, but avoid 
delaying beyond this point 
 
Crossing the native valve 
o 
Advance the graduated pigtail catheter to the ascending aorta and position the 
distal tip in the noncoronary cusp of the native aortic valve 
o 
Identify the ideal annular viewing plane using contrast injections at various 
angiographic angles, preferably in the left anterior oblique (LAO) projection.  
 
An aortogram with the three aortic cusps aligned in one (1) plane should 
be obtained in order to proceed with the procedure and guarantee an 
optimal working view for eventual implantation 
o 
Insert an angiographic catheter over a standard, J-tip guidewire into the primary 
access sheath and advance to the ascending aorta 
o 
Exchange the J-tip guidewire for a 0.035-in (0.889-mm) straight-tip guidewire. 
Advance the straight-tip guidewire across the native aortic valve into the left 
ventricle 
o 
After crossing the native aortic valve with the guidewire, advance the 
angiographic catheter into the left ventricle 
o 
Exchange the straight-tip guidewires for an exchange-length J-tip guidewire 
o 
Exchange the angiographic catheter for a 6Fr pigtail catheter 
o 
Remove the guidewire and connect the catheter to the transducer. Using both 
catheters, record the aortic pressure gradient 
o 
Using a right anterior oblique (RAO) projection, advance previously pigtail-
shaped, 0.035-in (0.889-mm) high-support guidewire through the pigtail catheter 
and position in the apex of the left ventricle 
o 
Remove the pigtail catheter while maintaining guidewire position in the left 
ventricle 
 
Rapid Pacing and Pre-dilatation of the Implant site 
o 
Insert the valvuloplasty balloon through the 18Fr introducer sheath and advance 
it to the ascending aorta 
o 
Perform a rapid pacing test. A successful test is defined as 1-to-1 pacing 
capture with an immediate drop in pressure and elimination of the systolic-
diastolic waveform 
o 
Reposition the angiographic equipment to the ideal viewing plane as previously 
described. Position the valvuloplasty balloon across the native valve, while 
maintaining strict fluoroscopic surveillance of the distal tip of the guidewire in the 
left ventricle (LV) 
o 
Perform BAV per hospital protocol and remove the valvuloplasty balloon while 
maintaining guidewire position across the native aortic valve 
o 
Balloon sizing directed to 1:1 sizing of the minimal annular diameter by 
computerized tomographic angiography (CTA) or echocardiogram with 
maximum 25 mm balloon 
o 
Perform full balloon expansion 
 
 

 
 
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 
Medtronic CoreValve™ Implantation 
o 
Insert the device over the 0.035-in (0.889-mm) guidewire and advance it, while 
maintaining strict fluoroscopic surveillance of the guidewire in the LV 
o 
When crossing the aortic arch, control the guidewire preventing it from moving 
forward 
o 
Advance the device through the native valve. Perform an angiogram to confirm 
that the graduated pigtail catheter is in position within the noncoronary cusp of 
the aortic root, preferably in the shallow LAO projection 
o 
Use Fluoroscopy to identify the appropriate landmarks 
o 
Place the bioprosthesis within the aortic annulus.  Optimal placement of the 
bioprosthesis is 4 mm - 6 mm below the annulus. The annulus is defined as the 
angiographic floor of the aortic root 
o 
After attaining optimal catheter position, slowly turn the micro knob and begin to 
deploy the bioprosthesis. As the inflow aspect of the bioprosthesis starts to flare 
outward, monitor bioprosthesis position under fluoroscopy 
o 
Caution: During implantation, if resistance to deployment is encountered (for 
example, the micro knob starts clicking or is tight or stuck), apply mild upward 
pressure to the macro slider while turning the micro knob. If the bioprosthesis 
still does not deploy, remove it from the patient and use another system 
o 
Perform an angiogram. Once annular contact is made, the bioprosthesis should 
not be advanced into a lower position 
o 
Continue deploying rapidly to the 2/3 deployment point; stop turning the micro 
knob 
o 
Perform an angiogram to assess the location of the bioprosthesis.  
o 
If the bioprosthesis is positioned low, carefully pull the DCS to reposition the 
bioprosthesis 
o 
Evaluate the valve position and valve function using hemodynamic, 
aortography, and possible echocardiography  
o 
When satisfactory position is achieved, continue to turn the micro knob until 
both frame loops disengage 
o 
Use orthogonal views under fluoroscopy to confirm that the frame loops have 
detached from the catheter tabs. If a frame loop is still attached to a catheter 
tab, under fluoroscopy, advance the catheter slightly and, if necessary, gently 
rotate the handle clockwise (<180°) and counterclockwise (<180°) to disengage 
the loop from the catheter tab 
o 
Withdraw the DCS carefully to the aorta avoiding contact with the inflow portion 
of the frame while maintaining guidewire position 
 
Medtronic CoreValve™ Post Deployment 
o 
Close the DCS capsule and remove the DCS through the 18Fr introducer 
sheath 
o 
Advance a 6Fr pigtail catheter over the guidewire into the left ventricle 
o 
Remove the guidewire and connect the pigtail catheter to the transducer 
o 
Using both pigtail catheters, record aortic pressure gradient 
o 
Withdraw 6Fr pigtail 
o 
Perform post-implant aortogram with the reference pigtail to assure coronary 
patency and assess aortic regurgitations.  Aortogram Acquisition Guidelines are 
located in Appendix R.6 
o 
Remove the 18Fr introducer sheath and complete the puncture site closure per 
hospital protocol 
o 
Perform contrast angiography of the primary vessels to verify the absence of 
any vascular complications with the reference pigtail 
o 
Remove the reference pigtail catheter over a standard guidewire 
o 
Remove the 6Fr introducer and close the access site per hospital protocol 
 
 

 
 
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 
Medtronic CoreValve™ Evolut R™ Implantation 
o 
Prepare the vascular access site according to standard practice 
o 
Predilate the native aortic valve with an appropriate diameter valvuloplasty 
balloon 
o 
Backload the catheter onto the guidewire. Insert the catheter tip and capsule 
through the access site, while maintaining the EnVeo InLine™ sheath tip 
against the proximal end of the capsule. Then, insert the EnVeo InLine™ sheath 
through the access site, maintaining contact with the capsule. Maintain 
guidewire position across the aortic valve. Confirm the position of the trigger 
before crossing the aortic arch 
o 
Under fluoroscopic guidance, advance the catheter and EnVeo InLine™ sheath 
over the guidewire to the aortic annulus. Do not rotate the catheter as it is 
advanced; rotating the handle does not rotate the capsule 
o 
Position the catheter so that the bioprosthesis is at the optimal depth relative to 
the valve annulus 
o 
To deploy the bioprosthesis, rotate the blue actuator in the direction of the 
arrows. The capsule retracts and exposes the bioprosthesis. Continue deploying 
the bioprosthesis in a controlled manner, adjusting valve position as necessary 
and noting the position of the radiopaque capsule marker band and paddle 
attachment 
o 
Warning: Use the blue actuator to deploy and recapture the bioprosthesis. Do 
not use the trigger for deploying or recapturing because it could cause 
inaccurate placement of the bioprosthesis 
o 
Note: Slight repositioning of a partially deployed bioprosthesis (before the 
radiopaque capsule marker band reaches the distal end of the paddle 
attachment) can be achieved by carefully withdrawing the catheter 
o 
Caution: Use the catheter handle to reposition the bioprosthesis. Do not use the 
outer catheter shaft 
o 
Before the radiopaque capsule marker band reaches the distal end of the 
paddle attachment, evaluate the bioprosthesis position 
o 
Note: During deployment, the blue actuator clicks as a notification before the 
radiopaque capsule marker band reaches the paddle attachment 
o 
Either complete bioprosthesis deployment or initiate bioprosthesis recapture 
 
 
Medtronic CoreValve™ Evolut R™ Recapture (Optional)  
o 
The bioprosthesis should only be recaptured and redeployed a maximum of 2 
times. The bioprosthesis can be recaptured a third time to remove the 
bioprosthesis from the subject 
o 
Rotate the blue actuator in the opposite direction of the arrows to recapture 
the bioprosthesis 
o 
Warning: Use the blue actuator to deploy and recapture the bioprosthesis.  
o 
Do not use the trigger for deploying or recapturing because it could cause 
inaccurate placement of the bioprosthesis 
o 
Continue rotating the blue actuator until the gap between the capsule and 
catheter tip is closed 
o 
Caution: Stop advancing the capsule once the gap to the catheter tip is 
closed. Advancing the capsule farther could damage the capsule 
o 
Reposition the recaptured bioprosthesis at the optimal depth relative to the 
valve annulus 
o 
Deploy the bioprosthesis 
o 
Either complete bioprosthesis deployment or initiate bioprosthesis recapture. 
If the bioprosthesis has been recaptured 2 times and then deployed in a non-
optimal position, recapture and withdraw the bioprosthesis 
 
 

 
 
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 
Medtronic CoreValve™ Evolut R™ Post Deployment 
o 
Close the catheter capsule before withdrawal 
o 
Caution: Close the capsule until it is aligned with the catheter tip. Do not 
overcapture the catheter tip, because it could interfere with catheter 
withdrawal through the introducer 
o 
Withdraw the catheter until the capsule meets the distal end of the EnVeo 
InLine™ sheath 
o 
Withdraw the catheter and EnVeo InLine™ sheath together, and dispose of 
the device in accordance with local regulations and hospital procedures 
o 
Perform routine aortogram to assess the bioprosthesis for proper expansion 
and function per the Aortogram Acquisition Guidelines located in Appendix 
R.6 
 
Ballooning as needed during the implant procedure is standard practice and should not be 
considered a reintervention. 

 
 
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Immediate Post-Procedure  
The procedure is considered complete after final angiography has been performed, and the 
introducer/InLine sheath has been removed from the subject.  Thereafter, if an introducer/InLine 
sheath is re-introduced, this is considered a repeat intervention, which must be documented on 
the reintervention Electronic Case Report Form (eCRF).  
 
Coronary Arteriogram 
 
Following the current recommendation all patients with prosthetic heart valves need 
endocarditis prophylaxis 
 
All patients should receive Deep Vein Thrombosis (DVT) prophylaxis with Heparin/Low 
Weight Molecular Heparin (LMWH) starting approximately 6 hours after TAVI if bleeding 
permits 
 
Anticoagulants should be discontinued per hospital standard 
 
Activated clotting time (ACT) should be monitored per hospital standards but 
recommendation is >250 seconds 
 
Cardiac Enzymes: CK within 8-12 hours post procedure and at any time when a clinical 
ischemic event is suspected.  
o 
CK-MB is required if CK is elevated >2X the laboratory upper limit of normal.  
o 
If a clinical event is confirmed, a total of 3 draws of cardiac enzymes within the 
first 24 hours (drawn approximately every 8 hours) following the clinical event 
should be obtained 
 
12-lead Electrocardiogram (ECG) to be performed within 48 hours of procedure 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) to be completed with 24 hours 
of procedure 
 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic 2D echocardiogram (TTE) should be performed within 
24-48 hours post-procedure or prior to discharge to assess device success.  
Echocardiograms will be performed according to Echocardiography Procedures found 
in Appendix R.7  
 
It is recommended that subjects are treated for a minimum of three months with dual 
anti-platelet medication 
o 
If the patient is on warfarin therapy post-procedure it is recommended that 
subjects are prescribed either daily: 
 
Aspirin (75 to 325 mg) or  
 
Clopidogrel (75 mg) (or ticlopidine, if clopidogrel is contraindicated) for 
at least three months following the procedure 
o 
If the patient will not be on warfarin therapy post-procedure it is recommended 
that subjects are prescribed daily: 
 
Aspirin (75to 325 mg) and  
 
Clopidogrel (75 mg) (or ticlopidine, if clopidogrel is contraindicated) for 
at least three months following the procedure 
 
Concomitant medications 
 
Adverse events review 
o 
Document all  adverse events, including all unanticipated adverse device effects 
(UADE) or unanticipated serious adverse device effects (USADE), technical 
observations, reinterventions or repeat admissions to the catheterization suite 
and deaths 
o 
Any patient with evidence of a new neurological event should have a neurology 
consult and subsequently an imaging trial if deemed necessary by the 
neurologist or stroke specialist 
o 
Any patient exposed to substantial radiation dose levels, as outlined in 
Appendix R.23, should be assessed for skin reactions 

 
 
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Post-Procedure Pacing Guidelines 
 
All patients should stay on telemetry until discharge 
 
Maintain temporary pacing until at least 48 hours post-implant in Cardiovascular 
Intensive Care Unit (CV-ICU) or local equivalent 
 
After 48 hours, obtain ECG and assess patient rhythm and conduction 
 
Based on assessment, and with the consult of an electrophysiologist as needed, take 
one of the following actions: 
o 
Discontinue temporary pacing 
o 
Continue temporary pacing for another 24 hours (longer if needed) to make 
further assessments 
o 
Place a permanent pacemaker according to ACC/AHA/HRS Guidelines for 
Device-Based Therapy of Cardiac Rhythm Abnormalities (Class I or IIb for 
Acquired Atrioventricular Block in Adults or Permanent Pacing in Chronic 
Bifascicular Block) as outlined in Appendix R.13 
o 
Prior to the permanent pacemaker implantation, document the reason for the 
placement of the permanent pacemaker via a 12-lead ECG 
o 
For complete heart block, review patient medications 
o 
Consider withholding some medications to assess for patient’s intrinsic rate and 
conduction 
o 
If heart block persists off medications, a permanent pacemaker should be 
considered 
o 
If a permanent pacemaker is required, a dual chamber system is recommended 
to optimize patient hemodynamics 
o 
For additional information refer to the Pacing Guidelines in Appendix R.13  
C.4.7.2 
Surgical Aortic Valve Replacement 
Minimum Standards for Surgical Aortic Valve Replacement  
Subjects randomized to SAVR should be treated according to the surgeon and hospital’s 
standard practices. The surgeon or co-surgeon performing the SAVR must be a trial investigator 
for the site. The choice of surgical valve is left to the discretion of the investigator. However, the 
use of a bioprosthetic valve is required. 
SAVR must be conducted as an isolated procedure with exception of subjects that have 
been randomized to SAVR with revascularization (eg. Aortic replacement or Maze 
procedures are not permitted). In cases of significant coronary artery disease that requires 
revascularization coronary artery bypass grafting (CABG) will be conducted concomitantly with 
SAVR.   
Additional concomitant cardiac and non-cardiac procedures are not permitted with the exception 
of the procedures outlined under Additional Procedural Considerations. 
General Procedural Considerations 
One of the key requirements for good surgical outcome is an excellent collaboration of the 
dedicated multidisciplinary teams consisting of typically two cardiac surgeons with SAVR 
experience, a cardiac anesthesia team, an experienced cardio technician as well as at least two 
operation theater nurses.  
 
Operation Theater 
Surgical aortic valve replacement is to be performed in an operative theater with state-of-the-art 
technical equipment with certified sterility standards, adequate illumination, laminar flow, 
dedicated scrub nurses, and on site full technical support.  
 
Perfusion 
A dedicated, experienced perfusion team with greater than 75 Extracorporeal Circulation (ECC) 
runs per cardio technician per year who can perform all current cardioplegia strategies and is 
familiar with deep hypothermic circulatory arrest (DHCA) is recommended.  The perfusion team 
should be capable of covering the full heart surgical spectrum including CABG, heart valve 
defect (HVD), Heart failure and assist devices, extracorporeal membrane oxygenation (ECMO) 
support, intra-aortic balloon pump (IABP), and cardiac transplant.   
 

 
 
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Pre-Procedure 
 
Pre-medication recommendations: 
o 
Discontinue warfarin therapy 3 days prior to the procedure, if applicable 
 
Confirm that the INR < 1.8 prior to the procedure 
o 
Administer antiplatelet therapy, per local standards 
o 
Consider adjunctive proton pump inhibitors, H2 receptor antagonists or antacids 
 
Routine Laboratory Tests: 
o 
Complete Blood Count 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
 
If the GFR < 60 cc/min, consider: 
 Discontinuation of NSAIDs and ACE inhibitors 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT) 
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
12-Lead Electrocardiogram 
 
One hour prior to the procedure, prophylactic antibiotic therapy of the Investigator’s 
choice should be initiated: 
o 
Cefuroxime 750mg IV 1 hour pre-procedure, then 6 hours and 12 hours post-
procedure 
o 
If allergic to Penicillin, prescribe Vancomycin 1g IV  
o 
Consider holding anti-hypertensives 
Surgical Considerations  
Surgical aortic valve replacement is typically performed with cardio-pulmonary bypass (CPB) on 
an arrested heart with a clamped aorta. Local practice and surgical standards should govern 
type of cardioplegia and the temperature/flow/pressure perfusion strategy as well as the 
activated clotting time used at either institution for safe CPB. Typically a minimum of 2 
liters/m²/minute with a systemic arterial blood pressure of 60mmHg during CPB should be 
maintained and possibly increased in the elderly patients.  
Cannulation for isolated SAVR CPB should be ascending aorta for arterial return unless there is 
ascending aortic arteriosclerosis or dilatation (>4cm in diameter), and right atrial for venous 
drainage. Embolic devices are not routinely used in SAVR. 
 

 
 
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Typical surgical workflow and general procedural recommendations 
 
Procedural set-up and Anatomic Evaluation: 
o 
The patient is prepared and draped 
o 
IV antibiotics should be administered following the local standard of care  
o 
Following the presternal skin incision the sternum is split 
o 
Prepare the mediastinum and open the pericardium  
o 
Inspect the ascending aorta for calcifications (including epiaortic scan if 
necessary) 
o 
Complete heparin application and arterial and venous cannulation 
o 
Initiate CPB, and at surgeons discretion, left heart venting via right upper 
pulmonary vein or pulmonary artery  
o 
Cross clamp the aorta and initiate cardioplegic arrest  
o 
Perform an aortotomy  
o 
Complete annular decalcification (the surgeon should take all possible means to 
prevent embolization of debris)  
 
Prosthesis Specific Sizing: 
 
If the aortic annulus does not permit valve replacement with a patient matched 
valve diameter, the aortic annulus should be enlarged at the surgeon’s 
discretion  
 
Valve Preparation and Implantation: 
o 
The valve prosthesis should be prepared following the manufacturer 
recommendations  
o 
After rinsing bioprosthetic valves should be kept wet throughout the procedure 
o 
Anchoring of the prosthesis with, for example, interrupted Teflon reinforced 
Tycron sutures or an equivalent technique is recommended 
o 
De-air and close the aortotomy 
o 
Insert temporary ventricular and atrial pacing wires and chest tubes  
o 
Wean from ECC hemostasis  
o 
Complete sternal wiring and layered closure 
 
Additional Procedural Considerations: 
o 
In case of concomitant significant subvalvular left ventricular outflow tract 
occlusion (LVOTO) then resection is recommended 
o 
If there is a significant patent foramen ovale (PFO) closure is recommended in 
cases of substantial right to left flow 
o 
It might be recommendable to apply CO2 surgical field flooding to ease de-airing  
 
Intraoperative Aortic Assessment     
o 
Transesophageal echo (TEE) is recommended in all cases to additionally 
assess for aortic calcifications before manipulating the aorta. In case of doubt 
an Epiaortic scan might further help for surgical decision making 
o 
Additionally the TEE should be used to assess for subvalvular LVOTO and 
patent foramen ovale 
 
 Before Termination of Surgery Repeat Intraoperative TEE     
o 
TEE is recommended to assess the postoperative SAVR result  
 
Assessment should include aortic valve function, central or paravalvular 
leakage, valve gradient, exclude remaining LVOTO from subvalvular 
stenosis as well as ventricular function with special emphasis on new 
segmental wall function abnormalities. 
 
Any regurgitation of more than trace should be critically evaluated and 
at surgeon’s discretion the valve re-inspected and if necessary 
changed. 
 

 
 
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Immediate Post-Procedure  
The procedure is considered complete at the time of skin closure. Immediately post-procedure 
the following tests and procedures must be performed and data collected: 
 
Cardiac Enzymes: CK within 8-12 hours post procedure and at any time when a clinical 
ischemic event is suspected.  
o 
CK-MB is required if CK is elevated >2X the laboratory upper limit of normal.  
o 
If a clinical event is confirmed, a total of 3 draws of cardiac enzymes within the 
first 24 hours (drawn approximately every 8 hours) following the clinical event 
should be obtained 
 
Concomitant Medications 
 
12-lead Electrocardiogram (ECG) to be performed within 48 hours of procedure 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) to be completed within 24 
hours of procedure 
 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic 2D echocardiogram (TTE) should be performed at 
least 24hours post-procedure but prior to discharge to assess device success 
(and no later than 7 days, whichever comes first)   
o 
Echocardiograms will be performed according to Echocardiography Procedures 
found in Appendix R.7  
 
Adverse Event review 
Post-Procedural Medication 
 
It is recommended that subjects are treated with aspirin (75-325mg daily) for a minimum 
of three months  
 
If warfarin therapy is indicated (eg. A-fib): maintain therapeutic anticoagulation with 
Heparin or Low Molecular Weight Heparin until INR between 2 and 3 is reached after 
loading with warfarin 
 
The preoperative antibiotic therapy may be repeated within the next 6 to 12 hours 
 
All patients should receive DVT prophylaxis with Heparin/LMWH starting approximately 
6 hours after SAVR if bleeding permits 
 
Following the current recommendation all patients with prosthetic heart valves need 
endocarditis prophylaxis 
Post-Procedure Pacing Guidelines 
 
All patients should stay on telemetry until discharge 
 
Maintain temporary pacing until at least 48 hours post-implant in CV-ICU or local 
equivalent 
 
After 48 hours, obtain ECG and assess patient rhythm and conduction 
 
Based on assessment, and with the consult of an electrophysiologist as needed, take 
one of the following actions: 
o 
Discontinue temporary pacing 
o 
Continue temporary pacing for another 24 hours (longer if needed) to make 
further assessments 
o 
Place a permanent pacemaker according to ACC/AHA/HRS Guidelines for 
Device-Based Therapy of Cardiac Rhythm Abnormalities (Class I or IIb for 
Acquired Atrioventricular Block in Adults or Permanent Pacing in Chronic 
Bifascicular Block) as outlined in Appendix R.13 
o 
Prior to the permanent pacemaker implantation, document the reason for the 
placement of the permanent pacemaker via a 12-lead ECG 
o 
For complete heart block, review patient medications 
o 
Consider withholding some medications to assess for patient’s intrinsic rate and 
conduction 
o 
If heart block persists off medications, a permanent pacemaker should be 
considered 
o 
If a permanent pacemaker is required, a dual chamber system is recommended 
to optimize patient hemodynamics 
o 
For additional information refer to the Pacing Guidelines in Appendix R.13 

 
 
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Assessments done at discharge (both SAVR and TAVI) 
C.4.8
Prior to hospital discharge (or within 7 days post-index procedure, whichever occurs first) the 
following tests and procedures must be performed and data collected: 
 
Physical Examination 
o 
Vital signs 
o 
Major system findings 
o 
Skin Assessment – refer to Radiation Exposure and Data Collection, Appendix 
R.23 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets)   
 
Routine Laboratory Tests: 
o 
Complete Blood Count: 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT) 
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
Neurological Assessments 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Modified Rankin Score (mRS) 
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic 2D echocardiogram (TTE) should be performed at 
least 24hours post-procedure but prior to discharge to assess device success 
(and no later than 7 days, whichever comes first)   
o 
Echocardiograms will be performed according to Echocardiography Procedures 
found in Appendix R.7 
 
12-lead Electrocardiogram 
 
Adverse Event review 

 
 
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Follow-Up Evaluations 
C.4.9
All randomized subjects will undergo in-clinic follow-up evaluations at the following time points 
post implant.   
All follow-up periods are defined as the number of days after the date of the index procedure 
(TAVI or SAVR).  
Day 0 = day of index procedure (TAVI or SAVR): 
 
30 days (- 7 days and + 14 days) 
 
3 months (90 ± 14 days) 
 
6 months (180 ± 30 days) 
 
12 months (365 ± 30 days) 
 
18 months (545 ± 60 days) 
 
24 months (730 ± 60 days) 
 
3 years (1080 ± 60 days) 
 
4 years(1440 ± 60 days) 
 
5 years (1800 ± 60 days) 
All randomized subjects will complete long-term follow-up through at least 5 years.  Based on 
clinical assessments or regulatory requirements, follow-up may be extended to up to 10 years 
post-index procedure. Upon completion of the final protocol visit (discontinuation) subject 
participation will be considered complete and the patient should then be followed per the local 
standard of care for their condition. 
Note: For subjects where the Index Procedure is never be attempted (eg. subject withdraws 
consent for the procedure but agrees to complete follow-up) follow-up intervals will be 
calculated from the 31st days post-randomization (i.e. the 1st day after the 30 day window 
from randomization to complete the Index Procedure). 
C.4.9.1 
30 Days 
The following assessments will be conducted at the 30 day visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
o 
Skin Assessment – refer to Radiation Exposure and Data Collection, Appendix 
R.23 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Routine Laboratory Tests: 
o 
Hemoglobin 
o 
Creatinine and Creatinine Clearance 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
12-lead Electrocardiogram 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event review 
 
 

 
 
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C.4.9.2 
3 Months 
The following assessments will be conducted via telephone at the 3 Month visit.   
 
Quality of Life Questionnaire 
o 
EQ-5D  
o 
SF-36 – in selected geographies.  Refer to Appendix R.12 for instructions on 
which geographies are required to collect the questionnaire 
C.4.9.3 
6 Months 
The following assessments will be conducted at the 6 Month visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
Quality of Life Questionnaires 
 
Adverse Event Review 
C.4.9.4 
12 Months 
The following assessments will be conducted at the 12 Month visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Neurological Assessments 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Modified Rankin Score (mRS) 
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event review 
 
 

 
 
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C.4.9.5 
18 Months 
The following assessments will be conducted at the 18 Month visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
12-lead Electrocardiogram 
 
Quality of Life Questionnaires 
 
Adverse Event review 
C.4.9.6 
24 Months 
The following assessments will be conducted at the 24 Month visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Concomitant medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Neurological Assessments 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Modified Rankin Score (mRS) 
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event review 
C.4.9.7 
3-5 Years 
The following assessments will be conducted at the 3, 4, and 5 year visits.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
Quality of Life Questionnaires 
 
Adverse Event review – refer to C.5.2 Reporting for AE reporting requirements post-24 
Months 
 
 

 
 
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 Echo Assessment 
C.4.10
Echocardiography is the cornerstone of baseline and follow-up imaging. A comprehensive 
transthoracic echocardiogram (TTE) to assess the morphology and function of the respective 
heart chambers and valves is mandatory prior to implant. Calculation of LVEF by visual 
assessment, measurement of left ventricular end-diastolic volume and diameter and inter-
ventricular septal thickness to characterize the left ventricle and transaortic jet velocity, mean 
transaortic gradient and aortic valve area by the continuity equation to illustrate AS severity are 
essential(1).  
Echo assessment will be conducted by a core laboratory. 
Sites should make every effort to utilize the same echo machine for all subjects at all required 
interval throughout the duration of the protocol.   
 Neurologic Assessment 
C.4.11
The incidence of new clinically detectable neurological events or deficits, or any comparative 
change in indices of higher cognitive function following  TAVI in the treatment of patients with 
symptomatic severe aortic stenosis is an important clinical endpoint. Therefore, a baseline and 
follow-up neurological examination by a qualified trial-trained neurologist or stroke specialist is 
mandatory and as outlined in section C.4.9 Follow-Up Evaluations.  Abbreviated Neurological 
Assessments, requiring completion of only the NIHSS, may be conducted by certified site 
personnel. 
If at any time there is change in a subject’s NIHSS score of ≥4 further assessments 
should be conducted to identify potential adverse events and additional neurological 
evaluations should be conducted by a neurologist or stroke specialist, if a neurological 
event is suspected.   
In case of a new neurological event, the diagnosis of stroke should be supported by 
complementary findings on neuro-imaging examination. The need for additional imaging is up to 
discretion of the Neurologist or Stroke Physician. Both diffusion-weighted Magnetic Resonance 
imaging and multi-slice Computed Tomography are valid neuro-imaging modalities (however 
CTA or MRA is preferred to CT or MRI), the selection of which will be left per institution’s 
standard of care.  
In addition to the neurological assessments at specified time periods, additional evaluations 
should be conducted, as follows during the course of the trial, if applicable: 
 
NIHSS:   
o 
For subjects with a new neurological event (stroke, TIA, or encephalopathy), 
additional NIHSS exams are to be performed at 30 days, and 3 months post-
event 
o 
NIHSS also to be done within 24 hours of any aortic valve or ascending aortic 
intervention 
 
Any patient with evidence of a new neurological event should have a 
neurology consult and an imaging study if deemed necessary 
 
NIHSS may be conducted by certified site personnel 
 
Modified Rankin Scale 
o 
For subjects with new neurological event, assessment to be performed at 7 
days or discharge (whichever occurs first), 30 days, and 3 months post-stroke 
 
All trial-required mRS testing should be conducted by a neurologist or 
stroke specialist  
 
Mini Mental State Exam (MMSE-2:SV) 
o 
For subjects with a new neurological event assessments are to be performed at 
30 days and 3 months post-stroke 
 
All trial-required MMSE testing should be conducted by a neurologist or 
stroke specialist  
Refer to the Appendix R.18 for a description of the Additional Neurological Testing. 

 
 
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Angiographic and Computed Tomography Assessment 
C.4.12
Complete angiographic (invasive or MSCT) assessment of the aortic bifurcation and ilio-femoral-
arterial tree is mandatory prior to the Heart Team review. 
An additional benefit of Multislice CT scan in the TAVI cohort is to obtain a thorough assessment 
of the anatomy of the left ventricular outflow tract (LVOT) up to the common femoral arteries. 
MSCT also provides information on coronary and carotid anatomy, and might identify occult 
malignancy which is also valuable information in SAVR cohort.   
The aortic valve calcification should be evaluated to determine grade of severity.  With respect 
to the elliptical shape of the virtual aortic annulus, the axial plane where the 3 basal aortic leaflet 
attachments can be identified simultaneously is used for measuring the maximum and minimum 
annular diameter (most often corresponding to 2 orthogonal sagittal and coronal planes)(53). 
Additionally the maximum diameters of the LVOT, sinuses of Valsalva and sinotubular junction 
are obtained. Maximum diameter, calcification and tortuosity of the ascending and descending 
thoracic aorta are evaluated. As for the iliofemoral tree, the minimal luminal diameter, plaque 
and calcification burden and tortuosity are assessed in order to judge transfemoral accessibility 
for the investigational TAVI device. 
 
 

 
 
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Data Collection 
C.4.13
All scheduled testing and procedures to be conducted during the baseline, index procedure, and 
follow-up assessments are summarized in Table 3. 
 
Table 3:  Schedule of Assessments 
 
 
 
Parameter 
Screening 
RANDOMIZATION  
Baseline 
(within 14 days of 
procedure) 
Procedure 
Discharge 
30 days 
3 Months 
6  Months 
12 Months 
18 Months 
24 Months 
3 – 5  years 
Informed consent (and in US HIPAA 
Authorization) 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
 
 
* 
 
 
 
 
 
 
 
 
Demographics and Medical history 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments  
 
 
 
 
 
 
 
 
 
 
 
NYHA Class 
 
 
 
 
 
 
 
 
 
 
 
Risk Assessments: STS Risk Score, Logistic 
EuroSCORE, EuroSCORE II, SYNTAX Score, 
and Katz Index 
 
 
 
 
 
 
 
 
 
 
 
Co-morbidities 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications11 
 
 
 
 
 
 
 
 
 
 
 
Routine Laboratory Tests 
 
 
1,2 
 
3 
 
 
 
 
 
 
Neurological Assessments7 (NIHSS, mRS, 
MMSE-2:SV and Additional Neurological 
Assessments)9 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Neurological Assessment     
(NIHSS only) 
 
 
8 
 
 
 
 
 
 
 
 
Transthoracic Echocardiogram (TTE) 
 
 
5 
 
 
 
 
 
 
 
Computed Tomography (CT) Angiogram 
(MSCT required at screening)6 
 
 
 
 
 
 
 
 
 
 
 
Coronary Arteriogram 
 
 
() 
 
 
 
 
 
 
 
 
Aortogram  
 
 
() 
 
 
 
 
 
 
 
 
12-lead Electrocardiogram 
 
 
4 
 
 
 
 
 
 
 
 
6 Minute Walk Test 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life Questionnaires (EQ-5D, KCCQ, 
and SF-36) 
 
12 
 
 
 
13
 
 
 
 
 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
10 

 
 
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* Document any changes to subject condition that affect inclusion/exclusion criteria, confirm the subject 
does not meet any exclusion criteria specific to the Index Procedure (eg. percutaneous coronary or 
peripheral intervention and evidence of an acute myocardial infarction which must not occur within 30 
days prior to the index procedure) 
(•)  TAVI subjects only (SAVR subjects will not have these assessments) 
1  Laboratory test results must be performed pre-procedure and CK to be obtained within 8-12 
hours post-procedure  
2  Pre-procedure 
3  Only hemoglobin, creatinine and creatinine clearance are required to be collected 
4  Electrocardiogram within 48 hours post-procedure 
5  TTE to be completed at least 24hours post-procedure but prior to discharge (and no later 
than 7 days post procedure) to assess device success 
6  All subjects should have screening thoracic and abdominal CT angiograms with complete 
visualization of both iliacs, femorals, and aorta (and subclavian/axillaries, if applicable), up to 
and including the aortic annulus 
7  In addition to the protocol required assessment (NIHSS and MMSE); for subjects with 
neurological event or stroke, additional NIHSS and MMSE exams are to be performed at 30 
days and 90 days post-event. mRS should be completed at 7 days post-event or discharge 
(whichever occurs first), 30 days, and 90 days post-event. NIHSS is also to be done within 24 
hours of any aortic valve or ascending aortic intervention 
8  NIHSS to be done within 24 hours post- procedure 
9  Additional Neurological Assessments include:  Visual Fields Testing, Gait Assessment, Hand 
Function, Writing Evaluation, and Drawing Assessment 
10  SAE, MAE, cardiovascular events, device-related events, including device-related technical 
observations, UADEs, USADEs, all stroke (CVAs), and death reports 
11  Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, beta-blockers, 
statins and anti-platelets)   
12   Quality of Life Questionnaires collected at baseline may be administered any time after the 
subject has provided informed consent but should be collected prior to informing the subject 
of randomization assignment   
13   Quality of Life Questionnaire – EQ-5D to be administered via telephone.  SF-36 will also be 
collected in selected geographies, refer to Appendix R.12 
 

 
 
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Unscheduled Follow-up Assessments 
C.4.14
If a subject returns to the institution between their scheduled follow-up visits the visit will be 
treated as an unscheduled visit and the assessments completed at this visit will be done at the 
discretion of the investigator. eCRFs are provided for unscheduled visits.   
 
Missed Follow-up Visits 
C.4.15
Every effort should be made to ensure subjects return to the clinic for all protocol required 
follow-up.  If the subject is unable to return for an in-person clinic visit, the Investigator, or 
designee, must document in the patient record the reason the subject was unable to complete 
the visit and, if applicable, follow the requirements for deviation reporting as outlined in Section 
C.4.18 Protocol Deviations. 
The Investigator should also make every effort to contact the subject or subject’s legal 
representative, within the visit window, to collect the subject’s vital status as well as information 
related to potential adverse events, safety data, and hospitalizations. 
 
Investigational Product Accountability 
C.4.16
The Investigator is responsible for maintenance of the Device Accountability Log. The log must 
detail the product and lot numbers as well as the location and status of all investigational 
devices (including DCS,CLS/ LS components, where applicable) received by the hospital and/or 
Investigator. At the end of the clinical trial the Principal Investigator must sign the original log, as 
applicable. 
This clinical trial will be conducted in some geographies where the TAV device or its 
components are commercially available.  In these geographies, the device will be used outside 
the current approved indication; therefore the TAV will be labeled as investigational.  Note, the 
DCS and CLS/LS components are identical to the CE marked CoreValve System and will be 
supplied within the approved commercial CE marked labeling. The Investigator must provide full 
accountability for each TAV from the time of receipt through disposition and/or return.  
Accountability for the each DCS and CLS/LS must include all dispositions within the clinical trial. 
In the US, commercial devices, as referenced in Table 1, are approved for use in the 
clinical trial, as necessary, in the event that an investigational device is not available. In 
the event that a commercial device is used in a study subject, the device use will be 
documented in the Device Accountability Log. 
In geographies where the device is not currently approved, the TAV, DCS, CLS/LS components 
will be labeled as investigational.  The Investigator must provide full accountability for each TAV, 
DCS, and CLS/LS from the time of receipt through disposition. 
At the end of the trial enrollment period, all remaining investigational product must be returned to 
Medtronic.  
 
Device Malfunction or Explant 
C.4.17
In the event of a device malfunction of the  TAV device or its components prior to implant or in 
the event that a TAV is explanted after implant (due to reintervention or autopsy), the TAV 
and/or affected components should be returned to Medtronic to the following:   
 
Medtronic, Inc.  
Attn: Explant Lab [PE#] 
1851 E. Deere Avenue 
Santa Ana, CA  92705-5720 
 
 
Additional details surrounding the device return process, including how to obtain the PE # 
(product experience number), are contained within the Medtronic explant kit and in Appendix 
R.11. 

 
 
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 Protocol Deviations 
C.4.18
A protocol deviation is defined as an event where the clinical investigator or site personnel did 
not conduct the trial according to the protocol or the Investigator agreement.  Deviations will be 
reported regardless of whether medically justifiable, pre-approved by Medtronic, or taken to 
protect the patient in an emergency. 
A protocol deviation form is to be completed for each trial protocol deviation, including, but not 
limited to: 
 
Failure to obtain informed consent 
 
Incorrect version of consent provided to patient 
 
Failure to obtain IRB/MEC protocol review and approval before starting the trial 
 
Enrollment of patient during an IRB/MEC approval lapse 
 
Clinical investigator exceeding enrollment limits specified by sponsor 
 
Patient did not meet inclusion/exclusion criteria 
 
Incorrectly performed testing 
 
Protocol-required testing and/or measurements not done or performed outside of 
window 
 
Source data permanently missing 
 
SAE, SADE, UADE or USADE not reported in the required timeframe 
FDA regulations [21 CFR 812.140] require that the Investigator maintain accurate, complete, 
and current records, including documents showing the dates of and reasons for each deviation 
from the protocol.  Relevant information for each deviation will be documented on a deviation 
form completed by site personnel and reviewed by the Investigator. 
FDA regulations  [21 CFR 812.150], ISO 14155 (2011), and local regulatory authorities (where 
applicable), require Investigators to obtain prior approval from the sponsor before initiating 
changes in or deviations from the protocol, except when necessary to protect the life or physical 
well-being of a patient in an emergency.   
Prior approval by the sponsor is expected in those situations in which the Investigator 
anticipates, contemplates or makes a conscious decision to depart from procedures specified in 
the protocol.  Prior approval is generally not expected in situations where unforeseen 
circumstances are beyond the Investigator’s control, but is still considered a deviation (eg. a trial 
subject who fails to attend a scheduled follow-up visit, a trial subject too ill to perform a protocol-
required test).  To obtain approval, the Investigator must call or email and discuss the potential 
deviation with the Medtronic trial manager or designee prior to initiating any changes.  If 
approval is granted, the Medtronic trial manager or designee will provide the applicable 
documentation to be maintained in the site files. 
FDA regulations require the Investigator to notify the sponsor and the reviewing IRB/MEC within 
5 working days of the following deviations [21 CFR 812.150]: 
 
a deviation from protocol to protect the life or physical wellbeing of a patient in an 
emergency 
 
failure to obtain an informed consent   
Investigators or an authorized designee must notify Medtronic as soon as possible by calling the 
trial manager or designee and completing the protocol deviation form. 
The Investigator is required to adhere to local IRB/MEC procedures for reporting deviations. 
The DSMB may review protocol deviations to ensure compliance and overall trial integrity. 

 
 
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Subject Withdrawal or Discontinuation 
C.4.19
All subjects will be encouraged to remain in the trial through the last follow-up visit at month 60.  
Subjects who discontinue participation prematurely after randomization will be included in the 
analysis of results (as appropriate) but they will not be replaced in the enrollment of total trial 
subjects. If a trial subject is discontinued from the trial early, the reason for discontinuation 
should be documented in the patient file and a Study Exit eCRF must be completed.  If 
discontinuation is because of safety concerns or lack of effectiveness, the subject shall be asked 
to be followed for collection of ongoing safety data outside the clinical investigation. 
The trial site and Sponsor will make every effort to have all subjects complete the follow up visit 
schedule.  A subject will not be considered lost-to-follow-up unless all efforts to obtain 
compliance are unsuccessful. At a minimum, the effort to obtain follow-up information must 
include three attempts to make contact via telephone and if contact via phone is not successful, 
a traceable letter from the Investigator must be sent to the subject’s last known address.  Should 
both telephone and mail efforts to contact the subject be unsuccessful, the subject’s primary 
physician should be contacted.  Subjects will then be deemed lost to follow up.  All contact 
efforts to obtain follow-up must be documented in both the subject’s medical records and in the 
trial eCRFs. 
If a subject officially withdraws from the trial but is willing to allow either regular vital status 
determinations for the trial or a one-time vital status determination, these are to be conducted 
per the follow-up visit schedule or only at the last planned follow-up visit, respectively, and may 
be conducted via telephone.   
If a subject discontinues the trial at any time, is withdrawn from the trial early, or completes all 
protocol required follow-up they should then be followed per the local standard of care for their 
condition. 
 Termination or Discontinuation of Trial 
C.4.20
Medtronic may decide to suspend or prematurely terminate the trial.  If the trial is terminated 
prematurely or suspended, Medtronic shall promptly inform the clinical investigators of the 
termination or suspension and the reason(s) for this. The investigator shall then promptly inform 
the reviewing MEC/IRB. 
Possible reasons for early trial termination include: 
 
Unanticipated Adverse Device Effect (UADE) or Unanticipated Serious Adverse 
Device Effect (USADE) presents an unreasonable risk to patients 
 
Recommendation from DSMB (eg. significant safety concerns, statistical futility) 
If the trial is terminated early, the Sponsor will, as soon as possible, provide a written statement 
to the Investigators to enable prompt notification of the IRB/MECs.  The Sponsor will also inform 
the FDA.  If the trial enrollment is terminated early, the follow-up visits will continue for all 
enrolled subjects. 
 
 

 
 
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C.5 
Adverse Events 
 
Definitions 
C.5.1
The definitions presented in this section allow for a clear understanding of adverse event data 
collection and subsequent analysis.  
C.5.1.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device.   
NOTE 1: This definition includes events related to the investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3:  For users or other persons, this definition is restricted to events related to investigational medical devices. 
The following events in Table 4 are expected to occur with any surgical implant and therefore 
should not be reported as AEs, unless they occur outside of the stated timeframe: 
Table 4:  Expected Events 
Description of the Event 
Timeframe (hours) from Procedure 
Anesthesia-related nausea and/or vomiting 
24 
Low-grade fever (<100oF or <37.8oC) 
48 
Back pain related to laying on the procedure table 
72 
Incisional pain (pain at access site) 
72 
Sleep problems or insomnia 
72 
Mild to moderate bruising or ecchymosis 
168 
C.5.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is an event that: 
 
Led to death 
 
Led to serious deterioration in the health of the subject, that either resulted in: 
o a life threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o inpatient or prolonged hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure of a body function  
 
Led to fetal distress, fetal death or a  congenital anomaly or birth defect 
NOTE:  Planned hospitalization for a pre-exiting condition, or a procedure required by the CIP, without serious 
deterioration in health, is not considered a serious adverse event. 
In addition to above standard definition of SAE, the following events will also be defined as 
serious in the SURTAVI Trial, including events that do not meet the above criteria for SAE. 
 
Stage 2 and 3 acute renal injuries 
 
Life-threatening and Major bleeding events 
 
Any new or worsening LBBB or RBBB that requires the placement of a permanent 
pacemaker and/or surgical or invasive intervention 
 
All myocardial infarctions 
 
Disabling strokes 
 
Major vascular complications 
Events that do not meet these criteria are considered non-serious. 
C.5.1.3 
Major Adverse Cardiovascular and Cerebrovascular Events 
Major adverse cardiovascular and cerebrovascular events (MACCE) is defined as a composite 
of: 
 
All-cause death 
 
Myocardial infarction (MI)  
 
All stroke, and 

 
 
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 
Reintervention (defined as any cardiac surgery or percutaneous reintervention catheter 
procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted 
valve) 
C.5.1.4 Major Adverse Event 
Major adverse event (MAE) includes: 
 
MACCE 
 
Acute kidney Injury  
 
Cardiac tamponade 
 
Prosthetic valve dysfunction  
 
Cardiogenic shock 
 
Prosthetic valve endocarditis 
 
Life-threatening, disabling or major bleeding  
 
Major vascular complication 
 
Cardiac perforation 
 
Valve malpositioning 
C.5.1.5 Adverse Device Effect (ADE) or Device-Related Adverse Event 
An ADE is an adverse event related to the use of an investigational medical device.  During this 
clinical investigation an event should be considered related to the device when it is the result of 
the Medtronic CoreValve™System (MCS) and CoreValve™ Evolut™ R System: 
 
The transcatheter aortic valve (TAV) 
 
The delivery catheter system (DCS) 
 
The compression loading system (CLS/LS) 
 
The implant procedure 
An event should be considered not related to the device when it is the result of: 
 
A pre-existing medical condition 
 
A new illness, injury or condition 
 
Medication 
NOTE 1:  This definition includes adverse events resulting from insufficient or inadequate instructions for use 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 
NOTE 2:  This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device. 
C.5.1.6 Serious Adverse Device Effects (SADEs) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event.   
C.5.1.7 Unanticipated Adverse Device Effect (UADE) 
An unanticipated adverse device effect or UADE is defined as “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 protocol or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with the device that relates to the rights, safety, 
or welfare of subjects” [21 CFR 812.3 (s)]. 
Those known adverse events related to the device, procedure or therapy are listed in Section O 
and in the Risk/Benefit Analysis section (Section D) of this document.  
 
 

 
 
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C.5.1.8 Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
NOTE:  Anticipated serious adverse device effect (ASADE) is an effect, which by its nature, incidence, severity or 
outcome has been identified in the risk analysis report. 
C.5.1.9 Device Deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance. 
NOTE:  Device deficiencies include malfunctions, use errors, and inadequate labeling. 
C.5.1.10 Technical Observation 
A technical observation is a defect, malfunction, or failure of any part of the TAV or its 
components.  This may pertain to the device or system not functioning according to its design 
intent. Each technical observation (whether or not associated with any untoward medical 
occurrence in a subject) will be reported on the Adverse Event (AE) eCRF and tabulated as an 
AE.   
 
Reporting 
C.5.2
Investigators are required to keep records on “all relevant observations, including records 
concerning adverse device effects (whether anticipated or unanticipated)” [21 CFR 812.140; ISO 
14155 (2011)].  Adverse event collection will begin from the point of trial enrollment to trial 
closure.   All new or worsening (from baseline) adverse events and technical observations will 
be captured on the AE eCRF through the 24month follow-up visit. It is the responsibility of the 
Investigator to assess the subject for adverse events and capture the required adverse event 
information on the AE eCRF.   
Once a subject has completed their 24-month scheduled follow-up visit only serious adverse 
events, major adverse events, cardiovascular events, device-related adverse events, including 
device related technical observations, unanticipated adverse device effects (UADE) or 
unanticipated serious adverse device effects (USADE), all strokes (CVAs) and deaths will be 
required to be reported. Reference section C.5.1 Adverse Events for event definitions and 
criteria. Medtronic representatives or their designees will conduct monitoring visits to review 
source documentation and verify the complete and accurate capturing of adverse events. 
The Investigator must also notify the responsible IRB/MEC regarding new and significant safety 
information and any event identified by Medtronic that requires expedited FDA, and/or local 
regulatory agency, reporting as serious, unexpected, and related to the investigational device. It 
is the responsibility of the investigator to ensure site specific IRB/MEC safety reporting 
requirements are met. 
Medtronic Clinical will ensure all device-related adverse events and all procedure-related SAEs 
are processed according to internal policies and procedures. When necessary, Medtronic Field 
Assurance will respond to sites in writing with the findings related to the product experiences.  
The general procedure for investigators reporting any adverse event is as follows: 
 
Report the event to Medtronic as soon as possible but no later than the timeframes 
outlined below.  (At the time of Site Initiation, sites will be provided with the telephone 
and other applicable contact information of the appropriate Medtronic designee). 
 
Complete all sections of the Adverse Event eCRF. 
 
Each unique event/diagnosis must be documented separately. 
 
Documented pre-existing conditions are not considered to be reportable AEs unless 
there is a change in the nature or severity of the condition. 
 
The Adverse Event eCRF must be reviewed by the Investigator.  
Reporting guidelines related to specific types of adverse events are outlined below. 
C.5.2.1 
Serious Adverse Events (SAEs) 
The Investigator shall notify the sponsor immediately but not later than within 3 calendar days of 
first learning of any SAE using the EDC system [MEDDEV 2.7/3].  If necessary, the Investigator 
may be requested to provide copies of source documentation regarding the event (eg., 
physician/nurse notes or summaries). The Investigator should also notify their IRB/MEC and, if 
applicable, local regulatory agencies, per their requirements. 

 
 
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Medtronic will conduct an evaluation of the event and if it is determined by Medtronic to be a 
UADE or USADE, it will be reported as described in the following sections. 
C.5.2.2 
Serious Adverse Device Effects 
The Investigator shall notify the sponsor immediately, but not later than within 3 calendar days 
of the first learning of any SADE. 
C.5.2.3 
Unanticipated Adverse Device Effects (UADE or USADE) 
Investigators must report any (potential) unanticipated adverse device effects, or unanticipated 
serious device effects, to Medtronic and their IRB/MEC immediately but no later than 3 calendar 
days after first learning of the event [MEDDEV 2.7/3].  UADEs and USADEs should be reported 
immediately to Medtronic via telephone as well as on an eCRF. The Investigator should also 
notify their IRB/MEC and, if applicable, local regulatory agencies, per their requirements. 
The Investigator should consider the device labeling and the Risk/Benefit Analysis section of this 
document (Section D) when determining whether an event is unanticipated or not. 
If an event is determined by Medtronic to be a UADE or USADE, Medtronic will report the event 
to all investigators to enable reporting to their respective IRB/MECs.  Medtronic will provide this 
notification within 10 working days after Medtronic first receives notice of the effect.  [21 CFR 
812.150] 
If Medtronic and the DSMB determine that the event presents an unreasonable risk to the 
participating subjects, Medtronic must terminate all investigations or parts of investigations 
presenting the risk in the clinical trial 5 working days after making that determination and not 
later than 15 working days after Medtronic first receives notice of the effect.  [21 CFR 812.46]  
Follow-up visits for enrolled subjects will continue according the schedule of assessments. 
C.5.2.4 
Device Deficiencies and Technical Observations 
Device Deficiency information and Technical Observations will be collected throughout the trial 
and reported to Medtronic. 
Device Deficiencies and Technical Observations should be reported on an Adverse Event 
eCRF. 
Device deficiencies that did not lead to an Adverse Event but could have led to an SADE: 
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate, 
require immediate reporting (see Table 6). Initial reporting may be done on the eCRF 
completing as much information as is available. The original completed eCRF must be submitted 
to Medtronic as soon as possible. 
C.5.2.5 
All Other Adverse Events 
The Investigator shall notify the sponsor within 15 calendar days of first learning of any other AE 
using the EDC system.  If necessary, the Investigator may be requested to provide copies of 
source documentation regarding the event (eg., physician/nurse notes or summaries). 
C.5.2.6 
Anticipated Adverse Events 
Potential risks associated with TAVI device or its components (inclusive of CoreValve and 
Evolut R systems) may include, but are not limited to, the following: 
 
Death 
 
Cardiac arrest 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary closure) 
 
Emergent surgery (eg., coronary artery bypass, heart valve replacement, valve explant) 
 
Multi-organ failure 
 
Heart failure 
 
Myocardial infarction 
 
Cardiogenic shock 
 
Respiratory insufficiency or respiratory failure 

 
 
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 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, ventricle, 
myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel 
 
Ascending aorta trauma 
 
Cardiac tamponade 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture 
o 
Bending (out-of-round configuration) of the valve frame 
o 
Under-expansion of the valve frame 
o 
Calcification 
o 
Pannus, (wear, tear, prolapse, or retraction in the valve leaflets) 
o 
Poor valve coaptation 
o 
Suture breaks or disruption 
o 
Leaks 
o 
Mal-sizing (prosthesis-patient mismatch) 
o 
Malposition (either too high or too low)/malplacement 
o 
Regurgitation, stenosis 
 
Thrombosis/embolus (including valve thrombosis) 
 
Valve migration/valve embolization 
 
Ancillary device embolization 
 
Emergent percutaneous coronary intervention (PCI) 
 
Emergent balloon valvuloplasty 
 
Major or minor bleeding that may or may not require transfusion or intervention 
(including life-threatening or disabling bleeding) 
 
Allergic reaction to antiplatelet agents, contrast medium, or anesthesia 
 
Infection (including septicemia and endocarditis) 
 
Stroke, TIA, or other neurological deficits 
 
Permanent disability 
 
Renal insufficiency or renal failure (including acute kidney injury) 
 
Mitral valve regurgitation or injury 
 
Tissue erosion 
 
Vascular access related complications (eg., dissection, perforation, pain, bleeding, 
hematoma, pseudoaneurysm, irreversible nerve injury, compartment syndrome, 
arteriovenous fistula, stenosis) 
 
Conduction system disturbances (eg., atrioventricular node block, left-bundle branch 
block, asystole), which may require a permanent pacemaker 
 
Cardiac arrhythmias 
 
Encephalopathy 
 
Pulmonary edema 
 
Pericardial effusion 
 
Pleural effusion 
 
Myocardial ischemia 
 
Peripheral ischemia 
 
Bowel ischemia 
 
Heart murmur 
 
Hemolysis 
 
Cerebral infarction-asymptomatic 
 
Non-emergent reoperation 
 
Inflammation 
 
Fever 
 
Hypotension or hypertension 

 
 
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 
Syncope 
 
Dyspnea 
 
Anemia 
 
Angina 
 
Abnormal lab values (including electrolyte imbalance) 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic 
valve and prolonged procedural time 
C.5.2.7 
Deaths 
The Investigator shall notify Medtronic immediately but not later than within 3 calendar days of 
learning of a subject’s death, whether or not the death is related to the investigational device.  
The Investigator should also notify his/her IRB/MEC and/or local regulatory agencies, if 
applicable, per their requirements. The Investigator should also attempt to determine, as 
conclusively as possible, whether such deaths are related to the investigational TAV device or 
its components.  When an autopsy is conducted, a copy of the report should be provided to 
Medtronic.  Medtronic will evaluate the event and if device-related and unexpected, the event 
will be reported as a UADE or USADE. 
Any subject death will be reported on the Study Exit eCRF and accompanied by an Adverse 
Event eCRF identifying the cause of death. 
C.5.2.8 
Vigilance Reporting 
A product complaint is defined as any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a medical device that has been placed on the market. 
It is the responsibility of the investigator to report all product complaint(s) associated with a 
medical device distributed by Medtronic, regardless whether they are related to intended use, 
misuse or abuse of the product. Reporting must be done as soon as possible and without undue 
delay and via the regular channels for market released products. Note that although the 
reporting of product complaints is not part of the clinical study, all potential complaints that are 
collected as part of this study will be reviewed by the responsible person at Medtronic and, if 
applicable, reported to the designated complaint handling unit. Medtronic will ensure timely 
reporting to meet global regulatory requirements. 
 
Clinical Events Committee (CEC) 
C.5.3
An independent Clinical Events Committee (CEC) will review and adjudicate, at a minimum, all 
deaths and primary endpoint related adverse events. The CEC will consist of, at a minimum, 
interventional cardiologists and cardiac surgeons who are not participants in the trial.  Additional 
specialist, such as neurologists, may also be selected as part of the CEC. 
The purpose of the CEC is to conduct a medical review and classify/adjudicate, at a minimum, 
all deaths and/or clinical endpoints collected in the trial according to definitions and processes 
outlined in the Medtronic CoreValve™ SURTAVI Trial protocol and the CEC charter, which will 
be developed and approved by Medtronic and the CEC members. 
All applicable events will be reviewed and adjudicated by a minimum of two CEC members. All 
other events will be reviewed and adjudicated by qualified internal Medtronic safety individual(s) 
to ensure they should not be adjudicated by the full CEC and that the events are appropriately 
classified by the investigator. 
Prior to event adjudication, the CEC will draft a charter to establish explicit rules outlining the 
minimum amount of data required and the algorithm followed in order to classify/adjudicate a 
trial endpoint related clinical event. CEC decisions will be documented in meeting minutes, 
which will be maintained in the trial file. 
 
Data Safety Monitoring Board (DSMB) 
C.5.4
An independent, unblinded DSMB will be established and will be comprised of at least 3 experts, 
including a chairperson.  The DSMB will have a minimum of one cardiac surgeon, one 
interventional cardiologist and one statistician, and will be independent of Medtronic and the trial 

 
 
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investigators.  Investigators participating in the trial may participate in the meetings to offer 
clarification surrounding events, but will not have voting privileges.  Medtronic personnel may 
facilitate the DSMB meeting but will not have voting privileges.  The DSMB will meet (via 
teleconference or in person) prior to the first subject enrollment to establish procedures for 
DSMB review, chairman appointment and guidelines for trial recommendations.  The full DSMB 
will meet on a periodic basis to perform a comprehensive data review and will meet more 
frequently when needed.  Primary and safety-related secondary endpoints may also be 
reviewed at these meetings. Meetings will consist of both open and closed sessions. 
The DSMB will also perform a supplemental review of, at a minimum, all serious adverse events 
and deaths and any other data requested by the DSMB on a more frequent periodic basis to 
ensure patient safety.  DSMB members will review the report, and when necessary provide 
recommendations about the conduct of the trial and/or request a full DSMB meeting.  
A DSMB charter will be developed and approved by Medtronic and the DSMB members. The 
committee will outline the criteria for both the full DSMB meeting and supplemental DSMB 
reviews within the DSMB charter. 
Following each full DSMB meeting, the board will report to Medtronic in writing and may 
recommend changes in the conduct of the trial.  These DSMB recommendations may include 
recommendations on trial status such as continuing the trial without modifications, continuing the 
trial with modifications, stopping the enrollment in the trial or a specific trial arm, or 
recommendations about trial conduct including recommendations around enrollment or protocol 
deviations.  
In the case of UADEs or USADEs, if Medtronic and the DSMB determine that the event presents 
an unreasonable risk to the participating subjects, Medtronic must terminate the clinical trial 
within 5 working days after making that determination and not later than 15 working days after 
Medtronic first receives notice of the effect. [21 CFR 812.46]. All clinical sites will be notified of 
this action.  
The DSMB may call additional meetings if, at any time, there is concern about any aspect of the 
trial.  All data presented at the meetings will be considered confidential and returned to the trial 
statistician at the closure of the DSMB meeting. 
Additional details about the DSMB are outlined in the DSMB charter. 

 
 
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C.6 
Statistical Methods and Analysis 
 
Statistical Considerations and Analysis 
C.6.1
This section describes the statistical considerations and analysis plans for the SURTAVI trial.  
The statistical analysis will be performed by the statistics department of Medtronic. As primary 
analysis all randomized subjects will be analyzed following the modified intention to treat (mITT) 
approach; ie. analyses will be conducted on the cohort of subjects who undergo an attempted 
trial treatment, analyzed according to the randomized assignment.  A secondary analysis of key 
objectives will be performed according to the therapy actually received. 
Roll-in subjects will not be included in the primary or secondary analysis; however, the data will 
be summarized separately with descriptive statistics. 
All follow-up periods are defined as the number of days after the procedure date. 
 
Reports 
C.6.2
Medtronic is responsible for the reports cited in Table 5 (Sponsor Reporting Responsibilities).  
These reports are subject to regulatory retention and inspection requirements.  In addition to the 
reports listed in Table 5, FDA, Competent Authorities, and local regulatory agencies, where 
applicable, or the reviewing IRB/MEC may request reports pertaining to any aspect of the 
clinical trial. 
 
Description of Baseline Variables 
C.6.3
Baseline demographic and clinical variables will be summarized for each of the treatment 
groups for the intention-to-treat (ITT), modified intent-to-treat (mITT), and implanted populations. 
All continuous variables will be summarized as means, medians, standard deviations,  
interquartile ranges, minima and maxima and compared between treatment groups using a 
Bayesian analog of a two-sample t-test or the non-parametric Wilcoxon rank-sum test.  
Categorical variables will be summarized as frequencies and percentages and compared 
between treatment groups using a Bayesian version of a comparison of proportions. 
 
Analysis Populations 
C.6.4
C.6.4.1 Screening Population 
All patients with symptomatic severe AS who provide informed consent will be considered 
screened and all available data will be entered into the EDC system.  
C.6.4.2 Randomized Population 
If the patient signs informed consent, meets all inclusion and none of the exclusion criteria, and 
the Heart Team determines the patient is suitable for randomization in the trial, then the subject 
is reviewed by the SURTAVI Screening Committee.  If the subject is approved by the Screening 
Committee and the subject is enrolled/randomized to either TAVI or SAVR the subject is added 
to the randomized population. Within the randomized population three sub-populations are 
distinguished: 
 
Intention to treat (ITT) population - Subjects are reported according to the randomized 
assignment, SAVR or TAVI, regardless of what, if any, therapy was actually received  
 
Modified intention to treat (mITT) population - Randomized subjects in whom a 
procedure is attempted. Subjects who undergo an attempted trial treatment are reported 
according to the randomized assignment, SAVR or TAVI, regardless of what, if any, 
therapy was actually received.  A procedure attempt is defined as when the subject is 
brought into the procedure room and any of the following have occurred: anesthesia 
administered, vascular line placed, TEE placed or any monitoring line placed  
 
Implanted population - population includes the mITT subjects who are actually 
implanted with either the investigational TAVI device or a surgical valve. Depending on 
context, subjects may be analyzed according to randomized treatment assignment or 
treatment actually received. 
The primary analysis for the primary objective and most secondary objectives will use the mITT 
population.   At the conclusion of the trial, an analysis using the ITT population will also be 
presented. 

 
 
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Primary Analysis 
C.6.5
The primary endpoint of all-cause mortality or disabling stroke at 24 months will be evaluated 
using the absolute difference of the TAVI rate and the SAVR rate for all-cause mortality or 
disabling stroke during a fixed follow-up of 24 months’ time. The hypothesis test is designed to 
show non-inferiority of TAVI to SAVR for the primary endpoint.  
C.6.5.1 
Hypothesis of Non-inferiority 
The primary objective is to establish that TAVI is non-inferior to SAVR for the primary endpoint.  
The hypothesis of interest is: 
H: ߨ் ൏ߨ஼൅ߜ 
where T and C denote binary rates of all-cause mortality or disabling stroke during a fixed 
follow-up of 24 months for the treatment (TAVI) and control (SAVR) groups, and ߜൌ0.07.  This 
trial is designed using Bayesian statistical techniques.  TAVI will be declared to be non-inferior 
to SAVR if it can be established that the posterior probability Pr(Hδ=0.07 | data) > Ψ, where Ψ is a 
pre-specified threshold value.  If, in addition, it can be shown that Pr(ܪ஺: ߨ் ൏ߨ஼൅0 | data) > 
ΨSUP, TAVI will be declared to be superior to SAVR.  The values chosen for Ψ and ΨSUP are 
described below. 
C.6.5.2 
Randomization, Sample Size and Analysis Plan 
Randomization will follow a 1:1 (treatment:control) allocation ratio and be stratified by site and 
need for revascularization, using a blocked randomization scheme with blocks of randomly 
varying sizes.  The sample size for the mITT population is 1600 subjects.   
Sample Size Justification 
The assumed values T = C = 0.17 are based on the data published by Iturra et al3 and 
CoreValve US Pivotal High Risk study results. As reported in the Iturra paper, the incidence of 
all-cause mortality at 30 days was 2.8% and the late all-cause mortality Kaplan-Meier rate at 24 
months was 12.1%. The overall 24-month all-cause mortality rate was approximately 15%. STS 
score reported in the Iturra paper (5.6 ± 1.1, n=502) was similar to the STS score for subjects 
currently enrolled in the SURTAVI study4 (5.6 ± 1.4, n=654), and it is believed that the 24-month 
all-cause mortality rate in SURTAVI will be approximately 15% at 24 months. The major stroke 
rate was 3.2% for subjects who survived to 1 year in the CoreValve Pivotal High Risk study.  
The High Risk study enrolled a higher-risk population than SURTAVI, therefore, the major stroke 
rate in the High Risk study is adjusted downward, and it is believed the disabling stroke rate at 
24 months would be approximately 2% in the SURTAVI study. Overall, the estimation of the all-
cause mortality or disabling stroke rate at 24 months is 17%.  
Although the pre-specified analysis methods are Bayesian, the sample size is guided by a 
standard frequentist non-inferiority power analysis.  Under the assumptions of T = C = 0.17, 
non-inferiority margin δ=0.07, 1:1 randomization, α= 0.05, and power = 95%, the method of 
Farrington and Manning5 as implemented in PASS 20086 indicates that the required sample size 
for a single-look analysis is 1258. To allow for up to 6% dropout, 1339 subjects must be 
accrued.  Furthermore, to compensate for power lost in a two-look group sequential analysis 
plan using Pocock-type alpha spending, the sample size would have to be increased by about 
12.5%7.  This leads to an estimated sample size of 1531. Thus a sample size of 1600 mITT 
subjects should provide ample power for establishing non-inferiority in the primary hypothesis 
test. 
 Analysis Plan 
An interim analysis (timed to occur when 1400 mITT subjects have reached 12 months)for the 
purpose of declaring an early win will be conducted.  At this analysis, If P(Hδ=0.07 | data) > Ψ, 
non-inferiority will be declared at this time, and a regulatory submission will follow.  Alternatively, 
                                                    
 
3 Iturra SA, Suri RM, Greason KL, et al. The Journal of thoracic and cardiovascular surgery 2014;147:127-132.  
4 Medtronic CoreValve SURTAVI Trial 2014 FDA Annual Progress Report;  
5 Farrington, C. P. and Manning, G. 1990. 'Test Statistics and Sample Size Formulae for Comparative Binomial Trials with Null 
6 Hintze, J. (2004). NCSS and PASS, Number Cruncher Statistical Systems. Kaysville UT. www.ncss.com 
7 Jennison C and Turnbull BW, Group Sequential Methods with Applications to Clinical Trials.  Boca Raton:  Chapman & Hall, 2000, p 27 

 
 
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if P(Hδ=0.07 | data) ≤ Ψ, all mITT subjects will be followed to 24 months, when a final analysis will 
occur.  At the final analysis, the standard for trial success will again be P(Hδ=0.07 | data) > Ψ.  
These two analyses are termed "Win Looks." 
If, at the early (interim) "Win Look," non-inferiority is established, a test of superiority will 
immediately follow.  If P(Hδ=0 | data) > ΨSUP, superiority will be established at this time.  
However, if P(Hδ=0 | data) ≤ ΨSUP, subjects will continue to be followed and analyzed according 
to the same analysis plan.  At the final "Win" analysis, if P(Hδ=0 | data) > ΨSUP, a delayed 
determination of superiority will be made.   
The statistical approach for these analyses is Bayesian. The prior distributions for T and C in 
these calculations are Beta (1,1).  The threshold Ψ is designated to be 0.971 for non-inferiority 
testing and ΨSUP =0.989 for superiority testing; these values are selected by trial-and-error to 
achieve a type I error (under simulation) of at most 0.05 for non-inferiority testing and at most 
0.025 for superiority testing. Of note, establishing P(Hδ=0 | data) > ΨSUP means that superiority 
has been established to a standard equivalent to a nominal significance level of 0.025 (1-sided), 
but this does not automatically mean that a labeling claim of superiority is supported.  See 
“Multiplicity Considerations” (Section C.12) for additional requirements regarding labeling claims 
on secondary objectives.  
Further details of planned analyses are provided in the SAP. 
 
Missing Data and Planned Sensitivity Analyses (Primary Objective) 
C.6.6
Every effort will be undertaken to minimize missing data.  However, some missing data is 
inevitable, and the trial is designed with the expectation that there may be up to 6% of primary 
data missing at 24 months.  The reasons for missing data will be described in detail and 
evaluated for assessment of possible bias.  The distribution of prognostic factors between 
patients with data and those without data will be examined to evaluate any potential sources of 
bias. 
 
Description of Performed Analysis, per population 
C.6.7
Any deviations from this section and/or the Statistical Analysis Plan will be described and 
justified in the Final Report or justified in a protocol amendment, as appropriate. 
C.6.7.1 
Analysis of Screening Population 
For the screening population only descriptive statistical analysis will be performed, on variables 
that are captured in the EDC system. 
C.6.7.2 
Analysis of ITT and mITT Populations 
For the subjects in the randomized population the primary analysis of the primary endpoint and 
inferential statistics for the following secondary endpoints will be performed on the ITT and mITT 
populations: 
 
Major adverse cardiovascular and cerebrovascular events (MACCE) 
 
Individual MACCE components 
 
Major adverse events (MAE)  
 
Conduction disturbance requiring permanent pacemaker implantation 
 
NYHA 
 
Six-minute walk test 
 
Ratio of days alive out of hospital versus total days alive 
 
Quality of life 
 
Echocardiographic assessment of valve performance  
 
Aortic valve disease-related hospitalizations 
 
Cardiovascular deaths and valve-related deaths 
 
Strokes and TIAs 
 
Per-procedural neurological injury 
 
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 
Length of index procedure hospital stay 
 
Device success 
 
Procedure success 
C.6.7.3 
Analysis of Implanted Population 
The endpoints listed in C.6.7.2 will also be performed on the implanted population.  Additionally, 
the implanted population will be used for analyzing the primary endpoint, secondary endpoint of 
prosthetic valve dysfunction, and echocardiographic assessment of valve performance.    
 
 

 
 
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Secondary Endpoints 
C.6.8
C.6.8.1 
Secondary Endpoints Compared Between TAVI and SAVR 
1. Incidence of Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  
MACCE is defined as a composite of: 
 
All-cause death 
 
Myocardial infarction (MI) 
 
All stroke, and 
 
Reintervention (defined as any cardiac surgery or percutaneous reintervention 
catheter procedure that repairs, otherwise alters or adjusts, or replaces a 
previously implanted valve) 
MACCE-incidence estimates will be provided for the two treatment groups at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  The 
statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
Additionally, incidence of MACCE will be compared at 30 days or hospital discharge, 
whichever is later.  The statistical method will be the Bayesian version of a comparison of 
proportions.  
2. The occurrence of individual MACCE components at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
 
MACCE components will be summarized and their incidence estimates provided at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
3. Major Adverse Events (MAE) and individual components at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years. 
 
MAE events and individual components will be summarized and the incidence of MAEs 
will be provided at 30 days, 6 months, 12 months, 18 months, 24 months, and annually 
thereafter up to 5 years The statistical method will be the Bayesian version of a 
comparison of proportions (with predictions). 
      Additionally, incidence of major vascular complications and incidence of major or life-
threatening bleeding events at 30 days or hospital discharge, whichever is longer, will also 
be compared using the Bayesian version of a comparison of proportions. 
 
4. Incidence of Early safety at 30 days defined as a composite of: 
 
All-cause mortality 
 
All stroke (disabling and non-disabling) 
 
Life-threatening bleeding 
 
Acute kidney injury—Stage 2 or 3 (including renal replacement therapy)  
 
Coronary artery obstruction requiring intervention 
 
Major vascular complication 
 
Valve-related dysfunction requiring repeat procedure (BAV, TAVI, or SAVR) 
 
All-cause death 
Early safety composite endpoint-incidence estimates will be provided for the two treatment 
groups at 30 days.  The statistical method will be the Bayesian version of a comparison of 
proportions. 
 
 

 
 
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5. Incidence of Clinical Efficacy (after 30 days) at 6 months, 12 months, 18 months, 24 
months and annually thereafter up to 5 years. Clinical efficacy defined as a composite of: 
 
All-cause mortality 
 
All stroke (disabling and non-disabling) 
 
Requiring hospitalizations for valve-related symptoms or worsening congestive 
heart failure 
 
NYHA class III or IV 
 
Valve-related dysfunction (mean aortic valve gradient ≥20 mmHg, EOA ≤0.9-1.1 
cm2 and/or DVI<0. 35m/s, AND/OR moderate or severe prosthetic valve 
regurgitation*) 
Clinical efficacy estimates will be provided for the two treatment groups at 6 months, 12 
months, 18 months, 24 months and annually thereafter up to 5 years.  The statistical 
method will be the Bayesian version of a comparison of proportions (with predictions). 
*Refers to VARC-2 definitions 
6. Incidence of Time-Related Safety at 30 days, 6 months, 12 months, 18 months, 24 months 
and annually thereafter up to 5 years. Time-Related Safety defined as a composite of: 
 
Structural valve deterioration: 
o 
Valve-related dysfunction (mean aortic valve gradient ≥20 mmHg, EOA ≤0.9-
1.1 cm2 and/or DVI<0.35m/s, AND/OR moderate or severe prosthetic valve 
regurgitation*) 
o 
Requiring repeat procedure (TAVI or SAVR) 
 
Prosthetic valve endocarditis 
 
Prosthetic valve thrombosis 
 
Thromboembolic events (eg. stroke) 
 
VARC bleeding, unless clearly unrelated to valve therapy (eg. trauma) 
Time related safety composite endpoint-incidence estimates will be provided for the two 
treatment groups at 30 days, 6 months, 12 months, 18 months, 24 months and annually 
thereafter up to 5 years.  The statistical method will be the Bayesian version of a 
comparison of proportions (with predictions). 
*Refers to VARC-2 definitions 
7. Conduction disturbance requiring permanent pacemaker implantation at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years. 
 
The incidence of conduction disturbance requiring permanent pacemaker implantation will 
be provided at 30 days, 6 months, 12 months, 18 months, 24 months, and annually 
thereafter up to 5 years, separately for new onset and pre-existing conduction disturbance.  
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
8. Change in NYHA class from baseline at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
 
For each subject with paired data, the number of classes changed from baseline (-3, -2, -
1, 0, 1, 2, or 3) will be calculated at 30 days, 6 months, 12 months, 18 months, 24 months, 
and annually thereafter up to 5 years. The endpoint will be evaluated between groups 
using a Bayesian version of a t-test. 
9. Change in distance walked during 6-minute walk test (6MWT) from baseline to 30 days, 
baseline to 12 months, and baseline to 24 months. 
All subjects who are able to perform the six-minute walk evaluation at the time of the 
follow-up visit will be included in the analysis. 
  The endpoint will be evaluated using a Bayesian version of a t-test. 
 
 

 
 
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10. Ratio of days alive out of hospital versus total days alive assessed at 12 months and 24 
months follow-up.  
 
The proportion of post procedure days alive out of hospital against total days alive will be 
compared between groups at 12 and 24 months.  The numerator will be the number of 
days alive out of hospital, and the denominator will be the number of post procedure days 
alive as of the last follow-up date.  All hospitalizations will be included in this analysis, 
including hospitalization for device implant.   
      In addition, days alive out of hospital will be compared between groups at 12 months and 
24 months.  
      The endpoint will be evaluated using a Bayesian version of a t-test. 
11. Quality of Life (QoL) change from baseline at 30 days, 3 months, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
 
The Kansas City Cardiomyopathy Questionnaire (KCCQ), SF-36, and EuroQoL (EQ-5D) 
will be assessed at baseline, 30 days, 6 months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years.  SF-36 and EQ-5D will also be assessed at 3 months.  
All subjects completing the questionnaires will be evaluated and the reasons for missing 
data will be provided. 
 
The endpoint will be evaluated using a Bayesian version of a t-test . 
12. Echocardiographic assessment of prosthetic valve performance at discharge, 6 months, 
12 months, 24 months, and annually thereafter up to 5 years using the following 
measures: 
 
transvalvular mean gradient 
 
effective orifice area 
 
degree of prosthetic aortic valve regurgitation (including transvalvular and 
paravalvular) 
The four echocardiographic measurements will be evaluated at discharge, 6 months, 12 
months, 24 months, and annually thereafter up to 5 years.  All implanted subjects 
undergoing echocardiography procedures will be evaluated.   
Continuous measures will be evaluated using a Bayesian version of a two-sample t-test.  
Categorical variables will be evaluated using Bayesian version of a comparison of 
polytomous outcomes.   
Additionally, incidence of moderate/severe aortic insufficiency at discharge will be 
compared between groups using the Bayesian version of a comparison of proportions. 
13. Aortic valve disease related hospitalizations  
 
The number of subjects re-hospitalized after the initial index procedure will be compared 
at 30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 
years.   
 
Incidence of recurrent hospitalization will be provided at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years.  The statistical method will be 
the Bayesian version of a comparison of proportions (with predictions).   
14. Cardiovascular deaths and valve-related deaths 
The number of subjects experiencing cardiovascular deaths and valve-related deaths at 
30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 
years.  Incidences will be compared between groups.  The statistical method will be the 
Bayesian version of a comparison of proportions (with predictions). 
 
 

 
 
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15. Strokes and TIAs 
The number of subjects with strokes (of any severity) and TIAs at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years. A separate analysis 
will be performed for each of the following: 
 
a composite of all strokes and TIAs 
 
disabling strokes only 
 
non-disabling strokes only 
 
TIAs only  
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
Additionally, incidence of all strokes at 30 days or hospital discharge, whichever is longer, 
will be compared between groups using the Bayesian version of a comparison of 
proportions. 
16. Peri-procedural Neurological Injury (Stroke, TIA, Encephalopathy) 
 
For each treatment group, the proportion of subjects with a neurologic injury (stroke, TIA, 
or encephalopathy) at discharge or at 7 days post-index procedure (whichever occurs first) 
will be calculated. The numerator will be the number of subjects with a neurologic injury 
(stroke, TIA, or encephalopathy) at discharge or at 7 days post-index procedure 
(whichever occurs first), and the denominator will be the number of subjects in that 
treatment group. Results will also be presented separately for disabling stroke, non-
disabling stroke, TIA, and encephalopathy.  Proportions will be compared between groups 
using Bayesian version of a comparison of proportions. 
17. Index procedure related MAEs 
 
Index procedure-related MAE events will be summarized and event rates will be provided 
at 30 days.  The numerator will be the number of procedure-related MAE events 
experienced by the end of the 30-day follow-up visit, and the denominator will be the 
number of subjects evaluated at the 30-day follow-up visit (or a later follow-up)  plus the 
number of subjects not evaluated but who experienced a procedure-related MAE event 
prior to the end of the follow-up visit window. 
 
The endpoint is descriptive and no statistical hypothesis test will be performed. 
18. Length of index procedure hospital stay 
 
The length of TAVI or SAVR hospital stay will be summarized for all subjects undergoing a 
trial procedure. 
 
The endpoint will be evaluated between groups using a Bayesian version of a t-test.  
19. Presence of atrial fibrillation at post-procedure, discharge, 30 days, 6 months, 12 months, 
18 months, 24 months, and annually thereafter up to 5 years. 
 
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
 
 

 
 
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C.6.8.2 Secondary Endpoints Assessed for TAVI Only 
The following secondary endpoints will be assessed for the TAVI cohort subjects only: 
20. Device success defined as follows: 
 
Absence of procedural mortality AND 
 
Correct positioning of a single prosthetic heart valve into the proper anatomical 
location AND 
 
Intended performance of the prosthetic heart valve (no prosthesis-patient 
mismatch and mean aortic valve gradient <20 mmHg or peak velocity <3 m/s, 
AND no moderate or severe prosthetic valve regurgitation*) 
o 
Assessed acutely in a resting state, either within 24-48 hours after the 
index procedure or before hospital discharge 
*Refers to VARC-2 definitions 
Device success, as defined above, will be calculated for all subjects undergoing the TAVI 
procedure.   
The endpoint is descriptive and no statistical hypothesis test will be performed. 
21. Procedural success, defined as device success and absence of in-hospital MACCE. 
 
Procedural success, as defined above, will be calculated for all randomized subjects 
undergoing the TAVI procedure.   
 
The endpoint is descriptive and no statistical hypothesis test will be performed. 
22. Evidence of prosthetic valve dysfunction at 30 days, 6 months, 12 months, 24 months, and 
annually thereafter up to 5 years. 
 
The number of subjects with evidence of prosthetic valve dysfunction will be evaluated at 
30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 
years.  Point estimates and 95% BCIs for each time point will be presented using methods 
described below in the Bayesian version of a comparison of proportions (with predictions).   
23. Resheath and Recapture (combined) success rate.  
The success rate will be analyzed for all subjects in whom the resheath or recapture 
feature is attempted. The number and percentage of successful resheath or recapture 
attempts combined will be calculated. Separate resheathing and recapturing success rates 
will also be calculated.  
The endpoint is descriptive and no statistical hypothesis test will be performed.  
 
Rationale for Selection of Trial Endpoints 
C.6.9
Trial endpoints were selected with following considerations: 
 
Clinically relevant and address important safety and performance aspects of the 
investigational TAVI device 
 
Objectively defined and measurable in the majority of subjects  
 
Consistent with current recommendations for endpoints in TAVI clinical studies and 
VARC-2 
 Multiplicity Considerations 
C.6.10
It is recognized that with a multiplicity of tests comes inflation in the chance of a false finding of 
superiority or non-inferiority.  Therefore, for the purpose of seeking approved labeling claims on 
designated secondary objectives, the following standard will be used:  If the primary objective 
demonstrates non-inferiority, claims will be sought for selected secondary non-inferiority and 
superiority objectives and for superiority on the primary objective metric.  These will be tested 
via a hierarchical (sequential) order that preserves the overall study-wise type I error rate at the 
level of 0.05, while requiring all non-inferiority tests to meet a nominal type I error rate of 0.05 
and all superiority tests to meet a nominal type I error rate of 0.025. The testing order is 
specified below.  The following objectives are tested in order, and testing continues if and only if 
all previous objectives have met their designated success criterion.   
 

 
 
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1. Primary endpoint (non-inferiority)  
2. Transvalvular mean gradient at 12 months (non-inferiority) 
3. Effective orifice area at 12 months (non-inferiority) 
4. Change in NYHA classification from baseline to 12 months (non-inferiority) 
5. Change in KCCQ score from baseline to 30 days (non-inferiority)  
All of the above are non-inferiority tests and are tested with a type I error standard of 0.05.  If all 
of the above tests meet their success criterion, the type I error rate of 0.05 that is passed on 
from the above tests will be split equally (using a Bonferroni justification) between the following 
parallel subfamilies, so that each subfamily is tested using a type I error rate of 0.025: 
Subfamily #1:  Primary endpoint (superiority) 
Subfamily #2: Secondary (superiority) objectives #5–#18 as enumerated below, tested 
in ordered sequence such that all α is passed on to subsequent tests if a test criterion 
is met, while all testing stops if a test criterion is not met.  This procedure controls the 
type I error rate of this subfamily at the level 0.025. 
 
It is not necessary to “pass” all objectives in one subfamily in order to test the objective(s) in the 
other subfamily.For the purposes of seeking claims, these objectives will only be evaluated 
once, at the same time as non-inferiority of the primary objective is established.  The only 
exception to this is the primary endpoint superiority test, which carries the possibility of a 
delayed determination of superiority (as described in Section 4.2.1) and may thus meet its 
success criterion at a different time. 
 
The remaining secondary objectives may be of interest for scientific or financial reasons but will 
not be the basis for supporting labeling claims; they are thus outside of the hierarchical testing 
procedure. Similarly, for those objectives that test non-inferiority, if non-inferiority is established, 
a test of superiority will also be conducted, but unless specifically itemized in the list, such 
superiority testing is not part of the hierarchical testing procedure; these superiority tests may be 
of interest for scientific or financial reasons but will not be the basis for supporting labeling 
claims. 
 
C.6.10.1 Secondary Endpoints Tested to Support Labeling Claims 
The following secondary endpoints will be tested, in order, to support labeling claims: 
1. Transvalvular mean gradient at 12 months (non-inferiority): TAVI vs. SAVR (secondary 
objective #12). The hypothesis of interest is  
H: µ TAVI < µ SAVR +5 
 
where µ TAVI and µ SAVR denote the average mean gradient from  at 12 months, measured 
in mmHg.  This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.95.   
2. Effective orifice area at 12 months (non-inferiority): TAVI vs. SAVR (secondary objective 
#12).  The hypothesis of interest is  
H: µ TAVI > µ SAVR – 0.1 
 
where µ TAVI and µ SAVR denote the mean effective orifice area at 12 months, measured in 
cm2.  This objective will be evaluated using a Bayesian version of a two-sample t-test (see 
Section C.11).  The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.95.   
3. Change in NYHA classification from baseline to 12 months (non-inferiority): TAVI vs. 
SAVR (secondary objective #8).  The hypothesis of interest is  
H: µ TAVI > µ SAVR - 0.375 

 
 
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where µ TAVI and µ SAVR denote the mean number of classification improvements in NYHA 
from baseline to 12 months.  For subjects with NYHA categories at both baseline and 12 
month visit, the NYHA classification improvements will be calculated as NYHAbaseline – 
NYHA12month. This objective will be evaluated using a Bayesian version of a two-sample t-
test (see Section C.11). The posterior probability P(H | data) will be calculated and 
compared to a threshold of 0.95.   
4. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 30 
days (non-inferiority): TAVI vs. SAVR (secondary objective #11).  The hypothesis of 
interest is  
H: µ TAVI > µ SAVR -5 
 
where µ TAVI and µ SAVR denote the mean improvements in the KCCQ score from baseline 
to 30 days.  For subjects with KCCQ score at both baseline and 30 days, the improvement 
in KCCQ will be calculated as KCCQ30day – KCCQbaseline.  This objective will be evaluated 
using a Bayesian version of a two-sample t-test (see Section C.11). The posterior 
probability P(H | data) will be calculated and compared to a threshold of 0.95.   
5. Length of index procedure hospital stay after TAVI vs. SAVR (secondary objective #18).  
The hypothesis of interest is  
H: µ TAVI < µ SAVR 
where µ TAVI and µ SAVR denote the mean length of index hospital stay.  This objective will 
be evaluated using a Bayesian version of a two-sample t-test (see Section C.11). The 
posterior probability P(H | data) will be calculated and compared to a threshold of 0.975. 
6. Transvalvular mean gradient at 12 months (superiority): TAVI vs. SAVR (secondary 
objective #12). The hypothesis of interest is  
H: µ TAVI < µ SAVR  
 
where µ TAVI and µ SAVR denote the average mean gradient from  at 12 months, measured 
in mmHg.  This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.975.   
7. Effective orifice area at 12 months (superiority): TAVI vs. SAVR (secondary objective #12).  
The hypothesis of interest is  
H: µ TAVI > µ SAVR  
 
where µ TAVI and µ SAVR denote the mean effective orifice area at 12 months, measured in 
cm2.  This objective will be evaluated using a Bayesian version of a two-sample t-test (see 
Section C.11). The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975.   
8. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 30 
days (superiority): TAVI vs. SAVR (secondary objective #11).  The hypothesis of interest is  
H: µ TAVI > µ SAVR  
 
where µ TAVI and µ SAVR denote the mean improvements in the KCCQ score from baseline 
to 30 days.  For subjects with KCCQ score at both baseline and 30 days, the improvement 
in KCCQ will be calculated as KCCQ30day – KCCQbaseline.  This objective will be evaluated 
using a Bayesian version of a two-sample t-test (see Section C.11). The posterior 
probability P(H | data) will be calculated and compared to a threshold of 0.975.   
 
9. Days alive out of the hospital at 12 months after TAVI vs. SAVR (secondary objective 
#10).  The hypothesis of interest is  
H: µ TAVI > µ SAVR 
where µ TAVI and µ SAVR denote the mean number of days alive out of the hospital at 12 
months.  This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.975. 

 
 
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10. Days alive out of the hospital at 24 months after TAVI vs. SAVR (secondary objective 
#10).  The hypothesis of interest is  
H: µ TAVI > µ SAVR 
where µ TAVI and µ SAVR denote the mean number of days alive out of the hospital at 24 
months.  This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.975. 
 
11. Change in SF-36 Physical Summary Scale from baseline to 3 months: TAVI vs. SAVR 
(secondary objective #11).  The hypothesis of interest is  
H: µ TAVI > µ SAVR 
 
where µ TAVI and µ SAVR denote the mean improvements in the SF-36 Physical Summary 
Scale from baseline to 3 months.  This objective will be evaluated using a Bayesian 
version of a two-sample t-test (see Section C.11). The posterior probability P(H | data) will 
be calculated and compared to a threshold of 0.975.   
12. Change in EQ-5D from baseline to 3 months: TAVI vs. SAVR (secondary objective #11).  
The hypothesis of interest is  
H: µ TAVI > µ SAVR 
 
where µ TAVI and µ SAVR denote the mean improvements in the EQ-5D from baseline to 3 
months.  This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.975.   
13. Incidence of MACCE at 30 days or hospital discharge, whichever is longer: TAVI vs. 
SAVR (secondary objective #1).  The hypothesis of interest is  
H:  TAVI <  SAVR 
 
where  TAVI and  SAVR denote the binary rate of MACCE at 30 days or hospital discharge 
(if longer).  The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975.  The statistical method will be the Bayesian version of a comparison of 
proportions (see Section C.11).   
14. Incidence of major vascular complications at 30 days or hospital discharge, whichever is 
longer: TAVI vs. SAVR (secondary objective #3).  The hypothesis of interest is 
H:  TAVI <  SAVR 
where  TAVI and  SAVR denote the binary rate of major vascular complications at 30 days 
or hospital discharge (if longer).  The posterior probability P(H | data) will be calculated 
and compared to a threshold of 0.975. The statistical method will be the Bayesian version 
of a comparison of proportions (see Section C.11).   
15. Incidence of major or life-threatening bleeding event at 30 days or hospital discharge, 
whichever is longer: TAVI vs. SAVR (secondary objective #3).  The hypothesis of interest 
is 
H:  TAVI <  SAVR 
where  TAVI and  SAVR denote the binary rate of major or life-threatening bleeding events 
at 30 days or hospital discharge (if longer).  The posterior probability P(H | data) will be 
calculated and compared to a threshold of 0.975. The statistical method will be the 
Bayesian version of a comparison of proportions (see Section C.11).   
16. Incidence of all strokes at 30 days or hospital discharge, whichever is longer: TAVI vs. 
SAVR (secondary objective #15).  The hypothesis of interest is 
H:  TAVI <  SAVR 
where  TAVI and  SAVR denote the binary rate of strokes at 30 days or hospital discharge (if 
longer).  The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975. The statistical method will be the Bayesian version of a comparison of 
proportions (see Section C.11).   

 
 
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17. Incidence of moderate/severe aortic insufficiency after TAVI vs. SAVR (secondary 
objective #12).  The hypothesis of interest is 
H:  TAVI <  SAVR 
where  TAVI and  SAVR denote the proportion of subjects with moderate/severe aortic 
insufficiency at the discharge echo.  The posterior probability P(H | data) will be calculated 
and compared to a threshold of 0.975. The statistical method will be the Bayesian version 
of a comparison of proportions (see Section C.11).   
18. New pacemaker implant rate for TAVI at 30 days or hospital discharge, whichever is 
longer (secondary objective #7).  The hypothesis of interest is 
H:  TAVI < 30% 
where  TAVI denote the binary rate of new pacemaker implants for TAVI at 30 days or 
hospital the discharge (if longer).  The posterior probability P(H | data) will be calculated 
and compared to a threshold of 0.975. The statistical method will be the Bayesian version 
of a comparison of proportions (see Section C.11).   
Other than the hierarchical testing procedure described above, no further multiplicity 
adjustments will be made in the analyses of the secondary endpoints.  Summary data from other 
secondary objectives, such as device success and procedural success from secondary 
objectives #20 and #21, respectively, may be provided in the device labeling.  However, no 
claims of statistical significance or other statistical inference will be made.   
 Heterogeneity/Poolability 
C.6.11
A poolability analysis among investigational centers, access site (ilio-femoral or non-ilio-
femoral), need for revascularization, and primary baseline demographics will be performed for 
the primary endpoint and will be described in the SAP. In particular, the primary endpoint and 
key secondary endpoints such as MACCE and MAE incidence will be examined for differences 
in outcome between genders, need for revascularization, and between access routes.  
Additionally, tests for these outcomes will be performed to evaluate potential interactions 
between treatment and gender and between treatments and need for revascularization and 
between treatment and access site. 
 Additional Analysis 
C.6.12
C.6.12.1 Pre-Defined Subgroups 
The following sub-groups will be analysed for publication purposes: 
 
Diabetes Mellitus (yes, no) 
 
Age [< 65 years of age (ie. Medicare population), 65-70 years of age, 71-74 years 
of age, 75-79 years of age and >=80 years of age] 
 
Gender (male, female) 
 
STS score 
 
Presence of co-morbidities 
 
Need for coronary revascularization 
A test for interaction between the treatment effect (SAVR versus TAVI) and the subgroup 
variable will be performed. 
These comparisons are not powered, and will be for exploratory purposes only, not to be used 
to support labeling claims.  
C.6.12.2 Analysis of VARC Endpoints and Definitions 
Endpoints 
Device success will be calculated per the definition outlined in O.2 as well as using the VARC-I 
definition, as appropriate. 
Definitions 
Events with definitions modified in revisions to VARC will be analyzed per both the definition 
outlined in O.2 and VARC-I.  Applicable terms include: 

 
 
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 
Acute Kidney Injury 
 
Bleeding 
 
Death  
 
Device Migration/ Valve Embolism 
 
Device Malplacement 
 
Myocardial Infarction 
 
Prosthetic Valve Dysfunction 
 
Stroke and TIA 
 
Vascular Complications 
 Health-Related Quality of Life (HRQoL) and Treatment Costs 
C.6.13
Health-related quality of life (HRQoL) and treatment costs will be assessed alongside the core 
clinical trial to evaluate the impact of the TAVI and SAVR strategies on a range of relevant 
quality of life (QoL) domains and also to evaluate the cost-effectiveness of the two treatment 
strategies. 
C.6.13.1 Quality of Life 
Health Related Quality of Life (HRQoL) and functional status will be assessed using a 
combination of generic and disease-specific measures selected to cover a broad range of health 
domains that may be affected by severe aortic stenosis disease, its treatment, and its 
complications: the Medical Outcomes Study 36-item Short Form (SF-36), the Kansas City 
Cardiomyopathy Questionnaire (KCCQ), and the EuroQoL Five Dimensions (EQ-5D). All 
patients will complete standardized, written questionnaires at baseline (prior to subject being 
informed of randomization), 30 days, 6 months, 12 months, 18 months, 24 months and annually 
thereafter up to 5 years.  At 3 months subjects will also be contacted via telephone to complete 
the EQ-5D, in select geographies SF-36 will also be collected Additional information regarding 
the HRQoL assessments and administration is located in Appendix R.12 Economic and Quality 
of Life Data Collection. 
C.6.13.2 Economic Outcomes/Cost-Effectiveness 
Data on resource utilization will be collected for the index hospitalization and through long-term 
follow-up for all enrolled subjects.  These resource items will include number and duration in-
patient stays in hospital by type of unit (eg. intensive care, high-dependency care and standard 
ward care); number of clinic visits (by type of physician); and details of the main procedure 
undertaken.  As part of the trial analysis, resource use estimates will be presented by 
randomized group (eg. mean per patient plus standard deviation).  This data, together with the 
EQ-5D data will provide an important input into cost effectiveness analysis.  However, as such 
analysis is likely to be based on a modeling framework, to include evidence from a number of 
sources (eg. a meta-analysis of other TAVI trials) and to vary according to the jurisdiction of 
interest, it is appropriate to detail the methods in separate protocols and analysis plans.  
 Use of Data for CE Mark 
C.6.14
Data from the TAVI arm may be utilized to seek CE Mark approval for the Intermediate Risk 
indication prior to trial completion.  This is expected to include the experience of approximately 
the first 100 TAVI subjects out to 30 days.  This analysis will not impact the Type I error rate of 
this trial as there will not be an early analysis of control (randomized) data, and no decisions to 
alter the pivotal trial are allowed based on this analysis.  This data will not be made public and a 
limited number of personnel will have access to the results. 
 

 
 
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C.7 
Data and Quality Management 
 
Electronic Data Capture 
C.7.1
Medtronic will use the Oracle Clinical Remote Data Capture database system for data collection. 
Oracle is a secure, password-protected, Part 11 compliant database which is backed up 
regularly (at a minimum once daily). 
 
Data Collection 
C.7.2
The investigator must ensure accuracy, completeness and timeliness of the data reported in the 
EDC system and in all other required reports. Data reported on the eCRFs which are derived 
from source documents must be consistent with the source documents or the discrepancies 
need to be justified in a documented rationale, signed and dated by the (principal) investigator, 
to be filed in the subject file. 
Required data will be recorded on the eCRFs by authorized site personnel as indicated on the 
Delegation of Authority Log. The eCRFs must be completed and/or updated to reflect the latest 
observations on the subjects participating in the trial. 
The investigator (or approved sub-investigator) will electronically sign the appropriate pages of 
each eCRF. 
The EDC system maintains an audit trail on entries, changes or corrections in CRFs. If a person 
only authorized to complete CRFs makes changes to an already signed CRF, the investigator 
shall re-sign this CRF. 
The sponsor and/or assigned designee will be responsible for the processing and quality control 
of the data. Data management will be done according to Medtronic SOPs and the applicable 
Data Management Plan. All trial-related documents must be retained for a period of at least 2 
years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational device. Medtronic will 
inform the investigator/institution when these documents are no longer required to be retained. 
No trial document or image should be destroyed without prior written agreement between the 
Sponsor and the investigator. Should the investigator wish to assign the trial records to another 
party or move them to another location, advance written notice should be given to the Sponsor. 
Copies of the eCRFs to be used are included in Appendix R.5. 
 
Core Laboratories Procedures 
C.7.3
Data from the core lab will be transferred to Medtronic and stored in the Oracle Clinical Remote 
Data Capture system as described in the Medtronic CoreValve™ SURTAVI Trial Data 
Management Plan. 
 
Source Documents 
C.7.4
Source documentation is defined as the first time the data appear and may include all clinical 
records, hospital records, surgery reports, autopsy reports, and any other material that contains 
original information used for trial data collection or adverse event reporting.  Where copies of the 
original source document as well as print outs of original electronic source documents are 
retained, these shall be signed and dated by a member of the investigation site team with a 
statement that it is a true reproduction of the original source document.  No eCRFs may serve 
as source documents. 
Source documentation may vary from site to site.  The source documents must be retained by 
the investigational site for a period of 2 years after trial conclusion and made available for 
monitoring or auditing by the sponsor’s representative or representatives of the FDA, IRB/MEC, 
and other applicable regulatory agencies.  The Investigator must ensure the availability of 
source documents from which the information on the eCRFs was derived. 
 
Maintenance and Calibration 
C.7.5
Sites should perform regular maintenance and calibration of all equipment relevant to protocol 
required assessments.  Maintenance and calibration should be conducted per local standards 
and ensure proper documentation must be on file for routine monitoring and audit, as applicable. 

 
 
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C.8 
Records and Reports 
 
Responsibilities of the Sponsor 
C.8.1
The Sponsor must maintain the following records, at a minimum: 
 
All essential correspondence related to the clinical trial 
 
Signed Investigator Agreement 
 
Curriculum vitae for each Investigator 
 
Records of device shipment and disposition (shipping receipts, material destruction 
records, etc.) 
 
Adverse event information  
 
Complaint documentation 
 
All data forms, prepared and signed by the Investigators and received source 
documentation and core lab reports 
 
Protocol and report of prior investigations 
 
Site monitoring reports 
 
Financial disclosure information 
The Sponsor is responsible for the preparation of, the accuracy of the data contained in, the 
review of and the submission of the reports listed in Table 5. 
 
Table 5:  Sponsor Reporting Responsibilities 
Report 
Submit to 
Description 
Unanticipated Adverse 
(Serious) Device Effects 
(UADE or USADE) 
IRB/MEC, 
Investigators, FDA, 
and local regulatory 
agencies, where 
applicable 
Medtronic will report on any confirmed 
unanticipated adverse device effect 
evaluation as soon as possible but no later 
than within 10 working days after first 
receiving notice of the effect. (21 CFR 
812.150) and in compliance with local 
regulatory requirements, as applicable. 
Withdrawal of IRB/MEC 
approval 
IRB/MEC, 
Investigators, FDA, 
and local regulatory 
agencies, where 
applicable 
Notification, when appropriate, will be made 
within 5 working days after Medtronic 
receives notice of withdrawal of IRB/MEC 
approval. 
Withdrawal of FDA  
approval 
IRB/MEC, 
Investigators 
Notification will be made within 5 working 
days after Medtronic receives notice of 
withdrawal of FDA approval. 
Current Investigator List 
FDA and local 
regulatory agencies, 
where applicable 
Medtronic will submit a current list of the 
names and addresses of all participating 
Investigators at six-month intervals, 
beginning six months after FDA approval of 
IDE. 
Progress Report 
IRB/MEC, 
Investigators, FDA 
A progress report will be submitted at least 
yearly. 
Recall and Device 
Disposition 
IRB/MEC, 
Investigators, FDA, 
and local regulatory 
agencies, where 
applicable 
Notification will be made within 30 working 
days of Medtronic’s request that an 
Investigator return, repair or otherwise 
dispose of any devices.  Such notification will 
state why the request was made. 
Final Report 
IRB/MEC, 
Investigators, FDA 
Notification will be made within 30 working 
days of the completion or termination of the 
investigation.  A final report will be submitted 
within six months after trial completion or 
termination. 

 
 
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Report 
Submit to 
Description 
Failure to obtain Informed 
Consent 
FDA 
Notification will be made within 5 working 
days after Medtronic’s receipt of such 
notification indicating Informed Consent was 
not obtained. 
Emergency Deviations from 
Investigational Plan 
FDA and local 
regulatory agencies, 
where applicable 
Notification will be made within 5 working 
days after Medtronic learns of an emergency 
deviation from the Investigational Plan where 
the deviation was made to protect the life or 
physical wellbeing of a subject. 
 
Responsibilities of the Investigator 
C.8.2
The Investigator is responsible for the preparation, review, signature, and retention of the 
records listed below: 
 
All essential correspondence that pertains to the investigation 
 
Device use/disposition records 
 
Records of each subject’s case history and exposure to the device.  Case histories 
include the CRFs and supporting data (source documentation), including, for example: 
o 
Signed and dated consent forms 
o 
Medical records, including, for example, progress notes of the physicians, the 
subject’s hospital chart(s) and the nurses’ notes 
o 
All adverse event information  
o 
A record of the exposure of each subject to the investigational device (eg., date 
of implant procedure and follow-up assessment dates) 
o 
Documentation of any deviation from the protocol, including the date and the 
rationale for such deviation 
 
Screening Logs, Enrollment Logs and Patient Identification Logs 
 
Signed Investigator Agreement, curriculum vitae and training records 
 
Protocol and any amendments 
 
IRB/MEC approval documentation, and where applicable, other local regulatory 
approvals 
The Investigator may withdraw from responsibility to maintain records by transferring custody to 
another person, who will accept responsibility for record and report maintenance. 
The Investigator is responsible for the preparation, review, signature, and submission of the 
reports listed below in.  These are also subject to inspection by government agencies and must 
be retained as specified above.   

 
 
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Table 6:  Investigator Reporting Responsibilities 
Report 
Submitted to 
Description 
Unanticipated Adverse 
(Serious) Device 
Effects (UADE or 
USADE) 
Sponsor, IRB/MEC, 
and local regulatory 
agencies, where 
applicable 
UADEs and USADEs should be reported 
immediately via telephone as well as on an eCRF. 
UADEs and USADEs must be submitted as soon 
as possible, but in no event later than 3 calendar 
days after the Investigator first learns of the effect. 
Serious Adverse 
Events and Deaths 
Sponsor,  and local 
regulatory agencies, 
where applicable 
The Investigator shall notify the sponsor 
immediately (i.e. within 3 calendar days of first 
learning of any SAE) [MEDDEV 2.7/3].  
Withdrawal of IRB/MEC 
approval 
Sponsor 
The Investigator must report a withdrawal of the 
reviewing IRB/MEC, approval within 5 working 
days. 
Progress Report 
Sponsor, IRB/MEC 
The Investigator must submit a progress report on 
an annual basis if the trial lasts longer than one 
year. 
Failure to obtain 
Informed Consent 
Sponsor, IRB/MEC 
The Investigator must make notification within 5 
working days after device implant. 
Final Report 
Sponsor, IRB/MEC 
This report must be submitted within 3 months 
after termination or completion of the 
investigation. 
Deviations from Investigational Plan (CFR 812.150) 
Emergency Use 
Sponsor, IRB/MEC 
Notification must be made within 5 working days 
of the occurrence of an emergency deviation 
made to protect the life or physical well-being of a 
subject. 
Planned deviation 
Sponsor, IRB/MEC, 
FDA 
If the deviation affects scientific soundness of the 
trial or the rights, safety, or welfare of the subject 
and is not an emergency, prior approval must be 
obtained from Medtronic, the reviewing IRB/MEC, 
and FDA. 
Other Deviations 
Sponsor 
Deviations that are beyond the control of the 
investigator (such as patient who fails to return to 
follow-up visit) or deviations that do not affect the 
scientific soundness of the trial or the rights, 
safety, or welfare of the subject and are not an 
emergency, should be submitted as they are 
identified by the site or Medtronic staff. 
 
 

 
 
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D RISK / BENEFIT ANALYSIS 
There are risks for participants in this trial.  However, it should be noted that most of the risks of 
trial participation are not materially different than those entailed by an individual who undergoes 
the same treatment outside of the context of this trial. 
Known adverse events that may result from TAVI (inclusive of CoreValve and Evolut R systems) 
include but may not be limited to:  
 
Death 
 
Cardiac arrest 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary closure) 
 
Emergent surgery (eg., coronary artery bypass, heart valve replacement, valve explant) 
 
Multi-organ failure 
 
Heart failure 
 
Myocardial infarction 
 
Cardiogenic shock 
 
Respiratory insufficiency or respiratory failure 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, ventricle, 
myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel 
 
Ascending aorta trauma 
 
Cardiac tamponade 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture 
o 
Bending (out-of-round configuration) of the valve frame 
o 
Under-expansion of the valve frame 
o 
Calcification 
o 
Pannus, (wear, tear, prolapse, or retraction in the valve leaflets) 
o 
Poor valve coaptation 
o 
Suture breaks or disruption 
o 
Leaks 
o 
Mal-sizing (prosthesis-patient mismatch) 
o 
Malposition (either too high or too low)/malplacement 
o 
Regurgitation, stenosis 
 
Thrombosis/embolus (including valve thrombosis) 
 
Valve migration/valve embolization 
 
Ancillary device embolization 
 
Emergent percutaneous coronary intervention (PCI) 
 
Emergent balloon valvuloplasty 
 
Major or minor bleeding that may or may not require transfusion or intervention 
(including life-threatening or disabling bleeding) 
 
Allergic reaction to antiplatelet agents, contrast medium, or anesthesia 
 
Infection (including septicemia and endocarditis) 
 
Stroke, TIA, or other neurological deficits 
 
Permanent disability 
 
Renal insufficiency or renal failure (including acute kidney injury) 
 
Mitral valve regurgitation or injury 
 
Tissue erosion 
 
Vascular access related complications (eg., dissection, perforation, pain, bleeding, 
hematoma, pseudoaneurysm, irreversible nerve injury, compartment syndrome, 
arteriovenous fistula, stenosis) 
 
Conduction system disturbances (eg., atrioventricular node block, left-bundle branch 
block, asystole), which may require a permanent pacemaker 

 
 
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 
Cardiac arrhythmias 
 
Encephalopathy 
 
Pulmonary edema 
 
Pericardial effusion 
 
Pleural effusion 
 
Myocardial ischemia 
 
Peripheral ischemia 
 
Bowel ischemia 
 
Heart murmur 
 
Hemolysis 
 
Cerebral infarction-asymptomatic 
 
Non-emergent reoperation 
 
Inflammation 
 
Fever 
 
Hypotension or hypertension 
 
Syncope 
 
Dyspnea 
 
Anemia 
 
Angina 
 
Abnormal lab values (including electrolyte imbalance) 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic 
valve and prolonged procedural time 
Additional information regarding risk analysis is located in the Investigator Brochures (Appendix 
R.21). 
D.1 
Methods to Minimize Risk 
The investigational plan is specifically designed to manage and minimize risks through careful 
patient selection, thorough training of investigators, adherence to the pre-determined time points 
to assess subject clinical status and regular clinical monitoring visits by Sponsor appointed 
monitoring personnel.  
In addition, an independent Data Safety Monitoring Board will monitor safety of the subjects 
throughout the trial. 
D.2 
Potential Benefits 
Patients treated with TAVI may experience improvement in quality of life, morbidity and mortality 
compared to traditional open-heart aortic valve replacement. Potential benefits include, but are 
not limited to, absence of open-heart surgery-related risks, reduced procedure time, reduced 
anesthesia procedure time, shorter hospital stay and earlier return to normal activities than after 
open-heart aortic valve replacement. 
There is no direct benefit associated to participation in this trial, but the information obtained 
during this trial will be used scientifically. The results of this trial can help physicians understand 
the implications of transcatheter treatment of patients with intermediate risk for surgery. 

 
 
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E DESCRIPTION OF MEDTRONIC COREVALVE™ SYSTEMS 
E.1 
Investigational Product Description 
 
Medtronic CoreValve System 
E.1.1
The Medtronic CoreValve™ System (MCS) consists of 3 components: the Transcatheter Aortic 
Valve Bioprosthesis (TAV) in  
Figure 2 below, the Delivery Catheter System (DCS) in Figure 3 and Figure 4, and the 
Compression Loading System (CLS) in Figure 5 and Figure 6. 
Transcatheter Aortic Valve Bioprosthesis 
Figure 2:  Transcatheter Aortic Valve (TAV) 
 
The TAV is manufactured by suturing valve leaflets and a skirt, made from a single layer of 
porcine pericardium, into a tri-leaflet configuration. The TAV is designed to replace the native 
aortic heart valve without open heart surgery and without concomitant surgical removal of the 
failed native valve. 
The bioprosthesis is processed with an antimineralization treatment of alpha-amino oleic acid 
(AOA) a compound derived from oleic acid, a naturally occurring long-chain fatty acid. 
The self-expanding multi-level frame is made of Nitinol and is radiopaque. 
The TAV is available for a range of aortic annulus and ascending aortic diameters as shown in 
Table 7 below. 
Table 7:  Medtronic CoreValve System Patient Anatomical Diameters 
CoreValve™ Evolut™ Bioprosthesis 
Model 
Size (mm) 
Aortic Annulus 
Diameter 
(range in mm) 
Ascending Aortic 
Diameter (mm) 
MCS-P4-23-AOA 
MCS-P4-23-AOA-US 
23 
18-20 
≤34 
CoreValve™ Bioprosthesis 
Model 
Size (mm) 
Aortic Annulus 
Diameter 
(range in mm) 
Ascending Aortic 
Diameter (mm) 
MCS-P3-26-AOA 
MCS-P3-26-AOA-US 
26 
20-23 
≤40 
MCS-P3-29-AOA 
MCS-P3-29-AOA-US 
29 
23-27 
≤43 

 
 
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MCS-P3-31-AOA 
MCS-P3-31-AOA-US 
31 
26-29 
≤43 
 
Delivery Catheter System 
The AccuTrak® DCS (DCS-C4-18FR and DCS-C4-18FR-US) is compatible with a 0.889-mm 
(0.035-in) guidewire. The working length of the AccuTrak® DCS is 112.5 cm. It incorporates a 
protective deployment sheath that houses and deploys the TAV. The AccuTrak® DCS can be 
used to house and deliver all commercially available sizes of the TAV (26mm, 29mm, and 31mm 
TAV). The outer diameter of the DCS is 12Fr, the stability layer is 15Fr and the outer diameter of 
the valve capsule is 18 Fr. 
Figure 3:  Delivery Catheter System (DCS) 
 
 
A new Delivery Catheter System (DCS-C4-18FR-23MM and DCS-C4-18F-23US) will be used to 
deploy 23mm Transcatheter Aortic Valve (TAV). The DCS-C4-18FR-23MM, DCS-C4-18FR-23 
and  DCS-C4-18FR-23US has a shortened Capsule and Plunger (5mm) for delivery of the 
23mm TAV but the working length of the new AccuTrak™ DCS is 112.5 cm similar to DCS-C4-
18FR used to deploy other TAV sizes. 
Figure 4:  Design Changes for Delivery Catheter System (DCS) specific to 23mm 
 
 
The AccuTrak® DCS features an integrated handle designed to provide the user with accurate 
and controlled deployment.  After the DCS is placed in the vicinity of the aortic annulus, the user 
retracts the deployment sheath, thereby deploying the TAV to the desired location.  In use, the 

 
 
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deployment sheath can be partially pulled back to evaluate the TAV location prior to fully 
releasing the TAV. In this way, the user can make slight adjustments to the TAV location if 
needed prior to release.  
Compression Loading Systems  
The CLS (Model CLS-3000-18FR and CLS-3000-18F-US) and next generation CLS (Model 
CLS4-18F and Model CLS4-18F-23) is a system of reduction cones and tubing, which is 
designed to gradually reduce the diameter of the TAV to an optimal diameter to facilitate manual 
loading of the TAV into the deployment sheath capsule of the DCS.  
The CLS is comprised of the following elements: 
 
inflow cone 
 
inflow tube (straight tube) 
 
outflow cap 
 
outflow cone 
 
outflow tube (tube with flared ends) 
  
Figure 5:  Compression Loading System (CLS) (Model CLS-3000-18 FR and CLS-3000-
18FR-US) 
 
 
Figure 6: Compression Loading System (CLS) Models CLS4-18F-C and CLS-3000-18FR-
US (left) and CLS4-18F-23-C (right) 
 
 
 
The inflow cone, outflow cone, and outflow cap components of the next generation CLS models 
are tinted, and the locking mechanism has been modified from the previous generation. The 
purpose and function of all CLS models is the same, but the next generation includes 2 models, 
one intended for use with the 23mm TAV (CLS4-18F-23-C), which has an orange tint, and 
another model intended for 26 mm, 29 mm & 31mm TAVs (CLS4-18F-C and CLS-3000-18F-
US), which has a blue tint. 
 
 

 
 
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Medtronic CoreValve Evolut R System 
E.1.2
The CoreValve™ Evolut™ R System is comprised of the following 3 components: Evolut R 
Transcatheter Aortic Valve (TAV) in Figure 7, EnVeo R Delivery Catheter System (DCS) with 
EnVeo R Inline Sheath in Figure 8 and the EnVeo R Loading System (LS) in Figure 9.  
Evolut R Transcatheter Aortic Valve (TAV) 
Figure 7: Evolut R Transcatheter Aortic Valve (TAV) 
 
 
 
The Evolut R TAV is available in three sizes (23mm, 26mm, and 29mm) in this trial, covering an 
aortic annulus diameter of 18 to 26mm. The TAV is comprised of three leaflets and a sealing 
skirt constructed from glutaraldehyde-fixated porcine pericardium, sewn to a compressible and 
self-expandable Nitinol support frame. The TAV is processed with an anti-mineralization 
treatment of alpha-amino oleic acid (AOA), a compound derived from oleic acid, a naturally 
occurring long-chain fatty acid.  
The TAV is available for a range of aortic annulus and ascending aortic diameters as shown in 
Table 8 below. 
Table 8: CoreValve™ Evolut™ R TAV Patient Anatomical Diameters 
CoreValve™ Evolut™ R Bioprosthesis 
Model 
Aortic Annulus Diameter 
(range in mm) 
Aortic Diameter at the 
Sino-tubular Junction 
(range in mm) 
EVOLUTR-23-C 
EVOLUTR-23-US 
18 – 20 
NA 
EVOLUTR-26-C 
EVOLUTR-26-US 
20 – 23 
NA 
EVOLUTR-29-C 
EVOLUTR-29-US 
23 – 26 
NA 
 
EnVeo R Catheter Delivery System with EnVeo Inline Sheath 
The EnVeo R delivery catheter system facilitates the placement of the TAV within the annulus of 
the aortic valve. The catheter assembly is flexible and compatible with a 0.035 in (0.889 mm) 
guidewire. The distal (deployment) end of the system features an atraumatic, radiopaque 
catheter tip and a capsule that covers and maintains the bioprosthesis in a crimped position. 
The capsule includes a distal flare to enable full recapture of the bioprosthesis after partial 
deployment. A stability layer is fixed at the handle and extends down the outside of the catheter 
shaft. It provides a barrier between the retractable catheter and the introducer sheath and vessel 
walls, thus enabling the catheter to retract freely.  

 
 
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The EnVeo R Inline Sheath is assembled over the stability layer, which functions as a 
hemostatic introducer sheath and minimizes the access site size to the capsule diameter. The 
EnVeo R Inline Sheath is also compatible with an 18 Fr introducer.  
The delivery catheter system consists of a catheter with an integrated handle to provide the user 
with accurate and controlled deployment. The handle is on the proximal end of the catheter and 
is used to load, deploy, recapture, and reposition the bioprosthesis. The handle features a gray 
front grip used to stabilize the system. The blue actuator turns to deploy the bioprosthesis 
precisely. Arrows on the actuator indicate the direction of rotation required to deploy the 
bioprosthesis. If desired, the blue actuator can be turned in the opposite direction to recapture 
the bioprosthesis if the radiopaque capsule marker band has not yet reached the distal end of 
the spindle. The blue actuator also features a trigger, which can be engaged to make macro 
adjustments to the capsule position. A blue hand rest connects to the blue actuator. The end of 
the handle features a tip-retrieval mechanism, which can be used to withdraw the catheter tip to 
meet the capsule after the device has been fully deployed.  
Figure 8: EnVeo R Delivery Catheter System 
 
 
The catheter packaging contains an integrated loading bath and a removable tray with 3 rinsing 
bowls for loading and rinsing the bioprosthesis. The integrated loading bath features a mirror, 
which aids in accurate placement of the bioprosthesis frame paddles during loading. In addition, 
the device packaging is swiveled and secured to facilitate the bioprosthesis loading procedure. 
EnVeo R Loading System 
The EnVeo R loading system facilitates manual loading of the TAV into the deployment sheath 
capsule of the catheter delivery system by gradually reducing the diameter of the bioprosthesis 
radially to an optimal diameter (Figure 9). The manual loading is performed during the procedure 
prior to implantation. The loading procedure is performed while immersing the loading system, 
the TAV, and the distal end of the catheter delivery system in cold sterile saline. 
 
 

 
 
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Figure 9: EnVeo R Loading System 
 
 
Medtronic may incorporate additional devices into this clinical trial providing they receive 
regulatory approval and the scientific soundness of the trial is not adversely affected.   
Additional information regarding the Medtronic CoreValve™ System and CoreValve™ Evolut™ R 
are available in the Investigator Brochures (Appendix R.21).  Note the Instructions For Use 
(IFU) are also located in Appendix R.22. 
 
 

 
 
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E.2 
Investigational Device Ordering, Storage, and Disposition 
The TAV and all required delivery components will be ordered through Medtronic. Medtronic will 
only allow shipment of investigational devices to the hospital or investigator when the Clinical 
Research Specialist has declared the investigation site ready to start the trial.   
Devices will be shipped to sites as needed based on subject enrollment/randomization and 
procedures scheduled.  Only one device should be used per patient, unless in case of device 
malfunctions or in case of complications. Sites will be supplied with sufficient device stock to 
complete scheduled procedures.  Upon completion of scheduled procedures all unused devices 
must be returned to Medtronic.  Instructions for device return are outlined on the Device 
Accountability Log. In the US, commercial devices, as referenced in Table 1, are approved for 
use in the clinical trial, as necessary, in the event that an investigational device is not available. 
Investigational devices must be stored in a secured area. The method of storage shall prevent 
the use of investigational devices outside the applications as mentioned in this Clinical 
Investigation Plan. In addition, all information for the use, storage and handling of the 
investigational device as indicated in the Investigator’s Brochure, must be taken into account. 
Instructions for Use and storage recommendations are outlined in Appendix R.22. 

 
 
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F MONITORING AND AUDITING 
F.1 
Monitoring 
The investigational site will be monitored to ensure compliance with the trial protocol, adherence 
to applicable regulations, and accuracy of trial data.  Monitoring visits will be conducted primarily 
to ensure the safety and wellbeing of the subjects is preserved.  Monitoring visits will also be 
used to verify that trial data submitted on case report forms are complete and accurate with 
respect to the subject records and to verify device accountability.   
The Investigator(s), his/her delegate(s) and the study coordinator(s) shall be accessible to 
during monitoring. Accessibility is of particular importance for reviewing data in the eCRF.  
Site personnel will complete eCRFs following each subject visit.  Trial data submitted will be 
reviewed against patient charts and other sources containing original records of patient data.  
Source document verification will be conducted via a risk based approach as outlined in the 
Monitoring Plan. 
The responsible individual for this trial is included on the title page of the CIP. 
The progress of the trial will be monitored by: 
 
On-site review, as deemed appropriate by the sponsor 
 
Telephone communications between the site personnel (eg., Investigator, Trial 
Coordinator) and trial monitors 
 
Review of eCRFs and the associated clinical records 
 
Review of regulatory documents 
Upon trial completion Site Closeout Visits will be conducted, as outlined in the Monitoring Plan. 
Monitoring and monitoring oversight will be provided by Medtronic Coronary and Structural 
Heart (Mounds View, MN, USA, and Maastricht, the Netherlands).  Representatives of 
Medtronic (i.e. contractors and designees) may also act as the trial monitors to the site.  
Medtronic will maintain an updated list of applicable representative and provide a copy to sites 
upon request. 
Prior to the first site activation a monitoring plan will be established outlining the above activities, 
as well as trial materials to be supplied to sites, the process for corrective and preventive actions 
and Investigator disqualification procedures. 
F.2 
Auditing 
Medtronic may conduct audits at participating clinical sites. The purpose of an audit is to verify 
the performance of the monitoring process and the trial conduct, independently of the personnel 
directly involved in the trial. Regulatory bodies, such as the Food and Drug Administration, may 
also perform inspections at participating sites. The investigator and/or institution shall permit 
Medtronic and regulatory bodies direct access to source data and documents. 

 
 
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G LABELING 
In Europe, the TAV component labeling will not carry the CE mark and the labeling will state for 
“clinical study purposes only” in accordance with ISO14155. The Investigational Instructions for 
Use (IFU) and labeling is supplied in English (and the local language, if required) with the TAV 
component and this will also not carry the CE mark.  The DCS and CLS/LS components are 
identical to the CE marked CoreValve System and will be supplied with the approved 
commercial CE marked labeling. 
In the United States and other geographies, where TAV is not currently approved, the TAV, DCS 
and CLS/LS will be labeled as Investigational. 
Instructions for Use and additional labeling are attached in Appendix R.22. 
H CONSENT MATERIALS 
The template consents for the trial are attached in Appendix R.1. 
I 
IRB/MEC INFORMATION 
IRB/MEC information is attached in Appendix R.2. 
J 
OTHER INSTITUTIONS 
Information regarding other institutions involved in this trial is located in Appendix R.3. 
K ADDITIONAL RECORDS AND REPORTS 
Information regarding additional Records and Reports can be in found in Appendix R.4. 
L REPORT OF PRIOR INVESTIGATIONS 
The Report of Prior Investigations (RPI) is attached in the Investigator Brochure in Appendix 
R.21. 

 
 
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M PUBLICATION POLICY 
Medtronic, as the Sponsor of this trial, recognizing the seminal importance of this investigation, 
is committed to the widespread dissemination of all primary and secondary endpoint results.  A 
publication plan will be implemented and followed.  At the conclusion of the trial, a multisite 
abstract reporting the primary results will be prepared by the Principal Investigators (in 
collaboration with others including but not limited to the Steering Committee, directors of the 
core laboratories, CEC, and Lead Investigators from high enrolling sites) and presented at an 
annual scientific meeting (eg., Transcatheter Cardiovascular Therapeutics, EuroPCR, the 
American Heart Association, or the American College of Cardiology).  A multisite publication will 
similarly be prepared for publication in a reputable scientific journal.  The publication of the 
principal results from any single site experience within the trial is not allowed until both the 
preparation and publication of the multisite results, and then only with written permission from 
Medtronic.  
Following analysis and presentation of the primary endpoint results, active participation of all 
committee members, Investigators from high enrolling sites, and core laboratory personnel will 
be solicited for data analysis and abstract and manuscript preparation.  Submission of all 
abstracts and publications regarding the primary endpoint and secondary endpoints from the 
trial requires approval by Medtronic and the Publications Committee. 
A separate publication plan will provide detailed information about the publication committee, 
authorship, publication proposals, and requests for data. 

 
 
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N AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN 
All amendments to the CIP shall be agreed between the sponsor and the clinical investigator(s).   
The investigator may propose appropriate modification(s) of the Clinical Investigation Plan or 
investigational device or investigational device use. Medtronic will review this proposal and 
decide whether the modification(s) will be implemented.  
Medtronic will submit any significant amendment to the Clinical Investigation Plan, including a 
justification for this amendment, to the appropriate regulatory authorities and to the investigators 
to obtain approval from their IRB/MEC. The investigator will only implement the amendment 
after approval of the IRB/MEC, regulatory authority and sponsor. 
Amendments will be recorded with a justification for the amendments in Table 9below: 
 
Table 9:  Clinical Investigation Plan Change History 
Version 
Description of Change 
Rationale for Change 
3.0 
Initial Release 
NA 
4.0 
 Inclusion/Exclusion Criteria updated 
 Device status updates: 
o Addition of 23mm PAV and 
applicable DCS 
o AOA CE mark status 
 Modification of statistical methods to 
relative risk design and addition of 
adaptive trial design 
 Addition of Canada as a participating 
geography 
 Appendix updates: 
o Informed Consent templates 
o Clinical Assessments 
o Investigator Brochure 
o Instructions For Use 
o Radiation Exposure and Data 
Collection 
 Changes based on FDA pre-IDE 
feedback 
 Device status updates: 
o 23mm PAV and applicable 
DCS CE mark approval 
o AOA CE mark approval 
5.0 
 Stroke classifications changed from 
major vs. minor to disabling vs. non-
disabling 
 Inclusion/Exclusion Criteria updated 
 Additional neurological testing added 
(mRS) 
 Clarification of local Heart Team 
composition and decision making 
 Appendix updates: 
o CMS Requirements for Coverage 
and Reimbursement – US ONLY 
– added
 Changes based on FDA IDE 
deficiencies 
 General updates and corrections 
6.0 
 Device status update – Canadian 
approval 
 Total number of investigational 
centers increased 
 Inclusion criteria #3 updated 
 Roll-in subjects added 
 Definitions of terms updated in 
alignment with VARC-2 
 Appendix updates: 
o Informed Consent templates 
o Echocardiography Acquisition 
Guidelines 
 Changes based on FDA 
recommendations 
 Publication of VARC-2 
 General updates and corrections 

 
 
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Version 
Description of Change 
Rationale for Change 
o Aortogram Acquisition Guidelines 
7.0   
OBSOLETED prior to 
distribution 
 Device Description updated to include 
EnVeo™ DCS and next generation 
CLS 
 FDA IDE supplement to 
incorporate EnVeo/G5 and the 
next generation CLS in the 
United States 
8.0 
 Modification to Patient Population (re-
defined Intermediate Risk) 
 Inclusion / Exclusion modifications 
and clarifications 
 Clarification of adverse event 
reporting requirements 
 All references to Percutaneous Aortic 
Valve (PAV) updated to Transcatheter 
Aortic Valve (TAV) 
 Addition of the next regeneration 
Compression Loading Systems 
 Appendix updates: 
o Informed Consent templates 
o Instructions for Use 
o Investigator Brochure 
o Echocardiography Acquisition 
Guidelines 
o Electrocardiogram (ECG) 
Submission 
 General updates and corrections 
 Updated trial utilization of core 
laboratories 
8.1 
 Inclusion criteria clarification 
 Updated to include upper limit of 
risk classification 
9.0 
 All references to Cardiovascular 
Department updated to Coronary and 
Structural Heart 
 Addition of CoreValve Evolut R 
System 
 All references to MCS TAVI updated 
to TAVI 
 Appendix updates: 
o Informed Consent templates 
o Other Institutions 
o Instruction for Use 
o Investigator Brochure 
 General updates and corrections 
 Updated to include the use of 
CoreValve Evolut R System  
 Updated change to Imaging Core 
Lab 
10.0 
 Updated Device Approval Status 
 Statistical Methods and Analysis: 
o Updated assumed event rates 
o Modified non-inferiority margin 
o Updated sample size look  
 Updated maximum sample 
size from 3700 to 2000 
 Appendix updates: 
o Informed consent templates 
 General updates and corrections 
 Updated Statistical Methods and 
Analysis per agreement from 
FDA 
11.0 
OBSOLETED prior to 
distribution 
 Updated Device Approval Status 
 Removed AR/AS/MR as SAEs in 
absence of clinical symptoms 
 Statistical Methods and Analysis 
 General updates and corrections 
 Updated Statistical Methods and 
Analysis per agreement from 
FDA 
12.0 
 Update Device Description 
 Removed moderate or severe mitral 
or aortic regurgitation or stenosis as 
default SAEs in absence of clinical 
symptoms 
 Added section about Vigilance 
Reporting 
 Statistical Methods and Analysis 
 Investigational Device Accountability 
 Appendix updates: 
o Informed consent templates 
 General updates and corrections 
 Updated Statistical Methods and 
Analysis  
 

 
 
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O ABBREVIATIONS AND DEFINITIONS 
O.1 
List of Abbreviations 
Please refer to Table 10 below for a list of abbreviations for use in the SURTAVI trial. 
Table 10:  List of Abbreviations 
Abbreviation 
Term 
2D 
Two Dimensional 
6MWT 
Six Minute Walk Test 
AE 
Adverse Event 
ACT 
Active Clotting Time 
ADE 
Adverse Device Effect 
AF 
Atrial Fibrillation 
AOA 
Alpha-amino Oleic Acid 
aPTT 
Activated Partial Thromboplastin Time 
AR 
Aortic Regurgitation 
AS 
Aortic Stenosis 
AVR 
Aortic Valve Replacement 
BAV 
Balloon Aortic Valvuloplasty 
BNP 
B-type Natriuretic Peptide 
BPM 
Beats Per Minute 
BP 
Blood Pressure 
BSA 
Body Surface Area 
CA 
Competent Authority 
CE 
European Conformity 
CEC 
Clinical Events Committee 
CFR 
U.S. Code of Federal Regulations 
CIP 
Clinical Investigation Plan 
CLS 
Compression Loading System 
CMS 
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTA 
Computerized tomographic angiography 
CVA 
Cerebrovascular Accident 
CV-ICU 
Cardiovascular Intensive Care Unit 
DCS 
Delivery Catheter System 
DHCA 
Deep Hypothermic Circulatory Arrest 
DSMB 
Data Safety Monitoring Board 
DVI 
Doppler Velocity Index 

 
 
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Abbreviation 
Term 
DVT 
Deep Vein Thrombosis 
ECC 
Extracorporeal Circulation 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOA 
Effective Orifice Area 
EQ-5D 
EuroQoL Five Dimensions 
EuroSCORE 
European System for Cardiac Operative Risk Evaluation 
FDA 
U.S. Food and Drug Administration 
Fr 
French 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HVD 
Heart Valve Dysfunction 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
IABP 
Intra-Aortic Balloon Pump 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IFU 
Instructions for use 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IXRS 
Interactive Voice/Web Response System 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LA 
Left Atrial/Atrium 
LAO 
Left Anterior Oblique 
LBBB 
Left Bundle Branch Block 
LMWH 
Low Molecular Weight Heparin 
LS 
Loading System 
LVEF 
Left Ventricular Ejection Fraction 
LVOT 
Left Ventricular Outflow Tract 
LVOTO 
Left Ventricular Outflow Tract Occlusion 
MACCE 
Major Adverse Cardiovascular and Cerebrovascular Event 
MAE 
Major Adverse Event 
MCS 
Medtronic CoreValve™ System 
MEC 
Medical Ethics Committee 
MI 
Myocardial Infarction 

 
 
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Abbreviation 
Term 
MMSE-2:SV 
Mini Mental State Exam 
NIHSS 
National Institute of Health Stroke Scale 
mRS 
Modified Rankin Score 
NYHA 
New York Heart Association 
PCI 
Percutaneous Coronary Intervention 
PE 
Product Experience 
PPM 
Patient Prosthesis Mismatch 
QoL 
Quality of Life 
RAO 
Right Anterior Oblique 
RBBB 
Right Bundle Branch Block 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SAP 
Statistical Analysis Plan 
SAVR 
Surgical Aortic Valve Replacement 
SF-36 
Short Form (36) Health Survey 
SOP 
Standard Operating Procedures 
STS 
Society of Thoracic Surgeons 
TAV 
Transcatheter Aortic Valve 
TAVI 
Transcatheter Aortic Valve Implant 
TEE 
Transesophageal Echocardiography 
TIA 
Transient Ischemic Attack 
TTE 
Transthoracic Echocardiography 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
 

 
 
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O.2 
Definitions of Terms 
ACUTE KIDNEY INJURY 
 Acute Kidney Injury will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Acute Kidney Injury (AKIN Classification)  
Stages 
Change in Serum Creatinine (up to 7 days post-index procedure) 
compared to Baseline 
Stage 1 
Increase in serum creatinine to 150-199% (1.5-1.9 x increase compared with 
baseline) OR increase of ≥ 0.3 mg/dl (≥26.4 µmol/L) OR urine output <0.5 
ml/kg/hour for >6 but <12 hours 
Stage 2* 
Increase in serum creatinine to 200-299% (> 2.0-2.9 x increase compared 
with baseline) OR urine output <0.5 ml/kg/hour for >12 but <24 hours 
Stage 3*/** 
Increase in serum creatinine to ≥300% (> 3 x increase compared with 
baseline) OR serum creatinine of > 4.0 mg/d (≥354 µmol/L) with an acute 
increase of at least 0.5 mg/dl (44 µmol/L) OR urine output <0.3 ml/kg/hour for 
>24 hours OR anuria for > 12 hours 
*  Stage 2 and 3 acute renal injuries will be considered to be serious adverse events. 
** Patients receiving renal replacement therapy are considered to meet Stage 3 criteria 
irrespective of other criteria 
ACUTE VESSEL OCCLUSION  
 The state of complete luminal obstruction with no antegrade blood flow. 
 ADVERSE EVENT (AE)  
An adverse event is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device.  
NOTE 1: This definition includes events related to the investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to investigational medical devices. 
 ADVERSE DEVICE EFFECT (ADE)  
Adverse event related to the use of an investigational medical device 
 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device 
 AORTIC DISSECTION 
Intimal tear resulting in blood splitting the aortic media and producing a false lumen that can 
progress in an antegrade or retrograde direction. Aortic dissection is further classified using 
Stanford classification (Types A and B) depending on whether ascending or descending aorta 
involved) or DeBakey classification (Types I, II and III) as shown below.  
 
 
 

 
 
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AORTIC REGURGITATION (AR) 
Aortic valve incompetence resulting in backward flow of blood. Reference Appendix R.7 
Echocardiography Acquisition Guidelines for additional information regarding assessment of 
aortic regurgitation. 
 
AORTIC STENOSIS (AS)  
A narrowing, stiffening or stricture of the aortic valve.  
Aortic stenosis of the native valve (i.e. inclusion criteria) will be defined based on the 2008 Focused Update Incorporated 
Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease (published in the 
October 2008 issues of Journal of the American College of Cardiology and Circulation) 
 
Aortic Stenosis 
Indicator 
Mild  
Moderate 
Severe 
Jet velocity (m/s) 
Less than 3.0 
3.0-4.0 
Greater than 4.0 
Mean gradient (mmHg) 
Less than 25 
25-40 
Greater than 40 
Valve area (cm2) 
Greater than 1.5 
1.0-1.5 
Less than 1.0 
Valve area index (cm2/m2) 
 
 
Less than 0.6 
 
Stenosis of trial valve will be defined based on the definition of the Valve Academic Research 
Consortium (VARC)-2 Updated Standardized Endpoint Definitions for Consensus Report for 
Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09.  See Prosthetic Valve 
Dysfunction – Prosthetic Aortic Valve Stenosis. 
ARRHYTHMIA 
Any variation from the normal rhythm of the heartbeat, including sinus arrhythmia, premature 
beat, heart block, atrial fibrillation, atrial flutter and tachycardia.  
 Major Arrhythmias: Complete heart block, ventricular tachycardia and ventricular fibrillation 
 Serious Arrhythmias: Any arrhythmia requiring surgical or invasive intervention or DC 
cardioversion 
ATRIAL FIBRILLATION 
Atrial fibrillation will be classified according to the International Consensus on Nomenclature and Classification of Atrial 
Fibrillation; A Collaborative Project of the Working Group on Arrhythmias and the Working Group on Cardiac Pacing of 
the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, Europace 2003, 
Vol 5. 
 Paroxysmal: spontaneous termination within 7 days and most often <48 hours 
 Persistent:  is not self-terminating; lasts longer than 7 days; or prior cardioversion 
 Permanent (accepted):  does not terminate, or terminated but relapsed; no cardioversion 
attempt 
 
 

 
 
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BLEEDING EVENT 
Bleeding event will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Life-threatening or Disabling Bleeding 
 Fatal bleeding (BARC  type 5) OR 
 Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, or 
pericardial necessitating pericardiocentesis, or intramuscular with compartment 
syndrome (BARC type 3b) OR  
 Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or 
surgery OR 
 Overt source of bleeding with drop in hemoglobin of ≥5 g/dL or whole blood or packed 
red blood cells (RBC) transfusion ≥4 units* (BARC type 3b) 
Major Bleeding  
(BARC type 3a) 
 Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0g/dL or 
requiring transfusion of 2-3 units of whole blood/RBC, or causing hospitalization or 
permanent injury or requiring surgery AND  
 Does not meet criteria of life-threatening or disabling bleeding  
Minor Bleeding  
(BARC type 2 or 3a, depending on severity) 
 Any bleeding worthy of clinical mention (eg. access site hematoma) that does not qualify 
as life-threatening, disabling or major  
*  Given one unit of packed RBC typically will raise blood hemoglobin concentration by 1g/dL, an estimated 
decrease in hemoglobin will be calculated. 
BARC = Bleeding Academic Research Consortium
Life-threatening and Major bleeding events are considered to be serious. 
BUNDLE BRANCH BLOCK 
ACC/AHA/HRS 2006 Key Data Elements and Definitions for Electrophysiological Studies and Procedures; A Report of 
the American College of Cardiology/ American Heart Association Task Force on Clinical Data Standards 
(ACC/AHA/HRS Writing Committee to Develop Data Standards on Electrophysiology), JACC, Vol. 48, No. 11, 2006. 
Left Bundle Branch Block (LBBB) 
 
QRS duration 120 ms or longer 
 
Delayed onset of intrinsicoid deflection in 1, V5, and V6 _60 ms 
 
Broad and notched or slurred R waves in I, aVL, V5, and V6 
 
rS or QS complexes in right precordial leads 
 
ST-segment and T waves in opposite polarity to the major QRS deflection 
Right Bundle Branch Block (RBBB) 
 
QRS duration _120 ms 
 
rsR= or rSR= complexes in V1 and V2 
 
Delayed onset of intrinsicoid deflection in V1 and V2 _50 ms 
 
Broad, slurred S wave in 1, V5, 
Any new or worsening LBBB or RBBB that requires the placement of a permanent pacemaker 
and/or other surgical or invasive intervention will be considered to be serious. 
 
 

 
 
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CARDIAC PERFORATION 
A laceration or tearing of the walls of the ventricles or atria of the heart, of the interatrial or 
interventricular septum, of the papillary muscles or chordae tendineae or of the one of the valves 
of the heart. 
Cardiac perforation events will be classified into additional subgroups according to the Valve Academic Research 
Consortium (VARC)-2; Updated Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 
2012-10-09 
Mitral valve apparatus damage or dysfunction 
Angiographic or echocardiographic evidence of new damage (chordae papillary muscle, or to the 
leaflet) to the mitral valve apparatus or dysfunction (eg. opening restrictions due to the THV) of 
the mitral valve during or after the TAVI procedure.  
Ventricular septal perforation 
Angiographic or echocardiographic evidence of a new septal perforation during or after the TAVI 
procedure.  
CARDIAC TAMPONADE 
Clinical syndrome caused by the accumulation of fluid in the pericardial space, resulting in 
reduced ventricular filling and subsequent hemodynamic compromise. 
CARDIOGENIC SHOCK 
Patient was, at the time of procedure, in a clinical state of hypoperfusion sustained for greater 
than 30 minutes, according to either of the following criteria:  
1. Systolic BP < 80 and/or Cardiac Index < 1.8 despite maximal treatment; or 
2. IV inotropes and/or IABP necessary to maintain Systolic BP > 80 and/or CI > 1.8 
 
CHRONIC RENAL INSUFFICIENCY 
Kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for or ≥3 months.  Kidney 
damage is defined as pathologic abnormalities or markers of damage, including abnormalities in 
blood or urine test or imaging studies. 
CONDUCTION DISTURBANCE REQUIRING PERMANENT PACEMAKER IMPLANTATION 
ACC/AHA 2006 Guidelines for the Management of Patients with Valvular Heart Disease (published in the August 1, 
2006, issues of Journal of the American College of Cardiology and Circulation) 
Any disturbance in the cardiac electrical conduction system that meets the American College of 
Cardiology (ACC)/American Heart Association (AHA)/ Heart Rhythm Society (HRS) Class I or IIa 
Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities for Acquired 
Atrioventricular Block in Adults or Permanent Pacing in Chronic Bifascicular Block. 
CONVERSION TO OPEN HEART SURGERY 
Valve Academic Research Consortium (VARC)-2; Updated Standardized Endpoint Definitions for Transcatheter Aortic 
Valve Implantation (TAVI); 2012-10-09. 
Conversion to open sternotomy during the TAVI procedure secondary to any procedure-related 
complications. 
CORONARY OBSTRUCTION 
Valve Academic Research Consortium (VARC)-2; Updated Standardized Endpoint Definitions for Transcatheter Aortic 
Valve Implantation (TAVI); 2012-10-09. 
Angiographic or echocardiographic evidence of a new, partial or complete, obstruction of a 
coronary ostium, either by the valve prosthesis itself, the native leaflets, calcifications, or 
dissection, occurring during or after the TAVI procedure. 
DEVICE DEFICIENCY 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance 
  
NOTE:  Device deficiencies include malfunctions, use errors, and inadequate labeling. 
 

 
 
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DEVICE RELATED  
Events that occur as the direct result of the Medtronic CoreValve™ System (MCS) or 
CoreValve™ Evolut R System as it relates to delivery, placement, efficacy or durability; these 
may involve the implanted device or the delivery system components. 
DEVICE RELATED COMPLICATIONS 
Complications associated with the device as it relates to delivery, placement, efficacy or 
durability; these may involve the implanted device or the delivery system.   
EMBOLISM 
Free flowing blood clot or lesion material that is located in the systemic or pulmonary circulation 
that occurs in the absence of infection after the immediate perioperative period. Embolism may 
be manifested by a neurological event or a noncerebral embolic event.  
ENCEPHALOPATHY 
Altered mental state (eg., seizures, delirium, confusion, hallucinations, dementia, coma, 
psychiatric episode, etc.).  
ENDOCARDITIS 
Implanted valve endocarditis: Any infection involving an implanted valve. The diagnosis of 
operated valvular endocarditis is based on one of the following criteria:  
 
re-operation with evidence of abscess, paravalvular leak, pus, or vegetation confirmed as 
secondary to infection by histological or bacteriologic studies;  
 
autopsy findings of abscess, pus, or vegetation involving a replaced valve; or  
 
in the absence of reoperation or autopsy, meeting of the Duke Criteria for endocarditis. 
Infective endocarditis is diagnosed based on Duke Criteria and necessitates 2 major criteria, 
or 1 major and 3 minor criteria, or 5 minor criteria 
Major criteria 1: Positive blood culture for infective endocarditis  
Typical microorganism consistent with infective endocarditis from 2 separate blood 
cultures, as noted below: 
 Viridans streptococci, Streptococcus bovis, or HACEK group (Haemophilus. 
Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella 
corrodens, Kingella or  
 Community-acquired Staphylococcus aureus or enterococci, in the absence of a 
primary focus  
-OR- 
Microorganisms consistent with infective endocarditis from persistently positive blood 
cultures defined as: 
 
Two positive cultures of blood samples drawn >12 hours apart, or  
 
All of 3 or a majority of 4 separate cultures of blood (with first and last sample drawn 
1 hour apart)  
Major criteria 2: Evidence of endocardial involvement 
Positive echocardiogram for infective endocarditis defined as: 
 oscillating intracardiac mass on valve or supporting structures, in the path of 
regurgitant jets, or on implanted material in the absence of an alternative anatomic 
explanation, or  
 abscess, or  
 new partial dehiscence of prosthetic valve  
-OR- 
 New valvular regurgitation (worsening or changing of pre-existing murmur not 
sufficient) 
Minor criteria 1: Predisposition: predisposing heart condition or intravenous drug use 
Minor criteria 2: Fever: temperature > 38.0° C (100.4° F) 
Minor criteria 3: Vascular phenomena: major arterial emboli, septic pulmonary infarcts, 
mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions 
Minor criteria 4: Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth spots, 
and rheumatoid factor 

 
 
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Minor criteria 5: Microbiological evidence: positive blood culture but does not meet a major 
criterion as noted above or serological evidence of active infection with organism consistent with 
infective endocarditis 
Minor criteria 6: Echocardiographic findings: consistent with infective endocarditis but do not 
meet a major criterion as noted above  
EXPLANT 
 Removal of the investigational valve implant for any reason, including post-mortem. 
HEMOLYSIS 
A plasma free hemoglobin value > 40 mg/dL is considered to be hemolysis and a reportable 
adverse event. 
 
Major hemolysis: A plasma free hemoglobin value > 40 mg/dL that requires 
intervention (i.e. iron replacement, blood transfusion, folic acid administration, 
corticosteroids, Intravenous immunoglobulin G (IVIG) and/or surgery).  Major hemolysis 
events will be considered to be serious adverse events. 
 
Minor hemolysis:  A plasma free hemoglobin value > 40 mg/dL that does not require 
intervention. 
INFECTION 
Elevated body temperature (fever), and White Blood Count (WBC) > 12,000/ml, and Significant 
leftward shift on Differential. 
MAJOR ADVERSE CARDIOVASCULAR AND CEREBROVASCULAR EVENTS (MACCE)  
Defined as a composite rate of  
 all-cause death  
 myocardial infarction (MI)   
 all stroke, and 
 reintervention (defined as any cardiac surgery or percutaneous reintervention catheter 
procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted 
valve) 
MAJOR ADVERSE EVENT (MAE) 
Major Adverse events include the following: 
 MACCE 
 Acute kidney Injury 
 Cardiac tamponade 
 Prosthetic valve dysfunction Cardiogenic shock 
 Prosthetic valve endocarditis 
 Life-threatening, disabling or major bleeding  
 Major vascular complication 
 Cardiac Perforation 
 Valve malpositioning 
 
 

 
 
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MITRAL REGURGITATION 
Mitral valve incompetence resulting in backward flow of blood.   
 
2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
 
Classification of the Severity of Valve Disease in Adults 
Mitral Regurgitation 
 
Mild
Moderate 
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+ 
2+ 
3-4+ 
Color Doppler jet area 
Small, central jet, < 
4cm2  or <20% LA 
area) 
Signs of > mild 
present but no criteria 
for severe MR 
Vena contracta with > 
0.7cm with large central 
MR jet (area >40% of LA 
area) or with a wall-
impinging jet of any size, 
swirling in LA 
Doppler vena contracta width 
(cm) 
< 0.3 
0.3-0.69 
≥ 0.70 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per 
beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.20 
0.29 – 0.39 
≥ 0.40 
Additional essential criteria 
Left atrial size 
Left ventricular size 
 
 
 
Enlarged 
Enlarged 
MITRAL STENOSIS 
A narrowing, stiffening or stricture of the mitral valve.  
2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
Mitral Stenosis 
 
Mild 
Moderate 
Severe 
Mean Gradient (mmHg) 
Less than 5 
5-10 
Greater than 10 
Pulmonary artery systolic 
pressure (mmHg) 
Less than 30 
30-50 
Greater than 50 
Valve area (cm2) 
Greater than 1.5 
1.0-1.5 
Less than 1.0 
 
 

 
 
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MORTALITY 
A serious adverse event that is classified by the following: 
All-cause mortality: All deaths from any cause after a valve intervention. This includes all 
cardiovascular and non-cardiovascular deaths.  
 Cardiovascular mortality:  
Cardiovascular death will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
A death meeting any one of the following criteria: 
 
Death due to proximate cardiac cause (eg. 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 non-structural valve dysfunction or other 
valve-related adverse events 
 
Sudden or unwitnessed death 
 
Death of unknown cause 
Non-cardiovascular mortality:  Any death in which primary cause of death is clearly related to 
another condition (eg. trauma, cancer, suicide)  
NOTE: All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established.  Specifically, any 
unexpected death even in subjects with coexisting potentially fatal non-cardiac disease (eg. cancer, infection) 
should be classified as cardiac. 
 
 

 
 
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MYOCARDIAL INFARCTION (MI) 
Myocardial infarction will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Peri-Procedural MI 
(<72 hours after the index procedure) 
1. New ischemic symptoms (eg. chest pain or shortness of breath), or new 
ischemic signs (eg. ventricular arrhythmias, new or worsening heart failure, new 
ST-segment changes, hemodynamic instability, new pathological Q-waves in at 
least two continuous leads, imaging evidence of new loss of viable myocardium 
or new wall motion abnormality) AND 
2. Elevated cardiac biomarkers (preferably CK-MB) within 72 hours after the index 
procedure, consisting of two or more post-procedure samples with a peak value 
exceeding 15x the upper reference limit (URL) for troponin or 5x for CK-MB.  If 
cardiac biomarkers are increased at baseline (>99th percentile), a further 
increase in at least 50% post-procedure is required AND the peak value must 
exceed the previously stated limit 
 
Spontaneous MI 
(> 72 hours after the index procedure) 
Any one of the following criteria: 
1. Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least 
one value above the 99th percentile URL, together with evidence of myocardial 
ischemia with at least one of the following: 
 
Symptoms of ischemia  
 
ECG changes indicative of new ischemia [new ST-T changes or new left 
bundle branch block (LBBB)]; 
 
New pathological Q waves in at least two contiguous leads; 
 
Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality 
2. Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST 
elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography 
and/or at autopsy, but death occurring before blood samples could be obtained, or at 
a time before the appearance of cardiac biomarkers in the blood. 
3. Pathological findings of an acute myocardial infarction. 
All myocardial infarctions will be considered serious adverse events. 
NEUROLOGICAL EVENT  
Any central, new neurological deficit, whether temporary or permanent and whether focal or 
global, that occurs after the subject emerges from anesthesia. 
 
 

 
 
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NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) 
Classification system for defining cardiac disease and related functional limitations into four 
broad categorizations: 
Class I 
Subject with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
Class II 
Subjects 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. 
Class III 
Subjects with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV 
Subjects with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
PARAVALVULAR AORTIC REGURGITATION 
Leakage due to a separation of the prosthetic valve from the annulus. Diagnosis of paravalvular 
leak may be obtained from echocardiogram; however definitive diagnosis is obtained at 
reoperation, explant, or autopsy.  
  
 (Refer to the definition of Aortic Regurgitation for additional paravalvular leak severity criteria)   
PATIENT PROSTHESIS MISMATCH (PPM) 
Patient prosthesis mismatch (PPM) is defined under the definition of Prosthetic Valve Dysfunction according to the Valve 
Academic Research Consortium (VARC)-2 Updated Standardized Endpoint Definitions for Consensus Report for 
Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09 
Reference prosthetic valve dysfunction. 
PERMANENT PACEMAKER IMPLANTATION  
Implantation of permanent pacemaker after the index procedure due to occurrence of conduction 
disturbances.  
 
Procedure-related: Permanent Pacemaker is implanted in subjects with new onset 
conduction disturbances or worsening of existing conduction disturbances 
 
Not related to procedure: Permanent Pacemaker is implanted in subjects with known 
conduction disturbances that did not advance after the index procedure. 
PROCEDURE RELATED COMPLICATIONS 
Complications associated with any part of the vascular access procedure, associated treatments 
or necessary secondary interventions that do not necessarily involve the device.  This includes 
morbidity associated with either pre-medication, or anesthesia, or other adjunct to the surgical 
procedure.  Other technical errors including inappropriate patient selection, inappropriate 
operator techniques, measurements, or judgment that do not involve the device itself are also 
included.   
PROCEDURAL SUCCESS 
 Defined as device success without occurrence of in-hospital MACCE. 
PROCEDURE-RELATED EVENTS 
All events occurring during or as a direct result of the index procedure.  
All events that occur before extubation and/or before access site closure are classified as 
procedure-related regardless of event timing. 
PROSTHETIC VALVE DYSFUNCTION 
Prosthetic Valve Dysfunction will be defined according to the Valve Academic Research Consortium (VARC)-2 Updated 
Standardized Endpoint Definitions for Consensus Report for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09 
 
Failure modes of prosthetic valve dysfunction include, but are not limited to, the following: 

 
 
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 
Aortic Stenosis 
o 
Stent creep 
o 
Pannus 
o 
Calcification 
o 
Support structure deformation (out-of-round configuration), under-expansion, 
fracture, or trauma (cardio-pulmonary resuscitation, blunt chest trauma) 
o 
Mal-sizing [prosthesis-patient mismatch(PPM)]  
o 
Endocarditis 
o 
Prosthetic valve thrombosis 
o 
Native leaflet prolapse impeding prosthetic leaflet motion 
 
Aortic Regurgitation 
o 
Pannus 
o 
Calcification 
o 
Support structure deformation (out-of-round configuration), recoil, under-expansion, 
fracture, insufficient radial strength, or trauma (cardio-pulmonary resuscitation, blunt 
chest trauma) 
o 
Endocarditis 
o 
Prosthetic valve thrombosis 
o 
Mal-position (too high, too low) 
o 
Acute mal-coaptation 
o 
Leaflet wear, tear/perforation, prolapse or retraction 
o 
Suture breakage or disruption 
o 
Native leaflet prolapse impeding prosthetic leaflet motion 
Prosthetic valve dysfunction will be considered serious when it meets the definition of a serious 
adverse event (SAE). 
 
 

 
 
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Prosthetic valve dysfunction 
Prosthetic aortic valve stenosis* 
 
Normal 
Mild Stenosis 
Moderate/Severe Stenosis 
Quantitative Parameters (Flow-dependent)† 
Peak velocity 
<3 m/s 
3-4 m/s 
>4 m/s 
Mean gradient 
<20 mmHg 
20-40 mmHg 
>40 mmHg 
Quantitative Parameters (Flow-independent)
  
Doppler velocity index‡ 
>0.35 
0.35-0.25 
<0.25 
Effective orifice area┼ 
>1.1 cm
2 
1.1-0.8 cm
2 
<0.8 cm
2 
Effective orifice area§ 
>0.9 cm
2 
0.9-0.6 cm
2 
<0.6 cm
2 
Prosthesis-patient mismatch (PPM) 
 
Insignificant 
Moderate 
Severe 
Indexed effective orifice 
area** 
>0.85 cm
2/m
2 
0.85-0.65 cm
2/m
2 
<0.65 cm
2/m
2 
Indexed effective orifice 
area†† 
>0.70 cm
2/m
2 
0.70-0.60 cm
2/m
2 
<0.60 cm
2/m
2 
Prosthetic aortic valve regurgitation 
 
Mild 
Moderate 
Severe 
Semi-quantitative Parameters 
Diastolic flow reversal in the 
descending aorta—PW  
Absent or brief early 
diastolic 
Intermediate 
Prominent, holodiastolic 
Circumferential extent of 
prosthetic valve paravalvular 
regurgitation (%)┼┼ 
<10% 
10-29% 
≥30% 
Quantitative Parameters‡ 
Regurgitant volume (ml/beat) 
<30 ml 
30-59 ml 
≥60 ml 
Regurgitant fraction (%) 
<30% 
30-49% 
≥50% 
EROA (cm
2)  
<0.10 cm
2 
0.10-0.29 cm
2 
≥0.30 cm
2 
*In conditions of normal or near normal stroke volume (50–70 mL) 
†These parameters are more affected by flow, including concomitant aortic regurgitation 
‡For LVOT >2.5 cm, significant stenosis criteria is <0.20 
┼Use in setting of BSA ≥1.6 cm
2 (note: dependent on the size of the valve and the size of the native annulus) 
§Use in setting of BSA <1.6 cm
2 
**Use in setting of BMI <30 kg/cm
2 
††Use in setting of BMI ≥30 kg/cm
2 
┼┼Not well-validated and may overestimate severity compared to quantitative Doppler 
 
Moderate or severe AS and AR will be considered a serious adverse event when the dysfunction 
is accompanied with clinical sequelae at the time of the event detection, and the clinical 
sequelae are chronologically and physiologically associated with the dysfunction. 

 
 
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RECURRENT HOSPITALIZATION  
Recurrent hospitalization is defined as a non-elective hospital admission for signs and 
symptoms related to aortic valve disease (as described below), as well as complications related 
to aortic valve procedures including neurological events, infection, additional procedures (eg. 
implant of permanent pacemaker), and renal failure.  For the purposes of the protocol a 
hospitalization is an admission that results in at least a one night stay (i.e., one midnight/change 
in calendar day).     
Overnight stays at nursing home facilities, extended care facilities, or emergency room visits that 
do not result in an in-patient admission do not meet the protocol definition of recurrent 
hospitalization.  Patients with signs and symptoms related to aortic valve disease (as described 
below) who are hospitalized for less than one night or who are treated and released from the 
emergency department or an outpatient clinic [including treatment for intravenous heart failure 
therapy (eg., inotropes, diuretics, and/or vasodilators)], does not meet the protocol definition of 
as recurrent hospitalizations. 
Aortic valve disease will be evaluated using documented evidence of the following signs and 
symptoms.  An independent Clinical Events Committee (CEC) will review all available source 
documentation for all hospitalizations to determine if they are aortic valve disease 
hospitalizations.  The CEC adjudication will be used for final analysis. 
Signs and Symptoms of Aortic Valve Disease 
Sign/Symtpom 
Definition 
Aortic Valve Dysfunction 
 
Shortness of breath/dyspnea  
A feeling of difficult or labored breathing that is out of proportion to 
the patient’s level of physical activity 
Exercise intolerance  
A condition where the patient is unable to do physical exercise at 
the level or for the duration that would be expected of someone in 
his/her general physical condition, or experiences unusually 
severe post-exercise pain, fatigue, or other negative effects 
Dizziness/syncope  
Lightheadness or unsteadiness of gait or a partial or complete 
loss of consciousness with interruption of awareness of oneself 
and ones surroundings 
Chest pain  
Discomfort and soreness in and around the chest 
Worsening Heart Failure 
Volume Overload 
 
Orthopnea 
Dyspnea in which the person can breathe comfortably only when 
standing or sitting erect  
Paroxysmal nocturnal dyspnea 
Acute dyspnea caused by the lung congestion and edema that 
results from partial heart failure and occurring suddenly at night, 
usually an hour or two after the individual has fallen asleep.  
Jugular venous distension 
With the patient is positioned under 45°, and the filling level of the 
jugular vein determined. An abnormal response is more than 3 
centimeters above the sternal angle.  
Hepatomegaly 
Palpation of the edge of the liver below the edge of the ribs 
without inspiration  
Peripheral edema 
Swelling of tissues, usually in the lower limbs, due to the 
accumulation of fluids.  
Pulmonary rales 
Small clicking, bubbling, or rattling sounds in the lung associated 
with inspiration  
Abdominal-jugular reflux 
An elevation of venous pressure visible in the jugular veins and 
measurable in the veins of the arm, produced in active or 
impending congestive heart failure by firm pressure with the flat 
hand over the abdomen.  
Radiographic evidence of 
pulmonary edema 
NA 
Elevated B-type natriuretic peptide 
level   
NA 
Hypoperfusion 
 
Narrow pulse pressure  
Pulse pressure < 30 mmHg  
Hypotension 
Systolic BP < 90 systolic 
Renal or hepatic dysfunction 
Rise in baseline creatinine by 25%  
Increase in LFT (SGOT, SGPT) > 2 times normal  
Low serum sodium concentration  
Serum sodium < 130 mEq/dL 
 

 
 
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REINTERVENTION 
Any surgical or percutaneous interventional catheter procedure that repairs, otherwise alters or 
adjusts, or replaces a previously implanted valve. In addition to surgical reoperations, balloon 
dilatation, interventional manipulation, repositioning, or retrieval, and other catheter-based 
interventions for valve-related complications are also considered reinterventions. Reintervention 
is further subdivided into surgical and percutaneous. 
RESPIRATORY INSUFFICIENCY 
Post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) 
ratio [FEV1/FVC] less than 70%. 
Post-bronchodilator FEV1 less than 80% predicted, with or without chronic symptoms (i.e., 
cough or sputum production). 
RESPIRATORY FAILURE 
The need for ventilatory support for > 72 hours associated with an inability to wean from the 
respirator for any reason. 
RIGHT VENTRICULAR INSUFFICIENCY 
Defined as sequelae of right ventricular failure including the following: 
 Significantly decreased right ventricular systolic and/or diastolic function 
 Tricuspid valvular regurgitation secondary to elevated pressure 
Clinical symptoms to include: 
o 
Hepatic congestion 
o 
Ascites 
o 
Anasarca 
o 
Presence of “hepato-jugular reflux” 
o 
Edema 
SERIOUS ADVERSE DEVICE EFFECT (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event 
SERIOUS ADVERSE EVENT (SAE) 
A serious adverse event (SAE) is an event that: 
 Led to death, 
 Led to serious deterioration in health of the subject, that either resulted in: 
o 
a life threatening illness or injury, or 
o 
a permanent impairment of a body structure or a body function, or 
o 
in-patient or prolonged hospitalization, or 
o 
medical or surgical intervention to prevent a life-threatening illness or injury or 
permanent impairment to a body structure or a body function  
 Led to fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE: Planned hospitalization for pre-existing condition, or a procedure required by per protocol, without serious 
deterioration in health, is not considered a serious adverse event.  
Events that do not meet these criteria are considered non-serious. 
 
 

 
 
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STROKE and TIA  
Stroke and TIA will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated Standardized 
Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09 and the FDA’s Current Thinking 
Regarding Neurological Assessments for Transcatheter Valve Trials (July 25, 2011). 
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 
 
Stroke: duration of a focal or global neurological deficit ≥ 24 hours; OR < 24 hours available 
neuroimaging documents a new hemorrhage or infarct; OR the neurologic deficit results in death 
 
TIA: duration of a focal or global neurological deficit <24 hours, any variable neuroimaging does 
not demonstrate a new hemorrhage or infarct 
 
No other readily identifiable non-stroke cause for the clinical presentations (eg. 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: 
o 
Neurology or neurosurgical specialist 
o 
Neuroimaging procedure (CT scan or brain MRI), but stroke be diagnosed on clinical 
grounds alone 
Stroke Classification 
 
Ischemic: an acute episode of focal cerebral, spinal or retinal dysfunctions caused by infarction of 
the central nervous system tissue 
 
Hemorrhagic: an acute episode of focal cerebral, spinal or spinal dysfunctions caused by 
intraparenchymal, intraventricular, or subarachnoid hemorrhage  
Stroke Definitions
 Disabling stroke: an mRS score of 2 or more at 90 days and an increase in at least one mRS 
category from an individual’s pre-stroke baseline 
 Non-disabling stroke: an mRS score of < 2 at 90 days or one that does not result in an increase in 
at least one mRS category from an individual’s pre-stroke baseline 
 
*   Patients with non-focal global encephalopathy will not be reported as a stroke without unequivocal evidence based 
upon neuroimaging studies 
+  Modified Rankin score assessments should be made by qualified individuals according to certification process.  
Clinically important disabilities (disabling strokes) will be considered to be serious adverse 
events. 
TAV-in-TAV DEPLOYMENT 
Valve malpositioning will be defined according to the Valve Academic Research Consortium (VARC) )-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
An additional valve prosthesis is implanted within a previously implanted prosthesis because of 
suboptimal device position and/or function, during or after the index procedure. 
TECHNICAL OBSERVATION 
A defect, malfunction, or failure of any part of the Medtronic CoreValve™ System or CoreValve™ 
Evolut R System. This may pertain to the device or delivery and/or loading system not 
functioning according to its design intent.  
TRICUSPID REGURGITATION 
2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
Severe tricuspid regurgitation: vena contracta width greater than 0.7cm and systolic reversal 
in hepatic veins.  
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report 
NOTE:   Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity or 
outcome has been identified in the risk analysis report. 
UNPLANNED USE OF CARDIOPULMONARY BYPASS (CPB) 
Valve Academic Research Consortium (VARC)-2; Updated Standardized Endpoint Definitions for Transcatheter Aortic 
Valve Implantation (TAVI); 2012-10-09. 

 
 
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Unplanned use of CPB for hemodynamic support at any time during the TAVI procedure. 
VALVE THROMBOSIS 
Any thrombus not caused by infection attached to or near the trial valve that occludes part of the 
blood flow path, interferes with valve function, or is sufficiently large to warrant treatment. Valve 
thrombus found at autopsy in a subject whose cause of death was not valve-related or found at 
operation for an unrelated indication should also be counted as valve thrombosis. 
VALVE MALPOSITIONING 
Valve malpositioning will be defined according to the Valve Academic Research Consortium (VARC) )-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Valve migration 
After initial correct positioning, the valve prosthesis moves upward or downward, within the 
aortic annulus from its initial position, with or without consequences 
Valve embolization 
The valve prosthesis moves during or after deployment such that it loses contact with the aortic 
annulus 
Ectopic valve deployment 
Permanent deployment of the valve prosthesis in a location other than the aortic root 
 
 

 
 
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VASCULAR COMPLICATIONS 
Vascular Complications will be defined according to the Valve Academic Research Consortium (VARC) )-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Vascular Access Site and Access Related Complications 
Major Vascular Complications  
 Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new 
apical aneurysm/pseudo-aneurysm OR 
 Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve injury, 
compartment syndrome, percutaneous closure device failure) leading to death, life-
threatening or major bleeding*, visceral ischemia or neurological impairment OR 
 Distal embolization (non-cerebral) from a vascular source requiring surgery or 
resulting in amputation or irreversible end-organ damage OR 
 The use of unplanned endovascular or surgical intervention associated with death, 
major bleeding, visceral ischaemia or neurological impairment OR 
 Any new ipsilateral lower extremity ischemia documented by patient symptoms, 
physical exam, and/or decreased or absent blood flow on lower extremity angiogram 
OR 
 Surgery for access site-related nerve injury OR 
 Permanent access site-related nerve injury 
 
Minor Vascular Complications 
 Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneuysms, hematomas, percutaneous closure 
device failure) not leading to death, life-threatening or major bleeding*, visceral 
ischemia or neurological impairment OR 
 Distal embolization treated with embolectomy and/or thrombectomy and not resulting 
in amputation or irreversible end-organ damage OR 
 Any unplanned endovascular stenting or unplanned surgical intervention not meeting 
the criteria for a major vascular complication OR 
 Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft)  
 
Percutaneous closure device failure 
 Failure of a closure device to achieve hemostasis at the arteriotomy site leading to 
alternative treatment (other than manual compression or adjunctive endovascular 
ballooning) 
Major vascular complications will be considered to be serious adverse events. 
*Refers to VARC bleeding definitions. 

 
 
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P TRIAL MANAGEMENT 
P.1 
Miscellaneous 
 
Insurance 
P.1.1
The Medtronic Bakken Research Center B.V. is a wholly owned subsidiary of Medtronic Inc., 
which as the parent company of such entity maintains appropriate clinical trial liability insurance 
coverage as required under applicable laws and regulations and will comply with applicable law 
and custom concerning specific insurance coverage. If required, a Clinical Trial Insurance 
statement/certificate will be provided to the IRB/MEC. 
 
Reimbursement 
P.1.2
Trial reimbursement is outlined in the Clinical Trial Agreement. 
 
Indemnification 
P.1.3
Indemnification will be done according to local laws. 
 
Subject confidentiality 
P.1.4
At all times throughout the trial confidentiality shall be observed by all parties involved. All 
information and data sent to parties involved in trial conduct concerning patients or their 
participation in this trial will be considered confidential. The patient identification number is to be 
recorded on all trial documents and will link the trial documents to the patient's name and 
medical record at the investigator's site. To maintain confidentiality, the patient's name or any 
other personal identifiers should not be recorded on any trial document other than the informed 
consent form. 
 
 

 
 
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Q REFERENCES 
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20. Thomas M, Wendler O. Transcatheter aortic valve implantation (TAVI): how to interpret the data and 
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comparison of patient characteristics and 30-day mortality outcomes after transcatheter aortic valve 
implantation and surgical aortic valve replacement for the treatment of aortic stenosis: a two-centre 
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46. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, DeGraba TJ, 
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Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and 
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SURTAVI 
SUrgical Replacement and Transcatheter 
Aortic Valve Implantation 
 
 
Appendix 
 
 
VERSION 12.0 
31 May 2016 
  
 
Sponsor: 
Medtronic, Inc. 
Clinical Research 
Mailstop: MVS66 
Mounds View South 
8200 Coral Sea St NE 
Mounds View, MN 55112 USA 
Medtronic Bakken Research Center 
Coronary and Structural Heart Department
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
 
 

 
 
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TABLE OF CONTENTS 
R 
APPENDICES .................................................................................................. 124 
R.1 
Sample Informed Consent ............................................................................................. 124 
R.1.1  United States....................................................................................................... 125 
R.1.2  United States – Roll-in Subjects .......................................................................... 140 
R.1.3  Europe ................................................................................................................ 153 
R.1.4  Canada ............................................................................................................... 166 
R.1.4  Canada – Roll-in Subjects ................................................................................... 182 
R.2 
List of Participating Investigational Centers ................................................................... 198 
R.3 
Other Institutions ........................................................................................................... 199 
R.4 
Additional Records and Reports .................................................................................... 200 
R.5 
Sample Case Report Forms .......................................................................................... 201 
R.6 
Aortogram Acquisition Guidelines ................................................................................. 202 
R.7 
Echocardiography Acquisition Guidelines ..................................................................... 204 
R.8 
Electrocardiogram (ECG) Submission ........................................................................... 225 
R.9 
Computed Tomography (CT) Angiography Acquisition Guidelines ................................ 226 
R.10  Interactive Voice/Web Response System (IXRS) .......................................................... 238 
R.11  Explanted Device/Pathology and Return Procedures .................................................... 239 
R.12  Economic and Quality of Life Data Collection ................................................................ 241 
R.12.1 
Health Economic Data Collection .................................................................... 241 
R.12.2 
Quality of Life Data Collection ......................................................................... 241 
R.12.2.1 
Schedule of Assessments .................................................................. 241 
R.12.2.2 
Questionnaires ................................................................................... 242 
R.13  Pacing Guidelines ......................................................................................................... 243 
R.14  Six Minute Walk Test Instructions ................................................................................. 247 
R.15  National Institute of Health Stroke Scale (NIHSS) ......................................................... 260 
R.16  Modified Rankin Scale (mRS) Instructions .................................................................... 264 
R.17  Mini Mental State Exam (MMSE-2:SV) .......................................................................... 265 
R.18  Additional Neurological Assessments ............................................................................ 266 
R.19  Medtronic CoreValve™ Clinical Assessment Guidelines ................................................ 268 
R.20  Katz Index of Independence in Activities of Daily Living ................................................ 269 
R.21  Investigator Brochure / Report of Prior Investigations for the Investigational Devices ... 270 
R.22  Investigational Devices Instructions For Use ................................................................. 271 
R.23  Radiation Exposure and Data Collection ....................................................................... 272 
R.24  SURTAVI Risk Model .................................................................................................... 275 
R.24.1 
 SURTAVI Risk Model Rationale ..................................................................... 275 
R.24.2 
 SURTAVI co-morbidity list .............................................................................. 278 
R.25  CMS Considerations for Coverage and Reimbursement – US ONLY ........................... 283 

 
 
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APPENDICES 
R.1 
Sample Informed Consent  
Attached are the informed consent form templates: 
 United States 
 United States - Roll-in Subjects 
 Europe 
 Canada 
 Canada – Roll-in Subjects 
 

 
 
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INFORMED CONSENT FORM  
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this research study and how you 
might take part in it. By signing this form, you will show that you understand and that you agree to 
take part in this research study. Your signature on this form is required before you can take part in 
this research study. 
BACKGROUND 
You are being asked to take part in a research study entitled “Medtronic CoreValve™ SURTAVI 
Trial” because you have a disease of your aortic valve.  This disease is called aortic stenosis. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the left 
ventricle (main pumping chamber of the heart) into the aorta (main artery delivering blood to the 
body). If the valve becomes abnormally narrow through a process of thickening and stiffening 
(aortic stenosis) the heart must work harder to pump the same amount of blood with each beat. 
As the heart works harder, the heart muscle thickens (hypertrophy), and the heart chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve is 
the standard treatment. 
As an alternative to open heart surgery, the Medtronic CoreValve™ System and Medtronic 
CoreValve™ Evolut R™ System have been developed to replace a diseased aortic heart valve 
without the need for open heart surgery. This system allows the percutaneous aortic valve (study 
valve) to be implanted (inserted) through a long, thin flexible tube that is inserted through an 
incision in the skin and threaded through the bloodstream (percutaneous). 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
You are being asked to participate in this study because doctors have determined your aortic valve 
is no longer working properly. However, your doctors have also decided that your risk of 
experiencing major problems while undergoing open-heart surgery is moderate due to medical 
reasons or anatomical reasons (relating to how and where your heart, aortic valve and blood 
vessels are placed within your body). This means that you doctor believes your health is acceptable 
for open-heart surgery, but there are still a risk of potential problems. 
PURPOSE OF THE STUDY 
The purpose of this clinical  study is to determine if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions as 
you. 
The study valve is considered an “investigational device”, which means that clinical studies are 
required to determine if it is safe and provides clinical benefit. Medtronic, Inc. is sponsoring this 
study to obtain data on the safety and performance of the investigational device. The Medtronic 
CoreValve™ System and Medtronic CoreValve™ Evolut™ R System includes the valves described 
below and two parts that help load and deliver the valves correctly.  
This study will involve approximately 1600 subjects at up to 115 hospitals in the United States and 
around the world, and is anticipated to take approximately 8 years to complete. Your participation in 

 
 
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this study is expected to last approximately five years from the day you are enrolled in the study. 
Annual follow-up may be extended to up to 10 years after the implant procedure. 
STUDY DEVICES 
Both study valves are made from animal tissue attached to a metal frame.  
The study valves are designed to be implanted (inserted) using a delivery system catheter (long, 
thin flexible tube) to replace your diseased aortic heart valve without open-heart surgery.  A unique 
feature of the Evolut R device is that it can be re-captured, making it easier for doctors to place the 
device in a correct position. Once it is implanted, CoreValve™ study valves acts in the same method 
of the native valve.   
 The Medtronic CoreValve system is approved by the US Food & Drug Administration (FDA) since 
2014and in other parts of the world since 2006. It has been implanted in over 45,000 patients. The 
Medtronic CoreValve™ System is currently approved for use in Europe, South America, and parts of 
Asia. The Medtronic CoreValve™ Evolut™ R system is currently approved in US and Europe. 
 
 
 
 
 
 
 
 
Figure 1: Medtronic CoreValve™ “Study Valve” 
 
 
 
 
 
 
 
Figure 2: Medtronic CoreValve™ Evolut™ R “Study Valve” 
 
 
 

 
 
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PROCEDURES TO BE FOLLOWED 
If you agree to be in this study, and after you have signed this informed consent form, data such as 
your age, gender, medical history and medication use will be recorded. You will undergo the 
following tests: 
 
Physical examination 
 
Computed tomography (CT) - a scan performed using an x-ray machine, which is linked to a 
computer to take pictures of your body. Sometimes a CT will require the use of a type of dye 
that makes the kidneys work harder and may be harmful to the kidneys. You may have an 
MRI in place of a CT scan if your doctor believes your kidneys are not working well enough 
for you to have a CT scan. MRI stands for magnetic resonance imaging and is a test that 
uses a strong magnet and a complex computer system to produce detailed images of your 
internal organs and soft body tissues. 
 
Blood tests (about 2 tablespoons) 
 
Echocardiography [transthoracic echocardiogram (TTE)] - a test that uses sound waves to 
take pictures of your heart and measure the degree of narrowing of your aortic valve; a probe 
with gel is placed on the outside of your chest to take pictures of your heart 
 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
 
Heart catheterization/angiography - a test that takes pictures of your heart and blood vessels; 
a special dye is injected through long, flexible tubes into the coronary arteries (vessels 
delivering blood to the heart) and bypass grafts if you have them 
If you are of child-bearing potential, we will ask you to take a pregnancy test. If you are pregnant, 
you will not be able to participate in this study. 
These procedures and tests are standard procedures and are not experimental. If you have already 
had any of these tests performed before, they may to be used for the study if your study doctor 
determines they don’t need to be repeated for study purposes.  
The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you will 
not be allowed to participate in the study. 
If your doctor and the committee decide you are eligible to be in the study your treatment will be 
determined in a way similar to flipping a coin, called randomization. You will be assigned to one of 
two groups. One group will receive a transcatheter aortic valve implant (TAVI), the other group will 
receive open-heart surgical aortic valve replacement (SAVR). On average, one out of every two 
participants will receive TAVI. The other participants will receive SAVR. You will not be able to 
choose your treatment assignment. 
Your enrollment in the study will begin once you sign this consent and you are assigned to your 
treatment group. 
If you are enrolled in the study, you will be required to have the following additional tests completed 
within 14 days prior to the procedure (TAVI or SAVR): 
• 
Physical exam, including a determination of neurological (brain) status where you will be 
asked to answer a series of questions and perform a series of tasks such as writing and 
drawing 
• 
Blood tests (about 2 tablespoons) 
• 
Walking test – a test that records your breathing, heart rate, and how you feel after 6 minutes 
of walking 

 
 
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• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life Questionnaires (QOL). 
Your personal physician will be informed about your participation in this clinical study. 
If you are assigned to the TAVI group: 
The study valve is an experimental valve which means you can only receive the valve if you are 
part of this study.  Your study doctor will decide if you will either receive the Medtronic CoreValve™ 
System or the Medtronic CoreValve™ Evolut™ R System. 
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor.  You may be advised to continue these medications for at 
least three months following your procedure.  
Before the procedure you will be given an antibiotic (a medicine that kills bacteria or germs) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about 2 tablespoons) and an ECG before the procedure.   
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary during 
the procedure, you will be put under general anesthesia at that time. 
Your study doctor will decide what locations are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary. These pictures are described in 
the next paragraphs.  Additionally, your study doctor will decide if performing a surgical incision to 
any of the site(s) is necessary. 
During the procedure you may have a transesophageal echocardiogram which is also called a TEE. 
This test uses sound waves to take a closer look at the inside structures of the heart. If your doctor 
decides these pictures are necessary, to perform the test you will swallow a thin flexible tube with a 
special tip. This tube sits in the esophagus (the tube that connects the mouth to the stomach). The 
special tip of the tube sends out sound waves (ultrasound) that echo within the chest wall. The 
esophagus is located behind the heart so these echoes are picked up and create a picture of the 
heart that is displayed on a video monitor. The pictures will allow your study doctor to take a closer 
look at your valve. 
You will have a temporary pacemaker put in place during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins and threaded 
through your vein into the right side of your heart. The wire is attached to a battery operated device 
outside of your body. This temporary pacemaker will help keep your heart rate (speed) and rhythm 
steady. This temporary pacemaker will not be removed for at least 48 hours after your TAVI 
procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. Balloon valvuloplasty is a procedure used to widen a stiff or narrowed heart valve. A 
wire and a thin tube are guided by x-rays through the heart and positioned through the diseased 
heart valve. A balloon is placed over the wire and inflated, enlarging the opening through the 
diseased valve allowing the study valve to be placed. 
Your doctor will then implant (insert) the study valve through the long, thin flexible tube that is 
inserted through an incision in the skin and threaded through the bloodstream. TAVI is performed 
using x-ray machines which will allow your doctor to see the study valve, your blood vessels and 

 
 
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heart. The study valve will be guided through your blood vessels to your existing aortic valve and 
then the study valve will be placed over your existing valve. 
During the TAVI procedure, your doctor will perform angiography (x-ray pictures) and ECGs 
(recordings of the electrical impulses of your heart through patches placed on the chest) to observe 
your heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study valve. 
If you are assigned to the SAVR group: 
Open heart surgery, surgical repair and/or replacement of your aortic valve, are not experimental 
procedures. 
If you are assigned to the SAVR group, your doctors will replace your diseased aortic valve through 
open heart surgery. During surgery, you are asleep under general anesthesia. SAVR often requires 
a median sternotomy, where the bone in the center of the chest (sternum) is split down the middle. 
The chest is then opened to provide your doctor with access to the heart and chest cavity, in order 
to replace your aortic valve. Your surgery is performed while the function of your heart is taken over 
by a heart lung machine (called CPB for cardiopulmonary bypass). 
You may have a TEE (a thin tube sits in the esophagus and sends out sounds waves to create a 
picture of your heart) and a temporary pacemaker (thin wire threaded through your vein to right side 
of heart to keep your heart rate and rhythm steady) during the procedure. 
Your doctor may remove any tissue and calcium deposits that are interfering with the normal 
function of the valve. Your damaged valve may be completely removed. The new valve will be 
sewn into the space where your own valve used to be. After your doctor makes sure your valve is 
working properly, blood flow will be restored to your heart and the incisions will be closed. You will 
also have blood drawn for testing before and after the procedure. 
If your doctor is unable to implant (insert) the study valve in you during the TAVI or SAVR 
procedure, you will still be considered enrolled in the study and will need to return to the clinic for 
the required follow-up visits as described in the “Follow-up Visits after TAVI and SAVR” section. 
After TAVI and SAVR Procedure: 
After the TAVI and SAVR procedure, your study doctors will continue to monitor your progress and 
recovery. 
You will have the following tests performed within the two days following the procedure and before 
you are discharged from the hospital: 
•  
Determination of neurological (brain) status where you will be asked to answer a series of 
questions and perform a series of tasks 
•  
Blood tests (about 2 tablespoons) 
•  
Echocardiogram (TTE) 
•  
ECG 
Follow-up Visits after TAVI and SAVR: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months (1 
year), 18 months, 24 months (2 years), and 3, 4, and 5 years after the procedure. Most of the 
follow-up tests and examinations are routine, not experimental. Each visit will take about 1 ½ to 2 
hours.  
 
Your evaluations at 30 days, 6 and 18 months will include: 
• 
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 

 
 
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• 
You will be asked about your health since the last follow-up visit 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Blood tests (about 2 tablespoons) – 30 day visit only 
• 
Walking test – 30 day visit only 
• 
Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12 months, 24 months, and 3, 4, 5 years will include: 
• 
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last clinic visit 
• 
Blood tests (about 2 tablespoons) 
• 
Echocardiogram (TTE) 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Walking test – 12 and 24 months visits only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted via phone to complete a 
Quality of Life Questionnaire. 
If , during the 5 years of follow-up, you have additional heart surgeries or cath lab procedures to 
work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological (brain) 
status within 24 hours after each additional procedure. 
If you have a stroke, have been inform by a doctor that you experienced a stroke, or experience  
any of the following symptoms, notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible: 
sudden numbness, tingling, loss of movement (especially on 1 side of the body), vision changes, 
confusion or trouble understanding simple statements, severe headaches, or seizures.  Any of 
these symptoms could indicate that you are having problems with your neurological (brain) function.  
If a doctor confirms that you had a stroke, you will be asked to come to the clinical to have tests 
performed to determine your neurological (brain) status where you will be asked to answer a series 
of questions and perform a series of tasks. These tests will be performed at 7 days, 30 days and 3 
months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or are 
hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis.  Your study doctor will determine if you will need to have another valve 
implanted.   
In the event of your death, we will request an autopsy. We will also request that either the whole 
heart and valve or just the valve are removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the investigational valve. 
Your family and your "legally authorized representatives", have the right to refuse the autopsy and 
refuse the request to remove the heart and/or valve even if you sign this consent form. 

 
 
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TAVI 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest – heart stops beating and blood flow through the body is interrupted or 
stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to improve 
blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  
 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able to 
supply oxygen to the body 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 

 
 
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 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, blood 
clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the device 
from where it was originally placed 
 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 
 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure is 
expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs in 
the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 
 
Permanent disability – injury that does not allow that impairs normal/previous physical 
or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 
 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 
 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result in 
a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed space 
that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  
o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical impulses 
to the heart to help your heart beat normally 

 
 
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o 
Atrio-ventricular node block – a block in the electrical path from the top part of 
the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom part 
of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part of 
the heart (ventricles) 
 
Encephalopathy – altered mental state 
 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 
 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 
 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic 
valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known. 
 
SAVR 
Although SAVR is not experimental there are potential risks associated with the procedure. These 
risks are the same even if you undergo the SAVR procedure and you decide not to participate in 
this study.  Some of these risks include, but may not be limited to the following: 
 
Obstruction of blood flow to the heart (angina) resulting in damage to the heart tissue 
 
(myocardial infarction/heart attack) 
 
Abnormal heart beat (cardiac arrhythmia and dysrhythmia) 
 
Blood leaking around the outside of the prosthetic valve (paravalvular leak) or any 
 
Problem with the valve that causes leaking of blood after the valve has closed 
(transvalvular leak). 
 
Damage to red blood cells (hemolysis) that can result in anemia (decreased red blood 
cells) 
 
Death 

 
 
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 
Inflammation of the lining of the heart (endocarditis) 
 
Heart failure 
 
Any problem with the prosthetic valve that causes narrowing of the valve opening 
(stenosis) 
 
Blood clots that develop in the heart of on the replacement valve. These clots may break 
loose and travel through the bloodstream (thromboembolism). This problem may cause 
stroke (decrease blood flow to the brain causing damage to the brain) or heart attack 
 
Failure of the valve to open and close properly 
If you become pregnant there maybe risks, discomforts, or side effects to you and the embryo/fetus 
that are not yet known.  Please notify your study doctor as soon as possible to discuss any of these 
potential risks. 
 
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how much 
radiation you will get, in the following descriptions the radiation is compared to the amounts that 
people are exposed to in daily life. There is radiation that naturally occurs from space and from 
rocks in the soil. This natural radiation is greater at higher altitudes. 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure is 
less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 
The estimated radiation exposure for the valve procedure is approximately 10-15 times the amount 
of radiation exposure received in one year from background radiation (naturally occurring radiation 
you are exposed to everyday). The exposure is approximately the amount an occupational worker 
is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have extra 
follow-up visits with your doctor to watch your recovery more closely. 
Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 
POSSIBLE BENEFITS 
The possible benefits you may receive from participating in this research are that you may be able 
to receive a new heart valve without having open-heart surgery. Another possible benefit is that 
your new valve may work better than the way your diseased valve currently works. This may 
improve how you feel and may improve your daily activity. 
Your participation in this research may improve procedures that may guide the future treatment of 
heart surgery, by using procedures that are less invasive, meaning less cutting, entering or 
breaking through the body, which may benefit others in the future. However, there is no guarantee 
that you will benefit from being in this research. 
ALTERNATIVE TREATMENTS 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to replace 
the aortic valve.  For patients who are at high risk for open heart surgery, other treatment options 

 
 
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include percutaneous (through an artery in the groin) aortic valve implantation, or medical 
management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study doctor 
about other treatment options you may have. 
IF PROBLEMS DEVELOP 
If you believe that you have been injured as a result of your participation in the study, you should 
notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible or in serious cases, go to the 
emergency room.  
Immediate necessary medical care is available at [Name of institution(s)] in the event that you are 
injured as a result of your participation in this research study.  
If you are assigned to the TAVI group  
Immediate necessary medical care is available at [name of institution] in the event that you are 
injured as a result of your participation in this research study.  
For those patients receiving the investigational device and the TAVI procedure, 
Medtronic has agreed to pay back [name of institutions that are parties to the CTA] for the costs of 
medical or surgical care they provide for any serious and unanticipated illness or injury under the 
following conditions: 
 
The illness or injury must be related to a defect or malfunction of the investigational device 
or in the TAVI procedure as described in the Protocol, and not related to procedures that 
are routine standard of care. 
 
The illness or injury cannot be caused by (a) the negligence or intentional misconduct of 
the study staff or [name of institutions that are parties to the CTA]; (b) because the study 
staff or [name of institution(s)] that are parties to the CTA] did not follow the protocol for the 
study; or (c) the natural progression of your illness. 
 
The illness or injury must have happened before the study closes (last patient is seen for 
the 5 year follow-up visit) at this [Name of institution(s)]. 
 
[Name of institution(s) that are parties to the CTA] must notify Medtronic within one year of 
the date the study closes at all study sites or before the study closes at this site, whichever 
is earlier. 
Subject to the above conditions, Medtronic will pay back the costs that are not covered by your 
health insurance or Medicare. The amount Medtronic will pay back is the amount Medicare pays 
[name of institution(s) that are parties to the CTA] plus 10%. 
If you are assigned to the SAVR group  
In the event of physical injury or physical illness related to a procedure required for the SAVR 
group, no monetary compensation or subsidized (paid) will be provided. Medical treatment will be 
routinely provided to you by any person involved in this study including the study doctors, or the 
hospital. Any immediate medical treatment, however, that may be necessary will be provided. 
By agreeing to the above, you do not waive any of your legal rights which you otherwise would 
have as a research subject, nor do you release the study sponsor (Medtronic, Inc.), study doctors, 
or the hospital from liability for negligence. 
PAYMENT FOR PARTICIPATION IN THE STUDY 
You will not be paid to take part in the study. However, you may be reimbursed for local mileage 
and parking expenses directly related to any study related visits. Your study doctor or research 
coordinator will tell you how to get reimbursement.  
There is no monetary advantage to the study doctor for participation in this study. 
MEDICAL EXPENSES 

 
 
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Your private or public health insurance company (for example Medicare) will be billed for the valve 
procedure and the cardiac catheterization and other procedures that are required by the study and 
you will be responsible for paying for any co-payment, co-insurance or deductible. It is possible that 
your private or public health insurance will not pay for some or all of the procedures, including the 
valve procedure or the cardiac catheterization procedure because you are participating in this 
study. Any costs not covered by your public or private insurance will be your responsibility. You 
should discuss the estimate of these costs with your study doctor. You will not be charged for the 
cost of collecting the data for this study and other clinic visits and diagnostic tests done solely for 
the purposes of this study. 
BASIS OF PARTICIPATION 
Your participation in this study is voluntary. If you refuse to be in this study there will be no penalty 
or loss of benefits to which you are otherwise entitled. You may withdraw from the study at any time 
and will not lose your benefits or be treated any differently as a result of withdrawing from the study. 
Any new findings (decisions or conclusions) that may influence your willingness to participate will 
be provided to you.  If you decide to leave the study before it is finished, please tell one of the 
persons listed in the section below “Obtaining Additional Information”. It may be requested that, if 
you withdraw, you return to your study doctor for a final visit. 
The study doctor may end your participation in the study at any time if: 
 
He or she determines it is not in the best interest of your health 
 
The study doctor loses contact with you and you do not return for your study visits as 
scheduled 
 
You refuse to allow the use of private health information during the course of the study 
The study doctor will make the decision and let you know if it is not possible for you to continue in 
the study. 
You may be removed from the study without your consent if the sponsor (Medtronic, Inc.) ends the 
study.  If this happens, you will be notified and the reasons will be explained to you.  Your physician 
will continue to provide the appropriate medical therapy. 
PERMISSION FOR ACCESS TO AND USE OF HEALTH INFORMATION 
This section governs how your health information will be used and shared by the study doctors 
during and after the study. The health information that may be used and shared includes all 
information collected during the study and any health information in your medical records that is 
relevant to the study. 
1. PROVIDERS’ DISCLOSURE OF HEALTH INFORMATION IN YOUR RECORDS 
You agree to permit [hospital and/or clinic], your doctors, and your other health care providers 
(“Providers”) to share health information in your medical records with [investigator(s)] and 
[his/her/his/her/its] staff (“Researchers”). You agree to permit Providers to share your health 
information: 
 
With the Researchers; 
 
With the study sponsor, Medtronic, Inc. and its agents and contractors (together 
“Medtronic”); 
 
As required by law; 
o With government organizations and review boards required to watch over the safety 
and effectiveness of medical products and therapies and the conduct of research; and 
o With other persons who are required to watch over the safety and effectiveness of 
medical products and therapies and the conduct of research. 
2. RESEARCHER’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
You agree to permit the Researchers to use and share your health information: 

 
 
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 
Among themselves to conduct the study; 
 
With other researchers in the study to conduct the study; 
 
With Medtronic; 
 
With government organizations and review boards required to watch over the safety and 
effectiveness of medical products and therapies and the conduct of research; and 
 
With other persons who are required to watch over the safety and effectiveness of medical 
products and therapies and the conduct of research. 
Once Providers or Researchers have shared your health information with a third party, the 
information may be subject to further sharing by the third party. Federal privacy laws may no longer 
protect it from further sharing. 
While the study is in progress, you will not be allowed to see your health information that is created 
or collected for the study. After the study is finished, you may see this information as described in 
the [hospital/clinical trial site]’s Notice of Information practices. 
This permission to share your health information does not have an ending date. You do not have to 
give this permission, but if you do not, you will not be allowed to be in the study. You may change 
your mind and take back this permission to use your health information at any time. To take back 
this permission, you must write to [name and contact information]. If you take back this permission, 
you cannot continue in the study. Even if you take back this permission, Medtronic and 
Researchers may continue to use and share the health information already received as described 
in this informed consent 
Economic Study 
This study contains a health economics review that will be done to compare the in-hospital, 12 
month and 24 month follow-up medical care resource utilization and cost for patients in each of the 
treatment groups.  As part of this study, you may be asked to sign a separate document that gives 
us your permission to review your billing information sent directly from the Medicare system in order 
to evaluate medical cost data.  This information will be kept strictly confidential and be used solely 
to assess the medical expenses which occur as a direct result of participating in the Medtronic 
CoreValve™SURTAVI Trial. 
Quality of Life Questionnaire 
Medtronic CoreValve™SURTAVI Trial will also contain a quality of life study. As part of this study, 
your research coordinator will have you or your legal representative complete a questionnaire 
called a Quality of Life Questionnaire.  You will need to complete this questionnaire when you are 
enrolled in the study and 1 month, 3 months, 6 months, 12 months, 18 months, 2 years, 3 years, 4 
years and 5 years after your study procedure. 
OBTAINING ADDITIONAL INFORMATION 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. The study doctor will inform you of any new significant information, when 
it becomes available, which may affect your willingness to continue to participate in this study. If 
you have any questions about this study or if you experience any health problems, you should 
contact Dr. Principal Investigator at xxx-xxx-xxxx. 
If you have questions about your rights as a participant in this study, you should contact the 
chairman of the Institutional Review Board at xxx-xxx-xxxx. 
MEDTRONIC’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
This section describes what Medtronic as study sponsor will do with the study data, including your 
health information received during the study. 

 
 
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Medtronic will keep your health information confidential in keeping with all applicable laws and 
regulations. Medtronic may use your health information to conduct this study. Medtronic may use 
your health information for other purposes, such as: 
 
Watch over and improve the performance of its device; 
 
New medical research; 
 
Proposals for making new medical products or procedures; and 
 
Other business purposes. 
Any reports or publications about the study or any other research will not include your name or a 
description of you. Any records identifying you will not be made publically available.  Information 
received during the study will not be used to market to you; your name will not be placed on any 
mailing lists or sold to anyone for marketing purposes. 
The US Food and Drug Administration’s regulations, as well as other applicable laws, control 
Medtronic’s work in developing and assuring the safety and quality performance of its medical 
devices. Medtronic may disclose your health information to the FDA, as well as to other US and 
foreign government authorities responsible for assuring the safety of medical devices. Medtronic 
also may disclose your health information to institutional review boards and other persons who are 
required to watch over the safety and effectiveness of medical products and therapies and the 
conduct of research. You agree to allow Medtronic to use study data in these ways. You also agree 
to allow FDA and other governmental authorities to inspect your health information. 
 
PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION  
Please indicate below whether you would like us to notify your primary care physician or your 
specialist of your participation in this study.   
(Initial only one box). 
 
Yes, I want the study doctor to inform my primary care physician/specialist of my 
participation in this study 
 
No. I do not want the study doctor to inform my primary care physician/specialist of 
my participation in this study. 
 
I do not have a primary care physician/specialist. 
 
 
The study doctor is my primary care physician/specialist. 
 
 

 
 
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CONSENT 
I confirm that: 
 
I have read the informed consent form of this study and my physician has answered all my 
questions regarding the study.  
 
I had sufficient time to consider my participation into this study, I am aware that 
participation into this study is completely voluntary, and I agree to follow the instructions 
from the investigator. 
 
I realize that I may decide to refuse participation or stop participation at any time without 
penalty and without affecting the quality of my health care or the relationship with my 
physician.  
 
I understand and agree that personal information about me will be collected from my 
medical records, used and processed (manually and by computer) by the manufacturer of a 
medical device used in my treatment or any other designated party that is involved in the 
study (e.g. hospital, physician, regulatory authorities, ethics committees).  
 
I understand and agree that representatives from Medtronic, regulatory authorities and the 
Institutional Review Board will be granted direct access to my medical records.  
 
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigation. 
 
I fully understand there is limited experience with this device in humans and that its safety 
and effectiveness have not been established and there are risks of serious complications 
associated with this study. 
 
I also understand that the doctors might determine after I give consent that it is not possible 
to implant the study valve. 
 
I hereby give my consent to participate in the “Medtronic CoreValve™SURTAVI Trial”. I have been 
given a copy of this consent form, and am also aware that the investigator will keep a copy in his or 
her files. 
 
 
__________________________________________ 
Patient Name (please print) 
 
 
__________________________________  
 
_______________ 
Patient Signature   
 
 
 
 
Date  
  (MM/DD/YYYY) 
 
 
Statement from Person Obtaining Consent 
I certify that I have explained the nature of the device and the study to the above-named person. 
I have also explained the contents of this informed consent form to the above-named person. I 
have asked whether or not there are any questions. I have answered any questions that were 
raised by this person. 
 
 
______________________________________ 
Person Obtaining Consent Name (please print) 
 
 
__________________________________  
 
_______________ 
Signature of Person Obtaining Consent  
 
 
Date  
(MM/DD/YYYY) 

 
 
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United States – Roll-in Subjects 
INFORMED CONSENT FORM  
FOR ROLL-IN SUBJECTS 
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this research study and how you 
might take part in it. By signing this form, you will show that you understand and that you agree to 
take part in this research study. Your signature on this form is required before you can take part 
in this research study. 
BACKGROUND 
You are being asked to take part in a research study entitled “Medtronic CoreValve™ SURTAVI 
Trial” because you have a disease of your aortic valve.  This disease is called aortic stenosis. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the left 
ventricle (main pumping chamber of the heart) into the aorta (main artery delivering blood to the 
body). If the valve becomes abnormally narrow through a process of thickening and stiffening 
(aortic stenosis) the heart must work harder to pump the same amount of blood with each beat. 
As the heart works harder, the heart muscle thickens (hypertrophy), and the heart chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve is 
the standard treatment. 
As an alternative to open heart surgery, the Medtronic CoreValve™ System and Medtronic 
CoreValve™ Evolut ™ R System have been developed to replace a diseased aortic heart valve 
without the need for open heart surgery. This system allows the percutaneous aortic valve (study 
valve) to be implanted (inserted) through a long, thin flexible tube that is inserted through an 
incision in the skin and threaded through the bloodstream (percutaneous). 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
You are being asked to participate in this study because doctors have determined your aortic 
valve is no longer working properly. However, your doctors have also decided that your risk of 
experiencing major problems while undergoing open-heart surgery is moderate due to medical 
reasons or anatomical reasons (relating to how and where your heart, aortic valve and blood 
vessels are placed within your body). This means that you doctor believes your health is 
acceptable for open-heart surgery, but there are still a risk of potential problems. 
PURPOSE OF THE STUDY 
The purpose of this clinical  study is to determine if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions 
as you. 
The study valve is considered an “investigational device”, which means that clinical studies are 
required to determine if it is safe and provides clinical benefit. Medtronic, Inc. is sponsoring this 
study to obtain data on the safety and performance of the investigational device. The Medtronic 
CoreValve™ System and Medtronic CoreValve™ Evolut™ R System includes the valves described 
below and two parts that help load and deliver the valves correctly. 
This study will involve approximately subjects at up to 115 hospitals in the United States and 
around the world, and is anticipated to take approximately 8 years to complete. Your participation 
in this study is expected to last approximately five years from the day you are enrolled in the 
study. Annual follow-up may be extended to up to 10 years after the implant procedure. 

 
 
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STUDY DEVICES 
Both study valves are made from animal tissue attached to a metal frame.  
The study valves are designed to be implanted (inserted) using a delivery system catheter (long, 
thin flexible tube) to replace your diseased aortic heart valve without open-heart surgery. A 
unique feature of the Evolut R device is that it can be re-captured, making it easier for doctors to 
place the device in a correct position. Once it is implanted, CoreValve™ study valves acts in the 
same method of the native valve. 
 
The Medtronic CoreValve system is approved by the US Food & Drug Administration (FDA) since 
2014 and it has been approved in other parts of the world since 2006. It has been implanted in 
over 45,000 patients. The Medtronic CoreValve™ System is currently approved for use in Europe, 
South America, and parts of Asia. The Medtronic CoreValve™ Evolut™ R system is currently being 
studied in Europe and Australia. 
 
 
 
 
 
 
 
 
 
 
 
Figure 3: Medtronic CoreValve™ “Study Valve” 
 
 
 
 
 
 
 
 
Figure 4: Medtronic CoreValve™ Evolut™ R “Study Valve” 
PROCEDURES TO BE FOLLOWED 
If you agree to be in this study, and after you have signed this informed consent form, data such 
as your age, gender, medical history and medication use will be recorded. You will undergo the 
following tests: 
• 
Physical examination 
• 
Computed tomography (CT) - a scan performed using an x-ray machine, which is linked to 
a computer to take pictures of your body. Sometimes a CT will require the use of a type of 

 
 
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dye that makes the kidneys work harder and may be harmful to the kidneys. You may have 
an MRI in place of a CT scan if your doctor believes your kidneys are not working well 
enough for you to have a CT scan. MRI stands for magnetic resonance imaging and is a 
test that uses a strong magnet and a complex computer system to produce detailed images 
of your internal organs and soft body tissues. 
• 
Blood tests (about 2 tablespoons) 
• 
Echocardiography (transthoracic echocardiogram (TTE)) - a test that uses sound waves to 
take pictures of your heart and measure the degree of narrowing of your aortic valve; a 
probe with gel is placed on the outside of your chest to take pictures of your heart 
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
• 
Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
If you are of child-bearing potential, we will ask you to take a pregnancy test. If you are pregnant, 
you will not be able to participate in this study. 
These procedures and tests are standard procedures and are not experimental. If you have 
already had any of these tests performed before, they may to be used for the study if your study 
doctor determines they don’t need to be repeated for study purposes.  
The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you 
will not be allowed to participate in the study. 
If your doctor and the committee decide you are eligible to be in the study, you will be one of the 
first three (3) patients at this hospital to be enrolled in this study. You will receive a transcatheter 
aortic valve implant (TAVI).  
Your enrollment in the study will begin once you sign this consent and you are assigned to the 
roll-in treatment group. If you are enrolled in the study, you will be required to have the following 
additional tests completed within 14 days prior to the procedure (TAVI): 
• 
Physical exam, including a determination of neurological (brain) status where you will be 
asked to answer a series of questions and perform a series of tasks such as writing and 
drawing 
• 
Blood tests (about 2 tablespoons) 
• 
Walking test – a test that records your breathing, heart rate, and how you feel after 6 
minutes of walking 
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life Questionnaires (QOL). 
TAVI Procedure: 
The study valve is an experimental valve which means you can only receive the valve if you are 
part of this study. Your study doctor will decide if you will either receive the Medtronic 
CoreValve™ System or the Medtronic CoreValve™ Evolut™ R System. 
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor.  You may be advised to continue these medications for at 
least three months following your procedure.  

 
 
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Before the procedure you will be given an antibiotic (a medicine that kills bacteria or germs) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about 2 tablespoons) and an ECG before the procedure.   
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary 
during the procedure, you will be put under general anesthesia at that time. 
Your study doctor will decide what locations are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary. These pictures are described 
in the next paragraphs.  Additionally, your study doctor will decide if performing a surgical incision 
to any of the site(s) is necessary. 
During the procedure you may have a transesophageal echocardiogram which is also called a 
TEE. This test uses sound waves to take a closer look at the inside structures of the heart. If your 
doctor decides this picture is necessary, to perform the test you will swallow a thin flexible tube 
with a special tip. This tube sits in the esophagus (the tube that connects the mouth to the 
stomach). The special tip of the tube sends out sound waves (ultrasound) that echo within the 
chest wall. The esophagus is located behind the heart so these echoes are picked up and create 
a picture of the heart that is displayed on a video monitor. The pictures will allow your study 
doctor to take a closer look at your valve. 
You will have a temporary pacemaker put in place during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins and threaded 
through your vein into the right side of your heart. The wire is attached to a battery operated 
device outside of your body. This temporary pacemaker will help keep your heart rate (speed) 
and rhythm steady. This temporary pacemaker will not be removed for at least 48 hours after 
your TAVI procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. Balloon valvuloplasty is a procedure used to widen a stiff or narrowed heart valve. A 
wire and a thin tube are guided by x-rays through the heart and positioned through the diseased 
heart valve. A balloon is placed over the wire and inflated, enlarging the opening through the 
diseased valve allowing the study valve to be placed. 
Your doctor will then implant (insert) the study valve through the long, thin flexible tube that is 
inserted through an incision in the skin and threaded through the bloodstream. TAVI is performed 
using x-ray machines which will allow your doctor to see the study valve, your blood vessels and 
heart. The study valve will be guided through your blood vessels to your existing aortic valve and 
then the study valve will be placed over your existing valve. 
During the TAVI procedure, your doctor will perform angiography (x-ray pictures) and ECGs 
(recordings of the electrical impulses of your heart through patches placed on the chest) to 
observe your heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study 
valve. 
AFTER TAVI PROCEDURE: 
After the TAVI procedure, your study doctors will continue to monitor your progress and recovery. 
You will have the following tests performed within the two days following the procedure and 
before you are discharged from the hospital: 
•  
Determination of neurological (brain) status where you will be asked to answer a series of 
questions and perform a series of tasks 
•  
Blood tests (about 2 tablespoons) 
•  
Echocardiogram (TTE) 

 
 
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•  
ECG 
FOLLOW-UP VISITS AFTER TAVI PROCEDURE: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months 
(1 year), 18 months, 24 months (2 years), and 3, 4, and 5 years after the procedure. Most of the 
follow-up tests and examinations are routine, not experimental. Each visit will take about 1 ½ to 2 
hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
• 
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Blood tests (about 2 tablespoons) – 30 day visit only 
• 
Walking test – 30 day visit only 
• 
Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12 months, 24 months, and 3, 4, 5 years will include: 
• 
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last clinic visit 
• 
Blood tests (about 2 tablespoons) 
• 
Echocardiogram (TTE) 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Walking test – 12 and 24 months visits only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted via phone to 
complete a Quality of Life Questionnaire. 
If, during the 5 years of follow-up, you have additional heart surgeries or cath lab procedures to 
work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological 
(brain) status within 24 hours after each additional procedure. 
If you have a stroke, have been inform by a doctor that you experienced a stroke, or experience  
any of the following symptoms, notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as 
possible: sudden numbness, tingling, loss of movement (especially on 1 side of the body), vision 
changes, confusion or trouble understanding simple statements, severe headaches, or seizures.  
Any of these symptoms could indicate that you are having problems with your neurological (brain) 
function.  If a doctor confirms that you had a stroke, you will be asked to come to the clinical to 
have tests performed to determine your neurological (brain) status where you will be asked to 
answer a series of questions and perform a series of tasks. These tests will be performed at 7 
days, 30 days and 3 months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or 
are hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis.  Your study doctor will determine if you will need to have another valve 
implanted.   
In the event of your death, we will request an autopsy. We will also request that either the whole 
heart and valve or just the valve are removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the investigational valve. 

 
 
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Your family and your "legally authorized representatives", have the right to refuse the autopsy 
and refuse the request to remove the heart and/or valve even if you sign this consent form. 
 
 
POSSIBLE RISKS AND DISCOMFORTS 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest –heart stops beating and blood flow through the body is interrupted 
or stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to 
improve blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  
 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able 
to supply oxygen to the body 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 

 
 
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o 
Stenosis – narrowing of the opening of the valve 
 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, 
blood clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the 
device from where it was originally placed 
 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 
 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure 
is expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs 
in the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 
 
Permanent disability – injury that does not allow that impairs normal/previous 
physical or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 
 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 
 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result 
in a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed 
space that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the 
heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  
o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical 
impulses to the heart to help your heart beat normally 

 
 
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o 
Atrio-ventricular node block – a block in the electrical path from the top part 
of the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom 
part of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part 
of the heart (ventricles) 
 
Encephalopathy – altered mental state 
 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 
 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 
 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic 
valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known.If you 
become pregnant there maybe risks, discomforts, or side effects to you and the embryo/fetus that 
are not yet known.  Please notify your study doctor as soon as possible to discuss any of these 
potential risks. 
 
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how 
much radiation you will get, in the following descriptions the radiation is compared to the amounts 
that people are exposed to in daily life. There is radiation that naturally occurs from space and 
from rocks in the soil. This natural radiation is greater at higher altitudes. 
 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure 
is less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 

 
 
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The estimated radiation exposure for the valve procedure is approximately 10-15 times the 
amount of radiation exposure received in one year from background radiation (naturally occurring 
radiation you are exposed to everyday). The exposure is approximately the amount an 
occupational worker is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have 
extra follow-up visits with your doctor to watch your recovery more closely. 
Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 
POSSIBLE BENEFITS 
The possible benefits you may receive from participating in this research are that you may be 
able to receive a new heart valve without having open-heart surgery. Another possible benefit is 
that your new valve may work better than the way your diseased valve currently works. This may 
improve how you feel and may improve your daily activity. 
Your participation in this research may improve procedures that may guide the future treatment of 
heart surgery, by using procedures that are less invasive, meaning less cutting, entering or 
breaking through the body, which may benefit others in the future. However, there is no 
guarantee that you will benefit from being in this research. 
ALTERNATIVE TREATMENTS 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other treatment 
options include percutaneous (through an artery in the groin) aortic valve implantation, or medical 
management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study 
doctor about other treatment options you may have. 
IF PROBLEMS DEVELOP 
If you believe that you have been injured as a result of your participation in the study, you should 
notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible or in serious cases, go to the 
emergency room.  
Immediate necessary medical care is available at [Name of institution(s)] in the event that you are 
injured as a result of your participation in this research study  
Medtronic has agreed to pay back [name of institutions that are parties to the CTA] for the costs 
of medical or surgical care they provide for any serious and unanticipated illness or injury under 
the following conditions: 
 
The illness or injury must be related to a defect or malfunction of the investigational 
device or in the TAVI procedure as described in the Protocol, and not related to 
procedures that are routine standard of care. 
 
The illness or injury cannot be caused by (a) the negligence or intentional misconduct of 
the study staff or [name of institutions that are parties to the CTA]; (b) because the study 
staff or [name of institution(s)] that are parties to the CTA] did not follow the protocol for 
the study; or (c) the natural progression of your illness. 
 
The illness or injury must have happened before the study closes (last patient is seen for 
the 5 year follow-up visit) at this [Name of institution(s)]. 
 
[Name of institution(s) that are parties to the CTA] must notify Medtronic within one year 
of the date the study closes at all study sites or before the study closes at this site, 
whichever is earlier. 
Subject to the above conditions, Medtronic will pay back the costs that are not covered by your 
health insurance or Medicare. The amount Medtronic will pay back is the amount Medicare pays 
[name of institution(s) that are parties to the CTA] plus 10%. 

 
 
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PAYMENT FOR PARTICIPATION IN THE STUDY 
You will not be paid to take part in the study. However, you may be reimbursed for local mileage 
and parking expenses directly related to any study related visits. Your study doctor or research 
coordinator will tell you how to get reimbursement.  
There is no monetary advantage to the study doctor for participation in this study. 
MEDICAL EXPENSES 
Your private or public health insurance company (for example Medicare) will be billed for the 
valve procedure and the cardiac catheterization and other procedures that are required by the 
study and you will be responsible for paying for any co-payment, co-insurance or deductible. It is 
possible that your private or public health insurance will not pay for some or all of the procedures, 
including the valve procedure or the cardiac catheterization procedure because you are 
participating in this study. Any costs not covered by your public or private insurance will be your 
responsibility. You should discuss the estimate of these costs with your study doctor. You will not 
be charged for the cost of collecting the data for this study and other clinic visits and diagnostic 
tests done solely for the purposes of this study. 
BASIS OF PARTICIPATION 
Your participation in this study is voluntary. If you refuse to be in this study there will be no 
penalty or loss of benefits to which you are otherwise entitled. You may withdraw from the study 
at any time and will not lose your benefits or be treated any differently as a result of withdrawing 
from the study. Any new findings (decisions or conclusions) that may influence your willingness to 
participate will be provided to you.  If you decide to leave the study before it is finished, please tell 
one of the persons listed in the section below “Obtaining Additional Information”. It may be 
requested that, if you withdraw, you return to your study doctor for a final visit. 
The study doctor may end your participation in the study at any time if: 
 
He or she determines it is not in the best interest of your health 
 
The study doctor loses contact with you and you do not return for your study visits as 
scheduled 
 
You refuse to allow the use of private health information during the course of the study 
The study doctor will make the decision and let you know if it is not possible for you to continue in 
the study. 
You may be removed from the study without your consent if the sponsor (Medtronic, Inc.) ends 
the study.  If this happens, you will be notified and the reasons will be explained to you.  Your 
physician will continue to provide the appropriate medical therapy. 
 
PERMISSION FOR ACCESS TO AND USE OF HEALTH INFORMATION 
This section governs how your health information will be used and shared by the study doctors 
during and after the study. The health information that may be used and shared includes all 
information collected during the study and any health information in your medical records that is 
relevant to the study. 
 
1. PROVIDERS’ DISCLOSURE OF HEALTH INFORMATION IN YOUR RECORDS 
You agree to permit [hospital and/or clinic], your doctors, and your other health care providers 
(“Providers”) to share health information in your medical records with [investigator(s)] and 
[his/her/his/her/its] staff (“Researchers”). You agree to permit Providers to share your health 
information: 
 
With the Researchers; 
 
With the study sponsor, Medtronic, Inc. and its agents and contractors (together 
“Medtronic”); 
 
As required by law; 

 
 
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o With government organizations and review boards required to watch over the safety 
and effectiveness of medical products and therapies and the conduct of research; 
and 
o With other persons who are required to watch over the safety and effectiveness of 
medical products and therapies and the conduct of research. 
2. RESEARCHER’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
You agree to permit the Researchers to use and share your health information: 
 
Among themselves to conduct the study; 
 
With other researchers in the study to conduct the study; 
 
With Medtronic; 
 
With government organizations and review boards required to watch over the safety and 
effectiveness of medical products and therapies and the conduct of research; and 
 
With other persons who are required to watch over the safety and effectiveness of 
medical products and therapies and the conduct of research. 
Once Providers or Researchers have shared your health information with a third party, the 
information may be subject to further sharing by the third party. Federal privacy laws may no 
longer protect it from further sharing. 
While the study is in progress, you will not be allowed to see your health information that is 
created or collected for the study. After the study is finished, you may see this information as 
described in the [hospital/clinical trial site]’s Notice of Information practices. 
This permission to share your health information does not have an ending date. You do not have 
to give this permission, but if you do not, you will not be allowed to be in the study. You may 
change your mind and take back this permission to use your health information at any time. To 
take back this permission, you must write to [name and contact information]. If you take back this 
permission, you cannot continue in the study. Even if you take back this permission, Medtronic 
and Researchers may continue to use and share the health information already received as 
described in this informed consent 
Economic Study 
This study contains a health economics review that will be done to compare the in-hospital, 12 
month and 24 month follow-up medical care resource utilization and cost for patients in each of 
the treatment groups.  As part of this study, you may be asked to sign a separate document that 
gives us your permission to review your billing information sent directly from the Medicare system 
in order to evaluate medical cost data.  This information will be kept strictly confidential and be 
used solely to assess the medical expenses which occur as a direct result of participating in the 
Medtronic CoreValve™ SURTAVI Trial. 
Quality of Life Questionnaire 
Medtronic CoreValve™ SURTAVI Trial will also contain a quality of life study. As part of this study, 
your research coordinator will have you or your legal representative complete a questionnaire 
called a Quality of Life Questionnaire.  You will need to complete this questionnaire when you are 
enrolled in the study and 1 month, 3 months, 6 months, 12 months, 18 months, 2 years, 3 years, 
4 years and 5 years after your study procedure. 
OBTAINING ADDITIONAL INFORMATION 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. The study doctor will inform you of any new significant information, 
when it becomes available, which may affect your willingness to continue to participate in this 
study. If you have any questions about this study or if you experience any health problems, you 
should contact Dr. Principal Investigator at xxx-xxx-xxxx. 
If you have questions about your rights as a participant in this study, you should contact the 
chairman of the Institutional Review Board at xxx-xxx-xxxx. 
MEDTRONIC’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 

 
 
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This section describes what Medtronic as study sponsor will do with the study data, including your 
health information received during the study. 
Medtronic will keep your health information confidential in keeping with all applicable laws and 
regulations. Medtronic may use your health information to conduct this study. Medtronic may use 
your health information for other purposes, such as: 
 
Watch over and improve the performance of its device; 
 
New medical research; 
 
Proposals for making new medical products or procedures; and 
 
Other business purposes. 
Any reports or publications about the study or any other research will not include your name or a 
description of you. Any records identifying you will not be made publically available.  Information 
received during the study will not be used to market to you; your name will not be placed on any 
mailing lists or sold to anyone for marketing purposes. 
The US Food and Drug Administration’s regulations, as well as other applicable laws, control 
Medtronic’s work in developing and assuring the safety and quality performance of its medical 
devices. Medtronic may disclose your health information to the FDA, as well as to other US and 
foreign government authorities responsible for assuring the safety of medical devices. Medtronic 
also may disclose your health information to institutional review boards and other persons who 
are required to watch over the safety and effectiveness of medical products and therapies and the 
conduct of research. You agree to allow Medtronic to use study data in these ways. You also 
agree to allow FDA and other governmental authorities to inspect your health information. 
 
PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION  
Please indicate below whether you would like us to notify your primary care physician or your 
specialist of your participation in this study.   
(Initial only one box). 
 
Yes, I want the study doctor to inform my primary care physician/specialist of my 
participation in this study 
 
No. I do not want the study doctor to inform my primary care physician/specialist of 
my participation in this study. 
 
I do not have a primary care physician/specialist. 
 
The study doctor is my primary care physician/specialist. 
 
 

 
 
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CONSENT 
I confirm that: 
 
I have read the informed consent form of this study and my physician has answered all 
my questions regarding the study.  
 
I had sufficient time to consider my participation into this study, I am aware that 
participation into this study is completely voluntary, and I agree to follow the instructions 
from the investigator. 
 
I realize that I may decide to refuse participation or stop participation at any time without 
penalty and without affecting the quality of my health care or the relationship with my 
physician.  
 
I understand and agree that personal information about me will be collected from my 
medical records, used and processed (manually and by computer) by the manufacturer of 
a medical device used in my treatment or any other designated party that is involved in 
the study (e.g. hospital, physician, regulatory authorities, ethics committees).  
 
I understand and agree that representatives from Medtronic, regulatory authorities and 
the Institutional Review Board will be granted direct access to my medical records.  
 
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigation. 
 
I fully understand there is limited experience with this device in humans and that its safety 
and effectiveness have not been established and there are risks of serious complications 
associated with this study. 
 
I also understand that the doctors might determine after I give consent that it is not 
possible to implant the study valve. 
 
I hereby give my consent to participate in the “Medtronic CoreValve™ SURTAVI Trial”. I have 
been given a copy of this consent form, and am also aware that the investigator will keep a copy 
in his or her files. 
 
 
__________________________________________ 
Patient Name (please print) 
 
 
__________________________________  
 
_______________ 
Patient Signature   
 
 
 
 
Date  
 (MM/DD/YYYY) 
 
 
Statement from Person Obtaining Consent 
I certify that I have explained the nature of the device and the study to the above-named person. 
I have also explained the contents of this informed consent form to the above-named person. I 
have asked whether or not there are any questions. I have answered any questions that were 
raised by this person. 
 
 
______________________________________ 
Person Obtaining Consent Name (please print) 
 
 
__________________________________  
 
_______________ 
Signature of Person Obtaining Consent  
 
 
Date  
(MM/DD/YYYY)

 
 
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PATIENT INFORMED CONSENT FORM - INFORMATION SHEET 
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this clinical study and how you 
might take part in it.  By signing this form, you will show that you understand and that you agree to 
take part in this clinical study.  Your signature on this form is required before you can take part in 
this clinical study. 
Background 
You are being asked to take part in a clinical study entitled “The Medtronic CoreValve™ SURTAVI 
Trial” because you have a disease of your aortic valve. This disease is called aortic stenosis. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the lower 
chamber of the heart (ventricle) into the main artery delivering blood to the body (aorta).  If the 
valve becomes abnormally narrow through a process of thickening and stiffening (aortic stenosis), 
then the heart must work harder to pump the same amount of blood with each beat.  As the heart 
works harder, the heart muscle thickens (hypertrophy), and the lower chamber (ventricle) may 
become larger (dilate). Open-heart surgery to replace the diseased aortic valve is the standard 
treatment. For some patients, the risk of experiencing major problems during open-heart surgery 
is greater because of other health problems.  
As an alternative to open-heart surgery, the Medtronic CoreValve™ System and Medtronic 
CoreValve™ Evolut™ R System have been developed to replace a diseased aortic heart valve 
without the need for open-heart surgery. This system allows the percutaneous aortic valve (study 
valve) to be implanted (inserted) through a long, thin flexible tube that is inserted through an 
incision in the skin and threaded through the bloodstream (percutaneous). 
You are being asked to participate in this study because doctors have determined your aortic 
valve is no longer working properly.  However, your doctors have also decided that your risk of 
experiencing major problems while undergoing open-heart surgery is moderate due to medical 
reasons or anatomical reasons (relating to how and where your heart, aortic valve and blood 
vessels are placed within your body). This means that your doctor believes your health is 
acceptable for open-heart surgery, but there is still a risk of potential problems. 
Purpose of the Study 
The purpose of this clinical study is to determine if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions 
as you. 
The Medtronic CoreValve™ System and Medtronic CoreValve™ Evolut™  R System are considered 
“investigational devices” by the United States Food and Drug Administration (FDA) which means 
that clinical studies are required to determine if it is safe and provides clinical benefit.  Medtronic, 
Inc. is sponsoring this study to obtain data on the safety and performance of the investigational 
devices and its delivery systems to gain FDA approval.   
The study will involve approximately 1600 patients and is being conducted at up to 115 hospitals 
in Europe, Canada and the United States and around the world. It is anticipated to take 
approximately eight years to complete.  Your participation in this study is expected to last 
approximately five years from the day you are enrolled. Annual follow-up may be extended to up 
to 10 years after the implant procedure. 
As a participant in the study, you have certain responsibilities. You have the responsibility to be 
truthful regarding your health and medication history. 
You are expected to return to your study doctor’s office for the study visits. The evaluations 
performed at these visits are a component of the study.  They are important for data collection and 
for monitoring that the investigational devices are working properly.  These evaluations will take 
place at baseline, implant procedure, discharge, and follow-up visits (30 days, 6, 12, 18, 24, 36, 
48, and 60 months). You should not take part in this study if you will not be available for the study 
visits.   

 
 
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You also have the responsibility to report any injuries, hospitalizations, emergency room visits or 
other medical visits, symptoms or complaints to the study doctor or study nurse as soon as 
possible.  
Study Devices 
Both study valves are made from animal tissue attached to a metal frame. The study valve is 
designed to be implanted (inserted) using a delivery system catheter (long, thin flexible tube) to 
replace your diseased aortic heart valve without open-heart surgery. A unique feature of the 
Evolut™ R device is that it can be re-captured, making it easier for doctors to place the device in a 
correct position. Once it is implanted, CoreValve™ study valves acts in the same method of the 
native valve. 
 
 
 
 
 
 
 
 
 
 
 
Figure 5: Medtronic CoreValve™  “Study Valve” 
 
 
 
 
 
 
 
 
 
 
 
Figure 6: Medtronic CoreValve™ Evolut™ R “Study Valve” 
 
The Medtronic CoreValve™ system was CE marked in 2006 and has been implanted in over 
45,000 patients. The Medtronic CoreValve Evolut R system is currently being studied in Europe 
and Australia.  
The CoreValve™ being implanted in this study is identical to the valve that was CE marked in 2006 
with the exception of adding a coating, but is being used outside the current approved patient 
population that is approved under the current CE mark. This coating is designed to help the study 
valve last longer (i.e. function as it is supposed to) and to help keep the study valve from 
becoming calcified like your native valve did.  The coating received CE mark in March 2012. 
 
Procedures to Be Followed 
 
If you agree to be in this study, and after you have signed this informed consent form, data 
such as your age, gender, ethnic origin, medical history and medication use will be 

 
 
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recorded.  You will undergo the following tests to determine if you are suitable for receiving 
the investigational device: 
 
Transthoracic echocardiography (TTE): a test that uses sound waves to take pictures of 
your heart and measure the degree of narrowing of your aortic valve; a probe is placed on 
the outside of your chest to take pictures of your heart 
 
Computed Tomography (CT): a scan performed using an x-ray machine, which is linked to a 
computer to take pictures of your heart and aortic valve 
 
If your doctor decides it is unsafe for you to have a CT scan, you will have a Magnetic 
Resonance Imaging (MRI) test.  MRI is a scan that uses the magnetic properties of your 
tissues to take pictures of your heart.  For the MRI test, you will lie on a special exam table 
while the pictures are taken. 
 
Blood tests: about two tablespoons 
 
An electrocardiogram (ECG): a test that records electrical impulses of your heart; patches 
are placed on the outside of your chest 
 
A physical examination 
 
Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into: the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
If you are of child-bearing potential, we will ask you to take a pregnancy test. If you are pregnant, 
you will not be able to participate in this study. 
All of these procedures and tests are standard procedures for patients with aortic valve disease, 
and are not experimental.  If you have already had any of these tests performed before, they may 
to be used for the study if your study doctor determines they do not need to be repeated for study 
purposes. 
The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you will 
not be allowed to participate in the study. 
If your doctors and the committee decide you are eligible to be in the study, your treatment will be 
determined in a way similar to flipping a coin, called randomization. You will be assigned to one of 
two groups. One group will receive a transcatheter aortic valve implant (TAVI), the other group will 
have an open-heart surgical aortic valve replacement (SAVR). One out of every two participants 
will receive TAVI. The other participants will receive SAVR. You will not be able to choose your 
treatment assignment. 
Your enrollment in the study will begin once you sign this consent and you are assigned to your 
treatment group.  If you are enrolled in the study; you will be required to have the following 
additional tests completed within 14 days prior to the procedure (TAVI or SAVR): 
• 
Physical exam, including a determination of neurological (brain) status where you will be 
asked to answer a series of questions and perform a series of tasks 
• 
Blood tests (about two tablespoons) 
• 
Six-Minute walking test – a test that records your breathing, heart rate, and how you feel  
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life (QOL) Questionnaires. 
If you are assigned to the TAVI group: 
Your study doctor will decide if you will either receive the Medtronic CoreValve™ System or the 
Medtronic CoreValve™ Evolut™ R System.  Before the TAVI procedure, it will be strongly 
recommended that you take blood thinning medications, used to prevent your blood from clotting 
(thickening). These medications will be described to you by your study doctor. You may be 

 
 
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advised to continue taking blood thinning medications for at least three months following your 
procedure.  
Before the procedure you will be given a medicine that kills bacteria or germs (antibiotic) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about two tablespoons) and an ECG before the procedure. 
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary 
during the procedure, you will be put under general anesthesia at that time.  
Your study doctor will decide what areas are best for inserting the long, thin flexible tubes required 
for TAVI and getting all of the pictures that are necessary. These pictures are described in the next 
paragraphs.  Additionally, your study doctor will decide if performing a surgical incision to any of 
the area(s) is necessary. 
During the procedure, you may have a transesophageal echocardiogram which is also called a 
TEE. This test uses sound waves to take a closer look at the inside structures of the heart. If your 
doctor decides this picture is necessary, to perform the test, you will swallow a thin flexible tube 
with a special tip. This tube sits in the tube that connects the mouth to the stomach (esophagus). 
The special tip of the tube sends out sound waves (ultrasound) that echo within the chest wall. 
The esophagus is located behind the heart so these echoes are picked up and create a picture of 
the heart that is displayed on a video monitor. The pictures will allow your study doctor to take a 
closer look at your valve. 
You will have a temporary pacemaker put in place during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins. It is then threaded 
through your vein into the right side of your heart. The wire is attached to a battery-operated 
device that is outside of your body. This temporary pacemaker will help keep your heart rate and 
beat steady. This temporary pacemaker will not be removed for at least 48 hours after your TAVI 
procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. This is a procedure used to widen a hard or thin heart valve. A wire and a thin tube are 
guided by x-rays through the heart and positioned through the diseased heart valve. A balloon is 
placed over the wire and inflated, enlarging the opening through the diseased valve allowing the 
study valve to be placed. 
Your doctor will then insert the study valve through the long, thin flexible tube that is inserted 
through an incision in the skin and threaded through the bloodstream. TAVI is performed using x-
ray machines which will allow your doctor to see the study valve, your blood vessels and heart. 
The study valve will be guided through your blood vessels to your existing aortic valve and then 
the study valve will be placed over your existing valve. 
During the TAVI procedure, your doctor will perform x-ray pictures (angiogram) and recordings of 
the electrical impulses of your heart through patches placed on the chest (ECG) to observe your 
heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study 
valve. 
If you are assigned to the SAVR group: 
If you are assigned to the SAVR group, your doctors will replace your diseased aortic valve 
through open-heart surgery. During surgery, you are asleep under general anesthesia. SAVR 
often requires a median sternotomy, where the bone in the center of the chest (sternum) is split 
down the middle. The chest is then opened to provide your doctor with access to the heart and 
chest cavity, in order to replace your aortic valve. Your surgery is performed while the function of 
your heart is taken over by a heart lung machine (called CPB for cardiopulmonary bypass). 

 
 
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You may have a TEE (a thin tube sits in the esophagus and sends out sounds waves to create a 
picture of your heart) and a temporary pacemaker (thin wire threaded through your vein to right 
side of heart to keep your heart rate and rhythm steady) during the procedure. 
Your doctor may remove any tissue and calcium deposits that are interfering with the normal 
function of the valve. Your damaged valve may be completely removed. The new valve will be 
sewn into the space where your own valve used to be. After your doctor makes sure your valve is 
working properly, blood flow will be restored to your heart and the incisions will be closed. You will 
also have blood drawn for testing before and after the procedure. 
After TAVI and SAVR Procedure: 
After your TAVI and SAVR procedure, your study doctors will continue to monitor your progress 
and recovery. 
You will have the following tests performed within the two days following your TAVI procedure and 
before you leave the hospital: 
•  
Determination of neurological (brain) status where you will be asked to answer a series of 
questions and perform a series of tasks 
•  
Blood tests (about two tablespoons) 
•  
Echocardiogram (TTE) 
•  
ECG 
Follow-up Visits after TAVI and SAVR: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months, 
18 months, 24 months (3 years) and 3, 4, and 5 years after the procedure. The follow-up tests and 
examinations are not experimental and most are performed on a routine basis. Each visit will take 
about 1 ½ to 2 hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
•  
Physical examination, including a determination of neurological (brain) status where you will 
be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
•  
Blood tests (about two tablespoons) – 30 day visit only 
 
Quality of Life (QoL) Questionnaires 
 
ECG 
• 
Six-Minute walking test – 30 day visit only 
• 
Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12, 24, 36, 48 and 60 months will include: 
•  
Physical examination, including a determination of neurological (brain) status where you will 
be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
•  
Echocardiogram (TTE) 
•  
QoL Questionnaires 
•  
ECG 
 
Six-Minute walking test – 12 and 24 months visit only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted via phone to complete 
a Quality of Life Questionnaire. 
If the study doctor is unable to implant the study valve, you will still be followed for safety and will 
need to return to the clinic for the required follow-up visits as described above. 
If, during the 5 years of follow-up, you have additional heart surgeries or cath lab procedures to 
work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological (brain) 
status within 24 hours after each additional procedure. 
If you have a stroke, have been informed by a doctor that you experienced a stroke, experience 
any of the following symptoms, notify your study doctor at xxx-xxx-xxxx as soon as possible: 
sudden numbness, tingling on, loss of movement (occurring on one side of the body), sudden 

 
 
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vision changes, confusion or trouble understanding simple statements, unable to speak, severe 
headaches, or seizures. Any of these symptoms could indicate that you are having problems with 
your neurological (brain) function. You will be asked to come to the clinical to have tests performed 
to determine your neurological (brain) status where you will be asked to answer a series of 
questions and perform a series of tasks. These tests will be performed at 7 days, 30 days and 3 
months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or 
are hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis. The study doctor will determine if you will need to have another valve 
implanted.  
In the event of your death and an autopsy is performed, the study doctor will ask your family or 
"legally authorized representatives" for either the whole heart and valve or just the valve are 
removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the investigational valve. 
Your family and your "legally authorized representatives", have the right to refuse the autopsy and 
refuse the request to remove the heart and/or valve even if you sign this consent form. 
POSSIBLE RISKS AND DISCOMFORTS 
TAVI 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest – heart stops beating and blood flow through the body is interrupted or 
stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to improve 
blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  
 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able to 
supply oxygen to the body 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 

 
 
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 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 
 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, 
blood clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the device 
from where it was originally placed 
 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 
 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure is 
expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs 
in the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 
 
Permanent disability – injury that does not allow that impairs normal/previous 
physical or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 
 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 
 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result 
in a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 

 
 
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o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed 
space that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the 
heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  
o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical 
impulses to the heart to help your heart beat normally 
o 
Atrio-ventricular node block – a block in the electrical path from the top part of 
the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom part 
of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part 
of the heart (ventricles) 
 
Encephalopathy – altered mental state 
 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 
 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 
 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic 
valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known. 
 
 

 
 
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SAVR 
Although SAVR is not experimental there are potential risks associated with the procedure. These 
risks are the same even if you undergo the SAVR procedure and you decide not to participate in 
this study.  Some of these risks include, but may not be limited to the following: 
 
Obstruction of blood flow to the heart (angina) resulting in damage to the heart tissue 
(myocardial infarction/heart attack) 
 
Abnormal heart beat (cardiac arrhythmia and dysrhythmia) 
 
Blood leaking around the outside of the prosthetic valve (paravalvular leak) or any problem 
with the valve that causes leaking of blood after the valve has closed (transvavular leak). 
 
Damage to red blood cells (hemolysis) that can result in anemia (decreased red blood cells) 
 
Death 
 
Inflammation of the lining of the heart (endocarditis) 
 
Heart failure 
 
Any problem with the prosthetic valve that causes narrowing of the valve opening (stenosis) 
 
Blood clots that develop in the heart of on the replacement valve. These clots may break 
loose and travel through the bloodstream (thromboembolism). This problem may cause 
stroke (decrease blood flow to the brain causing damage to the brain) or heart attack. 
 
Failure of the valve to open and close properly 
 
If you are or you become pregnant, there may be risks, discomforts or side effects to you and your 
unborn child that are not yet known.  
 
Some possible inconveniences may include, but is not limited to the following: 
 
Transportation to and from the clinic for follow-up visits 
 
Parking 
 
Follow-up visit scheduling 
 
There may be other discomforts and risks related to the device and/or this study that are not 
foreseen at this time.  
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how 
much radiation you will get, in the following descriptions the radiation is compared to the amounts 
that people are exposed to in daily life. There is radiation that naturally occurs from space and 
from rocks in the soil. This natural radiation is greater at higher altitudes. 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure is 
less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 
The estimated radiation exposure for the valve procedure is approximately 10-15 times the 
amount of radiation exposure received in one year from background radiation (naturally occurring 
radiation you are exposed to everyday). The exposure is approximately the amount an 
occupational worker is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have extra 
follow-up visits with your doctor to watch your recovery more closely. 
Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 

 
 
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Potential Benefits for You 
The possible benefits you may receive from participating in this clinical study are that you may be 
able to receive a new heart valve without having open-heart surgery.  Another possible benefit is 
that your new study valve may work better than the way your diseased valve currently works.  This 
may improve how you feel and may improve your daily activity.  However, there is no guarantee 
that you will benefit from being in this clinical study. 
Potential Benefits for Other Patients 
Your participation in this clinical study may improve procedures that may guide the future 
treatment of aortic stenosis, by using procedures that are less invasive (meaning less cutting, 
entering or breaking through the body), which may benefit others in the future. 
Alternative Therapy 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other treatment 
options include percutaneous (through an artery in the groin) aortic valve implantation, or medical 
management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study 
doctor about other treatment options you may have and their related benefits and risks. 
Compensation for Illness or Injury 
If you are physically injured as a result of your participation in this study, reasonable and 
appropriate medical treatment will be provided to you free of charge by the study sponsor, if such 
treatment is not already covered by your medical insurance. 
Medtronic maintains appropriate clinical trial liability insurance coverage as required under 
applicable laws and regulations and will comply with applicable local law and custom concerning 
specific insurance coverage.  If required, a Clinical Trial insurance statement/certificate will be 
provided to your Institution’s Ethics Committee.  
Compensation and Additional Costs 
You will not receive any compensation for your participation in this study (including follow up).  
There is no monetary advantage to the study doctor for participation in this study. 
You may request for reimbursement for costs associated with travel expenses for the purpose of 
the follow-up visits. 
Role of the Sponsor’s Representative 
Your study doctor will delegate study activities not only to other study personnel (both doctors and 
study nurses), but also sponsor representatives. These study activities may include support during 
the procedure and supporting during data collection throughout the study.  These activities are 
performed under supervision  of the study doctor and will not bias the data integrity in any way.  
Use of Personal Data/Confidentiality 
Your participation in this study is entirely confidential.  
While participating in this study the following personal data will be collected: 
 
medical and health data from your medical records  
 
data on your ethnic origins 
(Hereinafter “personal data”)  
Representatives of the institution or hospital in which you are treated, including your physician(s) 
who conduct(s) the study, the monitor(s) on behalf of the study sponsor and other designated 
parties that are involved in the study (for example third party data processors) have direct access 
to your personal data. Furthermore, representatives of national, European or other international 
regulatory bodies, members of the ethics committees or any other public authority may be granted 
direct access to your personal data in order to comply with legal and regulatory requirements. If it 

 
 
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is necessary, your personal data may also be transferred to the above-mentioned parties, which 
are located in the country in which you are treated and in member states of the European 
Economic Area but maybe also in countries where the European Directive on Data Protection 
does not apply. 
For conducting the study your personal data will be transferred to and processed by Medtronic 
(meaning the Medtronic, Inc. as well as all affiliates of this group of companies) or a third party 
designated by Medtronic – but solely in a key coded form, unless it may be impossible to make it 
anonymous, for instance, where your name cannot be removed from the data carrier, such as x-
ray, angiogram or echocardiography. This means that these data will be transferred to a Medtronic 
entity or a third party designated by Medtronic which is located in the country where you are 
treated, in a member state of the European Economic Area but maybe also in the United States or 
another country where the European Directive on Data Protection does not apply. 
Medtronic, or a third party designated by Medtronic, will process these data manually or by 
computer, including the use of internet or cloud computing. 
Your personal data are collected for medical research purposes, to gather information on the 
device and its performance during and after this study and may be used for obtaining 
assessments for approvals for the device, additional scientific research, educational purposes and 
publications as well as for future health studies.  
Study results may be published without disclosing your name or any other identifying 
characteristics. In all cases, your personal data will be handled at all times in accordance with 
appropriate confidentiality standards and all applicable data protection and privacy laws. 
You are entitled to access the personal data collected about you and to have inaccuracies 
corrected. 
If you agree upon, your personal physician will be informed about your participation in the study. 
Voluntary Participation 
Your participation in this study is entirely voluntary. You are free to refuse participation and you 
are free to discontinue participation in the study at any time without fear of penalty or loss of 
medical care. In addition, you will be notified in written form of any significant new findings that 
may develop during the course of the study or the reasons for any amendment to the study 
protocol which may relate to your willingness to continue your participation.  
Your physician, Medtronic, the Ethics Committee or the  Competent Authority may decide to 
terminate your participation in the study at any time without your prior consent. If this happens you 
will be notified and the reasons explained to you. 
Medtronic can also suspend or terminate the study at any time without your prior consent. If this 
happens, you will be notified and the reasons will be explained to you.  Your physician will 
continue to provide the appropriate medical treatment.  
If you discontinue your participation or if the study sponsor decides to terminate your participation 
in the study all your personal data collected for the study can still be used by the study sponsor 
unless you object and ask for deletion of the data. 
Questions 
In case of any question, you can contact one of the following people: 
Questions about the study: ………………………………… 
Questions in the event of illness or injury: …………………………………. 
Questions about patient rights: ………………………………………….  

 
 
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PATIENT INFORMED CONSENT FORM - SIGNATURE SHEET 
Medtronic CoreValve™ SURTAVI Trial 
I have read the patient information of this study and my physician has answered all my questions 
regarding the study.  
I had sufficient time to consider my participation into this study, I am aware that participation into 
this study is completely voluntary, and I agree to follow the instructions from the investigator. 
I realize that I may decide to refuse participation or stop participation at any time without penalty 
and without affecting the quality of my health care or the relationship with my physician.  
I understand and agree that personal data about me will be collected and used for the purpose of 
the study. For conducting the study these data will be transferred to and processed by Medtronic 
or third parties designated by Medtronic as described in the section ‘use of personal 
data/confidentiality.’ 
I understand and agree that representatives from Medtronic, regulatory authorities and the Ethics 
Committee will be granted direct access to my medical records.  
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the study. 
I understand that I am entitled to access the personal information collected about me and to have 
inaccuracies corrected. 
I have received a copy of the Patient Information and hereby I agree to participate voluntarily in 
and comply with this study. 
 
You may agree or disagree that your personal physician is informed on your participation in this study. 
Please, check one option below indicating your choice: 
 
! must be checked by patient 
 
I agree that my personal physician is informed about my participation in this study. 
 
I disagree that my personal physician is informed about my participation in this study. 
 
 
I agree to participate in this study and I have consented before the initiation of any study 
specific procedures. 
Patient: 
            
 
__________________________  
  ___________________    
 ____________________  
 
 
Name 
 
 
 
Signature 
 
 
Date (dd MMM yyyy) 
 
 
 
 
         Must be written by patient                     Must be written by patient 
 
 
 
          
 
 
  
 
 
 

 
 
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 Only persons officially trained and 
authorized on the delegated task list 
are allowed to sign off 
 
 
 
 
Study Doctor or designated person by Study Doctor: 
I have conducted the informed consent discussion. 
 
__________________________   ___________________   
 ___________________   
 Name  
 
 
 
Signature 
    
 Date (dd MMM yyyy) 
 
 
 
If patient is unable to read: 
I have attended the entire informed consent discussion. I attest that the information in the 
consent form and any other written information was accurately explained to, and 
apparently understood by, the patient. Informed consent was freely given by the patient. 
Impartial Witness: 
 
_________________________  _____________________  
________________   
 Name  
 
 
 
 Signature 
  
 Date (dd MMM yyyy) 
 
Section should be filled in by impartial witness 
 

 
 
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Canada 
INFORMED CONSENT FORM 
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this research study and how you 
might take part in it. By signing this form, you will show that you understand and that you agree to 
take part in this research study. Your signature on this form is required before you can take part in 
this research study. 
BACKGROUND 
You have been invited to participate in this research project because you have aortic stenosis (a 
disease of one of your heart valves). Before deciding to participate in the study you should be 
familiar with its requirements, risks and benefits. This document provides information about the 
study. It may contain words you do not fully understand. Please read it carefully and ask the study 
staff any questions you may have. They will discuss the study with you in detail. If you decide to 
participate, you will be asked to sign this form and a copy will be given to you. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the left 
ventricle (main pumping chamber of the heart) into the aorta (main artery delivering blood to the 
body). If the valve becomes abnormally narrow through a process of thickening and stiffening 
(aortic stenosis) the heart must work harder to pump the same amount of blood with each beat. 
As the heart works harder, the heart muscle thickens (hypertrophy), and the heart chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve is 
usually the standard treatment. 
As an alternative to open heart surgery, the Medtronic CoreValve™ System and Medtronic 
CoreValve™ Evolut™  R System have been developed to replace a diseased aortic heart valve 
without the need for open heart surgery. A description of the valves is included under the section 
Study Devices. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This website will 
not include information that can identify you. At most, the website will include a summary of the 
results. You can search this website at any time. 
You are being asked to participate in this study because doctors have determined your aortic valve 
is no longer working the way it should. However, your doctors have also decided that your risk of 
experiencing major problems while having open-heart surgery is moderate. This means that you 
doctor believes your health is good enough for open-heart surgery, but there is still a risk of 
potential problems. 
PURPOSE OF THE STUDY 
The purpose of this clinical study is to figure out if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions 
as you. 
The study valve is considered an “investigational device”, which means that Health Canada has 
not yet approved it to be used for standard of care purposes and is only allowed to be used for the 
study. Medtronic, Inc. is sponsoring this study to obtain data on the safety and performance of the 
investigational device. The Medtronic CoreValve™ System and Medtronic CoreValve™ Evolut™  
R System includes the valves described below and two parts that help load and deliver the valves 
correctly.  
This study will involve approximately 1600 subjects at up to 115 hospitals in the United States, 
Canada and around the world, and is anticipated to take approximately 8 years to complete. Your 
participation in this study is expected to last approximately five years from the day you are enrolled 
in the study.  Annual follow-up may be extended to up to 10 years after the implant procedure. 

 
 
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STUDY DEVICES 
Both study valves are made from animal tissue attached to a metal frame.  
The study valves are designed to be inserted using a long, thin flexible tube (delivery system) to 
replace your diseased aortic heart valve through an incision in the skin and threaded through the 
bloodstream (percutaneous) and without open-heart surgery.  A unique feature of the Evolut R 
device is that it can be re-captured, making it easier for doctors to place the device in a correct 
position. Once it is implanted, CoreValve™ study valves acts in the same method of the native 
valve. 
 
 
 
 
 
 
 
 
 
 
Figure 1: Medtronic CoreValve™ “Study Valve” 
 
 
 
 
 
 
 
 
 
 
Figure 2: Medtronic CoreValve™ Evolut™ R “Study Valve” 
 
Although the Medtronic CoreValve™ system and Medtronic CoreValve™ Evolut™ R system are not 
approved by the US Food & Drug Administration (FDA), or Health Canada, it has been approved 
in other parts of the world since 2006 and has been implanted in over 45,000 patients. 
The Medtronic CoreValve™ System is currently approved for use in Europe, South America, and 
parts of Asia. The Medtronic CoreValve™ Evolut™ R system is currently being studied in Europe 
and Australia. 
PROCEDURES TO BE FOLLOWED 
If you agree to be in this study, and after you have signed this informed consent form, information 
such as your age, gender, medical history and medication use will be recorded. You will have the 
following tests: 

 
 
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• Physical examination 
• Computed tomography (CT) - a scan performed using an x-ray machine that takes pictures 
of your body. Sometimes a CT will require the use of a type of dye that makes the kidneys 
work harder and may be harmful to the kidneys. You may have an MRI in place of a CT 
scan if your doctor believes your kidneys are not working well enough for you to have a CT 
scan. MRI stands for magnetic resonance imaging and is a test that also takes pictures of 
your internal organs. 
• Blood tests (about 2 tablespoons). These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they 
should as well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning 
as they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or 
other heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is 
working harder than normal to pump blood through your body 
• Echocardiography (transthoracic echocardiogram (TTE)) - a test that uses sound waves to 
take pictures of your heart and measure the degree of narrowing of your aortic valve; a 
probe with gel is placed on the outside of your chest to take pictures of your heart 
• Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
• Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
These procedures and tests are standard procedures required for the treatment of your disease 
and are not experimental. If you have already had any of these tests performed before, they may 
be used for the study if your study doctor determines they don’t need to be repeated for study 
purposes. The results from your exams and tests will be reviewed by your doctors who will 
determine if you are eligible to be in the study.   
The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you will 
not be allowed to participate in the study. 
If your doctors and the committee decide you are eligible to be in the study, your treatment will be 
determined in a way similar to flipping a coin, called randomization. You will be assigned to one of 
two groups. One group will receive a transcatheter aortic valve implant (TAVI); the other group will 
receive an open-heart surgical aortic valve replacement (SAVR). On average, one out of every two 
participants will receive TAVI. The other participants will receive SAVR. You will not be able to 
choose your treatment assignment. 
You will be considered enrolled in the study once you are assigned to a treatment group.  
If you are enrolled in the study, you will be required to have the following additional tests (for study 
purposes only) completed within 14 days prior to the procedure (TAVI or SAVR): 
• Physical exam, including determining your neurological (brain) status where you will be 
asked to answer a some questions and perform some tasks such as writing and drawing 
• Blood tests (about 2 tablespoons) These tests include the following: 

 
 
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o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they should 
as well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or 
other heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is 
working harder than normal to pump blood through your body 
• Walking test – a test that records your breathing, heart rate, and how you feel after 6 
minutes of walking 
• Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life Questionnaires (QOL).  Completing the questionnaires 
should take about 10-15 minutes each. 
Your personal physician will be informed about your participation in this clinical study. 
If you are assigned to the TAVI group: 
The study valve is an experimental valve which means you can only receive the valve if you are 
part of this study. Your study doctor will decide if you will either receive the Medtronic 
CoreValve™System or the Medtronic CoreValve™Evolut™ R System. 
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor.  You may be advised to continue these medications for at 
least three months after your procedure.  
Before the procedure you will be given an antibiotic (a medicine that kills bacteria or germs) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about 2 tablespoons) and an ECG before the procedure.   
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary during 
the procedure, you will be put under general anesthesia at that time. 
Your study doctor will decide what locations are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary. These pictures are described 
in the next paragraphs. 
During the procedure, one of the pictures that may be needed is a transesophageal 
echocardiogram which is also called a TEE. This test uses sound waves to take a closer look at 
the inside structures of the heart. If your doctor decides this picture is necessary, to perform the 
test you will swallow a thin flexible tube with a special tip. This tube sits in the esophagus (the tube 
that connects the mouth to the stomach). The special tip of the tube sends out sound waves 
(ultrasound) that echo within the chest wall. The esophagus is located behind the heart so these 
echoes are picked up and create a picture of the heart that is displayed on a video monitor. The 
pictures will allow your study doctor to take a closer look at your valve. 

 
 
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You will have a temporary pacemaker put in your heart during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins and threaded 
through your vein into the right side of your heart. The wire is attached to a battery operated 
device outside of your body. This temporary pacemaker will help keep your heart rate (speed) and 
rhythm steady. This temporary pacemaker will not be removed for at least 48 hours after your 
TAVI procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. Balloon valvuloplasty is a procedure used to widen a stiff or narrowed heart valve. A 
wire and a thin tube are guided by x-rays through the heart and positioned through the diseased 
heart valve. A balloon is placed over the wire and inflated, making the opening bigger through the 
diseased valve allowing the study valve to be placed. 
Your doctor will then implant (insert) the study valve through the long, thin flexible tube that is 
inserted through an incision in the skin and threaded through the bloodstream. TAVI is performed 
using x-ray machines which will allow your doctor to see the study valve, your blood vessels and 
heart. The study valve will be guided through your blood vessels and then it  will be placed over 
your existing aortic valve. 
During the TAVI procedure, your doctor will perform angiography (x-ray pictures) and ECGs 
(recordings of the electrical impulses of your heart through patches placed on the chest) to 
observe your heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study 
valve onto the tube that helps deliver the valve to the heart. 
If you are assigned to the SAVR group: 
Open heart surgery, surgical repair and/or replacement of your aortic valve, are not experimental 
procedure; meaning you could have this procedure if you did not take part in this study. 
If you are assigned to the SAVR group, your doctors will replace your diseased aortic valve 
through open heart surgery. During surgery, you are asleep under general anesthesia. SAVR often 
requires the bone in the center of the chest (sternum) to be split down the middle. The chest is 
then opened to provide your doctor with access to the heart and chest cavity, in order to replace 
your aortic valve. Your surgery is performed while the function of your heart is taken over by a 
heart lung machine (called CPB for cardiopulmonary bypass). 
You may have a TEE (a thin tube that sits in the esophagus and sends out sounds waves to 
create a picture of your heart) and a temporary pacemaker (thin wire threaded through your vein to 
right side of heart to keep your heart rate and rhythm steady) during the procedure. 
Your doctor may remove any tissue and calcium deposits (extra calcium that has collected on the 
valve) that are interfering with the normal function of the valve. Your damaged valve may be 
completely removed. The new valve will be sewn into the space where your own valve used to be. 
After your doctor makes sure your valve is working properly, blood flow will be returned to your 
heart and the incisions will be closed. You will also have blood drawn for testing before and after 
the procedure. 
If your doctor is unable to implant (insert) the a valve in you during the TAVI or SAVR procedure, 
you will still be considered enrolled in the study and will need to return to the clinic for the required 
follow-up visits as described in the “Follow-up Visits after TAVI and SAVR” section. 
After TAVI and SAVR Procedure: 
After the TAVI and SAVR procedure, your study doctors will continue to monitor your progress and 
recovery. 
You will have the following tests performed within the two days following the procedure and before 
you are discharged from the hospital: 
• Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 

 
 
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• Blood tests (about 2 tablespoons) These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they should as 
well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or other 
heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is working 
harder than normal to pump blood through your body 
•  Echocardiogram (TTE) 
•  ECG 
Follow-up Visits after TAVI and SAVR: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months (1 
year), 18 months, 24 months (2 years), and 3, 4, and 5 years after the procedure. Most of the 
follow-up tests and examinations are routine, not experimental. Each visit will take about 1 ½ to 2 
hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
 Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
 You will be asked about your health since the last follow-up visit 
 Quality of Life Questionnaires 
 ECG 
 Blood tests (about 2 tablespoons) – 30 day visit only 
o 
Hemoglobin – test how much of a protein that carries oxygen to your body's organs and 
tissues and transports carbon dioxide from your organs and tissues back to your lungs you 
have in your blood 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
 Walking test – 30 day visit only 
 Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12 months, 24 months, and 3, 4, 5 years will include: 
 Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
 You will be asked about your health since the last clinic visit 
 Blood tests (about 2 tablespoons) 
 Echocardiogram (TTE) 
 Quality of Life Questionnaires 
 ECG 
 Walking test – 12 and 24 months visits only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted by phone, by someone 
from your clinic, to complete a Quality of Life Questionnaire. 

 
 
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If, during the 5 years of follow-up you have additional heart surgeries or cath lab procedures to 
work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological (brain) 
status within 24 hours after each additional procedure. 
If you have a stroke, have been informed by a doctor that you experienced a stroke, or experience 
any of the following symptoms, notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as 
possible: sudden numbness, tingling, loss of movement (especially on 1 side of the body), vision 
changes, confusion or trouble understanding simple statements, severe headaches, or seizures.  
Any of these symptoms could indicate that you are having problems with your neurological (brain) 
function.  If a doctor confirms that you had a stroke, you will be asked to come to the clinical to 
have tests performed to determine your neurological (brain) status where you will be asked to 
answer a series of questions and perform a series of tasks. These tests will be performed at 7 
days, 30 days and 3 months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or 
are hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis.  Your study doctor will determine if you will need to have another valve 
implanted.   
In the event of your death, we would like to do an autopsy. We will ask that either your whole heart 
and valve or just the valve are removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the study valve. 
Your family and your "legally authorized representatives", has the right to refuse the autopsy and 
refuse the request to remove the heart and/or valve even if you sign this consent form.  You may 
still participate in this study if you do not want to have an autopsy done. 
POSSIBLE RISKS AND DISCOMFORTS 
TAVI 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest – heart stops beating and blood flow through the body is interrupted or 
stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to improve 
blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  
 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able to 
supply oxygen to the body 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 

 
 
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 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 
 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, 
blood clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the device 
from where it was originally placed 
 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 
 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure is 
expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs 
in the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 
 
Permanent disability – injury that does not allow that impairs normal/previous 
physical or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 
 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 

 
 
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 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result 
in a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed 
space that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the 
heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  
o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical 
impulses to the heart to help your heart beat normally 
o 
Atrio-ventricular node block – a block in the electrical path from the top part of 
the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom part 
of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part 
of the heart (ventricles) 
 
Encephalopathy – altered mental state 
 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 
 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 
 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 

 
 
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 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic 
valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known. 
 
SAVR 
Although SAVR is not experimental there are potential risks associated with this procedure and 
any surgery. These risks are the same even if you undergo the SAVR procedure and you decide 
not to participate in this study.  Your study doctor will explain these risks to you and you will be 
asked to sign a separate surgical informed consent.   
If you become pregnant there may be risks, discomforts, or side effects to you and the 
embryo/fetus that are not yet known.  Please notify your study doctor as soon as possible to 
discuss any of these potential risks. 
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how 
much radiation you will get,  in the following descriptions the radiation is compare  to the amounts 
that people are exposed to in daily life. There is radiation that naturally occurs from space and 
from rocks in the soil. This natural radiation is greater at higher altitudes. 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure is 
less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 
The estimated radiation exposure for the valve procedure is approximately 10-15 times the amount 
of radiation exposure received in one year from background radiation (naturally occurring radiation 
you are exposed to everyday). The exposure is approximately the amount an occupational worker 
is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have extra 
follow-up visits with your doctor to watch your recovery more closely. 
Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 
POSSIBLE BENEFITS 
The possible benefits you may receive from participating in this research are that you may be able 
to receive a new heart valve without having open-heart surgery.  
Your participation in this research may improve procedures that may guide the future treatment of 
heart surgery, by using procedures that are less invasive, meaning less cutting, entering or 
breaking through the body, which may benefit others in the future. However, there is no guarantee 
that you will benefit from being in this research. 
ALTERNATIVE TREATMENTS 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other treatment 
options include percutaneous (through an artery in the groin) aortic valve implantation, or medical 

 
 
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management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study 
doctor about other treatment options you may have. 
IF PROBLEMS DEVELOP 
If you believe that you have been injured as a result of your participation in the study, you should 
notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible or in serious cases, go to the 
emergency room.  
Immediate necessary medical care is available at [Name of institution(s)] in the event that you are 
injured as a result of your participation in this research study 
If you are assigned to the TAVI group  
For those patients receiving the investigational device and the TAVI procedure, 
Medtronic has agreed to pay back [name of institutions that are parties to the CTA] for the costs of 
reasonable medical or surgical care they provide for any serious and unanticipated illness or injury 
under the following conditions: 
 
The illness or injury must be directly related to a defect or malfunction of the investigational 
device or in the TAVI procedure as described in the Protocol, and not related to procedures 
that are routine standard of care. 
 
The illness or injury cannot be caused (a) by the negligence or intentional misconduct of the 
study staff or [name of institutions that are parties to the CTA]; (b) because the study staff or 
[name of institution(s)] that are parties to the CTA] did not follow the protocol for the study; 
or (c) by the natural progression of your illness. 
 
The illness or injury must have happened before the study closes (last patient is seen for the 
5 year follow-up visit) at this [Name of institution(s)]. 
 
[Name of institution(s) that are parties to the CTA] must notify Medtronic of the illness or 
injury within one year of the date the study closes at all study sites or before the study 
closes at this site, whichever is earlier. 
Subject to the above conditions, Medtronic will pay back the costs that are not covered by your 
applicable provincial health insurance or third party insurer. The amount Medtronic will pay back is 
the applicable provincial health insurance plan rate. 
 
If you are assigned to the SAVR group  
In the event of physical injury or physical illness related to a procedure required for the SAVR 
group, no monetary compensation or subsidy (payment) will be provided. Medical treatment will be 
routinely provided to you through your regular provincial health insurance plan. 
By agreeing to the above, you do not waive any of your legal rights which you otherwise would 
have as a research subject, nor do you release the study sponsor (Medtronic, Inc.), study doctors, 
or the hospital from liability for negligence. 
 
PAYMENT FOR PARTICIPATION IN THE STUDY 
You will not be paid to take part in the study. However, you may be reimbursed for local mileage 
and parking expenses directly related to any study-only related visits. Your study doctor or 
research coordinator will tell you how to get reimbursement.  
There is no monetary advantage to the study doctor for participation in this study. Your 
participation in this study may contribute to the development of commercial products from which 
Medtronic may receive economic benefit.  Medtronic is paying the study site for the work involved 
in collecting study data and managing the study at this site.  
MEDICAL EXPENSES 
All necessary medical procedures should be covered by Provincial Health Insurance Plan. 

 
 
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BASIS OF PARTICIPATION 
Your participation in this study is voluntary. If you refuse to be in this study there will be no penalty 
or loss of benefits to which you are otherwise entitled. You may withdraw from the study at any 
time and will not lose your benefits or be treated any differently as a result of withdrawing from the 
study. Any new findings (decisions or conclusions) that may influence your willingness to 
participate will be provided to you.  If you decide to leave the study before it is finished, please tell 
one of the persons listed in the section below “Obtaining Additional Information”. It may be 
requested that, if you withdraw, you return to your study doctor for a final visit. 
The study doctor may end your participation in the study at any time if: 
 He or she determines it is not in the best interest of your health 
 The study doctor loses contact with you and you do not return for your study visits as 
scheduled 
 You refuse to allow the use of private health information during the course of the study 
 
The study doctor will make the decision and let you know if it is not possible for you to continue in 
the study. 
You may be removed from the study without your consent if the sponsor (Medtronic, Inc.) ends the 
study.  If this happens, you will be notified and the reasons will be explained to you.  Your 
physician will continue to provide the appropriate medical care. 
What are my responsibilities as a research subject?  
As a subject in a research study, it is important that you: 
 Be truthful about your health and medication history; 
 Return to the office for the study visits that the physician has scheduled with you; 
 Call the study doctor’s office to reschedule a missed visit as soon as possible; 
 Report any injuries, hospitalizations, emergency room visits, symptoms or complaints to the 
study doctor or nurse as soon as possible. 
PERMISSION FOR ACCESS TO AND USE OF HEALTH INFORMATION 
While you take part in this research study, the researcher in charge and study staff will collect and 
take down information about you in a file. Only information necessary for the research study will be 
collected.  
The information in your file could include your past and present medical history, information about 
your way of life and test results from exams and procedures done during this study. Your file could 
also contain other information, such as your name, sex, date of birth and ethnic origin.  
All the information collected about you during the study will remain confidential as the law 
demands. To protect your privacy, your information will be identified with numbers and or letters. 
Only the researcher in charge of the study knows the numbers and or letters that link them to you.  
The study researcher will send the research study information collected about you to the sponsor 
or sponsor representatives. This information does not include your name or address.  
The sponsor will use the information collected about you only to reach the study goals as they are 
explained in this Informed Consent Form.  
The information collected about you can be shared by itself, or together with other information 
collected from other studies with government groups in Canada or in other countries, or with the 
people that do business with the study’s sponsor Medtronic. This means that your study 
information could be sent to other countries. The sponsor must respect applicable Canadian 
privacy laws and those in all the countries where your study information will be sent. Your study 
information will be kept for at least 25 years by the researcher in charge of the study and by the 
sponsor.  
The study information may help the government approve the sale of the study device. The study 
information may also be used for other reasons related to the study or to help develop future 
studies.  

 
 
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The study information could be printed in medical journals or shared with other people at scientific 
meetings, but, it will be impossible to identify you.  
To make sure the study is being done properly; your research study file as well as your medical file 
could be checked by a person authorized by the Research Ethics Board of the [Name of hospital 
or clinic(s)], or by the institution, by a person authorized by special people or groups (Health 
Canada) as well as by the sponsor’s representatives. These people and groups are obliged to 
respect your privacy.  
For your safety and to be able to reach you quickly, your family name, first name, how to contact 
you and the date you started and ended the study will be kept for one year after the study ends in 
a separate list kept by the researcher in charge of the study or by the institution.  
You have the right to look at your study file in order to check the information gathered about you 
and to correct it, if necessary, as long as the study researcher or the institution keeps this 
information. However, you may only have access to certain information once the study has ended 
so that the quality of the research study is protected. 
Economic Study 
This study contains a health economics review that will be done to compare the in-hospital, follow-
up medical care resource utilization and cost for patients in each of the treatment groups You may 
also be asked to sign a separate document that gives us your permission to review your billing 
information sent directly from your payer in order to evaluate medical cost data.  This information 
will be kept strictly confidential and be used solely to assess the medical expenses which occur as 
a direct result of participating in the Medtronic CoreValve™ SURTAVI Trial. 
Quality of Life Questionnaire 
Medtronic CoreValve™ SURTAVI Trial will also contain a quality of life study. As part of this study, 
your research coordinator will have you or your caregiver complete a questionnaire called a 
Quality of Life Questionnaire.  You will need to complete this questionnaire when you are enrolled 
in the study and 1 month, 3 months, 6 months, 12 months, 18 months, 2 years, 3 years, 4 years 
and 5 years after your study procedure. 
OBTAINING ADDITIONAL INFORMATION 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. The study doctor will inform you of any new significant information, when 
it becomes available, which may affect your willingness to continue to participate in this study. If 
you have any questions about this study or if you experience any health problems, you should 
contact Dr. Principal Investigator at xxx-xxx-xxxx. 
If you have questions about your rights as a participant in this study, you should contact the 
chairman of the Institutional Review Board at xxx-xxx-xxxx. 
 
MEDTRONIC’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
This section describes what Medtronic as study sponsor will do with the study data, including your 
health information received during the study. 
Medtronic will keep your health information confidential in keeping with all applicable laws and 
regulations. Medtronic may use your health information to conduct this study. Medtronic may use 
your health information for other purposes, such as: 
 
Watch over and improve the performance of its device; 
 
New medical research; 
 
Proposals for making new medical products or procedures; and 
 
Other business purposes. 
Any reports or publications about the study or any other research will not include your name or a 
description of you. Any records identifying you will not be made publically available.  Information 

 
 
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received during the study will not be used to market to you; your name will not be placed on any 
mailing lists or sold to anyone for marketing purposes. 
The United States Food and Drug Administration’s (FDA) and Health Canada’s regulations, as 
well as other applicable laws, control Medtronic’s work in developing and assuring the safety and 
quality performance of its medical devices. Medtronic may disclose your health information to the 
FDA, Health Canada, as well as to other U.S. and foreign government authorities responsible for 
assuring the safety of medical devices. Medtronic also may disclose your health information to 
research ethics boards and other persons who are required to watch over the safety and 
effectiveness of medical products and therapies and the conduct of research. In addition, 
Medtronic representatives or delegates of Medtronic may inspect/monitor your medical records 
during the course of the clinical study in order to ensure compliance with the study protocol and 
study procedures.  You agree to allow Medtronic to use study data in these ways. You also agree 
to allow Health Canada, the FDA and other governmental authorities to inspect your health 
information. 
You may change your mind and take back this permission to use your health information at any 
time. To take back this permission, you must write to [name and contact information]. If you take 
back this permission, you cannot continue in the study. Even if you take back this permission, 
Medtronic and Researchers may continue to use and share the health information already 
received as described in this Informed consent. 
 
PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION  
Please indicate below whether you would like us to notify your primary care physician or your 
specialist of your participation in this study.   
(Initial only one box). 
 
Yes, I want the study doctor to inform my primary care physician/specialist of my 
participation in this study 
 
No. I do not want the study doctor to inform my primary care physician/specialist of 
my participation in this study. 
 
I do not have a primary care physician/specialist. 
 
 
The study doctor is my primary care physician/specialist. 
 
 

 
 
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INFORMED CONSENT FOR THE MEDTRONIC 
SURTAVI TRIAL 
 
PATIENT INFORMED CONSENT FORM SIGNATURE SHEET  
I confirm that: 
 
I have read the informed consent form of this study and my physician has answered all my 
questions regarding the study.  
 
I had sufficient time to consider my participation into this study, I am aware that participation 
into this study is completely voluntary, and I agree to follow the instructions from the 
investigator. 
 
I realize that I may decide to refuse participation or stop participation at any time without 
penalty and without affecting the quality of my health care or the relationship with my 
physician.  
 
I understand and agree that personal information about me will be collected from my 
medical records, used and processed (manually and by computer) by the manufacturer of a 
medical device used in my treatment or any other designated party that is involved in the 
study (e.g. hospital, physician, regulatory authorities, ethics committees).  
 
I understand and agree that representatives from Medtronic, regulatory authorities and the 
Institutional Review Board will be granted direct access to my medical records.  
 
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigation. 
 
I understand that I am entitled to access the personal information collected about me and to 
have inaccuracies corrected. 
 
I fully understand there is limited experience with this device in humans and that its safety 
and effectiveness have not been established and there are risks of serious complications 
associated with this study. 
 
I also understand that the doctors might determine after I give consent that it is not possible 
to implant the study valve. 
 
Signature of the subject or subject’s legally authorized representative  
I hereby give my consent to participate in the “Medtronic CoreValve™SURTAVI Trial”. I have been 
given a copy of this consent form, and am also aware that the investigator will keep a copy in his 
or her files. 
 
 
 
 
 
 
 
 
 
Printed name of subject  
 
 
 
 
 
 
 
 
Signature of subject   
 
 
 
 
 
 
 
 
Date (must be written in by subject) 
 
 
 
 

 
 
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Signature of a witness in the event that the subject or subject’s legally authorized 
representative is unable to read or write 
 
 
 
 
 
 
 
 
Printed name of witness (if applicable) 
 
 
 
 
 
 
 
 
Signature of witness (if applicable) 
 
 
 
 
 
 
 
 
Date (must be written in by witness) 
 
 
Signature of the principal investigator or authorized designee for conducting the informed 
consent process 
 
 I certify that I have explained the nature of the device and the study to the above-named 
person. 
 I have also explained the contents of this informed consent form to the above-named 
person. I have asked whether or not there are any questions. I have answered any 
questions that were raised by this person. 
 
 
 
 
 
 
 
 
Printed name of principal investigator or authorized designee for conducting the informed 
consent process  
 
 
 
 
 
 
 
 
Signature of principal investigator or 
authorized designee  
 
 
 
 
 
 
 
Date (must be written in by principal 
investigator or authorized designee)  
 

 
 
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 R.1.4 
Canada – Roll-in Subjects 
INFORMED CONSENT FORM 
FOR ROLL-IN SUBJECTS 
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this research study and how you 
might take part in it. By signing this form, you will show that you understand and that you agree to 
take part in this research study. Your signature on this form is required before you can take part 
in this research study. 
BACKGROUND 
You have been invited to participate in this research project because you have aortic stenosis (a 
disease of one of your heart valves). Before deciding to participate in the study you should be 
familiar with its requirements, risks and benefits. This document provides information about the 
study. It may contain words you do not fully understand. Please read it carefully and ask the study 
staff any questions you may have. They will discuss the study with you in detail. If you decide to 
participate, you will be asked to sign this form and a copy will be given to you. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the left 
ventricle (main pumping chamber of the heart) into the aorta (main artery delivering blood to the 
body). If the valve becomes abnormally narrow through a process of thickening and stiffening 
(aortic stenosis) the heart must work harder to pump the same amount of blood with each beat. 
As the heart works harder, the heart muscle thickens (hypertrophy), and the heart chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve is 
usually the standard treatment. 
As an alternative to open heart surgery, the Medtronic CoreValve™ System and Medtronic 
CoreValve™ Evolut™  R System have been developed to replace a diseased aortic heart valve 
without the need for open heart surgery. A description of the study valve is included under the 
section Study Device. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This website will 
not include information that can identify you. At most, the website will include a summary of the 
results. You can search this website at any time. 
You are being asked to participate in this study because doctors have determined your aortic 
valve is no longer working the way it should. However, your doctors have also decided that your 
risk of experiencing major problems while having open-heart surgery is moderate. This means 
that you doctor believes your health is good enough for open-heart surgery, but there is still a risk 
of potential problems. 
PURPOSE OF THE STUDY 
The purpose of this clinical study is to figure out if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions 
as you. 
The study valve is considered an “investigational device”, which means that Health Canada has 
not yet approved it to be used for standard of care purposes and is only allowed to be used for 
the study. Medtronic, Inc. is sponsoring this study to obtain data on the safety and performance of 
the investigational device. The Medtronic CoreValve™ System and Medtronic CoreValve™ Evolut™ 
R System includes the valves described below and two parts that help load and deliver the valves 
correctly.  
This study will involve up to 2000 subjects at up to 115 hospitals in the United States, Canada 
and around the world, and is anticipated to take approximately 8 years to complete. Your 

 
 
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participation in this study is expected to last approximately five years from the day you are 
enrolled in the study.  Annual follow-up may be extended to up to 10 years after the implant 
procedure. 
STUDY DEVICES 
Both study valves are made from animal tissue attached to a metal frame.  
The study valves are designed to be inserted using a long, thin flexible tube (delivery system) to 
replace your diseased aortic heart valve through an incision in the skin and threaded through the 
bloodstream (percutaneous) and without open-heart surgery.  A unique feature of the Evolut R 
device is that it can be re-captured, making it easier for doctors to place the device in a correct 
position. Once it is implanted, CoreValve™ study valves acts in the same method of the native 
valve. 
 
 
 
 
 
 
 
 
 
Figure 1: Medtronic CoreValve™  “Study Valve” 
 
 
 
 
 
 
 
 
 
Figure 2: Medtronic CoreValve™ Evolut™ R “Study Valve” 
 
Although the Medtronic CoreValve™ system is not approved by the US Food & Drug 
Administration (FDA), or Health Canada, it has been approved in other parts of the world since 
2006 and has been implanted in over 45,000 patients. 
The Medtronic CoreValve™ System is currently approved for use in Europe, South America, and 
parts of Asia. The Medtronic CoreValve™ Evolut™ R system is currently being studied in Europe 
and Australia. 
PROCEDURES TO BE FOLLOWED 
If you agree to be in this study, and after you have signed this informed consent form, information 
such as your age, gender, medical history and medication use will be recorded. You will have the 
following tests: 

 
 
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• Physical examination 
• Computed tomography (CT) - a scan performed using an x-ray machine that takes pictures 
of your body. Sometimes a CT will require the use of a type of dye that makes the kidneys 
work harder and may be harmful to the kidneys. You may have an MRI in place of a CT 
scan if your doctor believes your kidneys are not working well enough for you to have a CT 
scan. MRI stands for magnetic resonance imaging and is a test that also takes pictures of 
your internal organs. 
• Blood tests (about 2 tablespoons). These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they 
should as well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning 
as they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or 
other heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is 
working harder than normal to pump blood through your body 
• Echocardiography (transthoracic echocardiogram (TTE)) - a test that uses sound waves to 
take pictures of your heart and measure the degree of narrowing of your aortic valve; a 
probe with gel is placed on the outside of your chest to take pictures of your heart 
• Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
• Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
These procedures and tests are standard procedures required for the treatment of your disease 
and are not experimental. If you have already had any of these tests performed before, they may 
be used for the study if your study doctor determines they don’t need to be repeated for study 
purposes.  
The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you 
will not be allowed to participate in the study. 
If your doctor and the committee decide you are eligible to be in the study, you will be one of the 
first three (3) patients at this hospital to be enrolled in this study. You will receive a transcatheter 
aortic valve implant (TAVI).  
Your enrollment in the study will begin once you sign this consent and you are assigned to the 
roll-in treatment group. If you are enrolled in the study, you will be required to have the following 
additional tests (for study purposes only) completed within 14 days prior to the procedure (TAVI): 
• Physical exam, including determining your neurological (brain) status where you will be 
asked to answer a some questions and perform some tasks such as writing and drawing 
• Blood tests (about 2 tablespoons) These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they should 
as well as make sure other minerals (enzymes) in your blood are normal 

 
 
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o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning 
as they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or 
other heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is 
working harder than normal to pump blood through your body 
• Walking test – a test that records your breathing, heart rate, and how you feel after 6 
minutes of walking 
• Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life Questionnaires (QOL).  Completing the 
questionnaires should take about 10-15 minutes each. 
Your personal physician will be informed about your participation in this clinical study. 
TAVI PROCEDURE: 
The study valve is an experimental valve which means you can only receive the valve if you are 
part of this study. Your study doctor will decide if you will either receive the Medtronic CoreValve™ 
System or the Medtronic CoreValve™ Evolut™ R System. 
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor.  You may be advised to continue these medications for at 
least three months after your procedure.  
Before the procedure you will be given an antibiotic (a medicine that kills bacteria or germs) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about 2 tablespoons) and an ECG before the procedure.   
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary 
during the procedure, you will be put under general anesthesia at that time. 
Your study doctor will decide what locations are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary.  
During the procedure you may have a transesophageal echocardiogram which is also called a 
TEE. This test uses sound waves to take a closer look at the inside structures of the heart. To 
perform the test you will swallow a thin flexible tube with a special tip. This tube sits in the 
esophagus (the tube that connects the mouth to the stomach). The special tip of the tube sends 
out sound waves (ultrasound) that echo within the chest wall. The esophagus is located behind 
the heart so these echoes are picked up and create a picture of the heart that is displayed on a 
video monitor. The pictures will allow your study doctor to take a closer look at your valve. 
You will have a temporary pacemaker put in your heart during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins and threaded 
through your vein into the right side of your heart. The wire is attached to a battery operated 
device outside of your body. This temporary pacemaker will help keep your heart rate (speed) 
and rhythm steady. This temporary pacemaker will not be removed for at least 48 hours after your 
TAVI procedure. 

 
 
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After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. Balloon valvuloplasty is a procedure used to widen a stiff or narrowed heart valve. A 
wire and a thin tube are guided by x-rays through the heart and positioned through the diseased 
heart valve. A balloon is placed over the wire and inflated, making the opening bigger through the 
diseased valve allowing the study valve to be placed. 
Your doctor will then implant (insert) the study valve through the long, thin flexible tube that is 
inserted through an incision in the skin and threaded through the bloodstream. TAVI is performed 
using x-ray machines which will allow your doctor to see the study valve, your blood vessels and 
heart. The study valve will be guided through your blood vessels and then it  will be placed over 
your existing aortic valve. 
During the TAVI procedure, your doctor will perform angiography (x-ray pictures) and ECGs 
(recordings of the electrical impulses of your heart through patches placed on the chest) to 
observe your heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study 
valve. 
AFTER TAVI PROCEDURE: 
After the TAVI procedure, your study doctors will continue to monitor your progress and recovery. 
You will have the following tests performed within the two days following the procedure and 
before you are discharged from the hospital: 
• Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
• Blood tests (about 2 tablespoons) These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they should 
as well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or other 
heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is working 
harder than normal to pump blood through your body 
•  Echocardiogram (TTE) 
•  ECG 
FOLLOW-UP VISITS AFTER TAVI: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months 
(1 year), 18 months, 24 months (2 years), and 3, 4, and 5 years after the procedure. Most of the 
follow-up tests and examinations are routine, not experimental. Each visit will take about 1 ½ to 2 
hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
 Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
 You will be asked about your health since the last follow-up visit 
 Quality of Life Questionnaires 

 
 
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 ECG 
 Blood tests (about 2 tablespoons) – 30 day visit only 
o 
Hemoglobin – test how much of a protein that carries oxygen to your body's organs and 
tissues and transports carbon dioxide from your organs and tissues back to your lungs 
you have in your blood 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
 Walking test – 30 day visit only 
 Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12 months, 24 months, and 3, 4, 5 years will include: 
 Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
 You will be asked about your health since the last clinic visit 
 Blood tests (about 2 tablespoons) 
 Echocardiogram (TTE) 
 Quality of Life Questionnaires 
 ECG 
 Walking test – 12 and 24 months visits only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted by phone, by 
someone from your clinic, to complete a Quality of Life Questionnaire. 
If, during the 5 years of follow-up,  you have had additional heart surgeries or cath lab procedures 
to work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological 
(brain) status within 24 hours after each additional procedure. 
If you have a stroke, have been informed by a doctor that you experienced a stroke, or 
experience any of the following symptoms, notify Dr. Principal Investigator at xxx-xxx-xxxx as 
soon as possible: sudden numbness, tingling, loss of movement (especially on 1 side of the 
body), vision changes, confusion or trouble understanding simple statements, severe headaches, 
or seizures.  Any of these symptoms could indicate that you are having problems with your 
neurological (brain) function.  If a doctor confirms that you had a stroke, you will be asked to 
come to the clinical to have tests performed to determine your neurological (brain) status where 
you will be asked to answer a series of questions and perform a series of tasks. These tests will 
be performed at 7 days, 30 days and 3 months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or 
are hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis.  Your study doctor will determine if you will need to have another valve 
implanted.   
In the event of your death, we would like to do an autopsy. We will ask that either your whole 
heart and valve or just the valve are removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the study valve. 
Your family and your "legally authorized representatives", has the right to refuse the autopsy and 
refuse the request to remove the heart and/or valve even if you sign this consent form.  You may 
still participate in this study if you do not want to have an autopsy done. 
POSSIBLE RISKS AND DISCOMFORTS 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 

 
 
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 
Death 
 
Cardiac arrest – heart stops beating and blood flow through the body is interrupted 
or stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to 
improve blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  
 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able 
to supply oxygen to the body 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 
 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, 
blood clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the 
device from where it was originally placed 
 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 

 
 
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 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure 
is expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs 
in the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 
 
Permanent disability – injury that does not allow that impairs normal/previous 
physical or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 
 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 
 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result 
in a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed 
space that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the 
heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  
o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical 
impulses to the heart to help your heart beat normally 
o 
Atrio-ventricular node block – a block in the electrical path from the top part 
of the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom 
part of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part 
of the heart (ventricles) 
 
Encephalopathy – altered mental state 

 
 
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 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 
 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 
 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic 
valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known. If you 
become pregnant there maybe risks, discomforts, or side effects to you and the embryo/fetus that 
are not yet known.  Please notify your study doctor as soon as possible to discuss any of these 
potential risks. 
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how 
much radiation you will get, in the following descriptions the radiation is compared to the amounts 
that people are exposed to in daily life. There is radiation that naturally occurs from space and 
from rocks in the soil. This natural radiation is greater at higher altitudes. 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure 
is less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 
The estimated radiation exposure for the valve procedure is approximately 10-15 times the 
amount of radiation exposure received in one year from background radiation (naturally occurring 
radiation you are exposed to everyday). The exposure is approximately the amount an 
occupational worker is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have extra 
follow-up visits with your doctor to watch your recovery more closely. 

 
 
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Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 
POSSIBLE BENEFITS 
The possible benefits you may receive from participating in this research are that you may be 
able to receive a new heart valve without having open-heart surgery.  
Your participation in this research may improve procedures that may guide the future treatment of 
heart surgery, by using procedures that are less invasive, meaning less cutting, entering or 
breaking through the body, which may benefit others in the future. However, there is no 
guarantee that you will benefit from being in this research. 
ALTERNATIVE TREATMENTS 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other treatment 
options include percutaneous (through an artery in the groin) aortic valve implantation, or medical 
management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study 
doctor about other treatment options you may have. 
IF PROBLEMS DEVELOP 
If you believe that you have been injured as a result of your participation in the study, you should 
notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible or in serious cases, go to the 
emergency room.  
Immediate necessary medical care is available at [Name of institution(s)] in the event that you are 
injured as a result of your participation in this research study. 
Medtronic has agreed to pay back [name of institutions that are parties to the CTA] for the costs 
of reasonable medical or surgical care they provide for any serious and unanticipated illness or 
injury under the following conditions: 
 
The illness or injury must be directly related to a defect or malfunction of the investigational 
device or in the TAVI procedure as described in the Protocol, and not related to procedures 
that are routine standard of care. 
 
The illness or injury cannot be caused (a) by the negligence or intentional misconduct of 
the study staff or [name of institutions that are parties to the CTA]; (b) because the study 
staff or [name of institution(s)] that are parties to the CTA] did not follow the protocol for the 
study; or (c) by the natural progression of your illness. 
 
The illness or injury must have happened before the study closes (last patient is seen for 
the 5 year follow-up visit) at this [Name of institution(s)]. 
 
[Name of institution(s) that are parties to the CTA] must notify Medtronic of the illness or 
injury within one year of the date the study closes at all study sites or before the study 
closes at this site, whichever is earlier. 
Subject to the above conditions, Medtronic will pay back the costs that are not covered by your 
applicable provincial health insurance or third party insurer. The amount Medtronic will pay back 
is the applicable provincial health insurance plan rate. 
PAYMENT FOR PARTICIPATION IN THE STUDY 
You will not be paid to take part in the study. However, you may be reimbursed for local mileage 
and parking expenses directly related to any study-only related visits. Your study doctor or 
research coordinator will tell you how to get reimbursement.  
There is no monetary advantage to the study doctor for participation in this study. Your 
participation in this study may contribute to the development of commercial products from which 
Medtronic may receive economic benefit.  Medtronic is paying the study site for the work involved 
in collecting study data and managing the study at this site.  
MEDICAL EXPENSES 

 
 
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All necessary medical procedures should be covered by Provincial Health Insurance Plan. 
BASIS OF PARTICIPATION 
Your participation in this study is voluntary. If you refuse to be in this study there will be no 
penalty or loss of benefits to which you are otherwise entitled. You may withdraw from the study 
at any time and will not lose your benefits or be treated any differently as a result of withdrawing 
from the study. Any new findings (decisions or conclusions) that may influence your willingness to 
participate will be provided to you.  If you decide to leave the study before it is finished, please tell 
one of the persons listed in the section below “Obtaining Additional Information”. It may be 
requested that, if you withdraw, you return to your study doctor for a final visit. 
The study doctor may end your participation in the study at any time if: 
 He or she determines it is not in the best interest of your health 
 The study doctor loses contact with you and you do not return for your study visits as 
scheduled 
 You refuse to allow the use of private health information during the course of the study 
 
The study doctor will make the decision and let you know if it is not possible for you to continue in 
the study. 
You may be removed from the study without your consent if the sponsor (Medtronic, Inc.) ends 
the study.  If this happens, you will be notified and the reasons will be explained to you.  Your 
physician will continue to provide the appropriate medical care. 
What are my responsibilities as a research subject?  
As a subject in a research study, it is important that you: 
 Be truthful about your health and medication history; 
 Return to the office for the study visits that the physician has scheduled with you; 
 Call the study doctor’s office to reschedule a missed visit as soon as possible; 
 Report any injuries, hospitalizations, emergency room visits, symptoms or complaints to the 
study doctor or nurse as soon as possible. 
 
 
PERMISSION FOR ACCESS TO AND USE OF HEALTH INFORMATION 
While you take part in this research study, the researcher in charge and study staff will collect and 
take down information about you in a file. Only information necessary for the research study will 
be collected.  
The information in your file could include your past and present medical history, information about 
your way of life and test results from exams and procedures done during this study. Your file 
could also contain other information, such as your name, sex, date of birth and ethnic origin.  
All the information collected about you during the study will remain confidential as the law 
demands. To protect your privacy, your information will be identified with numbers and or letters. 
Only the researcher in charge of the study knows the numbers and or letters that link them to you.  
The study researcher will send the research study information collected about you to the sponsor 
or sponsor representatives. This information does not include your name or address.  
The sponsor will use the information collected about you only to reach the study goals as they are 
explained in this Informed and Consent Form.  
The information collected about you can be shared by itself, or together with other information 
collected from other studies with government groups in Canada or in other countries, or with the 
people that do business with the study’s sponsor Medtronic. This means that your study 
information could be sent to other countries. The sponsor must respect applicable Canadian 
privacy laws and those in all the countries where your study information will be sent. Your study 
information will be kept for at least 25 years by the researcher in charge of the study and by the 
sponsor.  

 
 
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The study information may help the government approve the sale of the study device. The study 
information may also be used for other reasons related to the study or to help develop future 
studies.  
The study information could be printed in medical journals or shared with other people at scientific 
meetings, but, it will be impossible to identify you.  
To make sure the study is being done properly; your research study file as well as your medical 
file could be checked by a person authorized by the Research Ethics Board of the [Name of 
hospital or clinic(s)], or by the institution, by a person authorized by special people or groups 
(Health Canada) as well as by the sponsor’s representatives. These people and groups are 
obliged to respect your privacy.  
For your safety and to be able to reach you quickly, your family name, first name, how to contact 
you and the date you started and ended the study will be kept for one year after the study ends in 
a separate list kept by the researcher in charge of the study or by the institution.  
You have the right to look at your study file in order to check the information gathered about you 
and to correct it, if necessary, as long as the study researcher or the institution keeps this 
information. However, you may only have access to certain information once the study has ended 
so that the quality of the research study is protected. 
Economic Study 
This study contains a health economics review that will be done to compare the in-hospital, 
follow-up medical care resource utilization and cost for patients in each of the treatment groups 
You may also be asked to sign a separate document that gives us your permission to review your 
billing information sent directly from your payer in order to evaluate medical cost data.  This 
information will be kept strictly confidential and be used solely to assess the medical expenses 
which occur as a direct result of participating in the Medtronic CoreValve™ SURTAVI Trial. 
Quality of Life Questionnaire 
Medtronic CoreValve™ SURTAVI Trial will also contain a quality of life study. As part of this study, 
your research coordinator will have you or your caregiver complete a questionnaire called a 
Quality of Life Questionnaire.  You will need to complete this questionnaire when you are enrolled 
in the study and 1 month, 3 months, 6 months, 12 months, 18 months, 2 years, 3 years, 4 years 
and 5 years after your study procedure. 
OBTAINING ADDITIONAL INFORMATION 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. The study doctor will inform you of any new significant information, 
when it becomes available, which may affect your willingness to continue to participate in this 
study. If you have any questions about this study or if you experience any health problems, you 
should contact Dr. Principal Investigator at xxx-xxx-xxxx. 
If you have questions about your rights as a participant in this study, you should contact the 
chairman of the Institutional Review Board at xxx-xxx-xxxx. 
MEDTRONIC’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
This section describes what Medtronic as study sponsor will do with the study data, including your 
health information received during the study. 
Medtronic will keep your health information confidential in keeping with all applicable laws and 
regulations. Medtronic may use your health information to conduct this study. Medtronic may use 
your health information for other purposes, such as: 
 
Watch over and improve the performance of its device; 
 
New medical research; 
 
Proposals for making new medical products or procedures; and 
 
Other business purposes. 

 
 
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Any reports or publications about the study or any other research will not include your name or a 
description of you. Any records identifying you will not be made publically available.  Information 
received during the study will not be used to market to you; your name will not be placed on any 
mailing lists or sold to anyone for marketing purposes. 
The United States Food and Drug Administration’s (FDA) and Health Canada’s regulations, as 
well as other applicable laws, control Medtronic’s work in developing and assuring the safety and 
quality performance of its medical devices. Medtronic may disclose your health information to the 
FDA, Health Canada, as well as to other U.S. and foreign government authorities responsible for 
assuring the safety of medical devices. Medtronic also may disclose your health information to 
research ethics boards and other persons who are required to watch over the safety and 
effectiveness of medical products and therapies and the conduct of research. In addition, 
Medtronic representatives or delegates of Medtronic may inspect/monitor your medical records 
during the course of the clinical study in order to ensure compliance with the study protocol and 
study procedures.  You agree to allow Medtronic to use study data in these ways. You also agree 
to allow Health Canada, the FDA and other governmental authorities to inspect your health 
information. 
You may change your mind and take back this permission to use your health information at any 
time. To take back this permission, you must write to [name and contact information]. If you take 
back this permission, you cannot continue in the study. Even if you take back this permission, 
Medtronic and Researchers may continue to use and share the health information already 
received as described in this Informed consent. 

 
 
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PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION  
Please indicate below whether you would like us to notify your primary care physician or your 
specialist of your participation in this study.   
(Initial only one box). 
 
Yes, I want the study doctor to inform my primary care physician/specialist of my 
participation in this study 
 
No. I do not want the study doctor to inform my primary care physician/specialist of 
my participation in this study. 
 
I do not have a primary care physician/specialist. 
 
 
The study doctor is my primary care physician/specialist. 
 
 

 
 
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INFORMED CONSENT FOR THE MEDTRONIC 
SURTAVI TRIAL 
 
PATIENT INFORMED CONSENT FORM SIGNATURE SHEET  
I confirm that: 
 
I have read the informed consent form of this study and my physician has answered all my 
questions regarding the study.  
 
I had sufficient time to consider my participation into this study, I am aware that 
participation into this study is completely voluntary, and I agree to follow the instructions 
from the investigator. 
 
I realize that I may decide to refuse participation or stop participation at any time without 
penalty and without affecting the quality of my health care or the relationship with my 
physician.  
 
I understand and agree that personal information about me will be collected from my 
medical records, used and processed (manually and by computer) by the manufacturer of a 
medical device used in my treatment or any other designated party that is involved in the 
study (e.g. hospital, physician, regulatory authorities, ethics committees).  
 
I understand and agree that representatives from Medtronic, regulatory authorities and the 
Institutional Review Board will be granted direct access to my medical records.  
 
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigation. 
 
I understand that I am entitled to access the personal information collected about me and to 
have inaccuracies corrected. 
 
I fully understand there is limited experience with this device in humans and that its safety 
and effectiveness have not been established and there are risks of serious complications 
associated with this study. 
 
I also understand that the doctors might determine after I give consent that it is not possible 
to implant the study valve. 
 
Signature of the subject or subject’s legally authorized representative  
I hereby give my consent to participate in the “Medtronic CoreValve™SURTAVI Trial”. I have 
been given a copy of this consent form, and am also aware that the investigator will keep a copy 
in his or her files. 
 
 
 
 
 
 
 
 
 
Printed name of subject  
 
 
 
 
 
 
 
 
Signature of subject   
 
 
 
 
 
 
 
 
Date (must be written in by subject) 
 
 
 
 

 
 
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Signature of a witness in the event that the subject or subject’s legally authorized 
representative is unable to read or write 
 
 
 
 
 
 
 
 
Printed name of witness (if applicable) 
 
 
 
 
 
 
 
 
Signature of witness (if applicable) 
 
 
 
 
 
 
 
 
Date (must be written in by witness) 
 
 
Signature of the principal investigator or authorized designee for conducting the informed 
consent process 
 
 I certify that I have explained the nature of the device and the study to the above-named 
person. 
 I have also explained the contents of this informed consent form to the above-named 
person. I have asked whether or not there are any questions. I have answered any 
questions that were raised by this person. 
 
 
 
 
 
 
 
 
Printed name of principal investigator or authorized designee for conducting the informed 
consent process  
 
 
 
 
 
 
 
 
Signature of principal investigator or 
authorized designee  
 
 
 
 
 
 
 
Date (must be written in by principal 
investigator or authorized designee)  
 
 

 
 
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R.2 
List of Participating Investigational Centers 
The list of participating Investigational Centers will be provided under separate cover. 
 
 

 
 
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R.3 
Other Institutions 
The following institutions/organizations will participate in the Medtronic CoreValve SURTAVI Trial. 
An updated list of “Other Institutions” will be provided in progress reports and/or upon request. 
Clinical Events Committee (CEC) / Data Safety Monitoring Committee (DSMB): 
Cardialysis 
Westblaak 92 
3012 KM Rotterdam 
The Netherlands 
Explanted Device/Pathology Core Lab: 
CVPath Institute, Inc. 
 19 Firstfield Road 
 Gaithersburg, MD 20878 
Imaging Core Lab: 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
InteleGRIDTM (imaging sharing network):  
Intelemage, LLC 
5400 Kennedy Ave 
Cincinnati, OH 45213  
Interactive Voice/Web Response System (IXRS):  
United BioSource Corporation (UBC) 
303 2nd Street, Suite 700 
7th Floor South Tower 
San Francisco, CA 94107 
 

 
 
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R.4 
Additional Records and Reports 
No additional records and/or reports, other than those previously described in this investigational 
plan or required by FDA, will be maintained for this clinical investigation. 
 
 

 
 
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R.5 
Sample Case Report Forms 
Sample Case Report Forms (CRFs) will be provided under separate cover. 
 
 
 

 
 
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R.6 
Aortogram Acquisition Guidelines 
The purpose of the acquisition guidelines is to increase consistency and effectiveness in reviewing 
the procedural aortograms. 
1. Required aortogram:  
 
Index Procedure –TAVI 
2. Required cine runs: 
 
Pre-procedure aortogram in a projection with 3 aortic cusps aligned (for comparison of 
final aortogram with pre-procedure aortogram) 
 
Final aortogram at least 10 minutes after TAVI implantation in the exact same projection 
as the pre-procedure aortogram (in order to measure depth of implantation and assess 
grade of aortic regurgitation) 
NOTE:  If the apex is not clearly visible in the final projection and in case of adequate renal function, 
in order to assess grade of AR, perform an additional final aortogram in RAO 30° with 
visualization of the left ventricle in long axis, including the apex. 
3. Guidelines on how final aortogram after deployment of the valve should be performed: 
 
Use at least 20 ml of contrast, with an injection rate of 20 ml/sec 
 
Position the pigtail catheter in the upper third part of the frame 
 
Preferably use non-diluted contrast. 50%-diluted contrast is acceptable in case of renal 
insufficiency 
 
Use the angiographic projection with the three aortic cusps aligned in 1 plane: 
o 
Whenever available this optimal projection can be suggested by baseline MSCT 
exam 
o 
Pragmatic approach might be to use a shallow LAO or RAO projection, and adjust 
in a cranial or caudal position respectively to approach the optimal projection 
 
Confirm visualization of the left ventricular apex on the final aortogram 
 
Perform the final aortogram at least 10 minutes after deployment of the investigational 
TAVI device; include a time indication on the aortogram 
 
Use marker pigtail or provide the French-size of the pigtail catheter for calibration 
purpose 
4. General imaging and recording procedures: 
 
Use a fixed table system and biplane x-ray equipment, if available 
 
Recommended resolution: 1024 x 1024 pixels 
 
Preferred acquisition speed: 25 frames/second 
 
One single cine run should have a duration of at least 5 heart beats 
 
The digital clock should be activated 
 
The maximum magnification factor should be applied during cine run without losing the 
image of the entire frame 
 
There should be no overlap of the frame with other catheters or electrodes 
 
Foreshortening of the frame should be avoided as much as possible 
 
Upload all images to InteleGRID (secure electronic system used for transferring images) 
 
 

 
 
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5. Core lab analysis: 
The procedural aortograms may be analyzed by a core laboratory.  Analysis would include: 
 
Grade of aortic regurgitation 
 
Depth of implantation 
 
 
 
 
Figure 1: Example of depth of implantation measurement. 
 
 

 
 
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R.7 
Echocardiography Acquisition Guidelines 
1. Scope of the document 
These guidelines aim to increase consistency and effectiveness in collection and adjudication of 
echocardiography data of selected candidates for the SURTAVI trial. Optimal image acquisition, 
storage, and transmission will be described. 
2. Protocol required echocardiograms 
Transthoracic echocardiography is required at the following intervals: 
Screening 
- 45 days of Heart Team review 
Post-Procedure  
OR 
Discharge 
Between 24hrs post-procedure and hospital discharge (but no later than 7 
days from post Index Procedure) 
6 months 
± 30 days 
12 months 
± 30 days 
24 months 
± 60 days 
3,4,5 years 
± 60 days 
3. Four general rules for echocardiography recordings 
3.1 Rule #1 for overall recordings: adhere STRICTLY to the PROTOCOL regarding: 
 
number and order of recordings  as listed on the Table 
 
do not perform measurements on the echo recordings, except screening echo to be 
submitted for screening committee review (see measurements noted in section 4) 
 
at end of echo exam, export all required recordings in DICOM format and upload it to 
InteleGRID 
 
only one certified echocardiographer (+ 1 replacement) is allowed to participate in the 
study, he/she should print his/her name, fill in contact details and sign the transmittal form 
3.2 Rule #2 for Doppler recordings: 
 
Unless stated otherwise, all pulsed-wave and continuous-wave Doppler signals should be 
recorded at a sweep speed of 50-100 mm/sec (recording must contains minimum of three 
heartbeats) with optimized gain and filter setting, baseline position, and velocity range. 
3.3 Rule #3 for apical 2D views (4-, 5-, 2-, and 3-Chamber views)  
 
pay attention to ultrasound sector depth and gain settings 
 
the aortic valve should be out of scan plane in the 4-CH view  
 
please avoid patient or transducer motion and record during quite respiration unless 
stated otherwise 
 
make sure the entire LV myocardium (including epicardium and apex) is recorded in the 
scan sector in particular at end-diastole 
 
make sure Frame Rate is more than 30Hz for 2D grey-scale and around 20Hz for colour 
Doppler aortic regurgitation 
3.4 Rule #4 for EF calculation (apical 4- , 2-, and 3-Chamber views focused on LV) 
 
Record 3 runs (run 1: 3 beats, run 2: 3 beats, run 3: 10 beats) 
 
 
4. Data requirements 
Participating centers in the SURTAVI study should obtain the appropriate Doppler and 
echocardiography recordings to document the following variables. 

 
 
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 Aortic annulus long-axis diameter in mid-systole (screening/baseline only)* 
 LVOT long axis diameter in mid-systole 
 Sinus of Valsalva diameter (SOV) at end diastole (screening/baseline only)* 
 Sino-tubular junction diameter (STJ) at end diastole (screening/baseline only)* 
 Sinus of Valsalva height (SOVH) at end-diastole (screening/baseline only)* 
 Max aortic valve velocity (V2) by CW Doppler 
 Velocity time integral (VTI) across aortic valve by CW Doppler 
 Mean gradient across aortic valve (MGV2) by CW Doppler* 
 Peak LVOT velocity (V1) by PW Doppler 
 Velocity Ratio (V1 / V2) 
 Velocity time integral (VTI) of LVOT velocity by PW Doppler 
 Mean LVOT gradient (MGV1) by PW Doppler 
 Doppler Velocity Index (DVI) = VTILVOT / VTIAo 
 Grade of aortic transvalvular regurgitation 
 Grade of aortic paravalvular regurgitation 
 Grade of mitral regurgitation 
 PISA for MR (optional) 
 Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
 Left ventricular (LV) end-diastolic diameter (LVEDD) 
 Left ventricular (LV) end-systolic diameter (LVESD) 
 Interventricular septal thickness at end diastole 
 Left ventricular posterior wall thickness at end diastole 
 Left atrial diameter (AP linear dimension) at end systole 
 Left ventricular ejection fraction by visual estimate 
 Heart rate from Doppler signal 
 Mitral inflow “A” velocity 
 Mitral inflow “E” velocity 
 Mitral inflow E-wave deceleration time 
 Mitral annular tissue Doppler systolic velocity (septal and lateral) 
 Mitral annular tissue Doppler early diastolic velocity (septal and lateral) 
 Mitral annular tissue Doppler late diastolic velocity (septal and lateral) 
Procedures for acquiring aortic root measurements and key hemodynamic variables are described 
in the following sections. For Doppler velocities, the values reported should represent the average 
of measurements from at least three cardiac cycles for patients in sinus rhythm, and the average of 
measurements from five cardiac cycles for patients not in sinus rhythm. For aortic valve, TR jet, and 
tissue Doppler velocities, the reported values should represent the average of the highest velocities 
obtained from the same transducer position. 
* Screening/baseline measurements should be noted on the echo submitted for Screening 
Committee review. 
 

 
 
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5. 
Table 1. list of echo recordings (views) 
 Please include all LV walls including epicardium are within the scan sector 
 Please enter patient’s height, weight, and blood pressure during echo acquisition 
 Please optimize frame rate of 2D colour Doppler around 20 Hz if possible 
 Shift the colour flow zero baseline downwards or upwards in the regurgitant jet direction in the left PLAX view depending  
     on the jet orientation and upwards in the apical view 
 Record frozen images & cine loops in the following order: 
 
A: From parasternal long-axis window 
1. 2D greyscale standard view  
2. 2D Colour Doppler of mitral regurgitation (MR) 
3. 2D Colour Doppler of aortic (or prosthetic) regurgitation (AR) 
4. If AR is present, ZOOM & narrow sector with focus on vena contracta of regurgitant jet  
5. If AR is present, ZOOM & narrow sector, shift Nyquist 35-40 for PISA measurements  
6. 2D greyscale ZOOM for LV outflow tract diameter (LVOT) (3 recordings) 
7. 2D greyscale ZOOM at an intercostal space higher for aortic root / aortic prosthesis  
 
B: From parasternal short-axis window (use same depth setting) 
8. 2D greyscale LV at mitral valve level 
9. 2D greyscale LV at papillary muscle level  
10. 2D greyscale-guided M-mode at LV minor axis (LV dimensions, avoid papillary muscles) 
11. 2D greyscale LV at apical level: lower your transducer position by 1 or 2 intercostal spaces and record the LV as 
circular as possible, just proximal to the level with end-systolic LV luminal obliteration   
12. 2D greyscale aortic valve level (post TAVI the native annulus is usually identified by maximal calcification) 
13. 2D greyscale-guided M-mode of left atrial & aortic dimensions  
14. 2D Colour Doppler of AR: in post-TAVI start scanning from highest position and record first visible AR jet, scan more 
downwards and try to pick up additional jets – confirm origin of AR jets from PLAX 
15. 2D greyscale ZOOM & focussed on RV outflow tract (RVOT) – pulmonic valve should be visible 
16. 2D Colour Doppler of pulmonary regurgitation (PR) 
17. If PR is present, CWD of PR jet (include both systolic & diastolic signals)  
18. PWD of RVOT velocity (within 0.5 -1cm below the pulmonic valve) (frozen image) 
 
C: From special parasternal long-axis window (RV inflow) 
19. 2D Colour Doppler of tricuspid regurgitation (TR) 
20. If TR is present, CWD of TR jet (frozen image) 
 
D: From the apical 4-Chamber window 
21. 2D greyscale standard view  
22. 2D Colour Doppler of MR  
23. If MR is present, ZOOM & narrow sector, shift Nyquist 35-40 for PISA measurements  
24. If MR is present, CWD of MR jet (frozen image) 
25. 2D Colour Doppler of TR  
26. If TR is present, CWD of TR jet (frozen image) 

 
 
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27. PWD of transmitral flow at mitral valve tips – at a sweep speed of 50-100 mm/s (frozen image)  
28. Tissue Doppler of the septal mitral annulus – (frozen image) 
29. Tissue Doppler of the lateral mitral annulus – (frozen image)  
30. Tissue Doppler of RV free wall (frozen image) 
31. M-mode tricuspid annular plane systolic excursion (TAPSE) – (frozen image) 
32. 2D greyscale focussed on LV with decreased depth – three recordings: 3 beats, 3 beats, 10 beats) 
 
E: Apical 5-chamber window 
33. 2D greyscale standard view   
34. 2D Colour Doppler of AR 
35. If AR is present, ZOOM & narrow sector, shift Nyquist 35-40 for PISA measurements  
36. If AR is present, CWD of AR jet (frozen image) 
37. CWD of aortic forward flow (frozen image) 
38. PWD LVOT in native aortic valve: within 0.5 - 1cm below native aortic valve  
39. PWD LVOT in Core Valve, two recordings: immediately below and inside the inflow region of the stent 
 
F: Apical 2-Chamber window 
40. 2D greyscale standard view   
41. 2D greyscale focussed on LV with decreased depth – three recordings: 3 beats, 3 beats, 10 beats) 
 
G: Apical 3-chamber window 
42. 2D greyscale standard view   
43. 2D Colour Doppler of MR 
44. If MR is present, use ZOOM & narrow sector – shift Nyquist 35-40 for PISA measurements  
45. If MR is present, CWD of MR jet (frozen image)  
46. 2D Colour Doppler of AR     
47. If AR is present, CWD of AR jet (frozen image)  
48. If AR is present, use ZOOM & narrow sector– shift Nyquist 35-40 for PISA measurements  
49. CWD of aortic forward flow (frozen image) 
50. PWD LVOT in native aortic valve: within 0.5 - 1cm below native aortic valve  
51. PWD LVOT in Core Valve, two recordings: immediately below and inside the inflow region of the stent 
52. 2D greyscale focussed on LV with decreased depth – three recordings: 3 beats, 3 beats, 10 beats)  
 
H: special recordings 
53. Suprasternal PWD of descending aorta diastolic flow (frozen image) 
54. Subcostal PWD of abdominal aortic diastolic flow (frozen image) 
55. CWD right parasternal aortic forward flow (frozen image) 
56. 2D greyscale inferior vena cava – sniff test for changes in IVC diameter 
57. Optional – biplane imaging at LVOT long-axis for measurement of LVOT area in SAX  
58. Optional – 3D full volume acquisition of parasternal long-axis view focus LVOT and aortic root 
59. Optional – 3D apical full volume acquisition (single beat or 7 beats)  
60. Optional – 3D Colour Doppler from apical view – region of interest aortic valve for AR 

 
 
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6. 
Detailed instructions for acquisition of SURTAVI echocardiography recordings 
6.1 Quality control of the investigational site (initial site validation) 
 
The 1st subject with an echo examination submitted will be reviewed to assess the quality of 
the recording and the transmission and most importantly the ADHERENCE to the 
PROTOCOL. 
 
A “Core Laboratory Pre-Analysis” Report will be provided to the site 
6.2 Guidelines for study object confidentiality 
 
NO patients’ information should be present on the echocardiogram. 
 
Site-Patient identification: study subjects are to be identified by a specific study 
identification number as supplied by the sponsor.  
 
The following items should be entered in the patient identification section of ultrasound 
system and should be clearly shown on all digital cine loops or still frames. 
 Site-subject ID (XXXXX-YYYY) 
 date of exam and  
 study interval  
 
To ensure adherence to the USA HIPAA (Health Insurance Portability and Accountability 
Act of 1996) guidelines for study subject confidentiality, no study subject names or other 
Protected Health Information (date of birth, hospital record number, etc.) should be 
displayed. 
6.3 Submission 
 Upload all study echocardiograms to InteleGRID (secure electronic system used for 
transferring images) 
6.4 Further inquiries:  
 
For any questions, contact your monitor or Medtronic Clinical Research Specialist 
 

 
 
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7. 
Technical guidelines: how to optimize the echocardiography images 
7.1 General recording recommendations 
 
Ensure ultrasound machines are maintained as instructed by the manufacture 
 
Ensure calibration of distance, velocity and time on each image 
 
Keep persistence and smoothening off 
7.2 ECG gating 
 
All cine-loops and still frames must clearly display a single lead electrocardiographic 
recording in which P-, QRS-, and T-waves (but in particular the R wave) are clearly 
identifiable 
7.3 Number of recorded heart cycles  
 
In sinus rhythm, record three continuous beats for all cine-loops and still frames, unless 
indicated otherwise.  
 
In the presence of irregular/non-sinus rhythm, record 5-10 continuous beats.  
 
Try to exclude premature beats. 
7.4 Effects of respiration and timing of recordings  
 
During all recordings, respiration should be quiet.  
 
Tissue Doppler measurements should be recorded after non-forced end-expiration 
7.5 Two-dimensional echocardiography general settings 
 
Use harmonic-imaging mode with maximized (mechanical index >1) power output 
 
Gain (and time-gain compensation (TGC)) settings should be adjusted to eliminate 
background noise and to allow for a clear blood-tissue border.  
 
An optimal gain setting consists of a left ventricular cavity with minimal (but not completely 
absent) noise 
 
The greyscale / dynamic range should be adjusted to provide an image with marked 
contrast between light and dark areas 
 
The focus point should be set at the middle of the region of interest 
 
Depth settings should be minimized (do not display structures outside the region of interest) 
7.6 (Tissue) Doppler settings 
 
Use a display speed of 50 to 100 mm/sec and a sample volume length of 3-4 mm (in 
extremely low heart rates use a speed of 150 mm/sec).  
 
For mitral E-wave deceleration, time one recording is needed at a sweep speed of 150 
mm/s 
 
Adjust gain, filter settings, position and velocity range to maximize the velocity excursion 
 
Minimize the angle between the direction of motion of the investigated structure or flow and 
the Doppler beam 
 
Transmitral flow should be assessed at the tips of the mitral valve 
 
Annotate the tissue Doppler recordings  
7.7 Colour Doppler settings 
 
Minimize the colour sector and use a velocity range of approximately  60 cm/sec  
7.8 Parasternal long-axis view 
 
Minimize the angle between the left ventricle and aorta (the inferolateral wall should be as 
perpendicular as possible to the transducer) the anteroseptal wall is visualized at the same 
distance from the transducer as the anterior wall of the ascending aorta 
7.9 Apical two and four-chamber view 
 
The left ventricular apex should be visible in the top of the sector  
 
The aortic valve should be out of the image plane 
 
Maximize the internal long-axis of the left ventricle (avoid foreshortening) by looking for a 
window one intercostal space lower (in particular when the left ventricle does not appear 
ellipsoid) 

 
 
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 
To ensure that the proper rotation has been made for a two-chamber view, the transducer 
is angled posteriorly to intersect both papillary muscles symmetrically. Then the transducer 
is angled slightly anteriorly so that neither papillary muscle is seen in its long axis in this 
view 
7.10 Special considerations for aortic regurgitation by colour flow imaging1-3 
In addition to the abovementioned recommendations: 
 
Standardize the machine settings for all examinations. Keep the Frame Rate around 20 Hz 
when recording colour Doppler aortic regurgitation  
 
Colour gain should be set step by step just below the appearance of colour noise artefacts 
 
For Vena contracta: use a parasternal long-axis view in ZOOM mode with minimal colour 
sector size and imaging depth to maximize lateral and temporal resolution 
 
For PISA: Shift the colour flow zero baseline downwards or upwards in the regurgitant jet 
direction in the left PLAX view depending on the jet orientation and upwards in the apical 
view) 
7.10 Subcostal window 
In order to provide optimal image acquisition from subcostal window, the following steps are 
required:  
 
The knee-flexed position relaxes the upper abdominal muscles and thereby improves 
visualization 
 
From the subcostal four-chamber view, anti-clockwise rotation of the transducer permits 
visualization and pulsed Doppler examination of the upper abdominal aorta 

 
 
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8. 
Measurements of aortic root geometry4 
The following measurements of the aortic root are obtained from the parasternal long-axis view 
(screening/baseline exams only): 
 
Aortic annulus long axis diameter. The aortic annulus long axis diameter is measured 
perpendicular to the long axis of the root, measured between the endothelial point that 
trisects the posterior aortic wall, non-coronary cusp hinge and anterior mitral leaflet hinge 
(posterior hinge point), and the point that bisects the septal endocardium and the right 
coronary cusp hinge (anterior hinge point). Measurements should be made at mid-systole 
and inclusive of cusp calcifications (Figure 1). To accurately incorporate cusp calcification 
for aortic annulus sizing, measure from the white-black interfaces of the posterior and 
anterior aortic cusp hinge points and add 2 mm to the measurement. 
 
Sinus of Valsalva diameter (SoV). The SoV diameter is perpendicular to the long axis of 
the root and typically parallel to the aortic valve annulus. It is the widest intra-luminal 
distance within the sinuses (measured at end-diastole from inner edge to inner edge, 
Figure 2, A). 
 
Sino-tubular junction diameter (STJ). The STJ diameter is the intra-luminal diameter 
parallel to the SoV diameter, where the sinuses narrow and join the ascending aorta 
(measured at end-diastole from inner edge to inner edge, Figure 2, B). 
 
Sinus of Valsalva height (SoVH). The SoVH is the distance between the STJ and the 
aortic annulus long-annulus diameter (measured at end-diastole, Figure 3). 
 
Note: Measurements should be noted on images submitted for Screening Committee 
review 
  
 
 
 
Figure 1. Examples of measurement of the aortic annulus long axis diameter 
 

 
 
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Figure 2. Example of measurement of the Sinus of Valsalva (A) and Sino-Tubular Junction (B) diameters 
 
Figure 3. Example of measurement of the Sinus of Valsalva Height (C) 

 
 
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9. 
Measurement of Left Ventricular Outflow Tract (LVOT) Diameter 
The LVOT long axis diameter is measured in the parasternal long-axis view at early to mid systole. 
The optimal imaging plane is through the long axis of the aorta; therefore, the anterior and posterior 
walls of the aortic root should be parallel with the maximal aortic diameter. 
For native aortic valves, the LVOT long axis diameter is measured from the white-black interface of 
the septal endocardium to the anterior mitral leaflet, parallel to the aortic valve plane and within 0.5 
cm - 1 cm of the valve orifice (Figure 4)1. Following implantation of the CoreValve device, the LVOT 
diameters and the LVOT area are measured immediately proximal to the inflow aspect of the stent 
(Figure 5). 
 
Note: For optimal results, LVOT diameter is averaged from 3 measurements from 3 
consecutive high quality 2D ZOOM views. 
 
 
Figure 4. TTE mid-systolic frame showing measurement of LVOT diameter for derivation of native aortic valve area. 
 
 
Figure 5. Cursor placement for measurement of LVOT diameter for derivation of prosthetic effective orifice area 

 
 
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10. 
Measurement of LVOT Velocity5 
LVOT velocity is recorded with PW Doppler from the apical transducer position, either in the apical 
long-axis view or in the anteriorly angulated four-chamber view or “five-chamber view.” The PW 
sample volume is positioned just proximal to the aortic valve, with care to avoid the zone of pre-
valve acceleration. The recommended procedure is to initially place the sample volume within the 
aortic valve leaflets (prosthetic or native), and then gradually move it apically until a clear spectral 
waveform is observed with a well-defined peak and minimal spectral broadening (Figure 6). No 
opening click should be seen. The optimal sample volume placement is usually between 0.5 and 
1.0 cm upstream from the valve annulus.2 Post implantation, the sample volume should be placed 
at the entrance of the inlet of the TAV prosthesis. 
11. 
Measurement of Aortic Valve Velocity5 
The aortic valve velocity and VTI should be interrogated with CW Doppler from all transducer 
positions (apical, right parasternal, suprasternal notch, left supraclavicular, subcostal). The position 
that provides the highest velocity is used for measurements. A smooth velocity curve with a clear 
outer edge and maximal velocity should be recorded. The maximal velocity is measured at the 
outer edge of the dark signal; fine linear signals at the peak should not be included in 
measurements. The outer edge of the dark “envelope” of the velocity curve is traced to provide both 
the VTI for the continuity equation and the mean gradient (Figure 7).1 
 
             
 
Figure 6. An optimal LVOT signal shows a                          
Figure 7. CW Doppler of severe AS jet showing  
smooth velocity curve with a narrow velocity                       
measurement of maximal velocity and tracing of the 
range at each time point.                                                     
Velocity curve to calculate mean gradient. 
 
Note: Velocity tracings should be noted on images submitted for Screening Committee 
review 
Note: Fine linear signals at peak velocity should not be included in the velocity tracings! 

 
 
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12. Assessment of Aortic Regurgitation6,7 
 
Use all echo modalities: An integrated exam approach using colour flow, pulsed-wave 
(PW), and continuous-wave (CW) Doppler is used to assess the severity of transvalvular 
and paravalvular regurgitation. 
 
Use four views: Colour flow Doppler imaging should be performed from the parasternal 
long and short-axis views, and the apical long-axis and apical 5-chamber views. A 
recording of the aortic regurgitant signal should be obtained with CW Doppler. If the 
degree of aortic regurgitation appears more than mild by visual estimate, the velocity in 
the proximal descending aorta and the abdominal aorta should be recorded with PW 
Doppler. 
 
Severity: The degree of transvalvular and paravalvular AR will be graded as none, trace, 
mild, moderate, and severe based on the analysis of the parameters shown in Table 
2a.3,4    
o 
The category of “trace” is used in cases where regurgitation is barely detectable by 
colour Doppler.  
o 
Regurgitant signals observed to originate within the stent will be considered 
transvalvular, and regurgitant signals observed to originate outside the stent will be 
considered paravalvular.  
 
Paravalvular regurgitant jets will be characterized by the extent of the aortic regurgitant 
jet relative to the short axis circumference of the aortic valve (Table 2a- Valve Academic 
Research Consortium (VARC) Consensus Report for Transcatheter Aortic Valve 
Implantation (TAVI) and Table 2b.  Updated standardized endpoint definitions for 
transcatheter aortic valve implantation: the VARC-2 consensus document, and Table 3a 
and b -2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the 
Management of Patients With Valvular Heart Disease (published in the October 2008 
issues of Journal of the American College of Cardiology and Circulation).  
Table 2a. Parameters for evaluation of the severity of aortic regurgitation1, 6, 8 
Prosthetic Aortic Valve Regurgitation Criteria (Central and Paravalvular) 
Parameter 
Mild
Moderate  
Severe
Valve Structure and Motion 
 
Mechanical or bioprosthesis 
Usually normal 
Usually abnormal† 
Usually abnormal† 
Structural parameters 
 
Left ventricular size 
Normal ‡ 
Normal/ 
mildly dilated ‡ 
Dilated 
Doppler parameters (qualitative or semi quantitative)
 
Jet width in central jets (% LVO diameter): colour* 
 
Jet density: CW Doppler 
 
Jet deceleration rate (PHT┼, ms): CW Doppler** 
 
LV outflow vs. pulmonary flow: PW Doppler 
Diastolic: flow reversal in the descending aorta 
PW Doppler 
 
 
Circumferential extent of paraprosthetic AR (%) 
 
 
 
Narrow (≤25%) 
Incomplete or faint 
 
Slow (>500) 
Slightly increased 
 
 
Absent or brief 
early diastolic 
 
<10 
 
 
 
Intermediate (26-64%) 
Dense 
 
Variable (200-500) 
Intermediate 
 
 
Intermediate 
 
 
10-20 
 
 
 
Large (≥65%) 
Dense 
 
Steep (<200) 
Greatly Increased 
 
 
Prominent, 
Holodiastolic 
 
>20 
Doppler parameters (quantitative) 
 
Regurgitant volume (mL/beat) 
 
Regurgitant fraction (%) 
 
<30 
<30 
 
30-59 
30-50 
 
>60 
>50 
 
* 
Parameter applicable to central jets and is less accurate in eccentric jets 
**  Influenced by left ventricular compliance 
AR=aortic regurgitation; CW= continuous wave; LVO= left ventricular outflow; PW= pulsed wave 
┼ 
PHT is shortened with increasing LV diastolic pressure and vasodilator therapy, and may be lengthened in chronic adaptation 
to severe aortic regurgitation. As such, PH, in contrast to the other parameters, does not reflect the volumetric severity of aortic 
regurgitation, but rather its hemodynamic impact. Therefore, in the setting of acute paravalvular or transvalvular leaks, 
intermediate values between 200 and 500 ms should not be used to classify the degree of regurgitation. 
† 
Abnormal mechanical valves, for example, immobile occluder (valvular regurgitation), dehiscence or rocking (paravalvular 
regurgitation); abnormal biologic valves, for example, leaflet thickening or prolapse (valvular), dehiscence or rocking 
(paravalvular regurgitation). 

 
 
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‡ 
Applies to chronic, late postoperative AR in the absence of other etiologies. 
 
Table 2b. VARC-2 criteria for evaluation of the prosthetic valve dysfunction  
Prosthetic valve dysfunction 
Prosthetic aortic valve stenosis* 
 
Normal 
Mild Stenosis 
Moderate/Severe 
Stenosis 
Quantitative Parameters (Flow-dependent)† 
Peak velocity 
<3 m/s 
3-4 m/s 
>4 m/s 
Mean gradient 
<20 mmHg 
20-40 mmHg 
>40 mmHg 
Quantitative Parameters (Flow-independent) 
Doppler velocity index‡ 
>0.35 
0.35-0.25 
<0.25 
Effective orifice area¶ 
>1.1 cm
2 
1.1-0.8 cm
2 
<0.8 cm
2 
Effective orifice area§ 
>0.9 cm
2
0.9-0.6 cm
2
<0.6 cm
2
Prosthesis-patient mismatch (PPM)
 
Insignificant 
Moderate 
Severe 
Indexed effective orifice area** 
>0.85 cm
2/m
2 
0.85-0.65 cm
2/m
2 
<0.65 cm
2/m
2 
Indexed effective orifice area†† 
>0.70 cm
2/m
2 
0.70-0.60 cm
2/m
2 
<0.60 cm
2/m
2 
Prosthetic aortic valve regurgitation
 
Mild 
Moderate 
Severe 
Semi-quantitative Parameters 
Diastolic flow reversal in the descending 
aorta—PW  
Absent or brief early diastolic 
Intermediate 
Prominent, 
holodiastolic 
Circumferential extent of prosthetic valve 
paravalvular regurgitation (%)¶¶ 
<10% 
10-29% 
≥30% 
Quantitative Parameters‡ 
Regurgitant volume (ml/beat) 
<30 ml 
30-59 ml 
≥60 ml 
Regurgitant fraction (%) 
<30% 
30-49% 
≥50% 
EROA (cm
2)  
<0.10 cm
2 
0.10-0.29 cm
2 
≥0.30 cm
2 
*In conditions of normal or near normal stroke volume (50–70 mL) 
†These parameters are more affected by flow, including concomitant aortic regurgitation 
‡For LVOT >2.5 cm, significant stenosis criteria is <0.20 
¶Use in setting of BSA ≥1.6 cm
2 (note: dependent on the size of the valve and the size of the native annulus) 
§Use in setting of BSA <1.6 cm
2 
**Use in setting of BMI <30 kg/cm
2 
††Use in setting of BMI ≥30 kg/cm
2 
¶¶Not well-validated and may overestimate severity compared to quantitative Doppler 
 
From the publication entitled “Updated standardized endpoint definitions for transcatheter aortic valve implantation: the valve 
academic research consortium-2 consensus document. Kappetein AP, et al. J Am Coll Cardiol. 2012 Oct 9;60(15):1438-54.” 
 
 

 
 
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Table 3a. Parameters for evaluation of the severity of aortic regurgitation 
Classification of the Severity of Valve Disease in Adults with 
Aortic Regurgitation 
 
Mild
Moderate 
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+
2+
3-4+ 
Color Doppler jet width 
Central jet, width less 
25% of LVOT 
Greater than mild but 
no signs of AR 
Central jet, width greater 
than 65% LVOT 
Doppler vena contracta width (cm) 
Less than 0.3 
0.3-0.6 
Greater than 0.6 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.10 
0.10-0.29 
≥ 0.30 
Additional essential criteria 
Left ventricular size 
 
 
 
 
Increased 
 
 
13. 
Assessment of Mitral Regurgitation2, 8 
Colour flow Doppler imaging of the left atrium should be performed from the parasternal long-axis 
view, and from the apical four, two, and long axis views. Mitral regurgitant signals should be 
recorded with CW Doppler using a velocity scale that allows assessment of the density, shape, 
duration, and peak velocity of the mitral regurgitant signal. If the severity appears moderate or 
greater by visual assessment, pulmonary vein velocities should be recorded with PW Doppler to 
assess for the presence of systolic flow reversal. Grading of the severity of mitral regurgitation 
should be integrative using the parameters in Table 3b.4 
Table 3b. Classification of the Severity of Valve Disease in Adults Mitral Regurgitation 
Classification of the Severity of Valve Disease in Adults 
Mitral Regurgitation 
 
Mild
Moderate 
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+ 
2+ 
3-4+ 
Colour Doppler jet area 
Small, central jet, < 
4cm2  or <20% LA 
area) 
Signs of > mild 
present but no criteria 
for severe MR 
Vena contracta with > 
0.7cm with large central 
MR jet (area >40% of LA 
area) or with a wall-
impinging jet of any size, 
swirling in LA 
Doppler vena contracta width 
(cm) 
< 0.3 
0.3-0.69 
≥ 0.70 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per 
beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.20 
0.29 – 0.39 
≥ 0.40 
Additional essential criteria 
Left atrial size 
Left ventricular size 
 
 
 
Enlarged 
Enlarged 
 

 
 
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14. 
Assessment of Left Ventricular Function and Left Atrial Size9 
M-mode recordings of the left ventricle and left atrium should be obtained using 2-D guided beam 
alignment (Figures 7 and 8). Left ventricular chamber dimensions and wall thicknesses will be 
measured from 2D parasternal long axis views and should be utilized preferentially if M-mode 
images are suboptimal. Chamber dimensions are measured using the American Society of 
Echocardiography (ASE) measurement convention.5 In addition, standard 2-D views of the left 
ventricle should be obtained from parasternal and apical transducer positions for visual estimation 
and quantitative assessment of left ventricular ejection fraction by visual estimate.   
 
  
Figure 7. Measurement of left ventricular end-diastolic diameter (EDD) 
and end-systolic (ESD) from 2-D guided m-mode to optimize 
medial-lateral beam orientation. 
 
 
 
Figure 8. Measurement of left atrial diameter (LAD) by 2-D guided m-mode at end-systole. 

 
 
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15. 
Acquisition of Mitral Inflow Velocities 
A spectral Doppler recording of mitral inflow velocities should be obtained with PW Doppler in the 
apical 4-chamber view, using a 1 to 3 mm sample volume placed between the mitral leaflet tips 
during diastole (Figure 9). The spectral gain and wall filter settings should be optimized to clearly 
display the onset and cessation of left ventricular inflow.6  
  
\ 
 
Figure 9. Positioning of the sample volume for recording of mitral inflow velocities. 
16. 
Acquisition of Mitral Annular Tissue Doppler Velocities 
Mitral annular velocities should be obtained from the lateral and septal aspects of the mitral annulus 
using PW tissue Doppler performed in the apical 4-chamber view. The sample volume should be 
positioned at or 1 cm within the septal and lateral insertion sites of the mitral leaflets and adjusted 
as necessary (usually 5 to 10 mm) to cover the longitudinal excursion of the mitral annulus in both 
systole and diastole. Minimal angulations (<20 degrees) should be present between the ultrasound 
beam and the plane of cardiac motion.6 The Doppler gain should be minimized to prevent 
“blooming” of the signal to facilitate accurate measurement of the annular velocities. 

 
 
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17. 
Assessment of Device Migration 
CoreValve device placement site and migration will be assessed from the parasternal long axis 
view at each follow up point and compared to the initial post-procedural echo. A zoomed image of 
the left ventricular outflow tract including the anterior mitral leaflet and the anterior aortic wall should 
be included at each follow up echo. The location of the device will be determined by measurement 
of the distance from the proximal edge of the left ventricular outflow tract anteriorly, to the edge of 
the CoreValve device (Figure 10). Optimal placement of the valve should be within the left 
ventricular outflow tract just below the aortic annulus (Figure 11). 
 
 
Figure 10. Zoomed view of the left ventricular outflow tract (panel A) and schematic (panel B). Measurement of the distance 
from the proximal edge of the anterior aspect of the left ventricular outflow tract to the edge of the CoreValve device 
(arrows).  
 
 
Figure 11. Zoomed view of the left ventricular outflow tract. Panel A. Optimal device placement of the CoreValve device 
within the left ventricular outflow tract with the proximal edge of the device just below the aortic annulus. Panel B. Low 
placement of the CoreValve device extends beyond the left ventricular outflow tract into the left ventricular chamber, 
encroaching on anterior mitral valve leaflet. 
 

 
 
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18. Echo Core Lab Analysis5, 7 
Data generated by the Echo Core Lab will be the primary data used for analysis and reporting. 
Qualitative assessment of valvular regurgitation will be performed using the criteria previously 
described in sections 8 and 9 of this Appendix. The Echo Core Lab will report the following 
variables: 
 
Aortic annulus long-axis diameter in mid-systole (screening/baseline only) 
 
LVOT long axis diameter in mid-systole 
 
Sinus of Valsalva diameter (SOV) at end diastole (screening/baseline only) 
 
Sino-tubular junction diameter (STJ) at end diastole (screening/baseline only) 
 
Sinus of Valsalva height (SOVH) at end-diastole (screening/baseline only) 
 
Device location and migration 
 
Max aortic valve velocity (V2) by CW Doppler 
 
Velocity time integral (VTI) across aortic valve by CW Doppler 
 
Mean gradient across aortic valve (MGV2) by CW Doppler 
 
Peak LVOT velocity (V1) by PW Doppler 
 
Velocity Ratio (V1 / V2) 
 
Velocity time integral (VTI) of LVOT velocity by PW Doppler 
 
Mean LVOT gradient (MGV1) by PW Doppler 
 
Doppler Velocity Index (DVI) 
 
Grade of aortic transvalvular regurgitation 
 
Grade of aortic paravalvular regurgitation 
 
Grade of mitral regurgitation 
 
ERO for MR (if available) 
 
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
 
Left ventricular (LV) end-diastolic diameter (LVEDD) 
 
Left ventricular (LV) end-systolic diameter (LVESD) 
 
Interventricular septal thickness at end diastole 
 
Left ventricular posterior wall thickness at end diastole 
 
Left atrial diameter (AP linear dimension) at systole 
 
Left ventricular ejection fraction by visual estimate 
 
Heart rate 
 
Mitral inflow “A” velocity 
 
Mitral inflow “E” velocity 
 
Mitral inflow deceleration time 
 
Mitral annular tissue Doppler systolic (s) velocity (septal and lateral) 
 
Mitral annular tissue Doppler early diastolic (e´) velocity (septal and lateral) 
 
Mitral annular tissue Doppler late diastolic (a´) velocity (septal and lateral) 

 
 
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In addition, the following variables will be derived by the central database from the appropriate 
measurements reported by the Echo Core Lab5: 
 
Mean Transvalvular Gradient (Mean  P) Across the Prosthetic Valve in mmHg 
 
Mean  P = MGV2 - MGV1 
 
Where: MGV2 is the mean pressure gradient across the prosthesis in mmHg, and MGV1 is 
the mean pressure gradient from the left ventricular outflow tract in mmHg 
 
Peak Pressure Gradient (Peak  P) Across the Aortic Prosthetic Valve in mmHg 
 
Peak  P = 4 x (V2
2 - V1
2) 
 
Where: V2 is the peak velocity across the prosthesis in m/sec, and V1 is the peak velocity 
from the left ventricular outflow tract in m/sec 
 
Effective Orifice Area (EOA) in cm2 
 
EOA = LVOT Long Axis diameter2 x 0.785 x (VTIV1/VTIV2) 
 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 
is the velocity time integral of the aortic prosthesis in cm. Alternatively, using velocity 
instead of VTI for simplification: 
 
AVA = π(radius of LVOT)2 × VLVOT/ Vmax  
 
Where Vmax is the maximum flow velocity across aortic valve, VLVOT is the maximum velocity 
across the LVOT. 
 
Effective Orifice Area Index (EOAI) in cm2/m2 
 
EOAI = EOA/BSA 
 
Where: EOA is the effective orifice area in cm2, and BSA is the body surface area in m2 
 
Doppler Velocity Index = Velocity Time Integral Ratio (VTI Ratio) 
DVI = VTI Ratio = VTIV1/VTIV2 
 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 
is the time velocity integral of the prosthetic aortic valve in cm 
 
Stroke Volume (SV) in ml/beat 
 
SV = LVOT long axis diameter2 x 0.785 x VTIV1 
Where:VTIV1 is the velocity time integral from the left ventricular outflow tract in cm 
 
Cardiac Output (CO) in l/min 
 
CO = (SV x HR)/1000 
Where: SV is the stroke volume in ml/beat, and HR is the heart rate in beats per minute 
 
Left Ventricular Mass (LVM) in grams 
LVM = 0.83 x [(LVEDD + LVPW + IVS)3 - (LVEDD)3] +0.6 
Where: LVEDD is the left ventricular end-diastolic diameter in cm, LVPW is the left 
ventricular posterior wall thickness at end diastole in cm, and IVS is the interventricular wall 
thickness at end diastole in cm. 
 
Left Ventricular Mass Index (LVMI) in g/m2 body surface area  
LVMI = LVM/BSA 
Where: LVM is left ventricular mass in g, and BSA is body surface area in m2 
 
Fractional Shortening (FS) in %  
FS = [(LVEDD - LVESD)/LVEDD] x 100 
Where: LVEDD is left ventricular end-diastolic diameter in cm, and LVESD is left ventricular 
end-systolic diameter in cm 
 
Estimated Right Ventricular Systolic Pressure (RVSP) in mmHg 
RVSP = (4 x MVTR jet
2) + 10 
Where: MV TR jet is the max velocity of the tricuspid regurgitant jet, and 10 = the assumed 
mean right atrial pressure in mmHg 

 
 
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 
Aortic Regurgitant volume (ml/beat) and fraction (%)  
The regurgitant volume across the aortic valve may be calculated as the difference 
between the LVOT volume and the transmitral volume, assuming there is no significant 
mitral regurgitation  
RV = Total stroke volume – forward stroke volume  
RV = SVAV – SVMV  
RF = [RV/SV] x 100 
SVAV = 0.785 x (LVOT)2 x VTILVOT (by Pulsed-wave Doppler) 
SVMV = 0.785 x (DMV)2 x VTIMV (by Pulsed-wave Doppler) 
Where: SV is stroke volume in mL, AV is aortic valve and MV is mitral valve 
 
Regurgitant Orifice Area (EROA) 
The regurgitant orifice area or EROA represents the average size of the defect in the aortic 
valve during diastole and is proportional to regurgitant severity.  
The regurgitant orifice area may be calculated as the regurgitant volume multiplied by the 
VTI of the continuous wave Doppler jet 
EROAAV = RV / VTIAR jet (by Continuous-wave Doppler) 

 
 
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19. 
Echocardiography References 
1. 
Zoghbi WA, Chambers JB, Dumesnil JG, Foster E, Gottdiener JS, Grayburn PA, Khandheria BK, Levine 
RA, Marx GR, Miller FA, Jr., Nakatani S, Quinones MA, Rakowski H, Rodriguez LL, Swaminathan M, 
Waggoner AD, Weissman NJ, Zabalgoitia M. Recommendations for evaluation of prosthetic valves with 
echocardiography and doppler ultrasound: A report from the american society of echocardiography's 
guidelines and standards committee and the task force on prosthetic valves, developed in conjunction 
with the american college of cardiology cardiovascular imaging committee, cardiac imaging committee of 
the american heart association, the european association of echocardiography, a registered branch of the 
european society of cardiology, the japanese society of echocardiography and the canadian society of 
echocardiography, endorsed by the american college of cardiology foundation, american heart 
association, european association of echocardiography, a registered branch of the european society of 
cardiology, the japanese society of echocardiography, and canadian society of echocardiography. J Am 
Soc Echocardiogr. 2009;22:975-1014; quiz 1082-1014. 
2. 
Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C, Hagendorff A, Monin JL, 
Badano L, Zamorano JL. European association of echocardiography recommendations for the 
assessment of valvular regurgitation. Part 2: Mitral and tricuspid regurgitation (native valve disease). Eur J 
Echocardiogr. 2010;11:307-332. 
3. 
Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E, Monin JL, Pierard LA, 
Badano L, Zamorano JL. European association of echocardiography recommendations for the 
assessment of valvular regurgitation. Part 1: Aortic and pulmonary regurgitation (native valve disease). 
Eur J Echocardiogr. 2010;11:223-244. 
4. 
Evangelista A, Flachskampf FA, Erbel R, Antonini-Canterin F, Vlachopoulos C, Rocchi G, Sicari R, 
Nihoyannopoulos P, Zamorano J, Pepi M, Breithardt OA, Plonska-Gosciniak E. Echocardiography in 
aortic diseases: Eae recommendations for clinical practice. Eur J Echocardiogr. 2010;11:645-658. 
5. 
Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, Pellikka 
PA, Quinones M. Echocardiographic assessment of valve stenosis: Eae/ase recommendations for clinical 
practice. J Am Soc Echocardiogr. 2009;22:1-23; quiz 101-102. 
6. 
Zoghbi WA. New recommendations for evaluation of prosthetic valves with echocardiography and doppler 
ultrasound. Methodist Debakey Cardiovasc J. 2010;6:20-26. 
7. 
Chambers J, Shah PM. Recommendations for the echocardiographic assessment of replacement heart 
values. J Heart Valve Dis. 1995;4:9-13. 
8. 
Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran 
R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb 
JG, Windecker S, Serruys PW. Standardized endpoint definitions for transcatheter aortic valve 
implantation clinical trials: A consensus report from the valve academic research consortium. Eur Heart J. 
2011;32:205-217. 
9. 
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, 
Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for 
chamber quantification: A report from the american society of echocardiography's guidelines and 
standards committee and the chamber quantification writing group, developed in conjunction with the 
european association of echocardiography, a branch of the european society of cardiology. J Am Soc 
Echocardiogr. 2005;18:1440-1463. 
10. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the valve academic 
research consortium-2 consensus document. Kappetein AP, Head SJ, Généreux P, Piazza N, van 
Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff 
MW, Kodali S, Mack MJ, Mehran R, Rodés-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, 
Leon MB. J Am Coll Cardiol. 2012 Oct 9;60(15):1438-54. doi: 10.1016/j.jacc.2012.09.001” 
 
 
 
 
 

 
 
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Electrocardiogram (ECG) Submission 
The standard 12 lead ECG will be utilized as a diagnostic and prognostic tool in patients 
participating in this study.   
Acquisition: 
1. Standard 12-lead ECGs must be obtained (with the exception of implant procedure) 
2. ECG should be conducted with the subject at rest 
3. ECGs should be provided on a single page printout (i.e. lead strips are not acceptable) using 
standard amplification of 1mV/cm and paper speed of 25mm/sec (50mm/sec is strongly 
discouraged) 
4. Visible lead annotation 
5. More than 1 normal beat per lead. No average ECGs 
6. ECG without Pace-Maker beats is preferred 
Labeling: 
7. Protect subject confidentiality.  Effectively block out any subject confidential information 
recorded on the ECG  
8. ECG labels are to be placed on top of the tracing, being careful not to obstruct any of the 
lead recordings 
9. Labels with Study name will be provided by Medtronic and shall be filled out completely, 
including 
a) Site number 
b) Subject identification number 
c) ECG date and time  
d) Applicable visit/interval (i.e. screening, Discharge) 
10. Incomplete labeling will result in the generation of a data clarification query and untimely 
interpretation of the tracing 
Submission: 
11. Original ECGs are strongly encouraged but high quality photocopies with good visible 
gridline are accepted 
12. Submission of all ECGs within appropriate timeframe is imperative 
13. Upload all ECGs to InteleGRID (secure electronic system used for transferring images) 
 

 
 
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Computed Tomography (CT) Angiography Acquisition 
Guidelines 
Background 
Cardiac Multislice Computed Tomographic Angiography (Cardiac MSCT Angiography) is intended 
to evaluate aortic valve anatomy, aortic root dimensions for device sizing, and assessment of 
peripheral vessel dimensions and anatomy.  This appendix is meant as a guideline to help with the 
proper acquisition of the images necessary for assessment of the above mentioned items.  The 
primary objective should be to acquire the highest resolution images and perform the correct 
measurements, as specified below, by tailoring the acquisition to your particular hardware and 
experience.   
Equipment Requirements 
 
Multi-detector CT scanner (64-slice minimum) with ECG-gating capability 
o 
The scans acquired and submitted for analysis of the aortic root MUST be ECG-
gated 
o 
Non-gated scans in areas with cardiac motion lead to measurement inaccuracy and 
therefore incomplete information for device selection 
o 
Peripheral vessel image acquisition may be non-gated 
 
Ability to electronically transfer the imaging data via secure network (InteleGRID) 
Scans Acquired 
 
Chest Topogram 
 
ECG-gated contrast enhanced aortic root* 
 
Non ECG-gated contrast enhanced peripheral vessels* 
*Sub-millimeter slice thickness is required 
Scanning Procedures 
The scan protocol is similar to a CT coronary angiogram. The aim is to get adequate contrast in 
the region of interest which includes: endo-luminal surface for visualization of left heart, aorta, and 
peripheral access vessels (i.e., femorals and subclavians, when necessary). Temporal resolution 
should be optimized to reduce motion artifact. Spatial resolution should be as high as possible 
(goal is smallest isotropic voxel size). 
Step 1: Patient preparation 
 
Administer medication per institution standard practice for CT scanning (suggest avoid 
sublingual nitrate, avoid or caution with B-blockers) 
 
Attach ECG electrodes for gating of scan (suggest:  avoiding large respiratory muscles as 
these may introduce ECG-artifact). Verify quality and stability of ECG tracing on scanner 
console during an inspiratory breath hold 
 
Prepare large intravenous line (i.e., 18 or 20 gauge) for administration of contrast media 
 
Instruct patient to lie still during scan, even if they experience warmth or tingling due to the 
injection of contrast 
 
Instruct patient in practice breath-hold at end-inspiration for 10-15 seconds (duration 
required will depend on specific scanner performance). Assess heart rate variability during 
breath-hold. If heart rate is >65 bpm or unstable, consider cautious titration of beta-blockers 

 
 
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Step 2: Chest Topogram 
 
Acquire a chest topogram for use in planning the following imaging protocol 
 
Figure CTA-1:  Example image of chest topogram 
Step 3: ECG-gated contrast enhanced scan of aortic root 
The aim of this scan is to assess the aortic root and valve anatomy. Ensure the required scan 
parameters are used; these are listed below in Table 1. The following parameters are crucial to the 
optimum required scan: 
 
The recommended coverage area is from superior to the aortic arch to inferior to the 
cardiac apex. The minimum required coverage area is from 50mm above the aortic 
annulus to the inferior border of the heart.  Coverage less than this will not allow for proper 
assessment of the patients anatomic suitability 
 
The scan requires dynamic 4D acquisition using retrospective ECG-gating 
 
The required detector collimation is 0.4-0.625mm 
 
The required slice thickness is ≤ 0.8mm 
 
The recommended slice overlap is 0.4mm 
Contrast Enhanced Scan Execution 
 
Prepare iodinated contrast injection apparatus (recommendations in scan parameters are 
provided in Table 1) 
 
Set up scan parameters per the table below  
 
Instruct patient to lie still during scan, even if they experience warmth or tingling due to the 
injection of contrast 
 
Initiate contrast injection 
 
When contrast reaches threshold at bolus-tracking location, instruct patient to hold breath 
at end-inspiration, then initiate main scan protocol 
 
At completion of scan verify scan is of adequate quality 
 
Record amount of contrast given.  Note: this is not on the CRF, but is recommended in 
this patient population 
 
Record heart rate average and range.  Note: this is not on the CRF, but is recommended 
for explanation of image quality issues 

 
 
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Post-processing 
 
Verify heart rate ECG triggers are at consistent place in cardiac cycle, edit if necessary. 
Additional editing/removal of arrhythmias may be performed 
 
Reconstruct at multiple phases (10 increments of 10%), with ≤0.8mm slice thickness.  If 
the system has the capability, also reconstruct a “best systolic” and “best diastolic” phase. 
If image quality of the aortic root is not good in the end systolic phase the phase with the 
best image quality may be selected instead 
Table 1. Recommended Scan Parameters 
 
Recommended Parameters 
IV injection with iodine 
contrast 
80-100 (320mg/ml or higher), modify per patient as appropriate 
Injection rate 
4-6 mL/sec 
Bolus tracking, delay 
Delay time calculated using protocol for current scanner (bolus tracking or 
similar) with peak of contrast concentration in the ascending aorta during 
acquisition.  Bolus tracking is the preferred method.   
ECG Leads 
Required 
ECG-gating 
Retrospective (Prospective may be used in centers with much experience of 
the technique and in patients with stable heart rate) 
Scan direction 
Cranial-caudal 
Scan coverage 
From above the aortic arch to past the cardiac apex 
Detector collimation 
0.4 – 0.625 mm 
Pitch 
0.2–0.43 adapted to the heart rate 
Dose modulation 
Modulation and full current between 30 and 80% of the cardiac cycle (or no 
modulation i.e. full dose throughout) 
Slice thickness 
0.8mm 
Slice overlap 
0.4mm 
Reconstruction kernel 
Medium Smooth 
Post-processing 
Use single segmental reconstruction algorithm that minimizes motion artifact. 
Reconstruct at multiple phases (10 minimum, 20 preferred, increments of 5-
10%).  Reconstructed slice thickness  0.75-1mm. 
 

 
 
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Step 4: Non ECG-gated contrast enhanced scan of vessels  
The aim of this scan is to assess the peripheral access vessels and abdominal aorta for suitability 
for the procedure. 
 
 
Standard radiology CT angiography protocol should be used. 
 
Can be non ECG-gated 
 
Contrast Volume: 40-50 cc, Injection rate: 4 cc/sec.  Modify per patient as necessary to 
acquire good quality images 
 
Delay time calculated using protocol for current scanner (bolus tracking, etc) with peak of 
contrast concentration in the abdominal aorta and iliac arteries 
 
Suggested coverage areas:  
o 
Femoral access only screening: abdominal aorta above celiac artery and down to 
the femoral head.  Use this option there if you are confident that femoral access will 
be suitable for this patient 
o 
Subclavian access only screening: above the subclavian arteries and down to mid-
thorax.  Use this option if prior information (i.e., CT scan) exists which demonstrates 
that femoral access will not be possible in this patient 
o 
Combined access screening: above the subclavian arteries and down to the femoral 
head.  This is the recommended option.  An additional option for subclavian 
screening is to include the subclavian vessels in the ECG-gated portion and use 
femoral only screening for the rest of the vessels 
 
Source data reconstructed using sub-millimeter slice thickness 
Aortic Root and Peripheral Vessel Measurements 
CT measurements are conducted in different parts of the cardiac cycle to correlate most closely 
with corresponding echo measurements 
 
Systole for aortic annulus measurements 
 
Diastole for sinus of Valsalva diameters, sinus of Valsalva heights, maximum ascending 
aorta diameter, and aortic root angulation 
 
Table 2: Required CT Measurements 
 
•
Aortic annulus measurements (Systole)
–
Major aortic annulus diameter.
–
Orthogonal minor aortic annulus diameter.
–
Annulus perimeter.
•
Additional aortic root measurements (Diastole)
–
Maximum ascending aorta diameter at 40mm above 
annulus. 
–
Sinus of Valsalva diameters.
–
Sinus of Valsalva heights.
–
Aortic root angulation.
Measured on 
ECG-gated 
images of the 
chest.
Measured on 
Non ECG-
gated images 
of the 
vasculature.
•
Vessel measurements
–
Minimum and perpendicular abdominal aorta diameter.
–
Right and left common and external illiac artery min and 
perpendicular diameter at minimum diameter along path.
–
Right and left femoral artery min and perpendicular 
diameter at minimum diameter along path.
–
If non-iliofemoral access is planned: right and left 
subclavian artery min and perpendicular diameter at 
minimum diameter along path.

 
 
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Proper Aortic Annulus Measurements 
The aortic annulus is not co-planar with the planes of the body (i.e., axial, sagittal, or coronal). 
Therefore, multi-planar reformatting of the CT images to create a double-oblique axial image is 
required for annulus measurements. This reformatting is critical; if the plane is not correctly 
aligned, it may be going through the sinuses or the LVOT.  This can lead to improper device 
selection. 
The methods described here for measurement of the aortic annulus (virtual basal ring) are similar 
to those reported in Schultz et al. EuroIntervention Supplement (2010) Volume 6 (Supplement G) 
G6-G13.   
Step 1: Reformatting of Images 
 
Center image cross-hairs on aortic root in all windows where it is visible.  Lock cross-hairs 
so they remain orthogonal for all steps 
 
In the coronal window, rotate cross-hairs (horizontal line) counter-clockwise to align with 
virtual basal plane, as shown in Figure CTA-2 (upper left panel) 
 
In the sagittal window, the horizontal line has to be rotated clockwise or counter-clockwise 
to align with virtual basal plane, as shown in Figure CTA-2 (lower left panel) 
 
On the newly defined double-oblique axial image, scroll up and down through the aortic 
root until the most caudal attachment points of the three native leaflets come into view 
(indicated by arrowheads in Figure CTA-3 below). If one of the leaflets comes into view at 
a more cranial or caudal slice, adjust the coronal or sagittal cross-hairs until all three 
leaflets come into view on the same axial slice 
 
 
Figure CTA-2:  Example images in original orientation (axial, coronal and sagittal).  Red curved arrow and line indicate 
adjustment of coronal and sagittal planes to align with aortic basal annulus. 
 
Sagittal 
Coronal 
Axial 

 
 
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Figure CTA-3:  Example images of reformatted oblique coronal (upper left), oblique sagittal (lower left), double oblique 
axial (upper right) and 3D reconstruction lower right. Yellow arrowheads indicate most caudal attachment of three 
leaflets of aortic valve. 
 
 
For confirmation of the correct aortic annulus plane, scroll through the double oblique axial 
images starting in the mid sinus and ending at the level of the aortic annulus.  The sinuses 
should appear to be relatively the same size at the level of the mid-sinus and the leaflets 
should all disappear equally at the level of the annulus 
Step 2: Aortic Root Measurements 
Aortic Annulus Measurements 
 
Choose the cleanest systolic images for the aortic annulus measurements 
 
Aortic annulus measurements should be completed on the properly reformatted double-
oblique axial image at aortic annulus level 
 
Trace the perimeter of the basal annulus (Figure CTA-4, left).  Place cross-hairs at center 
of basal annulus, create major diameter through the center, create minor diameter defined 
as perpendicular to major and through center (Figure CTA-4, right).  Record perimeter, 
major and minor diameter measurements on the screening worksheet 
    
Figure CTA-4:  Example of perimeter measurement (left) and major and minor diameter measurements (right). 
 
 
Oblique 
Coronal 
Oblique 
Sagittal 
Double-oblique axial 

 
 
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Additional Aortic Root Measurements 
 
Choose the best diastolic images for measurement of sinus of Valsalva diameters, sinus 
of Valsalva heights, maximum ascending aorta diameter (40 mm from annulus), and aortic 
root angulation.  Sinus of Valsalva diameters, heights, and maximum ascending aorta 
diameter should be completed on reformatted images using the same reformatting 
technique as used for the aortic annulus measurements 
Sinus of Valsalva Diameters 
 
Select the double oblique axial image where the widest portion of the three sinuses is 
visible 
 
Measure a diameter from each commissure through the center of the root to the opposite 
sinus.  Complete for all three sinuses (Figure CTA-5) 
 
Figure CTA-5:  Example of sinus of Valsalva diameters. 
 

 
 
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Sinus of Valsalva Heights 
 
The sinotubular junction is typically not co-planar with the aortic annulus.  Therefore, a 
sinus of Valsalva height must be measured for each of the three sinuses.  This height is 
defined as the distance between the aortic annular plane and the tallest point in the sinus 
 
Choose the double oblique axial image so that it is located at the level of the aortic 
annulus.  The reformatting line representing the double oblique axial image should now be 
visible in the oblique coronal and oblique sagittal images at the level of the aortic annulus 
 
For the left coronary and non-coronary heights, use the oblique coronal image.  For the 
right coronary height, use the oblique sagittal image 
 
To complete the measurement, scroll through the oblique coronal or sagittal image 
(depending on which sinus you are measuring) and locate the heights location of the 
sinotubular junction.  On that image, measure the distance along the path of the aortic root 
from the aortic annular plane, marked by the reformatting line, to the sinotubular junction 
(Figure CTA-6). 
 
 
Figure CTA-6:  Example of sinus of Valsalva heights. 
 

 
 
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Maximum Ascending Aorta Diameter 
 
Choose the double oblique axial image so that it is located at the level of the aortic 
annulus.  The reformatting line representing the double oblique axial image should now be 
visible in the oblique coronal and oblique sagittal images at the level of the aortic annulus 
 
Choose the oblique coronal image that is in the center of the aortic root 
 
Measure a distance of 40mm from the line representing the aortic annular plane 
 
Center the images at this level, and reformat the images so that the double oblique is 
perpendicular to the ascending aorta at this level (Figure CTA-7) 
 
Measure the maximum diameter at this level (Figure CTA-7) 
 
 
 
Figure CTA-7:  Oblique coronal with measurement of 40mm above the aortic annulus (left) and double-oblique 
reformatted to be perpendicular to that location (right).   
 

 
 
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Aortic Root Angulation 
 
The aortic root angle measured in this study is the angle between the aortic annulus and 
the true axial plane of the patient 
 
To measure, use the standard coronal diastolic image, before any reformatting 
 
Scroll to the middle of the aortic root in these images (Figure CTA-8) 
 
Use the angle tool to draw a line first across the aortic annulus and second horizontal to 
the coronal image, which represents the axial plane of the patient.  Start the angle 
measurement in the upper left of the patient, so that the angle is to the lower right of the 
patient (Figure CTA-8) 
 
 
Figure CTA-8:  Aortic root angulation measurement on the standard coronal image.  Use the angle tool beginning at 
point 1, with point 2 on the lower right of the patient, and the final point on the lower left of the patient.  The first line, 
between points 1 and 2 should be along the aortic annulus.  The second line, between points 2 and 3, should be 
horizontal in the coronal image, which represents the axial plane of the patient. 

 
 
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Step 3:  Access Vessel Measurements 
Peripheral vessel measurements are made on non-gated CT and measured on images 
perpendicular to the vessel.  The intent of these measurements is to determine the minimum 
diameters for the potential access routes.  All vessel measurements should be completed on 
images that are perpendicular to the vessels of interest.  
Minimum Abdominal Aortic Diameter 
 
Use a stretched vessel view to locate the minimum luminal abdominal aortic diameter 
 
Measure the minimum lumen diameter and a perpendicular diameter on the image 
orthogonal to the vessel at the minimum location (Figure CTA-9) 
 
Figure CTA-9:  Example of minimum abdominal aortic diameter.  Stretched vessel (left), with the pink line at the location 
of the minimum luminal abdominal diameter.  Orthogonal image (right), showing the minimum luminal diameter and the 
perpendicular diameter. 
Peripheral Vessel Measurements 
 
These techniques are to be used for measurements on the following arteries: 
o 
Right and left femorals 
o 
Right and left common and external iliacs 
o 
If non-femoral access is planned – right and left subclavians 
 
Use a stretched vessel view to locate the minimum luminal diameter 
 
Measure the minimum lumen diameter and a perpendicular diameter on the image 
orthogonal to the vessel at the minimum location (Figure CTA-10) 
 
Figure CTA-10:  Example of the peripheral vessels and measurements for the right (left) and left (right) iliac arteries. 
 
 

 
 
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Additional CT Measurements 
 
In the case of a thoracic aortic aneurysm, measure the maximum diameter in the 
aneurysm. 
 
To determine the maximum location, use similar methods to the other vessel 
measurements (stretched vessel view) 
 
Complete the measurement on the orthogonal images and report the maximum diameter 
Prepare data for submission  
 
Data should be stored in DICOM 3.0 format 
 
If possible, de-identify all images prior to uploading 
 
Burn images to DICOM DVD/CD or upload to internal electronic records system 
 
Ensure all required images are included on DVD/CD or internal electronic records system 
for upload: 
o 
ECG-gated contrast enhanced aortic root.  Upload on 4 time-points: 30% & 40% 
(systole) and 60% & 70% (diastole).  If the system has “best-systolic” and “best-
diastolic,” only upload those 2 phases.   
o 
Non ECG-gated contrast enhanced peripheral vessels – upload entire set. 
o 
Screenshots of all measurements 
 
Upload all images to InteleGRID (secure electronic system used for transferring images) 
 
 

 
 
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Interactive Voice/Web Response System (IXRS) 
Medtronic will utilize an Interactive Voice/Web Response (IXRS) System to manage subject 
screen failures and randomization into the Medtronic CoreValve™SURTAVI Trial. 
The IXRS system will assign patients a Screening ID to be used for all patients that sign the 
Informed Consent Form and are considered for possible enrollment by the Heart Team. If a patient 
is screened and does not meet eligibility criteria, the IXRS system will capture the reason for 
screen failure and disposition of the patient (if known). 
Upon meeting eligibility criteria, the IXRS system will randomize the patient and assign a Subject 
ID to be used in the Oracle Clinical Database upon enrollment.   
The IXRS system will assign subjects within one of four groups:  
 
TAVI with planned PCI 
 
TAVI without planned PCI 
 
SAVR with planned CABG 
 
SAVR without planned CABG 
Users can sign in to the Medtronic CoreValve™SURTAVI Trial study web site by using the URL 
below and use the sign in box labeled "IVRS/IWRS Login": 
 www.bracketglobal.com/client-login 
The first time a user accesses the study website, they will be prompted to update their password. 
The password must be at least 8 characters in length and contain at least 1 capital letter and 1 
number or symbol. 
Remember that the User ID and Password are private and should not be shared with other 
individuals. 
For technical questions, contact UBC Technical Support at 888-794-0122 or at 
support@bracketglobal.com 
 
 

 
 
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Explanted Device/Pathology and Return Procedures 
In the event of a device malfunction of the investigational device prior to or during implant, or in the 
event that a TAV device is explanted after implant (due to reintervention or autopsy), the TAV 
device and/or affected device components should be returned to Medtronic. 
SHIPPING INSTRUCTIONS 
 System Malfunction (TAV Device, Delivery Catheter System (DCS) and/or 
Compression Loading System (CLS/LS) Before or During Procedure 
1. Always retain original product packaging until the procedure is completed. 
2. Place product back into original packaging if it was not clinically used (i.e. in contact with 
blood or body fluids) 
3. If clinically used, use heart valve return kit to ship the valve or CLS/LS. Use a DCS return 
kit for the DCS, if applicable. 
Explant of CoreValve at Reoperation 
1. Photograph the TAV in situ (if possible). 
2. If possible, indicate with a suture on the frame, the relation of the TAV device to the 
midpoint of the mitral valve. 
3. Following explantation, rinse blood from the lumen with a physiologic solution (e.g. 
Ringer’s lactate solution). 
4. Do not disturb or alter the valve leaflets in any way (as possible). 
5. Remove all packaging material and forms from kit. Temperature indicator should remain in 
box unless it has been activated. If it has been activated, discard noting that the kit is still 
usable. 
6. Immerse the TAV and any surrounding tissue in the solution provided in the explant kit. 
7. Place the jar into the yellow absorbent pouch and close, then into the zip lock bag and 
seal. 
Explant of CoreValve at Autopsy 
1. Remove all packaging material and forms from kit.  
2. If possible, leave aortic root intact with an ample margin between the valve and 
descending aorta. 
3. Whole hearts should be immersion fixed in formalin in the local autopsy suite or pathology 
lab for at least 24-48 hours prior to shipping. Note: hospitals or contract pathology labs 
should have formalin available for use. 
4. Use the plastic container provided in the return kit for fixing the heart. 
5. Before shipping, remove most of the formalin from the container and wrap the heart in the 
cloth specimen bag that is provided, which has been thoroughly soaked in formalin.  Place 
the heart and specimen bag back into the container. 
6. Label the outside of the container (lid and container) with the TAV device serial number, 
patient ID, center name and study name.   
7. Seal the container tightly and wrap the container-lid interface with parafilm (if available). 
 

 
 
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All Explants/Returns 
1. Complete the Product Experience Report (PER) form and email a copy to 
rs.structuralheartfieldassurance@medtronic.com to receive a PE number. 
a. If an adverse event form has already been reported for this event and a PE number 
has already been issued via the AE, use the PE number from the AE 
correspondence.  In this instance, sending the PER to field assurance to receive a 
PCR number is not required. 
2. Note the PE number on the Product Experience Report and place the completed form and 
autopsy heart in the box.  
3. Using the pre-paid/pre-printed form, ship by Federal Express or other overnight carrier if a 
form is not provided for your convenience. For further assistance, call the number below.  
If a return kit is required, contact Customer Service: 
1-800-556-4247 
All return product should be sent to:  
Medtronic, Inc. 
Attn: Explant Lab/ [PE #] 
1851 E. Deere Ave. 
Santa Ana, CA 92705-5720 
USA 
1-800-854-3570 
 

 
 
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Economic and Quality of Life Data Collection 
 R.12.1 
Health Economic Data Collection 
Throughout this trial, resource utilization data will be collected by the research coordinator along 
with clinical data using case report forms.   
Prior to enrollment in the study, patients will be asked to provide the information and permission to 
obtain such billing records for the length of their follow-up period.  All related data will be kept in a 
secure and confidential database.  
R.12.2 
Quality of Life Data Collection 
The QoL questionnaires will be administered to all subjects in languages where translation is 
available. It is not a deviation if a subject does not complete a Quality of Life Questionnaire 
because a translation is not available in the subject’s language. 
All QoL assessments will be by written, self-administered questionnaires. Ample, uninterrupted 
time should be provided for the subject to complete the questionnaires. Every effort should be 
made to have the subject complete the questionnaire him or herself.  If the subject is unable to 
complete the questionnaires, the caregiver may complete the questionnaires on their behalf. 
R.12.2.1 Schedule of Assessments 
Questionnaires are to be administered, per protocol: 
 
Baseline 
 
30 days 
 
3 months 
 
6 months 
 
12 months 
 
18 months 
 
24 months 
 
3 years 
 
4 years 
 
5 years 
Baseline Assessment: 
Questionnaires may be administered any time after the subject has provided informed consent but 
should be collected prior to informing the subject of their treatment assignment. 
3 month Assessment: 
Questionnaire(s) should be administered via telephone. 
 
EQ-5D – collected in all participating geographies 
 
SF-36 – collected is limited to subjects in: 
o 
Canada 
o 
Denmark 
o 
Netherlands 
o 
United Kingdom 
o 
United States 
 
 

 
 
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R.12.2.2 Questionnaires 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a validated self-administered 23-item 
questionnaire that quantifies physical limitations, symptoms, self-efficacy, social interference and 
quality of life.  
SF-36 
QualityMetric’s SF-36v2® Health Survey is a multi-purpose short-form that measures functional 
health and well-being from the patient’s point of view. 
EuroQoL EQ-5D 
The EQ-5D is a measure of self-reported health outcomes that is applicable to a wide range of 
health conditions and treatments. It consists of two parts: a descriptive system (Part I) and a visual 
analogue scale (VAS) (Part II). Part I of the scale consists of 5 single-item dimensions including: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has a 
3 point response scale designed to indicate the level of the problem. Part II uses a vertical 
graduated VAS (thermometer) to measure health status, ranging from worst imaginable health 
state to best imaginable health state. 
 

 
 
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Pacing Guidelines 
Recommendations for pacing pre-, peri- and post-operatively are provided below (see also 
respective investigational device Instructions For Use).  These are recommendations and final 
decisions should be made via clinical presentation and physician discretion.  Programmed settings 
for temporary and permanent pacing are per subject condition and physician discretion.   
Pre-operative Recommendations 
 
Ensure subject is informed about the placement of temporary pacing wires during the 
procedure and any additional associated risks. 
 
Ensure subject is informed about the potential for the placement of a permanent pacemaker 
and any additional associated risks. 
 
Obtain a baseline 12-lead ECG and assess for subject’s conduction status 
 
Subjects with a pre-existing permanent pacemaker only: Conduct a full interrogation and 
AV conduction assessment. Print a copy of the interrogation and save the data on a diskette.  
Label the diskette with labels provided by Medtronic, including center name, subject ID, date 
and time of visit/interrogation and type of visit. Retain the printout and diskette in the subject’s 
file for source verification.   
o Recommended AV conduction assessment:   
 
Conduct an atrial threshold test with a long AV delay (e.g. 350ms) in DDD mode. 
 
If the subject’s ventricular rhythm doesn't come through within the 350 ms, the 
subject would be considered dependent on ventricular pacing. 
Peri-operative Recommendations 
 
Prior to beginning the respective investigational device implant, place a temporary 4-5 Fr. 
balloon-tip pacing wire in a stable location within the right ventricular (a screw-tip wire may be 
used for more secure placement for subjects at high-risk for dislodgement, if necessary and 
experienced with implantation technique).   
o Whenever possible, use the upper torso venous system (e.g., jugular, sub-clavian) for 
temporary pacing wire access due to the recommendation to leave this system in for at 
least 48 hours post-procedure. 
o Use fluoroscopy to guide wire placement and stability. 
o Confirm sensing and capture 
o Program the backup pacing rate to minimize ventricular pacing (e.g. 30-40 bpm).  If heart 
block develops, adjustment the rate accordingly. 
 
Rapid pacing during balloon valvuloplasty 
o Conduct a rapid pacing test prior to balloon valvuloplasty.   
 
Successful test is defined as 1-to-1 pacing capture with an immediate drop in 
pressure and elimination of the systolic-diastolic waveform. 
Post-operative Recommendations 
 
All subjects should stay on telemetry until discharge 
 
Maintain temporary pacing until at least 48 hours post-implant 
o Ensure a clean, sterile environment is maintained 
 
After 48 hours, obtain ECG and assess subject rhythm and conduction 
o Based on assessment, and with the consult of an electrophysiologist as needed, take one 
of the following actions: 
 
Discontinue temporary pacing 
 
Continue temporary pacing for another 24 hours (longer if needed) to make further 
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 
Place a permanent pacemaker according to ACC/AHA/HRS Guidelines for Device-
Based Therapy of Cardiac Rhythm Abnormalities1(Class I or IIa for Acquired 
Atrioventricular Block in Adults or Permanent Pacing in Chronic Bifascicular Block) 
 Prior to the permanent pacemaker implantation, document the reason for the 
placement of the permanent pacemaker via a 12-lead ECG. 
 
For complete heart block, review subject medications.  Consider withholding some 
medications to assess for subject’s intrinsic rate and conduction.  If heart block persists off 
medications, a permanent pacemaker should be considered. 
 
If a permanent pacemaker is required, a dual chamber system is recommended to optimize 
subject hemodynamics. 
o Recommended AV conduction assessment:   
 
Conduct an atrial threshold test with a long AV delay 350ms) in DDD mode.   
 
If the subject’s ventricular rhythm doesn't come through within the 350 ms, the 
subject would be considered dependent on ventricular pacing. 
                                                    
 
1  ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: J Am Coll Cardiol 2008; 51:2085–105; 
Circulation 2008;117:2820–40
 

 
 
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ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities 
Recommendations for Acquired Atrioventricular Block in Adults 
Class I Permanent pacemaker implantation is indicated for: 
 
Third-degree and advanced second-degree atrioventricular (AV) block at any anatomic level 
associated with bradycardia with symptoms (including heart failure) or ventricular arrhythmias 
presumed to be due to AV block. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level associated with 
arrhythmias and other medical conditions that require drug therapy that results in 
symptomatic bradycardia. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level in awake, 
symptom-free patients in sinus rhythm, with documented periods of asystole greater than or 
equal to 3.0 seconds or any escape rate less than 40 bpm, or with an escape rhythm that is 
below the AV node. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level in awake, 
symptom-free patients with atrial fibrillation and bradycardia with 1 or more pauses of at least 
5 seconds or longer. (LOE: C)  
 
Third-degree and advanced second-degree AV block at any anatomic level after catheter 
ablation of the AV junction. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level associated with 
postoperative AV block that is not expected to resolve after cardiac surgery. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level associated with 
neuromuscular diseases with AV block, such as myotonic muscular dystrophy, Kearns-Sayre 
syndrome, Erb dystrophy (limb-girdle muscular dystrophy), and peroneal muscular atrophy, 
with or without symptoms. (LOE: B) 
 
Second-degree AV block with associated symptomatic bradycardia regardless of type or site 
of block. (LOE: B) 
 
Asymptomatic persistent third-degree AV block at any anatomic site with average awake 
ventricular rates of 40 bpm or faster if cardiomegaly or left ventricular (LV) dysfunction is 
present or if the site of block is below the AV node. (LOE: B) 
 
Second- or third-degree AV block during exercise in the absence of myocardial ischemia. 
(LOE: C)  
Class IIa Permanent pacemaker implantation is reasonable for: 
 
Persistent third-degree AV block with an escape rate greater than 40 bpm in asymptomatic 
adult patients without cardiomegaly. (LOE: C) 
 
Asymptomatic second-degree AV block at intra or infra-His levels found at 
electrophysiological study. (LOE: B) 
 
First- or second-degree AV block with symptoms similar to those of pacemaker syndrome or 
hemodynamic compromise. (LOE: B) 
 
Asymptomatic type II second-degree AV block with a narrow QRS. When type II second-
degree AV block occurs with a wide QRS, including isolated right bundle-branch block, 
pacing becomes a Class I recommendation (see Section 2.1.3, “Chronic Bifascicular Block,” 
in the full-text guidelines). (LOE: B) 
 

 
 
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Recommendations for Permanent Pacing in Chronic Bifascicular Block 
Class I Permanent pacemaker implantation is indicated for: 
1. Advanced second-degree AV block or intermittent third-degree AV block. (LOE: B) 
2. Type II second-degree AV block. (LOE: B) 
3. Alternating bundle-branch block. (LOE: C) 
 
Class IIa Permanent pacemaker implantation is reasonable for: 
 
Syncope not demonstrated to be due to AV block when other likely causes have been 
excluded, specifically ventricular tachycardia (VT). (LOE: B) 
 
Incidental finding at electrophysiological study of a markedly prolonged HV interval (greater 
than or equal to 100 milliseconds) in asymptomatic patients. (LOE: B) 
 
Incidental finding at electrophysiological study of pacing-induced infra-His block that is not 
physiological. (LOE: B) 
 
 

 
 
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Six Minute Walk Test Instructions 
American Thoracic Society 
ATS Statement: Guidelines for the Six-Minute Walk Test  
THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY WAS APPROVED BY 
THE ATS BOARD OF DIRECTORS MARCH 2002  
CONTENTS  
Purpose and Scope  
Background  
Indications and Limitations  
Contraindications  
Safety Issues  
Technical Aspects of the 6-Minute Walk Test  
Required Equipment  
Patient Preparation  
Measurements  
Quality Assurance  
Interpretation  
References  
PURPOSE AND SCOPE  
This statement provides practical guidelines for the 6-minute walk test (6MWT). Specifically, it 
reviews indications, details factors that influence results, presents a brief step-by-step protocol, 
outlines safety measures, describes proper patient preparation and procedures, and offers 
guidelines for clinical interpretation of results. These recommendations are not intended to limit the 
use of alternative protocols for research studies. We do not discuss the general topic of clinical 
exercise testing.  
As with other American Thoracic Society statements on pulmonary function testing, these 
guidelines come out of a consensus conference. Drafts were prepared by two members (P.L.E. and 
R.J.Z.) and were based on a comprehensive Medline literature search from 1970 through 2001, 
augmented by suggestions from other committee members. Each draft responded to comments 
from the working committee. The guidelines follow previously published methods as closely as 
possible and provide a rationale for each specific recommendation. The final recommendations 
represent a consensus of the committee. The committee recommends that these guidelines be 
reviewed in five years and in the meantime encourages further research in areas of controversy.  
BACKGROUND  
There are several modalities available for the objective evaluation of functional exercise capacity. 
Some provide a very complete assessment of all systems involved in exercise performance (high 
tech), whereas others provide basic information but are low tech and are simpler to perform. The 
modality used should be chosen based on the clinical question to be addressed and on available 
resources. The most popular clinical exercise tests in order of increasing complexity are stair 
climbing, a 6MWT, a shuttle-walk test, detection of exercise-induced asthma, a cardiac stress test 
(e.g., Bruce protocol), and a cardiopulmonary exercise test (1, 2). Other professional organizations 
have published standards for cardiac stress testing (3, 4).  
Assessment of functional capacity has traditionally been done by merely asking patients the 
following: "How many flights of stairs can you climb or how many blocks can you walk?" However, 
patients vary in their recollection and may report overestimations or underestimations of their true 
functional capacity. Objective measurements are usually better than self-reports. In the early 1960s, 
Balke developed a simple test to evaluate the functional capacity by measuring the distance walked 
during a defined period of time (5). A 12-minute field performance test was then developed to 
evaluate the level of physical fitness of healthy individuals (6). The walking test was also adapted to 
assess disability in patients with chronic bronchitis (7). In an attempt to accommodate patients with 
respiratory disease for whom walking 12 minutes was too exhausting, a 6-minute walk was found to 
perform as well as the 12-minute walk (8). A recent review of functional walking tests concluded that 

 
 
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"the 6MWT is easy to administer, better tolerated, and more reflective of activities of daily living than 
the other walk tests" (9).  
The 6MWT is a practical simple test that requires a 100-ft hallway but no exercise equipment or 
advanced training for technicians. Walking is an activity performed daily by all but the most severely 
impaired patients. This test measures the distance that a patient can quickly walk on a flat, hard 
surface in a period of 6 minutes (the 6MWD). It evaluates the global and integrated responses of all 
the systems involved during exercise, including the pulmonary and cardiovascular systems, 
systemic circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism. It 
does not provide specific information on the function of each of the different organs and systems 
involved in exercise or the mechanism of exercise limitation, as is possible with maximal 
cardiopulmonary exercise testing. The self-paced 6MWT assesses the submaximal level of 
functional capacity. Most patients do not achieve maximal exercise capacity during the 6MWT; 
instead, they choose their own intensity of exercise and are allowed to stop and rest during the test. 
However, because most activities of daily living are performed at submaximal levels of exertion, the 
6MWD may better reflect the functional exercise level for daily physical activities.  
INDICATIONS AND LIMITATIONS  
The strongest indication for the 6MWT is for measuring the response to medical interventions in 
patients with moderate to severe heart or lung disease. The 6MWT has also been used as a one-
time measure of functional status of patients, as well as a predictor of morbidity and mortality (see 
Table 1 for a list of these indications). The fact that investigators have used the 6MWT in these 
settings does not prove that the test is clinically useful (or the best test) for determining functional 
capacity or changes in functional capacity due to an intervention in patients with these diseases. 
Further studies are necessary to determine the utility of the 6MWT in various clinical situations.  
TABLE 1. Indications for the Six-Minute Walk Test  
Pretreatment and post treatment comparisons 
Lung transplantation (9, 10) 
Lung resection (11) 
Lung volume reduction surgery (12, 13) 
Pulmonary rehabilitation (14, 15) 
COPD (16–18) 
Pulmonary hypertension 
Heart failure (19, 20) 
Functional status (single measurement) 
COPD (21, 22) 
Cystic fibrosis (23, 24) 
Heart failure (25–27) 
Peripheral vascular disease (28, 29) 
Fibromyalgia (30) 
Older patients (31) 
Predictor of morbidity and mortality 
Heart failure (32, 33) 
COPD (34, 35) 
Primary pulmonary hypertension (10, 36) 
Definition of abbreviation: COPD = chronic obstructive pulmonary disease. 
Formal cardiopulmonary exercise testing provides a global assessment of the exercise response, 
an objective determination of functional capacity and impairment, determination of the appropriate 
intensity needed to perform prolonged exercise, quantification of factors limiting exercise, and a 
definition of the underlying pathophysiologic mechanisms such as the contribution of different organ 
systems involved in exercise. The 6MWT does not determine peak oxygen uptake, diagnose the 
cause of dyspnea on exertion, or evaluate the causes or mechanisms of exercise limitation (1, 2). 
The information provided by a 6MWT should be considered complementary to cardiopulmonary 
exercise testing, not a replacement for it. Despite the difference between these two functional tests, 
some good correlations between them have been reported. For example, a significant correlation (r 
= 0.73) between 6MWD and peak oxygen uptake has been reported for patients with end-stage 
lung diseases (36).  

 
 
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In some clinical situations, the 6MWT provides information that may be a better index of the 
patient's ability to perform daily activities than is peak oxygen uptake; for example, 6MWD 
correlates better with formal measures of quality of life (37). Changes in 6MWD after therapeutic 
interventions correlate with subjective improvement in dyspnea (38, 39). The reproducibility of the 
6MWD (with a coefficient of variation of approximately 8%) appears to be better than the 
reproducibility of 1-second forced expiratory volume in patients with chronic obstructive pulmonary 
disease (COPD) (8, 39–42). Questionnaire indices of functional status have a larger short-term 
variability (22–33%) than does the 6MWD (37).  
The shuttle-walking test is similar to the 6MWT, but it uses an audio signal from a tape cassette to 
direct the walking pace of the patient back and forth on a 10-m course (43–45). The walking speed 
is increased every minute, and the test ends when the patient cannot reach the turnaround point 
within the required time. The exercise performed is similar to a symptom-limited, maximal, 
incremental treadmill test. An advantage of the shuttle walking test is that it has a better correlation 
with peak oxygen uptake than the 6MWD (46, 47). Disadvantages include less validation, less 
widespread use, and more potential for cardiovascular problems.  
CONTRAINDICATIONS  
Absolute contraindications for the 6MWT include the following: unstable angina during the previous 
month and myocardial infarction during the previous month. Relative contraindications include a 
resting heart rate of more than 120, a systolic blood pressure of more than 180 mm Hg, and a 
diastolic blood pressure of more than 100 mm Hg.  
Patients with any of these findings should be referred to the physician ordering or supervising the 
test for individual clinical assessment and a decision about the conduct of the test. The results from 
a resting electrocardiogram done during the previous 6 months should also be reviewed before 
testing. Stable exertional angina is not an absolute contraindication for a 6MWT, but patients with 
these symptoms should perform the test after using their antiangina medication, and rescue nitrate 
medication should be readily available.  
Rationale 
Patients with the previously mentioned risk factors may be at increased risk for arrhythmias or 
cardiovascular collapse during testing. However, each patient determines the intensity of their 
exercise, and the test (without electrocardiogram monitoring) has been performed in thousands 
of older persons (31, 48) and thousands of patients with heart failure or cardiomyopathy (32, 49, 
50) without serious adverse events. The contraindications listed previously here were used by 
study investigators based on their impressions of the general safety of the 6MWT and their 
desire to be prudent, but it is unknown whether adverse events would occur if such patients 
performed a 6MWT; they are, therefore, listed as relative contraindications.  
SAFETY ISSUES  
1. Testing should be performed in a location where a rapid, appropriate response to an 
emergency is possible. The appropriate location of a crash cart should be determined by the 
physician supervising the facility.  
2. Supplies that must be available include oxygen, sublingual nitroglycerine, aspirin, and 
albuterol (metered dose inhaler or nebulizer). A telephone or other means should be in place 
to enable a call for help.  
3. The technician should be certified in cardiopulmonary resuscitation with a minimum of Basic 
Life Support by an American Health Association–approved cardiopulmonary resuscitation 
course. Advanced cardiac life support certification is desirable. Training, experience, and 
certification in related health care fields (registered nurse, registered respiratory therapist, 
certified pulmonary function technician, etc.) are also desirable. A certified individual should 
be readily available to respond if needed.  
4. Physicians are not required to be present during all tests. The physician ordering the test or a 
supervising laboratory physician may decide whether physician attendance at a specific test is 
required.  

 
 
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5. If a patient is on chronic oxygen therapy, oxygen should be given at their standard rate or as 
directed by a physician or a protocol.  
Reasons for immediately stopping a 6MWT include the following: (1) chest pain, (2) intolerable 
dyspnea, (3) leg cramps, (4) staggering, (5) diaphoresis, and (6) pale or ashen appearance.  
Technicians must be trained to recognize these problems and the appropriate responses. If a test is 
stopped for any of these reasons, the patient should sit or lie supine as appropriate depending on 
the severity or the event and the technician's assessment of the severity of the event and the risk of 
syncope. The following should be obtained based on the judgment of the technician: blood 
pressure, pulse rate, oxygen saturation, and a physician evaluation. Oxygen should be 
administered as appropriate.  
TECHNICAL ASPECTS OF THE 6MWT  
Location 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a hard 
surface that is seldom traveled. If the weather is comfortable, the test may be performed outdoors. 
The walking course must be 30 m in length. A 100-ft hallway is, therefore, required. The length of 
the corridor should be marked every 3 m. The turnaround points should be marked with a cone 
(such as an orange traffic cone). A starting line, which marks the beginning and end of each 60-m 
lap, should be marked on the floor using brightly colored tape.  
Rationale 
A shorter corridor requires patients to take more time to reverse directions more often, reducing 
the 6MWD. Most studies have used a 30-m corridor (51), but some have used 20- or 50-m 
corridors (52, 53). A recent multicenter study found no significant effect of the length of straight 
courses ranging from 50 to 164 ft, but patients walked farther on continuous (oval) tracks (mean 
92 ft farther) (54).  
The use of a treadmill to determine the 6MWD might save space and allow constant monitoring 
during the exercise, but the use of a treadmill for 6-minute walk testing is not recommended. 
Patients are unable to pace themselves on a treadmill. In one study of patients with severe lung 
disease, the mean distance walked on the treadmill during 6 minutes (with the speed adjusted 
by the patients) was shorter by a mean of 14% when compared with the standard 6MWD using 
a 100-ft hallway (55). The range of differences was wide, with patients walking between 400–
1,300 ft on the treadmill who walked 1,200 ft in the hallway. Treadmill test results, therefore, are 
not interchangeable with corridor tests.  
REQUIRED EQUIPMENT  
1. Countdown timer (or stopwatch)  
2. Mechanical lap counter  
3. Two small cones to mark the turnaround points  
4. A chair that can be easily moved along the walking course  
5. Worksheets on a clipboard  
6. A source of oxygen  
7. Sphygmomanometer  
8. Telephone  
9. Automated electronic defibrillator  

 
 
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PATIENT PREPARATION  
6. Comfortable clothing should be worn.  
7. Appropriate shoes for walking should be worn.  
8. Patients should use their usual walking aids during the test (cane, walker, etc.).  
9. The patient's usual medical regimen should be continued.  
10. A light meal is acceptable before early morning or early afternoon tests.  
11. Patients should not have exercised vigorously within 2 hours of beginning the test.  
MEASUREMENTS  
1. Repeat testing should be performed about the same time of day to minimize intraday 
variability.  
2. A "warm-up" period before the test should not be performed.  
3. The patient should sit at rest in a chair, located near the starting position, for at least 10 
minutes before the test starts. During this time, check for contraindications, measure pulse 
and blood pressure, and make sure that clothing and shoes are appropriate. Complete the 
first portion of the worksheet (see the APPENDIX).  
4. Pulse oximetry is optional. If it is performed, measure and record baseline heart rate and 
oxygen saturation (SpO2) and follow manufacturer's instructions to maximize the signal and 
to minimize motion artifact (56). Make sure the readings are stable before recording. Note 
pulse regularity and whether the oximeter signal quality is acceptable.  
The rationale for measuring oxygen saturation is that although the distance is the primary 
outcome measure, improvement during serial evaluations may be manifest either by an 
increased distance or by reduced symptoms with the same distance walked (38). The SpO2 
should not be used for constant monitoring during the exercise. The technician must not 
walk with the patient to observe the SpO2. If worn during the walk, the pulse oximeter must 
be lightweight (less than 2 pounds), battery powered, and held in place (perhaps by a 
"fanny pack") so that the patient does not have to hold or stabilize it and so that stride is not 
affected. Many pulse oximeters have considerable motion artifact that prevents accurate 
readings during the walk (57).  
5. Have the patient stand and rate
 their baseline dyspnea and overall
 fatigue using the Borg scale
 
(see Table 2 for the Borg scale
 and instructions [58]).
  
6. Set
 the lap counter to zero and the timer to 6 minutes. Assemble
 all necessary equipment (lap 
counter, timer, clipboard, Borg
 Scale, worksheet) and move to the starting point.
  
7. Instruct
 the patient as follows:
  
"The object of this test is to walk as far as possible for 6 minutes. You will walk back 
and forth in this hallway. Six minutes is a long time to walk, so you will be exerting 
yourself. You will probably get out of breath or become exhausted. You are permitted to 
slow down, to stop, and to rest as necessary. You may lean against the wall while 
resting, but resume walking as soon as you are able.  
You will be walking back and forth around the cones. You should pivot briskly around the 
cones and continue back the other way without hesitation. Now I'm going to show you. 
Please watch the way I turn without hesitation."  
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly.  
"Are you ready to do that? I am going to use this counter to keep track of the number of 
laps you complete. I will click it each time you turn around at this starting line. Remember 
that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or jog.  
Start now or whenever you are ready."  
 
 

 
 
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TABLE 2. The Borg scale 
0 
Nothing at all 
0.5 
Very, very slight (just noticeable) 
1 
Very slight 
2 
Slight (light) 
3 
Moderate 
4 
Somewhat severe 
5 
Severe (heavy) 
6 
 
7 
Very severe 
8 
 
9 
 
10 
Very, very severe (maximal) 
 
This Borg scale should be printed on heavy paper (11 inches high and perhaps laminated) in 
20-point type size. At the beginning of the 6-minute exercise, show the scale to the patient and 
ask the patient this: "Please grade your level of shortness of breath using this scale." Then ask 
this: 
"Please 
grade 
your 
level 
of 
fatigue 
using 
this 
scale." 
At the end of the exercise, remind the patient of the breathing number that they chose before 
the exercise and ask the patient to grade their breathing level again. Then ask the patient to 
grade their level of fatigue, after reminding them of their grade before the exercise. 
8. Position the patient at the starting line. You should also stand near the starting line during 
the test. Do not walk with the patient. As soon as the patient starts to walk, start the timer  
9. Do not talk to anyone during the walk. Use an even tone of voice when using the standard 
phrases of encouragement. Watch the patient. Do not get distracted and lose count of the 
laps. Each time the participant returns to the starting line, click the lap counter once (or 
mark the lap on the worksheet). Let the participant see you do it. Exaggerate the click using 
body language, like using a stopwatch at a race.  
After the first minute, tell the patient the following (in even tones): "You are doing well. You 
have 5 minutes to go."  
When the timer shows 4 minutes remaining, tell the patient the following: "Keep up the 
good work. You have 4 minutes to go."  
When the timer shows 3 minutes remaining, tell the patient the following: "You are doing 
well. You are halfway done."  
When the timer shows 2 minutes remaining, tell the patient the following: "Keep up the 
good work. You have only 2 minutes left."  
When the timer shows only 1 minute remaining, tell the patient: "You are doing well. You 
have only 1 minute to go."  
Do not use other words of encouragement (or body language to speed up).  
If the patient stops walking during the test and needs a rest, say this: "You can lean against 
the wall if you would like; then continue walking whenever you feel able." Do not stop the 
timer. If the patient stops before the 6 minutes are up and refuses to continue (or you 
decide that they should not continue), wheel the chair over for the patient to sit on, 
discontinue the walk, and note on the worksheet the distance, the time stopped, and the 
reason for stopping prematurely.  
When the timer is 15 seconds from completion, say this: "In a moment I'm going to tell you 
to stop. When I do, just stop right where you are and I will come to you."  
When the timer rings (or buzzes), say this: "Stop!" Walk over to the patient. Consider taking 
the chair if they look exhausted. Mark the spot where they stopped by placing a bean bag 
or a piece of tape on the floor.  
10. Post-test: Record the postwalk Borg dyspnea and fatigue levels and ask this: "What, if 
anything, kept you from walking farther?"  

 
 
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11. If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and then remove 
the sensor.  
12. Record the number of laps from the counter (or tick marks on the worksheet).  
13. Record the additional distance covered (the number of meters in the final partial lap) using 
the markers on the wall as distance guides. Calculate the total distance walked, rounding to 
the nearest meter, and record it on the worksheet.  
14. Congratulate the patient on good effort and offer a drink of water.  
QUALITY ASSURANCE  
Sources of Variability 
There are many sources of 6MWD variability (see Table 3). The sources of variability caused by the 
test procedure itself should be controlled as much as possible. This is done by following the 
standards found in this document and by using a quality-assurance program.  
TABLE 3. 6MWD Sources of Variability  
Factors reducing the 6MWD 
Shorter height 
Older age 
Higher body weight 
Female sex 
Impaired cognition 
A shorter corridor (more turns) 
Pulmonary disease (COPD, asthma, cystic fibrosis, interstitial lung disease) 
Cardiovascular disease (angina, MI, CHF, stroke, TIA, PVD, AAI) 
Musculoskeletal disorders (arthritis, ankle, knee, or hip injuries, muscle wasting, etc.) 
Factors increasing the 6MWD 
Taller height (longer legs) 
Male sex 
High motivation 
A patient who was previously performed the test 
Medication for a disabling disease taken just before the test 
Oxygen supplementation in patients with exercise induced hypoxemia 
 
Definition of abbreviations: COPD = chronic obstructive pulmonary disease; 6MWD = 6-minute walking distance.  
 
Practice Tests 
A practice test is not needed in most clinical settings but should be considered. If a practice test is 
done, wait for at least 1 hour before the second test and report the highest 6MWD as the patient's 
6MWD baseline.  
Rationale 
The 6MWD is only slightly higher for a second 6MWT performed a day later. The mean 
reported increase ranges from 0 to 17% (23, 27, 40, 41, 54, 59). A multicenter study of 470 
highly motivated patients with severe COPD performed two 6MWTs 1 day apart, and on 
average, the 6MWD was only 66 ft (5.8%) higher on the second day (54).  
Performance (without an intervention) usually reaches a plateau after two tests done within a 
week (8, 60). The training effect may be due to improved coordination, finding optimal stride 
length, and overcoming anxiety. The possibility of a practice or training effect from tests 
repeated after more than a month has not been studied or reported; however, it is likely that the 
effect of training wears off (does not persist) after a few weeks.  

 
 
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Technician Training and Experience 
Technicians who perform 6MWTs should be trained using the standard protocol and then 
supervised for several tests before performing them alone. They should also have completed 
cardiopulmonary resuscitation training.  
Rationale 
One multicenter study of older people found that after correction for many other factors, two of 
the technicians had mean 6MWDs that were approximately 7% lower than the other two sites 
(31).  
Encouragement 
Only the standardized phrases for encouragement (as specified previously here) must be used 
during the test.  
Rationale 
Encouragement significantly increases the distance walked (42). Reproducibility for tests with 
and without encouragement is similar. Some studies have used encouragement every 30 
seconds, every minute, or every 2 minutes. We have chosen every minute and standard 
phrases. Some studies (53) have instructed patients to walk as fast as possible. Although larger 
mean 6MWDs may be obtained thereby, we recommend that such phrases not be used, as they 
emphasize initial speed at the expense of earlier fatigue and possible excessive cardiac stress 
in some patients with heart disease.  
Supplemental Oxygen 
If oxygen supplementation is needed during the walks and serial tests are planned (after an 
intervention other than oxygen therapy), then during all walks by that patient oxygen should be 
delivered in the same way with the same flow. If the flow must be increased during subsequent 
visits due to worsening gas exchange, this should be noted on the worksheet and considered 
during interpretation of the change noted in 6MWD. The type of oxygen delivery device should also 
be noted on the report: for instance, the patient carried liquid oxygen or pushed or pulled an oxygen 
tank, the delivery was pulsed or continuous, or a technician walked behind the patient with the 
oxygen source (not recommended). Measurements of pulse and SpO2 should be made after waiting 
at least 10 minutes after any change in oxygen delivery.  
Rationale 
For patients with COPD or interstitial lung disease, oxygen supplementation increases the 
6MWD (17, 59, 61). Carrying a portable gas container (but not using it for supplemental 
oxygen) reduced the mean 6MWD by 14% in one study of patients with severe respiratory 
disability, but using the container to deliver supplemental oxygen during the exercise increased 
the mean 6MWD by 20–36% (59).  
Medications 
The type of medication, dose, and number of hours taken before the test should be noted.  
Rationale 
Significant improvement in the distance walked, or the dyspnea scale, after administration of 
bronchodilators has been demonstrated in patients with COPD (62, 63), as well as 
cardiovascular medications in patients with heart failure (19).  
INTERPRETATION  
Most 6MWTs will be done before and after intervention, and the primary question to be answered 
after both tests have been completed is whether the patient has experienced a clinically significant 
improvement. With a good quality-assurance program, with patients tested by the same technician, 
and after one or two practice tests, short-term reproducibility of the 6MWD is excellent (36). It is not 
known whether it is best for clinical purposes to express change in 6MWD as (1) an absolute value, 
(2) a percentage change, or (3) a change in the percentage of predicted value. Until further 
research is available, we recommend that change in 6MWD be expressed as an absolute value 
(e.g., the patient walked 50 m farther).  
A statistically significant mean increase in 6MWD in a group of study participants is often much less 
than a clinically significant increase in an individual patient. In one study of 112 patients (half of 
them women) with stable, severe COPD, the smallest difference in 6MWD that was associated with 
a noticeable clinical difference in the patients' perception of exercise performance was a mean of 54 

 
 
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m (95% confidence interval, 37–71 m) (64). This study suggests that for individual patients with 
COPD, an improvement of more than 70 m in the 6MWD after an intervention is necessary to be 
95% confident that the improvement was significant. In an observational study of 45 older patients 
with heart failure, the smallest difference in 6MWD that was associated with a noticeable difference 
in their global rating of worsening was a mean of 43 m (20). The 6MWD was more responsive to 
deterioration than to improvement in heart failure symptoms.  
Reported Mean Changes in 6MWD After Interventions 
Supplemental oxygen (6 L/min) during exercise in patients with COPD or interstitial lung disease 
increased mean 6MWD by approximately 83 m (36%) in one study (59). Patients taking an inhaled 
corticosteroid experienced a mean 33 m (8%) increase in 6MWD in an international COPD study 
(16). Patients with COPD in a study of the effects of exercise and diaphragmatic strength training 
experienced a mean increase in 6MWD of 50 m (20%) (65). Lung volume reduction surgery in 
patients with very severe COPD has been reported to increase 6MWD by a mean of 55 m (20%) 
(13).  
Cardiac rehabilitation in patients referred with various heart diseases increased 6MWD by a mean 
of 170 m (15%) in a recent study (66). In 25 older patients with heart failure, an angiotensin-
converting enzyme inhibitor medication (50 mg captopril per day) improved 6MWD a mean of 64 m 
(39%) compared with a mean increase of only 8% in those receiving a placebo (19).  
Interpreting Single Measurements of Functional Status 
Optimal reference equations from healthy population-based samples using standardized 6MWT 
methods are not yet available. In one study, the median 6MWD was approximately 580 m for 117 
healthy men and 500 m for 173 healthy women (48). A mean 6MWD of 630 m was reported by 
another study of 51 healthy older adults (53). Differences in the population sampled, type and 
frequency of encouragement, corridor length, and number of practice tests may account for reported 
differences in mean 6MWD in healthy persons. Age, height, weight, and sex independently affect 
the 6MWD in healthy adults; therefore, these factors should be taken into consideration when 
interpreting the results of single measurements made to determine functional status. We encourage 
investigators to publish reference equations for healthy persons using the previously mentioned 
standardized procedures.  
A low 6MWD is nonspecific and nondiagnostic. When the 6MWD is reduced, a thorough search for 
the cause of the impairment is warranted. The following tests may then be helpful: pulmonary 
function, cardiac function, ankle–arm index, muscle strength, nutritional status, orthopedic function, 
and cognitive function.  
Conclusions 
The 6MWT is a useful measure of functional capacity targeted at people with at least moderately 
severe impairment. The test has been widely used for preoperative and postoperative evaluation 
and for measuring the response to therapeutic interventions for pulmonary and cardiac disease. 
These guidelines provide a standardized approach to performing the 6MWT. The committee hopes 
that these guidelines will encourage further research into the 6MWT and allow direct comparisons 
among different studies.  
 
 

 
 
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APPENDIX  
The following elements should be present on the 6MWT worksheet and report: 
Lap counter:  __ __ __ __ __  __ __ __ __ __  __ __ __ __ __  
Patient name: ____________________      Patient ID# ___________  
Walk # ______    Tech ID: _________ Date: __________  
Gender: M F  Age: ____  Race: ____  Height: ___ft ____in, ____ meters  
Weight: ______ lbs, _____kg      Blood pressure: _____ / _____  
Medications taken before the test (dose and time): __________________  
Supplemental oxygen during the test: No  Yes, flow ______ L/min, type _____ 
 
Baseline 
End of Test 
 Time 
___:___ 
___:___ 
 Heart Rate 
_____ 
_____ 
 Dyspnea 
_____ 
_____ (Borg scale) 
 Fatigue 
_____ 
_____ (Borg scale) 
 SpO2 
_____ % 
_____ % 
Stopped or paused before 6 minutes? No  Yes, reason: _______________  
Other symptoms at end of exercise: angina  dizziness  hip, leg, or calf pain  
Number of laps: ____ (x60 meters) + final partial lap: _____ meters =  
Total distance walked in 6 minutes: ______ meters  
Predicted distance: _____ meters    Percent predicted: _____%  
 
Tech comments:  
 Interpretation (including comparison with a preintervention 6MWD): 
 
 

 
 
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Acknowledgments  
This statement was developed by the ATS Committee on Proficiency Standards for Clinical 
Pulmonary Function Laboratories.  
Members of the committee are:  
ROBERT O. CRAPO, M.D., Chair *  
RICHARD CASABURI, PH.D, M.D.  
ALLAN L. COATES, M.D.  
PAUL L. ENRIGHT, M.D.*  
NEIL R. MACINTYRE, M.D.  
ROY T. MCKAY, PH.D.  
DOUGLAS JOHNSON, M.D.  
JACK S. WANGER, M.S.  
R. JORGE ZEBALLOS, M.D.*  
Ad Hoc Committee members are:  
VERA BITTNER, M.D.  
CARL MOTTRAM, R.R.T.  
*Writing Committee Members  
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40.  Noseda A, Carpiaux J, Prigogine T, Schmerber J. Lung function, maximum and submaximum exercise 
testing in COPD patients: reproducibility over a long interval. Lung 1989;167:247–257.  
41.  Knox AJ, Morrison JF, Muers MF. Reproducibility of walking test results in chronic obstructive airways 
disease. Thorax 1988;43:388–392.  
42.  Guyatt GH, Pugsley SO, Sullivan MJ, Thompson PJ, Berman LB, Jones NL, Fallen EL, Taylor DW. 
Effect of encouragement on walking test performance. Thorax 1984;39:818–822.  
43.  Leger LA. A maximal multistage 20-m shuttle run test to predict VO2 max. Eur J Appl Physiol 
1982;49:1–12.  
44.  Singh SJ, Morgan MDL, Scott S, Walters D, Hardman AE. Development of a shuttle walking test of 
disability in patients with chronic airways obstruction. Thorax 1992;47:1019–1024.  
45.  Revill SM, Morgan MDL, Singh SJ, Williams J, Hardman AE. The endurance shuttle walk: a new field 
test for the assessment of endurance capacity in chronic obstructive pulmonary disease. Thorax 
1999;54:213–222.  
46.  Singh SJ, Morgan MDL, Hardman AE, Rowe C, Bardsley PA. Comparison of oxygen uptake during a 
conventional treadmill test and the shuttle walking test in chronic airflow limitation. Eur Respir J 1994;7: 
2016–2020.  
47.  Morales FJ, Martinez A, Mendez M, Agarrado A, Ortega F, Fernandez-Guerra J, Montemayor T, Burgos 
J. A shuttle walk test for assessment of functional capacity in chronic heart failure. Am Heart J 
1999;138:292–298.  
48.  Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit 
Care Med 1998;158:1384–1387.  

 
 
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49.  Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ. Long WA, Levy PS. Survival in primary pulmonary 
hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994;121:409–415.  
50.  Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical 
correlates and prognostic significance of six-minute walk test in patients with primary pulmonary 
hypertension. Am J Respir Crit Care Med 2000;161:487–492.  
51.  Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, Berman LB. The 6-minute 
walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985; 
132:919–923.  
52.  Lipkin DP, Scrivin AJ, Crake T, Poole-Wilson PA. Six minute walking test for assessing exercise 
capacity in chronic heart failure. BMJ 1986; 292:653–655.  
53.  Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur 
Respir J 1999;14:270–274.  
54.  Weiss RA, et al. Six minute walk test in severe COPD: reliability and effect of walking course layout and 
length. Paper presented at ACCP Conference; September 2000; San Francisco.  
55.  Stevens D, Elpern E, Sharma K, Szidon P, Ankin M, Kesten S. Comparison of hallway and treadmill six-
minute walk tests. Am J Respir Crit Care Med 1999;160:1540–1543.  
56.  Jensen LA, Onyskiw JE, Prasad NGN. Meta-analysis of arterial oxygen saturation monitoring by pulse 
oximetry in adults. Heart Lung 1998; 27:387–408.  
57.  Barthelemy JC, Geyssant A, Riffat J, Antoniadis A, Berruyer J, LaCour JR. Accuracy of pulse oximetry 
during moderate exercise: a comparative study. Scand J Clin Lab Invest 1990;50:533–539.  
58.  Borg GAV. Psycho-physical bases of perceived exertion. Med Sci Sports Exerc 1982;14:377–381.  
59.  Leach RM, Davidson AC, Chinn S, Twort CHC, Cameron IR, Batemen NT. Portable liquid oxygen and 
exercise ability in severe respiratory disability. Thorax 1992;47:781–789.  
60.  Mungall IPF, Hainsworth R. Assessment of respiratory function in patients with chronic obstructive 
airways disease. Thorax 1979;34:254–258.  
61.  Roberts CM, Bell J, Wedzicha JA. Comparison of the efficacy of a demand oxygen delivery system with 
continuous low flow oxygen in subjects with stable COPD and severe oxygen desaturation on walking. 
Thorax 1996;51:831–834.  
62.  Hay JG, Stone P, Carter J, Church S, Eyre-Brook A, Pearson MG, Woodcock AA, Calverley PM. 
Bronchodilator reversibility, exercise performance and breathlessness in stable chronic obstructive 
pulmonary disease. Eur Respir J 1992;5:659–664.  
63.  Grove A, Lipworth BJ, Reid P, Smith RP, Lamage L, Ingram CG, Jenkins RJ, Winter JH, Dhillon DP. 
Effects of regular salmeterol on lung function and exercise capacity in patients with COPD. Thorax 
1996;51:689–693.  
64.  Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH. Interpreting small differences in functional 
status: The six minute walk test in chronic lung disease patients. Am J Respir Crit Care Med 
1997;155:1278–1282.  
65.  Weiner P, Magadle R, Berar-Yanay N, Davidovich A, Weiner M. The cumulative effect of long-acting 
bronchodilators, exercise, and inspiratory muscle training on the perception of dyspnea in patients with 
advanced COPD. Chest 2000;118:672–678.  
66.  Bittner V, Sanderson B, Breland J, Adams C, Schuman C. Assessing functional capacity as an outcome 
in cardiac rehabilitation: role of the 6 minute walk test. Clinical Exercise Physiology 2000. 
 

 
 
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National Institute of Health Stroke Scale (NIHSS) 
Administer stroke scale items in the order listed. Record performance in each category after each 
subscale exam. Do not go back and change scores. Follow directions provided for each exam 
technique. Scores should reflect what the patient does, not what the clinician thinks the patient 
can do. The clinician should record answers while administering the exam and work quickly. 
Except where indicated, the patient should not be coached (i.e., repeated requests to patient to 
make a special effort). 
 
 Instructions  
Scale Definition  
Score  
1a. Level of Consciousness: The investigator 
must choose a response if a full evaluation is 
prevented by such obstacles as an endotracheal 
tube, 
language 
barrier, 
orotracheal 
trauma/bandages. A 3 is scored only if the 
patient makes no movement (other than reflexive 
posturing) in response to noxious stimulation.  
0 = Alert; keenly responsive.  
1 = Not alert; but arousable by minor 
stimulation to obey, answer, or 
respond.  
2 = Not alert; requires repeated 
stimulation to attend, or is obtunded 
and requires strong or painful 
stimulation to make movements (not 
stereotyped).  
3 = Responds only with reflex motor or 
autonomic effects or totally 
unresponsive, flaccid, and areflexic.  
______  
1b. LOC Questions: The patient is asked the 
month and his/her age. The answer must be 
correct - there is no partial credit for being close. 
Aphasic and stuporous patients who do not 
comprehend the questions will score 2. Patients 
unable to speak because of endotracheal 
intubation, orotracheal trauma, severe dysarthria 
from any cause, language barrier, or any other 
problem not secondary to aphasia are given a 1. 
It is important that only the initial answer be 
graded and that the examiner not "help" the 
patient with verbal or non-verbal cues.  
0 = Answers both questions correctly.  
1 = Answers one question correctly.  
2 = Answers neither question correctly.  
______  
1c. LOC Commands: The patient is asked to 
open and close the eyes and then to grip and 
release the non-paretic hand. Substitute another 
one step command if the hands cannot be used. 
Credit is given if an unequivocal attempt is made 
but not completed due to weakness. If the patient 
does not respond to command, the task should 
be demonstrated to him or her (pantomime), and 
the result scored (i.e., follows none, one or two 
commands). Patients with trauma, amputation, or 
other physical impediments should be given 
suitable one-step commands. Only the first 
attempt is scored.  
0 = Performs both tasks correctly.  
1 = Performs one task correctly.  
2 = Performs neither task correctly.  
______  
 
 

 
 
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2. Best Gaze: Only horizontal eye movements 
will 
be 
tested. 
Voluntary 
or 
reflexive 
(oculocephalic) eye movements will be scored, 
but caloric testing is not done. If the patient has a 
conjugate deviation of the eyes that can be 
overcome by voluntary or reflexive activity, the 
score will be 1. If a patient has an isolated 
peripheral nerve paresis (CN III, IV or VI), score 
a 1. Gaze is testable in all aphasic patients. 
Patients with ocular trauma, bandages, pre-
existing blindness, or other disorder of visual 
acuity or fields should be tested with reflexive 
movements, and a choice made 
by the 
investigator. Establishing eye contact and then 
moving about the patient from side to side will 
occasionally clarify the presence of a partial gaze 
palsy.  
0 = Normal.  
1 = Partial gaze palsy; gaze is abnormal 
in one or both eyes, but forced 
deviation or total gaze paresis is not 
present.  
2 = Forced deviation, or total gaze 
paresis not overcome by the 
oculocephalic maneuver.  
______  
3. Visual: Visual fields (upper and lower 
quadrants) are tested by confrontation, using 
finger counting or visual threat, as appropriate. 
Patients may be encouraged, but if they look at 
the side of the moving fingers appropriately, this 
can be scored as normal. If there is unilateral 
blindness or enucleation, visual fields in the 
remaining eye are scored. Score 1 only if a clear-
cut asymmetry, including quadrantanopia, is 
found. If patient is blind from any cause, score 3. 
Double simultaneous stimulation is performed at 
this point. If there is extinction, patient receives a 
1, and the results are used to respond to item 11. 
0 = No visual loss.  
1 = Partial hemianopia.  
2 = Complete hemianopia.  
3 = Bilateral hemianopia (blind including 
cortical blindness).  
______  
4. Facial Palsy: Ask – or use pantomime to 
encourage – the patient to show teeth or raise 
eyebrows and close eyes. Score symmetry of 
grimace in response to noxious stimuli in the 
poorly responsive or non-comprehending patient. 
If facial trauma/bandages, orotracheal tube, tape 
or other physical barriers obscure the face, these 
should be removed to the extent possible.  
0 = Normal symmetrical movements.  
1 = Minor paralysis (flattened nasolabial 
fold, asymmetry on smiling).  
2 = Partial paralysis (total or near-total 
paralysis of lower face).  
3 = Complete paralysis of one or both 
sides (absence of facial movement in 
the upper and lower face).  
______  
5. Motor Arm: The limb is placed in the 
appropriate position: extend the arms (palms 
down) 90 degrees (if sitting) or 45 degrees (if 
supine). Drift is scored if the arm falls before 10 
seconds. The aphasic patient is encouraged 
using urgency in the voice and pantomime, but 
not noxious stimulation. Each limb is tested in 
turn, beginning with the non-paretic arm. Only in 
the case of amputation or joint fusion at the 
shoulder, the examiner should record the score 
as untestable (UN), and clearly write the 
explanation for this choice.  
0 = No drift; limb holds 90 (or 45) 
degrees for full 10 seconds.  
1 = Drift; limb holds 90 (or 45) degrees, 
but drifts down before full 10 seconds; 
does not hit bed or other support.  
2 = Some effort against gravity; limb 
cannot get to or maintain (if cued) 90 
(or 45) degrees, drifts down to bed, 
but has some effort against gravity.  
3 = No effort against gravity; limb falls.  
4 = No movement.  
UN = Amputation or joint fusion, explain: 
_____________________  
5a. Left Arm  
5b. Right Arm  
______  
______  
 
 

 
 
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6. Motor Leg: The limb is placed in the 
appropriate position: hold the leg at 30 degrees 
(always tested supine). Drift is scored if the leg 
falls before 5 seconds. The aphasic patient is 
encouraged using urgency in the voice and 
pantomime, but not noxious stimulation. Each 
limb is tested in turn, beginning with the non-
paretic leg. Only in the case of amputation or 
joint fusion at the hip, the examiner should record 
the score as untestable (UN), and clearly write 
the explanation for this choice.  
0 = No drift; leg holds 30-degree 
position for full 5 seconds.  
1 = Drift; leg falls by the end of the 5-
second period but does not hit bed.  
2 = Some effort against gravity; leg 
falls to bed by 5 seconds, but has 
some effort against gravity.  
3 = No effort against gravity; leg falls to 
bed immediately.  
4 = No movement.  
UN = Amputation or joint fusion, explain: 
________________  
6a. Left Leg  
6b. Right 
______  
______  
7. Limb Ataxia: This item is aimed at finding 
evidence of a unilateral cerebellar lesion. Test 
with eyes open. In case of visual defect, ensure 
testing is done in intact visual field. The finger-
nose-finger and heel-shin tests are performed on 
both sides, and ataxia is scored only if present 
out of proportion to weakness. Ataxia is absent in 
the patient who cannot understand or is 
paralyzed. Only in the case of amputation or joint 
fusion, the examiner should record the score as 
untestable (UN), and clearly write the explanation 
for this choice. In case of blindness, test by 
having the patient touch nose from extended arm 
position.  
0 = Absent.  
1 = Present in one limb.  
2 = Present in two limbs.  
UN = Amputation or joint fusion, explain: 
________________  
______  
8. Sensory: Sensation or grimace to pinprick 
when tested, or withdrawal from noxious stimulus 
in the obtunded or aphasic patient. Only sensory 
loss attributed to stroke is scored as abnormal 
and the examiner should test as many body 
areas (arms [not hands], legs, trunk, face) as 
needed to accurately check for hemisensory loss. 
A score of 2, “severe or total sensory loss,” 
should only be given when a severe or total loss 
of sensation can be clearly demonstrated. 
Stuporous and aphasic patients will, therefore, 
probably score 1 or 0. The patient with brainstem 
stroke who has bilateral loss of sensation is 
scored 2. If the patient does not respond and is 
quadriplegic, score 2. Patients in a coma (item 
1a=3) are automatically given a 2 on this item.  
0 = Normal; no sensory loss.  
1 = Mild-to-moderate sensory loss; 
patient feels pinprick is less sharp or 
is dull on the affected side; or there is 
a loss of superficial pain with pinprick, 
but patient is aware of being touched.  
2 = Severe to total sensory loss; patient 
is not aware of being touched in the 
face, arm, and leg.  
______  
 
 

 
 
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9. Best Language: A great deal of information 
about comprehension will be obtained during the 
preceding sections of the examination. For this 
scale item, the patient is asked to describe what 
is happening in the attached picture, to name the 
items on the attached naming sheet and to read 
from 
the 
attached 
list 
of 
sentences. 
Comprehension is judged from responses here, 
as well as to all of the commands in the 
preceding general neurological exam. If visual 
loss interferes with the tests, ask the patient to 
identify objects placed in the hand, repeat, and 
produce speech. The intubated patient should be 
asked to write. The patient in a coma (item 1a=3) 
will automatically score 3 on this item. The 
examiner must choose a score for the patient 
with stupor or limited cooperation, but a score of 
3 should be used only if the patient is mute and 
follows no one-step commands.  
0 = No aphasia; normal.  
1 = Mild-to-moderate aphasia; some 
obvious loss of fluency or facility of 
comprehension, without significant 
limitation on ideas expressed or form 
of expression. Reduction of speech 
and/or comprehension, however, 
makes conversation about provided 
materials difficult or impossible. For 
example, in conversation about 
provided materials, examiner can 
identify picture or naming card content 
from patient’s response.  
2 = Severe aphasia; all communication is 
through fragmentary expression; great 
need for inference, questioning, and 
guessing by the listener. Range of 
information that can be exchanged is 
limited; listener carries burden of 
communication. Examiner cannot 
identify materials provided from 
patient response.  
3 = Mute, global aphasia; no usable 
speech or auditory comprehension.  
______  
10. Dysarthria: If patient is thought to be normal, 
an adequate sample of speech must be obtained 
by asking patient to read or repeat words from 
the attached list. If the patient has severe 
aphasia, the clarity of articulation of spontaneous 
speech can be rated. Only if the patient is 
intubated or has other physical barriers to 
producing speech, the examiner should record 
the score as untestable (UN), and clearly write an 
explanation for this choice. Do not tell the patient 
why he or she is being tested.  
0 = Normal.  
1 = Mild-to-moderate dysarthria; patient 
slurs at least some words and, at 
worst, can be understood with some 
difficulty.  
2 = Severe dysarthria; patient's speech 
is so slurred as to be unintelligible in 
the absence of or out of proportion to 
any dysphasia, or is mute/anarthric.  
UN = Intubated or other physical barrier, 
explain:________________________  
______  
11. 
Extinction 
and 
Inattention 
(formerly 
Neglect): 
Sufficient 
information 
to 
identify 
neglect may be obtained during the prior testing. 
If the patient has a severe visual loss preventing 
visual double simultaneous stimulation, and the 
cutaneous stimuli are normal, the score is 
normal. If the patient has aphasia but does 
appear to attend to both sides, the score is 
normal. The presence of visual spatial neglect or 
anosagnosia may also be taken as evidence of 
abnormality. Since the abnormality is scored only 
if present, the item is never untestable.  
0 = No abnormality.  
1 = Visual, tactile, auditory, spatial, or 
personal inattention or extinction to 
bilateral simultaneous stimulation in 
one of the sensory modalities.  
2 = Profound hemi-inattention or 
extinction to more than one 
modality; does not recognize own 
hand or orients to only one side of 
space.  
______  
 
 
 

 
 
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Modified Rankin Scale (mRS) Instructions  
Instructions:  
 
The mRS is to be determined after the NIHSS has been determined and graded and by the 
same rater.  
 
The determination of the scale should be made from 5 to 0, i.e., the order presented.  
 
The purpose of the mRS is to record whether the patient is dead, severely, moderately, or 
slightly disabled and if not dead or disabled, whether the patient is performing all usual 
activities without symptoms or not. Because subjects and family members may understate 
the severity of disability, it is important for the rating clinician to understand that the mRS is 
a clinical scale and not a patient-reported outcome. The rater may ask questions but must 
assess the disability whether or not in agreement with the subject or family.  
 
5 Severe disability; someone needs to be available at all times; care may be provided by either a 
trained or an untrained caregiver.  
Question: Does the person require constant care?  
4 Moderately severe disability; need for assistance with some basic ADL, but not requiring 
constant care.  
Question: Is assistance essential for eating, using the toilet, daily hygiene, or walking?  
3 Moderate disability; need for assistance with some instrumental ADL but not basic ADL.  
Question: Is assistance essential for preparing a simple meal, doing household chores, looking 
after money, shopping, or traveling locally?  
2 Slight disability; limitations in participation in usual social roles, but independent for ADL.  
Questions:  
 
Has there been a change in the person’s ability to work or look after others if these were 
roles before stroke?  
 
Has there been a change in the person’s ability to participate in previous social and 
leisure activities?  
 
Has the person had problems with relationships or become isolated?  
 
Do any of the following interfere with the subject's ability to perform all usual activities: 
difficulty reading or writing, difficulty speaking or finding the right word, problems with 
balance or coordination, visual problems, numbness (face, arms, legs, hands, feet), loss 
of movement (face, arms, legs, hands, feet), difficulty with swallowing, or other symptom 
resulting from stroke?  
1 No significant disability; symptoms present but not other limitations.  
Question: Does the subject have any symptoms that do not interfere with the performance of all 
usual activities?  
0 No symptoms at all; no limitations and no symptoms.  
Note:  The above questions are a modification of the questions from Wilson, et. al, Stroke. 2002:33:2243-2246 and are 
modified here for the use in percutaneous heart valve trials for the FDA Division of CV Devices.  
 

 
 
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Mini Mental State Exam (MMSE-2:SV) 
Mini Mental Status Exam1:  The MMSE-2 Standard Version should be used.    
 
Procedure: 
Administer the MMSE-2 exam utilizing the standardized worksheets provided. 
 
http://www.minimental.com/ 

 
 
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Additional Neurological Assessments 
Visual Field Testing 
Visual fields, (upper and lower quadrants) are tested by confrontation, using finger counting or 
visual threat as appropriate. 
Visual fields may be impaired by lesions anywhere in the neural visual pathways, from the optic 
nerves to the occipital lobes. 
• 
Individual eyes: 
In direct confrontation, examiner should sit directly in front of the patient, at the same level 
and approximately one meter apart. Ask the patient to cover one eye and maintain a fixed 
gaze on the examiners eye or nose. The examiner brings a small target (e.g. a match or a 
finger) from the periphery of the subject’s visual field into each of the 4 visual quadrants 
and requests that the patient indicate when they first visualize the object. Wiggling the 
target assists in the patients separating and defining it.  
Repeat the testing for the other eye.  
Any abnormalities in target detection should prompt detailed testing with more precise 
instruments.  
• 
Bilateral eyes:  
In the same position, and with the patients fixed gaze on the examiners nose or eyes, use 
finger counting or visual threat to identify any asymmetry in the visual field.  
Gait Assessment 
Not tested as part of the NIH Stroke Scale.  
Ask the patient to walk down a straight hallway under observation, if ambulatory.  
Note any apparent abnormalities of gait. (Ataxic, lateralized hemi-paretic, ‘shuffling’ or ‘small-
step’ or other abnormality).  
Hand Function 
• 
Motor assessment  
The extensors are weaker than the flexors in the upper extremities. Consequently, following 
a neurological event, the arm eventually assumes a flexed position. Therefore the biceps 
will be stronger than the triceps, the wrist and finger flexors stronger than the extensors. 
For this reason it is not a good idea to monitor for stroke progression by testing grip 
strength. Test finger extensor strength instead. 
Muscle power is classically graded on a scale of 0 – 5, with 0 being no power and 5 being 
normal power. For the purposes of documenting subtleties in potential deficits, power in 
finger muscle groups should be documented on a 0 – 10 scale as follows.  
Grade 0 
 
No muscle contraction  
Grade 2 
 
Muscle contraction without joint movement 
Grade 4 
 
Partial movement with gravity eliminated 
Grade 6 
 
Movement against gravity 
Grade 8 
 
Movement against some resistance 
Grade 10   
Normal strength 
(Use odd numbers to document when physical findings fall between grades). 
 
 

 
 
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• 
Finger Abductors 
Instruct the patient to “Spread your fingers apart, push your index finger towards the other 
hand. Don’t let me push it back”.  Push on the finger at the Proximal Interphalangeal (PIP) 
joint level.  
• 
Finger Adductors 
Ask patient to ‘grip a sheet of paper’ between their fingers. Try to pull the sheet away from 
them.  
• 
Finger Extensors 
Instruct the patient to “Keep your fingers out straight, and don’t let me bend them”. This is a 
test of extension at the metacarpophalangeal (MCP) joints. It is important to support the 
palm and apply pressure to the PIP joints, testing extension at only one set of joints, 
because extension at the PIP joints is performed by the small hand muscles.  
• 
Sensory Assessment 
In a seated position, ask the patient to place both hands on their lap with palms facing 
down. Instruct them to close their eyes, and using their index finger point to the position 
touched by the examiner on fingers of the opposite hand. Repeat for both hands. 
This should be documented as: ‘normal sensation’ or ‘can feel but unable to localize’ or ‘no 
sensation’ for each hand. 
Writing Evaluation 
Ask the patient to write two sentences about a particular subject. (e.g. their hometown). There is 
no time limit, and patient can be given time prior to neurological examination as necessary.  
Note the subject’s ‘use of paper’, including the position of writing. Also, note whether the written 
subject is appropriate to that asked, and the correctness of the grammar, spelling and syntax 
used.  
Document as ‘fail’ or ‘pass’ or ‘subject unable to attempt test’ if patient is unable.  
Drawing Assessment 
The ‘clock-drawing’ test is used for screening for cognitive impairment and dementia, and as a 
measure of spatial dysfunction and neglect. Doing the test requires verbal understanding, 
memory and spatially coded knowledge in addition to constructive skills.  
Constructional apraxia may occur with lesions in either the left or right parietal lobe, although it is 
more frequent after right parietal damage (visually dominant).  
Clock drawing has been used as a diagnostic measure of unilateral spatial neglect, with neglect 
patients omitting numbers on one half, with or without transposition of the numbers from the 
neglect side to the other, or demonstrating inattention to parts of the spatial layout of numbers.  
The test has a high correlation with the MMSE and other tests of cognitive dysfunction.  
 
Ask patient to draw the face of a clock and put the numbers in the correct position.  
 
Then ask patient to draw in the hands at a particular time (e.g., "twenty minutes after 
eight").  
 
There is no time limit. 
One point will be assigned for each of the following items completed (draws closed circle, 
includes all 12 correct numbers, places numbers in correct positions, places hands in correct 
positions) for a total of four points. 
 

 
 
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Medtronic CoreValve™ Clinical Assessment Guidelines 
Clinical Assessments will be collected to help assess the overall heath and frailty1 of study 
participants at the time of screening. These assessments include measures of nutrition, strength 
and balance, independence in average daily living, mental status, and medical comorbidities.   
The following are guidelines provided for administering the strength and balance examination. 
 
5-Meter Gait Speed: The Gait Test measures, in seconds, the time a person takes walk 5meters. 
Procedure: 
 
Accompany the patient to the designated area, which should be well-lit, unobstructed, and 
contain clearly indicated markings at 0 and 5 meters 
 
Position the patient with his/her feet behind and just touching the 0-meter start line 
 
Instruct the patient to “Walk at your comfortable pace” until a few steps past the 5-meter 
mark (the patient should not start to slow down before the 5-meter mark) 
 
Begin each trial on the word “Go” 
 
Start the timer with the first footfall after the 0-meter line 
 
Stop the timer with the first footfall after the 5-meter line 
 
Repeat 3 times, allowing sufficient time for recuperation between trials 
Note: Patient may use a walking aid (cane, walker). If the patient is receiving an IV drip, he/she 
should perform the test without the IV only if it can be interrupted temporarily without any potential 
risk to the patient, if not, then the patient may perform the test pushing the IV pole. 
 
Grip strength test2: The grip strength test is used to determine the strength in each of the 
participant’s hands. 
Procedure: 
 
Equipment: Hand Dynamometer 
 
Illustrate the use of the instrument to the participant prior to testing. 
 
The participant should be in a seated position. 
 
Ask the participant to squeeze the dynamometer with as much force as possible, being 
careful to squeeze only once for each measurement. 
 
Three trials should be made for the right hand followed by three trials for left hand with a 
pause of about 10-20 seconds between each trial to avoid the effects of muscle fatigue. 
 
The highest reading for each hand should be reported on the case report form. 
 
 
1 
 Fried
 LP et al, (2001). Frailty in older adults: Evidence for a phenotype. Journal of Gerontology: Medical Science , 56A 
(3), M146-M156. 
2 
 Luna-Heredia E, Martin-Pena G, Ruiz-Galiana J. Handgrip dynamometry in healthy adults. Clinical Nutrition 2005; 
24:250-258 
 

 
 
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Katz Index of Independence in Activities of Daily Living 
 
Activities 
Points (1 or 0) 
Independence 
(1 POINT) 
NO supervision, direction or 
personal assistance 
 
Dependence 
(0 Points) 
WITH supervision, direction, 
personal assistance or total 
assistance 
BATHING 
 
 
 
Points: __________ 
(1 POINT) Bathes self 
completely or needs help in 
bathing only a single part of 
the body such as the back, 
genital area or disabled 
extremity. 
(0 POINTS) Needs help with 
bathing more than one part of 
the body, getting in or out of 
the tub or shower. Requires 
total bathing. 
DRESSING 
 
 
 
Points: __________ 
(1 POINT) Gets clothes from 
closets and drawers and puts 
on clothes and outer garments 
complete with fasteners. May 
have help tying shoes. 
0 POINTS) Needs help with 
dressing self or needs to be 
completely dressed. 
TOILETING 
 
 
Points: ___________ 
(1 POINT) Goes to toilet, gets 
on and off, arranges clothes, 
cleans genital area without 
help 
(0 POINTS) Needs help 
transferring to the toilet, 
cleaning self or uses bedpan 
or commode. 
TRANSFERRING 
 
 
Points: ___________ 
(1 POINT) Moves in and out of 
bed or chair unassisted. 
Mechanical transferring aides 
are acceptable. 
(0 POINTS) Needs help in 
moving from bed to chair or 
requires a complete transfer. 
CONTINENCE 
 
Points: ___________ 
(1 POINT) Exercises complete 
self-control over urination and 
defecation. 
(0 POINTS) Is partially or 
totally incontinent of bowel or 
bladder. 
FEEDING 
 
 
Points: ____________ 
(1 POINT) Gets food from 
plate into mouth without help. 
Preparation of food may be 
done by another person. 
(0 POINTS) Needs partial or 
total help with feeding or 
requires parenteral feeding. 
 
 
TOTAL POINTS = _________    
6 = High (patient independent) 
0 = Low (patient very dependent) 
 
Slightly adapted from Katz S., Down, T.D., Cash, H.R. et al. (1970) 
Progress in the Development of the Index of ADL. Gerontologist 
10:20-30. Copyright The Gerontological Society of America 
 

 
 
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Investigator Brochure / Report of Prior Investigations for the 
Investigational Devices 
The geography-specific Investigator Brochure for the Medtronic CoreValve™ System and 
Medtronic CoreValve™ Evolut™ R System will be provided separately, as applicable.

 
 
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R.22 
Investigational Devices Instructions For Use 
The geography-specific Instructions For Use for the Medtronic CoreValve™ System and 
Medtronic CoreValve™ Evolut™ R System will be provided under separate cover. 
 

 
 
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Radiation Exposure and Data Collection 
The SURTAVI protocol requires several tests and procedures that expose subjects to radiation 
(angiograms, arteriograms and fluoroscopy).  These tests and procedures are essential to 
appropriate patient selection and proper deployment of the study valves. 
Procedure 
Interval 
Multi-slice Computed Tomorgraphy (MSCT) Angiogram 
Screening 
Coronary arteriogram 
Screening 
Index Procedure – TAVI only 
Aorotogram 
Index Procedure – TAVI only 
The following describes radiation exposure data collection requirements as well as parameters for 
additional subject follow-up. 
Follow-up and Data Collection 
Data regarding subject radiation exposure will be collected at all protocol intervals where radiation 
test or procedures are required.   
 
Screening 
 
Index-Procedure (TAVI only) 
o 
Percutaneous Coronary Intervention (PCI) – if staged approach 
 
Reintervention (Valve related) 
 
NOTE: Based on the protocol design, imaging required at screening may have been completed prior to the 
subject signing the informed consent form and data related to radiation exposure during the 
acquisition of the images may not be available.  Radiation exposure data missing from the 
subject record will not be considered a protocol deviation. 
Substantial Radiation Dose Level 
For purposes of SURTAVI, substantial radiation dose level (SRDL) is defined as meeting/exceeding 
one of the following: 
Dose Metric 
SRDL 
Total air kerma at IRP (K a,r) 
3 Gy 
Kerma-area product (Pka) 
250 Gy·cm2 
Fluoroscopy Time 
60 min 
 
In cases where SRDL is met or exceeded additional steps should be taken. 
 
Document the radiation dose the subject was exposed to in the medical record 
 
Include an explanation regarding the medical necessity 
 
Describe the planned follow-up 
 
Notify the subject and caregiver, if applicable 
o 
Instruct subject (and caregiver) to perform visual skin assessments at least once per 
week between in-clinic visits 
o 
If a hand-sized read area or rash is noted, contact the Investigator immediately to 
schedule a follow-up visit 
 
 
 

 
 
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To ensure signs and symptoms of radiation exposure are identified as soon as possible, subjects 
should have a routine visual skin assessment at the following protocol intervals: 
 
Baseline 
 
Immediate Post-Procedure – within 48 hours of TAVI 
 
Discharge 
 
30-days 
 
Additional follow-up should be scheduled at the Investigators discretion based on progression of 
symptoms, as applicable. 
 
If skin changes are noted at any interval additional follow-up should be scheduled with a 
dermatologist, or physician with the appropriate training and expertise for diagnosis and treatment.  
Long-term follow-up should be conducted in accordance with local standard of care. 
 
Skin assessment findings should be noted in the patient medical record and applicable adverse 
events should be reported. 
Threshold for Radiation Dose Exposure 
Chronology and Severity of Tissue Reactions From Single-Delivery Radiation Dose  
Single site 
(Gy) acute 
skin dose 
Prompt 
(<2 weeks) 
Early
(2–8 weeks) 
Mid term
(6–52 weeks) 
Long term
(<40 weeks) 
 
No observable 
effects expected 
 
 
 
2-5 
Transient erythema 
Epilation 
Recovery from hair 
loss 
None expected 
5-10 
Transient erythema 
Erythema, 
epilation 
Recovery; high 
doses cause 
prolonged erythema 
and permanent 
partial epilation 
Recovery; higher dose 
cause dermal 
atrophy/induration 
10-15 
Transient erythema  
Erythema, 
epilation; dry/moist 
desquamation  
Prolonged erythema 
permanent epilation  
Telangiectasia; dermal 
atrophy/induration  
>15 
Transient erythema; 
Very high dose 
causes moist 
desquamation 
edema/ulceration  
Erythema, 
epilation  
Dermal atrophy with 
secondary 
ulceration; 
atrophy/induration; 
High dose dermal 
necrosis surgical 
repair likely  
Telangietasia; dermal 
Late skin breakdown  
Modified: Balter S. Fluoroscopically guided interventional procedure: A review of radiation effects on skin and hair. 
NCRP SC 2–3, Feb 2010.  
List of Abbreviations 
 
 
 
Abbreviation 
Term 
Gy 
Gray 
IRP 
Interventional reference point 
KAP 
Kerma area product 
PSD 
Peak skin dose 
SDRL 
Substantial radiation dose level 

 
 
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References 
Balter, S. Moses, J. Managing Patient Dose in Interventional Cardiology.  Catheterization and Cardiovascular 
Interventions 2007; 70:244–249 
Chambers, et al. Radiation Safety Program for the Cardiac Catheterization Laboratory. Catheterization and 
Cardiovascular Interventions 2011; 77:546–556 
Hirshfield, et al. ACCF/AHA/HRS/SCAI Clinical Competence Statement on Physician Knowledge to Optimize 
Patient Safety and Image Quality in Fluoroscopically Guided Invasive Cardiovascular Procedures: A Report of 
the American College of Cardiology Foundation/American Heart Association/American College of Physicians 
Task Force on Clinical Competence and Training Circulation 2005, 111:511-532 
 

 
 
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SURTAVI Risk Model 
Risk assessment is essential in the strategy to approach patients with valvular heart disease in 
general and AS in particular. Various risk models primarily focusing on short-term mortality have 
been validated for AS patients (30-38). Some were initially derived from a broader patient 
population undergoing any type of cardiac surgery, others were more explicitly tailored to patients 
with AS. Most notably, contemporary scoring models tend to be consistent in lower risk patients 
but diverge with increasing risk profile. This can be partly explained by the fact that these models 
were extracted from large databases where the average patient risk is fairly low. Therefore such 
models are less well validated for higher risk patients and expectedly perform less well in the 
“outlier” population currently considered for TAVI (39).  
An in-depth reappraisal of existing scoring models reveals some concordant risk factors  (e.g. age, 
gender) but also established risk factors that are clearly missing (e.g. mediastinal radiation, 
porcelain aorta and frailty) (40-42). Furthermore definitions of individual components are not 
uniform and do not correspond to current suggested guidelines/definitions by respective 
professional societies.  
R.24.1  
SURTAVI Risk Model Rationale 
1.   Joint database 
Following the initial report by the Bern, Rotterdam collaboration (28) including 1122 patients 
with severe AS, four academic institutions in Bern, Rotterdam, Bad Nauheim and Munich have 
created a joint database on all consecutive patients with severe AS treated with either TAVI or 
SAVR between January 2006 and December 2009. 
Preliminary analysis on 3688 patients has been performed, including 789 TAVI and 2899 
SAVR patients.  
The pre-specified primary outcome was all cause mortality at 1 year. Patients were actively 
followed up after the index procedure and their vital status confirmed by outpatient clinic visit, 
telephone contact, review of medical records or national civil registries. 
2.   Statistical methods 
The propensity scores of SAVR patients were estimated using a probit model with all baseline 
characteristics as described above as independent variables. The propensity score is the 
probability that a patient would have been treated with SAVR given that patient's observed 
baseline characteristics. To ensure the quality of the matching using propensity scores the 
common support assumption was applied, using the Epanechnikov kernel probability density 
estimates. The IPT weighted multivariable analysis was used. The IPT weighted analyses 
used the inverse of the propensity score as weights in SAVR patients and the inverse of 1 
minus the propensity score in TAVI patients. All analyses were based on logistic regression 
models on the 1 year mortality and were performed in the overall dataset and stratified 
according to presence or absence of sufficient overlap of propensity scores (propensity score 
<0.675 versus ≥0.675). 
3.   Type of patient (patient selection) 
Preliminary analysis demonstrated a pre-dominance of patients with age >80 years old, and a 
logistic EuroSCORE <20% in the TAVI cohort (figure “scatterplot”). However, the majority of 
patients in the entire study population are between 65-and 83-years-old (figure “age 
distribution”).  
 

 
 
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Survival curves of the general Dutch 
population 
(derived 
from 
death 
register); and patients undergoing an 
AVR 
(derived 
from 
meta-analysis 
data), or an AVR with the additional 
risk 
factor 
of 
coronary 
sclerosis 
(derived from meta-analysis data). 
 
The range of both the EuroSCORE and STS 
score in a patient with 2 risk factors. The lower 
boundary indicates a score with risk factors that 
have little influence on the score, while the upper 
boundary indicates a score with risk factors that 
influence the score significantly 
 
 
 
 
 
 
 
 
 
 
 
 
As it is well-known that both the STS score and EuroSCORE are suboptimal in operative risk 
assessment, these models are only used for descriptive purposes (39). Age is the predominant 
predictor of mortality in general, and after valve surgery in particular. Furthermore, the impact of 
other risk factors appears to be accentuated in an older age population.  
 
 
The distribution of age in patients treated for 
aortic stenosis. The color indicates the 
percentage of patients treated with TAVI in the 
corresponding age group 
A scatterplot showing the age and corresponding 
EuroSCORE of patients treated for aortic stenosis. 
Indicated by colours are the treatment arms surgical 
aortic valve replacement and transcatheter aortic 
valve implantation. A previous commonly used 
EuroSCORE cut-off value of 20% is indicated in the 
graphic to show that many patients with lower scores 
are already treated by TAVI, but in lower ages this 
treatment 
remains 
limited 
due 
to 
the 
low 
EuroSCORE. 

 
 
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Therefore, we opt for a risk assessment based on age in combination with encoded co-morbidities 
selected from a pre-specified listing. Patients at intermediate risk are defined as age 70-74 years 
with 2 or 3 co-morbidities (cohort 1); age 75-79 years with 1 or 2 co-morbidities (cohort 2); and 
patients ≥80 years of age with ≤1 co-morbidities (cohort 3). 
In-depth analysis and translation of the risk profile mentioned above to the STS score (table STS 
below):  
 
Cohort 1: range of 0.9% to 10.2% in males, and 1.4% to 14.8% in females 
 
Cohort 2: range of 1.2% to 8.5% in males, and 1.8% to 12.4% in females 
 
Cohort 3*: range of 1.7% to 8.9% in males, and 2.6% to 12.7% in females 
 
 
STS score: ranges of scores are displayed as: score with least influential risk factors – score with most influential risk 
factors. *Upper age limit 91 years old 
 
In-depth analysis and translation of the risk profile mentioned above to the logistic EuroSCORE 
(Table EuroSCORE below):  
 
Cohort 1: range of 9.1% to 42.3% in males, and 12.2% to 50.5% in females 
 
Cohort 2: range of 7.2% to 32.1% in males, and 9.8% to 39.6% in females 
 
Cohort 3*: range of 6.6% to 27.8% in males, and 9.0% to 34.9% in females 
 
 
Euroscore: ranges of scores are displayed as: score with least influential risk factors – score with most influential risk 
factors. *Upper age limit 91 years old 
 
4.   Comparative patient outcome 
One-year mortality amounts to 30% in the overall high-risk matched population with a logistic 
EuroSCORE of 15.8%. The hazard ratio of propensity matched patients between SAVR and 
TAVI is 0.97. This suggests equipoise for both treatment strategies and is the legitimation for a 
randomized trial in this intermediate risk AS population. 
 

 
 
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R.24.2  
SURTAVI co-morbidity list  
 
Methodology for identifying enlisted co-morbidities: 
We first identified those components recurring in the previously published scoring models and 
looked for updated definitions by international professional societies. We then added missing risk 
factors, identified in the literature, which we felt, were essential. In addition, there exists an ‘open 
box’ to capture less prevalent and unanticipated risk factors (e.g. liver failure, mediastinal 
radiation, porcelain aorta, etc.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The above risk factors will guide the Heart Team in the selection of the treatment options but will 
not dictate patient allocation. The final decision treatment will be done by the local Heart Team.   
1. Significant concomitant Coronary Artery Disease: defined as ≥70% stenosis by invasive 
coronary angiography because the combination of revascularization and aortic valve 
replacement reduces the rates of perioperative MI, perioperative mortality, late mortality and 
morbidity when compared with patients not undergoing simultaneous revascularization 
(ACC/AHA/ESC class IC recommendation)(6, 43, 44). Previous CABG or PCI is not 
considered to have considerable impact on short term outcome.  
2. Frailty: in the absence of a generally accepted consensus definition Frailty is defined as 
suggested by Lee and co-workers by the presence of any 1 of the following(40):  
o 
Katz score(independence in Activities of Daily Living);  
o 
Ambulation (walking aid/assist?);  
o 
Diagnosis of (pre-)dementia. 
3. Left Ventricular dysfunction: defined as EF < 35%, with respect to the pivotal position of this 
particular threshold in the heart failure population (45). 
70 yrs of age 
and 2 or 3 risk factors 
75 yrs of age 
and 1 or 2 risk factors 
80 yrs of age 
And 0 or 1 risk factors 
Risk factors: 
 
 
Coronary artery disease requiring revascularization 
 
Frailty  
 
Left Ventricular dysfunction (EF <35%) 
 
Neurological dysfunction (with functional impairment) 
 
Pulmonary disease (Gold stage II)  
 
Peripheral vascular disease  
 
Renal disease (KDOQI Stage III) 
 
Redo cardiac surgery 
 
Pulmonary hypertension (syst PAP 60 mmHg at most recent measurement) 
 
Diabetes (R/ oral meds or insulin) 
 
‘Open Box’ capturing less prevalent risk factors (e.g. liver failure, mediastinal 
radiation, porcelain aorta, etc.) 

 
 
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4. Neurological dysfunction: Cerebro-Vascular Disease, documented by any one of the 
following: CVA (symptoms lasting >24 hours or imaging of an acute clinically relevant brain 
lesion in patients with rapidly vanishing symptoms); TIA (brief episode of neurological 
dysfunction caused by a focal disturbance of brain or retinal ischemia, with clinical 
symptoms with recovery within 24 hrs and without evidence of infarction); Non-invasive 
carotid test with > 60% diameter occlusion or prior carotid surgery or symptomatic carotid 
stenosis > 50%(46-49). Does not include neurological disease processes such as metabolic 
and/or anoxic ischemic encephalopathy. 
5. Pulmonary disease: COPD Gold Stage II: moderate COPD with worsening airflow limitation 
(FEV1/FVC <70%; 50% ≥ FEV1 <80% predicted), with shortness of breath typically 
developing on exertion(50). 
6. Peripheral vascular disease: adapted from the STS risk model: Claudication, either with 
exertion or at rest; Amputation for arterial vascular insufficiency; Vascular reconstruction, 
bypass surgery, or percutaneous intervention to the extremities; Documented aortic 
aneurysm with or without repair; Positive non-invasive 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) 
7.  Renal disease: at least moderate chronic kidney disease with GFR < 60 mL/min according 
to the National Kidney Foundation kidney disease outcome quality initiative advisory 
board(51). 
8. Redo cardiac surgery 
9. Pulmonary hypertension (> 60mmHg at most recent measurement) 
10. Diabetes Mellitus on oral or insulin therapy. 
11. OPEN BOX: e.g., extensive mediastinal radiation, chest wall deformity, Liver Failure Child-C 
 
 
 
 

 
 
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Patients available for screening 
 
All patients 
 
 
 
SAVR patients 
 
0
1
2
3
4
≥5
Total cases
<60
107
85
17
11
1
1
222
60‐64
47
37
15
8
0
0
107
65‐69
57
53
24
10
5
0
149
70‐74
60
66
47
10
5
4
192
75‐79
64
89
38
20
5
2
218
≥80
46
53
43
35
6
11
194
1082
SAVR
668/1082 61.7%
Random ‐‐> TAVI / SAVR
283/1082 26.2%
Too high risk
131/1082 12.1%
Comorbidities (n)
Age (yrs)
 
0
1
2
3
4
≥5
Total cases
<60
106
84
17
11
0
0
218
60‐64
47
37
14
6
0
0
104
65‐69
57
52
23
8
3
0
143
70‐74
59
65
44
5
4
0
177
75‐79
60
83
33
14
1
0
191
≥80
36
32
15
3
0
0
86
919
SAVR
649/919 70.6%
Random ‐‐> TAVI / SAVR
233/919 25.4%
Too high risk
37/919
4.0%
Comorbidities (n)
Age (yrs)

 
 
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TAVI patients 
 
 
 
 
 
 
 
0
1
2
3
4
≥5
Total Cases
≤ 60
1
1
0
0
1
1
4
60‐64
0
0
1
2
0
0
3
65‐69
0
1
1
2
2
0
6
70‐74
1
1
3
5
1
4
15
75‐79
4
6
5
6
4
2
27
≥ 80
10
21
28
32
6
11
108
163
SAVR
19/163 
11.7%
Random ‐‐> TAVI / SAVR
50/163
30.7%
Too high risk
94/163 
57.7%
Age (yrs)
Comorbidities (n)
Distribution of age and comorbidities in patients with severe aortic stenosis in the Rotterdam practice. In each age 
group, patients are divided by the total number of comorbidities as previously defined. 
Indicated in green are the patients that are too low risk for randomization (62%). Indicated by orange are patients 
that will be randomized in SURTAVI (26%). In blue are patients too high risk for randomization (12%). Therefore, it 
is estimated that every 1 in 4 patients meets the inclusion criteria for screening. 

 
 
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STS versus Euro Score 
This table illustrates the relative impact of common co-morbidities in STS score (vertical axis) and 
Euroscore (horizontal axis) risk model. This present panel relates specifically of a male patient of 
70 years old with 0, 1 or 2 risk factors.  
The black line separates the score values of the two respective models: below the line relates to 
STS score, above to Euroscore. 
The empty boxes indicate that the specific risk factor is not accounted for in the risk model, e.g. 
diabetes in Euroscore. 
If this patient has no co-morbidity he would have an STS score of 0.9 and a Euroscore of 3 (see 
first square in upper left corner). 
If this patient has a poor LVEF combined with peripheral vascular disease he would have a STS 
score of 1.5 and Euroscore of 15.5 
Redo surgery is displayed as “first reoperation / second reoperation”, and COPD as “moderate / 
severe”. Values indicated as “score - score” correspond to the range of scores possible when 
combining all 4 risk factors (for instance ‘moderate COPD + 1st redo’ - ‘severe COPD + 2nd redo’) 
DM = diabetes mellitus; PVD = peripheral vascular disease; CVD = cerebrovascular disease; 
LVEF = left ventricular ejection fraction; CAD = coronary artery disease; NYHA = New York Heart 
Association; COPD = chronic obstructive pulmonary disease; PH = pulmonary hypertension 
 

 
 
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R.25 
CMS Considerations for Coverage and Reimbursement – US 
ONLY 
The SURTAVI protocol outlines the minimum requirements for trial participation, patient screening 
by the local Heart Team, and conduct of the TAVI procedure. 
Within the United States, sites and Investigators should adhere to the following additional CMS 
requirements for coverage and reimbursementi, as applicable to the Medicare patient population 
enrolled in the study: 
Section C.4.2.1 Heart Team Composition 
Local Heart Teams should be comprised of a multidisciplinary team qualified by education and 
experience to determine appropriate patient treatment. 
 
Minimum Membership  
 
Interventional Cardiologist - ≥ 1 representative is required 
 
Cardiac Surgeon - ≥ 2 representatives are required 
 
Recommended Membership  
Additional members of the Heart Team should be included based on current standard practices 
and patient specific considerations, including but not limited to: 
 
Echocardiographer 
 
Anesthesiologist 
 
Cardiologist (general or referring physician) 
 
Geriatrician 
 
Neurologist or stroke specialist 
 
Radiologist or imaging specialist 
 
Heart Failure specialist 
 
Intesivist 
 
Nurse 
 
Social Worker 
 
Section C.4.6.1 TAVI 
TAVI Procedure 
 
Joint Participation 
o 
The heart team’s interventional cardiologist(s) and cardiac surgeon(s) must jointly 
participate in the intra-operative technical aspects of the TAVI procedure 
 
                                                    
 
i  
http://www.cms.gov/medicare-coverage-database/details/nca-decision-
memo.aspx?NCAId=257&ver=4&NcaName=Transcatheter+Aortic+Valve+Replacement+(TAVR)&bc=ACAAAAAAIAA
A&  

 
Version 1.0 
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Page 1 of 5 
27-JAN-2016 
 
 
 
 
SURTAVI Trial – Clinical Investigation Plan Version Distribution 
 
Version 
Date 
Version 
Description of Change 
Rationale for Change 
Geography 
Distribution 
18-Nov-2011 
3.0 
Initial Release 
NA 
• Europe only 
10-May-2012 
4.0 
• Inclusion/Exclusion Criteria 
updated 
• Device status updates: 
o Addition of 23mm PAV 
and applicable DCS 
o AOA CE mark status 
• Modification of statistical 
methods to relative risk 
design and addition of 
adaptive study design 
• Addition of Canada as a 
participating geography 
• Appendix updates: 
o Informed Consent 
templates 
o Clinical Assessments 
o Investigator Brochure 
o Instructions For Use 
o Radiation Exposure and 
Data Collection 
• Changes based on FDA 
pre-IDE feedback 
• Device status updates: 
o 23mm PAV and 
applicable DCS CE 
mark approval 
o AOA CE mark 
approval 
• Canada 
• Europe 
 
23-Jul-2012 
5.0 
• Stroke classifications 
changed from major vs. 
minor to disabling vs. non-
disabling 
• Inclusion/Exclusion Criteria 
updated 
• Additional neurological 
testing added (mRS) 
• Clarification of local Heart 
Team composition and 
decision making 
• Appendix updates: 
o CMS Requirements for 
Coverage and 
Reimbursement – US 
ONLY - added 
• Changes based on FDA 
IDE deficiencies 
• General updates and 
corrections 
• US only 
07-Nov-2012 
6.0 
• Device status update – 
Canadian approval 
• Total number of 
investigational centers 
• Changes based on FDA 
recommendations 
• Publication of VARC-2 
• General updates and 
• Canada 
• Europe 
• US – non-WIRB 
sites selected after 

 
Version 1.0 
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27-JAN-2016 
 
 
 
SURTAVI Trial – Clinical Investigation Plan Version Distribution 
 
Version 
Date 
Version 
Description of Change 
Rationale for Change 
Geography 
Distribution 
increased 
• Inclusion criteria #3 updated 
• Roll-in subjects added 
• Definitions of terms updated 
in alignment with VARC-2 
• Appendix updates: 
o Informed Consent 
templates 
o Echocardiography 
Acquisition Guidelines 
o Aortogram Acquisition 
Guidelines 
corrections 
03-JAN-2013 only 
23-Jan-2013 
7.0 
• Device Description updated 
to include EnVeo™ DCS and 
next generation CLS 
• Appendix updates: 
o Informed Consent 
templates 
 Europe 
 Canada 
 Canada, Roll-in 
o Echocardiography 
Acquisition Guidelines 
o Electrocardiogram (ECG) 
Submission 
• FDA IDE supplement to 
incorporate EnVeo/G5 
and the next generation 
CLS in the United States 
• General updates and 
corrections 
• NA – OBSOLETED 
prior to 
distribution 
10-Dec-2013 
8.0 
• Modification to Patient 
Population (re-defined 
Intermediate Risk) 
• Inclusion / Exclusion 
modifications and 
clarifications 
• Clarification of adverse 
event reporting 
requirements 
• All references to 
Percutaneous Aortic Valve 
(PAV) updated to 
Transcatheter Aortic Valve 
(TAV) 
• Addition of the next 
regeneration Compression 
Loading Systems 
• Appendix updates: 
o Informed Consent 
templates 
o Instructions for Use 
• General updates and 
corrections 
• Updated trial utilization 
of core laboratories 
• Canada 
• Europe 

 
Version 1.0 
Medtronic Confidential 
Page 3 of 5 
27-JAN-2016 
 
 
 
SURTAVI Trial – Clinical Investigation Plan Version Distribution 
 
Version 
Date 
Version 
Description of Change 
Rationale for Change 
Geography 
Distribution 
o Investigator Brochure 
o Echocardiography 
Acquisition Guidelines 
o Electrocardiogram (ECG) 
Submission 
08-May-2014 
8.1 
• Inclusion criteria clarification 
• Updated to include upper 
limit of risk classification 
• US 
14-Jan-2015 
9.0 
• All references to 
Cardiovascular Department 
updated to Coronary and 
Structural Heart 
• Addition of CoreValve Evolut 
R System 
• All references to MCS TAVI 
updated to TAVI 
• Appendix updates: 
o Informed Consent 
templates 
o Other Institutions 
o Instruction for Use 
o Investigator Brochure 
• General updates and 
corrections 
• Updated to include the 
use of CoreValve Evolut R 
System  
• Updated change to 
Imaging Core Lab 
• US 
23-Mar-2015 
10.0 
• Updated Device Approval 
Status 
• Statistical Methods and 
Analysis: 
o Updated assumed event 
rates 
o Modified non-inferiority 
margin 
o Updated sample size look  
 Updated maximum 
sample size from 3700 
to 2000 
• Appendix updates: 
o Informed consent 
templates 
• General updates and 
corrections 
• Updated Statistical 
Methods and Analysis per 
agreement from FDA 
• US 
22-Nov-2015 
11.0 
 
• Updated Device Approval 
Status 
• Removed AR/AS/MR as 
SAEs in absence of clinical 
symptoms 
• Statistical Methods and 
Analysis 
• General updates and 
corrections 
• Updated Statistical 
Methods and Analysis per 
agreement from FDA 
• N/A – obsoleted 
prior to 
distribution 
22-Nov-2015 
11.1 
• All references to 
Cardiovascular Department 
• General updates and 
corrections 
• N/A – obsoleted 
prior to 

 
Version 1.0 
Medtronic Confidential 
Page 4 of 5 
27-JAN-2016 
 
 
 
SURTAVI Trial – Clinical Investigation Plan Version Distribution 
 
Version 
Date 
Version 
Description of Change 
Rationale for Change 
Geography 
Distribution 
updated to Coronary and 
Structural Heart 
• All references to MCS TAVI 
updated to TAVI 
• Appendix updates: 
o Informed Consent 
templates 
o Other Institutions 
o Instruction for Use 
o Investigator Brochure 
• Updated Device Approval 
Status 
• Statistical Methods and 
Analysis: 
o Updated assumed event 
rates 
o Modified non-inferiority 
margin 
o Updated sample size look  
 Updated maximum 
sample size from 3700 
to 2000 
• Appendix updates: 
o Informed consent 
templates 
• Updated Device Approval 
Status 
• Removed AR/AS/MR as 
SAEs in absence of clinical 
symptoms 
• Statistical Methods and 
Analysis 
• Updated change to 
Imaging Core Lab 
• General updates and 
corrections 
• Updated Statistical 
Methods and Analysis per 
agreement from FDA 
distribution 
31-May-2016 
12.0 
• Updated Device Description 
• Removed moderate or 
severe mitral aortic 
regurgitation or stenosis as 
default SAEs in absence of 
clinical symptoms 
• Added section about 
Vigilance Reporting 
• Statistical Methods and 
Analysis 
• Investigational Device 
Accountability 
• Appendix Updates: 
o Informed consent 
• General updates and 
corrections 
• Updated Statistical 
Methods and Analysis 
• US only 

 
Version 1.0 
Medtronic Confidential 
Page 5 of 5 
27-JAN-2016 
 
 
 
SURTAVI Trial – Clinical Investigation Plan Version Distribution 
 
Version 
Date 
Version 
Description of Change 
Rationale for Change 
Geography 
Distribution 
templates 
31-May-2016 
12.1 
• Updated Device Description 
• Removed moderate or 
severe mitral aortic 
regurgitation or stenosis as 
default SAEs in absence of 
clinical symptoms 
• Added section about 
Vigilance Reporting 
• Statistical Methods and 
Analysis 
• Investigational Device 
Accountability 
• Appendix Updates: 
o Informed consent 
templates 
• General updates and 
corrections 
• Updated Statistical 
Methods and Analysis 
• Canada 
• Europe 
22-Nov-2015 
Single Arm 
Addendu
m version 
1.0 
Initial release of addendum  
N/A 
• US only 
 

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SURTAVI 
SUrgical Replacement and Transcatheter Aortic 
Valve Implantation 
 
 
Clinical Investigation Plan 
 
 
VERSION 12.1  
31 May 2016 
  
 
Sponsor: 
Medtronic, Inc. 
Clinical Research 
Mailstop: MVS66 
Mounds View South 
8200 Coral Sea St NE 
Mounds View, MN 55112 USA 
Medtronic Bakken Research Center 
Coronary and Structural Heart Department
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
 
 

 
 
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Contact Information Details* 
Study Chair 
Prof. Patrick W. Serruys, MD, PhD (Study Chair) 
Professor of Medicine 
Erasmus Medical Center 
Dept. of Interventional Cardiology, Thoraxcenter P.O. 
Box 21253000 CC Rotterdam, The Netherlands 
Dr. Nicolas M. Van Mieghem, MD, PhD (Deputy Study 
Chair) 
Interventional Cardiologist 
Erasmus Medical Center 
Dept. of Interventional Cardiology, Thoraxcenter Room 
BD 171 
's Gravendijkwal 230 
3015 CE Rotterdam, The Netherlands 
Principal Investigators 
Prof. Stephan Windecker, MD, PhD 
Head of Interventional Cardiology 
Bern University Hospital 
Department of Cardiology 
Swiss Cardiovascular Center Bern  
Freiburgstrasse 4  
CH-3010 Bern, Switzerland 
Prof. A. Pieter Kappetein, MD, PhD 
Cardio-Thoracic Surgeon 
Erasmus Medical Center  
Dept. of Thoracic Surgery  
Room BD 569  
's Gravendijkwal 230 
3015 CE Rotterdam, The Netherlands 
 
Prof. Rüdiger Lange, MD, PhD 
Direktor der Klinik für Herz- und Gefäßchirurgie 
Deutsches Herzzentrum München 
Lazarettstr. 36 
80636 München, Germany  
 
Prof. Thomas Walther, MD, PhD 
Direktor der Abteilung Herzchirurgie 
Kerckhoff-Klinik 
Benekestr. 2-8 
61231 Bad Nauheim; Germany 
Dr. Jeffrey J. Popma, MD 
Director, Interventional Cardiology 
Beth Israel Deaconess Medical Center 
185 Pilgrim Rd.  
Boston, MA 02215 USA 
Dr. Michael J. Reardon, MD 
Professor, Cardiothoracic Surgery 
The Methodist Hospital 
6550 Fannin St., Suite 1401 
Houston, TX 77030  USA 
Dr. David H. Adams, MD 
Marie-Josée and Henry R. Kravis Professor and 
Chairman 
Department of Cardiothoracic Surgery 
The Mount Sinai Medical Center 
1190 Fifth Avenue 
New York, NY 10029  USA 
 
 
 

 
 
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Trial Oversight 
Mike Boulware 
Clinical Research Manager 
Medtronic Coronary and Structural Heart 
Phone: (763) 514.9826 
Email: mike.j.boulware@medtronic.com 
 
Maarten Hollander – EU  
Clinical Research Manager 
Medtronic Bakken Research Center 
Phone: (+31-43) 3566864 
Email: maarten.hollander@medtronic.com 
 
Sponsor 
 
 
 
Medtronic, Inc. 
Clinical Research 
Mailstop: MVS66 
Mounds View South 
8200 Coral Sea Street NE 
Mounds View, MN 
55112 USA 
 
Medtronic Bakken Research Center  
Coronary and Structural Heart Department 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
Randomization System 
 
Randomization (IXRS) information will be provided 
in the investigator site file 
 
* Updated contact information will be provided as applicable.  Additional information regarding 
contacts listed above available upon request. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL and PROPRIETARY 
This document contains confidential information and is solely the property of Medtronic, Inc.  Acceptance of 
this document constitutes an agreement by the recipient that no unpublished information contained herein will 
be published or disclosed without the prior written approval of Medtronic, Inc.  This document may be 
disclosed to the appropriate Institutional Review Board (IRB)/Ethics Committee (EC) with the stipulation that 
the IRB/EC treats the information contained herein as the confidential property of Medtronic, Inc. 

 
 
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TABLE OF CONTENTS 
A 
SYNOPSIS ........................................................................................................... 8 
B 
PURPOSE .......................................................................................................... 15 
B.1 
Background ..................................................................................................................... 15 
B.2 
Investigational Devices and Intended Use ....................................................................... 17 
  Device Description ................................................................................................ 17 
B.2.1
B.2.1.1 
Medtronic CoreValve™ System .............................................................. 17 
  Device Approval Status ......................................................................................... 18 
B.2.2
B.2.2.1 
European Union ..................................................................................... 18 
B.2.2.2 
United States ......................................................................................... 18 
B.2.2.3 
Canada .................................................................................................. 18 
  Intended Use of the Device / Indications for Use ................................................... 19 
B.2.3
B.3 
Trial Objectives ............................................................................................................... 20 
  Primary .................................................................................................................. 20 
B.3.1
  Secondary ............................................................................................................. 20 
B.3.2
  Exploratory ............................................................................................................ 20 
B.3.3
C 
TRIAL PROTOCOL ............................................................................................ 21 
C.1 
Ethics and Regulatory Compliance ................................................................................. 21 
  Applicable Regulations .......................................................................................... 21 
C.1.1
  Institutional Review Board (IRB)/Medical Ethics Committee (MEC) ...................... 21 
C.1.2
  Regulatory Submission ......................................................................................... 21 
C.1.3
  Ethical Conduct of the Trial ................................................................................... 22 
C.1.4
C.2 
Trial Administration .......................................................................................................... 22 
  Steering Committee .............................................................................................. 22 
C.2.1
  Publication Committee .......................................................................................... 22 
C.2.2
C.3 
Methodology .................................................................................................................... 23 
  Purpose ................................................................................................................. 23 
C.3.1
  Patient Population ................................................................................................. 23 
C.3.2
  Design ................................................................................................................... 23 
C.3.3
  Investigational Centers .......................................................................................... 23 
C.3.4
  Number of Subjects ............................................................................................... 24 
C.3.5
  Inclusion/Exclusion Criteria ................................................................................... 24 
C.3.6
C.3.6.1 
Inclusion Criteria .................................................................................... 24 
C.3.6.2 
Exclusion Criteria ................................................................................... 24 
  Informed Consent .................................................................................................. 27 
C.3.7
  Revisions in Patient Information and Informed Consent Form ............................... 27 
C.3.8
  Enrollment Flowchart for Randomization to TAVI or SAVR ................................... 28 
C.3.9
 
Trial Training ..................................................................................................... 28 
C.3.10
C.4 
Trial Procedures .............................................................................................................. 29 
  Screening Procedures ........................................................................................... 29 
C.4.1
  Heart Team Procedures ........................................................................................ 31 
C.4.2
C.4.2.1 
Heart Team Composition ....................................................................... 31 
C.4.2.2 
Heart Team Review and Decision .......................................................... 31 
  Screening Committee ............................................................................................ 32 
C.4.3
  Roll-in Subjects ..................................................................................................... 32 
C.4.4
  Enrollment and Randomization ............................................................................. 32 
C.4.5
  Baseline Assessments .......................................................................................... 33 
C.4.6
  Transcatheter Aortic Valve Implant or Surgical Aortic Valve Replacement 
C.4.7
Procedure ............................................................................................................. 34 

 
 
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C.4.7.1 
TAVI ....................................................................................................... 34 
C.4.7.2 
Surgical Aortic Valve Replacement ........................................................ 39 
  Assessments done at discharge (both SAVR and TAVI) ....................................... 43 
C.4.8
  Follow-Up Evaluations ........................................................................................... 44 
C.4.9
C.4.9.1 
30 Days ................................................................................................. 44 
C.4.9.2 
3 Months ................................................................................................ 45 
C.4.9.3 
6 Months ................................................................................................ 45 
C.4.9.4 
12 Months .............................................................................................. 45 
C.4.9.5 
18 Months .............................................................................................. 46 
C.4.9.6 
24 Months .............................................................................................. 46 
C.4.9.7 
3-5 Years ............................................................................................... 46 
 
Echo Assessment ............................................................................................. 47 
C.4.10
 
Neurologic Assessment .................................................................................... 47 
C.4.11
 
Angiographic and Computed Tomography Assessment ................................... 48 
C.4.12
 
Data Collection ................................................................................................. 49 
C.4.13
 
Unscheduled Follow-up Assessments .............................................................. 51 
C.4.14
 
Missed Follow-up Visits .................................................................................... 51 
C.4.15
 
Investigational Product Accountability ............................................................... 51 
C.4.16
 
Device Malfunction or Explant ........................................................................... 51 
C.4.17
 
Protocol Deviations ........................................................................................... 52 
C.4.18
 
Subject Withdrawal or Discontinuation .............................................................. 53 
C.4.19
 
Termination or Discontinuation of Trial .............................................................. 53 
C.4.20
C.5 
Adverse Events ............................................................................................................... 54 
  Definitions ............................................................................................................. 54 
C.5.1
C.5.1.1 
Adverse Event ....................................................................................... 54 
C.5.1.2 
Serious Adverse Event .......................................................................... 54 
C.5.1.3 
Major Adverse Cardiovascular and Cerebrovascular Events ................. 54 
C.5.1.4 
Major Adverse Event .............................................................................. 55 
C.5.1.5 
Adverse Device Effect (ADE) or Device-Related Adverse Event ............ 55 
C.5.1.6 
Serious Adverse Device Effects (SADEs) .............................................. 55 
C.5.1.7 
Unanticipated Adverse Device Effect (UADE) ........................................ 55 
C.5.1.8 
Unanticipated Serious Adverse Device Effect (USADE) ........................ 56 
C.5.1.9 
Device Deficiency .................................................................................. 56 
C.5.1.10 
Technical Observation ......................................................................... 56 
  Reporting .............................................................................................................. 56 
C.5.2
C.5.2.1 
Serious Adverse Events (SAEs) ............................................................ 56 
C.5.2.2 
Serious Adverse Device Effects ............................................................. 57 
C.5.2.3 
Unanticipated Adverse Device Effects (UADE or USADE) ..................... 57 
C.5.2.4 
Device Deficiencies and Technical Observations ................................... 57 
C.5.2.5 
All Other Adverse Events ....................................................................... 57 
C.5.2.6 
Anticipated Adverse Events ................................................................... 57 
C.5.2.7 
Deaths ................................................................................................... 59 
C.5.2.8 
Vigilance Reporting ................................................................................ 59 
  Clinical Events Committee (CEC) .......................................................................... 59 
C.5.3
  Data Safety Monitoring Board (DSMB) .................................................................. 59 
C.5.4
C.6 
Statistical Methods and Analysis ..................................................................................... 61 
  Statistical Considerations and Analysis ................................................................. 61 
C.6.1
  Reports ................................................................................................................. 61 
C.6.2
  Description of Baseline Variables .......................................................................... 61 
C.6.3
  Analysis Populations ............................................................................................. 61 
C.6.4

 
 
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C.6.4.1 
Screening Population ............................................................................. 61 
C.6.4.2 
Randomized Population ......................................................................... 61 
  Primary Analysis ................................................................................................... 62 
C.6.5
C.6.5.1 
Hypothesis of Non-inferiority .................................................................. 62 
C.6.5.2 
Randomization, Sample Size and Analysis Plan .................................... 62 
  Missing Data and Planned Sensitivity Analyses (Primary Objective) ..................... 63 
C.6.6
  Description of Performed Analysis, per population ................................................ 63 
C.6.7
C.6.7.1 
Analysis of Screening Population ........................................................... 63 
C.6.7.2 
Analysis of ITT and mITT Populations ................................................... 63 
C.6.7.3 
Analysis of Implanted Population ........................................................... 64 
  Secondary Endpoints ............................................................................................ 65 
C.6.8
C.6.8.1 
Secondary Endpoints Compared Between TAVI and SAVR .................. 65 
C.6.8.2 
Secondary Endpoints Assessed for TAVI Only ...................................... 69 
  Rationale for Selection of Trial Endpoints .............................................................. 69 
C.6.9
 
Multiplicity Considerations ................................................................................. 69 
C.6.10
C.6.10.1 
Secondary Endpoints Tested to Support Labeling Claims ................... 70 
 
Heterogeneity/Poolability .................................................................................. 73 
C.6.11
 
Additional Analysis ............................................................................................ 73 
C.6.12
C.6.12.1 
Pre-Defined Subgroups ....................................................................... 73 
C.6.12.2 
Analysis of VARC Endpoints and Definitions ....................................... 73 
 
Health-Related Quality of Life (HRQoL) and Treatment Costs .......................... 74 
C.6.13
C.6.13.1 
Quality of Life ....................................................................................... 74 
C.6.13.2 
Economic Outcomes/Cost-Effectiveness ............................................. 74 
 
Use of Data for CE Mark ................................................................................... 74 
C.6.14
C.7 
Data and Quality Management ........................................................................................ 75 
  Electronic Data Capture ........................................................................................ 75 
C.7.1
  Data Collection ...................................................................................................... 75 
C.7.2
  Core Laboratories Procedures .............................................................................. 75 
C.7.3
  Source Documents ................................................................................................ 75 
C.7.4
  Maintenance and Calibration ................................................................................. 75 
C.7.5
C.8 
Records and Reports ...................................................................................................... 76 
  Responsibilities of the Sponsor ............................................................................. 76 
C.8.1
  Responsibilities of the Investigator ........................................................................ 77 
C.8.2
D 
RISK / BENEFIT ANALYSIS ............................................................................. 79 
D.1 
Methods to Minimize Risk ............................................................................................... 80 
D.2 
Potential Benefits ............................................................................................................ 80 
E 
DESCRIPTION OF MEDTRONIC COREVALVE™ SYSTEM ............................ 81 
E.1 
Investigational Product Description ................................................................................. 81 
  Medtronic CoreValve System ................................................................................ 81 
E.1.1
E.2 
Investigational Device Ordering, Storage, and Disposition .............................................. 85 
F 
MONITORING AND AUDITING ......................................................................... 85 
F.1 
Monitoring ....................................................................................................................... 85 
F.2 
Auditing ........................................................................................................................... 85 
G 
LABELING.......................................................................................................... 87 
H 
CONSENT MATERIALS .................................................................................... 87 
I 
IRB/MEC INFORMATION .................................................................................. 87 
J 
OTHER INSTITUTIONS ..................................................................................... 87 
K 
ADDITIONAL RECORDS AND REPORTS ....................................................... 87 

 
 
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L 
REPORT OF PRIOR INVESTIGATIONS ........................................................... 87 
M 
PUBLICATION POLICY ..................................................................................... 88 
N 
AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN.......................... 89 
O 
ABBREVIATIONS AND DEFINITIONS ............................................................. 91 
O.1 
List of Abbreviations ........................................................................................................ 91 
O.2 
Definitions of Terms ........................................................................................................ 94 
P 
TRIAL MANAGEMENT .................................................................................... 111 
P.1 
Miscellaneous ............................................................................................................... 111 
  Insurance ............................................................................................................ 111 
P.1.1
  Reimbursement ................................................................................................... 111 
P.1.2
  Indemnification .................................................................................................... 111 
P.1.3
  Subject confidentiality.......................................................................................... 111 
P.1.4
Q 
REFERENCES ................................................................................................. 112 
R 
APPENDICIES ................................................................................................. 118 
  
R.1 
Sample Informed Consent 
R.2 
List of Participating Investigational Centers 
R.3 
Other Institutions 
R.4 
Additional Records and Reports 
R.5 
Sample Case Report Forms 
R.6 
Aortogram Acquisition Guidelines 
R.7 
Echocardiography Acquisition Guidelines 
R.8 
Electrocardiogram (ECG) Submission 
R.9 
Computed Tomography (CT) Angiography Acquisition Guidelines 
R.10 Interactive Voice/Web Response System (IXRS)  
R.11 Explanted Device/Pathology and Return Procedures 
R.12 Economic and Quality of Life Data Collection 
R.13 Pacing Guidelines 
R.14 Six Minute Walk Test Instructions 
R.15 National Institute of Health Stroke Scale (NIHSS) 
R.16 Modified Rankin Scale (mRS) Instructions 
R.17 Mini Mental State Exam (MMSE-2:SV) 
R.18 Additional Neurological Assessments 
R.19 Medtronic CoreValve™ Clinical Assessment Guidelines 
R.20 Katz Index of Independence in Activities of Daily Living 
R.21 Investigator Brochure / Report of Prior Investigations 
R.22 Instuctions For Use 
R.23 Radiation Exposure and Data Collection 
R.24 SURTAVI Risk Model 
R.25 CMS Requirements for Coverage and Reimbursement – US ONLY 
 
 

 
 
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A SYNOPSIS 
Title of Trial: 
Surgical Replacement and Transcatheter Aortic Valve 
Implantation (SURTAVI) 
Name of Product: 
Medtronic CoreValve™ System 
Purpose: 
The purpose of this trial is to investigate the safety and 
efficacy of transcatheter aortic valve implantation 
(TAVI) in patients with severe, symptomatic Aortic 
Stenosis (AS) at intermediate surgical risk by 
randomizing patients to either Surgical Aortic Valve 
Replacement (SAVR) or TAVI.  
Design: 
Subjects will be randomized on a 1:1 basis to either 
transcatheter aortic valve implant (TAVI)or to surgical 
aortic valve replacement (SAVR) 
Primary Objective: 
The primary objective of this trial is to evaluate in a 
prospective randomized fashion whether TAVI is non-
inferior to SAVR with respect to composite endpoint of 
all-cause mortality and disabling stroke at 24 months in 
patients with symptomatic severe aortic stenosis and at 
intermediate surgical risk. 
Secondary Objective: 
The secondary objective of this trial is to assess 
differences in quality of life, clinical benefit (efficacy 
endpoints) and health economics in patients with 
symptomatic severe aortic stenosis and at intermediate 
risk treated with either Transcatheter Aortic Valve 
Implantation (TAVI) or Surgical Aortic Valve 
Replacement (SAVR). 
Exploratory Objective: 
An analysis will be conducted to determine if patients 
can be identified as intermediate risk for Transcatheter 
Aortic Valve Implantation (TAVI) based upon age and 
the presence of a defined list of co-morbidities 
commonly associated with patients undergoing TAVI 
procedures.   
Primary Endpoint: 
All-cause mortality or disabling stroke at 24 months 
Secondary Endpoints: 
The following secondary endpoints will be 
compared between TAVI and SAVR subjects 
cohorts: 
1. Incidence of Major Adverse Cardiovascular and 
Cerebrovascular Events (MACCE)- at 30 days, 6 
months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years.  MACCE is 
defined as a composite of: 
 All-cause death 
 Myocardial infarction (MI) 
 All stroke, and 
 Reintervention (defined as any cardiac surgery 
or percutaneous reintervention catheter 
procedure that repairs, otherwise alters or 
adjusts, or replaces a previously implanted 
valve) 
2. The occurrence of individual MACCE components 
at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
3. Major Adverse Events (MAE) and individual 
components at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 
years. 

 
 
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4. Incidence of Early safety at 30 days defined as a 
composite of: 
 All-cause mortality 
 All stroke (disabling and non-disabling) 
 Life-threatening bleeding 
 Acute kidney injury—Stage 2 or 3 (including 
renal replacement therapy)  
 Coronary artery obstruction requiring 
intervention 
 Major vascular complication 
 Valve-related dysfunction requiring repeat 
procedure (BAV, TAVI, or SAVR) 
 All-cause death 
Early safety composite endpoint-incidence 
estimates will be provided for the two treatment 
groups at 30 days. 
5. Incidence of Clinical Efficacy (after 30 days) at 6 
months, 12 months, 18 months, 24 months and 
annually thereafter up to 5 years. Clinical efficacy 
defined as a composite of: 
 All-cause mortality 
 All stroke (disabling and non-disabling) 
 Requiring hospitalizations for valve-related 
symptoms or worsening congestive heart failure 
 NYHA class III or IV 
 Valve-related dysfunction (mean aortic valve 
gradient ≥20 mmHg, effective orifice area (EOA) 
≤ 0.9-1.1 cm2 and/or doppler velocity index 
(DVI) < 0.35 m/s, AND/OR moderate or severe 
prosthetic valve regurgitation) 
Clinical efficacy estimates will be provided for the 
two treatment groups at 6 months, 12 months, 18 
months, 24 months and annually thereafter up to 5 
years. 
6. Incidence of Time-Related Safety at 30 days, 6 
months, 12 months, 18 months, 24 months and 
annually thereafter up to 5 years. Time-Related 
Safety defined as a composite of: 
 Structural valve deterioration: 
o Valve-related dysfunction (mean aortic valve 
gradient ≥20 mmHg, EOA ≤ 0.9-1.1 cm2 
and/or DVI < 0.35 m/s, AND/OR moderate or 
severe prosthetic valve regurgitation) 
o Requiring repeat procedure (TAVI or SAVR) 
 Prosthetic valve endocarditis 
 Prosthetic valve thrombosis 
 Thromboembolic events (eg. stroke) 
 VARC bleeding, unless clearly unrelated to 
valve therapy (eg. trauma) 
Time related safety composite endpoint-incidence 
estimates will be provided for the two treatment 
groups at 30 days, 6 months, 12 months, 18 
months, 24 months and annually thereafter up to 5 
years. 
7. Conduction disturbance requiring permanent 
pacemaker implantation at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually 
thereafter up to 5 years. 
8. Change in NYHA class from baseline at 30 days, 6 
months, 12 months, 18 months, 24 months, and 

 
 
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annually thereafter up to 5 years. 
9. Change in distance walked during 6-minute walk 
test (6MWT) from baseline to 30 days, baseline to 
12 months, and baseline to 24 months. 
10. Ratio of days alive out of hospital versus total days 
alive assessed at 12 months and 24 months follow-
up.  
11. Quality of Life (QoL) change from baseline at 30 
days, 3 months, 6 months, 12 months, 18 months, 
24 months, and annually thereafter up to 5 years. 
12. Echocardiographic assessment of prosthetic valve 
performance at discharge, 6 months, 12 months, 
24 months, and annually thereafter up to 5 years 
using the following measures: 
 Transvalvular mean gradient 
 Effective orifice area 
 Degree of prosthetic aortic valve regurgitation 
(transvalvular and paravalvular). 
13. Aortic valve disease related hospitalizations.  
14. Cardiovascular deaths and valve-related deaths. 
15. Strokes and TIAs. 
16. Peri-procedural neurological injury. 
17. Index procedure related MAEs. 
18. Length of index procedure hospital stay. 
19. Presence of atrial fibrillation at post-procedure, 
discharge, 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 
years. 
The following secondary endpoints will be 
assessed for the TAVI cohort subjects only: 
20. Device success defined as follows: 
 Absence of procedural mortality AND 
 Correct positioning of a single prosthetic heart 
valve into the proper anatomical location AND 
 Intended performance of the prosthetic heart 
valve (no prosthesis-patient mismatch and 
mean aortic valve gradient <20 mmHg or peak 
velocity <3 m/s, AND no moderate or severe 
prosthetic valve regurgitation) 
o Assessed acutely in resting state, either 
within 24-48 hours after the index procedure 
or before hospital discharge 
21. Procedural success, defined as device success 
and absence of in-hospital MACCE. 
22. Evidence of prosthetic valve dysfunction at 30 
days, 6 months, 12 months, 24 months, and 
annually thereafter up to 5 years. 
 
 
 

 
 
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Trial Sites: 
Up to 115 sites globally 
Sample Size: 
Approximately 1600 patients  
Patient Population: 
Patients who have symptomatic severe Aortic Stenosis 
who are determined by the Heart Team to be at 
intermediate surgical risk. 
Inclusion Criteria: 
1. Subject must have co-morbidities such that Heart 
Team agrees predicted risk of operative mortality is 
≥3% and <15% at 30 days (Intermediate Clinical 
Risk classification). Heart team evaluation of 
clinical surgical mortality risk for each patient 
includes the  calculated STS score for predicted 
risk of surgical mortality augmented by 
consideration of the overall clinical status and co-
morbidities unmeasured by the STS risk 
calculation; 
2. Heart Team unanimously agree on treatment 
proposal and eligibility for randomization based on 
their clinical judgment (including anatomy 
assessment, risk factors, etc.); 
3. Subject has severe aortic valve stenosis presenting 
with 
a) Critical aortic valve area defined as an initial 
aortic valve area of ≤1.0 cm2 or aortic valve 
area index < 0.6 cm2/m2  
AND 
b) Mean gradient > 40mmHg or Vmax > 4m/sec 
by resting echocardiogram or simultaneous 
pressure recordings at cardiac catheterization 
[or with dobutamine stress, if subject has a left 
ventricular ejection fraction (LVEF) <55%] or 
velocity ratio < 0.25; 
4. Subject is symptomatic from his/her aortic valve 
stenosis, as demonstrated by New York Heart 
Association (NYHA) Functional Class II or greater; 
5. Subject and the treating physician agree that the 
subject will return for all required post-procedure 
follow-up visits; 
6. Subject meets the legal minimum age to provide 
informed consent based on local regulatory 
requirements. 
 
 
 

 
 
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Exclusion Criteria: 
1. Subject has refused surgical aortic valve 
replacement (SAVR) as a treatment option; 
2. Any condition considered a contraindication for 
placement of a bioprosthetic valve (i.e. subject 
requires a mechanical valve); 
3. A known hypersensitivity or contraindication to all 
anticoagulation/antiplatelet regimens (including 
inability to be anticoagulated for the index 
procedure), nitinol, or sensitivity to contrast media 
which cannot be adequately pre-medicated; 
4. Blood dyscrasias as defined: leukopenia (WBC 
<1000mm3), thrombocytopenia (platelet count 
<50,000 cells/mm3), history of bleeding diathesis 
or coagulopathy; 
5. Ongoing sepsis, including active endocarditis; 
6. Any condition considered a contraindication to 
extracorporeal assistance; 
7. Any percutaneous coronary or peripheral 
interventional procedure performed within 30 days 
prior to randomization (Subjects with recent 
placement of drug eluting stent(s) should be 
assessed for ability to safely proceed with SAVR 
within the protocol timeframe); 
8. Symptomatic carotid or vertebral artery disease or 
successful treatment of carotid stenosis within six 
weeks of randomization;  
9. Cardiogenic shock manifested by low cardiac 
output, vasopressor dependence, or mechanical 
hemodynamic support; 
10. Recent (within 6 months of randomization) 
cerebrovascular accident (CVA) or transient 
ischemic attack (TIA); 
11. Active gastrointestinal (GI) bleeding that would 
preclude anticoagulation; 
12. Subject refuses a blood transfusion; 
13. Severe dementia (resulting in either inability to 
provide informed consent for the trial/procedure, 
prevents independent lifestyle outside of a chronic 
care facility, or will fundamentally complicate 
rehabilitation from the procedure or compliance 
with follow-up visits); 
14. Multivessel coronary artery disease with a Syntax 
score >22 and/or unprotected left main coronary 
artery (Syntax score calculation is not required for 
patients with history of previous revascularization 
if repeat revascularization is not planned); 
15. Estimated life expectancy of less than 24 months 
due to associated non-cardiac co-morbid 
conditions; 
16. Other medical, social, or psychological conditions 
that in the opinion of the Investigator precludes 
the subject from appropriate consent or 
adherence to the protocol required follow-up 
exams; 
17. Currently participating in an investigational drug or 
another device trial (excluding registries); 

 
 
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18. Evidence of an acute myocardial infarction ≤30 
days before the index procedure; 
19. Need for emergency surgery for any reason; 
20. True porcelain aorta (i.e. Heart Team agrees the 
aorta is not clampable for SAVR); 
21. Extensive mediastinal radiation; 
22. Liver failure (Child-C); 
23. Reduced ventricular function with left ventricular 
ejection fraction (LVEF) <20% as measured by 
resting echocardiogram; 
24. Uncontrolled atrial fibrillation (eg. resting heart rate 
> 120bpm); 
25. Pregnancy or intent to become pregnant prior to 
completion of all protocol follow-up requirements; 
26. End stage renal disease requiring chronic dialysis 
or creatinine clearance < 20 cc/min; 
27. Pulmonary Hypertension (systolic pressure> 
80mmHg); 
28. Severe Chronic Obstructive Pulmonary Disease 
(COPD) demonstrated by Forced Expiratory 
Volume (FEV1) < 750cc; 
29. Frailty assessments identify: 
 Subject is < 80 years of age and three or more 
of the following apply 
 Subject is ≥ 80 years of age and two or more of 
the following apply 
o Wheelchair bound 
o Resides in an institutional care facility (eg. 
nursing home, skilled care center) 
o Body Mass Index <20kg/m2 
o Grip strength <16kg 
o Katz Index score ≤4 
o Albumin <3.5 g/dL. 
30. Marfan syndrome or other known connective 
tissue disease that would necessitate aortic root 
replacement/intervention. 

 
 
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Anatomical Exclusion Criteria 
31. Native aortic annulus size <18 mm or >29 mm per 
the baseline diagnostic imaging; 
32. Pre-existing prosthetic heart valve in any position; 
33. Mixed aortic valve disease [aortic stenosis and 
aortic regurgitation with predominant aortic 
regurgitation (3-4+)]; 
34. Severe mitral or severe tricuspid regurgitation; 
35. Severe mitral stenosis; 
36. Hypertrophic obstructive cardiomyopathy; 
37. Echocardiographic or Multislice Computed 
Tomography (MSCT) evidence of new or 
untreated intracardiac mass, thrombus or 
vegetation; 
38. Ascending aorta diameter greater than maximum 
diameter relative to the native aortic annulus size: 
 
Aortic Annulus 
Diameter 
Ascending Aorta 
Diameter 
18 mm – 20 mm 
>34 mm 
20 mm – 23 mm 
>40 mm 
23 mm – 29 mm 
>43 mm 
39. Aortic root angulation (angle between plane of 
aortic valve annulus and horizontal 
plane/vertebrae)  
a) Femoral and left subclavian/axillary access > 
70°  
OR  
b)  Right subclavian/axillary access: Aortic root 
angulation > 30°; 
40. Congenital bicuspid or unicuspid valve verified by 
echocardiography; 
41. Sinus of Valsalva anatomy that would prevent 
adequate coronary perfusion. 
Vascular Exclusion Criteria 
42. Transarterial access not able to accommodate an 
18Fr sheath. 
Enrollment Phase: 
36 months 
Follow-up Evaluations: 
Subjects will be followed through 5 years with 
assessments at 30 days, 3 months, 6 months, 12 
months, 18 months, 24 months, and 3, 4, and 5 years 
post TAVI or post SAVR. The total trial duration is 
expected to be approximately 7 years. 
 
 
 

 
 
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B PURPOSE 
B.1 
Background 
Aortic valve stenosis (AS) is the most prevalent valve disorder in the adult population in 
developed countries affecting approximately 2% to 4% of people over 65 years of age (2, 3) . 
This corresponds to approximately 3 million people with AS in Europe and approximately 1.5 
million in the United States. One in five will eventually progress to symptomatic AS representing 
more than 900,000 patients in these two geographies.  
Patients with severe AS face a grim prognosis once they become symptomatic. The landmark 
paper on symptomatic AS by Ross and Braunwald in 1968 highlighted this premise: median 
survival averages only 2, 3 and 5 years after symptom onset of angina, syncope and heart 
failure respectively(4). Furthermore mortality is already substantial in the months following the 
first symptoms (5). The dismal prognosis of patients with untreated severe, symptomatic aortic 
stenosis has been recently corroborated in the conservative treatment arm of the PARTNER B 
cohort. Both, the ESC and ACC/AHA cardiology societies have endorsed guidelines on valvular 
heart disease emphasizing the need for surgical aortic valve replacement (SAVR) once 
symptoms develop or in case of impaired LV function (Level of evidence grade 1)(6, 7, 8).  
Physicians’ preferences for lesser invasive strategies have fuelled the ongoing interest in 
developing minimally invasive transcatheter therapies. Alain Cribier pioneered the transcatheter 
aortic valve implantation (TAVI) technology and reported the first-in-man experience of TAVI in a 
patient with symptomatic AS who was deemed inoperable in 2002(10). Subsequent feasibility 
studies validated the proof of concept (11, 12). The Edwards-SAPIEN valve (Edwards 
Lifesciences, Irvine, CA, USA) and the Medtronic CoreValve system (Medtronic Corporation, 
Minneapolis, MN, USA) were the first two TAVI platforms with CE mark approval, followed by 
the Symetis Acurate (Symetis, Ecublens, Switzerland) and JenaValve (JenaValve, Munich, 
Germany).  Numerous single-center and multi-center observational registries followed 
suggesting the safety and performance of the TAVI technology (13-17). The TAVI technology 
comes with its own specific complications (18), not necessarily overlapping with those of SAVR: 
vascular injury; stroke, cardiac injury such as heart block, coronary obstruction, and cardiac 
perforation; paravalvular leak; and valve misplacement. The non-uniformity in presenting 
respective data makes a comparison of results from different centers challenging (19, 20). The 
Valvular Academic Research Consortium (VARC), a FDA-endorsed collaboration between 
academic research organizations and professional societies in the United States and Europe is 
an initiative to generate a consensus statement on TAVI related definitions aiming to create 
order and uniformity making data more prone to analysis and comparison (21, 22).  
Technical refinements and commercial entrepreneurship have made the technology accessible 
to many centers worldwide. This might pose future implications since few randomized trials with 
TAVI have been performed.  
There are three types of medical practices.  The first is the institution with on-site interventional 
cardiologic and cardiothoracic surgical activity and with close inter-disciplinary collaboration, 
where interventional cardiologists and cardiothoracic surgeons reach a consensus on which 
patients to select for a specific surgical or interventional treatment strategy (9). These centers 
would reasonably respect and adhere to CE mark labeling indications. Second, there are 
centers where interventional cardiologists and cardiothoracic surgeons do not often convene, 
and usually work as two separate departments. Finally, there are practices with an interventional 
cardiology program but without on-site cardiothoracic surgery, estimated to make up 37% of all 
PCI centers in the European Union. Expectedly, these kinds of organizations without intimate 
collaboration between cardiothoracic surgeons and interventional cardiologists will look to 
broaden their interventional activities with an attractive innovation like TAVI. A worldwide 
practice that is less controlled would potentially cloud the safety and efficacy profile of the 
procedure. This criticism by the medical community and health authorities could jeopardize 
future reimbursement policies (23, 24). The advent of randomized trial data is crucial and this 
next step in establishing a new treatment strategy should not be taken for granted as 
governmental authorities entitled to grant premarket approval to cardiovascular devices are 
under increased scrutiny and quality control (25). 
After nearly a decade of worldwide mounting TAVI experience, the Cohort B arm of the much-
anticipated PARTNER (Placement of AoRTic TraNscathetER Valve Trial) trial representing the 
first randomized data set, reported a dramatic 20% absolute reduction in mortality in favor of 

 
 
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TAVI compared to medical therapy in patients who, as determined by surgeons could not 
undergo conventional surgical valve replacement (26).  
In the Cohort A of the PARTNER trial, patients for whom a surgeon and cardiologist concurred 
that the predicted risk of operative mortality was ≥15% and/or with a minimum STS score of 10 
were randomized to TAVI or SAVR. The trial completed its randomization in early 2009 and first 
data were presented at ACC in April 2011, reporting successful achievement of the primary 
endpoint (TAVR was non-inferior to AVR for all-cause mortality at 1 year). 
At the PCR London Valves meeting in October 2010, it was reported that over 22000 patients 
had been treated with TAVI worldwide. To date over 45,000 Medtronic CoreValve System have 
been implanted worldwide (data on file with Medtronic). Inevitably, with increased operator 
experience and access to the device, physicians will shift their attention to younger patients with 
a less pronounced operative risk due to the decreased invasiveness of the TAVI procedure as 
compared with SAVR, coupled with the safety and performance observed in the PARTNER trial 
and other literature reports in the extreme and high risk populations. Similar to the coronary 
revascularization arena (27), the blending of surgical and interventional expertise has created 
unique interdisciplinary dynamics paving the way for a randomized trial comparing TAVI with 
SAVR in a surgical intermediate risk patient population.  
It is in this spirit that the SURTAVI trial (SURgical and Transcatheter Aortic Valve Implantation) 
was conceived. The interdisciplinary approach and consensus of the Heart Team (the 
cardiothoracic surgeon, interventional cardiologist and other treating physicians if necessary) is 
crucial. This aspect of decision making cannot be over-emphasized and is essential for the 
quality of current medical practice in general and any planned randomized trial of TAVI versus 
SAVR in particular. The VARC publication (21, 22) on TAVI definitions and the accumulating 
TAVI expertise in Europe has created a unique momentum for such a randomized initiative 
complementary to the US Pivotal IDE randomized trial in AS patients with high operative risk.  
For a new technology to be accepted as a new asset for treating symptomatic AS several 
essential questions need to be answered: is the technology effective? Which patients are likely 
to benefit (patient selection)? How does this new strategy compare with the alternatives? And 
what is the cost of the intervention relative to alternatives? The proof of concept has been 
validated. The innovative and less invasive transcatheter approach should be at least as 
effective and safe as conventional SAVR or have proof of superiority for both safety and efficacy 
compared to medical therapy.  
The theoretical benefits of this transcatheter approach seem evident by avoiding the need of 
musculoskeletal incisions, cardioplegic arrest, aortic cross clamping, aortotomy, and full 
cardiopulmonary bypass. Ultimately the cost-effectiveness will determine whether the new 
treatment strategy is a valid option to be considered for reimbursement by governmental health 
institutions.  
 
 

 
 
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B.2 
Investigational Devices and Intended Use 
 
Device Description 
B.2.1
B.2.1.1 
Medtronic CoreValve™ System 
The Medtronic CoreValve™ System consists of the following product elements: 
 
Transcatheter Aortic Valve Bioprosthesis (TAV): consisting of a multi-level self-
expanding frame with porcine pericardial bioprosthesis.  The bioprosthesis is processed 
with an anti-mineralization treatment of alpha-amino oleic acid (AOA) a compound 
derived from oleic acid, a naturally occurring long-chain fatty acid. 
 
Delivery Catheter System (DCS): designed to house the tissue valve prosthesis in the 
collapsed position for transcatheter delivery to the patient’s aortic annulus. 
 
Compression Loading System (CLS): facilitates consistent and trauma-free manual 
loading of the TAV into the DCS. 
The models to be used are:   
 
Transcatheter Aortic Valve Prosthesis (TAV) - Models MCS-P4-23-AOA, MCS-P4-23-
AOA-US (23mm), MCS-P3-26-AOA, MCS-P3-26-AOA-US (26mm), MCS-P3-29-AOA, 
MCS-P3-29-AOA-US (29mm), and MCS-P3-31-AOA, MCS-P3-31-AOA-US (31mm)  
 
Delivery Catheter System (DCS) – AccuTrak®:  DCS-C4-18FR, DCS-C4-18F-US, DCS-
C4-18FR-23MM (US), and DCS-C4-18FR-23 (OUS) 
 
Compression Loading System (CLS) - Model CLS-3000-18FR, CLS4-18F, CLS-3000-
18FR-US, and CLS4-18F-23 
 
In the US, commercial devices, as referenced in the sections above and in Table 1, are 
approved for use in the clinical trial, as necessary, in the event that an investigational device is 
not available.  
Also, any future approved (i.e. CE marked) models or device iterations may be used in the trial. 
The TAV is adapted to a range of aortic annulus and ascending aorta diameters as shown in 
Table 1. 
Table 1:  Patient Anatomical Diameters  
CoreValve™ Evolut™ Bioprosthesis 
Model 
Aortic Annulus Diameter 
(range in mm) 
Aortic Diameter at the 
Sino-tubular Junction 
(range in mm) 
MCS-P4-23-AOA 
MCS-P4-23-AOA-US 
18-20 
≤34 
CoreValve™ Bioprosthesis 
Model 
Aortic Annulus Diameter 
(range in mm) 
Aortic Diameter at the 
Sino-tubular Junction 
(range in mm) 
MCS-P3-26-AOA 
MCS-P3-26-AOA-US 
20-23 
≤40 
MCS-P3-29-AOA 
MCS-P3-29-AOA-US 
23-27 
≤43 
MCS-P3-31-AOA 
MCS-P3-31-AOA-US 
26-29 
≤43 
 
 

 
 
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Device Approval Status 
B.2.2
The approval statuse of the Medtronic CoreValve™ System is outlined in Table 2 below. This 
table presents the current approval status for the CoreValve System where the clinical trial is 
conducted. 
Table 2: Device Approval Status 
Device Approval 
Status 
United States 
European Union 
Canada 
Medtronic CoreValve™ System 
TAV  
Market Released 
Market Released 
26mm, 29mm, and 
31mm - Market 
Released  
23mm - Investigational 
DCS 
Market Released 
Market Released 
Market Released 
CLS 
Market Released 
Market Released 
Market Released 
B.2.2.1 
European Union 
CoreValve 
The notified body granted an approval for CE Marking for the 18Fr CoreValve ReValving™ 
System (renamed to “Medtronic CoreValve System” after acquisition from CoreValve Inc. by 
Medtronic Inc. on 9 April 2009) effective March 1, 2007. Model MCS-P3-640 (26mm) and MCS-
P3-943 (29mm) received CE mark effective 2006) and MCS-P3-943 (31mm) received CE 
marked in July 2011.  AOA treated valves (26mm, 29mm, and 31mm) received CE mark in 
March 2012. The AOA treated 23mm valve (MCS-P4-23-AOA) received CE mark in May 2012 
(marketed as CoreValve™ Evolut™).  The models to be used in this trial, listed in Table 1, are 
identical to the CE marked devices.  The devices used in this trial will be used outside the 
current approved indication. The Medtronic CoreValve System is still under investigation for the 
intermediate risk indication. 
The Delivery Catheter System (DCS) with AccuTrak® Stability Layer was designed to optimize 
the valve positioning and will be used in this trial. CE mark approval was received in July 2010. 
The Delivery System for 23mm TAV (DCS-C4-18FR-23) has a shortened capsule and plunger 
to house and deliver the 23 mm TAV.   The DCS and CLS components used for this trial are the 
CE marked product.  
B.2.2.2 
United States 
CoreValve 
Medtronic submitted an Original IDE (G100012) to seek approval to initiate an Investigational 
Device Exemption for the Medtronic CoreValve System (size 26mm and 29mm). This trial was 
intended for use in subjects with severe symptomatic Aortic Stenosis (AS) necessitating aortic 
valve replacement in Extreme Risk and High Risk Patient Populations. This IDE was 
conditionally approved on October 13, 2010 and received full approval on November 10, 2011.  
Medtronic added an additional 31mm TAV size to the IDE via G100012/S24 followed by 23mm 
TAV via G100012/S31.  
The FDA granted marketing approval of CoreValve for Extreme Risk patients on January 17, 
2014 and High Risk patients on June 12, 2014. The devices used in this trial will be used 
outside the current approved indication.  The models to be used in this trial, listed in Table 1, 
are identical to the FDA approved devices.  FDA granted approval for the use of commercially 
labeled devices in the trial on August 6, 2014.  The devices used in this trial will be used outside 
the current approved indication.  The Medtronic CoreValve System is still under investigation for 
the intermediate risk indication.  
B.2.2.3 
Canada 
CoreValve 
The commercial application for the Medtronic CoreValve System (26mm and 29mm) was 
approved by Health Canada on August 2, 2012 and the 31mm on February 7, 2014. Medtronic 

 
 
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CoreValve System 23mm is available only via Special Access, which is considered 
investigational and may be used upon special access granted by Health Canada.  The models 
to be used in this trial, listed in Table 1, are identical to the Health Canada approved and 
Special Access devices.  The devices used in this trial will be used outside the current approved 
indication. The Medtronic CoreValve System is still under investigation for the intermediate risk 
indication. 
 
 
 
Intended Use of the Device / Indications for Use 
B.2.3
The Medtronic CoreValve™ System are intended/indicated for use in patients who have symptomatic 
severe aortic stenosis (AS) necessitating valve replacement and who are at intermediate surgical risk 
and presenting with anatomical dimensions as described in Table 1. 
 

 
 
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B.3 Trial Objectives 
 
Primary 
B.3.1
The primary objective of this trial is to evaluate in a prospective randomized fashion whether 
Transcatheter Aortic Valve Implantation (TAVI) is non-inferior to Surgical Aortic Valve 
Replacement (SAVR) with respect to the composite endpoint of all-cause mortality and disabling 
stroke at 24 months in patients with symptomatic severe aortic stenosis and at intermediate 
surgical risk.  
 
Secondary 
B.3.2
The secondary objective of this trial is to assess differences in quality of life, clinical benefit 
(efficacy endpoints) and health economics in patients with symptomatic severe aortic stenosis 
and at intermediate risk treated with either Transcatheter Aortic Valve Implantation (TAVI) or 
Surgical Aortic Valve Replacement (SAVR). 
 
Exploratory 
B.3.3
An analysis will be conducted to determine if patients can be identified as intermediate risk for 
Transcatheter Aortic Valve Implantation (TAVI) based upon age and the presence of a defined 
list of co-morbidities commonly associated with patients undergoing TAVI procedures.  A 
complete discussion of this exploratory objective can be found in Appendix R.24. 
 

 
 
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C TRIAL PROTOCOL 
C.1 
Ethics and Regulatory Compliance 
 
Applicable Regulations 
C.1.1
This trial will be conducted in compliance with the protocol, the Sponsor’s standard operating 
procedures and/or guidelines, the United States Food and Drug Administration (FDA) and local 
regulations where applicable, the International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines, ISO14155 (2011), and the Declaration of Helsinki (2008 and 
subsequent versions).  Additionally, the Medical Device Directive (MEDDEV 2.7/3) will be 
followed for Investigator reporting of Serious Adverse Events (SAEs) to the sponsor. 
 
Institutional Review Board (IRB)/Medical Ethics Committee (MEC) 
C.1.2
The trial will be conducted in accordance with 21 CFR 56 Institutional Review Boards and/or 
local regulations for Medical Ethics Committee (MEC).  The trial protocol and consent must be 
approved by the responsible Institutional Review Board (IRB) or MEC at each investigational 
site.  Trial activities must not commence prior to receipt of documentation of IRB/MEC approval 
by the site and Medtronic.  The Investigator and trial staff must comply with the requirements of 
their IRB/MEC. 
Prior to enrolling subjects in this trial, each investigation site’s IRB/MEC will be required to 
approve the current trial clinical investigation plan, the Patient Information and Informed Consent 
form, and any other written information to be provided to the subjects. In the US, Investigator 
must also utilize IRB approved Health Insurance Portability and Accountability Act (HIPAA) 
Authorization.  
IRB/MEC approval of the clinical trial must be received in the form of a letter and provided to 
Medtronic before commencement of the trial at an investigation site. The approval letter must 
contain enough information to identify the version or date of the documents approved. In 
addition the approval letter needs to be accompanied by an IRB/MEC roster or letter of 
compliance, to allow verification that the investigator, other center trial staff, and/or Medtronic 
personnel are not members of the IRB/MEC. If they are members of the IRB/MEC, written 
documentation is required stating that he/she did not participate in the approval process. 
Investigators must inform Medtronic of any change in status of IRB/MEC approval once the 
investigation site has started enrolment. 
 
Regulatory Submission 
C.1.3
Prior to enrolling any patients in the trial, all local regulatory requirements must be fulfilled. Each 
trial site must have written documentation of site/investigator readiness, including but not limited 
to IRB/MEC approval of the current version of the Investigational Plan, Informed Consent form, 
a signed Investigator’s Agreement, current investigator curriculum vitae, and documentation of 
training.  The coordinating and principal investigators shall agree to this investigational plan and 
any amendments and indicate their approval by signing and dating the Investigator’s 
Agreement. 
Approval from the Regulatory Authorities, if applicable, is required prior to the first patient 
enrollment in a particular center. Medtronic will obtain a copy of the approval letter, directly from 
the Regulatory Authorities. 
If any action is taken by an IRB/MEC with respect to the investigation, that information will be 
forwarded to Medtronic by the respective investigator. 
Other documents that are referred to in this Clinical Investigation Plan are listed below and will 
be made available upon request: 
 
Monitoring Plan 
 
Data Management Plan 
 
Statistical Analysis Plan 
 
Patient Information and Informed Consent Form 
 
Case Report Forms 
 

 
 
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Ethical Conduct of the Trial 
C.1.4
The trial will be conducted in accordance with the design and specific provisions of this protocol, 
in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and 
that are consistent with Good Clinical Practice (GCP) and the applicable regulatory 
requirements. 
The principles of the Declaration of Helsinki have all been implemented in this trial by means of 
the patient informed consent process, IRB/MEC approval, trial training, clinical trial registration, 
preclinical testing, risk benefit assessment, and publication policy.  
The sponsor will avoid improper influence on, or inducement of the subject, monitor, and 
investigator(s) or other parties participating in, or contributing to, the clinical investigation by 
implementing the patient informed consent process, clinical investigation agreements, and 
IRB/MEC review and approval. 
C.2 Trial Administration 
 
Steering Committee 
C.2.1
The Steering Committee will be an advisory body to Medtronic.  Their roles and responsibilities 
may include, but are not limited to the following: 
 
Overall conduct of the study with regard to  
o 
Protocol development and implementation 
o 
Study progress 
o 
Patient safety 
o 
Data quality and integrity 
 
Quality performance at individual sites 
o 
The Steering Committee will support site investigators in resolving any clinical 
or procedural issues that may impact patient well-being or integrity of the study 
o 
Any site placed on probation for any reason may be terminated from the study 
after an appropriate review by the Steering Committee 
 
Review of all Data Safety Monitoring Board (DSMB) recommendations 
 
Assess requests for sub-studies 
 
Assist with Publication efforts by disseminating study information through appropriate 
scientific sessions and publications 
o 
All requests for abstract and manuscript preparation and submission require 
Steering Committee review and approval. All final decisions will be made by 
Medtronic; however, the recommendations made by the Steering Committee 
will be highly considered 
 
Participate in Investigator Meetings (and other study related meetings) 
 
Serve as a contact for other study investigators (providing peer consultation) 
Prior to the onset of the trial, the Steering Committee will establish a charter.  The Steering 
Committee charter will be approved by Medtronic and the Steering Committee members. 
 
Publication Committee 
C.2.2
The Publication Committee will review and approve publication ideas and facilitate submissions, 
including abstracts and manuscripts.  The Publication Committee will consist of SURTAVI trial 
investigators (interventional cardiologists and cardiac surgeons) and Medtronic representatives. 
The Publication Committee will be responsible for: 
 
Defining and refining the publication strategy 
 
Overseeing the development of manuscripts, abstracts, and presentations 
 
Identifying and appointing the manuscript/abstract first author(s)/writer(s)/presenters(s) 
 
Reviewing the publication 
 

 
 
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C.3 Methodology 
 
Purpose 
C.3.1
The purpose of this trial is to investigate the safety and efficacy of transcatheter aortic valve 
implantation (TAVI) in patients with severe, symptomatic Aortic Stenosis (AS) at intermediate 
surgical risk by randomizing patients to either Surgical Aortic Valve Replacement (SAVR) or 
TAVI. Data from this trial will be used to support regulatory applications in seeking approval for 
the Medtronic CoreValve System in the intermediate surgical risk population. 
 
Patient Population 
C.3.2
Patients who have symptomatic severe Aortic Stenosis who are determined by the Heart Team 
to be at intermediate surgical risk. 
 
Design 
C.3.3
This trial is designed as a prospective, multi-center, multi-national, randomized, interventional 
trial to investigate the safety and efficacy of transcatheter aortic valve implantation (TAVI) in 
patients with severe, symptomatic Aortic Stenosis (AS) at intermediate surgical risk. 
Approximately 1600 subjects will be recruited in up to 115 investigational centers located in the 
United States, Canada and Europe.  The trial may be expanded to include additional 
geographies based on enrollment rates and identification of qualified centers. 
Subjects will be randomized on a 1:1 basis to either transcatheter aortic valve implant (TAVI) or 
to surgical aortic valve replacement (SAVR). 
To avoid bias in the trial population the following measures have been taken: 
 
All sponsor and external trial personnel will be trained on the Clinical Investigation Plan 
(CIP) and related trial materials; and 
 
Subjects will be screened to confirm trial eligibility with defined inclusion/exclusion 
criteria prior to enrollment. 
The total trial duration is expected to be approximately eight years. 
 
Investigational Centers 
C.3.4
Site distribution is anticipated to include up to 75 centers in the United States, 10 in Canada and 
30 in Europe. 
For this study, the following investigator/center selection minimum criteria are considered: 
 
Center must have sufficient patient population  
 
Each center’s Implant Team (i.e. 1st and 2nd operators) must have completed at least 30 
cumulative TAVI procedures  
 
There will be no other study ongoing during this study duration, which would prevent the 
center from meeting enrollment goals for SURTAVI or provide adequate staffing 
 
Investigator should have adequate staff that is accessible and has time to manage the 
study for 7 days per week, 24 hours per day 
 
Investigator, co-investigators, and study staff must be willing to provide his/her 
Curriculum Vitae 
 
Investigator and co-investigators must be willing to sign and comply with the protocol-
specific Investigator Agreement 
 
Center must be willing to comply with the Clinical Investigation Plan and data 
requirements, including reporting Adverse Events 
 
Center has demonstrated experience with conducting clinical (device) trials that comply 
with applicable regulatory standards 
 
Center is willing to participate in follow-up of patients for 5 years 
 
Center has an internet connection with sufficient speed of data transfer 
All investigators will be appropriately qualified practitioners legally entitled to practice, and 
experienced in the diagnosis and treatment of patients requiring an aortic valve treatment with a 
TAVI or SAVR.  

 
 
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For the purposes of the SURTAVI trial, it is imperative that Medtronic leverages highly qualified 
surgeons for the surgical aortic valve replacements (SAVR) that will occur as a part of the trial. 
The following minimum criteria will be used for all cardiac surgeons performing SAVRs in the 
SURTAVI trial:    
 
At least 5 years of experience post-residency 
 
At least 100 career aortic valve replacements post-residency 
 
At least 75 valve procedures in the last 3 years 
 
At least 35 surgical aortic valve replacements in the last 3 years 
 
At least 15 aortic valve replacements in the last year 
 
Number of Subjects 
C.3.5
Up to 2000 subjects will be randomized [1:1, TAVI: Surgical Aortic Valve Replacement (SAVR)]. 
The enrollment phase is anticipated to be approximately 36 months. Subjects will be followed 
through 5 years for assessment of long-term safety and efficacy endpoints.  The total trial 
duration is expected to be approximately 8 years. 
Enrollments shall not exceed 20% (approximately 400) of total randomized subjects at any 
individual site. Enrollment is competitive; therefore there is no set minimum number of subjects 
to be enrolled per site. Appropriate measures will be taken to monitor enrollment across 
geographies to ensure at least 40% of the total patient population is enrolled within the United 
States. 
 
 Inclusion/Exclusion Criteria 
C.3.6
C.3.6.1 
Inclusion Criteria 
To participate in this trial, the subject must meet ALL of the following inclusion criteria.  
1. 
Subject must have co-morbidities such that Heart Team agrees predicted risk of 
operative mortality is ≥3% and <15% at 30 days (Intermediate Clinical Risk 
classification). Heart team evaluation of clinical surgical mortality risk for each patient 
includes the  calculated STS score for predicted risk of surgical mortality augmented by 
consideration of the overall clinical status and co-morbidities unmeasured by the STS 
risk calculation; 
2. 
Heart Team unanimously agree on treatment proposal and eligibility for randomization 
based on their clinical judgment (including anatomy assessment, risk factors, etc.); 
3. 
Subject has severe aortic stenosis presenting with: 
a) Critical aortic valve area defined as an initial aortic valve area of ≤1.0 cm2 or 
aortic valve area index < 0.6 cm2/m2 
 
AND 
b) Mean gradient > 40mmHg or Vmax > 4m/sec by resting echocardiogram or 
simultaneous pressure recordings at cardiac catheterization [or with dobutamine 
stress, if subject has a left ventricular ejection fraction (LVEF) <55%] or velocity 
ratio < 0.25; 
4. 
Subject is symptomatic from his/her aortic valve stenosis, as demonstrated by New 
York Heart Association (NYHA) Functional Class II or greater; 
5. 
Subject and the treating physician agree that the subject will return for all required post-
procedure follow-up visits; 
6. 
Subject meets the legal minimum age to provide informed consent based on local 
regulatory requirements. 
C.3.6.2 
Exclusion Criteria 
Subjects are NOT eligible for trial participation if they meet ANY of the following exclusion 
criteria: 
1. Subject has refused surgical aortic valve replacement (SAVR) as a treatment option; 
2. Any condition considered a contraindication for placement of a bioprosthetic valve (i.e. 
subject requires a mechanical valve); 

 
 
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3. A known hypersensitivity or contraindication to all anticoagulation/antiplatelet regimens 
(or inability to be anticoagulated for the index procedure), nitinol, or sensitivity to 
contrast media which cannot be adequately pre-medicated; 
4. Blood dyscrasias as defined: leukopenia (WBC <1000mm3), thrombocytopenia (platelet 
count <50,000 cells/mm3), history of bleeding diathesis or coagulopathy; 
5. Ongoing sepsis, including active endocarditis; 
6. Any condition considered a contraindication to extracorporeal assistance; 
7. Any percutaneous coronary or peripheral interventional procedure performed within 30 
days prior to randomization (Subjects with recent placement of drug eluting stent(s) 
should be assessed for ability to safely proceed with SAVR within the protocol 
timeframe); 
8. Symptomatic carotid or vertebral artery disease or successful treatment of carotid 
stenosis within six weeks of randomization;  
9. Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or 
mechanical hemodynamic support; 
10. Recent (within 6 months of randomization) cerebrovascular accident (CVA) or transient 
ischemic attack (TIA); 
11. Active gastrointestinal (GI) bleeding that would preclude anticoagulation; 
12. Subject refuses a blood transfusion; 
13. Severe dementia (resulting in either inability to provide informed consent for the 
trial/procedure, prevents independent lifestyle outside of a chronic care facility, or will 
fundamentally complicate rehabilitation from the procedure or compliance with follow-up 
visits); 
14. Multivessel coronary artery disease with a Syntax score >22 and/or unprotected left 
main coronary artery (Syntax score calculation is not required for patients with history of 
previous revascularization if repeat revascularization is not planned); 
15. Estimated life expectancy of less than 24 months due to associated non-cardiac co-
morbid conditions; 
16. Other medical, social, or psychological conditions that in the opinion of the Investigator 
precludes the subject from appropriate consent or adherence to the protocol required 
follow-up exams; 
17. Currently participating in an investigational drug or another device trial (excluding 
registries); 
18. Evidence of an acute myocardial infarction ≤30 days before the index procedure; 
19. Need for emergency surgery for any reason; 
20. True porcelain aorta (i.e. Heart Team agrees the aorta is not clampable for SAVR); 
21. Extensive mediastinal radiation; 
22. Liver failure (Child-C); 
23. Reduced ventricular function with left ventricular ejection fraction (LVEF) <20% as 
measured by resting echocardiogram; 
24. Uncontrolled atrial fibrillation (eg. resting heart rate >120bpm); 
25. Pregnancy or intent to become pregnant prior to completion of all protocol follow-up 
requirements; 
26. End stage renal disease requiring chronic dialysis or creatinine clearance < 20 cc/min; 
27. Pulmonary Hypertension (systolic pressure> 80mmHg); 
28. Severe Chronic Obstructive Pulmonary Disease (COPD) demonstrated by Forced 
Expiratory Volume (FEV1) < 750cc; 
29. Frailty assessments identify: 
 Subject is < 80 years of age and three or more of the following apply 
 Subject is ≥ 80 years of age and two or more of the following apply 
o Wheelchair bound 
o Resides in an institutional care facility (eg. nursing home, skilled care center) 
o Body Mass Index < 20 kg/m2 
o Grip strength <16 kg 
o Katz Index score ≤ 4 

 
 
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o Albumin < 3.5 g/dL; 
30. Marfan syndrome or other known connective tissue disease that would necessitate 
aortic root replacement/intervention. 
Anatomical Exclusion Criteria 
31. Native aortic annulus size <18 mm or >29 mm per the baseline diagnostic imaging; 
32. Pre-existing prosthetic heart valve in any position; 
33. Mixed aortic valve disease [aortic stenosis and aortic regurgitation with predominant 
aortic regurgitation (3-4+)]; 
34. Severe mitral or severe tricuspid regurgitation; 
35. Severe mitral stenosis; 
36. Hypertrophic obstructive cardiomyopathy; 
37. Echocardiographic or Multislice Computed Tomography (MSCT) evidence of new or 
untreated intracardiac mass, thrombus or vegetation; 
38. Ascending aorta diameter greater than maximum diameter relative to the native aortic 
annulus size: 
 
Aortic Annulus Diameter
Ascending Aorta Diameter
18 mm – 20 mm
>34 mm
20 mm – 23 mm 
>40 mm 
23 mm – 29 mm 
>43 mm 
 
39. Aortic root angulation (angle between plane of aortic valve annulus and horizontal 
plane/vertebrae): 
a) Femoral and left subclavian/axillary access > 70°  
OR 
 
b) Right subclavian/axillary access: Aortic root angulation > 30°; 
40. Congenital bicuspid or unicuspid valve verified by echocardiography; 
41. Sinus of Valsalva anatomy that would prevent adequate coronary perfusion. 
Vascular Exclusion Criteria 
42. Transarterial access not able to accommodate an 18Fr sheath. 

 
 
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Informed Consent 
C.3.7
The investigator must obtain written informed consent prior to subjecting the subject to any trial 
related activity.  
Well in advance of the consent discussion, the subject should receive the MEC/IRB approved 
Patient Information and Informed Consent Form (ICF). During the consent discussion the 
investigator or his/her designee must fully inform the subject of all pertinent aspects of the trial 
including the approval of the MEC/IRB of the written Patient Information. If a subject is illiterate, 
an impartial witness must be present during the entire informed consent discussion. All items 
discussed in the Patient Information and the ICF must be explained. The language used shall be 
in the subject’s native language, as non-technical as possible and must be understandable to 
the subject and the impartial witness, where applicable.  
The subject must have ample time and opportunity to inquire about details of the trial, and to 
decide whether or not to participate in the clinical trial. All questions about the trial should be 
answered to the satisfaction of the subject. 
Neither the investigator, nor the investigation site staff shall coerce or unduly influence a subject 
to participate or to continue to participate in the clinical trial. The informed consent process shall 
not appear to waive the subject’s rights. 
When the subject decides to participate in the clinical trial, the ICF must be signed and 
personally dated by the subject and investigator. If applicable, the witness shall also sign and 
personally date the consent form to attest that the information in the Patient Information and 
Informed Consent Form was accurately explained and clearly understood by the subject, and 
that informed consent was freely given.  
Signing the ICF serves to document the written and verbal information that the Investigator or 
authorized delegate provides to the patient, the patient understanding of the information, and 
their agreement to participate.  The Investigator or authorized delegate must document in the 
patient’s medical records that the patient was consented and the date on which the consent was 
obtained.  The original signed consent form will be retained in the patient’s trial records.  A copy 
of the informed consent will be provided to the patient and a copy placed in the patient’s medical 
record. 
Data relating to the trial might be made available to third parties (for example in case of an audit 
performed by regulatory authorities), provided the data are treated as confidential and that the 
subject’s privacy is guaranteed.  In the United States, “Protected Health Information” will be 
maintained in compliance with the Health Insurance Portability and Accountability Act of 1996 
(HIPAA). 
 
Revisions in Patient Information and Informed Consent Form 
C.3.8
Medtronic will inform the investigators whenever information becomes available that may be 
relevant to the subject’s continued participation in the trial. The revised information will be sent 
to the investigator for approval by the IRB/MEC. After approval by the IRB/MEC, a copy of this 
information must be provided to the participating subjects, and the informed consent process as 
described above needs to be repeated. The investigator or his/her designee should inform the 
subject in a timely manner. 
 

 
 
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Enrollment Flowchart for Randomization to TAVI or SAVR 
C.3.9
 
Figure 1: Enrollment Flowchart 
  
 
If the patient meets all of the inclusion criteria and none of the exclusion and Heart Team 
determines the patient is eligible for randomization in the SURTAVI trial, subjects will be 
randomized on a 1:1 basis to either TAVI or SAVR.  Randomization will be stratified by the need 
for coronary revascularization. In case of required coronary revascularization, concomitant 
percutaneous coronary intervention (PCI) and TAVI is encouraged; however staging is left at the 
discretion of the operator. Coronary artery bypass graft (CABG) should be conducted during the 
index procedure. 
 Trial Training 
C.3.10
Prior to investigational site activation or subsequent involvement in trial activities, Medtronic (or 
designee) will provide trial training relevant and pertinent to the involvement of personnel 
conducting trial activities, including investigator responsibilities, adverse event reporting as well 
as device training (if necessary, usage and handling of device under investigation). Training may 
be conducted via Site Initiation Visits, Investigator and Coordinator Meetings, and/or other 
media sessions. The sponsor will maintain documentation of attendance at each of these 
training opportunities, as applicable.  

 
 
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Additionally, Medtronic representative(s) may be present at each site’s TAVI procedures as part 
of the ongoing training process. 
C.4 Trial Procedures 
 
Screening Procedures 
C.4.1
Prior to any trial-specific tests or procedures, written informed consent must be obtained from 
the subject. Failure to obtain a signed and hand dated informed consent prior to the procedure 
constitutes a protocol violation, which is reportable to the IRB/MEC, the Food and Drug 
Administration (FDA), and other regulatory authorities as applicable. 
All potential subjects for trial entry must be screened for eligibility. All patients with symptomatic 
severe AS that provide informed consent will be entered into the Electronic Data Capture (EDC) 
system and total number of patients screened will be counted.  The reasons why a patient did 
not enter the Heart Team meeting will be collected (eg. patient does not meet inclusion criteria 
or meets an exclusion criteria) and, age, STS score, and available screening data.  
Data readily available in the patient’s medical record may be utilized to fulfill screening 
requirements and do not need to be repeated. If not previously completed, the following tests 
and procedures must be performed prior to randomization to verify eligibility. The recommended 
timeframe for these tests and procedures is within 30 days prior to submission to the Heart 
Team, unless otherwise specified. 
 
Demographics and Medical History 
 
Clinical Assessments – Refer to Appendix R.19 
o 
5-Meter Gait Speed 
o 
Grip Strength 
 
Physical Examination including:   
o 
Vital signs, weight, height, and body surface area (BSA);  
 
BSA will be calculated from height and weight by use of the formula by 
Dubois and Dubois (BSA = 0.007184 × weight [kg]0.425 × height [m]0.725)] 
o 
Major systems findings 
 
NYHA Classification 
 
Risk Assessments: 
o 
STS Risk Score – Dataset Version 2.73 
o 
Logistic EuroSCORE 
o 
EuroSCORE II 
o 
SYNTAX Score 
o 
Katz Index of Independence in Activities of Daily Living 
 
Co-morbidities 
 
Routine Laboratory Tests: 
o 
Complete Blood Count: 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance  
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT)  
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
 

 
 
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 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic two-dimensional (2D) echocardiogram (TTE) is 
required within 365 days prior to review by the Heart Team to confirm diagnosis 
of severe aortic stenosis(AS) including: 
 
Aortic valve area / indexed aortic valve area 
 
Mean gradient / peak velocity / velocity ratio 
o 
If a historical TTE is used to confirm AS diagnosis a repeat TTE must be 
performed within 45 days prior to review by the Heart Team to: 
 
Assess: 
 
Aortic regurgitation 
 
Mitral and tricuspid valve status (stenosis and regurgitation)  
 
LVEF 
 
Rule out: 
 
New or recent MI 
 
New or untreated intracardiac mass, thrombus  or vegetation 
 
Congenital bicuspid or unicuspid valve 
o 
If the patient recently underwent balloon aortic valvuloplasty (BAV), a TTE 
should be obtained post-BAV; within 45 days prior to review by the Heart Team 
to reconfirm all inclusion/exclusion echocardiographic parameters 
o 
Protocol required echocardiograms should be performed according to the 
Echocardiography Procedures found in Appendix R.7. 
 
Multi-Slice Computed Tomography (MSCT) Angiogram 
o 
Multi-Slice Computed Tomography (MSCT) angiograms with complete 
visualization of both iliacs, femorals and aorta (and subclavian/axillaries, if 
applicable), up to and including the aortic annulus.  In the situation where 
subjects have compromised renal function that precludes contrast media, 
Magnetic Resonance (MR) imaging may be used as an alternative.  MSCT 
angiograms should be performed according to the Computed Topography (CT) 
Angiography Acquisition Guidelines found in Appendix R.9. If the MSCT 
angiogram was conducted in the last 365 days and subject has not had a 
peripheral vascular intervention since the time of the image, a more recent 
exam is not required as long as visualization of both iliacs and femorals (and 
subclavian/axillaries, if applicable) to the aorta can be viewed.  However, if the 
subject had a peripheral vascular intervention, the exam must be repeated after 
the intervention and within 90 days of review by the Heart Team. 
 
Coronary Arteriogram 
o 
Selective coronary arteriography to assess the presence and severity of 
coronary artery disease which should include angiograms of both coronary 
arteries and all bypass grafts (if applicable). If the coronary arteriogram has 
been performed within the last 365 days and the subject qualifies for the trial 
(no significant coronary artery disease), a more recent exam is not required.  
However, if the subject had evidence of significant coronary artery disease 
and/or received a coronary intervention, the exam must be repeated after the 
intervention and within 90 days of review by the Heart Team. 
 
12-lead Electrocardiogram (ECG) 
 
 

 
 
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Heart Team Procedures 
C.4.2
Each center will utilize a Heart Team to make determinations regarding eligibility of the 
prospective subject to be randomized in the SURTAVI trial. 
C.4.2.1 
Heart Team Composition 
Local Heart Teams must be comprised of a multidisciplinary team qualified by education and 
experience to determine appropriate patient treatment. 
Minimum Membership1  
 
Interventional Cardiologist - ≥ 1 representative is required 
 
Cardiac Surgeon - ≥ 1 representative is required 
Additional Membership Considerations  
Additional members of the Heart Team should be included based on current standard practices 
and patient specific consideration, including but not limited to: 
 
Echocardiographer 
 
Anesthesiologist 
 
Cardiologist (general or referring physician) 
 
Geriatrician 
 
Neurologist or stroke specialist 
 
Radiologist or imaging specialist 
 
Heart Failure specialist 
 
Intensivist 
 
Nurse(s) 
 
Social Worker 
C.4.2.2 
Heart Team Review and Decision 
Prior to determining if a patient is eligible for randomization the Heart Team will review each 
patient’s screening data and confirm the following: 
 
STS risk calculation was properly performed 
 
Any additional risk factors not accounted for in the STS risk calculator that may increase 
the level of surgical risk: 
o 
Heart Team should consider the following potential incremental risks: 
 
Age ≥ 75 
 
BNP ≥ 550pg/mL or NT proBNP ≥ 3200pg/mL 
 
Prior Stroke/TIA 
 
FEV1 750-1000cc 
 
Home / Supplemental oxygen 
 
Nocturnal Bi-level Positive Airway Pressure 
 
5-Meter Gait Speed ≥ 6 seconds 
 
Severe Diastolic Dysfunction (Grade III or IV) 
 
Liver Disease (Child A or B) 
 
Pulmonary Hypertension (systolic pressure 60-80mmHg) 
 
Frailty (eg. BMI <21 kg/m2, Albumin <3.5 g/dL, etc.) 
 
Other risks, as deemed applicable 
o 
Confirm the incremental risk, as determined by the Heart Team, does not 
result in a risk definition higher than intermediate risk 
 
 All inclusion criteria are met and none of the exclusion criteria 
 
Both the reviewing Interventional Cardiologist and Cardiac Surgeon(s) must unanimously agree 
the patient has a predicted risk of operative mortality ≥ 3% and < 15% and appropriate for trial 
enrollment.  The decision of the local Heart Team must be documented on the “Heart Team 
Decision” form and signed by the reviewing Interventional Cardiologist and Cardiac Surgeon(s). 
                                                    
 
1  US only - Protocol criteria for Heart Team approval may not meet the minimum requirements outlined by Centers for 
Medicare and Medicaid Services (CMS) for reimbursement.  Reference Appendix R.25 for additional information. 

 
 
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Screening Committee 
C.4.3
The Screening Committee will ensure appropriate and consistent patient selection across all 
sites.  Prior to the onset of the trial, a charter will be drafted to that outline roles and 
responsibilities as well as describe the Screening Committee process.   
Final decisions on patient eligibility will be made by the Screening Committee.  
 
Roll-in Subjects 
C.4.4
For participating centers who meet the requirement of 30 cumulative TAVI procedures but have 
no previous CoreValve experience (eg. Investigational centers where CoreValve is not 
commercially available and/or centers that did not participate in the US Pivotal Extreme/High 
Risk protocols) the first three successfully enrolled subjects will be considered “roll-in” subjects, 
will not be randomized, and will automatically be assigned to TAVI.  A maximum of three 
successful roll-in subjects are allowed per center.  
The purpose of the roll-in subjects is to provide investigators the time for training and 
familiarization with the investigational TAVI device. The Training and Education team will review 
recommendations made by Medtronic field support, Medtronic CoreValve Proctors and the 
Steering Committee for transition of sites from the roll-in phase to the randomization phase of 
enrollment after the first three subjects have been treated.   
A subject will be considered a treated roll-in subject once the TAVI delivery catheter system 
(DCS) is introduced into the subject. A site must have three treated roll-in subjects before they 
can be evaluated to move into the randomization phase. The Training and Education team or 
designee will review and document their decisions based on the technique of the investigators, 
as well as the frequency, severity and nature of events in the roll-in subjects. 
Roll-in subjects will complete in-clinic follow-up evaluations at the following time points post 
implant as subjects randomized to TAVI.  However, the results for the roll-in population will be 
analyzed separately from the randomized population.   
 
Enrollment and Randomization 
C.4.5
Prior to randomization and enrollment of a subject, the following must occur: 
 
Confirm patient signed informed consent 
 
Confirm patient meets all of the inclusion and none of the exclusion criteria, including 
approval by the Heart Team 
Subjects will be considered enrolled into the trial at the time of randomization2 (i.e. time of 
treatment assignment).  Randomization will occur only if the patient meets all inclusion criteria 
and does not meet any exclusion criteria and has been assessed by the Heart Team as being 
an appropriate candidate for randomization in the SURTAVI trial.   
Due to the inclusion/exclusion criteria, not all patients that consent to the trial will be enrolled.  
All sites will be required to maintain a record of patients screened for the trial meeting general 
inclusion criteria who have signed the approved informed consent document.  For subjects that 
do not meet trial criteria, the reason for not continuing in the trial must be documented and 
recorded in the EDC system.  Patients consented but not randomized will be considered screen 
failures and no further trial-related follow-up will be required. 
Subjects must have their TAVI or SAVR procedure no later than 30 days post-randomization.  
Trial randomization will not be blinded.  Once randomization is complete and a treatment arm is 
assigned, crossover from SAVR to TAVI treatment is not permitted.  The sponsor will strictly 
monitor device dispensation to ensure that only those subjects randomized to the TAVI 
treatment arm receive the Medtronic CoreValve™ TAV. 
Distribution of the subjects within the trial groups will be controlled at the implanting sites by 
means of central randomization using interactive voice/web randomization service (IXRS).  The 
randomization scheme will be securely stored at the IXRS provider. 
                                                    
 
2   Based on protocol design, the time of enrollment will be the same as randomization which is a deviation from ISO 
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Randomization with an assignment to the treatment arm or control arm (TAVI or SAVR) will be 
executed in a 1:1 ratio. Stratified randomization by investigational site and by the need for 
coronary revascularization will be used to ensure subjects will be allocated to each comparison 
group proportionately. Additionally, a blocked randomization scheme with random block sizes 
will be used within each stratum. 
 
Baseline Assessments 
C.4.6
The following baseline assessments should occur within 14 days prior to the index procedure. 
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
o 
Skin assessment – refer to Radiation Exposure and Data Collection, Appendix 
R.23 
 
NYHA classification 
 
Concomitant medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Routine Laboratory Tests: 
o 
Complete Blood Count 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT) 
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
Neurological Assessments: 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Modified Rankin Score (mRS)  
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
12-lead Electrocardiogram (ECG) 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
o 
Questionnaires may be administered any time after the subject has provided 
informed consent but should be collected prior to informing the subject of their 
treatment assignment 
 
Adverse Event Review 
 
 

 
 
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Transcatheter Aortic Valve Implant or Surgical Aortic Valve Replacement 
C.4.7
Procedure 
C.4.7.1 
TAVI 
General Procedural Considerations  
Transcatheter Aortic Valve Implantation (TAVI) requires meticulous preparation and typically a 
multi-disciplinary team approach involving among others, interventional cardiologists, cardiac 
imaging specialists, cardio-thoracic surgeons and anesthesiologists.  
Within the United States, additional requirements apply for composition of the intra-
operative team for TAVI procedures.  Requirements are outlined in Appendix R.25. 
In case of significant coronary artery disease that requires revascularization, the Heart Team will 
assess the feasibility of performing PCI simultaneously with the TAVI procedure based on the 
coronary lesion characteristics. When it is anticipated PCI can be performed in timely fashion 
with only a limited amount of additional contrast medium it is encouraged to perform PCI 
concomitant with the TAVI. When PCI is deemed challenging requiring relatively more time and 
contrast medium, staged PCI is recommended: TAVI will then be performed at least 7 days after 
PCI.  
The implantation procedure itself takes place either in a catheterization laboratory with adequate 
hygiene precautions or ideally in a hybrid operating room equipped for state-of-the-art 
transcatheter and/or surgical procedures.  
The execution of the TAVI involves an operating team typically consisting of 1 or 2 operators, an 
anesthesia team and at least 2 nurses/technicians. Medtronic representative(s) (eg. Therapy 
Development Specialists, proctors, etc.) may be present during TAVI procedures for training 
process, to perform valve loading or to provide general case support. 
Both the dedicated “valve team” and the operators should have the expertise to select the 
appropriate access route and device size on a patient-per-patient basis. 
All patients undergoing TAVI should be treated using the iliofemoral access route by default (first 
treatment strategy). Additional non-iliofemoral access routes will only be used in case iliofemoral 
access is not feasible.  Alternative access is limited to subclavian and direct aortic. 
The use of an embolic protection device during the TAVI procedure is not permitted. 

 
 
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Pre-Procedure 
 
Pre-medication recommendations: 
o 
If the subject is currently on warfarin therapy, or local equivalent, prior to the 
procedure: 
 
Discontinue warfarin therapy 3 days prior to the procedure 
 
Confirm that the INR < 1.8 prior to the procedure 
 
Administer antiplatelet therapy: 
 
Aspirin (75- 325 mg) daily or  
 
Clopidogrel (75 mg) daily (or ticlopidine if clopidogrel is 
contraindicated) for 3 days prior to the procedure 
o 
If the subject is currently not on warfarin therapy prior to the procedure: 
 
Aspirin (75-325 mg) on the day of the procedure and 
 
Clopidogrel (300 mg)  
o 
Consider adjunctive proton pump inhibitors, H2 antagonists or antacids 
 
Routine Laboratory Tests: 
o 
Complete Blood Count 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
 
If the GFR < 60 cc/min, consider: 
 
Fluid hydration on the day prior to the procedure 
 
Discontinuation of NSAIDs and ACE inhibitors 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT) 
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
12-lead Electrocardiogram (ECG) 
TAVI Procedure 
 
Medications 
One hour prior to the procedure, prophylactic antibiotic therapy of the Investigator’s 
choice should be initiated: 
o 
Cefuroxime 750mg intravenous (IV) 1 hour pre-procedure, then 6 hours and 12 
hours post-procedure 
o 
If allergic to Penicillin, prescribe Vancomycin 1g IV  
o 
Consider holding anti-hypertensives 
 
Anesthesia and Procedural Set Up 
o 
Establish a central venous line  
o 
Administer general anesthesia or conscious sedation per hospital protocol 
o 
Prior to beginning the investigational TAVI device system implant, place a 
temporary 4-5 Fr. balloon-tip pacing wire in a stable location within the right 
ventricular (a screw-tip wire may be used for more secure placement for 
subjects at high-risk for dislodgement, if necessary) 
o 
Whenever possible, use the upper torso venous system (eg. jugular, subclavian) 
for temporary pacing wire access 
o 
Use fluoroscopy to guide wire placement and stability 
o 
Confirm sensing and capture 
o 
Program the backup pacing rate to minimize ventricular pacing (eg. 30-40 bpm). 
If heart block develops, adjust the rate accordingly 
o 
Record ECG and angiogram during the procedure 
 
Vascular Access 

 
 
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o 
The primary access artery will be used to introduce the CoreValve device and 
the balloon catheter; the secondary access artery will be used to introduce the 
reference pigtail 
o 
Insert a 6Fr introducer sheath into the secondary access artery 
o 
Insert 18Fr introducer sheath into the primary access artery using hospital 
protocol (either percutaneously or surgical cut down) 
o 
Administer anticoagulant therapy according to hospital protocol. If heparin is 
administered as an anticoagulant, check activated clotting time (ACT) at five 
minutes and monitor every 30-60 minutes after initial bolus of heparin  
o 
Maintain ACT ≥ 250 seconds 
o 
Anticoagulant may be administered at any time prior to this point, but avoid 
delaying beyond this point 
 
Crossing the native valve 
o 
Advance the graduated pigtail catheter to the ascending aorta and position the 
distal tip in the noncoronary cusp of the native aortic valve 
o 
Identify the ideal annular viewing plane using contrast injections at various 
angiographic angles, preferably in the left anterior oblique (LAO) projection.  
 
An aortogram with the three aortic cusps aligned in one (1) plane should 
be obtained in order to proceed with the procedure and guarantee an 
optimal working view for eventual implantation 
o 
Insert an angiographic catheter over a standard, J-tip guidewire into the primary 
access sheath and advance to the ascending aorta 
o 
Exchange the J-tip guidewire for a 0.035-in (0.889-mm) straight-tip guidewire. 
Advance the straight-tip guidewire across the native aortic valve into the left 
ventricle 
o 
After crossing the native aortic valve with the guidewire, advance the 
angiographic catheter into the left ventricle 
o 
Exchange the straight-tip guidewires for an exchange-length J-tip guidewire 
o 
Exchange the angiographic catheter for a 6Fr pigtail catheter 
o 
Remove the guidewire and connect the catheter to the transducer. Using both 
catheters, record the aortic pressure gradient 
o 
Using a right anterior oblique (RAO) projection, advance previously pigtail-
shaped, 0.035-in (0.889-mm) high-support guidewire through the pigtail catheter 
and position in the apex of the left ventricle 
o 
Remove the pigtail catheter while maintaining guidewire position in the left 
ventricle 
 
Rapid Pacing and Pre-dilatation of the Implant site 
o 
Insert the valvuloplasty balloon through the 18Fr introducer sheath and advance 
it to the ascending aorta 
o 
Perform a rapid pacing test. A successful test is defined as 1-to-1 pacing 
capture with an immediate drop in pressure and elimination of the systolic-
diastolic waveform 
o 
Reposition the angiographic equipment to the ideal viewing plane as previously 
described. Position the valvuloplasty balloon across the native valve, while 
maintaining strict fluoroscopic surveillance of the distal tip of the guidewire in the 
left ventricle (LV) 
o 
Perform BAV per hospital protocol and remove the valvuloplasty balloon while 
maintaining guidewire position across the native aortic valve 
o 
Balloon sizing directed to 1:1 sizing of the minimal annular diameter by 
computerized tomographic angiography (CTA) or echocardiogram with 
maximum 25 mm balloon 
o 
Perform full balloon expansion 
 
 

 
 
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 
Medtronic CoreValve™ Implantation 
o 
Insert the device over the 0.035-in (0.889-mm) guidewire and advance it, while 
maintaining strict fluoroscopic surveillance of the guidewire in the LV 
o 
When crossing the aortic arch, control the guidewire preventing it from moving 
forward 
o 
Advance the device through the native valve. Perform an angiogram to confirm 
that the graduated pigtail catheter is in position within the noncoronary cusp of 
the aortic root, preferably in the shallow LAO projection 
o 
Use Fluoroscopy to identify the appropriate landmarks 
o 
Place the bioprosthesis within the aortic annulus.  Optimal placement of the 
bioprosthesis is 4 mm - 6 mm below the annulus. The annulus is defined as the 
angiographic floor of the aortic root 
o 
After attaining optimal catheter position, slowly turn the micro knob and begin to 
deploy the bioprosthesis. As the inflow aspect of the bioprosthesis starts to flare 
outward, monitor bioprosthesis position under fluoroscopy 
o 
Caution: During implantation, if resistance to deployment is encountered (for 
example, the micro knob starts clicking or is tight or stuck), apply mild upward 
pressure to the macro slider while turning the micro knob. If the bioprosthesis 
still does not deploy, remove it from the patient and use another system 
o 
Perform an angiogram. Once annular contact is made, the bioprosthesis should 
not be advanced into a lower position 
o 
Continue deploying rapidly to the 2/3 deployment point; stop turning the micro 
knob 
o 
Perform an angiogram to assess the location of the bioprosthesis.  
o 
If the bioprosthesis is positioned low, carefully pull the DCS to reposition the 
bioprosthesis 
o 
Evaluate the valve position and valve function using hemodynamic, 
aortography, and possible echocardiography  
o 
When satisfactory position is achieved, continue to turn the micro knob until 
both frame loops disengage 
o 
Use orthogonal views under fluoroscopy to confirm that the frame loops have 
detached from the catheter tabs. If a frame loop is still attached to a catheter 
tab, under fluoroscopy, advance the catheter slightly and, if necessary, gently 
rotate the handle clockwise (<180°) and counterclockwise (<180°) to disengage 
the loop from the catheter tab 
o 
Withdraw the DCS carefully to the aorta avoiding contact with the inflow portion 
of the frame while maintaining guidewire position 
 
Medtronic CoreValve™ Post Deployment 
o 
Close the DCS capsule and remove the DCS through the 18Fr introducer 
sheath 
o 
Advance a 6Fr pigtail catheter over the guidewire into the left ventricle 
o 
Remove the guidewire and connect the pigtail catheter to the transducer 
o 
Using both pigtail catheters, record aortic pressure gradient 
o 
Withdraw 6Fr pigtail 
o 
Perform post-implant aortogram with the reference pigtail to assure coronary 
patency and assess aortic regurgitations.  Aortogram Acquisition Guidelines are 
located in Appendix R.6 
o 
Remove the 18Fr introducer sheath and complete the puncture site closure per 
hospital protocol 
o 
Perform contrast angiography of the primary vessels to verify the absence of 
any vascular complications with the reference pigtail 
o 
Remove the reference pigtail catheter over a standard guidewire 
o 
Remove the 6Fr introducer and close the access site per hospital protocol 
 
Ballooning as needed during the implant procedure is standard practice and should not be 
considered a reintervention. 

 
 
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Immediate Post-Procedure  
The procedure is considered complete after final angiography has been performed, and the 
introducer/InLine sheath has been removed from the subject.  Thereafter, if an introducer/InLine 
sheath is re-introduced, this is considered a repeat intervention, which must be documented on 
the reintervention Electronic Case Report Form (eCRF).  
 
Coronary Arteriogram 
 
Following the current recommendation all patients with prosthetic heart valves need 
endocarditis prophylaxis 
 
All patients should receive Deep Vein Thrombosis (DVT) prophylaxis with Heparin/Low 
Weight Molecular Heparin (LMWH) starting approximately 6 hours after TAVI if bleeding 
permits 
 
Anticoagulants should be discontinued per hospital standard 
 
Activated clotting time (ACT) should be monitored per hospital standards but 
recommendation is >250 seconds 
 
Cardiac Enzymes: CK within 8-12 hours post procedure and at any time when a clinical 
ischemic event is suspected.  
o 
CK-MB is required if CK is elevated >2X the laboratory upper limit of normal.  
o 
If a clinical event is confirmed, a total of 3 draws of cardiac enzymes within the 
first 24 hours (drawn approximately every 8 hours) following the clinical event 
should be obtained 
 
12-lead Electrocardiogram (ECG) to be performed within 48 hours of procedure 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) to be completed with 24 hours 
of procedure 
 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic 2D echocardiogram (TTE) should be performed within 
24-48 hours post-procedure or prior to discharge to assess device success.  
Echocardiograms will be performed according to Echocardiography Procedures found 
in Appendix R.7  
 
It is recommended that subjects are treated for a minimum of three months with dual 
anti-platelet medication 
o 
If the patient is on warfarin therapy post-procedure it is recommended that 
subjects are prescribed either daily: 
 
Aspirin (75 to 325 mg) or  
 
Clopidogrel (75 mg) (or ticlopidine, if clopidogrel is contraindicated) for 
at least three months following the procedure 
o 
If the patient will not be on warfarin therapy post-procedure it is recommended 
that subjects are prescribed daily: 
 
Aspirin (75to 325 mg) and  
 
Clopidogrel (75 mg) (or ticlopidine, if clopidogrel is contraindicated) for 
at least three months following the procedure 
 
Concomitant medications 
 
Adverse events review 
o 
Document all  adverse events, including all unanticipated adverse device effects 
(UADE) or unanticipated serious adverse device effects (USADE), technical 
observations, reinterventions or repeat admissions to the catheterization suite 
and deaths 
o 
Any patient with evidence of a new neurological event should have a neurology 
consult and subsequently an imaging trial if deemed necessary by the 
neurologist or stroke specialist 
o 
Any patient exposed to substantial radiation dose levels, as outlined in 
Appendix R.23, should be assessed for skin reactions 

 
 
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Post-Procedure Pacing Guidelines 
 
All patients should stay on telemetry until discharge 
 
Maintain temporary pacing until at least 48 hours post-implant in Cardiovascular 
Intensive Care Unit (CV-ICU) or local equivalent 
 
After 48 hours, obtain ECG and assess patient rhythm and conduction 
 
Based on assessment, and with the consult of an electrophysiologist as needed, take 
one of the following actions: 
o 
Discontinue temporary pacing 
o 
Continue temporary pacing for another 24 hours (longer if needed) to make 
further assessments 
o 
Place a permanent pacemaker according to ACC/AHA/HRS Guidelines for 
Device-Based Therapy of Cardiac Rhythm Abnormalities (Class I or IIb for 
Acquired Atrioventricular Block in Adults or Permanent Pacing in Chronic 
Bifascicular Block) as outlined in Appendix R.13 
o 
Prior to the permanent pacemaker implantation, document the reason for the 
placement of the permanent pacemaker via a 12-lead ECG 
o 
For complete heart block, review patient medications 
o 
Consider withholding some medications to assess for patient’s intrinsic rate and 
conduction 
o 
If heart block persists off medications, a permanent pacemaker should be 
considered 
o 
If a permanent pacemaker is required, a dual chamber system is recommended 
to optimize patient hemodynamics 
o 
For additional information refer to the Pacing Guidelines in Appendix R.13  
C.4.7.2 
Surgical Aortic Valve Replacement 
Minimum Standards for Surgical Aortic Valve Replacement  
Subjects randomized to SAVR should be treated according to the surgeon and hospital’s 
standard practices. The surgeon or co-surgeon performing the SAVR must be a trial investigator 
for the site. The choice of surgical valve is left to the discretion of the investigator. However, the 
use of a bioprosthetic valve is required. 
SAVR must be conducted as an isolated procedure with exception of subjects that have 
been randomized to SAVR with revascularization (eg. Aortic replacement or Maze 
procedures are not permitted). In cases of significant coronary artery disease that requires 
revascularization coronary artery bypass grafting (CABG) will be conducted concomitantly with 
SAVR.   
Additional concomitant cardiac and non-cardiac procedures are not permitted with the exception 
of the procedures outlined under Additional Procedural Considerations. 
General Procedural Considerations 
One of the key requirements for good surgical outcome is an excellent collaboration of the 
dedicated multidisciplinary teams consisting of typically two cardiac surgeons with SAVR 
experience, a cardiac anesthesia team, an experienced cardio technician as well as at least two 
operation theater nurses.  
 
Operation Theater 
Surgical aortic valve replacement is to be performed in an operative theater with state-of-the-art 
technical equipment with certified sterility standards, adequate illumination, laminar flow, 
dedicated scrub nurses, and on site full technical support.  
 
Perfusion 
A dedicated, experienced perfusion team with greater than 75 Extracorporeal Circulation (ECC) 
runs per cardio technician per year who can perform all current cardioplegia strategies and is 
familiar with deep hypothermic circulatory arrest (DHCA) is recommended.  The perfusion team 
should be capable of covering the full heart surgical spectrum including CABG, heart valve 
defect (HVD), Heart failure and assist devices, extracorporeal membrane oxygenation (ECMO) 
support, intra-aortic balloon pump (IABP), and cardiac transplant.   
 

 
 
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Pre-Procedure 
 
Pre-medication recommendations: 
o 
Discontinue warfarin therapy 3 days prior to the procedure, if applicable 
 
Confirm that the INR < 1.8 prior to the procedure 
o 
Administer antiplatelet therapy, per local standards 
o 
Consider adjunctive proton pump inhibitors, H2 receptor antagonists or antacids 
 
Routine Laboratory Tests: 
o 
Complete Blood Count 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
 
If the GFR < 60 cc/min, consider: 
 Discontinuation of NSAIDs and ACE inhibitors 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT) 
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
12-Lead Electrocardiogram 
 
One hour prior to the procedure, prophylactic antibiotic therapy of the Investigator’s 
choice should be initiated: 
o 
Cefuroxime 750mg IV 1 hour pre-procedure, then 6 hours and 12 hours post-
procedure 
o 
If allergic to Penicillin, prescribe Vancomycin 1g IV  
o 
Consider holding anti-hypertensives 
Surgical Considerations  
Surgical aortic valve replacement is typically performed with cardio-pulmonary bypass (CPB) on 
an arrested heart with a clamped aorta. Local practice and surgical standards should govern 
type of cardioplegia and the temperature/flow/pressure perfusion strategy as well as the 
activated clotting time used at either institution for safe CPB. Typically a minimum of 2 
liters/m²/minute with a systemic arterial blood pressure of 60mmHg during CPB should be 
maintained and possibly increased in the elderly patients.  
Cannulation for isolated SAVR CPB should be ascending aorta for arterial return unless there is 
ascending aortic arteriosclerosis or dilatation (>4cm in diameter), and right atrial for venous 
drainage. Embolic devices are not routinely used in SAVR. 
 

 
 
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Typical surgical workflow and general procedural recommendations 
 
Procedural set-up and Anatomic Evaluation: 
o 
The patient is prepared and draped 
o 
IV antibiotics should be administered following the local standard of care  
o 
Following the presternal skin incision the sternum is split 
o 
Prepare the mediastinum and open the pericardium  
o 
Inspect the ascending aorta for calcifications (including epiaortic scan if 
necessary) 
o 
Complete heparin application and arterial and venous cannulation 
o 
Initiate CPB, and at surgeons discretion, left heart venting via right upper 
pulmonary vein or pulmonary artery  
o 
Cross clamp the aorta and initiate cardioplegic arrest  
o 
Perform an aortotomy  
o 
Complete annular decalcification (the surgeon should take all possible means to 
prevent embolization of debris)  
 
Prosthesis Specific Sizing: 
 
If the aortic annulus does not permit valve replacement with a patient matched 
valve diameter, the aortic annulus should be enlarged at the surgeon’s 
discretion  
 
Valve Preparation and Implantation: 
o 
The valve prosthesis should be prepared following the manufacturer 
recommendations  
o 
After rinsing bioprosthetic valves should be kept wet throughout the procedure 
o 
Anchoring of the prosthesis with, for example, interrupted Teflon reinforced 
Tycron sutures or an equivalent technique is recommended 
o 
De-air and close the aortotomy 
o 
Insert temporary ventricular and atrial pacing wires and chest tubes  
o 
Wean from ECC hemostasis  
o 
Complete sternal wiring and layered closure 
 
Additional Procedural Considerations: 
o 
In case of concomitant significant subvalvular left ventricular outflow tract 
occlusion (LVOTO) then resection is recommended 
o 
If there is a significant patent foramen ovale (PFO) closure is recommended in 
cases of substantial right to left flow 
o 
It might be recommendable to apply CO2 surgical field flooding to ease de-airing  
 
Intraoperative Aortic Assessment     
o 
Transesophageal echo (TEE) is recommended in all cases to additionally 
assess for aortic calcifications before manipulating the aorta. In case of doubt 
an Epiaortic scan might further help for surgical decision making 
o 
Additionally the TEE should be used to assess for subvalvular LVOTO and 
patent foramen ovale 
 
 Before Termination of Surgery Repeat Intraoperative TEE     
o 
TEE is recommended to assess the postoperative SAVR result  
 
Assessment should include aortic valve function, central or paravalvular 
leakage, valve gradient, exclude remaining LVOTO from subvalvular 
stenosis as well as ventricular function with special emphasis on new 
segmental wall function abnormalities. 
 
Any regurgitation of more than trace should be critically evaluated and 
at surgeon’s discretion the valve re-inspected and if necessary 
changed. 
 

 
 
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Immediate Post-Procedure  
The procedure is considered complete at the time of skin closure. Immediately post-procedure 
the following tests and procedures must be performed and data collected: 
 
Cardiac Enzymes: CK within 8-12 hours post procedure and at any time when a clinical 
ischemic event is suspected.  
o 
CK-MB is required if CK is elevated >2X the laboratory upper limit of normal.  
o 
If a clinical event is confirmed, a total of 3 draws of cardiac enzymes within the 
first 24 hours (drawn approximately every 8 hours) following the clinical event 
should be obtained 
 
Concomitant Medications 
 
12-lead Electrocardiogram (ECG) to be performed within 48 hours of procedure 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) to be completed within 24 
hours of procedure 
 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic 2D echocardiogram (TTE) should be performed at 
least 24hours post-procedure but prior to discharge to assess device success 
(and no later than 7 days, whichever comes first)   
o 
Echocardiograms will be performed according to Echocardiography Procedures 
found in Appendix R.7  
 
Adverse Event review 
Post-Procedural Medication 
 
It is recommended that subjects are treated with aspirin (75-325mg daily) for a minimum 
of three months  
 
If warfarin therapy is indicated (eg. A-fib): maintain therapeutic anticoagulation with 
Heparin or Low Molecular Weight Heparin until INR between 2 and 3 is reached after 
loading with warfarin 
 
The preoperative antibiotic therapy may be repeated within the next 6 to 12 hours 
 
All patients should receive DVT prophylaxis with Heparin/LMWH starting approximately 
6 hours after SAVR if bleeding permits 
 
Following the current recommendation all patients with prosthetic heart valves need 
endocarditis prophylaxis 
Post-Procedure Pacing Guidelines 
 
All patients should stay on telemetry until discharge 
 
Maintain temporary pacing until at least 48 hours post-implant in CV-ICU or local 
equivalent 
 
After 48 hours, obtain ECG and assess patient rhythm and conduction 
 
Based on assessment, and with the consult of an electrophysiologist as needed, take 
one of the following actions: 
o 
Discontinue temporary pacing 
o 
Continue temporary pacing for another 24 hours (longer if needed) to make 
further assessments 
o 
Place a permanent pacemaker according to ACC/AHA/HRS Guidelines for 
Device-Based Therapy of Cardiac Rhythm Abnormalities (Class I or IIb for 
Acquired Atrioventricular Block in Adults or Permanent Pacing in Chronic 
Bifascicular Block) as outlined in Appendix R.13 
o 
Prior to the permanent pacemaker implantation, document the reason for the 
placement of the permanent pacemaker via a 12-lead ECG 
o 
For complete heart block, review patient medications 
o 
Consider withholding some medications to assess for patient’s intrinsic rate and 
conduction 
o 
If heart block persists off medications, a permanent pacemaker should be 
considered 
o 
If a permanent pacemaker is required, a dual chamber system is recommended 
to optimize patient hemodynamics 
o 
For additional information refer to the Pacing Guidelines in Appendix R.13 

 
 
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Assessments done at discharge (both SAVR and TAVI) 
C.4.8
Prior to hospital discharge (or within 7 days post-index procedure, whichever occurs first) the 
following tests and procedures must be performed and data collected: 
 
Physical Examination 
o 
Vital signs 
o 
Major system findings 
o 
Skin Assessment – refer to Radiation Exposure and Data Collection, Appendix 
R.23 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets)   
 
Routine Laboratory Tests: 
o 
Complete Blood Count: 
 
White Blood Count 
 
Hematocrit 
 
Hemoglobin 
 
Platelet Count 
o 
Creatinine and Creatinine Clearance 
o 
Cardiac Enzymes (CK/CK-MB) 
o 
International Normalized Ratio (INR), if applicable  
o 
Activated Partial Thromboplastin Time (aPTT) 
o 
B-type Natriuretic Peptide  (BNP) or NT-proBNP 
o 
Liver Panel:  
 
ALT 
 
AST  
 
Albumin  
o 
Sodium  
o 
Potassium 
 
Neurological Assessments 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Modified Rankin Score (mRS) 
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
Transthoracic Echocardiogram (TTE) 
o 
Comprehensive transthoracic 2D echocardiogram (TTE) should be performed at 
least 24hours post-procedure but prior to discharge to assess device success 
(and no later than 7 days, whichever comes first)   
o 
Echocardiograms will be performed according to Echocardiography Procedures 
found in Appendix R.7 
 
12-lead Electrocardiogram 
 
Adverse Event review 

 
 
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Follow-Up Evaluations 
C.4.9
All randomized subjects will undergo in-clinic follow-up evaluations at the following time points 
post implant.   
All follow-up periods are defined as the number of days after the date of the index procedure 
(TAVI or SAVR).  
Day 0 = day of index procedure (TAVI or SAVR): 
 
30 days (- 7 days and + 14 days) 
 
3 months (90 ± 14 days) 
 
6 months (180 ± 30 days) 
 
12 months (365 ± 30 days) 
 
18 months (545 ± 60 days) 
 
24 months (730 ± 60 days) 
 
3 years (1080 ± 60 days) 
 
4 years(1440 ± 60 days) 
 
5 years (1800 ± 60 days) 
All randomized subjects will complete long-term follow-up through at least 5 years.  Based on 
clinical assessments or regulatory requirements, follow-up may be extended to up to 10 years 
post-index procedure. Upon completion of the final protocol visit (discontinuation) subject 
participation will be considered complete and the patient should then be followed per the local 
standard of care for their condition. 
Note: For subjects where the Index Procedure is never be attempted (eg. subject withdraws 
consent for the procedure but agrees to complete follow-up) follow-up intervals will be 
calculated from the 31st days post-randomization (i.e. the 1st day after the 30 day window 
from randomization to complete the Index Procedure). 
C.4.9.1 
30 Days 
The following assessments will be conducted at the 30 day visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
o 
Skin Assessment – refer to Radiation Exposure and Data Collection, Appendix 
R.23 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Routine Laboratory Tests: 
o 
Hemoglobin 
o 
Creatinine and Creatinine Clearance 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
12-lead Electrocardiogram 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event review 
 
 

 
 
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C.4.9.2 
3 Months 
The following assessments will be conducted via telephone at the 3 Month visit.   
 
Quality of Life Questionnaire 
o 
EQ-5D  
o 
SF-36 – in selected geographies.  Refer to Appendix R.12 for instructions on 
which geographies are required to collect the questionnaire 
C.4.9.3 
6 Months 
The following assessments will be conducted at the 6 Month visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
Quality of Life Questionnaires 
 
Adverse Event Review 
C.4.9.4 
12 Months 
The following assessments will be conducted at the 12 Month visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Neurological Assessments 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Modified Rankin Score (mRS) 
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event review 
 
 

 
 
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C.4.9.5 
18 Months 
The following assessments will be conducted at the 18 Month visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Concomitant Medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
12-lead Electrocardiogram 
 
Quality of Life Questionnaires 
 
Adverse Event review 
C.4.9.6 
24 Months 
The following assessments will be conducted at the 24 Month visit.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Concomitant medications 
o 
Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, 
beta-blockers, statins and anti-platelets) 
 
Neurological Assessments 
o 
National Institute of Health Stroke Scale (NIHSS) 
o 
Modified Rankin Score (mRS) 
o 
Mini-Mental State Exam (MMSE-2:SV) 
o 
Additional Neurological testing: 
 
Visual Fields Testing 
 
Gait Assessment 
 
Hand Function 
 
Writing Evaluation 
 
Drawing Assessment 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
6 Minute Walk Test 
 
Quality of Life Questionnaires 
 
Adverse Event review 
C.4.9.7 
3-5 Years 
The following assessments will be conducted at the 3, 4, and 5 year visits.   
 
Physical examination 
o 
Vital signs 
o 
Major system findings 
 
NYHA classification 
 
Abbreviated Neurological Assessment 
o 
National Institute of Health Stroke Scale (NIHSS) 
 
Transthoracic Echocardiogram (TTE) 
 
12-lead Electrocardiogram 
 
Quality of Life Questionnaires 
 
Adverse Event review – refer to C.5.2 Reporting for AE reporting requirements post-24 
Months 
 
 

 
 
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 Echo Assessment 
C.4.10
Echocardiography is the cornerstone of baseline and follow-up imaging. A comprehensive 
transthoracic echocardiogram (TTE) to assess the morphology and function of the respective 
heart chambers and valves is mandatory prior to implant. Calculation of LVEF by visual 
assessment, measurement of left ventricular end-diastolic volume and diameter and inter-
ventricular septal thickness to characterize the left ventricle and transaortic jet velocity, mean 
transaortic gradient and aortic valve area by the continuity equation to illustrate AS severity are 
essential(1).  
Echo assessment will be conducted by a core laboratory. 
Sites should make every effort to utilize the same echo machine for all subjects at all required 
interval throughout the duration of the protocol.   
 Neurologic Assessment 
C.4.11
The incidence of new clinically detectable neurological events or deficits, or any comparative 
change in indices of higher cognitive function following TAVI in the treatment of patients with 
symptomatic severe aortic stenosis is an important clinical endpoint. Therefore, a baseline and 
follow-up neurological examination by a qualified trial-trained neurologist or stroke specialist is 
mandatory and as outlined in section C.4.9 Follow-Up Evaluations.  Abbreviated Neurological 
Assessments, requiring completion of only the NIHSS, may be conducted by certified site 
personnel. 
If at any time there is change in a subject’s NIHSS score of ≥4 further assessments 
should be conducted to identify potential adverse events and additional neurological 
evaluations should be conducted by a neurologist or stroke specialist, if a neurological 
event is suspected.   
In case of a new neurological event, the diagnosis of stroke should be supported by 
complementary findings on neuro-imaging examination. The need for additional imaging is up to 
discretion of the Neurologist or Stroke Physician. Both diffusion-weighted Magnetic Resonance 
imaging and multi-slice Computed Tomography are valid neuro-imaging modalities (however 
CTA or MRA is preferred to CT or MRI), the selection of which will be left per institution’s 
standard of care.  
In addition to the neurological assessments at specified time periods, additional evaluations 
should be conducted, as follows during the course of the trial, if applicable: 
 
NIHSS:   
o 
For subjects with a new neurological event (stroke, TIA, or encephalopathy), 
additional NIHSS exams are to be performed at 30 days, and 3 months post-
event 
o 
NIHSS also to be done within 24 hours of any aortic valve or ascending aortic 
intervention 
 
Any patient with evidence of a new neurological event should have a 
neurology consult and an imaging study if deemed necessary 
 
NIHSS may be conducted by certified site personnel 
 
Modified Rankin Scale 
o 
For subjects with new neurological event, assessment to be performed at 7 
days or discharge (whichever occurs first), 30 days, and 3 months post-stroke 
 
All trial-required mRS testing should be conducted by a neurologist or 
stroke specialist  
 
Mini Mental State Exam (MMSE-2:SV) 
o 
For subjects with a new neurological event assessments are to be performed at 
30 days and 3 months post-stroke 
 
All trial-required MMSE testing should be conducted by a neurologist or 
stroke specialist  
Refer to the Appendix R.18 for a description of the Additional Neurological Testing. 

 
 
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Angiographic and Computed Tomography Assessment 
C.4.12
Complete angiographic (invasive or MSCT) assessment of the aortic bifurcation and ilio-femoral-
arterial tree is mandatory prior to the Heart Team review. 
An additional benefit of Multislice CT scan in the TAVI cohort is to obtain a thorough assessment 
of the anatomy of the left ventricular outflow tract (LVOT) up to the common femoral arteries. 
MSCT also provides information on coronary and carotid anatomy, and might identify occult 
malignancy which is also valuable information in SAVR cohort.   
The aortic valve calcification should be evaluated to determine grade of severity.  With respect 
to the elliptical shape of the virtual aortic annulus, the axial plane where the 3 basal aortic leaflet 
attachments can be identified simultaneously is used for measuring the maximum and minimum 
annular diameter (most often corresponding to 2 orthogonal sagittal and coronal planes)(53). 
Additionally the maximum diameters of the LVOT, sinuses of Valsalva and sinotubular junction 
are obtained. Maximum diameter, calcification and tortuosity of the ascending and descending 
thoracic aorta are evaluated. As for the iliofemoral tree, the minimal luminal diameter, plaque 
and calcification burden and tortuosity are assessed in order to judge transfemoral accessibility 
for the investigational TAVI device. 
 
 

 
 
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Data Collection 
C.4.13
All scheduled testing and procedures to be conducted during the baseline, index procedure, and 
follow-up assessments are summarized in Table 3. 
 
Table 3:  Schedule of Assessments 
 
 
 
Parameter 
Screening 
RANDOMIZATION  
Baseline 
(within 14 days of 
procedure) 
Procedure 
Discharge 
30 days 
3 Months 
6  Months 
12 Months 
18 Months 
24 Months 
3 – 5  years 
Informed consent (and in US HIPAA 
Authorization) 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
 
 
* 
 
 
 
 
 
 
 
 
Demographics and Medical history 
 
 
 
 
 
 
 
 
 
 
 
Physical Examination 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessments  
 
 
 
 
 
 
 
 
 
 
 
NYHA Class 
 
 
 
 
 
 
 
 
 
 
 
Risk Assessments: STS Risk Score, Logistic 
EuroSCORE, EuroSCORE II, SYNTAX Score, 
and Katz Index 
 
 
 
 
 
 
 
 
 
 
 
Co-morbidities 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications11 
 
 
 
 
 
 
 
 
 
 
 
Routine Laboratory Tests 
 
 
1,2 
 
3 
 
 
 
 
 
 
Neurological Assessments7 (NIHSS, mRS, 
MMSE-2:SV and Additional Neurological 
Assessments)9 
 
 
 
 
 
 
 
 
 
 
 
Abbreviated Neurological Assessment     
(NIHSS only) 
 
 
8 
 
 
 
 
 
 
 
 
Transthoracic Echocardiogram (TTE) 
 
 
5 
 
 
 
 
 
 
 
Computed Tomography (CT) Angiogram 
(MSCT required at screening)6 
 
 
 
 
 
 
 
 
 
 
 
Coronary Arteriogram 
 
 
() 
 
 
 
 
 
 
 
 
Aortogram  
 
 
() 
 
 
 
 
 
 
 
 
12-lead Electrocardiogram 
 
 
4 
 
 
 
 
 
 
 
 
6 Minute Walk Test 
 
 
 
 
 
 
 
 
 
 
 
Quality of Life Questionnaires (EQ-5D, KCCQ, 
and SF-36) 
 
12 
 
 
 
13
 
 
 
 
 
Adverse Events 
 
 
 
 
 
 
 
 
 
 
10 

 
 
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* Document any changes to subject condition that affect inclusion/exclusion criteria, confirm the subject 
does not meet any exclusion criteria specific to the Index Procedure (eg. percutaneous coronary or 
peripheral intervention and evidence of an acute myocardial infarction which must not occur within 30 
days prior to the index procedure) 
(•)  TAVI subjects only (SAVR subjects will not have these assessments) 
1  Laboratory test results must be performed pre-procedure and CK to be obtained within 8-12 
hours post-procedure  
2  Pre-procedure 
3  Only hemoglobin, creatinine and creatinine clearance are required to be collected 
4  Electrocardiogram within 48 hours post-procedure 
5  TTE to be completed at least 24hours post-procedure but prior to discharge (and no later 
than 7 days post procedure) to assess device success 
6  All subjects should have screening thoracic and abdominal CT angiograms with complete 
visualization of both iliacs, femorals, and aorta (and subclavian/axillaries, if applicable), up to 
and including the aortic annulus 
7  In addition to the protocol required assessment (NIHSS and MMSE); for subjects with 
neurological event or stroke, additional NIHSS and MMSE exams are to be performed at 30 
days and 90 days post-event. mRS should be completed at 7 days post-event or discharge 
(whichever occurs first), 30 days, and 90 days post-event. NIHSS is also to be done within 24 
hours of any aortic valve or ascending aortic intervention 
8  NIHSS to be done within 24 hours post- procedure 
9  Additional Neurological Assessments include:  Visual Fields Testing, Gait Assessment, Hand 
Function, Writing Evaluation, and Drawing Assessment 
10  SAE, MAE, cardiovascular events, device-related events, including device-related technical 
observations, UADEs, USADEs, all stroke (CVAs), and death reports 
11  Use of relevant medications (diuretics, aspirin, anticoagulants, ACE-I, ARB, beta-blockers, 
statins and anti-platelets)   
12   Quality of Life Questionnaires collected at baseline may be administered any time after the 
subject has provided informed consent but should be collected prior to informing the subject 
of randomization assignment   
13   Quality of Life Questionnaire – EQ-5D to be administered via telephone.  SF-36 will also be 
collected in selected geographies, refer to Appendix R.12 
 

 
 
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Unscheduled Follow-up Assessments 
C.4.14
If a subject returns to the institution between their scheduled follow-up visits the visit will be 
treated as an unscheduled visit and the assessments completed at this visit will be done at the 
discretion of the investigator. eCRFs are provided for unscheduled visits.   
 
Missed Follow-up Visits 
C.4.15
Every effort should be made to ensure subjects return to the clinic for all protocol required 
follow-up.  If the subject is unable to return for an in-person clinic visit, the Investigator, or 
designee, must document in the patient record the reason the subject was unable to complete 
the visit and, if applicable, follow the requirements for deviation reporting as outlined in Section 
C.4.18 Protocol Deviations. 
The Investigator should also make every effort to contact the subject or subject’s legal 
representative, within the visit window, to collect the subject’s vital status as well as information 
related to potential adverse events, safety data, and hospitalizations. 
 
Investigational Product Accountability 
C.4.16
The Investigator is responsible for maintenance of the Device Accountability Log. The log must 
detail the product and lot numbers as well as the location and status of all investigational 
devices (including DCS,CLS/ LS components, where applicable) received by the hospital and/or 
Investigator. At the end of the clinical trial the Principal Investigator must sign the original log, as 
applicable. 
This clinical trial will be conducted in some geographies where the TAV device or its 
components are commercially available.  In these geographies, the device will be used outside 
the current approved indication; therefore the TAV will be labeled as investigational.  Note, the 
DCS and CLS/LS components are identical to the CE marked CoreValve System and will be 
supplied within the approved commercial CE marked labeling. The Investigator must provide full 
accountability for each TAV from the time of receipt through disposition and/or return.  
Accountability for the each DCS and CLS/LS must include all dispositions within the clinical trial.  
In the US, commercially labeled devices may be used in the trial, as necessary in the event that 
the investigational device is not available. All commercial components must have full 
accountability for each component from the time of receipt through disposition and/or trial. In the 
event that a commercial device is used in a study subject, the device use will be documented in 
the Device Accountability Log. 
In geographies where the device is not currently approved, the TAV, DCS, CLS/LS components 
will be labeled as investigational.  The Investigator must provide full accountability for each TAV, 
DCS, and CLS/LS from the time of receipt through disposition. 
At the end of the trial enrollment period, all remaining investigational product must be returned to 
Medtronic.  
 
Device Malfunction or Explant 
C.4.17
In the event of a device malfunction of the  TAV device or its components prior to implant or in 
the event that a TAV is explanted after implant (due to reintervention or autopsy), the TAV 
and/or affected components should be returned to Medtronic to the following:   
 
Medtronic, Inc.  
Attn: Explant Lab [PE#] 
1851 E. Deere Avenue 
Santa Ana, CA  92705-5720 
 
 
Additional details surrounding the device return process, including how to obtain the PE # 
(product experience number), are contained within the Medtronic explant kit and in Appendix 
R.11. 

 
 
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 Protocol Deviations 
C.4.18
A protocol deviation is defined as an event where the clinical investigator or site personnel did 
not conduct the trial according to the protocol or the Investigator agreement.  Deviations will be 
reported regardless of whether medically justifiable, pre-approved by Medtronic, or taken to 
protect the patient in an emergency. 
A protocol deviation form is to be completed for each trial protocol deviation, including, but not 
limited to: 
 
Failure to obtain informed consent 
 
Incorrect version of consent provided to patient 
 
Failure to obtain IRB/MEC protocol review and approval before starting the trial 
 
Enrollment of patient during an IRB/MEC approval lapse 
 
Clinical investigator exceeding enrollment limits specified by sponsor 
 
Patient did not meet inclusion/exclusion criteria 
 
Incorrectly performed testing 
 
Protocol-required testing and/or measurements not done or performed outside of 
window 
 
Source data permanently missing 
 
SAE, SADE, UADE or USADE not reported in the required timeframe 
FDA regulations [21 CFR 812.140] require that the Investigator maintain accurate, complete, 
and current records, including documents showing the dates of and reasons for each deviation 
from the protocol.  Relevant information for each deviation will be documented on a deviation 
form completed by site personnel and reviewed by the Investigator. 
FDA regulations  [21 CFR 812.150], ISO 14155 (2011), and local regulatory authorities (where 
applicable), require Investigators to obtain prior approval from the sponsor before initiating 
changes in or deviations from the protocol, except when necessary to protect the life or physical 
well-being of a patient in an emergency.   
Prior approval by the sponsor is expected in those situations in which the Investigator 
anticipates, contemplates or makes a conscious decision to depart from procedures specified in 
the protocol.  Prior approval is generally not expected in situations where unforeseen 
circumstances are beyond the Investigator’s control, but is still considered a deviation (eg. a trial 
subject who fails to attend a scheduled follow-up visit, a trial subject too ill to perform a protocol-
required test).  To obtain approval, the Investigator must call or email and discuss the potential 
deviation with the Medtronic trial manager or designee prior to initiating any changes.  If 
approval is granted, the Medtronic trial manager or designee will provide the applicable 
documentation to be maintained in the site files. 
FDA regulations require the Investigator to notify the sponsor and the reviewing IRB/MEC within 
5 working days of the following deviations [21 CFR 812.150]: 
 
a deviation from protocol to protect the life or physical wellbeing of a patient in an 
emergency 
 
failure to obtain an informed consent   
Investigators or an authorized designee must notify Medtronic as soon as possible by calling the 
trial manager or designee and completing the protocol deviation form. 
The Investigator is required to adhere to local IRB/MEC procedures for reporting deviations. 
The DSMB may review protocol deviations to ensure compliance and overall trial integrity. 

 
 
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Subject Withdrawal or Discontinuation 
C.4.19
All subjects will be encouraged to remain in the trial through the last follow-up visit at month 60.  
Subjects who discontinue participation prematurely after randomization will be included in the 
analysis of results (as appropriate) but they will not be replaced in the enrollment of total trial 
subjects. If a trial subject is discontinued from the trial early, the reason for discontinuation 
should be documented in the patient file and a Study Exit eCRF must be completed.  If 
discontinuation is because of safety concerns or lack of effectiveness, the subject shall be asked 
to be followed for collection of ongoing safety data outside the clinical investigation. 
The trial site and Sponsor will make every effort to have all subjects complete the follow up visit 
schedule.  A subject will not be considered lost-to-follow-up unless all efforts to obtain 
compliance are unsuccessful. At a minimum, the effort to obtain follow-up information must 
include three attempts to make contact via telephone and if contact via phone is not successful, 
a traceable letter from the Investigator must be sent to the subject’s last known address.  Should 
both telephone and mail efforts to contact the subject be unsuccessful, the subject’s primary 
physician should be contacted.  Subjects will then be deemed lost to follow up.  All contact 
efforts to obtain follow-up must be documented in both the subject’s medical records and in the 
trial eCRFs. 
If a subject officially withdraws from the trial but is willing to allow either regular vital status 
determinations for the trial or a one-time vital status determination, these are to be conducted 
per the follow-up visit schedule or only at the last planned follow-up visit, respectively, and may 
be conducted via telephone.   
If a subject discontinues the trial at any time, is withdrawn from the trial early, or completes all 
protocol required follow-up they should then be followed per the local standard of care for their 
condition. 
 Termination or Discontinuation of Trial 
C.4.20
Medtronic may decide to suspend or prematurely terminate the trial.  If the trial is terminated 
prematurely or suspended, Medtronic shall promptly inform the clinical investigators of the 
termination or suspension and the reason(s) for this. The investigator shall then promptly inform 
the reviewing MEC/IRB. 
Possible reasons for early trial termination include: 
 
Unanticipated Adverse Device Effect (UADE) or Unanticipated Serious Adverse 
Device Effect (USADE) presents an unreasonable risk to patients 
 
Recommendation from DSMB (eg. significant safety concerns, statistical futility) 
If the trial is terminated early, the Sponsor will, as soon as possible, provide a written statement 
to the Investigators to enable prompt notification of the IRB/MECs.  The Sponsor will also inform 
the FDA.  If the trial enrollment is terminated early, the follow-up visits will continue for all 
enrolled subjects. 
 
 

 
 
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C.5 
Adverse Events 
 
Definitions 
C.5.1
The definitions presented in this section allow for a clear understanding of adverse event data 
collection and subsequent analysis.  
C.5.1.1 
Adverse Event 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device.   
NOTE 1: This definition includes events related to the investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3:  For users or other persons, this definition is restricted to events related to investigational medical devices. 
The following events in Table 4 are expected to occur with any surgical implant and therefore 
should not be reported as AEs, unless they occur outside of the stated timeframe: 
Table 4:  Expected Events 
Description of the Event 
Timeframe (hours) from Procedure 
Anesthesia-related nausea and/or vomiting 
24 
Low-grade fever (<100oF or <37.8oC) 
48 
Back pain related to laying on the procedure table 
72 
Incisional pain (pain at access site) 
72 
Sleep problems or insomnia 
72 
Mild to moderate bruising or ecchymosis 
168 
C.5.1.2 
Serious Adverse Event 
A serious adverse event (SAE) is an event that: 
 
Led to death 
 
Led to serious deterioration in the health of the subject, that either resulted in: 
o a life threatening illness or injury, or 
o a permanent impairment of a body structure or a body function, or 
o inpatient or prolonged hospitalization, or 
o medical or surgical intervention to prevent life-threatening illness or injury or 
permanent impairment to a body structure of a body function  
 
Led to fetal distress, fetal death or a  congenital anomaly or birth defect 
NOTE:  Planned hospitalization for a pre-exiting condition, or a procedure required by the CIP, without serious 
deterioration in health, is not considered a serious adverse event. 
In addition to above standard definition of SAE, the following events will also be defined as 
serious in the SURTAVI Trial, including events that do not meet the above criteria for SAE. 
 
Stage 2 and 3 acute renal injuries 
 
Life-threatening and Major bleeding events 
 
Any new or worsening LBBB or RBBB that requires the placement of a permanent 
pacemaker and/or surgical or invasive intervention 
 
 
 
All myocardial infarctions 
 
Disabling strokes 
 
Major vascular complications 
Events that do not meet these criteria are considered non-serious. 
C.5.1.3 
Major Adverse Cardiovascular and Cerebrovascular Events 
Major adverse cardiovascular and cerebrovascular events (MACCE) is defined as a composite 
of: 
 
All-cause death 
 
Myocardial infarction (MI)  
 
All stroke, and 

 
 
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 
Reintervention (defined as any cardiac surgery or percutaneous reintervention catheter 
procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted 
valve) 
C.5.1.4 Major Adverse Event 
Major adverse event (MAE) includes: 
 
MACCE 
 
Acute kidney Injury  
 
Cardiac tamponade 
 
Prosthetic valve dysfunction  
 
Cardiogenic shock 
 
Prosthetic valve endocarditis 
 
Life-threatening, disabling or major bleeding  
 
Major vascular complication 
 
Cardiac perforation 
 
Valve malpositioning 
C.5.1.5 Adverse Device Effect (ADE) or Device-Related Adverse Event 
An ADE is an adverse event related to the use of an investigational medical device.  During this 
clinical investigation an event should be considered related to the device when it is the result of 
the Medtronic CoreValve™System (MCS) System: 
 
The transcatheter aortic valve (TAV) 
 
The delivery catheter system (DCS) 
 
The compression loading system (CLS/LS) 
 
The implant procedure 
An event should be considered not related to the device when it is the result of: 
 
A pre-existing medical condition 
 
A new illness, injury or condition 
 
Medication 
NOTE 1:  This definition includes adverse events resulting from insufficient or inadequate instructions for use 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 
NOTE 2:  This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device. 
C.5.1.6 Serious Adverse Device Effects (SADEs) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event.   
C.5.1.7 Unanticipated Adverse Device Effect (UADE) 
An unanticipated adverse device effect or UADE is defined as “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 protocol or application (including a supplementary plan or application), or any 
other unanticipated serious problem associated with the device that relates to the rights, safety, 
or welfare of subjects” [21 CFR 812.3 (s)]. 
Those known adverse events related to the device, procedure or therapy are listed in Section O 
and in the Risk/Benefit Analysis section (Section D) of this document.  
 
 

 
 
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C.5.1.8 Unanticipated Serious Adverse Device Effect (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report. 
NOTE:  Anticipated serious adverse device effect (ASADE) is an effect, which by its nature, incidence, severity or 
outcome has been identified in the risk analysis report. 
C.5.1.9 Device Deficiency 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance. 
NOTE:  Device deficiencies include malfunctions, use errors, and inadequate labeling. 
C.5.1.10 Technical Observation 
A technical observation is a defect, malfunction, or failure of any part of the TAV or its 
components.  This may pertain to the device or system not functioning according to its design 
intent. Each technical observation (whether or not associated with any untoward medical 
occurrence in a subject) will be reported on the Adverse Event (AE) eCRF and tabulated as an 
AE.   
 
Reporting 
C.5.2
Investigators are required to keep records on “all relevant observations, including records 
concerning adverse device effects (whether anticipated or unanticipated)” [21 CFR 812.140; ISO 
14155 (2011)].  Adverse event collection will begin from the point of trial enrollment to trial 
closure.   All new or worsening (from baseline) adverse events and technical observations will 
be captured on the AE eCRF through the 24month follow-up visit. It is the responsibility of the 
Investigator to assess the subject for adverse events and capture the required adverse event 
information on the AE eCRF.   
Once a subject has completed their 24-month scheduled follow-up visit only serious adverse 
events, major adverse events, cardiovascular events, device-related adverse events, including 
device related technical observations, unanticipated adverse device effects (UADE) or 
unanticipated serious adverse device effects (USADE), all strokes (CVAs) and deaths will be 
required to be reported. Reference section C.5.1 Adverse Events for event definitions and 
criteria. Medtronic representatives or their designees will conduct monitoring visits to review 
source documentation and verify the complete and accurate capturing of adverse events. 
The Investigator must also notify the responsible IRB/MEC regarding new and significant safety 
information and any event identified by Medtronic that requires expedited FDA, and/or local 
regulatory agency, reporting as serious, unexpected, and related to the investigational device. It 
is the responsibility of the investigator to ensure site specific IRB/MEC safety reporting 
requirements are met. 
Medtronic Clinical will ensure all device-related adverse events and all procedure-related SAEs 
are processed according to internal policies and procedures. When necessary, Medtronic Field 
Assurance will respond to sites in writing with the findings related to the product experiences.  
The general procedure for investigators reporting any adverse event is as follows: 
 
Report the event to Medtronic as soon as possible but no later than the timeframes 
outlined below.  (At the time of Site Initiation, sites will be provided with the telephone 
and other applicable contact information of the appropriate Medtronic designee). 
 
Complete all sections of the Adverse Event eCRF. 
 
Each unique event/diagnosis must be documented separately. 
 
Documented pre-existing conditions are not considered to be reportable AEs unless 
there is a change in the nature or severity of the condition. 
 
The Adverse Event eCRF must be reviewed by the Investigator.  
Reporting guidelines related to specific types of adverse events are outlined below. 
C.5.2.1 
Serious Adverse Events (SAEs) 
The Investigator shall notify the sponsor immediately but not later than within 3 calendar days of 
first learning of any SAE using the EDC system [MEDDEV 2.7/3].  If necessary, the Investigator 
may be requested to provide copies of source documentation regarding the event (eg., 
physician/nurse notes or summaries). The Investigator should also notify their IRB/MEC and, if 
applicable, local regulatory agencies, per their requirements. 

 
 
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Medtronic will conduct an evaluation of the event and if it is determined by Medtronic to be a 
UADE or USADE, it will be reported as described in the following sections. 
C.5.2.2 
Serious Adverse Device Effects 
The Investigator shall notify the sponsor immediately, but not later than within 3 calendar days 
of the first learning of any SADE. 
C.5.2.3 
Unanticipated Adverse Device Effects (UADE or USADE) 
Investigators must report any (potential) unanticipated adverse device effects, or unanticipated 
serious device effects, to Medtronic and their IRB/MEC immediately but no later than 3 calendar 
days after first learning of the event [MEDDEV 2.7/3].  UADEs and USADEs should be reported 
immediately to Medtronic via telephone as well as on an eCRF. The Investigator should also 
notify their IRB/MEC and, if applicable, local regulatory agencies, per their requirements. 
The Investigator should consider the device labeling and the Risk/Benefit Analysis section of this 
document (Section D) when determining whether an event is unanticipated or not. 
If an event is determined by Medtronic to be a UADE or USADE, Medtronic will report the event 
to all investigators to enable reporting to their respective IRB/MECs.  Medtronic will provide this 
notification within 10 working days after Medtronic first receives notice of the effect.  [21 CFR 
812.150] 
If Medtronic and the DSMB determine that the event presents an unreasonable risk to the 
participating subjects, Medtronic must terminate all investigations or parts of investigations 
presenting the risk in the clinical trial 5 working days after making that determination and not 
later than 15 working days after Medtronic first receives notice of the effect.  [21 CFR 812.46]  
Follow-up visits for enrolled subjects will continue according the schedule of assessments. 
C.5.2.4 
Device Deficiencies and Technical Observations 
Device Deficiency information and Technical Observations will be collected throughout the trial 
and reported to Medtronic. 
Device Deficiencies and Technical Observations should be reported on an Adverse Event 
eCRF. 
Device deficiencies that did not lead to an Adverse Event but could have led to an SADE: 
a) if either suitable action had not been taken, 
b) if intervention had not been made, or 
c) if circumstances had been less fortunate, 
require immediate reporting (see Table 6). Initial reporting may be done on the eCRF 
completing as much information as is available. The original completed eCRF must be submitted 
to Medtronic as soon as possible. 
C.5.2.5 
All Other Adverse Events 
The Investigator shall notify the sponsor within 15 calendar days of first learning of any other AE 
using the EDC system.  If necessary, the Investigator may be requested to provide copies of 
source documentation regarding the event (eg., physician/nurse notes or summaries). 
C.5.2.6 
Anticipated Adverse Events 
Potential risks associated with TAVI device or its components may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary closure) 
 
Emergent surgery (eg., coronary artery bypass, heart valve replacement, valve explant) 
 
Multi-organ failure 
 
Heart failure 
 
Myocardial infarction 
 
Cardiogenic shock 
 
Respiratory insufficiency or respiratory failure 

 
 
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 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, ventricle, 
myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel 
 
Ascending aorta trauma 
 
Cardiac tamponade 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture 
o 
Bending (out-of-round configuration) of the valve frame 
o 
Under-expansion of the valve frame 
o 
Calcification 
o 
Pannus, (wear, tear, prolapse, or retraction in the valve leaflets) 
o 
Poor valve coaptation 
o 
Suture breaks or disruption 
o 
Leaks 
o 
Mal-sizing (prosthesis-patient mismatch) 
o 
Malposition (either too high or too low)/malplacement 
o 
Regurgitation, stenosis 
 
Thrombosis/embolus (including valve thrombosis) 
 
Valve migration/valve embolization 
 
Ancillary device embolization 
 
Emergent percutaneous coronary intervention (PCI) 
 
Emergent balloon valvuloplasty 
 
Major or minor bleeding that may or may not require transfusion or intervention 
(including life-threatening or disabling bleeding) 
 
Allergic reaction to antiplatelet agents, contrast medium, or anesthesia 
 
Infection (including septicemia and endocarditis) 
 
Stroke, TIA, or other neurological deficits 
 
Permanent disability 
 
Renal insufficiency or renal failure (including acute kidney injury) 
 
Mitral valve regurgitation or injury 
 
Tissue erosion 
 
Vascular access related complications (eg., dissection, perforation, pain, bleeding, 
hematoma, pseudoaneurysm, irreversible nerve injury, compartment syndrome, 
arteriovenous fistula, stenosis) 
 
Conduction system disturbances (eg., atrioventricular node block, left-bundle branch 
block, asystole), which may require a permanent pacemaker 
 
Cardiac arrhythmias 
 
Encephalopathy 
 
Pulmonary edema 
 
Pericardial effusion 
 
Pleural effusion 
 
Myocardial ischemia 
 
Peripheral ischemia 
 
Bowel ischemia 
 
Heart murmur 
 
Hemolysis 
 
Cerebral infarction-asymptomatic 
 
Non-emergent reoperation 
 
Inflammation 
 
Fever 
 
Hypotension or hypertension 

 
 
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 
Syncope 
 
Dyspnea 
 
Anemia 
 
Angina 
 
Abnormal lab values (including electrolyte imbalance) 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic 
valve and prolonged procedural time 
C.5.2.7 
Deaths 
The Investigator shall notify Medtronic immediately but not later than within 3 calendar days of 
learning of a subject’s death, whether or not the death is related to the investigational device.  
The Investigator should also notify his/her IRB/MEC and/or local regulatory agencies, if 
applicable, per their requirements. The Investigator should also attempt to determine, as 
conclusively as possible, whether such deaths are related to the investigational TAV device or 
its components.  When an autopsy is conducted, a copy of the report should be provided to 
Medtronic.  Medtronic will evaluate the event and if device-related and unexpected, the event 
will be reported as a UADE or USADE. 
Any subject death will be reported on the Study Exit eCRF and accompanied by an Adverse 
Event eCRF identifying the cause of death. 
C.5.2.8 
Vigilance Reporting 
A product complaint is defined as any written, electronic or oral communication that alleges 
deficiencies related to the identity, quality, durability, reliability, safety, effectiveness or 
performance of a medical device that has been placed on the market. 
It is the responsibility of the investigator to report all product complaint(s) associated with a 
medical device distributed by Medtronic, regardless whether they are related to intended use, 
misuse or abuse of the product. Reporting must be done as soon as possible and without undue 
delay and via the regular channels for market released products. Note that although the 
reporting of product complaints is not part of the clinical study, all potential complaints that are 
collected as part of this study will be reviewed by the responsible person at Medtronic and, if 
applicable, reported to the designated complaint handling unit. Medtronic will ensure timely 
reporting to meet global regulatory requirements. 
 
Clinical Events Committee (CEC) 
C.5.3
An independent Clinical Events Committee (CEC) will review and adjudicate, at a minimum, all 
deaths and primary endpoint related adverse events. The CEC will consist of, at a minimum, 
interventional cardiologists and cardiac surgeons who are not participants in the trial.  Additional 
specialist, such as neurologists, may also be selected as part of the CEC. 
The purpose of the CEC is to conduct a medical review and classify/adjudicate, at a minimum, 
all deaths and/or clinical endpoints collected in the trial according to definitions and processes 
outlined in the Medtronic CoreValve™ SURTAVI Trial protocol and the CEC charter, which will 
be developed and approved by Medtronic and the CEC members. 
All applicable events will be reviewed and adjudicated by a minimum of two CEC members. All 
other events will be reviewed and adjudicated by qualified internal Medtronic safety individual(s) 
to ensure they should not be adjudicated by the full CEC and that the events are appropriately 
classified by the investigator. 
Prior to event adjudication, the CEC will draft a charter to establish explicit rules outlining the 
minimum amount of data required and the algorithm followed in order to classify/adjudicate a 
trial endpoint related clinical event. CEC decisions will be documented in meeting minutes, 
which will be maintained in the trial file. 
 
Data Safety Monitoring Board (DSMB) 
C.5.4
An independent, unblinded DSMB will be established and will be comprised of at least 3 experts, 
including a chairperson.  The DSMB will have a minimum of one cardiac surgeon, one 
interventional cardiologist and one statistician, and will be independent of Medtronic and the trial 

 
 
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investigators.  Investigators participating in the trial may participate in the meetings to offer 
clarification surrounding events, but will not have voting privileges.  Medtronic personnel may 
facilitate the DSMB meeting but will not have voting privileges.  The DSMB will meet (via 
teleconference or in person) prior to the first subject enrollment to establish procedures for 
DSMB review, chairman appointment and guidelines for trial recommendations.  The full DSMB 
will meet on a periodic basis to perform a comprehensive data review and will meet more 
frequently when needed.  Primary and safety-related secondary endpoints may also be 
reviewed at these meetings. Meetings will consist of both open and closed sessions. 
The DSMB will also perform a supplemental review of, at a minimum, all serious adverse events 
and deaths and any other data requested by the DSMB on a more frequent periodic basis to 
ensure patient safety.  DSMB members will review the report, and when necessary provide 
recommendations about the conduct of the trial and/or request a full DSMB meeting.  
A DSMB charter will be developed and approved by Medtronic and the DSMB members. The 
committee will outline the criteria for both the full DSMB meeting and supplemental DSMB 
reviews within the DSMB charter. 
Following each full DSMB meeting, the board will report to Medtronic in writing and may 
recommend changes in the conduct of the trial.  These DSMB recommendations may include 
recommendations on trial status such as continuing the trial without modifications, continuing the 
trial with modifications, stopping the enrollment in the trial or a specific trial arm, or 
recommendations about trial conduct including recommendations around enrollment or protocol 
deviations.  
In the case of UADEs or USADEs, if Medtronic and the DSMB determine that the event presents 
an unreasonable risk to the participating subjects, Medtronic must terminate the clinical trial 
within 5 working days after making that determination and not later than 15 working days after 
Medtronic first receives notice of the effect. [21 CFR 812.46]. All clinical sites will be notified of 
this action.  
The DSMB may call additional meetings if, at any time, there is concern about any aspect of the 
trial.  All data presented at the meetings will be considered confidential and returned to the trial 
statistician at the closure of the DSMB meeting. 
Additional details about the DSMB are outlined in the DSMB charter. 

 
 
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C.6 
Statistical Methods and Analysis 
 
Statistical Considerations and Analysis 
C.6.1
This section describes the statistical considerations and analysis plans for the SURTAVI trial.  
The statistical analysis will be performed by the statistics department of Medtronic. As primary 
analysis all randomized subjects will be analyzed following the modified intention to treat (mITT) 
approach; ie. analyses will be conducted on the cohort of subjects who undergo an attempted 
trial treatment, analyzed according to the randomized assignment.  A secondary analysis of key 
objectives will be performed according to the therapy actually received. 
Roll-in subjects will not be included in the primary or secondary analysis; however, the data will 
be summarized separately with descriptive statistics. 
All follow-up periods are defined as the number of days after the procedure date. 
 
Reports 
C.6.2
Medtronic is responsible for the reports cited in Table 5 (Sponsor Reporting Responsibilities).  
These reports are subject to regulatory retention and inspection requirements.  In addition to the 
reports listed in Table 5, FDA, Competent Authorities, and local regulatory agencies, where 
applicable, or the reviewing IRB/MEC may request reports pertaining to any aspect of the 
clinical trial. 
 
Description of Baseline Variables 
C.6.3
Baseline demographic and clinical variables will be summarized for each of the treatment 
groups for the intention-to-treat (ITT), modified intent-to-treat (mITT), and implanted populations. 
All continuous variables will be summarized as means, medians, standard deviations,  
interquartile ranges, minima and maxima and compared between treatment groups using a 
Bayesian analog of a two-sample t-test or the non-parametric Wilcoxon rank-sum test.  
Categorical variables will be summarized as frequencies and percentages and compared 
between treatment groups using a Bayesian version of a comparison of proportions. 
 
Analysis Populations 
C.6.4
C.6.4.1 Screening Population 
All patients with symptomatic severe AS who provide informed consent will be considered 
screened and all available data will be entered into the EDC system.  
C.6.4.2 Randomized Population 
If the patient signs informed consent, meets all inclusion and none of the exclusion criteria, and 
the Heart Team determines the patient is suitable for randomization in the trial, then the subject 
is reviewed by the SURTAVI Screening Committee.  If the subject is approved by the Screening 
Committee and the subject is enrolled/randomized to either TAVI or SAVR the subject is added 
to the randomized population. Within the randomized population three sub-populations are 
distinguished: 
 
Intention to treat (ITT) population - Subjects are reported according to the randomized 
assignment, SAVR or TAVI, regardless of what, if any, therapy was actually received  
 
Modified intention to treat (mITT) population - Randomized subjects in whom a 
procedure is attempted. Subjects who undergo an attempted trial treatment are reported 
according to the randomized assignment, SAVR or TAVI, regardless of what, if any, 
therapy was actually received.  A procedure attempt is defined as when the subject is 
brought into the procedure room and any of the following have occurred: anesthesia 
administered, vascular line placed, TEE placed or any monitoring line placed  
 
Implanted population - population includes the mITT subjects who are actually 
implanted with either the investigational TAVI device or a surgical valve. Depending on 
context, subjects may be analyzed according to randomized treatment assignment or 
treatment actually received. 
The primary analysis for the primary objective and most secondary objectives will use the mITT 
population.   At the conclusion of the trial, an analysis using the ITT population will also be 
presented. 

 
 
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Primary Analysis 
C.6.5
The primary endpoint of all-cause mortality or disabling stroke at 24 months will be evaluated 
using the absolute difference of the TAVI rate and the SAVR rate for all-cause mortality or 
disabling stroke during a fixed follow-up of 24 months’ time. The hypothesis test is designed to 
show non-inferiority of TAVI to SAVR for the primary endpoint.  
C.6.5.1 
Hypothesis of Non-inferiority 
The primary objective is to establish that TAVI is non-inferior to SAVR for the primary endpoint.  
The hypothesis of interest is: 
H: ߨ் ൏ߨ஼൅ߜ 
where T and C denote binary rates of all-cause mortality or disabling stroke during a fixed 
follow-up of 24 months for the treatment (TAVI) and control (SAVR) groups, and ߜൌ0.07.  This 
trial is designed using Bayesian statistical techniques.  TAVI will be declared to be non-inferior 
to SAVR if it can be established that the posterior probability Pr(Hδ=0.07 | data) > Ψ, where Ψ is a 
pre-specified threshold value.  If, in addition, it can be shown that Pr(ܪ஺: ߨ் ൏ߨ஼൅0 | data) > 
ΨSUP, TAVI will be declared to be superior to SAVR.  The values chosen for Ψ and ΨSUP are 
described below. 
C.6.5.2 
Randomization, Sample Size and Analysis Plan 
Randomization will follow a 1:1 (treatment:control) allocation ratio and be stratified by site and 
need for revascularization, using a blocked randomization scheme with blocks of randomly 
varying sizes.  The sample size for the mITT population is 1600 subjects.  
Sample Size Justification 
The assumed values T = C = 0.17 are based on the data published by Iturra et al3 and 
CoreValve US Pivotal High Risk study results. As reported in the Iturra paper, the incidence of 
all-cause mortality at 30 days was 2.8% and the late all-cause mortality Kaplan-Meier rate at 24 
months was 12.1%. The overall 24-month all-cause mortality rate was approximately 15%. STS 
score reported in the Iturra paper (5.6 ± 1.1, n=502) was similar to the STS score for subjects 
currently enrolled in the SURTAVI study4 (5.6 ± 1.4, n=654), and it is believed that the 24-month 
all-cause mortality rate in SURTAVI will be approximately 15% at 24 months. The major stroke 
rate was 3.2% for subjects who survived to 1 year in the CoreValve Pivotal High Risk study.  
The High Risk study enrolled a higher-risk population than SURTAVI, therefore, the major stroke 
rate in the High Risk study is adjusted downward, and it is believed the disabling stroke rate at 
24 months would be approximately 2% in the SURTAVI study. Overall, the estimation of the all-
cause mortality or disabling stroke rate at 24 months is 17%.  
Although the pre-specified analysis methods are Bayesian, the sample size is guided by a 
standard frequentist non-inferiority power analysis.  Under the assumptions of T = C = 0.17, 
non-inferiority margin δ=0.07, 1:1 randomization, α= 0.05, and power = 95%, the method of 
Farrington and Manning5 as implemented in PASS 20086 indicates that the required sample size 
for a single-look analysis is 1258. To allow for up to 6% dropout, 1339 subjects must be 
accrued.  Furthermore, to compensate for power lost in a two-look group sequential analysis 
plan using Pocock-type alpha spending, the sample size would have to be increased by about 
12.5%7.  This leads to an estimated sample size of 1531.  Thus a sample size of 1600 mITT 
subjects should provide ample power for establishing non-inferiority in the primary hypothesis 
test. 
Analysis Plan 
 An interim analysis (timed to occur when 1400 mITT subjects have reached 12 months) for the 
purpose of declaring an early win will be conducted.  At this analysis, If P(Hδ=0.07 | data) > Ψ, 
                                                    
 
3 Iturra SA, Suri RM, Greason KL, et al. The Journal of thoracic and cardiovascular surgery 2014;147:127-132.  
4 Medtronic CoreValve SURTAVI Trial 2014 FDA Annual Progress Report;  
5 Farrington, C. P. and Manning, G. 1990. 'Test Statistics and Sample Size Formulae for Comparative Binomial Trials with Null 
6 Hintze, J. (2004). NCSS and PASS, Number Cruncher Statistical Systems. Kaysville UT. www.ncss.com 
7 Jennison C and Turnbull BW, Group Sequential Methods with Applications to Clinical Trials.  Boca Raton:  Chapman & Hall, 2000, p 27 

 
 
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non-inferiority will be declared at this time, and a regulatory submission will follow.  Alternatively, 
if P(Hδ=0.07 | data) ≤ Ψ, all mITT subjects will be followed to 24 months, when a final analysis will 
occur.  At the final analysis, the standard for trial success will again be P(Hδ=0.07 | data) > Ψ.  
These two analyses are termed "Win Looks." 
If, at the early (interim) "Win Look," non-inferiority is established, a test of superiority will 
immediately follow.  If P(Hδ=0 | data) > ΨSUP, superiority will be established at this time.  
However, if P(Hδ=0 | data) ≤ ΨSUP, subjects will continue to be followed and analyzed according 
to the same analysis plan.  At the final "Win" analysis, if P(Hδ=0 | data) > ΨSUP, a delayed 
determination of superiority will be made.   
The statistical approach for these analyses is Bayesian. The prior distributions for T and C in 
these calculations are Beta (1,1).  The threshold Ψ is designated to be 0.971 for non-inferiority 
testing and ΨSUP =0.989 for superiority testing; these values are selected by trial-and-error to 
achieve a type I error (under simulation) of at most 0.05 for non-inferiority testing and at most 
0.025 for superiority testing. Of note, establishing P(Hδ=0 | data) > ΨSUP means that superiority 
has been established to a standard equivalent to a nominal significance level of 0.025 (1-sided), 
but this does not automatically mean that a labeling claim of superiority is supported.  See 
“Multiplicity Considerations” (Section C.12) for additional requirements regarding labeling claims 
on secondary objectives.  
Further details of planned analyses are provided in the SAP. 
 
Missing Data and Planned Sensitivity Analyses (Primary Objective) 
C.6.6
Every effort will be undertaken to minimize missing data.  However, some missing data is 
inevitable, and the trial is designed with the expectation that there may be up to 6% of primary 
data missing at 24 months.  The reasons for missing data will be described in detail and 
evaluated for assessment of possible bias.  The distribution of prognostic factors between 
patients with data and those without data will be examined to evaluate any potential sources of 
bias. 
 
Description of Performed Analysis, per population 
C.6.7
Any deviations from this section and/or the Statistical Analysis Plan will be described and 
justified in the Final Report or justified in a protocol amendment, as appropriate. 
C.6.7.1 
Analysis of Screening Population 
For the screening population only descriptive statistical analysis will be performed, on variables 
that are captured in the EDC system. 
C.6.7.2 
Analysis of ITT and mITT Populations 
For the subjects in the randomized population the primary analysis of the primary endpoint and 
inferential statistics for the following secondary endpoints will be performed on the ITT and mITT 
populations: 
 
Major adverse cardiovascular and cerebrovascular events (MACCE) 
 
Individual MACCE components 
 
Major adverse events (MAE)  
 
Conduction disturbance requiring permanent pacemaker implantation 
 
NYHA 
 
Six-minute walk test 
 
Ratio of days alive out of hospital versus total days alive 
 
Quality of life 
 
Echocardiographic assessment of valve performance  
 
Aortic valve disease-related hospitalizations 
 
Cardiovascular deaths and valve-related deaths 
 
Strokes and TIAs 
 
Per-procedural neurological injury 

 
 
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 
Index procedure-related MAEs 
 
Length of index procedure hospital stay 
 
Device success 
 
Procedure success 
C.6.7.3 
Analysis of Implanted Population 
The endpoints listed in C.6.7.2 will also be performed on the implanted population.  Additionally, 
the implanted population will be used for analyzing the primary endpoint, secondary endpoint of 
prosthetic valve dysfunction, and echocardiographic assessment of valve performance.    
 
 

 
 
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Secondary Endpoints 
C.6.8
C.6.8.1 
Secondary Endpoints Compared Between TAVI and SAVR 
1. Incidence of Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  
MACCE is defined as a composite of: 
 
All-cause death 
 
Myocardial infarction (MI) 
 
All stroke, and 
 
Reintervention (defined as any cardiac surgery or percutaneous reintervention 
catheter procedure that repairs, otherwise alters or adjusts, or replaces a 
previously implanted valve) 
MACCE-incidence estimates will be provided for the two treatment groups at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  The 
statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
Additionally, incidence of MACCE will be compared at 30 days or hospital discharge, 
whichever is later.  The statistical method will be the Bayesian version of a comparison of 
proportions.  
2. The occurrence of individual MACCE components at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
 
MACCE components will be summarized and their incidence estimates provided at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
3. Major Adverse Events (MAE) and individual components at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years. 
 
MAE events and individual components will be summarized and the incidence of MAEs 
will be provided at 30 days, 6 months, 12 months, 18 months, 24 months, and annually 
thereafter up to 5 years The statistical method will be the Bayesian version of a 
comparison of proportions (with predictions). 
      Additionally, incidence of major vascular complications and incidence of major or life-
threatening bleeding events at 30 days or hospital discharge, whichever is longer, will also 
be compared using the Bayesian version of a comparison of proportions. 
 
4. Incidence of Early safety at 30 days defined as a composite of: 
 
All-cause mortality 
 
All stroke (disabling and non-disabling) 
 
Life-threatening bleeding 
 
Acute kidney injury—Stage 2 or 3 (including renal replacement therapy)  
 
Coronary artery obstruction requiring intervention 
 
Major vascular complication 
 
Valve-related dysfunction requiring repeat procedure (BAV, TAVI, or SAVR) 
 
All-cause death 
Early safety composite endpoint-incidence estimates will be provided for the two treatment 
groups at 30 days.  The statistical method will be the Bayesian version of a comparison of 
proportions. 
 
 

 
 
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5. Incidence of Clinical Efficacy (after 30 days) at 6 months, 12 months, 18 months, 24 
months and annually thereafter up to 5 years. Clinical efficacy defined as a composite of: 
 
All-cause mortality 
 
All stroke (disabling and non-disabling) 
 
Requiring hospitalizations for valve-related symptoms or worsening congestive 
heart failure 
 
NYHA class III or IV 
 
Valve-related dysfunction (mean aortic valve gradient ≥20 mmHg, EOA ≤0.9-1.1 
cm2 and/or DVI<0. 35m/s, AND/OR moderate or severe prosthetic valve 
regurgitation*) 
Clinical efficacy estimates will be provided for the two treatment groups at 6 months, 12 
months, 18 months, 24 months and annually thereafter up to 5 years.  The statistical 
method will be the Bayesian version of a comparison of proportions (with predictions). 
*Refers to VARC-2 definitions 
6. Incidence of Time-Related Safety at 30 days, 6 months, 12 months, 18 months, 24 months 
and annually thereafter up to 5 years. Time-Related Safety defined as a composite of: 
 
Structural valve deterioration: 
o 
Valve-related dysfunction (mean aortic valve gradient ≥20 mmHg, EOA ≤0.9-
1.1 cm2 and/or DVI<0.35m/s, AND/OR moderate or severe prosthetic valve 
regurgitation*) 
o 
Requiring repeat procedure (TAVI or SAVR) 
 
Prosthetic valve endocarditis 
 
Prosthetic valve thrombosis 
 
Thromboembolic events (eg. stroke) 
 
VARC bleeding, unless clearly unrelated to valve therapy (eg. trauma) 
Time related safety composite endpoint-incidence estimates will be provided for the two 
treatment groups at 30 days, 6 months, 12 months, 18 months, 24 months and annually 
thereafter up to 5 years.  The statistical method will be the Bayesian version of a 
comparison of proportions (with predictions). 
*Refers to VARC-2 definitions 
7. Conduction disturbance requiring permanent pacemaker implantation at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years. 
 
The incidence of conduction disturbance requiring permanent pacemaker implantation will 
be provided at 30 days, 6 months, 12 months, 18 months, 24 months, and annually 
thereafter up to 5 years, separately for new onset and pre-existing conduction disturbance.  
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
8. Change in NYHA class from baseline at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
 
For each subject with paired data, the number of classes changed from baseline (-3, -2, -
1, 0, 1, 2, or 3) will be calculated at 30 days, 6 months, 12 months, 18 months, 24 months, 
and annually thereafter up to 5 years. The endpoint will be evaluated between groups 
using a Bayesian version of a t-test. 
9. Change in distance walked during 6-minute walk test (6MWT) from baseline to 30 days, 
baseline to 12 months, and baseline to 24 months. 
All subjects who are able to perform the six-minute walk evaluation at the time of the 
follow-up visit will be included in the analysis. 
  The endpoint will be evaluated using a Bayesian version of a t-test. 
 
 

 
 
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10. Ratio of days alive out of hospital versus total days alive assessed at 12 months and 24 
months follow-up.  
 
The proportion of post procedure days alive out of hospital against total days alive will be 
compared between groups at 12 and 24 months.  The numerator will be the number of 
days alive out of hospital, and the denominator will be the number of post procedure days 
alive as of the last follow-up date.  All hospitalizations will be included in this analysis, 
including hospitalization for device implant.   
      In addition, days alive out of hospital will be compared between groups at 12 months and 
24 months.  
      The endpoint will be evaluated using a Bayesian version of a t-test. 
11. Quality of Life (QoL) change from baseline at 30 days, 3 months, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
 
The Kansas City Cardiomyopathy Questionnaire (KCCQ), SF-36, and EuroQoL (EQ-5D) 
will be assessed at baseline, 30 days, 6 months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years.  SF-36 and EQ-5D will also be assessed at 3 months.  
All subjects completing the questionnaires will be evaluated and the reasons for missing 
data will be provided. 
 
The endpoint will be evaluated using a Bayesian version of a t-test. 
12. Echocardiographic assessment of prosthetic valve performance at discharge, 6 months, 
12 months, 24 months, and annually thereafter up to 5 years using the following 
measures: 
 
transvalvular mean gradient 
 
effective orifice area 
 
degree of prosthetic aortic valve regurgitation (including transvalvular and 
paravalvular) 
The four echocardiographic measurements will be evaluated at discharge, 6 months, 12 
months, 24 months, and annually thereafter up to 5 years.  All implanted subjects 
undergoing echocardiography procedures will be evaluated.   
Continuous measures will be evaluated using a Bayesian version of a two-sample t-test.  
Categorical variables will be evaluated using Bayesian version of a comparison of 
polytomous outcomes.   
Additionally, incidence of moderate/severe aortic insufficiency at discharge will be 
compared between groups using the Bayesian version of a comparison of proportions. 
13. Aortic valve disease related hospitalizations  
 
The number of subjects re-hospitalized after the initial index procedure will be compared 
at 30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 
years.   
 
Incidence of recurrent hospitalization will be provided at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years.  The statistical method will be 
the Bayesian version of a comparison of proportions (with predictions).   
14. Cardiovascular deaths and valve-related deaths 
The number of subjects experiencing cardiovascular deaths and valve-related deaths at 
30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 
years.  Incidences will be compared between groups.  The statistical method will be the 
Bayesian version of a comparison of proportions (with predictions). 
 
 

 
 
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15. Strokes and TIAs 
The number of subjects with strokes (of any severity) and TIAs at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years. A separate analysis 
will be performed for each of the following: 
 
a composite of all strokes and TIAs 
 
disabling strokes only 
 
non-disabling strokes only 
 
TIAs only  
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
Additionally, incidence of all strokes at 30 days or hospital discharge, whichever is longer, 
will be compared between groups using the Bayesian version of a comparison of 
proportions. 
16. Peri-procedural Neurological Injury (Stroke, TIA, Encephalopathy) 
 
For each treatment group, the proportion of subjects with a neurologic injury (stroke, TIA, 
or encephalopathy) at discharge or at 7 days post-index procedure (whichever occurs first) 
will be calculated. The numerator will be the number of subjects with a neurologic injury 
(stroke, TIA, or encephalopathy) at discharge or at 7 days post-index procedure 
(whichever occurs first), and the denominator will be the number of subjects in that 
treatment group. Results will also be presented separately for disabling stroke, non-
disabling stroke, TIA, and encephalopathy.  Proportions will be compared between groups 
using Bayesian version of a comparison of proportions. 
17. Index procedure related MAEs 
 
Index procedure-related MAE events will be summarized and event rates will be provided 
at 30 days.  The numerator will be the number of procedure-related MAE events 
experienced by the end of the 30-day follow-up visit, and the denominator will be the 
number of subjects evaluated at the 30-day follow-up visit (or a later follow-up)  plus the 
number of subjects not evaluated but who experienced a procedure-related MAE event 
prior to the end of the follow-up visit window. 
 
The endpoint is descriptive and no statistical hypothesis test will be performed. 
18. Length of index procedure hospital stay 
 
The length of TAVI or SAVR hospital stay will be summarized for all subjects undergoing a 
trial procedure. 
 
The endpoint will be evaluated between groups using a Bayesian version of a t-test. 
19. Presence of atrial fibrillation at post-procedure, discharge, 30 days, 6 months, 12 months, 
18 months, 24 months, and annually thereafter up to 5 years. 
 
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
 
 

 
 
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C.6.8.2 Secondary Endpoints Assessed for TAVI Only 
The following secondary endpoints will be assessed for the TAVI cohort subjects only: 
20. Device success defined as follows: 
 
Absence of procedural mortality AND 
 
Correct positioning of a single prosthetic heart valve into the proper anatomical 
location AND 
 
Intended performance of the prosthetic heart valve (no prosthesis-patient 
mismatch and mean aortic valve gradient <20 mmHg or peak velocity <3 m/s, 
AND no moderate or severe prosthetic valve regurgitation*) 
o 
Assessed acutely in a resting state, either within 24-48 hours after the 
index procedure or before hospital discharge 
*Refers to VARC-2 definitions 
Device success, as defined above, will be calculated for all subjects undergoing the TAVI 
procedure.   
The endpoint is descriptive and no statistical hypothesis test will be performed. 
21. Procedural success, defined as device success and absence of in-hospital MACCE. 
 
Procedural success, as defined above, will be calculated for all randomized subjects 
undergoing the TAVI procedure.   
 
The endpoint is descriptive and no statistical hypothesis test will be performed. 
22. Evidence of prosthetic valve dysfunction at 30 days, 6 months, 12 months, 24 months, and 
annually thereafter up to 5 years. 
 
The number of subjects with evidence of prosthetic valve dysfunction will be evaluated at 
30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 
years.  Point estimates and 95% BCIs for each time point will be presented using methods 
described below in the Bayesian version of a comparison of proportions (with predictions).   
23. Resheath and Recapture (combined) success rate.  
The success rate will be analyzed for all subjects in whom the resheath or recapture 
feature is attempted. The number and percentage of successful resheath or recapture 
attempts combined will be calculated. Separate resheathing and recapturing success rates 
will also be calculated.  
The endpoint is descriptive and no statistical hypothesis test will be performed.  
 
Rationale for Selection of Trial Endpoints 
C.6.9
Trial endpoints were selected with following considerations: 
 
Clinically relevant and address important safety and performance aspects of the 
investigational TAVI device 
 
Objectively defined and measurable in the majority of subjects  
 
Consistent with current recommendations for endpoints in TAVI clinical studies and 
VARC-2 
 Multiplicity Considerations 
C.6.10
It is recognized that with a multiplicity of tests comes inflation in the chance of a false finding of 
superiority or non-inferiority.  Therefore, for the purpose of seeking approved labeling claims on 
designated secondary objectives, the following standard will be used:  If the primary objective 
demonstrates non-inferiority, claims will be sought for selected secondary non-inferiority and 
superiority objectives and for superiority on the primary objective metric.  These will be tested 
via a hierarchical (sequential) testing order that preserves the overall study-wise type I error rate 
at the level of 0.05, while requiring all non-inferiority tests to meet a nominal type I error rate of 
0.05 and all superiority tests to meet a nominal type I error rate of 0.025. The testing order is 
specified below.  The following objectives are tested in order, and testing continues if and only if 
all previous objectives have met their designated success criterion.   
1.  Primary endpoint (non-inferiority)  

 
 
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2. Transvalvular mean gradient at 12 months (non-inferiority) 
3. Effective orifice area at 12 months (non-inferiority) 
4. Change in NYHA classification from baseline to 12 months (non-inferiority) 
5. Change in KCCQ score from baseline to 30 days (non-inferiority)  
All of the above are non-inferiority tests and are tested with a type I error standard of 0.05.  If all 
of the above tests meet their success criterion, the type I error rate of 0.05 that is passed on 
from the above tests will be split equally (using a Bonferroni justification) between the following 
parallel subfamilies, so that each subfamily is tested using a type I error rate of 0.025: 
Subfamily #1:  Primary endpoint (superiority) 
Subfamily #2:  Secondary (superiority) objectives #5–#18 as enumerated below, 
tested in ordered sequence such that all α is passed on to subsequent tests if a test 
criterion is met, while all testing stops if a test criterion is not met.  This procedure 
controls the type I error rate of this subfamily at the level 0.025. 
 
It is not necessary to “pass” all objectives in one subfamily in order to test the objective(s) in the 
other subfamily. For the purposes of seeking claims, these objectives will only be evaluated 
once, at the same time as non-inferiority of the primary objective is established.  The only 
exception to this is the primary endpoint superiority test, which carries the possibility of a 
delayed determination of superiority (as described in Section 4.2.1) and may thus meet its 
success criterion at a different time. 
 
The remaining secondary objectives may be of interest for scientific or financial reasons but will 
not be the basis for supporting labeling claims; they are thus outside of the hierarchical testing 
procedure. Similarly, for those objectives that test non-inferiority, if non-inferiority is established, 
a test of superiority will also be conducted, but unless specifically itemized in the list, such 
superiority testing is not part of the hierarchical testing procedure; these superiority tests may be 
of interest for scientific or financial reasons but will not be the basis for supporting labeling 
claims. 
 
C.6.10.1 Secondary Endpoints Tested to Support Labeling Claims 
The following secondary endpoints will be tested, in order, to support labeling claims: 
1. Transvalvular mean gradient at 12 months (non-inferiority): TAVI vs. SAVR (secondary 
objective #12). The hypothesis of interest is  
H: µ TAVI < µ SAVR +5 
 
where µ TAVI and µ SAVR denote the average mean gradient from  at 12 months, measured 
in mmHg.  This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.95.   
2. Effective orifice area at 12 months (non-inferiority): TAVI vs. SAVR (secondary objective 
#12).  The hypothesis of interest is  
H: µ TAVI > µ SAVR – 0.1 
 
where µ TAVI and µ SAVR denote the mean effective orifice area at 12 months, measured in 
cm2.  This objective will be evaluated using a Bayesian version of a two-sample t-test (see 
Section C.11). The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.95.   
3. Change in NYHA classification from baseline to 12 months (non-inferiority): TAVI vs. 
SAVR (secondary objective #8).  The hypothesis of interest is  
H: µ TAVI > µ SAVR - 0.375 
 
where µ TAVI and µ SAVR denote the mean number of classification improvements in NYHA 
from baseline to 12 months.  For subjects with NYHA categories at both baseline and 12 

 
 
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month visit, the NYHA classification improvements will be calculated as NYHAbaseline – 
NYHA12month. This objective will be evaluated using a Bayesian version of a two-sample t-
test (see Section C.11). The posterior probability P(H | data) will be calculated and 
compared to a threshold of 0.95.   
4. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 30 
days (non-inferiority): TAVI vs. SAVR (secondary objective #11).  The hypothesis of 
interest is  
H: µ TAVI > µ SAVR -5 
 
where µ TAVI and µ SAVR denote the mean improvements in the KCCQ score from baseline 
to 30 days.  For subjects with KCCQ score at both baseline and 30 days, the improvement 
in KCCQ will be calculated as KCCQ30day – KCCQbaseline.  This objective will be evaluated 
using a Bayesian version of a two-sample t-test (see Section C.11). The posterior 
probability P(H | data) will be calculated and compared to a threshold of 0.95.   
5. Length of index procedure hospital stay after TAVI vs. SAVR (secondary objective #18).  
The hypothesis of interest is  
H: µ TAVI < µ SAVR 
where µ TAVI and µ SAVR denote the mean length of index hospital stay.  This objective will 
be evaluated using a Bayesian version of a two-sample t-test (see Section C.11). The 
posterior probability P(H | data) will be calculated and compared to a threshold of 0.975. 
6. Transvalvular mean gradient at 12 months (superiority): TAVI vs. SAVR (secondary 
objective #12). The hypothesis of interest is  
H: µ TAVI < µ SAVR  
 
where µ TAVI and µ SAVR denote the average mean gradient from  at 12 months, measured 
in mmHg.  This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.975.   
7. Effective orifice area at 12 months (superiority): TAVI vs. SAVR (secondary objective #12).  
The hypothesis of interest is  
H: µ TAVI > µ SAVR  
 
where µ TAVI and µ SAVR denote the mean effective orifice area at 12 months, measured in 
cm2.  This objective will be evaluated using a Bayesian version of a two-sample t-test (see 
Section C.11). The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975.   
8. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 30 
days (superiority): TAVI vs. SAVR (secondary objective #11).  The hypothesis of interest is  
H: µ TAVI > µ SAVR  
 
where µ TAVI and µ SAVR denote the mean improvements in the KCCQ score from baseline 
to 30 days.  For subjects with KCCQ score at both baseline and 30 days, the improvement 
in KCCQ will be calculated as KCCQ30day – KCCQbaseline.  This objective will be evaluated 
using a Bayesian version of a two-sample t-test (see Section C.11). The posterior 
probability P(H | data) will be calculated and compared to a threshold of 0.975.   
 
9. Days alive out of the hospital at 12 months after TAVI vs. SAVR (secondary objective 
#10).  The hypothesis of interest is  
H: µ TAVI > µ SAVR 
where µ TAVI and µ SAVR denote the mean number of days alive out of the hospital at 12 
months.  This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.975. 
10. Days alive out of the hospital at 24 months after TAVI vs. SAVR (secondary objective 
#10).  The hypothesis of interest is  

 
 
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H: µ TAVI > µ SAVR 
where µ TAVI and µ SAVR denote the mean number of days alive out of the hospital at 24 
months.  This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.975. 
 
11. Change in SF-36 Physical Summary Scale from baseline to 3 months: TAVI vs. SAVR 
(secondary objective #11).  The hypothesis of interest is  
H: µ TAVI > µ SAVR 
 
where µ TAVI and µ SAVR denote the mean improvements in the SF-36 Physical Summary 
Scale from baseline to 3 months.  This objective will be evaluated using a Bayesian 
version of a two-sample t-test (see Section C.11). The posterior probability P(H | data) will 
be calculated and compared to a threshold of 0.975.   
12. Change in EQ-5D from baseline to 3 months: TAVI vs. SAVR (secondary objective #11).  
The hypothesis of interest is  
H: µ TAVI > µ SAVR 
 
where µ TAVI and µ SAVR denote the mean improvements in the EQ-5D from baseline to 3 
months. This objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared 
to a threshold of 0.975.   
13. Incidence of MACCE at 30 days or hospital discharge, whichever is longer: TAVI vs. 
SAVR (secondary objective #1).  The hypothesis of interest is  
H:  TAVI <  SAVR 
 
where  TAVI and  SAVR denote the binary rate of MACCE at 30 days or hospital discharge 
(if longer).  The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975.  The statistical method will be the Bayesian version of a comparison of 
proportions (see Section C.11).   
14. Incidence of major vascular complications at 30 days or hospital discharge, whichever is 
longer: TAVI vs. SAVR (secondary objective #3).  The hypothesis of interest is 
H:  TAVI <  SAVR 
where  TAVI and  SAVR denote the binary rate of major vascular complications at 30 days 
or hospital discharge (if longer).  The posterior probability P(H | data) will be calculated 
and compared to a threshold of 0.975. The statistical method will be the Bayesian version 
of a comparison of proportions (see Section C.11).   
15. Incidence of major or life-threatening bleeding event at 30 days or hospital discharge, 
whichever is longer: TAVI vs. SAVR (secondary objective #3).  The hypothesis of interest 
is 
H:  TAVI <  SAVR 
where  TAVI and  SAVR denote the binary rate of major or life-threatening bleeding events 
at 30 days or hospital discharge (if longer).  The posterior probability P(H | data) will be 
calculated and compared to a threshold of 0.975. The statistical method will be the 
Bayesian version of a comparison of proportions (see Section C.11).   
16. Incidence of all strokes at 30 days or hospital discharge, whichever is longer: TAVI vs. 
SAVR (secondary objective #15).  The hypothesis of interest is 
H:  TAVI <  SAVR 
where  TAVI and  SAVR denote the binary rate of strokes at 30 days or hospital discharge (if 
longer).  The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975. The statistical method will be the Bayesian version of a comparison of 
proportions (see Section C.11).   
17. Incidence of moderate/severe aortic insufficiency after TAVI vs. SAVR (secondary 
objective #12).  The hypothesis of interest is 

 
 
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H:  TAVI <  SAVR 
where  TAVI and  SAVR denote the proportion of subjects with moderate/severe aortic 
insufficiency at the discharge echo.  The posterior probability P(H | data) will be calculated 
and compared to a threshold of 0.975. The statistical method will be the Bayesian version 
of a comparison of proportions (see Section C.11).   
18. New pacemaker implant rate for TAVI at 30 days or hospital discharge, whichever is 
longer (secondary objective #7).  The hypothesis of interest is 
H:  TAVI < 30% 
where  TAVI denote the binary rate of new pacemaker implants for TAVI at 30 days or 
hospital the discharge (if longer).  The posterior probability P(H | data) will be calculated 
and compared to a threshold of 0.975. The statistical method will be the Bayesian version 
of a comparison of proportions (see Section C.11).   
Other than the hierarchical testing procedure described above, no further multiplicity 
adjustments will be made in the analyses of the secondary endpoints.  Summary data from other 
secondary objectives, such as device success and procedural success from secondary 
objectives #20 and #21, respectively, may be provided in the device labeling.  However, no 
claims of statistical significance or other statistical inference will be made.   
 Heterogeneity/Poolability 
C.6.11
A poolability analysis among investigational centers, access site (ilio-femoral or non-ilio-
femoral), need for revascularization, and primary baseline demographics will be performed for 
the primary endpoint and will be described in the SAP. In particular, the primary endpoint and 
key secondary endpoints such as MACCE and MAE incidence will be examined for differences 
in outcome between genders, need for revascularization, and between access routes.  
Additionally, tests for these outcomes will be performed to evaluate potential interactions 
between treatment and gender and between treatments and need for revascularization and 
between treatment and access site. 
 Additional Analysis 
C.6.12
C.6.12.1 Pre-Defined Subgroups 
The following sub-groups will be analysed for publication purposes: 
 
Diabetes Mellitus (yes, no) 
 
Age [< 65 years of age (ie. Medicare population), 65-70 years of age, 71-74 years 
of age, 75-79 years of age and >=80 years of age] 
 
Gender (male, female) 
 
STS score 
 
Presence of co-morbidities 
 
Need for coronary revascularization 
A test for interaction between the treatment effect (SAVR versus TAVI) and the subgroup 
variable will be performed. 
These comparisons are not powered, and will be for exploratory purposes only, not to be used 
to support labeling claims.  
C.6.12.2 Analysis of VARC Endpoints and Definitions 
Endpoints 
Device success will be calculated per the definition outlined in O.2 as well as using the VARC-I 
definition, as appropriate. 
Definitions 
Events with definitions modified in revisions to VARC will be analyzed per both the definition 
outlined in O.2 and VARC-I.  Applicable terms include: 
 
Acute Kidney Injury 
 
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 
Death  
 
Device Migration/ Valve Embolism 
 
Device Malplacement 
 
Myocardial Infarction 
 
Prosthetic Valve Dysfunction 
 
Stroke and TIA 
 
Vascular Complications 
 Health-Related Quality of Life (HRQoL) and Treatment Costs 
C.6.13
Health-related quality of life (HRQoL) and treatment costs will be assessed alongside the core 
clinical trial to evaluate the impact of the TAVI and SAVR strategies on a range of relevant 
quality of life (QoL) domains and also to evaluate the cost-effectiveness of the two treatment 
strategies. 
C.6.13.1 Quality of Life 
Health Related Quality of Life (HRQoL) and functional status will be assessed using a 
combination of generic and disease-specific measures selected to cover a broad range of health 
domains that may be affected by severe aortic stenosis disease, its treatment, and its 
complications: the Medical Outcomes Study 36-item Short Form (SF-36), the Kansas City 
Cardiomyopathy Questionnaire (KCCQ), and the EuroQoL Five Dimensions (EQ-5D). All 
patients will complete standardized, written questionnaires at baseline (prior to subject being 
informed of randomization), 30 days, 6 months, 12 months, 18 months, 24 months and annually 
thereafter up to 5 years.  At 3 months subjects will also be contacted via telephone to complete 
the EQ-5D, in select geographies SF-36 will also be collected Additional information regarding 
the HRQoL assessments and administration is located in Appendix R.12 Economic and Quality 
of Life Data Collection. 
C.6.13.2 Economic Outcomes/Cost-Effectiveness 
Data on resource utilization will be collected for the index hospitalization and through long-term 
follow-up for all enrolled subjects.  These resource items will include number and duration in-
patient stays in hospital by type of unit (eg. intensive care, high-dependency care and standard 
ward care); number of clinic visits (by type of physician); and details of the main procedure 
undertaken.  As part of the trial analysis, resource use estimates will be presented by 
randomized group (eg. mean per patient plus standard deviation).  This data, together with the 
EQ-5D data will provide an important input into cost effectiveness analysis.  However, as such 
analysis is likely to be based on a modeling framework, to include evidence from a number of 
sources (eg. a meta-analysis of other TAVI trials) and to vary according to the jurisdiction of 
interest, it is appropriate to detail the methods in separate protocols and analysis plans.  
 Use of Data for CE Mark 
C.6.14
Data from the TAVI arm may be utilized to seek CE Mark approval for the Intermediate Risk 
indication prior to trial completion.  This is expected to include the experience of approximately 
the first 100 TAVI subjects out to 30 days.  This analysis will not impact the Type I error rate of 
this trial as there will not be an early analysis of control (randomized) data, and no decisions to 
alter the pivotal trial are allowed based on this analysis.  This data will not be made public and a 
limited number of personnel will have access to the results. 
 

 
 
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C.7 
Data and Quality Management 
 
Electronic Data Capture 
C.7.1
Medtronic will use the Oracle Clinical Remote Data Capture database system for data collection. 
Oracle is a secure, password-protected, Part 11 compliant database which is backed up 
regularly (at a minimum once daily). 
 
Data Collection 
C.7.2
The investigator must ensure accuracy, completeness and timeliness of the data reported in the 
EDC system and in all other required reports. Data reported on the eCRFs which are derived 
from source documents must be consistent with the source documents or the discrepancies 
need to be justified in a documented rationale, signed and dated by the (principal) investigator, 
to be filed in the subject file. 
Required data will be recorded on the eCRFs by authorized site personnel as indicated on the 
Delegation of Authority Log. The eCRFs must be completed and/or updated to reflect the latest 
observations on the subjects participating in the trial. 
The investigator (or approved sub-investigator) will electronically sign the appropriate pages of 
each eCRF. 
The EDC system maintains an audit trail on entries, changes or corrections in CRFs. If a person 
only authorized to complete CRFs makes changes to an already signed CRF, the investigator 
shall re-sign this CRF. 
The sponsor and/or assigned designee will be responsible for the processing and quality control 
of the data. Data management will be done according to Medtronic SOPs and the applicable 
Data Management Plan. All trial-related documents must be retained for a period of at least 2 
years after the last approval of a marketing application and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational device. Medtronic will 
inform the investigator/institution when these documents are no longer required to be retained. 
No trial document or image should be destroyed without prior written agreement between the 
Sponsor and the investigator. Should the investigator wish to assign the trial records to another 
party or move them to another location, advance written notice should be given to the Sponsor. 
Copies of the eCRFs to be used are included in Appendix R.5. 
 
Core Laboratories Procedures 
C.7.3
Data from the core lab will be transferred to Medtronic and stored in the Oracle Clinical Remote 
Data Capture system as described in the Medtronic CoreValve™ SURTAVI Trial Data 
Management Plan. 
 
Source Documents 
C.7.4
Source documentation is defined as the first time the data appear and may include all clinical 
records, hospital records, surgery reports, autopsy reports, and any other material that contains 
original information used for trial data collection or adverse event reporting.  Where copies of the 
original source document as well as print outs of original electronic source documents are 
retained, these shall be signed and dated by a member of the investigation site team with a 
statement that it is a true reproduction of the original source document.  No eCRFs may serve 
as source documents. 
Source documentation may vary from site to site.  The source documents must be retained by 
the investigational site for a period of 2 years after trial conclusion and made available for 
monitoring or auditing by the sponsor’s representative or representatives of the FDA, IRB/MEC, 
and other applicable regulatory agencies.  The Investigator must ensure the availability of 
source documents from which the information on the eCRFs was derived. 
 
Maintenance and Calibration 
C.7.5
Sites should perform regular maintenance and calibration of all equipment relevant to protocol 
required assessments.  Maintenance and calibration should be conducted per local standards 
and ensure proper documentation must be on file for routine monitoring and audit, as applicable. 

 
 
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C.8 
Records and Reports 
 
Responsibilities of the Sponsor 
C.8.1
The Sponsor must maintain the following records, at a minimum: 
 
All essential correspondence related to the clinical trial 
 
Signed Investigator Agreement 
 
Curriculum vitae for each Investigator 
 
Records of device shipment and disposition (shipping receipts, material destruction 
records, etc.) 
 
Adverse event information  
 
Complaint documentation 
 
All data forms, prepared and signed by the Investigators and received source 
documentation and core lab reports 
 
Protocol and report of prior investigations 
 
Site monitoring reports 
 
Financial disclosure information 
The Sponsor is responsible for the preparation of, the accuracy of the data contained in, the 
review of and the submission of the reports listed in Table 5. 
 
Table 5:  Sponsor Reporting Responsibilities 
Report 
Submit to 
Description 
Unanticipated Adverse 
(Serious) Device Effects 
(UADE or USADE) 
IRB/MEC, 
Investigators, FDA, 
and local regulatory 
agencies, where 
applicable 
Medtronic will report on any confirmed 
unanticipated adverse device effect 
evaluation as soon as possible but no later 
than within 10 working days after first 
receiving notice of the effect. (21 CFR 
812.150) and in compliance with local 
regulatory requirements, as applicable. 
Withdrawal of IRB/MEC 
approval 
IRB/MEC, 
Investigators, FDA, 
and local regulatory 
agencies, where 
applicable 
Notification, when appropriate, will be made 
within 5 working days after Medtronic 
receives notice of withdrawal of IRB/MEC 
approval. 
Withdrawal of FDA  
approval 
IRB/MEC, 
Investigators 
Notification will be made within 5 working 
days after Medtronic receives notice of 
withdrawal of FDA approval. 
Current Investigator List 
FDA and local 
regulatory agencies, 
where applicable 
Medtronic will submit a current list of the 
names and addresses of all participating 
Investigators at six-month intervals, 
beginning six months after FDA approval of 
IDE. 
Progress Report 
IRB/MEC, 
Investigators, FDA 
A progress report will be submitted at least 
yearly. 
Recall and Device 
Disposition 
IRB/MEC, 
Investigators, FDA, 
and local regulatory 
agencies, where 
applicable 
Notification will be made within 30 working 
days of Medtronic’s request that an 
Investigator return, repair or otherwise 
dispose of any devices.  Such notification will 
state why the request was made. 
Final Report 
IRB/MEC, 
Investigators, FDA 
Notification will be made within 30 working 
days of the completion or termination of the 
investigation.  A final report will be submitted 
within six months after trial completion or 
termination. 

 
 
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Report 
Submit to 
Description 
Failure to obtain Informed 
Consent 
FDA 
Notification will be made within 5 working 
days after Medtronic’s receipt of such 
notification indicating Informed Consent was 
not obtained. 
Emergency Deviations from 
Investigational Plan 
FDA and local 
regulatory agencies, 
where applicable 
Notification will be made within 5 working 
days after Medtronic learns of an emergency 
deviation from the Investigational Plan where 
the deviation was made to protect the life or 
physical wellbeing of a subject. 
 
Responsibilities of the Investigator 
C.8.2
The Investigator is responsible for the preparation, review, signature, and retention of the 
records listed below: 
 
All essential correspondence that pertains to the investigation 
 
Device use/disposition records 
 
Records of each subject’s case history and exposure to the device.  Case histories 
include the CRFs and supporting data (source documentation), including, for example: 
o 
Signed and dated consent forms 
o 
Medical records, including, for example, progress notes of the physicians, the 
subject’s hospital chart(s) and the nurses’ notes 
o 
All adverse event information  
o 
A record of the exposure of each subject to the investigational device (eg., date 
of implant procedure and follow-up assessment dates) 
o 
Documentation of any deviation from the protocol, including the date and the 
rationale for such deviation 
 
Screening Logs, Enrollment Logs and Patient Identification Logs 
 
Signed Investigator Agreement, curriculum vitae and training records 
 
Protocol and any amendments 
 
IRB/MEC approval documentation, and where applicable, other local regulatory 
approvals 
The Investigator may withdraw from responsibility to maintain records by transferring custody to 
another person, who will accept responsibility for record and report maintenance. 
The Investigator is responsible for the preparation, review, signature, and submission of the 
reports listed below in.  These are also subject to inspection by government agencies and must 
be retained as specified above.   

 
 
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Table 6:  Investigator Reporting Responsibilities 
Report 
Submitted to 
Description 
Unanticipated Adverse 
(Serious) Device 
Effects (UADE or 
USADE) 
Sponsor, IRB/MEC, 
and local regulatory 
agencies, where 
applicable 
UADEs and USADEs should be reported 
immediately via telephone as well as on an eCRF. 
UADEs and USADEs must be submitted as soon 
as possible, but in no event later than 3 calendar 
days after the Investigator first learns of the effect. 
Serious Adverse 
Events and Deaths 
Sponsor,  and local 
regulatory agencies, 
where applicable 
The Investigator shall notify the sponsor 
immediately (i.e. within 3 calendar days of first 
learning of any SAE) [MEDDEV 2.7/3].  
Withdrawal of IRB/MEC 
approval 
Sponsor 
The Investigator must report a withdrawal of the 
reviewing IRB/MEC, approval within 5 working 
days. 
Progress Report 
Sponsor, IRB/MEC 
The Investigator must submit a progress report on 
an annual basis if the trial lasts longer than one 
year. 
Failure to obtain 
Informed Consent 
Sponsor, IRB/MEC 
The Investigator must make notification within 5 
working days after device implant. 
Final Report 
Sponsor, IRB/MEC 
This report must be submitted within 3 months 
after termination or completion of the 
investigation. 
Deviations from Investigational Plan (CFR 812.150) 
Emergency Use 
Sponsor, IRB/MEC 
Notification must be made within 5 working days 
of the occurrence of an emergency deviation 
made to protect the life or physical well-being of a 
subject. 
Planned deviation 
Sponsor, IRB/MEC, 
FDA 
If the deviation affects scientific soundness of the 
trial or the rights, safety, or welfare of the subject 
and is not an emergency, prior approval must be 
obtained from Medtronic, the reviewing IRB/MEC, 
and FDA. 
Other Deviations 
Sponsor 
Deviations that are beyond the control of the 
investigator (such as patient who fails to return to 
follow-up visit) or deviations that do not affect the 
scientific soundness of the trial or the rights, 
safety, or welfare of the subject and are not an 
emergency, should be submitted as they are 
identified by the site or Medtronic staff. 
 
 

 
 
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D RISK / BENEFIT ANALYSIS 
There are risks for participants in this trial.  However, it should be noted that most of the risks of 
trial participation are not materially different than those entailed by an individual who undergoes 
the same treatment outside of the context of this trial. 
Known adverse events that may result from TAVI  include but may not be limited to:  
 
Death 
 
Cardiac arrest 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary closure) 
 
Emergent surgery (eg., coronary artery bypass, heart valve replacement, valve explant) 
 
Multi-organ failure 
 
Heart failure 
 
Myocardial infarction 
 
Cardiogenic shock 
 
Respiratory insufficiency or respiratory failure 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, ventricle, 
myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel 
 
Ascending aorta trauma 
 
Cardiac tamponade 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture 
o 
Bending (out-of-round configuration) of the valve frame 
o 
Under-expansion of the valve frame 
o 
Calcification 
o 
Pannus, (wear, tear, prolapse, or retraction in the valve leaflets) 
o 
Poor valve coaptation 
o 
Suture breaks or disruption 
o 
Leaks 
o 
Mal-sizing (prosthesis-patient mismatch) 
o 
Malposition (either too high or too low)/malplacement 
o 
Regurgitation, stenosis 
 
Thrombosis/embolus (including valve thrombosis) 
 
Valve migration/valve embolization 
 
Ancillary device embolization 
 
Emergent percutaneous coronary intervention (PCI) 
 
Emergent balloon valvuloplasty 
 
Major or minor bleeding that may or may not require transfusion or intervention 
(including life-threatening or disabling bleeding) 
 
Allergic reaction to antiplatelet agents, contrast medium, or anesthesia 
 
Infection (including septicemia and endocarditis) 
 
Stroke, TIA, or other neurological deficits 
 
Permanent disability 
 
Renal insufficiency or renal failure (including acute kidney injury) 
 
Mitral valve regurgitation or injury 
 
Tissue erosion 
 
Vascular access related complications (eg., dissection, perforation, pain, bleeding, 
hematoma, pseudoaneurysm, irreversible nerve injury, compartment syndrome, 
arteriovenous fistula, stenosis) 
 
Conduction system disturbances (eg., atrioventricular node block, left-bundle branch 
block, asystole), which may require a permanent pacemaker 
 
Cardiac arrhythmias 

 
 
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 
Encephalopathy 
 
Pulmonary edema 
 
Pericardial effusion 
 
Pleural effusion 
 
Myocardial ischemia 
 
Peripheral ischemia 
 
Bowel ischemia 
 
Heart murmur 
 
Hemolysis 
 
Cerebral infarction-asymptomatic 
 
Non-emergent reoperation 
 
Inflammation 
 
Fever 
 
Hypotension or hypertension 
 
Syncope 
 
Dyspnea 
 
Anemia 
 
Angina 
 
Abnormal lab values (including electrolyte imbalance) 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the aortic 
valve and prolonged procedural time 
Additional information regarding risk analysis is located in the Investigator Brochures (Appendix 
R.21). 
D.1 
Methods to Minimize Risk 
The investigational plan is specifically designed to manage and minimize risks through careful 
patient selection, thorough training of investigators, adherence to the pre-determined time points 
to assess subject clinical status and regular clinical monitoring visits by Sponsor appointed 
monitoring personnel.  
In addition, an independent Data Safety Monitoring Board will monitor safety of the subjects 
throughout the trial. 
D.2 
Potential Benefits 
Patients treated with TAVI may experience improvement in quality of life, morbidity and mortality 
compared to traditional open-heart aortic valve replacement. Potential benefits include, but are 
not limited to, absence of open-heart surgery-related risks, reduced procedure time, reduced 
anesthesia procedure time, shorter hospital stay and earlier return to normal activities than after 
open-heart aortic valve replacement. 
There is no direct benefit associated to participation in this trial, but the information obtained 
during this trial will be used scientifically. The results of this trial can help physicians understand 
the implications of transcatheter treatment of patients with intermediate risk for surgery. 

 
 
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E DESCRIPTION OF MEDTRONIC COREVALVE™ SYSTEM 
E.1 
Investigational Product Description 
 
Medtronic CoreValve System 
E.1.1
The Medtronic CoreValve™ System (MCS) consists of 3 components: the Transcatheter Aortic 
Valve Bioprosthesis (TAV) in  
Figure 2 below, the Delivery Catheter System (DCS) in Figure 3 and Figure 4, and the 
Compression Loading System (CLS) in Figure 5 and Figure 6. 
Transcatheter Aortic Valve Bioprosthesis 
Figure 2:  Transcatheter Aortic Valve (TAV) 
 
The TAV is manufactured by suturing valve leaflets and a skirt, made from a single layer of 
porcine pericardium, into a tri-leaflet configuration. The TAV is designed to replace the native 
aortic heart valve without open heart surgery and without concomitant surgical removal of the 
failed native valve. 
The bioprosthesis is processed with an antimineralization treatment of alpha-amino oleic acid 
(AOA) a compound derived from oleic acid, a naturally occurring long-chain fatty acid. 
The self-expanding multi-level frame is made of Nitinol and is radiopaque. 
The TAV is available for a range of aortic annulus and ascending aortic diameters as shown in 
Table 7 below. 
Table 7:  Medtronic CoreValve System Patient Anatomical Diameters 
CoreValve™ Evolut™ Bioprosthesis 
Model 
Size (mm) 
Aortic Annulus 
Diameter 
(range in mm) 
Ascending Aortic 
Diameter (mm) 
MCS-P4-23-AOA 
MCS-P4-23-AOA-US 
23 
18-20 
≤34 
CoreValve™ Bioprosthesis 
Model 
Size (mm) 
Aortic Annulus 
Diameter 
(range in mm) 
Ascending Aortic 
Diameter (mm) 
MCS-P3-26-AOA 
MCS-P3-26-AOA-US 
26 
20-23 
≤40 
MCS-P3-29-AOA 
MCS-P3-29-AOA-US 
29 
23-27 
≤43 

 
 
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MCS-P3-31-AOA 
MCS-P3-31-AOA-US 
31 
26-29  
≤43 

 
 
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Delivery Catheter System 
The AccuTrak® DCS (DCS-C4-18FR and DCS-C4-18FR-US) is compatible with a 0.889-mm 
(0.035-in) guidewire. The working length of the AccuTrak® DCS is 112.5 cm. It incorporates a 
protective deployment sheath that houses and deploys the TAV. The AccuTrak® DCS can be 
used to house and deliver all commercially available sizes of the TAV (26mm, 29mm, and 31mm 
TAV). The outer diameter of the DCS is 12Fr, the stability layer is 15Fr and the outer diameter of 
the valve capsule is 18 Fr. 
Figure 3:  Delivery Catheter System (DCS) 
 
 
A new Delivery Catheter System (DCS-C4-18FR-23MM and DCS-C4-18F-23US) will be used to 
deploy 23mm Transcatheter Aortic Valve (TAV). The DCS-C4-18FR-23MM and DCS-C4-18FR-
23 and  DCS-C4-18FR- has a shortened Capsule and Plunger (5mm) for delivery of the 23mm 
TAV but the working length of the new AccuTrak™ DCS is 112.5 cm similar to DCS-C4-18FR 
used to deploy other TAV sizes. 
Figure 4:  Design Changes for Delivery Catheter System (DCS) specific to 23mm 
 
 
The AccuTrak® DCS features an integrated handle designed to provide the user with accurate 
and controlled deployment.  After the DCS is placed in the vicinity of the aortic annulus, the user 
retracts the deployment sheath, thereby deploying the TAV to the desired location.  In use, the 
deployment sheath can be partially pulled back to evaluate the TAV location prior to fully 
releasing the TAV. In this way, the user can make slight adjustments to the TAV location if 
needed prior to release.  
 
 

 
 
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Compression Loading Systems  
The CLS (Model CLS-3000-18FR and CLS-3000-18FR-US) and next generation CLS (Model 
CLS4-18F and Model CLS4-18F-23) is a system of reduction cones and tubing, which is 
designed to gradually reduce the diameter of the TAV to an optimal diameter to facilitate manual 
loading of the TAV into the deployment sheath capsule of the DCS.  
The CLS is comprised of the following elements: 
 
inflow cone 
 
inflow tube (straight tube) 
 
outflow cap 
 
outflow cone 
 
outflow tube (tube with flared ends) 
  
Figure 5:  Compression Loading System (CLS) (Model CLS-3000-18 FR and CLS-3000-
18FR-US) 
 
 
Figure 6: Compression Loading System (CLS) Models CLS4-18F-C and CLS-3000-18FR-
US (left) and CLS4-18F-23-C (right) 
 
 
 
The inflow cone, outflow cone, and outflow cap components of the next generation CLS models 
are tinted, and the locking mechanism has been modified from the previous generation. The 
purpose and function of all CLS models is the same, but the next generation includes 2 models, 
one intended for use with the 23mm TAV (CLS4-18F-23-C), which has an orange tint, and 
another model intended for 26 mm, 29 mm & 31mm TAVs (CLS4-18F-C and CLS-3000-18FR-
US), which has a blue tint. 
 
 

 
 
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E.2 
Investigational Device Ordering, Storage, and Disposition 
The TAV and all required delivery components will be ordered through Medtronic. Medtronic will 
only allow shipment of investigational devices to the hospital or investigator when the Clinical 
Research Specialist has declared the investigation site ready to start the trial.   
Devices will be shipped to sites as needed based on subject enrollment/randomization and 
procedures scheduled.  Only one device should be used per patient, unless in case of device 
malfunctions or in case of complications. Sites will be supplied with sufficient device stock to 
complete scheduled procedures.  Upon completion of scheduled procedures all unused devices 
must be returned to Medtronic.  Instructions for device return are outlined on the Device 
Accountability Log. In the US, commercial devices, as referenced in Table 1, are approved for 
use in the clinical trial, as necessary, in the event that an investigational device is not available. 
Investigational devices must be stored in a secured area. The method of storage shall prevent 
the use of investigational devices outside the applications as mentioned in this Clinical 
Investigation Plan. In addition, all information for the use, storage and handling of the 
investigational device as indicated in the Investigator’s Brochure, must be taken into account. 
Instructions for Use and storage recommendations are outlined in Appendix R.22. 
F MONITORING AND AUDITING 
F.1 
Monitoring 
The investigational site will be monitored to ensure compliance with the trial protocol, adherence 
to applicable regulations, and accuracy of trial data.  Monitoring visits will be conducted primarily 
to ensure the safety and wellbeing of the subjects is preserved.  Monitoring visits will also be 
used to verify that trial data submitted on case report forms are complete and accurate with 
respect to the subject records and to verify device accountability.   
The Investigator(s), his/her delegate(s) and the study coordinator(s) shall be accessible to 
during monitoring. Accessibility is of particular importance for reviewing data in the eCRF.  
Site personnel will complete eCRFs following each subject visit.  Trial data submitted will be 
reviewed against patient charts and other sources containing original records of patient data.  
Source document verification will be conducted via a risk based approach as outlined in the 
Monitoring Plan. 
The responsible individual for this trial is included on the title page of the CIP. 
The progress of the trial will be monitored by: 
 
On-site review, as deemed appropriate by the sponsor 
 
Telephone communications between the site personnel (eg., Investigator, Trial 
Coordinator) and trial monitors 
 
Review of eCRFs and the associated clinical records 
 
Review of regulatory documents 
Upon trial completion Site Closeout Visits will be conducted, as outlined in the Monitoring Plan. 
Monitoring and monitoring oversight will be provided by Medtronic Coronary and Structural 
Heart (Mounds View, MN, USA, and Maastricht, the Netherlands).  Representatives of 
Medtronic (i.e. contractors and designees) may also act as the trial monitors to the site.  
Medtronic will maintain an updated list of applicable representative and provide a copy to sites 
upon request. 
Prior to the first site activation a monitoring plan will be established outlining the above activities, 
as well as trial materials to be supplied to sites, the process for corrective and preventive actions 
and Investigator disqualification procedures. 
F.2 
Auditing 
Medtronic may conduct audits at participating clinical sites. The purpose of an audit is to verify 
the performance of the monitoring process and the trial conduct, independently of the personnel 
directly involved in the trial. Regulatory bodies, such as the Food and Drug Administration, may 

 
 
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also perform inspections at participating sites. The investigator and/or institution shall permit 
Medtronic and regulatory bodies direct access to source data and documents. 

 
 
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G LABELING 
In Europe, the TAV component labeling will not carry the CE mark and the labeling will state for 
“clinical study purposes only” in accordance with ISO14155. The Investigational Instructions for 
Use (IFU) and labeling is supplied in English (and the local language, if required) with the TAV 
component and this will also not carry the CE mark.  The DCS and CLS components are 
identical to the CE marked CoreValve System and will be supplied with the approved 
commercial CE marked labeling. 
In the United States and other geographies, where TAV is not currently approved, the TAV, DCS 
and CLS will be labeled as Investigational. 
Instructions for Use and additional labeling are attached in Appendix R.22. 
H CONSENT MATERIALS 
The template consents for the trial are attached in Appendix R.1. 
I 
IRB/MEC INFORMATION 
IRB/MEC information is attached in Appendix R.2. 
J 
OTHER INSTITUTIONS 
Information regarding other institutions involved in this trial is located in Appendix R.3. 
K ADDITIONAL RECORDS AND REPORTS 
Information regarding additional Records and Reports can be in found in Appendix R.4. 
L REPORT OF PRIOR INVESTIGATIONS 
The Report of Prior Investigations (RPI) is attached in the Investigator Brochure in Appendix 
R.21. 

 
 
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M PUBLICATION POLICY 
Medtronic, as the Sponsor of this trial, recognizing the seminal importance of this investigation, 
is committed to the widespread dissemination of all primary and secondary endpoint results.  A 
publication plan will be implemented and followed.  At the conclusion of the trial, a multisite 
abstract reporting the primary results will be prepared by the Principal Investigators (in 
collaboration with others including but not limited to the Steering Committee, directors of the 
core laboratories, CEC, and Lead Investigators from high enrolling sites) and presented at an 
annual scientific meeting (eg., Transcatheter Cardiovascular Therapeutics, EuroPCR, the 
American Heart Association, or the American College of Cardiology).  A multisite publication will 
similarly be prepared for publication in a reputable scientific journal.  The publication of the 
principal results from any single site experience within the trial is not allowed until both the 
preparation and publication of the multisite results, and then only with written permission from 
Medtronic.  
Following analysis and presentation of the primary endpoint results, active participation of all 
committee members, Investigators from high enrolling sites, and core laboratory personnel will 
be solicited for data analysis and abstract and manuscript preparation.  Submission of all 
abstracts and publications regarding the primary endpoint and secondary endpoints from the 
trial requires approval by Medtronic and the Publications Committee. 
A separate publication plan will provide detailed information about the publication committee, 
authorship, publication proposals, and requests for data. 

 
 
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N AMENDMENTS TO THE CLINICAL INVESTIGATION PLAN 
All amendments to the CIP shall be agreed between the sponsor and the clinical investigator(s).   
The investigator may propose appropriate modification(s) of the Clinical Investigation Plan or 
investigational device or investigational device use. Medtronic will review this proposal and 
decide whether the modification(s) will be implemented.  
Medtronic will submit any significant amendment to the Clinical Investigation Plan, including a 
justification for this amendment, to the appropriate regulatory authorities and to the investigators 
to obtain approval from their IRB/MEC. The investigator will only implement the amendment 
after approval of the IRB/MEC, regulatory authority and sponsor. 
Amendments will be recorded with a justification for the amendments in Table 8 below: 
 
Table 8:  Clinical Investigation Plan Change History 
Version 
Description of Change 
Rationale for Change 
3.0 
Initial Release 
NA 
4.0 
 Inclusion/Exclusion Criteria updated 
 Device status updates: 
o Addition of 23mm PAV and 
applicable DCS 
o AOA CE mark status 
 Modification of statistical methods to 
relative risk design and addition of 
adaptive trial design 
 Addition of Canada as a participating 
geography 
 Appendix updates: 
o Informed Consent templates 
o Clinical Assessments 
o Investigator Brochure 
o Instructions For Use 
o Radiation Exposure and Data 
Collection 
 Changes based on FDA pre-IDE 
feedback 
 Device status updates: 
o 23mm PAV and applicable 
DCS CE mark approval 
o AOA CE mark approval 
5.0 
 Stroke classifications changed from 
major vs. minor to disabling vs. non-
disabling 
 Inclusion/Exclusion Criteria updated 
 Additional neurological testing added 
(mRS) 
 Clarification of local Heart Team 
composition and decision making 
 Appendix updates: 
o CMS Requirements for Coverage 
and Reimbursement – US ONLY 
– added
 Changes based on FDA IDE 
deficiencies 
 General updates and corrections 
6.0 
 Device status update – Canadian 
approval 
 Total number of investigational 
centers increased 
 Inclusion criteria #3 updated 
 Roll-in subjects added 
 Definitions of terms updated in 
alignment with VARC-2 
 Appendix updates: 
o Informed Consent templates 
o Echocardiography Acquisition 
Guidelines 
 Changes based on FDA 
recommendations 
 Publication of VARC-2 
 General updates and corrections 

 
 
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Version 
Description of Change 
Rationale for Change 
o Aortogram Acquisition Guidelines 
7.0   
OBSOLETED prior to 
distribution 
 Device Description updated to include 
EnVeo™ DCS and next generation 
CLS 
 FDA IDE supplement to 
incorporate EnVeo/G5 and the 
next generation CLS in the 
United States 
8.0 
 Modification to Patient Population (re-
defined Intermediate Risk) 
 Inclusion / Exclusion modifications 
and clarifications 
 Clarification of adverse event 
reporting requirements 
 All references to Percutaneous Aortic 
Valve (PAV) updated to Transcatheter 
Aortic Valve (TAV) 
 Addition of the next regeneration 
Compression Loading Systems 
 Appendix updates: 
o Informed Consent templates 
o Instructions for Use 
o Investigator Brochure 
o Echocardiography Acquisition 
Guidelines 
o Electrocardiogram (ECG) 
Submission 
 General updates and corrections 
 Updated trial utilization of core 
laboratories 
8.1 
 Inclusion criteria clarification 
 Updated to include upper limit of 
risk classification 
9.0 
 All references to Cardiovascular 
Department updated to Coronary and 
Structural Heart 
 All references to MCS TAVI updated 
to TAVI 
 Appendix updates: 
o Informed Consent templates 
o Other Institutions 
o Instruction for Use 
o Investigator Brochure 
 General updates and corrections 
 Updated change to Imaging Core 
Lab 
10.0 
 Updated Device Approval Status 
 Statistical Methods and Analysis: 
o Updated assumed event rates 
o Modified non-inferiority margin 
o Updated sample size look  
 Updated maximum sample 
size from 3700 to 2000 
 Appendix updates: 
o Informed consent templates 
 General updates and corrections 
 Updated Statistical Methods and 
Analysis per agreement from 
FDA 
11.1 
OBSOLETED prior to 
distribution 
 Updated Device Approval Status 
 Removed AR/AS/MR as SAEs in 
absence of clinical symptoms 
 Statistical Methods and Analysis 
 General updates and corrections 
 Updated Statistical Methods and 
Analysis per agreement from 
FDA 
12.1 
 Update Device Description 
 Removed moderate or severe mitral 
or aortic regurgitation or stenosis as a 
default  SAEs in absence of clinical 
symptoms 
 Added section about Vigilance 
Reporting 
 Investigational Device Accountability 
 Statistical Methods and Analysis 
 Appendix updates: 
o Informed consent templates 
 General updates and corrections 
 Updated Statistical Methods and 
Analysis  
 
 
 

 
 
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O ABBREVIATIONS AND DEFINITIONS 
O.1 
List of Abbreviations 
Please refer to Table 9 below for a list of abbreviations for use in the SURTAVI trial. 
Table 9:  List of Abbreviations 
Abbreviation 
Term 
2D 
Two Dimensional 
6MWT 
Six Minute Walk Test 
AE 
Adverse Event 
ACT 
Active Clotting Time 
ADE 
Adverse Device Effect 
AF 
Atrial Fibrillation 
AOA 
Alpha-amino Oleic Acid 
aPTT 
Activated Partial Thromboplastin Time 
AR 
Aortic Regurgitation 
AS 
Aortic Stenosis 
AVR 
Aortic Valve Replacement 
BAV 
Balloon Aortic Valvuloplasty 
BNP 
B-type Natriuretic Peptide 
BPM 
Beats Per Minute 
BP 
Blood Pressure 
BSA 
Body Surface Area 
CA 
Competent Authority 
CE 
European Conformity 
CEC 
Clinical Events Committee 
CFR 
U.S. Code of Federal Regulations 
CIP 
Clinical Investigation Plan 
CLS 
Compression Loading System 
CMS 
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CT 
Computed Tomography 
CTA 
Computerized tomographic angiography 
CVA 
Cerebrovascular Accident 
CV-ICU 
Cardiovascular Intensive Care Unit 
DCS 
Delivery Catheter System 
DHCA 
Deep Hypothermic Circulatory Arrest 
DSMB 
Data Safety Monitoring Board 
DVI 
Doppler Velocity Index 

 
 
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Abbreviation 
Term 
DVT 
Deep Vein Thrombosis 
ECC 
Extracorporeal Circulation 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EOA 
Effective Orifice Area 
EQ-5D 
EuroQoL Five Dimensions 
EuroSCORE 
European System for Cardiac Operative Risk Evaluation 
FDA 
U.S. Food and Drug Administration 
Fr 
French 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
HVD 
Heart Valve Dysfunction 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart Rate 
IABP 
Intra-Aortic Balloon Pump 
ICF 
Informed Consent Form 
IDE 
Investigational Device Exemption 
IFU 
Instructions for use 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
Intravenous 
IXRS 
Interactive Voice/Web Response System 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
LA 
Left Atrial/Atrium 
LAO 
Left Anterior Oblique 
LBBB 
Left Bundle Branch Block 
LMWH 
Low Molecular Weight Heparin 
LVEF 
Left Ventricular Ejection Fraction 
LVOT 
Left Ventricular Outflow Tract 
LVOTO 
Left Ventricular Outflow Tract Occlusion 
MACCE 
Major Adverse Cardiovascular and Cerebrovascular Event 
MAE 
Major Adverse Event 
MCS 
Medtronic CoreValve™ System 
MEC 
Medical Ethics Committee 
MI 
Myocardial Infarction 
MMSE-2:SV 
Mini Mental State Exam 

 
 
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Abbreviation 
Term 
NIHSS 
National Institute of Health Stroke Scale 
mRS 
Modified Rankin Score 
NYHA 
New York Heart Association 
PCI 
Percutaneous Coronary Intervention 
PE 
Product Experience 
PPM 
Patient Prosthesis Mismatch 
QoL 
Quality of Life 
RAO 
Right Anterior Oblique 
RBBB 
Right Bundle Branch Block 
SAE 
Serious Adverse Event 
SADE 
Serious Adverse Device Effect 
SAP 
Statistical Analysis Plan 
SAVR 
Surgical Aortic Valve Replacement 
SF-36 
Short Form (36) Health Survey 
SOP 
Standard Operating Procedures 
STS 
Society of Thoracic Surgeons 
TAV 
Transcatheter Aortic Valve 
TAVI 
Transcatheter Aortic Valve Implant 
TEE 
Transesophageal Echocardiography 
TIA 
Transient Ischemic Attack 
TTE 
Transthoracic Echocardiography 
UADE 
Unanticipated Adverse Device Effect 
USADE 
Unanticipated Serious Adverse Device Effect 
 

 
 
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O.2 
Definitions of Terms 
ACUTE KIDNEY INJURY 
 Acute Kidney Injury will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Acute Kidney Injury (AKIN Classification)  
Stages 
Change in Serum Creatinine (up to 7 days post-index procedure) 
compared to Baseline 
Stage 1 
Increase in serum creatinine to 150-199% (1.5-1.9 x increase compared with 
baseline) OR increase of ≥ 0.3 mg/dl (≥26.4 µmol/L) OR urine output <0.5 
ml/kg/hour for >6 but <12 hours 
Stage 2* 
Increase in serum creatinine to 200-299% (> 2.0-2.9 x increase compared 
with baseline) OR urine output <0.5 ml/kg/hour for >12 but <24 hours 
Stage 3*/** 
Increase in serum creatinine to ≥300% (> 3 x increase compared with 
baseline) OR serum creatinine of > 4.0 mg/d (≥354 µmol/L) with an acute 
increase of at least 0.5 mg/dl (44 µmol/L) OR urine output <0.3 ml/kg/hour for 
>24 hours OR anuria for > 12 hours 
*  Stage 2 and 3 acute renal injuries will be considered to be serious adverse events. 
** Patients receiving renal replacement therapy are considered to meet Stage 3 criteria 
irrespective of other criteria 
ACUTE VESSEL OCCLUSION  
 The state of complete luminal obstruction with no antegrade blood flow. 
 ADVERSE EVENT (AE)  
An adverse event is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the investigational medical device.  
NOTE 1: This definition includes events related to the investigational medical device or the comparator. 
NOTE 2: This definition includes events related to the procedures involved. 
NOTE 3: For users or other persons, this definition is restricted to events related to investigational medical devices. 
 ADVERSE DEVICE EFFECT (ADE)  
Adverse event related to the use of an investigational medical device 
 
NOTE 1: This definition includes adverse events resulting from insufficient or inadequate instructions for use, 
deployment, implantation, installation, or operation, or any malfunction of the investigational medical device. 
NOTE 2: This definition includes any event resulting from use error or from intentional misuse of the investigational 
medical device 
 AORTIC DISSECTION 
Intimal tear resulting in blood splitting the aortic media and producing a false lumen that can 
progress in an antegrade or retrograde direction. Aortic dissection is further classified using 
Stanford classification (Types A and B) depending on whether ascending or descending aorta 
involved) or DeBakey classification (Types I, II and III) as shown below.  
 
 
 

 
 
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AORTIC REGURGITATION (AR) 
Aortic valve incompetence resulting in backward flow of blood. Reference Appendix R.7 
Echocardiography Acquisition Guidelines for additional information regarding assessment of 
aortic regurgitation. 
 
AORTIC STENOSIS (AS)  
A narrowing, stiffening or stricture of the aortic valve.  
Aortic stenosis of the native valve (i.e. inclusion criteria) will be defined based on the 2008 Focused Update Incorporated 
Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease (published in the 
October 2008 issues of Journal of the American College of Cardiology and Circulation) 
 
Aortic Stenosis 
Indicator 
Mild  
Moderate 
Severe 
Jet velocity (m/s) 
Less than 3.0 
3.0-4.0 
Greater than 4.0 
Mean gradient (mmHg) 
Less than 25 
25-40 
Greater than 40 
Valve area (cm2) 
Greater than 1.5 
1.0-1.5 
Less than 1.0 
Valve area index (cm2/m2) 
 
 
Less than 0.6 
 
Stenosis of trial valve will be defined based on the definition of the Valve Academic Research 
Consortium (VARC)-2 Updated Standardized Endpoint Definitions for Consensus Report for 
Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09.  See Prosthetic Valve 
Dysfunction – Prosthetic Aortic Valve Stenosis. 
ARRHYTHMIA 
Any variation from the normal rhythm of the heartbeat, including sinus arrhythmia, premature 
beat, heart block, atrial fibrillation, atrial flutter and tachycardia.  
 Major Arrhythmias: Complete heart block, ventricular tachycardia and ventricular fibrillation 
 Serious Arrhythmias: Any arrhythmia requiring surgical or invasive intervention or DC 
cardioversion 
ATRIAL FIBRILLATION 
Atrial fibrillation will be classified according to the International Consensus on Nomenclature and Classification of Atrial 
Fibrillation; A Collaborative Project of the Working Group on Arrhythmias and the Working Group on Cardiac Pacing of 
the European Society of Cardiology and the North American Society of Pacing and Electrophysiology, Europace 2003, 
Vol 5. 
 Paroxysmal: spontaneous termination within 7 days and most often <48 hours 
 Persistent:  is not self-terminating; lasts longer than 7 days; or prior cardioversion 
 Permanent (accepted):  does not terminate, or terminated but relapsed; no cardioversion 
attempt 
 
 

 
 
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BLEEDING EVENT 
Bleeding event will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Life-threatening or Disabling Bleeding 
 Fatal bleeding (BARC  type 5) OR 
 Bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, or 
pericardial necessitating pericardiocentesis, or intramuscular with compartment 
syndrome (BARC type 3b) OR  
 Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or 
surgery OR 
 Overt source of bleeding with drop in hemoglobin of ≥5 g/dL or whole blood or packed 
red blood cells (RBC) transfusion ≥4 units* (BARC type 3b) 
Major Bleeding  
(BARC type 3a) 
 Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0g/dL or 
requiring transfusion of 2-3 units of whole blood/RBC, or causing hospitalization or 
permanent injury or requiring surgery AND  
 Does not meet criteria of life-threatening or disabling bleeding  
Minor Bleeding  
(BARC type 2 or 3a, depending on severity) 
 Any bleeding worthy of clinical mention (eg. access site hematoma) that does not qualify 
as life-threatening, disabling or major  
*  Given one unit of packed RBC typically will raise blood hemoglobin concentration by 1g/dL, an estimated 
decrease in hemoglobin will be calculated. 
BARC = Bleeding Academic Research Consortium
Life-threatening and Major bleeding events are considered to be serious. 
BUNDLE BRANCH BLOCK 
ACC/AHA/HRS 2006 Key Data Elements and Definitions for Electrophysiological Studies and Procedures; A Report of 
the American College of Cardiology/ American Heart Association Task Force on Clinical Data Standards 
(ACC/AHA/HRS Writing Committee to Develop Data Standards on Electrophysiology), JACC, Vol. 48, No. 11, 2006. 
Left Bundle Branch Block (LBBB) 
 
QRS duration 120 ms or longer 
 
Delayed onset of intrinsicoid deflection in 1, V5, and V6 _60 ms 
 
Broad and notched or slurred R waves in I, aVL, V5, and V6 
 
rS or QS complexes in right precordial leads 
 
ST-segment and T waves in opposite polarity to the major QRS deflection 
Right Bundle Branch Block (RBBB) 
 
QRS duration _120 ms 
 
rsR= or rSR= complexes in V1 and V2 
 
Delayed onset of intrinsicoid deflection in V1 and V2 _50 ms 
 
Broad, slurred S wave in 1, V5, 
Any new or worsening LBBB or RBBB that requires the placement of a permanent pacemaker 
and/or other surgical or invasive intervention will be considered to be serious. 
 
 

 
 
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CARDIAC PERFORATION 
A laceration or tearing of the walls of the ventricles or atria of the heart, of the interatrial or 
interventricular septum, of the papillary muscles or chordae tendineae or of the one of the valves 
of the heart. 
Cardiac perforation events will be classified into additional subgroups according to the Valve Academic Research 
Consortium (VARC)-2; Updated Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 
2012-10-09 
Mitral valve apparatus damage or dysfunction 
Angiographic or echocardiographic evidence of new damage (chordae papillary muscle, or to the 
leaflet) to the mitral valve apparatus or dysfunction (eg. opening restrictions due to the THV) of 
the mitral valve during or after the TAVI procedure.  
Ventricular septal perforation 
Angiographic or echocardiographic evidence of a new septal perforation during or after the TAVI 
procedure.  
CARDIAC TAMPONADE 
Clinical syndrome caused by the accumulation of fluid in the pericardial space, resulting in 
reduced ventricular filling and subsequent hemodynamic compromise. 
CARDIOGENIC SHOCK 
Patient was, at the time of procedure, in a clinical state of hypoperfusion sustained for greater 
than 30 minutes, according to either of the following criteria:  
1. Systolic BP < 80 and/or Cardiac Index < 1.8 despite maximal treatment; or 
2. IV inotropes and/or IABP necessary to maintain Systolic BP > 80 and/or CI > 1.8 
 
CHRONIC RENAL INSUFFICIENCY 
Kidney damage or glomerular filtration rate (GFR) <60 mL/min/1.73 m2 for or ≥3 months.  Kidney 
damage is defined as pathologic abnormalities or markers of damage, including abnormalities in 
blood or urine test or imaging studies. 
CONDUCTION DISTURBANCE REQUIRING PERMANENT PACEMAKER IMPLANTATION 
ACC/AHA 2006 Guidelines for the Management of Patients with Valvular Heart Disease (published in the August 1, 
2006, issues of Journal of the American College of Cardiology and Circulation) 
Any disturbance in the cardiac electrical conduction system that meets the American College of 
Cardiology (ACC)/American Heart Association (AHA)/ Heart Rhythm Society (HRS) Class I or IIa 
Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities for Acquired 
Atrioventricular Block in Adults or Permanent Pacing in Chronic Bifascicular Block. 
CONVERSION TO OPEN HEART SURGERY 
Valve Academic Research Consortium (VARC)-2; Updated Standardized Endpoint Definitions for Transcatheter Aortic 
Valve Implantation (TAVI); 2012-10-09. 
Conversion to open sternotomy during the TAVI procedure secondary to any procedure-related 
complications. 
CORONARY OBSTRUCTION 
Valve Academic Research Consortium (VARC)-2; Updated Standardized Endpoint Definitions for Transcatheter Aortic 
Valve Implantation (TAVI); 2012-10-09. 
Angiographic or echocardiographic evidence of a new, partial or complete, obstruction of a 
coronary ostium, either by the valve prosthesis itself, the native leaflets, calcifications, or 
dissection, occurring during or after the TAVI procedure. 
DEVICE DEFICIENCY 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, safety or 
performance 
  
NOTE:  Device deficiencies include malfunctions, use errors, and inadequate labeling. 
 

 
 
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DEVICE RELATED  
Events that occur as the direct result of the Medtronic CoreValve™ System (MCS) as it relates to 
delivery, placement, efficacy or durability; these may involve the implanted device or the delivery 
system components. 
DEVICE RELATED COMPLICATIONS 
Complications associated with the device as it relates to delivery, placement, efficacy or 
durability; these may involve the implanted device or the delivery system.   
EMBOLISM 
Free flowing blood clot or lesion material that is located in the systemic or pulmonary circulation 
that occurs in the absence of infection after the immediate perioperative period. Embolism may 
be manifested by a neurological event or a noncerebral embolic event.  
ENCEPHALOPATHY 
Altered mental state (eg., seizures, delirium, confusion, hallucinations, dementia, coma, 
psychiatric episode, etc.).  
ENDOCARDITIS 
Implanted valve endocarditis: Any infection involving an implanted valve. The diagnosis of 
operated valvular endocarditis is based on one of the following criteria:  
 
re-operation with evidence of abscess, paravalvular leak, pus, or vegetation confirmed as 
secondary to infection by histological or bacteriologic studies;  
 
autopsy findings of abscess, pus, or vegetation involving a replaced valve; or  
 
in the absence of reoperation or autopsy, meeting of the Duke Criteria for endocarditis. 
Infective endocarditis is diagnosed based on Duke Criteria and necessitates 2 major criteria, 
or 1 major and 3 minor criteria, or 5 minor criteria 
Major criteria 1: Positive blood culture for infective endocarditis  
Typical microorganism consistent with infective endocarditis from 2 separate blood 
cultures, as noted below: 
 Viridans streptococci, Streptococcus bovis, or HACEK group (Haemophilus. 
Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella 
corrodens, Kingella or  
 Community-acquired Staphylococcus aureus or enterococci, in the absence of a 
primary focus  
-OR- 
Microorganisms consistent with infective endocarditis from persistently positive blood 
cultures defined as: 
 
Two positive cultures of blood samples drawn >12 hours apart, or  
 
All of 3 or a majority of 4 separate cultures of blood (with first and last sample drawn 
1 hour apart)  
Major criteria 2: Evidence of endocardial involvement 
Positive echocardiogram for infective endocarditis defined as: 
 oscillating intracardiac mass on valve or supporting structures, in the path of 
regurgitant jets, or on implanted material in the absence of an alternative anatomic 
explanation, or  
 abscess, or  
 new partial dehiscence of prosthetic valve  
-OR- 
 New valvular regurgitation (worsening or changing of pre-existing murmur not 
sufficient) 
Minor criteria 1: Predisposition: predisposing heart condition or intravenous drug use 
Minor criteria 2: Fever: temperature > 38.0° C (100.4° F) 
Minor criteria 3: Vascular phenomena: major arterial emboli, septic pulmonary infarcts, 
mycotic aneurysm, intracranial hemorrhage, conjunctival hemorrhages, and Janeway lesions 
Minor criteria 4: Immunologic phenomena: glomerulonephritis, Osler's nodes, Roth spots, 
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Minor criteria 5: Microbiological evidence: positive blood culture but does not meet a major 
criterion as noted above or serological evidence of active infection with organism consistent with 
infective endocarditis 
Minor criteria 6: Echocardiographic findings: consistent with infective endocarditis but do not 
meet a major criterion as noted above  
EXPLANT 
 Removal of the investigational valve implant for any reason, including post-mortem. 
HEMOLYSIS 
A plasma free hemoglobin value > 40 mg/dL is considered to be hemolysis and a reportable 
adverse event. 
 
Major hemolysis: A plasma free hemoglobin value > 40 mg/dL that requires 
intervention (i.e. iron replacement, blood transfusion, folic acid administration, 
corticosteroids, Intravenous immunoglobulin G (IVIG) and/or surgery).  Major hemolysis 
events will be considered to be serious adverse events. 
 
Minor hemolysis:  A plasma free hemoglobin value > 40 mg/dL that does not require 
intervention. 
INFECTION 
Elevated body temperature (fever), and White Blood Count (WBC) > 12,000/ml, and Significant 
leftward shift on Differential. 
MAJOR ADVERSE CARDIOVASCULAR AND CEREBROVASCULAR EVENTS (MACCE)  
Defined as a composite rate of  
 all-cause death  
 myocardial infarction (MI)   
 all stroke, and 
 reintervention (defined as any cardiac surgery or percutaneous reintervention catheter 
procedure that repairs, otherwise alters or adjusts, or replaces a previously implanted 
valve) 
MAJOR ADVERSE EVENT (MAE) 
Major Adverse events include the following: 
 MACCE 
 Acute kidney Injury 
 Cardiac tamponade 
 Prosthetic valve dysfunction  
 Cardiogenic shock 
 Prosthetic valve endocarditis 
 Life-threatening, disabling or major bleeding  
 Major vascular complication 
 Cardiac Perforation 
 Valve malpositioning 
 
 

 
 
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MITRAL REGURGITATION 
Mitral valve incompetence resulting in backward flow of blood.   
 
2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
 
Classification of the Severity of Valve Disease in Adults 
Mitral Regurgitation 
 
Mild
Moderate 
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+ 
2+ 
3-4+ 
Color Doppler jet area 
Small, central jet, < 
4cm2  or <20% LA 
area) 
Signs of > mild 
present but no criteria 
for severe MR 
Vena contracta with > 
0.7cm with large central 
MR jet (area >40% of LA 
area) or with a wall-
impinging jet of any size, 
swirling in LA 
Doppler vena contracta width 
(cm) 
< 0.3 
0.3-0.69 
≥ 0.70 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per 
beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.20 
0.29 – 0.39 
≥ 0.40 
Additional essential criteria 
Left atrial size 
Left ventricular size 
 
 
 
Enlarged 
Enlarged 
MITRAL STENOSIS 
A narrowing, stiffening or stricture of the mitral valve.  
2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
Mitral Stenosis 
 
Mild 
Moderate 
Severe 
Mean Gradient (mmHg) 
Less than 5 
5-10 
Greater than 10 
Pulmonary artery systolic 
pressure (mmHg) 
Less than 30 
30-50 
Greater than 50 
Valve area (cm2) 
Greater than 1.5 
1.0-1.5 
Less than 1.0 
 
 

 
 
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MORTALITY 
A serious adverse event that is classified by the following: 
All-cause mortality: All deaths from any cause after a valve intervention. This includes all 
cardiovascular and non-cardiovascular deaths.  
 Cardiovascular mortality:  
Cardiovascular death will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
A death meeting any one of the following criteria: 
 
Death due to proximate cardiac cause (eg. 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 non-structural valve dysfunction or other 
valve-related adverse events 
 
Sudden or unwitnessed death 
 
Death of unknown cause 
Non-cardiovascular mortality:  Any death in which primary cause of death is clearly related to 
another condition (eg. trauma, cancer, suicide)  
NOTE: All deaths are considered cardiac unless an unequivocal non-cardiac cause can be established.  Specifically, any 
unexpected death even in subjects with coexisting potentially fatal non-cardiac disease (eg. cancer, infection) 
should be classified as cardiac. 
 
 

 
 
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MYOCARDIAL INFARCTION (MI) 
Myocardial infarction will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Peri-Procedural MI 
(<72 hours after the index procedure) 
1. New ischemic symptoms (eg. chest pain or shortness of breath), or new 
ischemic signs (eg. ventricular arrhythmias, new or worsening heart failure, new 
ST-segment changes, hemodynamic instability, new pathological Q-waves in at 
least two continuous leads, imaging evidence of new loss of viable myocardium 
or new wall motion abnormality) AND 
2. Elevated cardiac biomarkers (preferably CK-MB) within 72 hours after the index 
procedure, consisting of two or more post-procedure samples with a peak value 
exceeding 15x the upper reference limit (URL) for troponin or 5x for CK-MB.  If 
cardiac biomarkers are increased at baseline (>99th percentile), a further 
increase in at least 50% post-procedure is required AND the peak value must 
exceed the previously stated limit 
 
Spontaneous MI 
(> 72 hours after the index procedure) 
Any one of the following criteria: 
1. Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least 
one value above the 99th percentile URL, together with evidence of myocardial 
ischemia with at least one of the following: 
 
Symptoms of ischemia 
 
ECG changes indicative of new ischemia [new ST-T changes or new left 
bundle branch block (LBBB)]; 
 
New pathological Q waves in at least two contiguous leads; 
 
Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality 
2. Sudden, unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumably new ST 
elevation, or new LBBB, and/or evidence of fresh thrombus by coronary angiography 
and/or at autopsy, but death occurring before blood samples could be obtained, or at 
a time before the appearance of cardiac biomarkers in the blood. 
3. Pathological findings of an acute myocardial infarction. 
All myocardial infarctions will be considered serious adverse events. 
NEUROLOGICAL EVENT  
Any central, new neurological deficit, whether temporary or permanent and whether focal or 
global, that occurs after the subject emerges from anesthesia. 
 
 

 
 
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NEW YORK HEART ASSOCIATION CLASSIFICATION (NYHA) 
Classification system for defining cardiac disease and related functional limitations into four 
broad categorizations: 
Class I 
Subject with cardiac disease but without resulting limitations of physical 
activity. Ordinary physical activity does not cause undue fatigue, palpitation, 
dyspnea, or anginal pain. 
Class II 
Subjects 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. 
Class III 
Subjects with cardiac disease resulting in marked limitation of physical 
activity. They are comfortable at rest. Less than ordinary physical activity 
causes fatigue, palpitation, dyspnea, or anginal pain. 
Class IV 
Subjects with cardiac disease resulting in inability to carry on any physical 
activity without discomfort. Symptoms of cardiac insufficiency or of the 
anginal syndrome may be present even at rest. If any physical activity is 
undertaken, discomfort is increased. 
PARAVALVULAR AORTIC REGURGITATION 
Leakage due to a separation of the prosthetic valve from the annulus. Diagnosis of paravalvular 
leak may be obtained from echocardiogram; however definitive diagnosis is obtained at 
reoperation, explant, or autopsy.  
 (Refer to the definition of Aortic Regurgitation for additional paravalvular leak severity criteria)   
PATIENT PROSTHESIS MISMATCH (PPM) 
Patient prosthesis mismatch (PPM) is defined under the definition of Prosthetic Valve Dysfunction according to the Valve 
Academic Research Consortium (VARC)-2 Updated Standardized Endpoint Definitions for Consensus Report for 
Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09 
Reference prosthetic valve dysfunction. 
PERMANENT PACEMAKER IMPLANTATION  
Implantation of permanent pacemaker after the index procedure due to occurrence of conduction 
disturbances.  
 
Procedure-related: Permanent Pacemaker is implanted in subjects with new onset 
conduction disturbances or worsening of existing conduction disturbances 
 
Not related to procedure: Permanent Pacemaker is implanted in subjects with known 
conduction disturbances that did not advance after the index procedure. 
PROCEDURE RELATED COMPLICATIONS 
Complications associated with any part of the vascular access procedure, associated treatments 
or necessary secondary interventions that do not necessarily involve the device.  This includes 
morbidity associated with either pre-medication, or anesthesia, or other adjunct to the surgical 
procedure.  Other technical errors including inappropriate patient selection, inappropriate 
operator techniques, measurements, or judgment that do not involve the device itself are also 
included.   
PROCEDURAL SUCCESS 
 Defined as device success without occurrence of in-hospital MACCE. 
PROCEDURE-RELATED EVENTS 
All events occurring during or as a direct result of the index procedure.  
All events that occur before extubation and/or before access site closure are classified as 
procedure-related regardless of event timing. 
PROSTHETIC VALVE DYSFUNCTION 
Prosthetic Valve Dysfunction will be defined according to the Valve Academic Research Consortium (VARC)-2 Updated 
Standardized Endpoint Definitions for Consensus Report for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09 
 
Failure modes of prosthetic valve dysfunction include, but are not limited to, the following: 
 
Aortic Stenosis 

 
 
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o 
Stent creep 
o 
Pannus 
o 
Calcification 
o 
Support structure deformation (out-of-round configuration), under-expansion, 
fracture, or trauma (cardio-pulmonary resuscitation, blunt chest trauma) 
o 
Mal-sizing [prosthesis-patient mismatch(PPM)]  
o 
Endocarditis 
o 
Prosthetic valve thrombosis 
o 
Native leaflet prolapse impeding prosthetic leaflet motion 
 
Aortic Regurgitation 
o 
Pannus 
o 
Calcification 
o 
Support structure deformation (out-of-round configuration), recoil, under-expansion, 
fracture, insufficient radial strength, or trauma (cardio-pulmonary resuscitation, blunt 
chest trauma) 
o 
Endocarditis 
o 
Prosthetic valve thrombosis 
o 
Mal-position (too high, too low) 
o 
Acute mal-coaptation 
o 
Leaflet wear, tear/perforation, prolapse or retraction 
o 
Suture breakage or disruption 
o 
Native leaflet prolapse impeding prosthetic leaflet motion 
Prosthetic valve dysfunction will be considered serious when it meets the definition of a serious 
adverse event (SAE). 
 
 

 
 
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Prosthetic valve dysfunction 
Prosthetic aortic valve stenosis* 
 
Normal 
Mild Stenosis 
Moderate/Severe Stenosis 
Quantitative Parameters (Flow-dependent)† 
Peak velocity 
<3 m/s 
3-4 m/s 
>4 m/s 
Mean gradient 
<20 mmHg 
20-40 mmHg 
>40 mmHg 
Quantitative Parameters (Flow-independent)
  
Doppler velocity index‡ 
>0.35 
0.35-0.25 
<0.25 
Effective orifice area┼ 
>1.1 cm
2 
1.1-0.8 cm
2 
<0.8 cm
2 
Effective orifice area§ 
>0.9 cm
2 
0.9-0.6 cm
2 
<0.6 cm
2 
Prosthesis-patient mismatch (PPM) 
 
Insignificant 
Moderate 
Severe 
Indexed effective orifice 
area** 
>0.85 cm
2/m
2 
0.85-0.65 cm
2/m
2 
<0.65 cm
2/m
2 
Indexed effective orifice 
area†† 
>0.70 cm
2/m
2 
0.70-0.60 cm
2/m
2 
<0.60 cm
2/m
2 
Prosthetic aortic valve regurgitation 
 
Mild 
Moderate 
Severe 
Semi-quantitative Parameters 
Diastolic flow reversal in the 
descending aorta—PW  
Absent or brief early 
diastolic 
Intermediate 
Prominent, holodiastolic 
Circumferential extent of 
prosthetic valve paravalvular 
regurgitation (%)┼┼ 
<10% 
10-29% 
≥30% 
Quantitative Parameters‡ 
Regurgitant volume (ml/beat) 
<30 ml 
30-59 ml 
≥60 ml 
Regurgitant fraction (%) 
<30% 
30-49% 
≥50% 
EROA (cm
2)  
<0.10 cm
2 
0.10-0.29 cm
2 
≥0.30 cm
2 
*In conditions of normal or near normal stroke volume (50–70 mL) 
†These parameters are more affected by flow, including concomitant aortic regurgitation 
‡For LVOT >2.5 cm, significant stenosis criteria is <0.20 
┼Use in setting of BSA ≥1.6 cm
2 (note: dependent on the size of the valve and the size of the native annulus) 
§Use in setting of BSA <1.6 cm
2 
**Use in setting of BMI <30 kg/cm
2 
††Use in setting of BMI ≥30 kg/cm
2 
┼┼Not well-validated and may overestimate severity compared to quantitative Doppler 
 
Moderate or severe AS and AR will be considered a serious adverse event when the dysfunction 
is accompanied with clinical sequelae at the time of the event detection, and the clinical 
sequelae are chronologically and physiologically associated with the dysfunction. 

 
 
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RECURRENT HOSPITALIZATION  
Recurrent hospitalization is defined as a non-elective hospital admission for signs and 
symptoms related to aortic valve disease (as described below), as well as complications related 
to aortic valve procedures including neurological events, infection, additional procedures (eg. 
implant of permanent pacemaker), and renal failure.  For the purposes of the protocol a 
hospitalization is an admission that results in at least a one night stay (i.e., one midnight/change 
in calendar day).     
Overnight stays at nursing home facilities, extended care facilities, or emergency room visits that 
do not result in an in-patient admission do not meet the protocol definition of recurrent 
hospitalization.  Patients with signs and symptoms related to aortic valve disease (as described 
below) who are hospitalized for less than one night or who are treated and released from the 
emergency department or an outpatient clinic [including treatment for intravenous heart failure 
therapy (eg., inotropes, diuretics, and/or vasodilators)], does not meet the protocol definition of 
as recurrent hospitalizations. 
Aortic valve disease will be evaluated using documented evidence of the following signs and 
symptoms.  An independent Clinical Events Committee (CEC) will review all available source 
documentation for all hospitalizations to determine if they are aortic valve disease 
hospitalizations.  The CEC adjudication will be used for final analysis. 
Signs and Symptoms of Aortic Valve Disease 
Sign/Symtpom 
Definition 
Aortic Valve Dysfunction 
 
Shortness of breath/dyspnea  
A feeling of difficult or labored breathing that is out of proportion to 
the patient’s level of physical activity 
Exercise intolerance  
A condition where the patient is unable to do physical exercise at 
the level or for the duration that would be expected of someone in 
his/her general physical condition, or experiences unusually 
severe post-exercise pain, fatigue, or other negative effects 
Dizziness/syncope  
Lightheadness or unsteadiness of gait or a partial or complete 
loss of consciousness with interruption of awareness of oneself 
and ones surroundings 
Chest pain  
Discomfort and soreness in and around the chest 
Worsening Heart Failure 
Volume Overload 
 
Orthopnea 
Dyspnea in which the person can breathe comfortably only when 
standing or sitting erect  
Paroxysmal nocturnal dyspnea 
Acute dyspnea caused by the lung congestion and edema that 
results from partial heart failure and occurring suddenly at night, 
usually an hour or two after the individual has fallen asleep.  
Jugular venous distension 
With the patient is positioned under 45°, and the filling level of the 
jugular vein determined. An abnormal response is more than 3 
centimeters above the sternal angle.  
Hepatomegaly 
Palpation of the edge of the liver below the edge of the ribs 
without inspiration  
Peripheral edema 
Swelling of tissues, usually in the lower limbs, due to the 
accumulation of fluids.  
Pulmonary rales 
Small clicking, bubbling, or rattling sounds in the lung associated 
with inspiration  
Abdominal-jugular reflux 
An elevation of venous pressure visible in the jugular veins and 
measurable in the veins of the arm, produced in active or 
impending congestive heart failure by firm pressure with the flat 
hand over the abdomen.  
Radiographic evidence of 
pulmonary edema 
NA 
Elevated B-type natriuretic peptide 
level   
NA 
Hypoperfusion 
 
Narrow pulse pressure  
Pulse pressure < 30 mmHg  
Hypotension 
Systolic BP < 90 systolic 
Renal or hepatic dysfunction 
Rise in baseline creatinine by 25%  
Increase in LFT (SGOT, SGPT) > 2 times normal  
Low serum sodium concentration  
Serum sodium < 130 mEq/dL 
REINTERVENTION 

 
 
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Any surgical or percutaneous interventional catheter procedure that repairs, otherwise alters or 
adjusts, or replaces a previously implanted valve. In addition to surgical reoperations, balloon 
dilatation, interventional manipulation, repositioning, or retrieval, and other catheter-based 
interventions for valve-related complications are also considered reinterventions. Reintervention 
is further subdivided into surgical and percutaneous. 
RESPIRATORY INSUFFICIENCY 
Post-bronchodilator forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) 
ratio [FEV1/FVC] less than 70%. 
Post-bronchodilator FEV1 less than 80% predicted, with or without chronic symptoms (i.e., 
cough or sputum production). 
RESPIRATORY FAILURE 
The need for ventilatory support for > 72 hours associated with an inability to wean from the 
respirator for any reason. 
RIGHT VENTRICULAR INSUFFICIENCY 
Defined as sequelae of right ventricular failure including the following: 
 Significantly decreased right ventricular systolic and/or diastolic function 
 Tricuspid valvular regurgitation secondary to elevated pressure 
Clinical symptoms to include: 
o 
Hepatic congestion 
o 
Ascites 
o 
Anasarca 
o 
Presence of “hepato-jugular reflux” 
o 
Edema 
SERIOUS ADVERSE DEVICE EFFECT (SADE) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event 
SERIOUS ADVERSE EVENT (SAE) 
A serious adverse event (SAE) is an event that: 
 Led to death, 
 Led to serious deterioration in health of the subject, that either resulted in: 
o 
a life threatening illness or injury, or 
o 
a permanent impairment of a body structure or a body function, or 
o 
in-patient or prolonged hospitalization, or 
o 
medical or surgical intervention to prevent a life-threatening illness or injury or 
permanent impairment to a body structure or a body function  
 Led to fetal distress, fetal death or a congenital abnormality or birth defect 
NOTE: Planned hospitalization for pre-existing condition, or a procedure required by per protocol, without serious 
deterioration in health, is not considered a serious adverse event.  
Events that do not meet these criteria are considered non-serious. 
 
 

 
 
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STROKE and TIA  
Stroke and TIA will be defined according to the Valve Academic Research Consortium (VARC)-2; Updated Standardized 
Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09 and the FDA’s Current Thinking 
Regarding Neurological Assessments for Transcatheter Valve Trials (July 25, 2011). 
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 
 
Stroke: duration of a focal or global neurological deficit ≥ 24 hours; OR < 24 hours available 
neuroimaging documents a new hemorrhage or infarct; OR the neurologic deficit results in death 
 
TIA: duration of a focal or global neurological deficit <24 hours, any variable neuroimaging does 
not demonstrate a new hemorrhage or infarct 
 
No other readily identifiable non-stroke cause for the clinical presentations (eg. 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: 
o 
Neurology or neurosurgical specialist 
o 
Neuroimaging procedure (CT scan or brain MRI), but stroke be diagnosed on clinical 
grounds alone 
Stroke Classification 
 
Ischemic: an acute episode of focal cerebral, spinal or retinal dysfunctions caused by infarction of 
the central nervous system tissue 
 
Hemorrhagic: an acute episode of focal cerebral, spinal or spinal dysfunctions caused by 
intraparenchymal, intraventricular, or subarachnoid hemorrhage  
Stroke Definitions
 Disabling stroke: an mRS score of 2 or more at 90 days and an increase in at least one mRS 
category from an individual’s pre-stroke baseline 
 Non-disabling stroke: an mRS score of < 2 at 90 days or one that does not result in an increase in 
at least one mRS category from an individual’s pre-stroke baseline 
 
*   Patients with non-focal global encephalopathy will not be reported as a stroke without unequivocal evidence based 
upon neuroimaging studies 
+  Modified Rankin score assessments should be made by qualified individuals according to certification process.  
Clinically important disabilities (disabling strokes) will be considered to be serious adverse 
events. 
TAV-in-TAV DEPLOYMENT 
Valve malpositioning will be defined according to the Valve Academic Research Consortium (VARC) )-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
An additional valve prosthesis is implanted within a previously implanted prosthesis because of 
suboptimal device position and/or function, during or after the index procedure. 
TECHNICAL OBSERVATION 
A defect, malfunction, or failure of any part of the Medtronic CoreValve™ System. This may 
pertain to the device or delivery and/or loading system not functioning according to its design 
intent.  
TRICUSPID REGURGITATION 
2008 Focused Update Incorporated into the ACC/AHA 2006 Guidelines for the Management of Patients with Valvular 
Heart Disease (published in the October 2008 issues of Journal of the American College of Cardiology and Circulation) 
Severe tricuspid regurgitation: vena contracta width greater than 0.7cm and systolic reversal 
in hepatic veins.  
UNANTICIPATED SERIOUS ADVERSE DEVICE EFFECT (USADE) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current version of the risk analysis report 
NOTE:   Anticipated serious adverse device effect (ASADE) is an effect which by its nature, incidence, severity or 
outcome has been identified in the risk analysis report. 
UNPLANNED USE OF CARDIOPULMONARY BYPASS (CPB) 
Valve Academic Research Consortium (VARC)-2; Updated Standardized Endpoint Definitions for Transcatheter Aortic 
Valve Implantation (TAVI); 2012-10-09. 

 
 
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Unplanned use of CPB for hemodynamic support at any time during the TAVI procedure. 
VALVE THROMBOSIS 
Any thrombus not caused by infection attached to or near the trial valve that occludes part of the 
blood flow path, interferes with valve function, or is sufficiently large to warrant treatment. Valve 
thrombus found at autopsy in a subject whose cause of death was not valve-related or found at 
operation for an unrelated indication should also be counted as valve thrombosis. 
VALVE MALPOSITIONING 
Valve malpositioning will be defined according to the Valve Academic Research Consortium (VARC) )-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Valve migration 
After initial correct positioning, the valve prosthesis moves upward or downward, within the 
aortic annulus from its initial position, with or without consequences 
Valve embolization 
The valve prosthesis moves during or after deployment such that it loses contact with the aortic 
annulus 
Ectopic valve deployment 
Permanent deployment of the valve prosthesis in a location other than the aortic root 
 
 

 
 
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VASCULAR COMPLICATIONS 
Vascular Complications will be defined according to the Valve Academic Research Consortium (VARC) )-2; Updated 
Standardized Endpoint Definitions for Transcatheter Aortic Valve Implantation (TAVI); 2012-10-09. 
Vascular Access Site and Access Related Complications 
Major Vascular Complications  
 Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new 
apical aneurysm/pseudo-aneurysm OR 
 Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneurysm, hematoma, irreversible nerve injury, 
compartment syndrome, percutaneous closure device failure) leading to death, life-
threatening or major bleeding*, visceral ischemia or neurological impairment OR 
 Distal embolization (non-cerebral) from a vascular source requiring surgery or 
resulting in amputation or irreversible end-organ damage OR 
 The use of unplanned endovascular or surgical intervention associated with death, 
major bleeding, visceral ischaemia or neurological impairment OR 
 Any new ipsilateral lower extremity ischemia documented by patient symptoms, 
physical exam, and/or decreased or absent blood flow on lower extremity angiogram 
OR 
 Surgery for access site-related nerve injury OR 
 Permanent access site-related nerve injury 
 
Minor Vascular Complications 
 Access site or access-related vascular injury (dissection, stenosis, perforation, 
rupture, arterio-venous fistula, pseudoaneuysms, hematomas, percutaneous closure 
device failure) not leading to death, life-threatening or major bleeding*, visceral 
ischemia or neurological impairment OR 
 Distal embolization treated with embolectomy and/or thrombectomy and not resulting 
in amputation or irreversible end-organ damage OR 
 Any unplanned endovascular stenting or unplanned surgical intervention not meeting 
the criteria for a major vascular complication OR 
 Vascular repair or the need for vascular repair (via surgery, ultrasound-guided 
compression, transcatheter embolization, or stent-graft)  
 
Percutaneous closure device failure 
 Failure of a closure device to achieve hemostasis at the arteriotomy site leading to 
alternative treatment (other than manual compression or adjunctive endovascular 
ballooning) 
Major vascular complications will be considered to be serious adverse events. 
*Refers to VARC bleeding definitions. 

 
 
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P TRIAL MANAGEMENT 
P.1 
Miscellaneous 
 
Insurance 
P.1.1
The Medtronic Bakken Research Center B.V. is a wholly owned subsidiary of Medtronic Inc., 
which as the parent company of such entity maintains appropriate clinical trial liability insurance 
coverage as required under applicable laws and regulations and will comply with applicable law 
and custom concerning specific insurance coverage. If required, a Clinical Trial Insurance 
statement/certificate will be provided to the IRB/MEC. 
 
Reimbursement 
P.1.2
Trial reimbursement is outlined in the Clinical Trial Agreement. 
 
Indemnification 
P.1.3
Indemnification will be done according to local laws. 
 
Subject confidentiality 
P.1.4
At all times throughout the trial confidentiality shall be observed by all parties involved. All 
information and data sent to parties involved in trial conduct concerning patients or their 
participation in this trial will be considered confidential. The patient identification number is to be 
recorded on all trial documents and will link the trial documents to the patient's name and 
medical record at the investigator's site. To maintain confidentiality, the patient's name or any 
other personal identifiers should not be recorded on any trial document other than the informed 
consent form. 
 
 

 
 
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Q REFERENCES 
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37. Nowicki ER, Birkmeyer NJ, Weintraub RW, Leavitt BJ, Sanders JH, Dacey LJ, Clough RA, Quinn RD, 
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Surg 2004; 77(6):1966-1977. 
38. van Gameren M, Kappetein AP, Steyerberg EW, Venema AC, Berenschot EA, Hannan EL, Bogers AJ, 
Takkenberg JJ. Do we need separate risk stratification models for hospital mortality after heart valve 
surgery? Ann Thorac Surg 2008; 85(3):921-930. 
39. van Gameren M, Piazza N, Bogers AJ, Takkenberg JJ, Kappetein AP. How to assess risks of valve 
surgery: quality, implementation and future of risk models. Heart 2009; 95(23):1958-1963. 
40. Lee DH, Buth KJ, Martin BJ, Yip AM, Hirsch GM. Frail patients are at increased risk for mortality and 
prolonged institutional care after cardiac surgery. Circulation; 121(8):973-978. 
41. Chang AS, Smedira NG, Chang CL, Benavides MM, Myhre U, Feng J, Blackstone EH, Lytle BW. 
Cardiac surgery after mediastinal radiation: extent of exposure influences outcome. J Thorac 
Cardiovasc Surg 2007; 133(2):404-413. 
42. Girardi LN, Krieger KH, Mack CA, Isom OW. No-clamp technique for valve repair or replacement in 
patients with a porcelain aorta. Ann Thorac Surg 2005; 80(5):1688-1692. 
43. Wijns W, Kolh P, Danchin N, Di Mario C, Falk V, Folliguet T, Garg S, Huber K, James S, Knuuti J, 
Lopez-Sendon J, Marco J, Menicanti L, Ostojic M, Piepoli MF, Pirlet C, Pomar JL, Reifart N, Ribichini 
FL, Schalij MJ, Sergeant P, Serruys PW, Silber S, Sousa Uva M, Taggart D, Vahanian A, Auricchio A, 
Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, Hobbs R, Kearney P, McDonagh T, 
Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas PE, Widimsky P, Alfieri O, Dunning 
J, Elia S, Kappetein P, Lockowandt U, Sarris G, Vouhe P, von Segesser L, Agewall S, Aladashvili A, 
Alexopoulos D, Antunes MJ, Atalar E, Brutel de la Riviere A, Doganov A, Eha J, Fajadet J, Ferreira R, 
Garot J, Halcox J, Hasin Y, Janssens S, Kervinen K, Laufer G, Legrand V, Nashef SA, Neumann FJ, 
Niemela K, Nihoyannopoulos P, Noc M, Piek JJ, Pirk J, Rozenman Y, Sabate M, Starc R, Thielmann 
M, Wheatley DJ, Windecker S, Zembala M. Guidelines on myocardial revascularization: The Task 
Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the 
European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J; 31(20):2501-2555. 
44. Lund O, Nielsen TT, Pilegaard HK, Magnussen K, Knudsen MA. The influence of coronary artery 
disease and bypass grafting on early and late survival after valve replacement for aortic stenosis. J 
Thorac Cardiovasc Surg 1990; 100(3):327-337. 
45. Dickstein K, Vardas PE, Auricchio A, Daubert JC, Linde C, McMurray J, Ponikowski P, Priori SG, 
Sutton R, van Veldhuisen DJ, Vahanian A, Bax J, Ceconi C, Dean V, Filippatos G, Funck-Brentano C, 
Hobbs R, Kearney P, McDonagh T, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Tendera M, Vardas 
P, Widimsky P, Anker SD, Blanc JJ, Gasparini M, Hoes AW, Israel CW, Kalarus Z, Merkely B, 
Swedberg K, Camm AJ. 2010 Focused Update of ESC Guidelines on device therapy in heart failure: 
an update of the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart 
failure and the 2007 ESC guidelines for cardiac and resynchronization therapy. Developed with the 
special contribution of the Heart Failure Association and the European Heart Rhythm Association. Eur 
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46. Goldstein LB, Adams R, Alberts MJ, Appel LJ, Brass LM, Bushnell CD, Culebras A, DeGraba TJ, 
Gorelick PB, Guyton JR, Hart RG, Howard G, Kelly-Hayes M, Nixon JV, Sacco RL. Primary prevention 
of ischemic stroke: a guideline from the American Heart Association/American Stroke Association 
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Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical 
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T. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack: a 
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Harbaugh R, Johnston SC, Katzan I, Kelly-Hayes M, Kenton EJ, Marks M, Sacco RL, Schwamm LH. 
Update to the AHA/ASA recommendations for the prevention of stroke in patients with stroke and 
transient ischemic attack. Stroke 2008; 39(5):1647-1652. 
49. O'Brien SM, Shahian DM, Filardo G, Ferraris VA, Haan CK, Rich JB, Normand SL, DeLong ER, 
Shewan CM, Dokholyan RS, Peterson ED, Edwards FH, Anderson RP. The Society of Thoracic 
Surgeons 2008 cardiac surgery risk models: part 2--isolated valve surgery. Ann Thorac Surg 2009; 
88(1 Suppl):S23-42. 
50. Pauwels RA, Buist AS, Calverley PM, Jenkins CR, Hurd SS. Global strategy for the diagnosis, 
management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative 
for Chronic Obstructive Lung Disease (GOLD) Workshop summary. Am J Respir Crit Care Med 2001; 
163(5):1256-1276. 
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G. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, 
classification, and stratification. Ann Intern Med 2003; 139(2):137-147. 
52. Zoghbi WA, Chambers JB, Dumesnil JG, Foster E, Gottdiener JS, Grayburn PA, Khandheria BK, 
Levine RA, Marx GR, Miller FA, Jr., Nakatani S, Quinones MA, Rakowski H, Rodriguez LL, 
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Cardiac Imaging Committee of the American Heart Association, the European Association of 
Echocardiography, a registered branch of the European Society of Cardiology, the Japanese Society 
of Echocardiography and the Canadian Society of Echocardiography, endorsed by the American 
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22(9):975-1014; quiz 1082-1014. 
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SURTAVI 
SUrgical Replacement and Transcatheter 
Aortic Valve Implantation 
 
 
Appendix 
 
 
VERSION 12.1 
31 May 2016 
  
 
Sponsor: 
Medtronic, Inc. 
Clinical Research 
Mailstop: MVS66 
Mounds View South 
8200 Coral Sea St NE 
Mounds View, MN 55112 USA 
Medtronic Bakken Research Center 
Coronary and Structural Heart Department
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
 
 
 

 
 
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TABLE OF CONTENTS 
R 
APPENDICES .................................................................................................. 118 
R.1 
Sample Informed Consent ............................................................................................. 118 
R.1.1  United States....................................................................................................... 119 
R.1.2  United States – Roll-in Subjects .......................................................................... 134 
R.1.3  Europe ................................................................................................................ 147 
R.1.4  Canada ............................................................................................................... 160 
R.1.4  Canada – Roll-in Subjects ................................................................................... 176 
R.2 
List of Participating Investigational Centers ................................................................... 192 
R.3 
Other Institutions ........................................................................................................... 193 
R.4 
Additional Records and Reports .................................................................................... 194 
R.5 
Sample Case Report Forms .......................................................................................... 195 
R.6 
Aortogram Acquisition Guidelines ................................................................................. 196 
R.7 
Echocardiography Acquisition Guidelines ..................................................................... 198 
R.8 
Electrocardiogram (ECG) Submission ........................................................................... 219 
R.9 
Computed Tomography (CT) Angiography Acquisition Guidelines ................................ 220 
R.10  Interactive Voice/Web Response System (IXRS) .......................................................... 232 
R.11  Explanted Device/Pathology and Return Procedures .................................................... 233 
R.12  Economic and Quality of Life Data Collection ................................................................ 235 
R.12.1 
Health Economic Data Collection .................................................................... 235 
R.12.2 
Quality of Life Data Collection ......................................................................... 235 
R.12.2.1 
Schedule of Assessments .................................................................. 235 
R.12.2.2 
Questionnaires ................................................................................... 236 
R.13  Pacing Guidelines ......................................................................................................... 237 
R.14  Six Minute Walk Test Instructions ................................................................................. 241 
R.15  National Institute of Health Stroke Scale (NIHSS) ......................................................... 254 
R.16  Modified Rankin Scale (mRS) Instructions .................................................................... 258 
R.17  Mini Mental State Exam (MMSE-2:SV) .......................................................................... 259 
R.18  Additional Neurological Assessments ............................................................................ 260 
R.19  Medtronic CoreValve™ Clinical Assessment Guidelines ................................................ 262 
R.20  Katz Index of Independence in Activities of Daily Living ................................................ 263 
R.21  Investigator Brochure / Report of Prior Investigations for the Investigational Devices ... 264 
R.22  Investigational Devices Instructions For Use ................................................................. 265 
R.23  Radiation Exposure and Data Collection ....................................................................... 266 
R.24  SURTAVI Risk Model .................................................................................................... 269 
R.24.1 
 SURTAVI Risk Model Rationale ..................................................................... 269 
R.24.2 
 SURTAVI co-morbidity list .............................................................................. 272 
R.25  CMS Considerations for Coverage and Reimbursement – US ONLY ........................... 277 

 
 
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APPENDICES 
R.1 
Sample Informed Consent  
Attached are the informed consent form templates: 
 United States 
 United States - Roll-in Subjects 
 Europe 
 Canada 
 Canada – Roll-in Subjects 
 

 
 
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R.1.1 
United States 
INFORMED CONSENT FORM  
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this research study and how you 
might take part in it. By signing this form, you will show that you understand and that you agree to 
take part in this research study. Your signature on this form is required before you can take part in 
this research study. 
BACKGROUND 
You are being asked to take part in a research study entitled “Medtronic CoreValve™ SURTAVI 
Trial” because you have a disease of your aortic valve.  This disease is called aortic stenosis. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the left 
ventricle (main pumping chamber of the heart) into the aorta (main artery delivering blood to the 
body). If the valve becomes abnormally narrow through a process of thickening and stiffening 
(aortic stenosis) the heart must work harder to pump the same amount of blood with each beat. 
As the heart works harder, the heart muscle thickens (hypertrophy), and the heart chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve is 
the standard treatment. 
As an alternative to open heart surgery, the Medtronic CoreValve™ System has been developed to 
replace a diseased aortic heart valve without the need for open heart surgery. This system allows 
the percutaneous aortic valve (study valve) to be implanted (inserted) through a long, thin flexible 
tube that is inserted through an incision in the skin and threaded through the bloodstream 
(percutaneous). 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
You are being asked to participate in this study because doctors have determined your aortic valve 
is no longer working properly. However, your doctors have also decided that your risk of 
experiencing major problems while undergoing open-heart surgery is moderate due to medical 
reasons or anatomical reasons (relating to how and where your heart, aortic valve and blood 
vessels are placed within your body). This means that you doctor believes your health is acceptable 
for open-heart surgery, but there are still a risk of potential problems. 
PURPOSE OF THE STUDY 
The purpose of this clinical  study is to determine if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions as 
you. 
The study valve is considered an “investigational device”, which means that clinical studies are 
required to determine if it is safe and provides clinical benefit. Medtronic, Inc. is sponsoring this 
study to obtain data on the safety and performance of the investigational device. The Medtronic 
CoreValve™ System includes the valve described below and two parts that help load and deliver the 
valves correctly.  
This study will involve approximately 1600 subjects at up to 115 hospitals in the United States and 
around the world, and is anticipated to take approximately 8 years to complete. Your participation in 

 
 
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this study is expected to last approximately five years from the day you are enrolled in the study. 
Annual follow-up may be extended to up to 10 years after the implant procedure. 
STUDY DEVICES 
The study valve is made from animal tissue attached to a metal frame.  
The study valve is designed to be implanted (inserted) using a delivery system catheter (long, thin 
flexible tube) to replace your diseased aortic heart valve without open-heart surgery.  Once it is 
implanted, CoreValve™ study valves acts in the same method of the native valve.   
The Medtronic CoreValve system is approved by the US Food & Drug Administration (FDA) since 
2014 and it has been approved in other parts of the world since 2006. It has been implanted in over 
45,000 patients. The Medtronic CoreValve™ System is currently approved for use in Europe, South 
America, and parts of Asia.  
 
 
 
 
 
 
 
 
PROCEDURES TO BE FOLLOWED 
If you agree to be in this study, and after you have signed this informed consent form, data such as 
your age, gender, medical history and medication use will be recorded. You will undergo the 
following tests: 
 
Physical examination 
 
Computed tomography (CT) - a scan performed using an x-ray machine, which is linked to a 
computer to take pictures of your body. Sometimes a CT will require the use of a type of dye 
that makes the kidneys work harder and may be harmful to the kidneys. You may have an 
MRI in place of a CT scan if your doctor believes your kidneys are not working well enough 
for you to have a CT scan. MRI stands for magnetic resonance imaging and is a test that 
uses a strong magnet and a complex computer system to produce detailed images of your 
internal organs and soft body tissues. 
 
Blood tests (about 2 tablespoons) 
 
Echocardiography [transthoracic echocardiogram (TTE)] - a test that uses sound waves to 
take pictures of your heart and measure the degree of narrowing of your aortic valve; a probe 
with gel is placed on the outside of your chest to take pictures of your heart 
 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
 
Heart catheterization/angiography - a test that takes pictures of your heart and blood vessels; 
a special dye is injected through long, flexible tubes into the coronary arteries (vessels 
delivering blood to the heart) and bypass grafts if you have them 

 
 
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If you are of child-bearing potential, we will ask you to take a pregnancy test. If you are pregnant, 
you will not be able to participate in this study. 
These procedures and tests are standard procedures and are not experimental. If you have already 
had any of these tests performed before, they may to be used for the study if your study doctor 
determines they don’t need to be repeated for study purposes.  
The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you will 
not be allowed to participate in the study. 
If your doctor and the committee decide you are eligible to be in the study your treatment will be 
determined in a way similar to flipping a coin, called randomization. You will be assigned to one of 
two groups. One group will receive a transcatheter aortic valve implant (TAVI), the other group will 
receive open-heart surgical aortic valve replacement (SAVR). On average, one out of every two 
participants will receive TAVI. The other participants will receive SAVR. You will not be able to 
choose your treatment assignment. 
Your enrollment in the study will begin once you sign this consent and you are assigned to your 
treatment group. 
If you are enrolled in the study, you will be required to have the following additional tests completed 
within 14 days prior to the procedure (TAVI or SAVR): 
• 
Physical exam, including a determination of neurological (brain) status where you will be 
asked to answer a series of questions and perform a series of tasks such as writing and 
drawing 
• 
Blood tests (about 2 tablespoons) 
• 
Walking test – a test that records your breathing, heart rate, and how you feel after 6 minutes 
of walking 
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life Questionnaires (QOL). 
Your personal physician will be informed about your participation in this clinical study. 
If you are assigned to the TAVI group: 
The study valve is an experimental valve which means you can only receive the valve if you are 
part of this study.   
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor.  You may be advised to continue these medications for at 
least three months following your procedure.  
Before the procedure you will be given an antibiotic (a medicine that kills bacteria or germs) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about 2 tablespoons) and an ECG before the procedure.   
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary during 
the procedure, you will be put under general anesthesia at that time. 

 
 
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Your study doctor will decide what locations are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary. These pictures are described in 
the next paragraphs.  Additionally, your study doctor will decide if performing a surgical incision to 
any of the site(s) is necessary. 
During the procedure you may have a transesophageal echocardiogram which is also called a TEE. 
This test uses sound waves to take a closer look at the inside structures of the heart. If your doctor 
decides these pictures are necessary, to perform the test you will swallow a thin flexible tube with a 
special tip. This tube sits in the esophagus (the tube that connects the mouth to the stomach). The 
special tip of the tube sends out sound waves (ultrasound) that echo within the chest wall. The 
esophagus is located behind the heart so these echoes are picked up and create a picture of the 
heart that is displayed on a video monitor. The pictures will allow your study doctor to take a closer 
look at your valve. 
You will have a temporary pacemaker put in place during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins and threaded 
through your vein into the right side of your heart. The wire is attached to a battery operated device 
outside of your body. This temporary pacemaker will help keep your heart rate (speed) and rhythm 
steady. This temporary pacemaker will not be removed for at least 48 hours after your TAVI 
procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. Balloon valvuloplasty is a procedure used to widen a stiff or narrowed heart valve. A 
wire and a thin tube are guided by x-rays through the heart and positioned through the diseased 
heart valve. A balloon is placed over the wire and inflated, enlarging the opening through the 
diseased valve allowing the study valve to be placed. 
Your doctor will then implant (insert) the study valve through the long, thin flexible tube that is 
inserted through an incision in the skin and threaded through the bloodstream. TAVI is performed 
using x-ray machines which will allow your doctor to see the study valve, your blood vessels and 
heart. The study valve will be guided through your blood vessels to your existing aortic valve and 
then the study valve will be placed over your existing valve. 
During the TAVI procedure, your doctor will perform angiography (x-ray pictures) and ECGs 
(recordings of the electrical impulses of your heart through patches placed on the chest) to observe 
your heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study valve. 
If you are assigned to the SAVR group: 
Open heart surgery, surgical repair and/or replacement of your aortic valve, are not experimental 
procedures. 
If you are assigned to the SAVR group, your doctors will replace your diseased aortic valve through 
open heart surgery. During surgery, you are asleep under general anesthesia. SAVR often requires 
a median sternotomy, where the bone in the center of the chest (sternum) is split down the middle. 
The chest is then opened to provide your doctor with access to the heart and chest cavity, in order 
to replace your aortic valve. Your surgery is performed while the function of your heart is taken over 
by a heart lung machine (called CPB for cardiopulmonary bypass). 
You may have a TEE (a thin tube sits in the esophagus and sends out sounds waves to create a 
picture of your heart) and a temporary pacemaker (thin wire threaded through your vein to right side 
of heart to keep your heart rate and rhythm steady) during the procedure. 
Your doctor may remove any tissue and calcium deposits that are interfering with the normal 
function of the valve. Your damaged valve may be completely removed. The new valve will be 
sewn into the space where your own valve used to be. After your doctor makes sure your valve is 

 
 
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working properly, blood flow will be restored to your heart and the incisions will be closed. You will 
also have blood drawn for testing before and after the procedure. 
If your doctor is unable to implant (insert) the study valve in you during the TAVI or SAVR 
procedure, you will still be considered enrolled in the study and will need to return to the clinic for 
the required follow-up visits as described in the “Follow-up Visits after TAVI and SAVR” section. 
After TAVI and SAVR Procedure: 
After the TAVI and SAVR procedure, your study doctors will continue to monitor your progress and 
recovery. 
You will have the following tests performed within the two days following the procedure and before 
you are discharged from the hospital: 
•  
Determination of neurological (brain) status where you will be asked to answer a series of 
questions and perform a series of tasks 
•  
Blood tests (about 2 tablespoons) 
•  
Echocardiogram (TTE) 
•  
ECG 
Follow-up Visits after TAVI and SAVR: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months (1 
year), 18 months, 24 months (2 years), and 3, 4, and 5 years after the procedure. Most of the 
follow-up tests and examinations are routine, not experimental. Each visit will take about 1 ½ to 2 
hours.  
 
Your evaluations at 30 days, 6 and 18 months will include: 
• 
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Blood tests (about 2 tablespoons) – 30 day visit only 
• 
Walking test – 30 day visit only 
• 
Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12 months, 24 months, and 3, 4, 5 years will include: 
• 
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last clinic visit 
• 
Blood tests (about 2 tablespoons) 
• 
Echocardiogram (TTE) 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Walking test – 12 and 24 months visits only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted via phone to complete a 
Quality of Life Questionnaire. 
If, during the 5 years of follow-up, you have additional heart surgeries or cath lab procedures to 
work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological (brain) 
status within 24 hours after each additional procedure. 

 
 
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If you have a stroke, have been inform by a doctor that you experienced a stroke, or experience  
any of the following symptoms, notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible: 
sudden numbness, tingling, loss of movement (especially on 1 side of the body), vision changes, 
confusion or trouble understanding simple statements, severe headaches, or seizures.  Any of 
these symptoms could indicate that you are having problems with your neurological (brain) function.  
If a doctor confirms that you had a stroke, you will be asked to come to the clinical to have tests 
performed to determine your neurological (brain) status where you will be asked to answer a series 
of questions and perform a series of tasks. These tests will be performed at 7 days, 30 days and 3 
months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or are 
hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis.  Your study doctor will determine if you will need to have another valve 
implanted.   
In the event of your death, we will request an autopsy. We will also request that either the whole 
heart and valve or just the valve are removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the investigational valve. 
Your family and your "legally authorized representatives", have the right to refuse the autopsy and 
refuse the request to remove the heart and/or valve even if you sign this consent form. 

 
 
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TAVI 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest – heart stops beating and blood flow through the body is interrupted or 
stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to improve 
blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  
 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able to 
supply oxygen to the body 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 

 
 
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 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, blood 
clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the device 
from where it was originally placed 
 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 
 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure is 
expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs in 
the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 
 
Permanent disability – injury that does not allow that impairs normal/previous physical 
or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 
 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 
 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result in 
a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed space 
that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  
o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical impulses 
to the heart to help your heart beat normally 

 
 
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o 
Atrio-ventricular node block – a block in the electrical path from the top part of 
the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom part 
of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part of 
the heart (ventricles) 
 
Encephalopathy – altered mental state 
 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 
 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 
 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the 
aortic valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known. 
 
SAVR 
Although SAVR is not experimental there are potential risks associated with the procedure. These 
risks are the same even if you undergo the SAVR procedure and you decide not to participate in 
this study.  Some of these risks include, but may not be limited to the following: 
 
Obstruction of blood flow to the heart (angina) resulting in damage to the heart tissue 
 
(myocardial infarction/heart attack) 
 
Abnormal heart beat (cardiac arrhythmia and dysrhythmia) 
 
Blood leaking around the outside of the prosthetic valve (paravalvular leak) or any 
 
Problem with the valve that causes leaking of blood after the valve has closed 
(transvalvular leak). 
 
Damage to red blood cells (hemolysis) that can result in anemia (decreased red blood 
cells) 
 
Death 

 
 
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 
Inflammation of the lining of the heart (endocarditis) 
 
Heart failure 
 
Any problem with the prosthetic valve that causes narrowing of the valve opening 
(stenosis) 
 
Blood clots that develop in the heart of on the replacement valve. These clots may break 
loose and travel through the bloodstream (thromboembolism). This problem may cause 
stroke (decrease blood flow to the brain causing damage to the brain) or heart attack 
 
Failure of the valve to open and close properly 
If you become pregnant there maybe risks, discomforts, or side effects to you and the embryo/fetus 
that are not yet known.  Please notify your study doctor as soon as possible to discuss any of these 
potential risks. 
 
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how much 
radiation you will get, in the following descriptions the radiation is compared to the amounts that 
people are exposed to in daily life. There is radiation that naturally occurs from space and from 
rocks in the soil. This natural radiation is greater at higher altitudes. 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure is 
less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 
The estimated radiation exposure for the valve procedure is approximately 10-15 times the amount 
of radiation exposure received in one year from background radiation (naturally occurring radiation 
you are exposed to everyday). The exposure is approximately the amount an occupational worker 
is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have extra 
follow-up visits with your doctor to watch your recovery more closely. 
Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 
POSSIBLE BENEFITS 
The possible benefits you may receive from participating in this research are that you may be able 
to receive a new heart valve without having open-heart surgery. Another possible benefit is that 
your new valve may work better than the way your diseased valve currently works. This may 
improve how you feel and may improve your daily activity. 
Your participation in this research may improve procedures that may guide the future treatment of 
heart surgery, by using procedures that are less invasive, meaning less cutting, entering or 
breaking through the body, which may benefit others in the future. However, there is no guarantee 
that you will benefit from being in this research. 
ALTERNATIVE TREATMENTS 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to replace 
the aortic valve.  For patients who are at high risk for open heart surgery, other treatment options 

 
 
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include percutaneous (through an artery in the groin) aortic valve implantation, or medical 
management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study doctor 
about other treatment options you may have. 
IF PROBLEMS DEVELOP 
If you believe that you have been injured as a result of your participation in the study, you should 
notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible or in serious cases, go to the 
emergency room.  
Immediate necessary medical care is available at [Name of institution(s)] in the event that you are 
injured as a result of your participation in this research study.  
If you are assigned to the TAVI group  
Immediate necessary medical care is available at [name of institution] in the event that you are 
injured as a result of your participation in this research study.  
For those patients receiving the investigational device and the TAVI procedure, 
Medtronic has agreed to pay back [name of institutions that are parties to the CTA] for the costs of 
medical or surgical care they provide for any serious and unanticipated illness or injury under the 
following conditions: 
 
The illness or injury must be related to a defect or malfunction of the investigational device 
or in the TAVI procedure as described in the Protocol, and not related to procedures that 
are routine standard of care. 
 
The illness or injury cannot be caused by (a) the negligence or intentional misconduct of 
the study staff or [name of institutions that are parties to the CTA]; (b) because the study 
staff or [name of institution(s)] that are parties to the CTA] did not follow the protocol for the 
study; or (c) the natural progression of your illness. 
 
The illness or injury must have happened before the study closes (last patient is seen for 
the 5 year follow-up visit) at this [Name of institution(s)]. 
 
[Name of institution(s) that are parties to the CTA] must notify Medtronic within one year of 
the date the study closes at all study sites or before the study closes at this site, whichever 
is earlier. 
Subject to the above conditions, Medtronic will pay back the costs that are not covered by your 
health insurance or Medicare. The amount Medtronic will pay back is the amount Medicare pays 
[name of institution(s) that are parties to the CTA] plus 10%. 
If you are assigned to the SAVR group  
In the event of physical injury or physical illness related to a procedure required for the SAVR 
group, no monetary compensation or subsidized (paid) will be provided. Medical treatment will be 
routinely provided to you by any person involved in this study including the study doctors, or the 
hospital. Any immediate medical treatment, however, that may be necessary will be provided. 
By agreeing to the above, you do not waive any of your legal rights which you otherwise would 
have as a research subject, nor do you release the study sponsor (Medtronic, Inc.), study doctors, 
or the hospital from liability for negligence. 
PAYMENT FOR PARTICIPATION IN THE STUDY 
You will not be paid to take part in the study. However, you may be reimbursed for local mileage 
and parking expenses directly related to any study related visits. Your study doctor or research 
coordinator will tell you how to get reimbursement.  
There is no monetary advantage to the study doctor for participation in this study. 
MEDICAL EXPENSES 

 
 
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Your private or public health insurance company (for example Medicare) will be billed for the valve 
procedure and the cardiac catheterization and other procedures that are required by the study and 
you will be responsible for paying for any co-payment, co-insurance or deductible. It is possible that 
your private or public health insurance will not pay for some or all of the procedures, including the 
valve procedure or the cardiac catheterization procedure because you are participating in this 
study. Any costs not covered by your public or private insurance will be your responsibility. You 
should discuss the estimate of these costs with your study doctor. You will not be charged for the 
cost of collecting the data for this study and other clinic visits and diagnostic tests done solely for 
the purposes of this study. 
BASIS OF PARTICIPATION 
Your participation in this study is voluntary. If you refuse to be in this study there will be no penalty 
or loss of benefits to which you are otherwise entitled. You may withdraw from the study at any time 
and will not lose your benefits or be treated any differently as a result of withdrawing from the study. 
Any new findings (decisions or conclusions) that may influence your willingness to participate will 
be provided to you.  If you decide to leave the study before it is finished, please tell one of the 
persons listed in the section below “Obtaining Additional Information”. It may be requested that, if 
you withdraw, you return to your study doctor for a final visit. 
The study doctor may end your participation in the study at any time if: 
 
He or she determines it is not in the best interest of your health 
 
The study doctor loses contact with you and you do not return for your study visits as 
scheduled 
 
You refuse to allow the use of private health information during the course of the study 
The study doctor will make the decision and let you know if it is not possible for you to continue in 
the study. 
You may be removed from the study without your consent if the sponsor (Medtronic, Inc.) ends the 
study.  If this happens, you will be notified and the reasons will be explained to you.  Your physician 
will continue to provide the appropriate medical therapy. 
PERMISSION FOR ACCESS TO AND USE OF HEALTH INFORMATION 
This section governs how your health information will be used and shared by the study doctors 
during and after the study. The health information that may be used and shared includes all 
information collected during the study and any health information in your medical records that is 
relevant to the study. 
1. PROVIDERS’ DISCLOSURE OF HEALTH INFORMATION IN YOUR RECORDS 
You agree to permit [hospital and/or clinic], your doctors, and your other health care providers 
(“Providers”) to share health information in your medical records with [investigator(s)] and 
[his/her/his/her/its] staff (“Researchers”). You agree to permit Providers to share your health 
information: 
 
With the Researchers; 
 
With the study sponsor, Medtronic, Inc. and its agents and contractors (together 
“Medtronic”); 
 
As required by law; 
o With government organizations and review boards required to watch over the safety 
and effectiveness of medical products and therapies and the conduct of research; and 
o With other persons who are required to watch over the safety and effectiveness of 
medical products and therapies and the conduct of research. 
2. RESEARCHER’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
You agree to permit the Researchers to use and share your health information: 

 
 
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 
Among themselves to conduct the study; 
 
With other researchers in the study to conduct the study; 
 
With Medtronic; 
 
With government organizations and review boards required to watch over the safety and 
effectiveness of medical products and therapies and the conduct of research; and 
 
With other persons who are required to watch over the safety and effectiveness of medical 
products and therapies and the conduct of research. 
Once Providers or Researchers have shared your health information with a third party, the 
information may be subject to further sharing by the third party. Federal privacy laws may no longer 
protect it from further sharing. 
While the study is in progress, you will not be allowed to see your health information that is created 
or collected for the study. After the study is finished, you may see this information as described in 
the [hospital/clinical trial site]’s Notice of Information practices. 
This permission to share your health information does not have an ending date. You do not have to 
give this permission, but if you do not, you will not be allowed to be in the study. You may change 
your mind and take back this permission to use your health information at any time. To take back 
this permission, you must write to [name and contact information]. If you take back this permission, 
you cannot continue in the study. Even if you take back this permission, Medtronic and 
Researchers may continue to use and share the health information already received as described 
in this informed consent 
Economic Study 
This study contains a health economics review that will be done to compare the in-hospital, 12 
month and 24 month follow-up medical care resource utilization and cost for patients in each of the 
treatment groups.  As part of this study, you may be asked to sign a separate document that gives 
us your permission to review your billing information sent directly from the Medicare system in order 
to evaluate medical cost data.  This information will be kept strictly confidential and be used solely 
to assess the medical expenses which occur as a direct result of participating in the Medtronic 
CoreValve™ SURTAVI Trial. 
Quality of Life Questionnaire 
Medtronic CoreValve™ SURTAVI Trial will also contain a quality of life study. As part of this study, 
your research coordinator will have you or your legal representative complete a questionnaire 
called a Quality of Life Questionnaire.  You will need to complete this questionnaire when you are 
enrolled in the study and 1 month, 3 months, 6 months, 12 months, 18 months, 2 years, 3 years, 4 
years and 5 years after your study procedure. 
OBTAINING ADDITIONAL INFORMATION 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. The study doctor will inform you of any new significant information, when 
it becomes available, which may affect your willingness to continue to participate in this study. If 
you have any questions about this study or if you experience any health problems, you should 
contact Dr. Principal Investigator at xxx-xxx-xxxx. 
If you have questions about your rights as a participant in this study, you should contact the 
chairman of the Institutional Review Board at xxx-xxx-xxxx. 
MEDTRONIC’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
This section describes what Medtronic as study sponsor will do with the study data, including your 
health information received during the study. 

 
 
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Medtronic will keep your health information confidential in keeping with all applicable laws and 
regulations. Medtronic may use your health information to conduct this study. Medtronic may use 
your health information for other purposes, such as: 
 
Watch over and improve the performance of its device; 
 
New medical research; 
 
Proposals for making new medical products or procedures; and 
 
Other business purposes. 
Any reports or publications about the study or any other research will not include your name or a 
description of you. Any records identifying you will not be made publically available.  Information 
received during the study will not be used to market to you; your name will not be placed on any 
mailing lists or sold to anyone for marketing purposes. 
The US Food and Drug Administration’s regulations, as well as other applicable laws, control 
Medtronic’s work in developing and assuring the safety and quality performance of its medical 
devices. Medtronic may disclose your health information to the FDA, as well as to other US and 
foreign government authorities responsible for assuring the safety of medical devices. Medtronic 
also may disclose your health information to institutional review boards and other persons who are 
required to watch over the safety and effectiveness of medical products and therapies and the 
conduct of research. You agree to allow Medtronic to use study data in these ways. You also agree 
to allow FDA and other governmental authorities to inspect your health information. 
 
PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION  
Please indicate below whether you would like us to notify your primary care physician or your 
specialist of your participation in this study.   
(Initial only one box). 
 
Yes, I want the study doctor to inform my primary care physician/specialist of my 
participation in this study 
 
No. I do not want the study doctor to inform my primary care physician/specialist of 
my participation in this study. 
 
I do not have a primary care physician/specialist. 
 
 
The study doctor is my primary care physician/specialist. 
 
 

 
 
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CONSENT 
I confirm that: 
 
I have read the informed consent form of this study and my physician has answered all my 
questions regarding the study.  
 
I had sufficient time to consider my participation into this study, I am aware that 
participation into this study is completely voluntary, and I agree to follow the instructions 
from the investigator. 
 
I realize that I may decide to refuse participation or stop participation at any time without 
penalty and without affecting the quality of my health care or the relationship with my 
physician.  
 
I understand and agree that personal information about me will be collected from my 
medical records, used and processed (manually and by computer) by the manufacturer of a 
medical device used in my treatment or any other designated party that is involved in the 
study (e.g. hospital, physician, regulatory authorities, ethics committees).  
 
I understand and agree that representatives from Medtronic, regulatory authorities and the 
Institutional Review Board will be granted direct access to my medical records.  
 
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigation. 
 
I fully understand there is limited experience with this device in humans and that its safety 
and effectiveness have not been established and there are risks of serious complications 
associated with this study. 
 
I also understand that the doctors might determine after I give consent that it is not possible 
to implant the study valve. 
 
I hereby give my consent to participate in the “Medtronic CoreValve™SURTAVI Trial”. I have been 
given a copy of this consent form, and am also aware that the investigator will keep a copy in his or 
her files. 
 
 
__________________________________________ 
Patient Name (please print) 
 
 
__________________________________  
 
_______________ 
Patient Signature   
 
 
 
 
Date  
  (MM/DD/YYYY) 
 
 
Statement from Person Obtaining Consent 
I certify that I have explained the nature of the device and the study to the above-named person. 
I have also explained the contents of this informed consent form to the above-named person. I 
have asked whether or not there are any questions. I have answered any questions that were 
raised by this person. 
 
 
______________________________________ 
Person Obtaining Consent Name (please print) 
 
 
__________________________________  
 
_______________ 
Signature of Person Obtaining Consent  
 
 
Date  
(MM/DD/YYYY) 

 
 
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United States – Roll-in Subjects 
INFORMED CONSENT FORM  
FOR ROLL-IN SUBJECTS 
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this research study and how you 
might take part in it. By signing this form, you will show that you understand and that you agree to 
take part in this research study. Your signature on this form is required before you can take part 
in this research study. 
BACKGROUND 
You are being asked to take part in a research study entitled “Medtronic CoreValve™ SURTAVI 
Trial” because you have a disease of your aortic valve.  This disease is called aortic stenosis. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the left 
ventricle (main pumping chamber of the heart) into the aorta (main artery delivering blood to the 
body). If the valve becomes abnormally narrow through a process of thickening and stiffening 
(aortic stenosis) the heart must work harder to pump the same amount of blood with each beat. 
As the heart works harder, the heart muscle thickens (hypertrophy), and the heart chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve is 
the standard treatment. 
As an alternative to open heart surgery, the Medtronic CoreValve™ System has been developed 
to replace a diseased aortic heart valve without the need for open heart surgery. This system 
allows the percutaneous aortic valve (study valve) to be implanted (inserted) through a long, thin 
flexible tube that is inserted through an incision in the skin and threaded through the bloodstream 
(percutaneous). 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
You are being asked to participate in this study because doctors have determined your aortic 
valve is no longer working properly. However, your doctors have also decided that your risk of 
experiencing major problems while undergoing open-heart surgery is moderate due to medical 
reasons or anatomical reasons (relating to how and where your heart, aortic valve and blood 
vessels are placed within your body). This means that you doctor believes your health is 
acceptable for open-heart surgery, but there are still a risk of potential problems. 
PURPOSE OF THE STUDY 
The purpose of this clinical  study is to determine if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions 
as you. 
The study valve is considered an “investigational device”, which means that clinical studies are 
required to determine if it is safe and provides clinical benefit. Medtronic, Inc. is sponsoring this 
study to obtain data on the safety and performance of the investigational device. The Medtronic 
CoreValve™ System includes the valve described below and two parts that help load and deliver 
the valves correctly. 
This study will involve approximately 1600 subjects at up to 115 hospitals in the United States 
and around the world, and is anticipated to take approximately 8 years to complete. Your 
participation in this study is expected to last approximately five years from the day you are 
enrolled in the study. Annual follow-up may be extended to up to 10 years after the implant 
procedure. 

 
 
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STUDY DEVICES 
The study valve are made from animal tissue attached to a metal frame.  
The study valve is designed to be implanted (inserted) using a delivery system catheter (long, thin 
flexible tube) to replace your diseased aortic heart valve without open-heart surgery. Once it is 
implanted, CoreValve™ study valves acts in the same method of the native valve. 
 
The Medtronic CoreValve system is approved by the US Food & Drug Administration (FDA) since 
2014 and it has been approved in other parts of the world since 2006. It has been implanted in 
over 45,000 patients. The Medtronic CoreValve™ System is currently approved for use in Europe, 
South America, and parts of Asia.  
 
 
 
 
 
 
 
 
 
 
 
PROCEDURES TO BE FOLLOWED 
If you agree to be in this study, and after you have signed this informed consent form, data such 
as your age, gender, medical history and medication use will be recorded. You will undergo the 
following tests: 
• 
Physical examination 
• 
Computed tomography (CT) - a scan performed using an x-ray machine, which is linked to 
a computer to take pictures of your body. Sometimes a CT will require the use of a type of 
dye that makes the kidneys work harder and may be harmful to the kidneys. You may have 
an MRI in place of a CT scan if your doctor believes your kidneys are not working well 
enough for you to have a CT scan. MRI stands for magnetic resonance imaging and is a 
test that uses a strong magnet and a complex computer system to produce detailed images 
of your internal organs and soft body tissues. 
• 
Blood tests (about 2 tablespoons) 
• 
Echocardiography (transthoracic echocardiogram (TTE)) - a test that uses sound waves to 
take pictures of your heart and measure the degree of narrowing of your aortic valve; a 
probe with gel is placed on the outside of your chest to take pictures of your heart 
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
• 
Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
If you are of child-bearing potential, we will ask you to take a pregnancy test. If you are pregnant, 
you will not be able to participate in this study. 
These procedures and tests are standard procedures and are not experimental. If you have 
already had any of these tests performed before, they may to be used for the study if your study 
doctor determines they don’t need to be repeated for study purposes.  

 
 
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The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you 
will not be allowed to participate in the study. 
If your doctor and the committee decide you are eligible to be in the study, you will be one of the 
first three (3) patients at this hospital to be enrolled in this study. You will receive a transcatheter 
aortic valve implant (TAVI).  
Your enrollment in the study will begin once you sign this consent and you are assigned to the 
roll-in treatment group. If you are enrolled in the study, you will be required to have the following 
additional tests completed within 14 days prior to the procedure (TAVI): 
• 
Physical exam, including a determination of neurological (brain) status where you will be 
asked to answer a series of questions and perform a series of tasks such as writing and 
drawing 
• 
Blood tests (about 2 tablespoons) 
• 
Walking test – a test that records your breathing, heart rate, and how you feel after 6 
minutes of walking 
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life Questionnaires (QOL). 
TAVI Procedure: 
The study valve is an experimental valve which means you can only receive the valve if you are 
part of this study.  
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor.  You may be advised to continue these medications for at 
least three months following your procedure.  
Before the procedure you will be given an antibiotic (a medicine that kills bacteria or germs) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about 2 tablespoons) and an ECG before the procedure.   
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary 
during the procedure, you will be put under general anesthesia at that time. 
Your study doctor will decide what locations are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary. These pictures are described 
in the next paragraphs.  Additionally, your study doctor will decide if performing a surgical incision 
to any of the site(s) is necessary. 
During the procedure you may have a transesophageal echocardiogram which is also called a 
TEE. This test uses sound waves to take a closer look at the inside structures of the heart. If your 
doctor decides this picture is necessary, to perform the test you will swallow a thin flexible tube 
with a special tip. This tube sits in the esophagus (the tube that connects the mouth to the 
stomach). The special tip of the tube sends out sound waves (ultrasound) that echo within the 
chest wall. The esophagus is located behind the heart so these echoes are picked up and create 
a picture of the heart that is displayed on a video monitor. The pictures will allow your study 
doctor to take a closer look at your valve. 

 
 
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You will have a temporary pacemaker put in place during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins and threaded 
through your vein into the right side of your heart. The wire is attached to a battery operated 
device outside of your body. This temporary pacemaker will help keep your heart rate (speed) 
and rhythm steady. This temporary pacemaker will not be removed for at least 48 hours after 
your TAVI procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. Balloon valvuloplasty is a procedure used to widen a stiff or narrowed heart valve. A 
wire and a thin tube are guided by x-rays through the heart and positioned through the diseased 
heart valve. A balloon is placed over the wire and inflated, enlarging the opening through the 
diseased valve allowing the study valve to be placed. 
Your doctor will then implant (insert) the study valve through the long, thin flexible tube that is 
inserted through an incision in the skin and threaded through the bloodstream. TAVI is performed 
using x-ray machines which will allow your doctor to see the study valve, your blood vessels and 
heart. The study valve will be guided through your blood vessels to your existing aortic valve and 
then the study valve will be placed over your existing valve. 
During the TAVI procedure, your doctor will perform angiography (x-ray pictures) and ECGs 
(recordings of the electrical impulses of your heart through patches placed on the chest) to 
observe your heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study 
valve. 
AFTER TAVI PROCEDURE: 
After the TAVI procedure, your study doctors will continue to monitor your progress and recovery. 
You will have the following tests performed within the two days following the procedure and 
before you are discharged from the hospital: 
•  
Determination of neurological (brain) status where you will be asked to answer a series of 
questions and perform a series of tasks 
•  
Blood tests (about 2 tablespoons) 
•  
Echocardiogram (TTE) 
•  
ECG 
FOLLOW-UP VISITS AFTER TAVI PROCEDURE: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months 
(1 year), 18 months, 24 months (2 years), and 3, 4, and 5 years after the procedure. Most of the 
follow-up tests and examinations are routine, not experimental. Each visit will take about 1 ½ to 2 
hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
• 
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Blood tests (about 2 tablespoons) – 30 day visit only 
• 
Walking test – 30 day visit only 
• 
Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12 months, 24 months, and 3, 4, 5 years will include: 
• 
Physical examination, including a determination of neurological (brain) status where you 
will be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last clinic visit 

 
 
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• 
Blood tests (about 2 tablespoons) 
• 
Echocardiogram (TTE) 
• 
Quality of Life Questionnaires 
• 
ECG 
• 
Walking test – 12 and 24 months visits only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted via phone to 
complete a Quality of Life Questionnaire. 
If, during the 5 years of follow-up, you have additional heart surgeries or cath lab procedures to 
work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological 
(brain) status within 24 hours after each additional procedure. 
If you have a stroke, have been inform by a doctor that you experienced a stroke, or experience  
any of the following symptoms, notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as 
possible: sudden numbness, tingling, loss of movement (especially on 1 side of the body), vision 
changes, confusion or trouble understanding simple statements, severe headaches, or seizures.  
Any of these symptoms could indicate that you are having problems with your neurological (brain) 
function.  If a doctor confirms that you had a stroke, you will be asked to come to the clinical to 
have tests performed to determine your neurological (brain) status where you will be asked to 
answer a series of questions and perform a series of tasks. These tests will be performed at 7 
days, 30 days and 3 months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or 
are hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis.  Your study doctor will determine if you will need to have another valve 
implanted.   
In the event of your death, we will request an autopsy. We will also request that either the whole 
heart and valve or just the valve are removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the investigational valve. 
Your family and your "legally authorized representatives", have the right to refuse the autopsy 
and refuse the request to remove the heart and/or valve even if you sign this consent form. 
 
POSSIBLE RISKS AND DISCOMFORTS 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest –heart stops beating and blood flow through the body is interrupted 
or stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to 
improve blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  

 
 
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 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able 
to supply oxygen to the body 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 
 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, 
blood clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the 
device from where it was originally placed 
 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 
 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure 
is expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs 
in the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 

 
 
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 
Permanent disability – injury that does not allow that impairs normal/previous 
physical or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 
 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 
 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result 
in a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed 
space that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the 
heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  
o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical 
impulses to the heart to help your heart beat normally 
o 
Atrio-ventricular node block – a block in the electrical path from the top part 
of the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom 
part of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part 
of the heart (ventricles) 
 
Encephalopathy – altered mental state 
 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 

 
 
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 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 
 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the 
aortic valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known. If you 
become pregnant there maybe risks, discomforts, or side effects to you and the embryo/fetus that 
are not yet known.  Please notify your study doctor as soon as possible to discuss any of these 
potential risks. 
 
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how 
much radiation you will get, in the following descriptions the radiation is compared to the amounts 
that people are exposed to in daily life. There is radiation that naturally occurs from space and 
from rocks in the soil. This natural radiation is greater at higher altitudes. 
 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure 
is less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 
The estimated radiation exposure for the valve procedure is approximately 10-15 times the 
amount of radiation exposure received in one year from background radiation (naturally occurring 
radiation you are exposed to everyday). The exposure is approximately the amount an 
occupational worker is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have 
extra follow-up visits with your doctor to watch your recovery more closely. 
Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 
POSSIBLE BENEFITS 
The possible benefits you may receive from participating in this research are that you may be 
able to receive a new heart valve without having open-heart surgery. Another possible benefit is 
that your new valve may work better than the way your diseased valve currently works. This may 
improve how you feel and may improve your daily activity. 
Your participation in this research may improve procedures that may guide the future treatment of 
heart surgery, by using procedures that are less invasive, meaning less cutting, entering or 
breaking through the body, which may benefit others in the future. However, there is no 
guarantee that you will benefit from being in this research. 
ALTERNATIVE TREATMENTS 

 
 
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The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other treatment 
options include percutaneous (through an artery in the groin) aortic valve implantation, or medical 
management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study 
doctor about other treatment options you may have. 
IF PROBLEMS DEVELOP 
If you believe that you have been injured as a result of your participation in the study, you should 
notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible or in serious cases, go to the 
emergency room.  
Immediate necessary medical care is available at [Name of institution(s)] in the event that you are 
injured as a result of your participation in this research study  
Medtronic has agreed to pay back [name of institutions that are parties to the CTA] for the costs 
of medical or surgical care they provide for any serious and unanticipated illness or injury under 
the following conditions: 
 
The illness or injury must be related to a defect or malfunction of the investigational 
device or in the TAVI procedure as described in the Protocol, and not related to 
procedures that are routine standard of care. 
 
The illness or injury cannot be caused by (a) the negligence or intentional misconduct of 
the study staff or [name of institutions that are parties to the CTA]; (b) because the study 
staff or [name of institution(s)] that are parties to the CTA] did not follow the protocol for 
the study; or (c) the natural progression of your illness. 
 
The illness or injury must have happened before the study closes (last patient is seen for 
the 5 year follow-up visit) at this [Name of institution(s)]. 
 
[Name of institution(s) that are parties to the CTA] must notify Medtronic within one year 
of the date the study closes at all study sites or before the study closes at this site, 
whichever is earlier. 
Subject to the above conditions, Medtronic will pay back the costs that are not covered by your 
health insurance or Medicare. The amount Medtronic will pay back is the amount Medicare pays 
[name of institution(s) that are parties to the CTA] plus 10%. 
PAYMENT FOR PARTICIPATION IN THE STUDY 
You will not be paid to take part in the study. However, you may be reimbursed for local mileage 
and parking expenses directly related to any study related visits. Your study doctor or research 
coordinator will tell you how to get reimbursement.  
There is no monetary advantage to the study doctor for participation in this study. 
MEDICAL EXPENSES 
Your private or public health insurance company (for example Medicare) will be billed for the 
valve procedure and the cardiac catheterization and other procedures that are required by the 
study and you will be responsible for paying for any co-payment, co-insurance or deductible. It is 
possible that your private or public health insurance will not pay for some or all of the procedures, 
including the valve procedure or the cardiac catheterization procedure because you are 
participating in this study. Any costs not covered by your public or private insurance will be your 
responsibility. You should discuss the estimate of these costs with your study doctor. You will not 
be charged for the cost of collecting the data for this study and other clinic visits and diagnostic 
tests done solely for the purposes of this study. 
BASIS OF PARTICIPATION 
Your participation in this study is voluntary. If you refuse to be in this study there will be no 
penalty or loss of benefits to which you are otherwise entitled. You may withdraw from the study 
at any time and will not lose your benefits or be treated any differently as a result of withdrawing 
from the study. Any new findings (decisions or conclusions) that may influence your willingness to 

 
 
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participate will be provided to you.  If you decide to leave the study before it is finished, please tell 
one of the persons listed in the section below “Obtaining Additional Information”. It may be 
requested that, if you withdraw, you return to your study doctor for a final visit. 
The study doctor may end your participation in the study at any time if: 
 
He or she determines it is not in the best interest of your health 
 
The study doctor loses contact with you and you do not return for your study visits as 
scheduled 
 
You refuse to allow the use of private health information during the course of the study 
The study doctor will make the decision and let you know if it is not possible for you to continue in 
the study. 
You may be removed from the study without your consent if the sponsor (Medtronic, Inc.) ends 
the study.  If this happens, you will be notified and the reasons will be explained to you.  Your 
physician will continue to provide the appropriate medical therapy. 
 
PERMISSION FOR ACCESS TO AND USE OF HEALTH INFORMATION 
This section governs how your health information will be used and shared by the study doctors 
during and after the study. The health information that may be used and shared includes all 
information collected during the study and any health information in your medical records that is 
relevant to the study. 
 
1. PROVIDERS’ DISCLOSURE OF HEALTH INFORMATION IN YOUR RECORDS 
You agree to permit [hospital and/or clinic], your doctors, and your other health care providers 
(“Providers”) to share health information in your medical records with [investigator(s)] and 
[his/her/his/her/its] staff (“Researchers”). You agree to permit Providers to share your health 
information: 
 
With the Researchers; 
 
With the study sponsor, Medtronic, Inc. and its agents and contractors (together 
“Medtronic”); 
 
As required by law; 
o With government organizations and review boards required to watch over the safety 
and effectiveness of medical products and therapies and the conduct of research; 
and 
o With other persons who are required to watch over the safety and effectiveness of 
medical products and therapies and the conduct of research. 
2. RESEARCHER’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
You agree to permit the Researchers to use and share your health information: 
 
Among themselves to conduct the study; 
 
With other researchers in the study to conduct the study; 
 
With Medtronic; 
 
With government organizations and review boards required to watch over the safety and 
effectiveness of medical products and therapies and the conduct of research; and 
 
With other persons who are required to watch over the safety and effectiveness of 
medical products and therapies and the conduct of research. 
Once Providers or Researchers have shared your health information with a third party, the 
information may be subject to further sharing by the third party. Federal privacy laws may no 
longer protect it from further sharing. 
While the study is in progress, you will not be allowed to see your health information that is 
created or collected for the study. After the study is finished, you may see this information as 
described in the [hospital/clinical trial site]’s Notice of Information practices. 

 
 
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This permission to share your health information does not have an ending date. You do not have 
to give this permission, but if you do not, you will not be allowed to be in the study. You may 
change your mind and take back this permission to use your health information at any time. To 
take back this permission, you must write to [name and contact information]. If you take back this 
permission, you cannot continue in the study. Even if you take back this permission, Medtronic 
and Researchers may continue to use and share the health information already received as 
described in this informed consent 
Economic Study 
This study contains a health economics review that will be done to compare the in-hospital, 12 
month and 24 month follow-up medical care resource utilization and cost for patients in each of 
the treatment groups.  As part of this study, you may be asked to sign a separate document that 
gives us your permission to review your billing information sent directly from the Medicare system 
in order to evaluate medical cost data.  This information will be kept strictly confidential and be 
used solely to assess the medical expenses which occur as a direct result of participating in the 
Medtronic CoreValve™ SURTAVI Trial. 
Quality of Life Questionnaire 
Medtronic CoreValve™ SURTAVI Trial will also contain a quality of life study. As part of this study, 
your research coordinator will have you or your legal representative complete a questionnaire 
called a Quality of Life Questionnaire.  You will need to complete this questionnaire when you are 
enrolled in the study and 1 month, 3 months, 6 months, 12 months, 18 months, 2 years, 3 years, 
4 years and 5 years after your study procedure. 
OBTAINING ADDITIONAL INFORMATION 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. The study doctor will inform you of any new significant information, 
when it becomes available, which may affect your willingness to continue to participate in this 
study. If you have any questions about this study or if you experience any health problems, you 
should contact Dr. Principal Investigator at xxx-xxx-xxxx. 
If you have questions about your rights as a participant in this study, you should contact the 
chairman of the Institutional Review Board at xxx-xxx-xxxx. 
MEDTRONIC’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
This section describes what Medtronic as study sponsor will do with the study data, including your 
health information received during the study. 
Medtronic will keep your health information confidential in keeping with all applicable laws and 
regulations. Medtronic may use your health information to conduct this study. Medtronic may use 
your health information for other purposes, such as: 
 
Watch over and improve the performance of its device; 
 
New medical research; 
 
Proposals for making new medical products or procedures; and 
 
Other business purposes. 
Any reports or publications about the study or any other research will not include your name or a 
description of you. Any records identifying you will not be made publically available.  Information 
received during the study will not be used to market to you; your name will not be placed on any 
mailing lists or sold to anyone for marketing purposes. 
The US Food and Drug Administration’s regulations, as well as other applicable laws, control 
Medtronic’s work in developing and assuring the safety and quality performance of its medical 
devices. Medtronic may disclose your health information to the FDA, as well as to other US and 
foreign government authorities responsible for assuring the safety of medical devices. Medtronic 
also may disclose your health information to institutional review boards and other persons who 
are required to watch over the safety and effectiveness of medical products and therapies and the 
conduct of research. You agree to allow Medtronic to use study data in these ways. You also 
agree to allow FDA and other governmental authorities to inspect your health information. 
 

 
 
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PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION  
Please indicate below whether you would like us to notify your primary care physician or your 
specialist of your participation in this study.   
(Initial only one box). 
 
Yes, I want the study doctor to inform my primary care physician/specialist of my 
participation in this study 
 
No. I do not want the study doctor to inform my primary care physician/specialist of 
my participation in this study. 
 
I do not have a primary care physician/specialist. 
 
The study doctor is my primary care physician/specialist. 
 
 

 
 
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CONSENT 
I confirm that: 
 
I have read the informed consent form of this study and my physician has answered all 
my questions regarding the study.  
 
I had sufficient time to consider my participation into this study, I am aware that 
participation into this study is completely voluntary, and I agree to follow the instructions 
from the investigator. 
 
I realize that I may decide to refuse participation or stop participation at any time without 
penalty and without affecting the quality of my health care or the relationship with my 
physician.  
 
I understand and agree that personal information about me will be collected from my 
medical records, used and processed (manually and by computer) by the manufacturer of 
a medical device used in my treatment or any other designated party that is involved in 
the study (e.g. hospital, physician, regulatory authorities, ethics committees).  
 
I understand and agree that representatives from Medtronic, regulatory authorities and 
the Institutional Review Board will be granted direct access to my medical records.  
 
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigation. 
 
I fully understand there is limited experience with this device in humans and that its safety 
and effectiveness have not been established and there are risks of serious complications 
associated with this study. 
 
I also understand that the doctors might determine after I give consent that it is not 
possible to implant the study valve. 
 
I hereby give my consent to participate in the “Medtronic CoreValve™ SURTAVI Trial”. I have 
been given a copy of this consent form, and am also aware that the investigator will keep a copy 
in his or her files. 
 
 
__________________________________________ 
Patient Name (please print) 
 
 
__________________________________  
 
_______________ 
Patient Signature   
 
 
 
 
Date  
 (MM/DD/YYYY) 
 
 
Statement from Person Obtaining Consent 
I certify that I have explained the nature of the device and the study to the above-named person. 
I have also explained the contents of this informed consent form to the above-named person. I 
have asked whether or not there are any questions. I have answered any questions that were 
raised by this person. 
 
 
______________________________________ 
Person Obtaining Consent Name (please print) 
 
 
__________________________________  
 
_______________ 
Signature of Person Obtaining Consent  
 
 
Date  
(MM/DD/YYYY)

 
 
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PATIENT INFORMED CONSENT FORM - INFORMATION SHEET 
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this clinical study and how you 
might take part in it.  By signing this form, you will show that you understand and that you agree to 
take part in this clinical study.  Your signature on this form is required before you can take part in 
this clinical study. 
Background 
You are being asked to take part in a clinical study entitled “The Medtronic CoreValve™ SURTAVI 
Trial” because you have a disease of your aortic valve. This disease is called aortic stenosis. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the lower 
chamber of the heart (ventricle) into the main artery delivering blood to the body (aorta).  If the 
valve becomes abnormally narrow through a process of thickening and stiffening (aortic stenosis), 
then the heart must work harder to pump the same amount of blood with each beat.  As the heart 
works harder, the heart muscle thickens (hypertrophy), and the lower chamber (ventricle) may 
become larger (dilate). Open-heart surgery to replace the diseased aortic valve is the standard 
treatment. For some patients, the risk of experiencing major problems during open-heart surgery 
is greater because of other health problems.  
As an alternative to open-heart surgery, the Medtronic CoreValve™ System has been developed to 
replace a diseased aortic heart valve without the need for open-heart surgery. This system allows 
the percutaneous aortic valve (study valve) to be implanted (inserted) through a long, thin flexible 
tube that is inserted through an incision in the skin and threaded through the bloodstream 
(percutaneous). 
You are being asked to participate in this study because doctors have determined your aortic 
valve is no longer working properly.  However, your doctors have also decided that your risk of 
experiencing major problems while undergoing open-heart surgery is moderate due to medical 
reasons or anatomical reasons (relating to how and where your heart, aortic valve and blood 
vessels are placed within your body). This means that your doctor believes your health is 
acceptable for open-heart surgery, but there is still a risk of potential problems. 
Purpose of the Study 
The purpose of this clinical study is to determine if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions 
as you. 
The Medtronic CoreValve™ System is considered an “investigational device” by the United States 
Food and Drug Administration (FDA) which means that clinical studies are required to determine if 
it is safe and provides clinical benefit.  Medtronic, Inc. is sponsoring this study to obtain data on 
the safety and performance of the investigational device and its delivery system to gain FDA 
approval.   
The study will involve approximately 1600 patients and is being conducted at up to 115 hospitals 
in Europe, Canada and the United States and around the world. It is anticipated to take 
approximately eight years to complete.  Your participation in this study is expected to last 
approximately five years from the day you are enrolled. Annual follow-up may be extended to up 
to 10 years after the implant procedure. 
As a participant in the study, you have certain responsibilities. You have the responsibility to be 
truthful regarding your health and medication history. 
You are expected to return to your study doctor’s office for the study visits. The evaluations 
performed at these visits are a component of the study.  They are important for data collection and 
for monitoring that the investigational device is working properly.  These evaluations will take 
place at baseline, implant procedure, discharge, and follow-up visits (30 days, 6, 12, 18, 24, 36, 
48, and 60 months). You should not take part in this study if you will not be available for the study 
visits.   

 
 
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You also have the responsibility to report any injuries, hospitalizations, emergency room visits or 
other medical visits, symptoms or complaints to the study doctor or study nurse as soon as 
possible.  
Study Device 
The study valve is made from animal tissue attached to a metal frame. The study valve is 
designed to be implanted (inserted) using a delivery system catheter (long, thin flexible tube) to 
replace your diseased aortic heart valve without open-heart surgery. Once it is implanted, 
CoreValve™ study valve acts in the same method of the native valve. 
 
 
 
 
 
 
 
 
 
 
 
The Medtronic CoreValve™ system was CE marked in 2006 and has been implanted in over 
45,000 patients. The CoreValve™ being implanted in this study is identical to the valve that was CE 
marked in 2006 with the exception of adding a coating, but is being used outside the current 
approved patient population that is approved under the current CE mark. This coating is designed 
to help the study valve last longer (i.e. function as it is supposed to) and to help keep the study 
valve from becoming calcified like your native valve did.  The coating received CE mark in March 
2012. 
 
Procedures to Be Followed 
 
If you agree to be in this study, and after you have signed this informed consent form, data 
such as your age, gender, ethnic origin, medical history and medication use will be 
recorded.  You will undergo the following tests to determine if you are suitable for receiving 
the investigational device: 
 
Transthoracic echocardiography (TTE): a test that uses sound waves to take pictures of 
your heart and measure the degree of narrowing of your aortic valve; a probe is placed on 
the outside of your chest to take pictures of your heart 
 
Computed Tomography (CT): a scan performed using an x-ray machine, which is linked to a 
computer to take pictures of your heart and aortic valve 
 
If your doctor decides it is unsafe for you to have a CT scan, you will have a Magnetic 
Resonance Imaging (MRI) test.  MRI is a scan that uses the magnetic properties of your 
tissues to take pictures of your heart.  For the MRI test, you will lie on a special exam table 
while the pictures are taken. 
 
Blood tests: about two tablespoons 
 
An electrocardiogram (ECG): a test that records electrical impulses of your heart; patches 
are placed on the outside of your chest 
 
A physical examination 
 
Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into: the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
If you are of child-bearing potential, we will ask you to take a pregnancy test. If you are pregnant, 
you will not be able to participate in this study. 

 
 
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All of these procedures and tests are standard procedures for patients with aortic valve disease, 
and are not experimental.  If you have already had any of these tests performed before, they may 
to be used for the study if your study doctor determines they do not need to be repeated for study 
purposes. 
The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you will 
not be allowed to participate in the study. 
If your doctors and the committee decide you are eligible to be in the study, your treatment will be 
determined in a way similar to flipping a coin, called randomization. You will be assigned to one of 
two groups. One group will receive a transcatheter aortic valve implant (TAVI), the other group will 
have an open-heart surgical aortic valve replacement (SAVR). One out of every two participants 
will receive TAVI. The other participants will receive SAVR. You will not be able to choose your 
treatment assignment. 
Your enrollment in the study will begin once you sign this consent and you are assigned to your 
treatment group.  If you are enrolled in the study; you will be required to have the following 
additional tests completed within 14 days prior to the procedure (TAVI or SAVR): 
• 
Physical exam, including a determination of neurological (brain) status where you will be 
asked to answer a series of questions and perform a series of tasks 
• 
Blood tests (about two tablespoons) 
• 
Six-Minute walking test – a test that records your breathing, heart rate, and how you feel  
• 
Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life (QOL) Questionnaires. 
If you are assigned to the TAVI group: 
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor. You may be advised to continue taking blood thinning 
medications for at least three months following your procedure.  
Before the procedure you will be given a medicine that kills bacteria or germs (antibiotic) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about two tablespoons) and an ECG before the procedure. 
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary 
during the procedure, you will be put under general anesthesia at that time.  
Your study doctor will decide what areas are best for inserting the long, thin flexible tubes required 
for TAVI and getting all of the pictures that are necessary. These pictures are described in the next 
paragraphs.  Additionally, your study doctor will decide if performing a surgical incision to any of 
the area(s) is necessary. 
During the procedure, you may have a transesophageal echocardiogram which is also called a 
TEE. This test uses sound waves to take a closer look at the inside structures of the heart. If your 
doctor decides this picture is necessary, to perform the test, you will swallow a thin flexible tube 
with a special tip. This tube sits in the tube that connects the mouth to the stomach (esophagus). 
The special tip of the tube sends out sound waves (ultrasound) that echo within the chest wall. 
The esophagus is located behind the heart so these echoes are picked up and create a picture of 
the heart that is displayed on a video monitor. The pictures will allow your study doctor to take a 
closer look at your valve. 

 
 
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You will have a temporary pacemaker put in place during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins. It is then threaded 
through your vein into the right side of your heart. The wire is attached to a battery-operated 
device that is outside of your body. This temporary pacemaker will help keep your heart rate and 
beat steady. This temporary pacemaker will not be removed for at least 48 hours after your TAVI 
procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. This is a procedure used to widen a hard or thin heart valve. A wire and a thin tube are 
guided by x-rays through the heart and positioned through the diseased heart valve. A balloon is 
placed over the wire and inflated, enlarging the opening through the diseased valve allowing the 
study valve to be placed. 
Your doctor will then insert the study valve through the long, thin flexible tube that is inserted 
through an incision in the skin and threaded through the bloodstream. TAVI is performed using x-
ray machines which will allow your doctor to see the study valve, your blood vessels and heart. 
The study valve will be guided through your blood vessels to your existing aortic valve and then 
the study valve will be placed over your existing valve. 
During the TAVI procedure, your doctor will perform x-ray pictures (angiogram) and recordings of 
the electrical impulses of your heart through patches placed on the chest (ECG) to observe your 
heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study 
valve. 
If you are assigned to the SAVR group: 
If you are assigned to the SAVR group, your doctors will replace your diseased aortic valve 
through open-heart surgery. During surgery, you are asleep under general anesthesia. SAVR 
often requires a median sternotomy, where the bone in the center of the chest (sternum) is split 
down the middle. The chest is then opened to provide your doctor with access to the heart and 
chest cavity, in order to replace your aortic valve. Your surgery is performed while the function of 
your heart is taken over by a heart lung machine (called CPB for cardiopulmonary bypass). 
You may have a TEE (a thin tube sits in the esophagus and sends out sounds waves to create a 
picture of your heart) and a temporary pacemaker (thin wire threaded through your vein to right 
side of heart to keep your heart rate and rhythm steady) during the procedure. 
Your doctor may remove any tissue and calcium deposits that are interfering with the normal 
function of the valve. Your damaged valve may be completely removed. The new valve will be 
sewn into the space where your own valve used to be. After your doctor makes sure your valve is 
working properly, blood flow will be restored to your heart and the incisions will be closed. You will 
also have blood drawn for testing before and after the procedure. 
After TAVI and SAVR Procedure: 
After your TAVI and SAVR procedure, your study doctors will continue to monitor your progress 
and recovery. 
You will have the following tests performed within the two days following your TAVI procedure and 
before you leave the hospital: 
•  
Determination of neurological (brain) status where you will be asked to answer a series of 
questions and perform a series of tasks 
•  
Blood tests (about two tablespoons) 
•  
Echocardiogram (TTE) 
•  
ECG 
Follow-up Visits after TAVI and SAVR: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months, 
18 months, 24 months (3 years) and 3, 4, and 5 years after the procedure. The follow-up tests and 

 
 
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examinations are not experimental and most are performed on a routine basis. Each visit will take 
about 1 ½ to 2 hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
•  
Physical examination, including a determination of neurological (brain) status where you will 
be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
•  
Blood tests (about two tablespoons) – 30 day visit only 
 
Quality of Life (QoL) Questionnaires 
 
ECG 
• 
Six-Minute walking test – 30 day visit only 
• 
Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12, 24, 36, 48 and 60 months will include: 
•  
Physical examination, including a determination of neurological (brain) status where you will 
be asked to answer a series of questions and perform a series of tasks 
• 
You will be asked about your health since the last follow-up visit 
•  
Echocardiogram (TTE) 
•  
QoL Questionnaires 
•  
ECG 
 
Six-Minute walking test – 12 and 24 months visit only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted via phone to complete 
a Quality of Life Questionnaire. 
If the study doctor is unable to implant the study valve, you will still be followed for safety and will 
need to return to the clinic for the required follow-up visits as described above. 
If, during the 5 years of follow-up, you have additional heart surgeries or cath lab procedures to 
work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological (brain) 
status within 24 hours after each additional procedure. 
If you have a stroke, have been informed by a doctor that you experienced a stroke, experience 
any of the following symptoms, notify your study doctor at xxx-xxx-xxxx as soon as possible: 
sudden numbness, tingling on, loss of movement (occurring on one side of the body), sudden 
vision changes, confusion or trouble understanding simple statements, unable to speak, severe 
headaches, or seizures. Any of these symptoms could indicate that you are having problems with 
your neurological (brain) function. You will be asked to come to the clinical to have tests performed 
to determine your neurological (brain) status where you will be asked to answer a series of 
questions and perform a series of tasks. These tests will be performed at 7 days, 30 days and 3 
months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or 
are hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis. The study doctor will determine if you will need to have another valve 
implanted.  
In the event of your death and an autopsy is performed, the study doctor will ask your family or 
"legally authorized representatives" for either the whole heart and valve or just the valve are 
removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the investigational valve. 
Your family and your "legally authorized representatives", have the right to refuse the autopsy and 
refuse the request to remove the heart and/or valve even if you sign this consent form. 
POSSIBLE RISKS AND DISCOMFORTS 

 
 
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TAVI 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest – heart stops beating and blood flow through the body is interrupted or 
stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to improve 
blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  
 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able to 
supply oxygen to the body 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 
 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, 
blood clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the device 
from where it was originally placed 

 
 
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 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 
 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure is 
expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs 
in the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 
 
Permanent disability – injury that does not allow that impairs normal/previous 
physical or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 
 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 
 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result 
in a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed 
space that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the 
heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  
o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical 
impulses to the heart to help your heart beat normally 
o 
Atrio-ventricular node block – a block in the electrical path from the top part of 
the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom part 
of the heart (ventricle) 
o 
Asystole – when the heart stops beating 

 
 
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o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part 
of the heart (ventricles) 
 
Encephalopathy – altered mental state 
 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 
 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 
 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the 
aortic valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known. 
 
 
SAVR 
Although SAVR is not experimental there are potential risks associated with the procedure. These 
risks are the same even if you undergo the SAVR procedure and you decide not to participate in 
this study.  Some of these risks include, but may not be limited to the following: 
 
Obstruction of blood flow to the heart (angina) resulting in damage to the heart tissue 
(myocardial infarction/heart attack) 
 
Abnormal heart beat (cardiac arrhythmia and dysrhythmia) 
 
Blood leaking around the outside of the prosthetic valve (paravalvular leak) or any problem 
with the valve that causes leaking of blood after the valve has closed (transvavular leak). 
 
Damage to red blood cells (hemolysis) that can result in anemia (decreased red blood cells) 
 
Death 
 
Inflammation of the lining of the heart (endocarditis) 
 
Heart failure 
 
Any problem with the prosthetic valve that causes narrowing of the valve opening (stenosis) 
 
Blood clots that develop in the heart of on the replacement valve. These clots may break 
loose and travel through the bloodstream (thromboembolism). This problem may cause 
stroke (decrease blood flow to the brain causing damage to the brain) or heart attack. 
 
Failure of the valve to open and close properly 
 
If you are or you become pregnant, there may be risks, discomforts or side effects to you and your 
unborn child that are not yet known.  
 

 
 
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Some possible inconveniences may include, but is not limited to the following: 
 
Transportation to and from the clinic for follow-up visits 
 
Parking 
 
Follow-up visit scheduling 
 
There may be other discomforts and risks related to the device and/or this study that are not 
foreseen at this time.  
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how 
much radiation you will get, in the following descriptions the radiation is compared to the amounts 
that people are exposed to in daily life. There is radiation that naturally occurs from space and 
from rocks in the soil. This natural radiation is greater at higher altitudes. 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure is 
less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 
The estimated radiation exposure for the valve procedure is approximately 10-15 times the 
amount of radiation exposure received in one year from background radiation (naturally occurring 
radiation you are exposed to everyday). The exposure is approximately the amount an 
occupational worker is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have extra 
follow-up visits with your doctor to watch your recovery more closely. 
Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 
Potential Benefits for You 
The possible benefits you may receive from participating in this clinical study are that you may be 
able to receive a new heart valve without having open-heart surgery.  Another possible benefit is 
that your new study valve may work better than the way your diseased valve currently works.  This 
may improve how you feel and may improve your daily activity.  However, there is no guarantee 
that you will benefit from being in this clinical study. 
Potential Benefits for Other Patients 
Your participation in this clinical study may improve procedures that may guide the future 
treatment of aortic stenosis, by using procedures that are less invasive (meaning less cutting, 
entering or breaking through the body), which may benefit others in the future. 
Alternative Therapy 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other treatment 
options include percutaneous (through an artery in the groin) aortic valve implantation, or medical 
management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study 
doctor about other treatment options you may have and their related benefits and risks. 
Compensation for Illness or Injury 

 
 
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If you are physically injured as a result of your participation in this study, reasonable and 
appropriate medical treatment will be provided to you free of charge by the study sponsor, if such 
treatment is not already covered by your medical insurance. 
Medtronic maintains appropriate clinical trial liability insurance coverage as required under 
applicable laws and regulations and will comply with applicable local law and custom concerning 
specific insurance coverage.  If required, a Clinical Trial insurance statement/certificate will be 
provided to your Institution’s Ethics Committee.  
Compensation and Additional Costs 
You will not receive any compensation for your participation in this study (including follow up).  
There is no monetary advantage to the study doctor for participation in this study. 
You may request for reimbursement for costs associated with travel expenses for the purpose of 
the follow-up visits. 
Role of the Sponsor’s Representative 
Your study doctor will delegate study activities not only to other study personnel (both doctors and 
study nurses), but also sponsor representatives. These study activities may include support during 
the procedure and supporting during data collection throughout the study.  These activities are 
performed under supervision of the study doctor and will not bias the data integrity in any way.  
Use of Personal Data/Confidentiality 
Your participation in this study is entirely confidential.  
While participating in this study the following personal data will be collected: 
 
medical and health data from your medical records  
 
data on your ethnic origins 
(Hereinafter “personal data”)  
Representatives of the institution or hospital in which you are treated, including your physician(s) 
who conduct(s) the study, the monitor(s) on behalf of the study sponsor and other designated 
parties that are involved in the study (for example third party data processors) have direct access 
to your personal data. Furthermore, representatives of national, European or other international 
regulatory bodies, members of the ethics committees or any other public authority may be granted 
direct access to your personal data in order to comply with legal and regulatory requirements. If it 
is necessary, your personal data may also be transferred to the above-mentioned parties, which 
are located in the country in which you are treated and in member states of the European 
Economic Area but maybe also in countries where the European Directive on Data Protection 
does not apply. 
For conducting the study your personal data will be transferred to and processed by Medtronic 
(meaning the Medtronic, Inc. as well as all affiliates of this group of companies) or a third party 
designated by Medtronic – but solely in a key coded form, unless it may be impossible to make it 
anonymous, for instance, where your name cannot be removed from the data carrier, such as x-
ray, angiogram or echocardiography. This means that these data will be transferred to a Medtronic 
entity or a third party designated by Medtronic which is located in the country where you are 
treated, in a member state of the European Economic Area but maybe also in the United States or 
another country where the European Directive on Data Protection does not apply. 
Medtronic, or a third party designated by Medtronic, will process these data manually or by 
computer, including the use of internet or cloud computing. 
Your personal data are collected for medical research purposes, to gather information on the 
device and its performance during and after this study and may be used for obtaining 
assessments for approvals for the device, additional scientific research, educational purposes and 
publications as well as for future health studies.  

 
 
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Study results may be published without disclosing your name or any other identifying 
characteristics. In all cases, your personal data will be handled at all times in accordance with 
appropriate confidentiality standards and all applicable data protection and privacy laws. 
You are entitled to access the personal data collected about you and to have inaccuracies 
corrected. 
If you agree upon, your personal physician will be informed about your participation in the study. 
Voluntary Participation 
Your participation in this study is entirely voluntary. You are free to refuse participation and you 
are free to discontinue participation in the study at any time without fear of penalty or loss of 
medical care. In addition, you will be notified in written form of any significant new findings that 
may develop during the course of the study or the reasons for any amendment to the study 
protocol which may relate to your willingness to continue your participation.  
Your physician, Medtronic, the Ethics Committee or the Competent Authority may decide to 
terminate your participation in the study at any time without your prior consent. If this happens you 
will be notified and the reasons explained to you. 
Medtronic can also suspend or terminate the study at any time without your prior consent. If this 
happens, you will be notified and the reasons will be explained to you.  Your physician will 
continue to provide the appropriate medical treatment.  
If you discontinue your participation or if the study sponsor decides to terminate your participation 
in the study all your personal data collected for the study can still be used by the study sponsor 
unless you object and ask for deletion of the data. 
Questions 
In case of any question, you can contact one of the following people: 
Questions about the study: ………………………………… 
Questions in the event of illness or injury: …………………………………. 
Questions about patient rights: ………………………………………….  

 
 
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PATIENT INFORMED CONSENT FORM - SIGNATURE SHEET 
Medtronic CoreValve™ SURTAVI Trial 
I have read the patient information of this study and my physician has answered all my questions 
regarding the study.  
I had sufficient time to consider my participation into this study, I am aware that participation into 
this study is completely voluntary, and I agree to follow the instructions from the investigator. 
I realize that I may decide to refuse participation or stop participation at any time without penalty 
and without affecting the quality of my health care or the relationship with my physician.  
I understand and agree that personal data about me will be collected and used for the purpose of 
the study. For conducting the study these data will be transferred to and processed by Medtronic 
or third parties designated by Medtronic as described in the section ‘use of personal 
data/confidentiality.’ 
I understand and agree that representatives from Medtronic, regulatory authorities and the Ethics 
Committee will be granted direct access to my medical records.  
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the study. 
I understand that I am entitled to access the personal information collected about me and to have 
inaccuracies corrected. 
I have received a copy of the Patient Information and hereby I agree to participate voluntarily in 
and comply with this study. 
 
You may agree or disagree that your personal physician is informed on your participation in this study. 
Please, check one option below indicating your choice: 
 
! must be checked by patient 
 
I agree that my personal physician is informed about my participation in this study. 
 
I disagree that my personal physician is informed about my participation in this study. 
 
 
I agree to participate in this study and I have consented before the initiation of any study 
specific procedures. 
Patient: 
            
 
__________________________  
  ___________________    
 ____________________  
 
 
Name 
 
 
 
Signature 
 
 
Date (dd MMM yyyy) 
 
 
 
 
         Must be written by patient                     Must be written by patient 
 
 
 
          
 
 
  
 
 
 

 
 
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 Only persons officially trained and 
authorized on the delegated task list 
are allowed to sign off 
 
 
 
 
Study Doctor or designated person by Study Doctor: 
I have conducted the informed consent discussion. 
 
__________________________   ___________________   
 ___________________   
 Name  
 
 
 
Signature 
    
 Date (dd MMM yyyy) 
 
 
 
If patient is unable to read: 
I have attended the entire informed consent discussion. I attest that the information in the 
consent form and any other written information was accurately explained to, and 
apparently understood by, the patient. Informed consent was freely given by the patient. 
Impartial Witness: 
 
_________________________  _____________________  
________________   
 Name  
 
 
 
 Signature 
  
 Date (dd MMM yyyy) 
 
Section should be filled in by impartial witness 
 

 
 
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INFORMED CONSENT FORM 
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this research study and how you 
might take part in it. By signing this form, you will show that you understand and that you agree to 
take part in this research study. Your signature on this form is required before you can take part in 
this research study. 
BACKGROUND 
You have been invited to participate in this research project because you have aortic stenosis (a 
disease of one of your heart valves). Before deciding to participate in the study you should be 
familiar with its requirements, risks and benefits. This document provides information about the 
study. It may contain words you do not fully understand. Please read it carefully and ask the study 
staff any questions you may have. They will discuss the study with you in detail. If you decide to 
participate, you will be asked to sign this form and a copy will be given to you. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the left 
ventricle (main pumping chamber of the heart) into the aorta (main artery delivering blood to the 
body). If the valve becomes abnormally narrow through a process of thickening and stiffening 
(aortic stenosis) the heart must work harder to pump the same amount of blood with each beat. 
As the heart works harder, the heart muscle thickens (hypertrophy), and the heart chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve is 
usually the standard treatment. 
As an alternative to open heart surgery, the Medtronic CoreValve™ System has been developed 
to replace a diseased aortic heart valve without the need for open heart surgery. A description of 
the valves is included under the section Study Devices. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This website will 
not include information that can identify you. At most, the website will include a summary of the 
results. You can search this website at any time. 
You are being asked to participate in this study because doctors have determined your aortic valve 
is no longer working the way it should. However, your doctors have also decided that your risk of 
experiencing major problems while having open-heart surgery is moderate. This means that your 
doctor believes your health is good enough for open-heart surgery, but there is still a risk of 
potential problems. 
PURPOSE OF THE STUDY 
The purpose of this clinical study is to figure out if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions 
as you. 
The study valve is considered an “investigational device”, which means that Health Canada has 
not yet approved it to be used for standard of care purposes and is only allowed to be used for the 
study. Medtronic, Inc. is sponsoring this study to obtain data on the safety and performance of the 
investigational device. The Medtronic CoreValve™ System includes the valve described below 
and two parts that help load and deliver the valves correctly.  
This study will involve approximately 1600 subjects at up to 115 hospitals in the United States, 
Canada and around the world, and is anticipated to take approximately 8 years to complete. Your 
participation in this study is expected to last approximately five years from the day you are enrolled 
in the study.  Annual follow-up may be extended to up to 10 years after the implant procedure. 

 
 
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STUDY DEVICES 
The study valve is made from animal tissue attached to a metal frame.  
The study valve is designed to be inserted using a long, thin flexible tube (delivery system) to 
replace your diseased aortic heart valve through an incision in the skin and threaded through the 
bloodstream (percutaneous) and without open-heart surgery.  Once it is implanted, CoreValve™ 
study valve acts in the same method of the native valve. 
 
 
 
 
 
 
 
 
 
 
 
Although the Medtronic CoreValve™ system is not approved by the US Food & Drug Administration 
(FDA), or Health Canada, it has been approved in other parts of the world since 2006 and has 
been implanted in over 45,000 patients. 
The Medtronic CoreValve™ System is currently approved for use in Europe, South America, and 
parts of Asia. 
PROCEDURES TO BE FOLLOWED 
If you agree to be in this study, and after you have signed this informed consent form, information 
such as your age, gender, medical history and medication use will be recorded. You will have the 
following tests: 
• Physical examination 
• Computed tomography (CT) - a scan performed using an x-ray machine that takes pictures 
of your body. Sometimes a CT will require the use of a type of dye that makes the kidneys 
work harder and may be harmful to the kidneys. You may have an MRI in place of a CT 
scan if your doctor believes your kidneys are not working well enough for you to have a CT 
scan. MRI stands for magnetic resonance imaging and is a test that also takes pictures of 
your internal organs. 
• Blood tests (about 2 tablespoons). These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they 
should as well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning 
as they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or 
other heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 

 
 
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o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is 
working harder than normal to pump blood through your body 
• Echocardiography (transthoracic echocardiogram (TTE)) - a test that uses sound waves to 
take pictures of your heart and measure the degree of narrowing of your aortic valve; a 
probe with gel is placed on the outside of your chest to take pictures of your heart 
• Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
• Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
These procedures and tests are standard procedures required for the treatment of your disease 
and are not experimental. If you have already had any of these tests performed before, they may 
be used for the study if your study doctor determines they don’t need to be repeated for study 
purposes. The results from your exams and tests will be reviewed by your doctors who will 
determine if you are eligible to be in the study.   
The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you will 
not be allowed to participate in the study. 
If your doctors and the committee decide you are eligible to be in the study, your treatment will be 
determined in a way similar to flipping a coin, called randomization. You will be assigned to one of 
two groups. One group will receive a transcatheter aortic valve implant (TAVI); the other group will 
receive an open-heart surgical aortic valve replacement (SAVR). On average, one out of every two 
participants will receive TAVI. The other participants will receive SAVR. You will not be able to 
choose your treatment assignment. 
You will be considered enrolled in the study once you are assigned to a treatment group.  
If you are enrolled in the study, you will be required to have the following additional tests (for study 
purposes only) completed within 14 days prior to the procedure (TAVI or SAVR): 
• Physical exam, including determining your neurological (brain) status where you will be 
asked to answer a some questions and perform some tasks such as writing and drawing 
• Blood tests (about 2 tablespoons) These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they should 
as well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or 
other heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is 
working harder than normal to pump blood through your body 
• Walking test – a test that records your breathing, heart rate, and how you feel after 6 
minutes of walking 
• Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 

 
 
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You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life Questionnaires (QOL).  Completing the questionnaires 
should take about 10-15 minutes each. 
Your personal physician will be informed about your participation in this clinical study. 
If you are assigned to the TAVI group: 
The study valve is an experimental valve which means you can only receive the valve if you are 
part of this study.  
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor.  You may be advised to continue these medications for at 
least three months after your procedure.  
Before the procedure you will be given an antibiotic (a medicine that kills bacteria or germs) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about 2 tablespoons) and an ECG before the procedure.   
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary during 
the procedure, you will be put under general anesthesia at that time. 
Your study doctor will decide what locations are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary. These pictures are described 
in the next paragraphs. 
During the procedure, one of the pictures that may be needed is a transesophageal 
echocardiogram which is also called a TEE. This test uses sound waves to take a closer look at 
the inside structures of the heart. If your doctor decides this picture is necessary, to perform the 
test you will swallow a thin flexible tube with a special tip. This tube sits in the esophagus (the tube 
that connects the mouth to the stomach). The special tip of the tube sends out sound waves 
(ultrasound) that echo within the chest wall. The esophagus is located behind the heart so these 
echoes are picked up and create a picture of the heart that is displayed on a video monitor. The 
pictures will allow your study doctor to take a closer look at your valve. 
You will have a temporary pacemaker put in your heart during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins and threaded 
through your vein into the right side of your heart. The wire is attached to a battery operated 
device outside of your body. This temporary pacemaker will help keep your heart rate (speed) and 
rhythm steady. This temporary pacemaker will not be removed for at least 48 hours after your 
TAVI procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. Balloon valvuloplasty is a procedure used to widen a stiff or narrowed heart valve. A 
wire and a thin tube are guided by x-rays through the heart and positioned through the diseased 
heart valve. A balloon is placed over the wire and inflated, making the opening bigger through the 
diseased valve allowing the study valve to be placed. 
Your doctor will then implant (insert) the study valve through the long, thin flexible tube that is 
inserted through an incision in the skin and threaded through the bloodstream. TAVI is performed 
using x-ray machines which will allow your doctor to see the study valve, your blood vessels and 
heart. The study valve will be guided through your blood vessels and then it will be placed over 
your existing aortic valve. 
During the TAVI procedure, your doctor will perform angiography (x-ray pictures) and ECGs 
(recordings of the electrical impulses of your heart through patches placed on the chest) to 
observe your heart function and make sure that the study valve fits and works properly. 

 
 
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Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study 
valve onto the tube that helps deliver the valve to the heart. 
If you are assigned to the SAVR group: 
Open heart surgery, surgical repair and/or replacement of your aortic valve, are not experimental 
procedure; meaning you could have this procedure if you did not take part in this study. 
If you are assigned to the SAVR group, your doctors will replace your diseased aortic valve 
through open heart surgery. During surgery, you are asleep under general anesthesia. SAVR often 
requires the bone in the center of the chest (sternum) to be split down the middle. The chest is 
then opened to provide your doctor with access to the heart and chest cavity, in order to replace 
your aortic valve. Your surgery is performed while the function of your heart is taken over by a 
heart lung machine (called CPB for cardiopulmonary bypass). 
You may have a TEE (a thin tube that sits in the esophagus and sends out sounds waves to 
create a picture of your heart) and a temporary pacemaker (thin wire threaded through your vein to 
right side of heart to keep your heart rate and rhythm steady) during the procedure. 
Your doctor may remove any tissue and calcium deposits (extra calcium that has collected on the 
valve) that are interfering with the normal function of the valve. Your damaged valve may be 
completely removed. The new valve will be sewn into the space where your own valve used to be. 
After your doctor makes sure your valve is working properly, blood flow will be returned to your 
heart and the incisions will be closed. You will also have blood drawn for testing before and after 
the procedure. 
If your doctor is unable to implant (insert) the a valve in you during the TAVI or SAVR procedure, 
you will still be considered enrolled in the study and will need to return to the clinic for the required 
follow-up visits as described in the “Follow-up Visits after TAVI and SAVR” section. 
After TAVI and SAVR Procedure: 
After the TAVI and SAVR procedure, your study doctors will continue to monitor your progress and 
recovery. 
You will have the following tests performed within the two days following the procedure and before 
you are discharged from the hospital: 
• Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
• Blood tests (about 2 tablespoons) These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they should as 
well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or other 
heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is working 
harder than normal to pump blood through your body 
•  Echocardiogram (TTE) 
•  ECG 
Follow-up Visits after TAVI and SAVR: 

 
 
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You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months (1 
year), 18 months, 24 months (2 years), and 3, 4, and 5 years after the procedure. Most of the 
follow-up tests and examinations are routine, not experimental. Each visit will take about 1 ½ to 2 
hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
 Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
 You will be asked about your health since the last follow-up visit 
 Quality of Life Questionnaires 
 ECG 
 Blood tests (about 2 tablespoons) – 30 day visit only 
o 
Hemoglobin – test how much of a protein that carries oxygen to your body's organs and 
tissues and transports carbon dioxide from your organs and tissues back to your lungs you 
have in your blood 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
 Walking test – 30 day visit only 
 Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12 months, 24 months, and 3, 4, 5 years will include: 
 Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
 You will be asked about your health since the last clinic visit 
 Blood tests (about 2 tablespoons) 
 Echocardiogram (TTE) 
 Quality of Life Questionnaires 
 ECG 
 Walking test – 12 and 24 months visits only 
In addition to the in-clinic follow-up visits, at 3 months you will be contacted by phone, by someone 
from your clinic, to complete a Quality of Life Questionnaire. 
If, during the 5 years of follow-up you have additional heart surgeries or cath lab procedures to 
work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological (brain) 
status within 24 hours after each additional procedure. 
If you have a stroke, have been informed by a doctor that you experienced a stroke, or experience 
any of the following symptoms, notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as 
possible: sudden numbness, tingling, loss of movement (especially on 1 side of the body), vision 
changes, confusion or trouble understanding simple statements, severe headaches, or seizures.  
Any of these symptoms could indicate that you are having problems with your neurological (brain) 
function.  If a doctor confirms that you had a stroke, you will be asked to come to the clinical to 
have tests performed to determine your neurological (brain) status where you will be asked to 
answer a series of questions and perform a series of tasks. These tests will be performed at 7 
days, 30 days and 3 months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or 
are hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis.  Your study doctor will determine if you will need to have another valve 
implanted.   

 
 
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In the event of your death, we would like to do an autopsy. We will ask that either your whole heart 
and valve or just the valve are removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the study valve. 
Your family and your "legally authorized representatives", has the right to refuse the autopsy and 
refuse the request to remove the heart and/or valve even if you sign this consent form.  You may 
still participate in this study if you do not want to have an autopsy done. 
POSSIBLE RISKS AND DISCOMFORTS 
TAVI 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest – heart stops beating and blood flow through the body is interrupted or 
stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to improve 
blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  
 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able to 
supply oxygen to the body 
 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 

 
 
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o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 
 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, 
blood clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the device 
from where it was originally placed 
 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 
 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure is 
expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs 
in the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 
 
Permanent disability – injury that does not allow that impairs normal/previous 
physical or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 
 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 
 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result 
in a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed 
space that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the 
heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  

 
 
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o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical 
impulses to the heart to help your heart beat normally 
o 
Atrio-ventricular node block – a block in the electrical path from the top part of 
the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom part 
of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part 
of the heart (ventricles) 
 
Encephalopathy – altered mental state 
 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 
 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 
 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the 
aortic valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known. 
 
SAVR 
Although SAVR is not experimental there are potential risks associated with this procedure and 
any surgery. These risks are the same even if you undergo the SAVR procedure and you decide 
not to participate in this study.  Your study doctor will explain these risks to you and you will be 
asked to sign a separate surgical informed consent.   
If you become pregnant there may be risks, discomforts, or side effects to you and the 
embryo/fetus that are not yet known.  Please notify your study doctor as soon as possible to 
discuss any of these potential risks. 
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how 
much radiation you will get, in the following descriptions the radiation is compare  to the amounts 

 
 
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that people are exposed to in daily life. There is radiation that naturally occurs from space and 
from rocks in the soil. This natural radiation is greater at higher altitudes. 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure is 
less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 
The estimated radiation exposure for the valve procedure is approximately 10-15 times the amount 
of radiation exposure received in one year from background radiation (naturally occurring radiation 
you are exposed to everyday). The exposure is approximately the amount an occupational worker 
is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have extra 
follow-up visits with your doctor to watch your recovery more closely. 
Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 
POSSIBLE BENEFITS 
The possible benefits you may receive from participating in this research are that you may be able 
to receive a new heart valve without having open-heart surgery.  
Your participation in this research may improve procedures that may guide the future treatment of 
heart surgery, by using procedures that are less invasive, meaning less cutting, entering or 
breaking through the body, which may benefit others in the future. However, there is no guarantee 
that you will benefit from being in this research. 
ALTERNATIVE TREATMENTS 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other treatment 
options include percutaneous (through an artery in the groin) aortic valve implantation, or medical 
management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study 
doctor about other treatment options you may have. 
IF PROBLEMS DEVELOP 
If you believe that you have been injured as a result of your participation in the study, you should 
notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible or in serious cases, go to the 
emergency room.  
Immediate necessary medical care is available at [Name of institution(s)] in the event that you are 
injured as a result of your participation in this research study 
If you are assigned to the TAVI group  
For those patients receiving the investigational device and the TAVI procedure, 
Medtronic has agreed to pay back [name of institutions that are parties to the CTA] for the costs of 
reasonable medical or surgical care they provide for any serious and unanticipated illness or injury 
under the following conditions: 
 
The illness or injury must be directly related to a defect or malfunction of the investigational 
device or in the TAVI procedure as described in the Protocol, and not related to procedures 
that are routine standard of care. 
 
The illness or injury cannot be caused (a) by the negligence or intentional misconduct of the 
study staff or [name of institutions that are parties to the CTA]; (b) because the study staff or 

 
 
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[name of institution(s)] that are parties to the CTA] did not follow the protocol for the study; 
or (c) by the natural progression of your illness. 
 
The illness or injury must have happened before the study closes (last patient is seen for the 
5 year follow-up visit) at this [Name of institution(s)]. 
 
[Name of institution(s) that are parties to the CTA] must notify Medtronic of the illness or 
injury within one year of the date the study closes at all study sites or before the study 
closes at this site, whichever is earlier. 
Subject to the above conditions, Medtronic will pay back the costs that are not covered by your 
applicable provincial health insurance or third party insurer. The amount Medtronic will pay back is 
the applicable provincial health insurance plan rate. 
 
If you are assigned to the SAVR group  
In the event of physical injury or physical illness related to a procedure required for the SAVR 
group, no monetary compensation or subsidy (payment) will be provided. Medical treatment will be 
routinely provided to you through your regular provincial health insurance plan. 
By agreeing to the above, you do not waive any of your legal rights which you otherwise would 
have as a research subject, nor do you release the study sponsor (Medtronic, Inc.), study doctors, 
or the hospital from liability for negligence. 
 
PAYMENT FOR PARTICIPATION IN THE STUDY 
You will not be paid to take part in the study. However, you may be reimbursed for local mileage 
and parking expenses directly related to any study-only related visits. Your study doctor or 
research coordinator will tell you how to get reimbursement.  
There is no monetary advantage to the study doctor for participation in this study. Your 
participation in this study may contribute to the development of commercial products from which 
Medtronic may receive economic benefit.  Medtronic is paying the study site for the work involved 
in collecting study data and managing the study at this site.  
MEDICAL EXPENSES 
All necessary medical procedures should be covered by Provincial Health Insurance Plan. 
BASIS OF PARTICIPATION 
Your participation in this study is voluntary. If you refuse to be in this study there will be no penalty 
or loss of benefits to which you are otherwise entitled. You may withdraw from the study at any 
time and will not lose your benefits or be treated any differently as a result of withdrawing from the 
study. Any new findings (decisions or conclusions) that may influence your willingness to 
participate will be provided to you.  If you decide to leave the study before it is finished, please tell 
one of the persons listed in the section below “Obtaining Additional Information”. It may be 
requested that, if you withdraw, you return to your study doctor for a final visit. 
The study doctor may end your participation in the study at any time if: 
 He or she determines it is not in the best interest of your health 
 The study doctor loses contact with you and you do not return for your study visits as 
scheduled 
 You refuse to allow the use of private health information during the course of the study 
 
The study doctor will make the decision and let you know if it is not possible for you to continue in 
the study. 
You may be removed from the study without your consent if the sponsor (Medtronic, Inc.) ends the 
study.  If this happens, you will be notified and the reasons will be explained to you.  Your 
physician will continue to provide the appropriate medical care. 

 
 
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What are my responsibilities as a research subject?  
As a subject in a research study, it is important that you: 
 Be truthful about your health and medication history; 
 Return to the office for the study visits that the physician has scheduled with you; 
 Call the study doctor’s office to reschedule a missed visit as soon as possible; 
 Report any injuries, hospitalizations, emergency room visits, symptoms or complaints to the 
study doctor or nurse as soon as possible. 
PERMISSION FOR ACCESS TO AND USE OF HEALTH INFORMATION 
While you take part in this research study, the researcher in charge and study staff will collect and 
take down information about you in a file. Only information necessary for the research study will be 
collected.  
The information in your file could include your past and present medical history, information about 
your way of life and test results from exams and procedures done during this study. Your file could 
also contain other information, such as your name, sex, date of birth and ethnic origin.  
All the information collected about you during the study will remain confidential as the law 
demands. To protect your privacy, your information will be identified with numbers and or letters. 
Only the researcher in charge of the study knows the numbers and or letters that link them to you.  
The study researcher will send the research study information collected about you to the sponsor 
or sponsor representatives. This information does not include your name or address.  
The sponsor will use the information collected about you only to reach the study goals as they are 
explained in this Informed Consent Form.  
The information collected about you can be shared by itself, or together with other information 
collected from other studies with government groups in Canada or in other countries, or with the 
people that do business with the study’s sponsor Medtronic. This means that your study 
information could be sent to other countries. The sponsor must respect applicable Canadian 
privacy laws and those in all the countries where your study information will be sent. Your study 
information will be kept for at least 25 years by the researcher in charge of the study and by the 
sponsor.  
The study information may help the government approve the sale of the study device. The study 
information may also be used for other reasons related to the study or to help develop future 
studies.  
The study information could be printed in medical journals or shared with other people at scientific 
meetings, but, it will be impossible to identify you.  
To make sure the study is being done properly; your research study file as well as your medical file 
could be checked by a person authorized by the Research Ethics Board of the [Name of hospital 
or clinic(s)], or by the institution, by a person authorized by special people or groups (Health 
Canada) as well as by the sponsor’s representatives. These people and groups are obliged to 
respect your privacy.  
For your safety and to be able to reach you quickly, your family name, first name, how to contact 
you and the date you started and ended the study will be kept for one year after the study ends in 
a separate list kept by the researcher in charge of the study or by the institution.  
You have the right to look at your study file in order to check the information gathered about you 
and to correct it, if necessary, as long as the study researcher or the institution keeps this 
information. However, you may only have access to certain information once the study has ended 
so that the quality of the research study is protected. 
Economic Study 
This study contains a health economics review that will be done to compare the in-hospital, follow-
up medical care resource utilization and cost for patients in each of the treatment groups You may 
also be asked to sign a separate document that gives us your permission to review your billing 
information sent directly from your payer in order to evaluate medical cost data.  This information 

 
 
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will be kept strictly confidential and be used solely to assess the medical expenses which occur as 
a direct result of participating in the Medtronic CoreValve™ SURTAVI Trial. 
Quality of Life Questionnaire 
Medtronic CoreValve™ SURTAVI Trial will also contain a quality of life study. As part of this study, 
your research coordinator will have you or your caregiver complete a questionnaire called a 
Quality of Life Questionnaire.  You will need to complete this questionnaire when you are enrolled 
in the study and 1 month, 3 months, 6 months, 12 months, 18 months, 2 years, 3 years, 4 years 
and 5 years after your study procedure. 
OBTAINING ADDITIONAL INFORMATION 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. The study doctor will inform you of any new significant information, when 
it becomes available, which may affect your willingness to continue to participate in this study. If 
you have any questions about this study or if you experience any health problems, you should 
contact Dr. Principal Investigator at xxx-xxx-xxxx. 
If you have questions about your rights as a participant in this study, you should contact the 
chairman of the Institutional Review Board at xxx-xxx-xxxx. 
 
MEDTRONIC’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
This section describes what Medtronic as study sponsor will do with the study data, including your 
health information received during the study. 
Medtronic will keep your health information confidential in keeping with all applicable laws and 
regulations. Medtronic may use your health information to conduct this study. Medtronic may use 
your health information for other purposes, such as: 
 
Watch over and improve the performance of its device; 
 
New medical research; 
 
Proposals for making new medical products or procedures; and 
 
Other business purposes. 
Any reports or publications about the study or any other research will not include your name or a 
description of you. Any records identifying you will not be made publically available.  Information 
received during the study will not be used to market to you; your name will not be placed on any 
mailing lists or sold to anyone for marketing purposes. 
The United States Food and Drug Administration’s (FDA) and Health Canada’s regulations, as 
well as other applicable laws, control Medtronic’s work in developing and assuring the safety and 
quality performance of its medical devices. Medtronic may disclose your health information to the 
FDA, Health Canada, as well as to other U.S. and foreign government authorities responsible for 
assuring the safety of medical devices. Medtronic also may disclose your health information to 
research ethics boards and other persons who are required to watch over the safety and 
effectiveness of medical products and therapies and the conduct of research. In addition, 
Medtronic representatives or delegates of Medtronic may inspect/monitor your medical records 
during the course of the clinical study in order to ensure compliance with the study protocol and 
study procedures.  You agree to allow Medtronic to use study data in these ways. You also agree 
to allow Health Canada, the FDA and other governmental authorities to inspect your health 
information. 
You may change your mind and take back this permission to use your health information at any 
time. To take back this permission, you must write to [name and contact information]. If you take 
back this permission, you cannot continue in the study. Even if you take back this permission, 
Medtronic and Researchers may continue to use and share the health information already 
received as described in this Informed consent. 
 
PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION  

 
 
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Please indicate below whether you would like us to notify your primary care physician or your 
specialist of your participation in this study.   
(Initial only one box). 
 
Yes, I want the study doctor to inform my primary care physician/specialist of my 
participation in this study 
 
No. I do not want the study doctor to inform my primary care physician/specialist of 
my participation in this study. 
 
I do not have a primary care physician/specialist. 
 
 
The study doctor is my primary care physician/specialist. 
 
 

 
 
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INFORMED CONSENT FOR THE MEDTRONIC 
SURTAVI TRIAL 
 
PATIENT INFORMED CONSENT FORM SIGNATURE SHEET  
I confirm that: 
 
I have read the informed consent form of this study and my physician has answered all my 
questions regarding the study.  
 
I had sufficient time to consider my participation into this study, I am aware that participation 
into this study is completely voluntary, and I agree to follow the instructions from the 
investigator. 
 
I realize that I may decide to refuse participation or stop participation at any time without 
penalty and without affecting the quality of my health care or the relationship with my 
physician.  
 
I understand and agree that personal information about me will be collected from my 
medical records, used and processed (manually and by computer) by the manufacturer of a 
medical device used in my treatment or any other designated party that is involved in the 
study (e.g. hospital, physician, regulatory authorities, ethics committees).  
 
I understand and agree that representatives from Medtronic, regulatory authorities and the 
Institutional Review Board will be granted direct access to my medical records.  
 
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigation. 
 
I understand that I am entitled to access the personal information collected about me and to 
have inaccuracies corrected. 
 
I fully understand there is limited experience with this device in humans and that its safety 
and effectiveness have not been established and there are risks of serious complications 
associated with this study. 
 
I also understand that the doctors might determine after I give consent that it is not possible 
to implant the study valve. 
 
Signature of the subject or subject’s legally authorized representative  
I hereby give my consent to participate in the “Medtronic CoreValve™SURTAVI Trial”. I have been 
given a copy of this consent form, and am also aware that the investigator will keep a copy in his 
or her files. 
 
 
 
 
 
 
 
 
 
Printed name of subject  
 
 
 
 
 
 
 
 
Signature of subject   
 
 
 
 
 
 
 
 
Date (must be written in by subject) 
 
 
 
 

 
 
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Signature of a witness in the event that the subject or subject’s legally authorized 
representative is unable to read or write 
 
 
 
 
 
 
 
 
Printed name of witness (if applicable) 
 
 
 
 
 
 
 
 
Signature of witness (if applicable) 
 
 
 
 
 
 
 
 
Date (must be written in by witness) 
 
 
Signature of the principal investigator or authorized designee for conducting the informed 
consent process 
 
 I certify that I have explained the nature of the device and the study to the above-named 
person. 
 I have also explained the contents of this informed consent form to the above-named 
person. I have asked whether or not there are any questions. I have answered any 
questions that were raised by this person. 
 
 
 
 
 
 
 
 
Printed name of principal investigator or authorized designee for conducting the informed 
consent process  
 
 
 
 
 
 
 
 
Signature of principal investigator or 
authorized designee  
 
 
 
 
 
 
 
Date (must be written in by principal 
investigator or authorized designee)  
 

 
 
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 R.1.4 
Canada – Roll-in Subjects 
INFORMED CONSENT FORM 
FOR ROLL-IN SUBJECTS 
Medtronic CoreValve™ SURTAVI Trial 
You are being asked to read this form so that you understand this research study and how you 
might take part in it. By signing this form, you will show that you understand and that you agree to 
take part in this research study. Your signature on this form is required before you can take part 
in this research study. 
BACKGROUND 
You have been invited to participate in this research project because you have aortic stenosis (a 
disease of one of your heart valves). Before deciding to participate in the study you should be 
familiar with its requirements, risks and benefits. This document provides information about the 
study. It may contain words you do not fully understand. Please read it carefully and ask the study 
staff any questions you may have. They will discuss the study with you in detail. If you decide to 
participate, you will be asked to sign this form and a copy will be given to you. 
The aortic valve is one of the four heart valves that control the flow of blood into and out of the 
heart. The aortic valve lets oxygen-containing blood to be pumped out of the heart, from the left 
ventricle (main pumping chamber of the heart) into the aorta (main artery delivering blood to the 
body). If the valve becomes abnormally narrow through a process of thickening and stiffening 
(aortic stenosis) the heart must work harder to pump the same amount of blood with each beat. 
As the heart works harder, the heart muscle thickens (hypertrophy), and the heart chamber 
(ventricle) may become larger (dilate). Open-heart surgery to replace the diseased aortic valve is 
usually the standard treatment. 
As an alternative to open heart surgery, the Medtronic CoreValve™ System has been developed 
to replace a diseased aortic heart valve without the need for open heart surgery. A description of 
the study valve is included under the section Study Device. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This website will 
not include information that can identify you. At most, the website will include a summary of the 
results. You can search this website at any time. 
You are being asked to participate in this study because doctors have determined your aortic 
valve is no longer working the way it should. However, your doctors have also decided that your 
risk of experiencing major problems while having open-heart surgery is moderate. This means 
that you doctor believes your health is good enough for open-heart surgery, but there is still a risk 
of potential problems. 
PURPOSE OF THE STUDY 
The purpose of this clinical study is to figure out if replacing the aortic valve without open-heart 
surgery is as safe as or safer than open-heart surgery in patients with similar medical conditions 
as you. 
The study valve is considered an “investigational device”, which means that Health Canada has 
not yet approved it to be used for standard of care purposes and is only allowed to be used for 
the study. Medtronic, Inc. is sponsoring this study to obtain data on the safety and performance of 
the investigational device. The Medtronic CoreValve™ System includes the valve described below 
and two parts that help load and deliver the valves correctly.  
This study will involve up to 2000 subjects at up to 115 hospitals in the United States, Canada 
and around the world, and is anticipated to take approximately 8 years to complete. Your 
participation in this study is expected to last approximately five years from the day you are 

 
 
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enrolled in the study.  Annual follow-up may be extended to up to 10 years after the implant 
procedure. 
STUDY DEVICES 
The study valve is made from animal tissue attached to a metal frame.  
The study valve is designed to be inserted using a long, thin flexible tube (delivery system) to 
replace your diseased aortic heart valve through an incision in the skin and threaded through the 
bloodstream (percutaneous) and without open-heart surgery.  Once it is implanted, CoreValve™ 
study valves acts in the same method of the native valve. 
 
 
 
 
 
 
 
 
 
Although the Medtronic CoreValve™ system is not approved by the US Food & Drug 
Administration (FDA), or Health Canada, it has been approved in other parts of the world since 
2006 and has been implanted in over 45,000 patients. 
The Medtronic CoreValve™ System is currently approved for use in Europe, South America, and 
parts of Asia.  
PROCEDURES TO BE FOLLOWED 
If you agree to be in this study, and after you have signed this informed consent form, information 
such as your age, gender, medical history and medication use will be recorded. You will have the 
following tests: 
• Physical examination 
• Computed tomography (CT) - a scan performed using an x-ray machine that takes pictures 
of your body. Sometimes a CT will require the use of a type of dye that makes the kidneys 
work harder and may be harmful to the kidneys. You may have an MRI in place of a CT 
scan if your doctor believes your kidneys are not working well enough for you to have a CT 
scan. MRI stands for magnetic resonance imaging and is a test that also takes pictures of 
your internal organs. 
• Blood tests (about 2 tablespoons). These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they 
should as well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning 
as they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or 
other heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 

 
 
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o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is 
working harder than normal to pump blood through your body 
• Echocardiography (transthoracic echocardiogram (TTE)) - a test that uses sound waves to 
take pictures of your heart and measure the degree of narrowing of your aortic valve; a 
probe with gel is placed on the outside of your chest to take pictures of your heart 
• Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
• Heart catheterization/angiography - a test that takes pictures of your heart and blood 
vessels; a special dye is injected through long, flexible tubes into the coronary arteries 
(vessels delivering blood to the heart) and bypass grafts if you have them 
These procedures and tests are standard procedures required for the treatment of your disease 
and are not experimental. If you have already had any of these tests performed before, they may 
be used for the study if your study doctor determines they don’t need to be repeated for study 
purposes.  
The results from your exams and tests will be reviewed by your doctor and a committee of study 
doctors who will determine if you are eligible to be in the study. 
Your study doctor and the committee may determine after reviewing your test results that you are 
not eligible to be in the study and/or it will not be possible to implant the study valve.  If so, you 
will not be allowed to participate in the study. 
If your doctor and the committee decide you are eligible to be in the study, you will be one of the 
first three (3) patients at this hospital to be enrolled in this study. You will receive a transcatheter 
aortic valve implant (TAVI).  
Your enrollment in the study will begin once you sign this consent and you are assigned to the 
roll-in treatment group. If you are enrolled in the study, you will be required to have the following 
additional tests (for study purposes only) completed within 14 days prior to the procedure (TAVI): 
• Physical exam, including determining your neurological (brain) status where you will be 
asked to answer a some questions and perform some tasks such as writing and drawing 
• Blood tests (about 2 tablespoons) These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they should 
as well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning 
as they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or 
other heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is 
working harder than normal to pump blood through your body 
• Walking test – a test that records your breathing, heart rate, and how you feel after 6 
minutes of walking 
• Electrocardiogram (ECG) - a test that records electrical impulses of your heart; patches are 
placed on the outside of your chest 
You will also be asked to complete surveys about the quality of your life and your ability to do 
normal daily activities, called Quality of Life Questionnaires (QOL).  Completing the 
questionnaires should take about 10-15 minutes each. 
Your personal physician will be informed about your participation in this clinical study. 

 
 
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TAVI PROCEDURE: 
The study valve is an experimental valve which means you can only receive the valve if you are 
part of this study.  
Before the TAVI procedure, it will be strongly recommended that you take blood thinning 
medications, used to prevent your blood from clotting (thickening). These medications will be 
described to you by your study doctor.  You may be advised to continue these medications for at 
least three months after your procedure.  
Before the procedure you will be given an antibiotic (a medicine that kills bacteria or germs) to 
decrease your chance of developing an infection. Your study doctor will choose the antibiotic that 
he or she thinks is best suited for you and decide whether you need additional medication. 
You will also have blood tests (about 2 tablespoons) and an ECG before the procedure.   
Immediately prior to the procedure, you will receive medications to make you more relaxed and 
comfortable during the procedure. Your study doctor may decide that general anesthesia is 
necessary, meaning you need to be put to sleep for the procedure. Your doctor will inform you of 
this need before the procedure. Additionally, if your study doctor decides that it is necessary 
during the procedure, you will be put under general anesthesia at that time. 
Your study doctor will decide what locations are best for inserting the long, thin flexible tubes 
required for TAVI and getting all of the pictures that are necessary.  
During the procedure you may have a transesophageal echocardiogram which is also called a 
TEE. This test uses sound waves to take a closer look at the inside structures of the heart. To 
perform the test you will swallow a thin flexible tube with a special tip. This tube sits in the 
esophagus (the tube that connects the mouth to the stomach). The special tip of the tube sends 
out sound waves (ultrasound) that echo within the chest wall. The esophagus is located behind 
the heart so these echoes are picked up and create a picture of the heart that is displayed on a 
video monitor. The pictures will allow your study doctor to take a closer look at your valve. 
You will have a temporary pacemaker put in your heart during the TAVI procedure. A temporary 
pacemaker is a thin wire inserted through your skin and into one of your veins and threaded 
through your vein into the right side of your heart. The wire is attached to a battery operated 
device outside of your body. This temporary pacemaker will help keep your heart rate (speed) 
and rhythm steady. This temporary pacemaker will not be removed for at least 48 hours after your 
TAVI procedure. 
After your study doctor has taken a good look at your valve, a balloon valvuloplasty will be 
performed. Balloon valvuloplasty is a procedure used to widen a stiff or narrowed heart valve. A 
wire and a thin tube are guided by x-rays through the heart and positioned through the diseased 
heart valve. A balloon is placed over the wire and inflated, making the opening bigger through the 
diseased valve allowing the study valve to be placed. 
Your doctor will then implant (insert) the study valve through the long, thin flexible tube that is 
inserted through an incision in the skin and threaded through the bloodstream. TAVI is performed 
using x-ray machines which will allow your doctor to see the study valve, your blood vessels and 
heart. The study valve will be guided through your blood vessels and then it  will be placed over 
your existing aortic valve. 
During the TAVI procedure, your doctor will perform angiography (x-ray pictures) and ECGs 
(recordings of the electrical impulses of your heart through patches placed on the chest) to 
observe your heart function and make sure that the study valve fits and works properly. 
Doctors from other hospitals who have experience with the TAVI procedure may assist your study 
doctor with the procedure. Medtronic staff may assist the physician in the loading of the study 
valve. 
AFTER TAVI PROCEDURE: 
After the TAVI procedure, your study doctors will continue to monitor your progress and recovery. 

 
 
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You will have the following tests performed within the two days following the procedure and 
before you are discharged from the hospital: 
• Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
• Blood tests (about 2 tablespoons) These tests include the following: 
o 
Complete blood count - counting the amount of white and red blood cells you have 
o 
Blood chemistry – tests to make sure your liver and kidneys are working as they should 
as well as make sure other minerals (enzymes) in your blood are normal 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
o 
Cardiac Enzymes (CK/CK-MB) – test to make sure you have no had heart attack or other 
heart problems 
o 
International Normalized Ratio – only if you are taking a medicine called coumadin or 
warfarin.  The test shows how fast your blood clots and if your medication dosage is 
working 
o 
Activated Partial Thromboplastin Time – test to determine the thickness of your blood 
o 
B-Type Natriuretic Peptide (BNP) or NT-proBNP – tests that show if your heart is working 
harder than normal to pump blood through your body 
•  Echocardiogram (TTE) 
•  ECG 
FOLLOW-UP VISITS AFTER TAVI: 
You will need to return to the clinic for required follow-up visits at 30 days, 6 months, 12 months 
(1 year), 18 months, 24 months (2 years), and 3, 4, and 5 years after the procedure. Most of the 
follow-up tests and examinations are routine, not experimental. Each visit will take about 1 ½ to 2 
hours.  
Your evaluations at 30 days, 6 and 18 months will include: 
 Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
 You will be asked about your health since the last follow-up visit 
 Quality of Life Questionnaires 
 ECG 
 Blood tests (about 2 tablespoons) – 30 day visit only 
o 
Hemoglobin – test how much of a protein that carries oxygen to your body's organs and 
tissues and transports carbon dioxide from your organs and tissues back to your lungs 
you have in your blood 
o 
Creatinine and Creatinine clearance - tests to make sure your kidneys are functioning as 
they should 
 Walking test – 30 day visit only 
 Echocardiogram (TTE) – 6 month visit only 
Your evaluation at 12 months, 24 months, and 3, 4, 5 years will include: 
 Physical exam, including determining your neurological (brain) status where you will be asked 
to answer a some questions and perform some tasks such as writing and drawing 
 You will be asked about your health since the last clinic visit 
 Blood tests (about 2 tablespoons) 
 Echocardiogram (TTE) 
 Quality of Life Questionnaires 
 ECG 
 Walking test – 12 and 24 months visits only 

 
 
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In addition to the in-clinic follow-up visits, at 3 months you will be contacted by phone, by 
someone from your clinic, to complete a Quality of Life Questionnaire. 
If, during the 5 years of follow-up,  you have had additional heart surgeries or cath lab procedures 
to work on or replace your aortic valve or study valve, you will be asked to answer questions and 
perform activities that will help the study doctors and nurses to determine your neurological 
(brain) status within 24 hours after each additional procedure. 
If you have a stroke, have been informed by a doctor that you experienced a stroke, or 
experience any of the following symptoms, notify Dr. Principal Investigator at xxx-xxx-xxxx as 
soon as possible: sudden numbness, tingling, loss of movement (especially on 1 side of the 
body), vision changes, confusion or trouble understanding simple statements, severe headaches, 
or seizures.  Any of these symptoms could indicate that you are having problems with your 
neurological (brain) function.  If a doctor confirms that you had a stroke, you will be asked to 
come to the clinical to have tests performed to determine your neurological (brain) status where 
you will be asked to answer a series of questions and perform a series of tasks. These tests will 
be performed at 7 days, 30 days and 3 months after you have any of these symptoms. 
If you have any other problems or complications, are seen by any other doctors for problems, or 
are hospitalized during your participation in this study you should immediately notify Dr. Principal 
Investigator at xxx-xxx-xxxx. 
If the study valve is removed for any reason, we will request that it be returned to Medtronic for 
additional analysis.  Your study doctor will determine if you will need to have another valve 
implanted.   
In the event of your death, we would like to do an autopsy. We will ask that either your whole 
heart and valve or just the valve are removed and returned to Medtronic for additional analysis. 
The autopsy and the removal of the heart and/or valve would be done to provide additional 
information about the research and the study valve. 
Your family and your "legally authorized representatives", has the right to refuse the autopsy and 
refuse the request to remove the heart and/or valve even if you sign this consent form.  You may 
still participate in this study if you do not want to have an autopsy done. 
POSSIBLE RISKS AND DISCOMFORTS 
Potential risks associated with the implantation of the study valve may include, but are not limited 
to, the following: 
 
Death 
 
Cardiac arrest – heart stops beating and blood flow through the body is interrupted 
or stopped 
 
Coronary occlusion, obstruction, or vessel spasm (including acute coronary 
closure) – blockage or closure of an artery that supplies the heart with blood 
 
Emergent surgery 
o 
Coronary artery bypass – (CABG) a surgery where the chest is opened to 
place new vessels around the existing blocked vessels of the heart to 
improve blood supply to the heart. 
o 
Heart valve replacement – replacing the existing heart valve with a new heart 
valve 
o 
Valve explant – the removal of the existing valve 
 
Multi-organ failure – more than one organ of the body not functioning correctly 
 
Heart failure – heart does not pump blood to the body  
 
Myocardial infarction -  decreased blood flow to the heart causing death of heart 
muscle cells 
 
Cardiogenic shock – failure of the heart to pump enough blood to the body organs 
 
Respiratory insufficiency or respiratory failure – not enough oxygen  or not able 
to supply oxygen to the body 

 
 
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 
Cardiovascular injury (including rupture, perforation, or dissection of vessels, 
ventricle, myocardium, or valvular structures that may require intervention) 
 
Perforation of the myocardium or a vessel – a hole in the heart muscle or a blood 
vessel 
 
Ascending aorta trauma – injury to the large blood vessel leading blood away from 
the heart 
 
Cardiac tamponade – the constriction or inability of the heart to pump due to buildup 
of blood or fluid around the lining of the heart 
 
Cardiac failure or low cardiac output 
 
Prosthetic valve dysfunction including, but not limited to: 
o 
Fracture (break) in the valve frame 
o 
Bending of the valve frame 
o 
The valve frame does not open (expand) all the way 
o 
Calcification (build-up of calcium on the valve) 
o 
Pannus – the formation of scar tissue that may cover or block the valve from 
functioning normally 
o 
Wear, tear or movement forward (prolapse) or backward (retraction) from the 
normal position of the valve leaflets 
o 
The valve leaflets do not close together 
o 
A break in the stitches (sutures) of the valve frame or leaflets 
o 
Leakage through or around the valve or valve frame 
o 
Incorrect size of the valve implanted 
o 
Incorrect position of the valve, either too high or too low 
o 
Regurgitation – backward flow of blood through the valve 
o 
Stenosis – narrowing of the opening of the valve 
 
Thrombosis/embolus (including valve thrombosis) - an abnormal particle (air, 
blood clots) floating in the blood stream or attached to an object, including the valve 
 
Valve migration/valve embolization – upward or downward movement of the 
device from where it was originally placed 
 
Ancillary device embolization – a broken piece of the tube that delivers the valve 
floating in the blood stream 
 
Emergent percutaneous coronary intervention (PCI) – a procedure through the 
vessels inside the body and heart used to treat or open narrowed vessels of the heart 
 
Emergent balloon valvuloplasty (balloon valvuloplasty during the TAVI procedure 
is expected) – a procedure through the vessels inside the body and heart in which a 
narrowed heart valve is stretched open by a balloon 
 
Bleeding that may or may not require transfusion or intervention  
 
Allergic reaction to: 
o 
Antiplatelet agents (blood thinning medication) 
o 
Contrast medium (dye used to see vessels with x-ray), or  
o 
Anesthesia (medication used to put you to sleep during the procedure) 
 
Infection (including septicemia and endocarditis) – an abnormal growth of germs 
in the body or body part 
 
Stroke, TIA, or other neurological deficits – decreased blood flow to the brain 
causing death of brain cells 
 
Permanent disability – injury that does not allow that impairs normal/previous 
physical or mental function 
 
Renal insufficiency or renal failure (including acute kidney injury) – failure of the 
kidneys to work correctly 

 
 
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 
Mitral valve regurgitation or injury – a leaking valve between the left upper (left 
atrium) and left lower (left ventricle) parts of the heart where blood flows backward 
through the valve or damage to the valve that may cause it to not function correctly 
 
Tissue erosion – damage to the tissue of the heart or blood vessels that could result 
in a tear or hole 
 
Vascular access related complications, such as: 
o 
Dissection -  a tear in a blood vessel 
o 
Perforation – puncture of a blood vessel 
o 
Pain 
o 
Bleeding 
o 
Hematoma –blood collecting under the skin 
o 
Pseudoaneurysm - blood collecting on the outside of a vessel wall causing a 
balloon-like widening 
o 
Irreversible nerve damage – permanent damage to nerves 
o 
Compartment syndrome – squeezing of nerves and muscles in a closed 
space that could cause muscle or nerve damage 
o 
Arteriovenous fistula – abnormal connection between an artery vessel that 
takes blood away from the heart and a vein vessel that takes blood to the 
heart 
o 
Stenosis – narrowing of a vessel (artery) 
 
Cardiac arrhythmias  
o 
Disturbances in the electrical system of the heart that may result in the 
permanent placement of a device (pacemaker) that delivers electrical 
impulses to the heart to help your heart beat normally 
o 
Atrio-ventricular node block – a block in the electrical path from the top part 
of the heart (atria) to the bottom part of the heart (ventricle) 
o 
Bundle branch block – a delay or block in the electrical path in the bottom 
part of the heart (ventricle) 
o 
Asystole – when the heart stops beating 
o 
Ventricular arrhythmias – abnormal fast or slow heart beats in the lower part 
of the heart (ventricles) 
 
Encephalopathy – altered mental state 
 
Pulmonary edema – fluid build-up in or in the space around the lungs 
 
Pericardial effusion – fluid around the heart 
 
Pleural effusion – fluid build-up in the space around the lungs that makes breathing 
difficult 
 
Myocardial ischemia – reduced or interrupted blood supply to the heart 
 
Peripheral ischemia – reduced or interrupted blood supply to arms and legs 
 
Bowel ischemia – decrease blood supply to the intestines 
 
Heart murmur – an extra or unusual sound hear during a heartbeat 
 
Hemolysis – break down of blood cells 
 
Cerebral infarction-asymptomatic – silent stroke 
 
Non-emergent reoperation 
 
Inflammation – swelling of tissue 
 
Fever – increase in body temperature 
 
Hypotension or hypertension – low or high blood pressure 
 
Syncope – fainting  
 
Dyspnea – shortness of breath 
 
Anemia – not enough oxygen carrying cells in the blood 

 
 
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 
Angina – chest pain 
 
Abnormal lab values (including electrolyte imbalance) – changes in blood test 
results 
 
Exposure to radiation through fluoroscopy and angiography 
 
Delivery catheter malfunction resulting in need for additional re-crossing of the 
aortic valve and prolonged procedural time 
 
There may also be additional risks, discomforts, or side effects that are not yet known. If you 
become pregnant there maybe risks, discomforts, or side effects to you and the embryo/fetus that 
are not yet known.  Please notify your study doctor as soon as possible to discuss any of these 
potential risks. 
RADIATION EXPOSURE RISKS 
Some of the test and procedures that are part of this study require exposure to radiation (x-rays).  
These tests or treatments involve a small amount of radiation. To give you an idea about how 
much radiation you will get, in the following descriptions the radiation is compared to the amounts 
that people are exposed to in daily life. There is radiation that naturally occurs from space and 
from rocks in the soil. This natural radiation is greater at higher altitudes. 
CT of Chest and Abdomen and Coronary Angiography 
The radiation exposure received from the screening tests (CTA of abdomen and thorax and 
coronary angiogram) is approximately 10 times the radiation exposure received in one year from 
background radiation (naturally occurring radiation you are exposed to everyday). The exposure 
is less than the radiation exposure limit an occupational worker is allowed to receive in one year. 
Valve implantation 
The estimated radiation exposure for the valve procedure is approximately 10-15 times the 
amount of radiation exposure received in one year from background radiation (naturally occurring 
radiation you are exposed to everyday). The exposure is approximately the amount an 
occupational worker is allowed to receive in one year. 
There are additional risks or side effects from being exposed to x-rays.  Most side effects do not 
occur often and resolve without major problems.  It is possible that skin reddening or other 
alterations to the skin’s appearance may occur if you are exposed to enough radiation during the 
procedure or if you have recently had another cardiac angiogram. You should contact your doctor 
in the event that you observe this. If you have a reaction to the x-rays you may need to have extra 
follow-up visits with your doctor to watch your recovery more closely. 
Your doctor will explain to you how many x-rays you will receive, what x-rays are part of your 
normal care and what, if any, are extra for the study. 
POSSIBLE BENEFITS 
The possible benefits you may receive from participating in this research are that you may be 
able to receive a new heart valve without having open-heart surgery.  
Your participation in this research may improve procedures that may guide the future treatment of 
heart surgery, by using procedures that are less invasive, meaning less cutting, entering or 
breaking through the body, which may benefit others in the future. However, there is no 
guarantee that you will benefit from being in this research. 
ALTERNATIVE TREATMENTS 
The current long-term effective treatment for severe aortic stenosis is open heart surgery to 
replace the aortic valve.  For patients who are at high risk for open heart surgery, other treatment 
options include percutaneous (through an artery in the groin) aortic valve implantation, or medical 
management to relieve symptoms, which may include balloon valvuloplasty.  Ask your study 
doctor about other treatment options you may have. 
IF PROBLEMS DEVELOP 

 
 
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If you believe that you have been injured as a result of your participation in the study, you should 
notify Dr. Principal Investigator at xxx-xxx-xxxx as soon as possible or in serious cases, go to the 
emergency room.  
Immediate necessary medical care is available at [Name of institution(s)] in the event that you are 
injured as a result of your participation in this research study. 
Medtronic has agreed to pay back [name of institutions that are parties to the CTA] for the costs 
of reasonable medical or surgical care they provide for any serious and unanticipated illness or 
injury under the following conditions: 
 
The illness or injury must be directly related to a defect or malfunction of the investigational 
device or in the TAVI procedure as described in the Protocol, and not related to procedures 
that are routine standard of care. 
 
The illness or injury cannot be caused (a) by the negligence or intentional misconduct of 
the study staff or [name of institutions that are parties to the CTA]; (b) because the study 
staff or [name of institution(s)] that are parties to the CTA] did not follow the protocol for the 
study; or (c) by the natural progression of your illness. 
 
The illness or injury must have happened before the study closes (last patient is seen for 
the 5 year follow-up visit) at this [Name of institution(s)]. 
 
[Name of institution(s) that are parties to the CTA] must notify Medtronic of the illness or 
injury within one year of the date the study closes at all study sites or before the study 
closes at this site, whichever is earlier. 
Subject to the above conditions, Medtronic will pay back the costs that are not covered by your 
applicable provincial health insurance or third party insurer. The amount Medtronic will pay back 
is the applicable provincial health insurance plan rate. 
PAYMENT FOR PARTICIPATION IN THE STUDY 
You will not be paid to take part in the study. However, you may be reimbursed for local mileage 
and parking expenses directly related to any study-only related visits. Your study doctor or 
research coordinator will tell you how to get reimbursement.  
There is no monetary advantage to the study doctor for participation in this study. Your 
participation in this study may contribute to the development of commercial products from which 
Medtronic may receive economic benefit.  Medtronic is paying the study site for the work involved 
in collecting study data and managing the study at this site.  
MEDICAL EXPENSES 
All necessary medical procedures should be covered by Provincial Health Insurance Plan. 
BASIS OF PARTICIPATION 
Your participation in this study is voluntary. If you refuse to be in this study there will be no 
penalty or loss of benefits to which you are otherwise entitled. You may withdraw from the study 
at any time and will not lose your benefits or be treated any differently as a result of withdrawing 
from the study. Any new findings (decisions or conclusions) that may influence your willingness to 
participate will be provided to you.  If you decide to leave the study before it is finished, please tell 
one of the persons listed in the section below “Obtaining Additional Information”. It may be 
requested that, if you withdraw, you return to your study doctor for a final visit. 
The study doctor may end your participation in the study at any time if: 
 He or she determines it is not in the best interest of your health 
 The study doctor loses contact with you and you do not return for your study visits as 
scheduled 
 You refuse to allow the use of private health information during the course of the study 
 
The study doctor will make the decision and let you know if it is not possible for you to continue in 
the study. 

 
 
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You may be removed from the study without your consent if the sponsor (Medtronic, Inc.) ends 
the study.  If this happens, you will be notified and the reasons will be explained to you.  Your 
physician will continue to provide the appropriate medical care. 
What are my responsibilities as a research subject?  
As a subject in a research study, it is important that you: 
 Be truthful about your health and medication history; 
 Return to the office for the study visits that the physician has scheduled with you; 
 Call the study doctor’s office to reschedule a missed visit as soon as possible; 
 Report any injuries, hospitalizations, emergency room visits, symptoms or complaints to the 
study doctor or nurse as soon as possible. 
 
 
PERMISSION FOR ACCESS TO AND USE OF HEALTH INFORMATION 
While you take part in this research study, the researcher in charge and study staff will collect and 
take down information about you in a file. Only information necessary for the research study will 
be collected.  
The information in your file could include your past and present medical history, information about 
your way of life and test results from exams and procedures done during this study. Your file 
could also contain other information, such as your name, sex, date of birth and ethnic origin.  
All the information collected about you during the study will remain confidential as the law 
demands. To protect your privacy, your information will be identified with numbers and or letters. 
Only the researcher in charge of the study knows the numbers and or letters that link them to you.  
The study researcher will send the research study information collected about you to the sponsor 
or sponsor representatives. This information does not include your name or address.  
The sponsor will use the information collected about you only to reach the study goals as they are 
explained in this Informed and Consent Form.  
The information collected about you can be shared by itself, or together with other information 
collected from other studies with government groups in Canada or in other countries, or with the 
people that do business with the study’s sponsor Medtronic. This means that your study 
information could be sent to other countries. The sponsor must respect applicable Canadian 
privacy laws and those in all the countries where your study information will be sent. Your study 
information will be kept for at least 25 years by the researcher in charge of the study and by the 
sponsor.  
The study information may help the government approve the sale of the study device. The study 
information may also be used for other reasons related to the study or to help develop future 
studies.  
The study information could be printed in medical journals or shared with other people at scientific 
meetings, but, it will be impossible to identify you.  
To make sure the study is being done properly; your research study file as well as your medical 
file could be checked by a person authorized by the Research Ethics Board of the [Name of 
hospital or clinic(s)], or by the institution, by a person authorized by special people or groups 
(Health Canada) as well as by the sponsor’s representatives. These people and groups are 
obliged to respect your privacy.  
For your safety and to be able to reach you quickly, your family name, first name, how to contact 
you and the date you started and ended the study will be kept for one year after the study ends in 
a separate list kept by the researcher in charge of the study or by the institution.  
You have the right to look at your study file in order to check the information gathered about you 
and to correct it, if necessary, as long as the study researcher or the institution keeps this 
information. However, you may only have access to certain information once the study has ended 
so that the quality of the research study is protected. 

 
 
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Economic Study 
This study contains a health economics review that will be done to compare the in-hospital, 
follow-up medical care resource utilization and cost for patients in each of the treatment groups 
You may also be asked to sign a separate document that gives us your permission to review your 
billing information sent directly from your payer in order to evaluate medical cost data.  This 
information will be kept strictly confidential and be used solely to assess the medical expenses 
which occur as a direct result of participating in the Medtronic CoreValve™ SURTAVI Trial. 
Quality of Life Questionnaire 
Medtronic CoreValve™ SURTAVI Trial will also contain a quality of life study. As part of this study, 
your research coordinator will have you or your caregiver complete a questionnaire called a 
Quality of Life Questionnaire.  You will need to complete this questionnaire when you are enrolled 
in the study and 1 month, 3 months, 6 months, 12 months, 18 months, 2 years, 3 years, 4 years 
and 5 years after your study procedure. 
OBTAINING ADDITIONAL INFORMATION 
You are encouraged and have the right to ask questions at any time concerning potential and/or 
known risks of this study. The study doctor will inform you of any new significant information, 
when it becomes available, which may affect your willingness to continue to participate in this 
study. If you have any questions about this study or if you experience any health problems, you 
should contact Dr. Principal Investigator at xxx-xxx-xxxx. 
If you have questions about your rights as a participant in this study, you should contact the 
chairman of the Institutional Review Board at xxx-xxx-xxxx. 
MEDTRONIC’S USE AND DISCLOSURE OF YOUR HEALTH INFORMATION 
This section describes what Medtronic as study sponsor will do with the study data, including your 
health information received during the study. 
Medtronic will keep your health information confidential in keeping with all applicable laws and 
regulations. Medtronic may use your health information to conduct this study. Medtronic may use 
your health information for other purposes, such as: 
 
Watch over and improve the performance of its device; 
 
New medical research; 
 
Proposals for making new medical products or procedures; and 
 
Other business purposes. 
Any reports or publications about the study or any other research will not include your name or a 
description of you. Any records identifying you will not be made publically available.  Information 
received during the study will not be used to market to you; your name will not be placed on any 
mailing lists or sold to anyone for marketing purposes. 
The United States Food and Drug Administration’s (FDA) and Health Canada’s regulations, as 
well as other applicable laws, control Medtronic’s work in developing and assuring the safety and 
quality performance of its medical devices. Medtronic may disclose your health information to the 
FDA, Health Canada, as well as to other U.S. and foreign government authorities responsible for 
assuring the safety of medical devices. Medtronic also may disclose your health information to 
research ethics boards and other persons who are required to watch over the safety and 
effectiveness of medical products and therapies and the conduct of research. In addition, 
Medtronic representatives or delegates of Medtronic may inspect/monitor your medical records 
during the course of the clinical study in order to ensure compliance with the study protocol and 
study procedures.  You agree to allow Medtronic to use study data in these ways. You also agree 
to allow Health Canada, the FDA and other governmental authorities to inspect your health 
information. 
You may change your mind and take back this permission to use your health information at any 
time. To take back this permission, you must write to [name and contact information]. If you take 
back this permission, you cannot continue in the study. Even if you take back this permission, 

 
 
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Medtronic and Researchers may continue to use and share the health information already 
received as described in this Informed consent. 

 
 
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PRIMARY CARE PHYSICIAN / SPECIALIST NOTIFICATION OPTION  
Please indicate below whether you would like us to notify your primary care physician or your 
specialist of your participation in this study.   
(Initial only one box). 
 
Yes, I want the study doctor to inform my primary care physician/specialist of my 
participation in this study 
 
No. I do not want the study doctor to inform my primary care physician/specialist of 
my participation in this study. 
 
I do not have a primary care physician/specialist. 
 
 
The study doctor is my primary care physician/specialist. 
 
 

 
 
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INFORMED CONSENT FOR THE MEDTRONIC 
SURTAVI TRIAL 
 
PATIENT INFORMED CONSENT FORM SIGNATURE SHEET  
I confirm that: 
 
I have read the informed consent form of this study and my physician has answered all my 
questions regarding the study.  
 
I had sufficient time to consider my participation into this study, I am aware that 
participation into this study is completely voluntary, and I agree to follow the instructions 
from the investigator. 
 
I realize that I may decide to refuse participation or stop participation at any time without 
penalty and without affecting the quality of my health care or the relationship with my 
physician.  
 
I understand and agree that personal information about me will be collected from my 
medical records, used and processed (manually and by computer) by the manufacturer of a 
medical device used in my treatment or any other designated party that is involved in the 
study (e.g. hospital, physician, regulatory authorities, ethics committees).  
 
I understand and agree that representatives from Medtronic, regulatory authorities and the 
Institutional Review Board will be granted direct access to my medical records.  
 
I understand and agree that the physician(s) / hospital will release the relevant personal 
information about me for the purpose of the clinical investigation. 
 
I understand that I am entitled to access the personal information collected about me and to 
have inaccuracies corrected. 
 
I fully understand there is limited experience with this device in humans and that its safety 
and effectiveness have not been established and there are risks of serious complications 
associated with this study. 
 
I also understand that the doctors might determine after I give consent that it is not possible 
to implant the study valve. 
 
Signature of the subject or subject’s legally authorized representative  
I hereby give my consent to participate in the “Medtronic CoreValve™SURTAVI Trial”. I have 
been given a copy of this consent form, and am also aware that the investigator will keep a copy 
in his or her files. 
 
 
 
 
 
 
 
 
 
Printed name of subject  
 
 
 
 
 
 
 
 
Signature of subject   
 
 
 
 
 
 
 
 
Date (must be written in by subject) 
 
 
 
 

 
 
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Signature of a witness in the event that the subject or subject’s legally authorized 
representative is unable to read or write 
 
 
 
 
 
 
 
 
Printed name of witness (if applicable) 
 
 
 
 
 
 
 
 
Signature of witness (if applicable) 
 
 
 
 
 
 
 
 
Date (must be written in by witness) 
 
 
Signature of the principal investigator or authorized designee for conducting the informed 
consent process 
 
 I certify that I have explained the nature of the device and the study to the above-named 
person. 
 I have also explained the contents of this informed consent form to the above-named 
person. I have asked whether or not there are any questions. I have answered any 
questions that were raised by this person. 
 
 
 
 
 
 
 
 
Printed name of principal investigator or authorized designee for conducting the informed 
consent process  
 
 
 
 
 
 
 
 
Signature of principal investigator or 
authorized designee  
 
 
 
 
 
 
 
Date (must be written in by principal 
investigator or authorized designee)  
 
 

 
 
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R.2 
List of Participating Investigational Centers 
The list of participating Investigational Centers will be provided under separate cover. 
 
 

 
 
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R.3 
Other Institutions 
The following institutions/organizations will participate in the Medtronic CoreValve SURTAVI Trial. 
An updated list of “Other Institutions” will be provided in progress reports and/or upon request. 
Clinical Events Committee (CEC) / Data Safety Monitoring Committee (DSMB): 
Cardialysis 
Westblaak 92 
3012 KM Rotterdam 
The Netherlands 
Explanted Device/Pathology Core Lab: 
CVPath Institute, Inc. 
 19 Firstfield Road 
 Gaithersburg, MD 20878 
Imaging Core Lab: 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
InteleGRIDTM (imaging sharing network):  
Intelemage, LLC 
5400 Kennedy Ave 
Cincinnati, OH 45213  
Interactive Voice/Web Response System (IXRS):  
United BioSource Corporation (UBC) 
303 2nd Street, Suite 700 
7th Floor South Tower 
San Francisco, CA 94107 
 

 
 
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R.4 
Additional Records and Reports 
No additional records and/or reports, other than those previously described in this investigational 
plan or required by FDA, will be maintained for this clinical investigation. 
 
 

 
 
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R.5 
Sample Case Report Forms 
Sample Case Report Forms (CRFs) will be provided under separate cover. 
 
 
 

 
 
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Aortogram Acquisition Guidelines 
The purpose of the acquisition guidelines is to increase consistency and effectiveness in reviewing 
the procedural aortograms. 
1. Required aortogram:  
 
Index Procedure –TAVI 
2. Required cine runs: 
 
Pre-procedure aortogram in a projection with 3 aortic cusps aligned (for comparison of 
final aortogram with pre-procedure aortogram) 
 
Final aortogram at least 10 minutes after TAVI implantation in the exact same projection 
as the pre-procedure aortogram (in order to measure depth of implantation and assess 
grade of aortic regurgitation) 
NOTE:  If the apex is not clearly visible in the final projection and in case of adequate renal function, 
in order to assess grade of AR, perform an additional final aortogram in RAO 30° with 
visualization of the left ventricle in long axis, including the apex. 
3. Guidelines on how final aortogram after deployment of the valve should be performed: 
 
Use at least 20 ml of contrast, with an injection rate of 20 ml/sec 
 
Position the pigtail catheter in the upper third part of the frame 
 
Preferably use non-diluted contrast. 50%-diluted contrast is acceptable in case of renal 
insufficiency 
 
Use the angiographic projection with the three aortic cusps aligned in 1 plane: 
o 
Whenever available this optimal projection can be suggested by baseline MSCT 
exam 
o 
Pragmatic approach might be to use a shallow LAO or RAO projection, and adjust 
in a cranial or caudal position respectively to approach the optimal projection 
 
Confirm visualization of the left ventricular apex on the final aortogram 
 
Perform the final aortogram at least 10 minutes after deployment of the investigational 
TAVI device; include a time indication on the aortogram 
 
Use marker pigtail or provide the French-size of the pigtail catheter for calibration 
purpose 
4. General imaging and recording procedures: 
 
Use a fixed table system and biplane x-ray equipment, if available 
 
Recommended resolution: 1024 x 1024 pixels 
 
Preferred acquisition speed: 25 frames/second 
 
One single cine run should have a duration of at least 5 heart beats 
 
The digital clock should be activated 
 
The maximum magnification factor should be applied during cine run without losing the 
image of the entire frame 
 
There should be no overlap of the frame with other catheters or electrodes 
 
Foreshortening of the frame should be avoided as much as possible 
 
Upload all images to InteleGRID (secure electronic system used for transferring images) 
 
 

 
 
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5. Core lab analysis: 
The procedural aortograms may be analyzed by a core laboratory.  Analysis would include: 
 
Grade of aortic regurgitation 
 
Depth of implantation 
 
 
 
 
Figure 1: Example of depth of implantation measurement. 
 
 

 
 
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Echocardiography Acquisition Guidelines 
1. Scope of the document 
These guidelines aim to increase consistency and effectiveness in collection and adjudication of 
echocardiography data of selected candidates for the SURTAVI trial. Optimal image acquisition, 
storage, and transmission will be described. 
2. Protocol required echocardiograms 
Transthoracic echocardiography is required at the following intervals: 
Screening 
- 45 days of Heart Team review 
Post-Procedure  
OR 
Discharge 
Between 24hrs post-procedure and hospital discharge (but no later than 7 
days from post Index Procedure) 
6 months 
± 30 days 
12 months 
± 30 days 
24 months 
± 60 days 
3,4,5 years 
± 60 days 
3. Four general rules for echocardiography recordings 
3.1 Rule #1 for overall recordings: adhere STRICTLY to the PROTOCOL regarding: 
 
number and order of recordings  as listed on the Table 
 
do not perform measurements on the echo recordings, except screening echo to be 
submitted for screening committee review (see measurements noted in section 4) 
 
at end of echo exam, export all required recordings in DICOM format and upload it to 
InteleGRID 
 
only one certified echocardiographer (+ 1 replacement) is allowed to participate in the 
study, he/she should print his/her name, fill in contact details and sign the transmittal form 
3.2 Rule #2 for Doppler recordings: 
 
Unless stated otherwise, all pulsed-wave and continuous-wave Doppler signals should be 
recorded at a sweep speed of 50-100 mm/sec (recording must contains minimum of three 
heartbeats) with optimized gain and filter setting, baseline position, and velocity range. 
3.3 Rule #3 for apical 2D views (4-, 5-, 2-, and 3-Chamber views)  
 
pay attention to ultrasound sector depth and gain settings 
 
the aortic valve should be out of scan plane in the 4-CH view  
 
please avoid patient or transducer motion and record during quite respiration unless 
stated otherwise 
 
make sure the entire LV myocardium (including epicardium and apex) is recorded in the 
scan sector in particular at end-diastole 
 
make sure Frame Rate is more than 30Hz for 2D grey-scale and around 20Hz for colour 
Doppler aortic regurgitation 
3.4 Rule #4 for EF calculation (apical 4- , 2-, and 3-Chamber views focused on LV) 
 
Record 3 runs (run 1: 3 beats, run 2: 3 beats, run 3: 10 beats) 
 
 
4. Data requirements 
Participating centers in the SURTAVI study should obtain the appropriate Doppler and 
echocardiography recordings to document the following variables. 

 
 
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 Aortic annulus long-axis diameter in mid-systole (screening/baseline only)* 
 LVOT long axis diameter in mid-systole 
 Sinus of Valsalva diameter (SOV) at end diastole (screening/baseline only)* 
 Sino-tubular junction diameter (STJ) at end diastole (screening/baseline only)* 
 Sinus of Valsalva height (SOVH) at end-diastole (screening/baseline only)* 
 Max aortic valve velocity (V2) by CW Doppler 
 Velocity time integral (VTI) across aortic valve by CW Doppler 
 Mean gradient across aortic valve (MGV2) by CW Doppler* 
 Peak LVOT velocity (V1) by PW Doppler 
 Velocity Ratio (V1 / V2) 
 Velocity time integral (VTI) of LVOT velocity by PW Doppler 
 Mean LVOT gradient (MGV1) by PW Doppler 
 Doppler Velocity Index (DVI) = VTILVOT / VTIAo 
 Grade of aortic transvalvular regurgitation 
 Grade of aortic paravalvular regurgitation 
 Grade of mitral regurgitation 
 PISA for MR (optional) 
 Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
 Left ventricular (LV) end-diastolic diameter (LVEDD) 
 Left ventricular (LV) end-systolic diameter (LVESD) 
 Interventricular septal thickness at end diastole 
 Left ventricular posterior wall thickness at end diastole 
 Left atrial diameter (AP linear dimension) at end systole 
 Left ventricular ejection fraction by visual estimate 
 Heart rate from Doppler signal 
 Mitral inflow “A” velocity 
 Mitral inflow “E” velocity 
 Mitral inflow E-wave deceleration time 
 Mitral annular tissue Doppler systolic velocity (septal and lateral) 
 Mitral annular tissue Doppler early diastolic velocity (septal and lateral) 
 Mitral annular tissue Doppler late diastolic velocity (septal and lateral) 
Procedures for acquiring aortic root measurements and key hemodynamic variables are described 
in the following sections. For Doppler velocities, the values reported should represent the average 
of measurements from at least three cardiac cycles for patients in sinus rhythm, and the average of 
measurements from five cardiac cycles for patients not in sinus rhythm. For aortic valve, TR jet, and 
tissue Doppler velocities, the reported values should represent the average of the highest velocities 
obtained from the same transducer position. 
* Screening/baseline measurements should be noted on the echo submitted for Screening 
Committee review. 
 

 
 
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5. 
Table 1. list of echo recordings (views) 
 Please include all LV walls including epicardium are within the scan sector 
 Please enter patient’s height, weight, and blood pressure during echo acquisition 
 Please optimize frame rate of 2D colour Doppler around 20 Hz if possible 
 Shift the colour flow zero baseline downwards or upwards in the regurgitant jet direction in the left PLAX view depending  
     on the jet orientation and upwards in the apical view 
 Record frozen images & cine loops in the following order: 
 
A: From parasternal long-axis window 
1. 2D greyscale standard view  
2. 2D Colour Doppler of mitral regurgitation (MR) 
3. 2D Colour Doppler of aortic (or prosthetic) regurgitation (AR) 
4. If AR is present, ZOOM & narrow sector with focus on vena contracta of regurgitant jet  
5. If AR is present, ZOOM & narrow sector, shift Nyquist 35-40 for PISA measurements  
6. 2D greyscale ZOOM for LV outflow tract diameter (LVOT) (3 recordings) 
7. 2D greyscale ZOOM at an intercostal space higher for aortic root / aortic prosthesis  
 
B: From parasternal short-axis window (use same depth setting) 
8. 2D greyscale LV at mitral valve level 
9. 2D greyscale LV at papillary muscle level  
10. 2D greyscale-guided M-mode at LV minor axis (LV dimensions, avoid papillary muscles) 
11. 2D greyscale LV at apical level: lower your transducer position by 1 or 2 intercostal spaces and record the LV as 
circular as possible, just proximal to the level with end-systolic LV luminal obliteration   
12. 2D greyscale aortic valve level (post TAVI the native annulus is usually identified by maximal calcification) 
13. 2D greyscale-guided M-mode of left atrial & aortic dimensions  
14. 2D Colour Doppler of AR: in post-TAVI start scanning from highest position and record first visible AR jet, scan more 
downwards and try to pick up additional jets – confirm origin of AR jets from PLAX 
15. 2D greyscale ZOOM & focussed on RV outflow tract (RVOT) – pulmonic valve should be visible 
16. 2D Colour Doppler of pulmonary regurgitation (PR) 
17. If PR is present, CWD of PR jet (include both systolic & diastolic signals)  
18. PWD of RVOT velocity (within 0.5 -1cm below the pulmonic valve) (frozen image) 
 
C: From special parasternal long-axis window (RV inflow) 
19. 2D Colour Doppler of tricuspid regurgitation (TR) 
20. If TR is present, CWD of TR jet (frozen image) 
 
D: From the apical 4-Chamber window 
21. 2D greyscale standard view  
22. 2D Colour Doppler of MR  
23. If MR is present, ZOOM & narrow sector, shift Nyquist 35-40 for PISA measurements  
24. If MR is present, CWD of MR jet (frozen image) 
25. 2D Colour Doppler of TR  
26. If TR is present, CWD of TR jet (frozen image) 

 
 
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27. PWD of transmitral flow at mitral valve tips – at a sweep speed of 50-100 mm/s (frozen image)  
28. Tissue Doppler of the septal mitral annulus – (frozen image) 
29. Tissue Doppler of the lateral mitral annulus – (frozen image)  
30. Tissue Doppler of RV free wall (frozen image) 
31. M-mode tricuspid annular plane systolic excursion (TAPSE) – (frozen image) 
32. 2D greyscale focussed on LV with decreased depth – three recordings: 3 beats, 3 beats, 10 beats) 
 
E: Apical 5-chamber window 
33. 2D greyscale standard view   
34. 2D Colour Doppler of AR 
35. If AR is present, ZOOM & narrow sector, shift Nyquist 35-40 for PISA measurements  
36. If AR is present, CWD of AR jet (frozen image) 
37. CWD of aortic forward flow (frozen image) 
38. PWD LVOT in native aortic valve: within 0.5 - 1cm below native aortic valve  
39. PWD LVOT in Core Valve, two recordings: immediately below and inside the inflow region of the stent 
 
F: Apical 2-Chamber window 
40. 2D greyscale standard view   
41. 2D greyscale focussed on LV with decreased depth – three recordings: 3 beats, 3 beats, 10 beats) 
 
G: Apical 3-chamber window 
42. 2D greyscale standard view   
43. 2D Colour Doppler of MR 
44. If MR is present, use ZOOM & narrow sector – shift Nyquist 35-40 for PISA measurements  
45. If MR is present, CWD of MR jet (frozen image)  
46. 2D Colour Doppler of AR     
47. If AR is present, CWD of AR jet (frozen image)  
48. If AR is present, use ZOOM & narrow sector– shift Nyquist 35-40 for PISA measurements  
49. CWD of aortic forward flow (frozen image) 
50. PWD LVOT in native aortic valve: within 0.5 - 1cm below native aortic valve  
51. PWD LVOT in Core Valve, two recordings: immediately below and inside the inflow region of the stent 
52. 2D greyscale focussed on LV with decreased depth – three recordings: 3 beats, 3 beats, 10 beats)  
 
H: special recordings 
53. Suprasternal PWD of descending aorta diastolic flow (frozen image) 
54. Subcostal PWD of abdominal aortic diastolic flow (frozen image) 
55. CWD right parasternal aortic forward flow (frozen image) 
56. 2D greyscale inferior vena cava – sniff test for changes in IVC diameter 
57. Optional – biplane imaging at LVOT long-axis for measurement of LVOT area in SAX  
58. Optional – 3D full volume acquisition of parasternal long-axis view focus LVOT and aortic root 
59. Optional – 3D apical full volume acquisition (single beat or 7 beats)  
60. Optional – 3D Colour Doppler from apical view – region of interest aortic valve for AR 

 
 
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6. 
Detailed instructions for acquisition of SURTAVI echocardiography recordings 
6.1 Quality control of the investigational site (initial site validation) 
 
The 1st subject with an echo examination submitted will be reviewed to assess the quality of 
the recording and the transmission and most importantly the ADHERENCE to the 
PROTOCOL. 
 
A “Core Laboratory Pre-Analysis” Report will be provided to the site 
6.2 Guidelines for study object confidentiality 
 
NO patients’ information should be present on the echocardiogram. 
 
Site-Patient identification: study subjects are to be identified by a specific study 
identification number as supplied by the sponsor.  
 
The following items should be entered in the patient identification section of ultrasound 
system and should be clearly shown on all digital cine loops or still frames. 
 Site-subject ID (XXXXX-YYYY) 
 date of exam and  
 study interval  
 
To ensure adherence to the USA HIPAA (Health Insurance Portability and Accountability 
Act of 1996) guidelines for study subject confidentiality, no study subject names or other 
Protected Health Information (date of birth, hospital record number, etc.) should be 
displayed. 
6.3 Submission 
 Upload all study echocardiograms to InteleGRID (secure electronic system used for 
transferring images) 
6.4 Further inquiries:  
 
For any questions, contact your monitor or Medtronic Clinical Research Specialist 
 

 
 
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7. 
Technical guidelines: how to optimize the echocardiography images 
7.1 General recording recommendations 
 
Ensure ultrasound machines are maintained as instructed by the manufacture 
 
Ensure calibration of distance, velocity and time on each image 
 
Keep persistence and smoothening off 
7.2 ECG gating 
 
All cine-loops and still frames must clearly display a single lead electrocardiographic 
recording in which P-, QRS-, and T-waves (but in particular the R wave) are clearly 
identifiable 
7.3 Number of recorded heart cycles  
 
In sinus rhythm, record three continuous beats for all cine-loops and still frames, unless 
indicated otherwise.  
 
In the presence of irregular/non-sinus rhythm, record 5-10 continuous beats.  
 
Try to exclude premature beats. 
7.4 Effects of respiration and timing of recordings  
 
During all recordings, respiration should be quiet.  
 
Tissue Doppler measurements should be recorded after non-forced end-expiration 
7.5 Two-dimensional echocardiography general settings 
 
Use harmonic-imaging mode with maximized (mechanical index >1) power output 
 
Gain (and time-gain compensation (TGC)) settings should be adjusted to eliminate 
background noise and to allow for a clear blood-tissue border.  
 
An optimal gain setting consists of a left ventricular cavity with minimal (but not completely 
absent) noise 
 
The greyscale / dynamic range should be adjusted to provide an image with marked 
contrast between light and dark areas 
 
The focus point should be set at the middle of the region of interest 
 
Depth settings should be minimized (do not display structures outside the region of interest) 
7.6 (Tissue) Doppler settings 
 
Use a display speed of 50 to 100 mm/sec and a sample volume length of 3-4 mm (in 
extremely low heart rates use a speed of 150 mm/sec).  
 
For mitral E-wave deceleration, time one recording is needed at a sweep speed of 150 
mm/s 
 
Adjust gain, filter settings, position and velocity range to maximize the velocity excursion 
 
Minimize the angle between the direction of motion of the investigated structure or flow and 
the Doppler beam 
 
Transmitral flow should be assessed at the tips of the mitral valve 
 
Annotate the tissue Doppler recordings  
7.7 Colour Doppler settings 
 
Minimize the colour sector and use a velocity range of approximately  60 cm/sec  
7.8 Parasternal long-axis view 
 
Minimize the angle between the left ventricle and aorta (the inferolateral wall should be as 
perpendicular as possible to the transducer) the anteroseptal wall is visualized at the same 
distance from the transducer as the anterior wall of the ascending aorta 
7.9 Apical two and four-chamber view 
 
The left ventricular apex should be visible in the top of the sector  
 
The aortic valve should be out of the image plane 
 
Maximize the internal long-axis of the left ventricle (avoid foreshortening) by looking for a 
window one intercostal space lower (in particular when the left ventricle does not appear 
ellipsoid) 

 
 
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 
To ensure that the proper rotation has been made for a two-chamber view, the transducer 
is angled posteriorly to intersect both papillary muscles symmetrically. Then the transducer 
is angled slightly anteriorly so that neither papillary muscle is seen in its long axis in this 
view 
7.10 Special considerations for aortic regurgitation by colour flow imaging1-3 
In addition to the abovementioned recommendations: 
 
Standardize the machine settings for all examinations. Keep the Frame Rate around 20 Hz 
when recording colour Doppler aortic regurgitation  
 
Colour gain should be set step by step just below the appearance of colour noise artefacts 
 
For Vena contracta: use a parasternal long-axis view in ZOOM mode with minimal colour 
sector size and imaging depth to maximize lateral and temporal resolution 
 
For PISA: Shift the colour flow zero baseline downwards or upwards in the regurgitant jet 
direction in the left PLAX view depending on the jet orientation and upwards in the apical 
view) 
7.10 Subcostal window 
In order to provide optimal image acquisition from subcostal window, the following steps are 
required:  
 
The knee-flexed position relaxes the upper abdominal muscles and thereby improves 
visualization 
 
From the subcostal four-chamber view, anti-clockwise rotation of the transducer permits 
visualization and pulsed Doppler examination of the upper abdominal aorta 

 
 
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8. 
Measurements of aortic root geometry4 
The following measurements of the aortic root are obtained from the parasternal long-axis view 
(screening/baseline exams only): 
 
Aortic annulus long axis diameter. The aortic annulus long axis diameter is measured 
perpendicular to the long axis of the root, measured between the endothelial point that 
trisects the posterior aortic wall, non-coronary cusp hinge and anterior mitral leaflet hinge 
(posterior hinge point), and the point that bisects the septal endocardium and the right 
coronary cusp hinge (anterior hinge point). Measurements should be made at mid-systole 
and inclusive of cusp calcifications (Figure 1). To accurately incorporate cusp calcification 
for aortic annulus sizing, measure from the white-black interfaces of the posterior and 
anterior aortic cusp hinge points and add 2 mm to the measurement. 
 
Sinus of Valsalva diameter (SoV). The SoV diameter is perpendicular to the long axis of 
the root and typically parallel to the aortic valve annulus. It is the widest intra-luminal 
distance within the sinuses (measured at end-diastole from inner edge to inner edge, 
Figure 2, A). 
 
Sino-tubular junction diameter (STJ). The STJ diameter is the intra-luminal diameter 
parallel to the SoV diameter, where the sinuses narrow and join the ascending aorta 
(measured at end-diastole from inner edge to inner edge, Figure 2, B). 
 
Sinus of Valsalva height (SoVH). The SoVH is the distance between the STJ and the 
aortic annulus long-annulus diameter (measured at end-diastole, Figure 3). 
 
Note: Measurements should be noted on images submitted for Screening Committee 
review 
  
 
 
 
Figure 1. Examples of measurement of the aortic annulus long axis diameter 
 

 
 
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Figure 2. Example of measurement of the Sinus of Valsalva (A) and Sino-Tubular Junction (B) diameters 
 
Figure 3. Example of measurement of the Sinus of Valsalva Height (C) 

 
 
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9. 
Measurement of Left Ventricular Outflow Tract (LVOT) Diameter 
The LVOT long axis diameter is measured in the parasternal long-axis view at early to mid systole. 
The optimal imaging plane is through the long axis of the aorta; therefore, the anterior and posterior 
walls of the aortic root should be parallel with the maximal aortic diameter. 
For native aortic valves, the LVOT long axis diameter is measured from the white-black interface of 
the septal endocardium to the anterior mitral leaflet, parallel to the aortic valve plane and within 0.5 
cm - 1 cm of the valve orifice (Figure 4)1. Following implantation of the CoreValve device, the LVOT 
diameters and the LVOT area are measured immediately proximal to the inflow aspect of the stent 
(Figure 5). 
 
Note: For optimal results, LVOT diameter is averaged from 3 measurements from 3 
consecutive high quality 2D ZOOM views. 
 
 
Figure 4. TTE mid-systolic frame showing measurement of LVOT diameter for derivation of native aortic valve area. 
 
 
Figure 5. Cursor placement for measurement of LVOT diameter for derivation of prosthetic effective orifice area 

 
 
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10. 
Measurement of LVOT Velocity5 
LVOT velocity is recorded with PW Doppler from the apical transducer position, either in the apical 
long-axis view or in the anteriorly angulated four-chamber view or “five-chamber view.” The PW 
sample volume is positioned just proximal to the aortic valve, with care to avoid the zone of pre-
valve acceleration. The recommended procedure is to initially place the sample volume within the 
aortic valve leaflets (prosthetic or native), and then gradually move it apically until a clear spectral 
waveform is observed with a well-defined peak and minimal spectral broadening (Figure 6). No 
opening click should be seen. The optimal sample volume placement is usually between 0.5 and 
1.0 cm upstream from the valve annulus.2 Post implantation, the sample volume should be placed 
at the entrance of the inlet of the TAV prosthesis. 
11. 
Measurement of Aortic Valve Velocity5 
The aortic valve velocity and VTI should be interrogated with CW Doppler from all transducer 
positions (apical, right parasternal, suprasternal notch, left supraclavicular, subcostal). The position 
that provides the highest velocity is used for measurements. A smooth velocity curve with a clear 
outer edge and maximal velocity should be recorded. The maximal velocity is measured at the 
outer edge of the dark signal; fine linear signals at the peak should not be included in 
measurements. The outer edge of the dark “envelope” of the velocity curve is traced to provide both 
the VTI for the continuity equation and the mean gradient (Figure 7).1 
 
             
 
Figure 6. An optimal LVOT signal shows a                          
Figure 7. CW Doppler of severe AS jet showing  
smooth velocity curve with a narrow velocity                       
measurement of maximal velocity and tracing of the 
range at each time point.                                                     
Velocity curve to calculate mean gradient. 
 
Note: Velocity tracings should be noted on images submitted for Screening Committee 
review 
Note: Fine linear signals at peak velocity should not be included in the velocity tracings! 

 
 
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12. Assessment of Aortic Regurgitation6,7 
 
Use all echo modalities: An integrated exam approach using colour flow, pulsed-wave 
(PW), and continuous-wave (CW) Doppler is used to assess the severity of transvalvular 
and paravalvular regurgitation. 
 
Use four views: Colour flow Doppler imaging should be performed from the parasternal 
long and short-axis views, and the apical long-axis and apical 5-chamber views. A 
recording of the aortic regurgitant signal should be obtained with CW Doppler. If the 
degree of aortic regurgitation appears more than mild by visual estimate, the velocity in 
the proximal descending aorta and the abdominal aorta should be recorded with PW 
Doppler. 
 
Severity: The degree of transvalvular and paravalvular AR will be graded as none, trace, 
mild, moderate, and severe based on the analysis of the parameters shown in Table 
2a.3,4    
o 
The category of “trace” is used in cases where regurgitation is barely detectable by 
colour Doppler.  
o 
Regurgitant signals observed to originate within the stent will be considered 
transvalvular, and regurgitant signals observed to originate outside the stent will be 
considered paravalvular.  
 
Paravalvular regurgitant jets will be characterized by the extent of the aortic regurgitant 
jet relative to the short axis circumference of the aortic valve (Table 2a- Valve Academic 
Research Consortium (VARC) Consensus Report for Transcatheter Aortic Valve 
Implantation (TAVI) and Table 2b.  Updated standardized endpoint definitions for 
transcatheter aortic valve implantation: the VARC-2 consensus document, and Table 3a 
and b -2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the 
Management of Patients With Valvular Heart Disease (published in the October 2008 
issues of Journal of the American College of Cardiology and Circulation).  
Table 2a. Parameters for evaluation of the severity of aortic regurgitation1, 6, 8 
Prosthetic Aortic Valve Regurgitation Criteria (Central and Paravalvular) 
Parameter 
Mild
Moderate  
Severe
Valve Structure and Motion 
 
Mechanical or bioprosthesis 
Usually normal 
Usually abnormal† 
Usually abnormal† 
Structural parameters 
 
Left ventricular size 
Normal ‡ 
Normal/ 
mildly dilated ‡ 
Dilated 
Doppler parameters (qualitative or semi quantitative)
 
Jet width in central jets (% LVO diameter): colour* 
 
Jet density: CW Doppler 
 
Jet deceleration rate (PHT┼, ms): CW Doppler** 
 
LV outflow vs. pulmonary flow: PW Doppler 
Diastolic: flow reversal in the descending aorta 
PW Doppler 
 
 
Circumferential extent of paraprosthetic AR (%) 
 
 
 
Narrow (≤25%) 
Incomplete or faint 
 
Slow (>500) 
Slightly increased 
 
 
Absent or brief 
early diastolic 
 
<10 
 
 
 
Intermediate (26-64%) 
Dense 
 
Variable (200-500) 
Intermediate 
 
 
Intermediate 
 
 
10-20 
 
 
 
Large (≥65%) 
Dense 
 
Steep (<200) 
Greatly Increased 
 
 
Prominent, 
Holodiastolic 
 
>20 
Doppler parameters (quantitative) 
 
Regurgitant volume (mL/beat) 
 
Regurgitant fraction (%) 
 
<30 
<30 
 
30-59 
30-50 
 
>60 
>50 
 
* 
Parameter applicable to central jets and is less accurate in eccentric jets 
**  Influenced by left ventricular compliance 
AR=aortic regurgitation; CW= continuous wave; LVO= left ventricular outflow; PW= pulsed wave 
┼ 
PHT is shortened with increasing LV diastolic pressure and vasodilator therapy, and may be lengthened in chronic adaptation 
to severe aortic regurgitation. As such, PH, in contrast to the other parameters, does not reflect the volumetric severity of aortic 
regurgitation, but rather its hemodynamic impact. Therefore, in the setting of acute paravalvular or transvalvular leaks, 
intermediate values between 200 and 500 ms should not be used to classify the degree of regurgitation. 
† 
Abnormal mechanical valves, for example, immobile occluder (valvular regurgitation), dehiscence or rocking (paravalvular 
regurgitation); abnormal biologic valves, for example, leaflet thickening or prolapse (valvular), dehiscence or rocking 
(paravalvular regurgitation). 

 
 
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‡ 
Applies to chronic, late postoperative AR in the absence of other etiologies. 
 
Table 2b. VARC-2 criteria for evaluation of the prosthetic valve dysfunction  
Prosthetic valve dysfunction 
Prosthetic aortic valve stenosis* 
 
Normal 
Mild Stenosis 
Moderate/Severe 
Stenosis 
Quantitative Parameters (Flow-dependent)† 
Peak velocity 
<3 m/s 
3-4 m/s 
>4 m/s 
Mean gradient 
<20 mmHg 
20-40 mmHg 
>40 mmHg 
Quantitative Parameters (Flow-independent) 
Doppler velocity index‡ 
>0.35 
0.35-0.25 
<0.25 
Effective orifice area¶ 
>1.1 cm
2 
1.1-0.8 cm
2 
<0.8 cm
2 
Effective orifice area§ 
>0.9 cm
2
0.9-0.6 cm
2
<0.6 cm
2
Prosthesis-patient mismatch (PPM)
 
Insignificant 
Moderate 
Severe 
Indexed effective orifice area** 
>0.85 cm
2/m
2 
0.85-0.65 cm
2/m
2 
<0.65 cm
2/m
2 
Indexed effective orifice area†† 
>0.70 cm
2/m
2 
0.70-0.60 cm
2/m
2 
<0.60 cm
2/m
2 
Prosthetic aortic valve regurgitation
 
Mild 
Moderate 
Severe 
Semi-quantitative Parameters 
Diastolic flow reversal in the descending 
aorta—PW  
Absent or brief early diastolic 
Intermediate 
Prominent, 
holodiastolic 
Circumferential extent of prosthetic valve 
paravalvular regurgitation (%)¶¶ 
<10% 
10-29% 
≥30% 
Quantitative Parameters‡ 
Regurgitant volume (ml/beat) 
<30 ml 
30-59 ml 
≥60 ml 
Regurgitant fraction (%) 
<30% 
30-49% 
≥50% 
EROA (cm
2)  
<0.10 cm
2 
0.10-0.29 cm
2 
≥0.30 cm
2 
*In conditions of normal or near normal stroke volume (50–70 mL) 
†These parameters are more affected by flow, including concomitant aortic regurgitation 
‡For LVOT >2.5 cm, significant stenosis criteria is <0.20 
¶Use in setting of BSA ≥1.6 cm
2 (note: dependent on the size of the valve and the size of the native annulus) 
§Use in setting of BSA <1.6 cm
2 
**Use in setting of BMI <30 kg/cm
2 
††Use in setting of BMI ≥30 kg/cm
2 
¶¶Not well-validated and may overestimate severity compared to quantitative Doppler 
 
From the publication entitled “Updated standardized endpoint definitions for transcatheter aortic valve implantation: the valve 
academic research consortium-2 consensus document. Kappetein AP, et al. J Am Coll Cardiol. 2012 Oct 9;60(15):1438-54.” 
 
 

 
 
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Table 3a. Parameters for evaluation of the severity of aortic regurgitation 
Classification of the Severity of Valve Disease in Adults with 
Aortic Regurgitation 
 
Mild
Moderate 
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+
2+
3-4+ 
Color Doppler jet width 
Central jet, width less 
25% of LVOT 
Greater than mild but 
no signs of AR 
Central jet, width greater 
than 65% LVOT 
Doppler vena contracta width (cm) 
Less than 0.3 
0.3-0.6 
Greater than 0.6 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.10 
0.10-0.29 
≥ 0.30 
Additional essential criteria 
Left ventricular size 
 
 
 
 
Increased 
 
 
13. 
Assessment of Mitral Regurgitation2, 8 
Colour flow Doppler imaging of the left atrium should be performed from the parasternal long-axis 
view, and from the apical four, two, and long axis views. Mitral regurgitant signals should be 
recorded with CW Doppler using a velocity scale that allows assessment of the density, shape, 
duration, and peak velocity of the mitral regurgitant signal. If the severity appears moderate or 
greater by visual assessment, pulmonary vein velocities should be recorded with PW Doppler to 
assess for the presence of systolic flow reversal. Grading of the severity of mitral regurgitation 
should be integrative using the parameters in Table 3b.4 
Table 3b. Classification of the Severity of Valve Disease in Adults Mitral Regurgitation 
Classification of the Severity of Valve Disease in Adults 
Mitral Regurgitation 
 
Mild
Moderate 
Severe 
Qualitative 
 
 
 
 
Angiographic grade 
1+ 
2+ 
3-4+ 
Colour Doppler jet area 
Small, central jet, < 
4cm2  or <20% LA 
area) 
Signs of > mild 
present but no criteria 
for severe MR 
Vena contracta with > 
0.7cm with large central 
MR jet (area >40% of LA 
area) or with a wall-
impinging jet of any size, 
swirling in LA 
Doppler vena contracta width 
(cm) 
< 0.3 
0.3-0.69 
≥ 0.70 
Quantitative (cath or echo) 
 
 
 
Regurgitant volume (mL per 
beat) 
< 30 
30-59 
≥ 60 
Regurgitant fraction (%) 
< 30 
30-49 
≥ 50 
Regurgitant orifice area (cm2) 
< 0.20 
0.29 – 0.39 
≥ 0.40 
Additional essential criteria 
Left atrial size 
Left ventricular size 
 
 
 
Enlarged 
Enlarged 
 

 
 
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14. 
Assessment of Left Ventricular Function and Left Atrial Size9 
M-mode recordings of the left ventricle and left atrium should be obtained using 2-D guided beam 
alignment (Figures 7 and 8). Left ventricular chamber dimensions and wall thicknesses will be 
measured from 2D parasternal long axis views and should be utilized preferentially if M-mode 
images are suboptimal. Chamber dimensions are measured using the American Society of 
Echocardiography (ASE) measurement convention.5 In addition, standard 2-D views of the left 
ventricle should be obtained from parasternal and apical transducer positions for visual estimation 
and quantitative assessment of left ventricular ejection fraction by visual estimate.   
 
  
Figure 7. Measurement of left ventricular end-diastolic diameter (EDD) 
and end-systolic (ESD) from 2-D guided m-mode to optimize 
medial-lateral beam orientation. 
 
 
 
Figure 8. Measurement of left atrial diameter (LAD) by 2-D guided m-mode at end-systole. 

 
 
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15. 
Acquisition of Mitral Inflow Velocities 
A spectral Doppler recording of mitral inflow velocities should be obtained with PW Doppler in the 
apical 4-chamber view, using a 1 to 3 mm sample volume placed between the mitral leaflet tips 
during diastole (Figure 9). The spectral gain and wall filter settings should be optimized to clearly 
display the onset and cessation of left ventricular inflow.6  
  
\ 
 
Figure 9. Positioning of the sample volume for recording of mitral inflow velocities. 
16. 
Acquisition of Mitral Annular Tissue Doppler Velocities 
Mitral annular velocities should be obtained from the lateral and septal aspects of the mitral annulus 
using PW tissue Doppler performed in the apical 4-chamber view. The sample volume should be 
positioned at or 1 cm within the septal and lateral insertion sites of the mitral leaflets and adjusted 
as necessary (usually 5 to 10 mm) to cover the longitudinal excursion of the mitral annulus in both 
systole and diastole. Minimal angulations (<20 degrees) should be present between the ultrasound 
beam and the plane of cardiac motion.6 The Doppler gain should be minimized to prevent 
“blooming” of the signal to facilitate accurate measurement of the annular velocities. 

 
 
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17. 
Assessment of Device Migration 
CoreValve device placement site and migration will be assessed from the parasternal long axis 
view at each follow up point and compared to the initial post-procedural echo. A zoomed image of 
the left ventricular outflow tract including the anterior mitral leaflet and the anterior aortic wall should 
be included at each follow up echo. The location of the device will be determined by measurement 
of the distance from the proximal edge of the left ventricular outflow tract anteriorly, to the edge of 
the CoreValve device (Figure 10). Optimal placement of the valve should be within the left 
ventricular outflow tract just below the aortic annulus (Figure 11). 
 
 
Figure 10. Zoomed view of the left ventricular outflow tract (panel A) and schematic (panel B). Measurement of the distance 
from the proximal edge of the anterior aspect of the left ventricular outflow tract to the edge of the CoreValve device 
(arrows).  
 
 
Figure 11. Zoomed view of the left ventricular outflow tract. Panel A. Optimal device placement of the CoreValve device 
within the left ventricular outflow tract with the proximal edge of the device just below the aortic annulus. Panel B. Low 
placement of the CoreValve device extends beyond the left ventricular outflow tract into the left ventricular chamber, 
encroaching on anterior mitral valve leaflet. 
 

 
 
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18. Echo Core Lab Analysis5, 7 
Data generated by the Echo Core Lab will be the primary data used for analysis and reporting. 
Qualitative assessment of valvular regurgitation will be performed using the criteria previously 
described in sections 8 and 9 of this Appendix. The Echo Core Lab will report the following 
variables: 
 
Aortic annulus long-axis diameter in mid-systole (screening/baseline only) 
 
LVOT long axis diameter in mid-systole 
 
Sinus of Valsalva diameter (SOV) at end diastole (screening/baseline only) 
 
Sino-tubular junction diameter (STJ) at end diastole (screening/baseline only) 
 
Sinus of Valsalva height (SOVH) at end-diastole (screening/baseline only) 
 
Device location and migration 
 
Max aortic valve velocity (V2) by CW Doppler 
 
Velocity time integral (VTI) across aortic valve by CW Doppler 
 
Mean gradient across aortic valve (MGV2) by CW Doppler 
 
Peak LVOT velocity (V1) by PW Doppler 
 
Velocity Ratio (V1 / V2) 
 
Velocity time integral (VTI) of LVOT velocity by PW Doppler 
 
Mean LVOT gradient (MGV1) by PW Doppler 
 
Doppler Velocity Index (DVI) 
 
Grade of aortic transvalvular regurgitation 
 
Grade of aortic paravalvular regurgitation 
 
Grade of mitral regurgitation 
 
ERO for MR (if available) 
 
Max tricuspid regurgitant (TR) jet velocity (if TR is present) 
 
Left ventricular (LV) end-diastolic diameter (LVEDD) 
 
Left ventricular (LV) end-systolic diameter (LVESD) 
 
Interventricular septal thickness at end diastole 
 
Left ventricular posterior wall thickness at end diastole 
 
Left atrial diameter (AP linear dimension) at systole 
 
Left ventricular ejection fraction by visual estimate 
 
Heart rate 
 
Mitral inflow “A” velocity 
 
Mitral inflow “E” velocity 
 
Mitral inflow deceleration time 
 
Mitral annular tissue Doppler systolic (s) velocity (septal and lateral) 
 
Mitral annular tissue Doppler early diastolic (e´) velocity (septal and lateral) 
 
Mitral annular tissue Doppler late diastolic (a´) velocity (septal and lateral) 

 
 
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In addition, the following variables will be derived by the central database from the appropriate 
measurements reported by the Echo Core Lab5: 
 
Mean Transvalvular Gradient (Mean  P) Across the Prosthetic Valve in mmHg 
 
Mean  P = MGV2 - MGV1 
 
Where: MGV2 is the mean pressure gradient across the prosthesis in mmHg, and MGV1 is 
the mean pressure gradient from the left ventricular outflow tract in mmHg 
 
Peak Pressure Gradient (Peak  P) Across the Aortic Prosthetic Valve in mmHg 
 
Peak  P = 4 x (V2
2 - V1
2) 
 
Where: V2 is the peak velocity across the prosthesis in m/sec, and V1 is the peak velocity 
from the left ventricular outflow tract in m/sec 
 
Effective Orifice Area (EOA) in cm2 
 
EOA = LVOT Long Axis diameter2 x 0.785 x (VTIV1/VTIV2) 
 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 
is the velocity time integral of the aortic prosthesis in cm. Alternatively, using velocity 
instead of VTI for simplification: 
 
AVA = π(radius of LVOT)2 × VLVOT/ Vmax  
 
Where Vmax is the maximum flow velocity across aortic valve, VLVOT is the maximum velocity 
across the LVOT. 
 
Effective Orifice Area Index (EOAI) in cm2/m2 
 
EOAI = EOA/BSA 
 
Where: EOA is the effective orifice area in cm2, and BSA is the body surface area in m2 
 
Doppler Velocity Index = Velocity Time Integral Ratio (VTI Ratio) 
DVI = VTI Ratio = VTIV1/VTIV2 
 
Where: VTIV1 is the velocity time integral of the left ventricular outflow tract in cm, and VTIV2 
is the time velocity integral of the prosthetic aortic valve in cm 
 
Stroke Volume (SV) in ml/beat 
 
SV = LVOT long axis diameter2 x 0.785 x VTIV1 
Where:VTIV1 is the velocity time integral from the left ventricular outflow tract in cm 
 
Cardiac Output (CO) in l/min 
 
CO = (SV x HR)/1000 
Where: SV is the stroke volume in ml/beat, and HR is the heart rate in beats per minute 
 
Left Ventricular Mass (LVM) in grams 
LVM = 0.83 x [(LVEDD + LVPW + IVS)3 - (LVEDD)3] +0.6 
Where: LVEDD is the left ventricular end-diastolic diameter in cm, LVPW is the left 
ventricular posterior wall thickness at end diastole in cm, and IVS is the interventricular wall 
thickness at end diastole in cm. 
 
Left Ventricular Mass Index (LVMI) in g/m2 body surface area  
LVMI = LVM/BSA 
Where: LVM is left ventricular mass in g, and BSA is body surface area in m2 
 
Fractional Shortening (FS) in %  
FS = [(LVEDD - LVESD)/LVEDD] x 100 
Where: LVEDD is left ventricular end-diastolic diameter in cm, and LVESD is left ventricular 
end-systolic diameter in cm 
 
Estimated Right Ventricular Systolic Pressure (RVSP) in mmHg 
RVSP = (4 x MVTR jet
2) + 10 
Where: MV TR jet is the max velocity of the tricuspid regurgitant jet, and 10 = the assumed 
mean right atrial pressure in mmHg 

 
 
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 
Aortic Regurgitant volume (ml/beat) and fraction (%)  
The regurgitant volume across the aortic valve may be calculated as the difference 
between the LVOT volume and the transmitral volume, assuming there is no significant 
mitral regurgitation  
RV = Total stroke volume – forward stroke volume  
RV = SVAV – SVMV  
RF = [RV/SV] x 100 
SVAV = 0.785 x (LVOT)2 x VTILVOT (by Pulsed-wave Doppler) 
SVMV = 0.785 x (DMV)2 x VTIMV (by Pulsed-wave Doppler) 
Where: SV is stroke volume in mL, AV is aortic valve and MV is mitral valve 
 
Regurgitant Orifice Area (EROA) 
The regurgitant orifice area or EROA represents the average size of the defect in the aortic 
valve during diastole and is proportional to regurgitant severity.  
The regurgitant orifice area may be calculated as the regurgitant volume multiplied by the 
VTI of the continuous wave Doppler jet 
EROAAV = RV / VTIAR jet (by Continuous-wave Doppler) 

 
 
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19. 
Echocardiography References 
1. 
Zoghbi WA, Chambers JB, Dumesnil JG, Foster E, Gottdiener JS, Grayburn PA, Khandheria BK, Levine 
RA, Marx GR, Miller FA, Jr., Nakatani S, Quinones MA, Rakowski H, Rodriguez LL, Swaminathan M, 
Waggoner AD, Weissman NJ, Zabalgoitia M. Recommendations for evaluation of prosthetic valves with 
echocardiography and doppler ultrasound: A report from the american society of echocardiography's 
guidelines and standards committee and the task force on prosthetic valves, developed in conjunction 
with the american college of cardiology cardiovascular imaging committee, cardiac imaging committee of 
the american heart association, the european association of echocardiography, a registered branch of the 
european society of cardiology, the japanese society of echocardiography and the canadian society of 
echocardiography, endorsed by the american college of cardiology foundation, american heart 
association, european association of echocardiography, a registered branch of the european society of 
cardiology, the japanese society of echocardiography, and canadian society of echocardiography. J Am 
Soc Echocardiogr. 2009;22:975-1014; quiz 1082-1014. 
2. 
Lancellotti P, Moura L, Pierard LA, Agricola E, Popescu BA, Tribouilloy C, Hagendorff A, Monin JL, 
Badano L, Zamorano JL. European association of echocardiography recommendations for the 
assessment of valvular regurgitation. Part 2: Mitral and tricuspid regurgitation (native valve disease). Eur J 
Echocardiogr. 2010;11:307-332. 
3. 
Lancellotti P, Tribouilloy C, Hagendorff A, Moura L, Popescu BA, Agricola E, Monin JL, Pierard LA, 
Badano L, Zamorano JL. European association of echocardiography recommendations for the 
assessment of valvular regurgitation. Part 1: Aortic and pulmonary regurgitation (native valve disease). 
Eur J Echocardiogr. 2010;11:223-244. 
4. 
Evangelista A, Flachskampf FA, Erbel R, Antonini-Canterin F, Vlachopoulos C, Rocchi G, Sicari R, 
Nihoyannopoulos P, Zamorano J, Pepi M, Breithardt OA, Plonska-Gosciniak E. Echocardiography in 
aortic diseases: Eae recommendations for clinical practice. Eur J Echocardiogr. 2010;11:645-658. 
5. 
Baumgartner H, Hung J, Bermejo J, Chambers JB, Evangelista A, Griffin BP, Iung B, Otto CM, Pellikka 
PA, Quinones M. Echocardiographic assessment of valve stenosis: Eae/ase recommendations for clinical 
practice. J Am Soc Echocardiogr. 2009;22:1-23; quiz 101-102. 
6. 
Zoghbi WA. New recommendations for evaluation of prosthetic valves with echocardiography and doppler 
ultrasound. Methodist Debakey Cardiovasc J. 2010;6:20-26. 
7. 
Chambers J, Shah PM. Recommendations for the echocardiographic assessment of replacement heart 
values. J Heart Valve Dis. 1995;4:9-13. 
8. 
Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP, Krucoff MW, Mack M, Mehran 
R, Miller C, Morel MA, Petersen J, Popma JJ, Takkenberg JJ, Vahanian A, van Es GA, Vranckx P, Webb 
JG, Windecker S, Serruys PW. Standardized endpoint definitions for transcatheter aortic valve 
implantation clinical trials: A consensus report from the valve academic research consortium. Eur Heart J. 
2011;32:205-217. 
9. 
Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, 
Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for 
chamber quantification: A report from the american society of echocardiography's guidelines and 
standards committee and the chamber quantification writing group, developed in conjunction with the 
european association of echocardiography, a branch of the european society of cardiology. J Am Soc 
Echocardiogr. 2005;18:1440-1463. 
10. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the valve academic 
research consortium-2 consensus document. Kappetein AP, Head SJ, Généreux P, Piazza N, van 
Mieghem NM, Blackstone EH, Brott TG, Cohen DJ, Cutlip DE, van Es GA, Hahn RT, Kirtane AJ, Krucoff 
MW, Kodali S, Mack MJ, Mehran R, Rodés-Cabau J, Vranckx P, Webb JG, Windecker S, Serruys PW, 
Leon MB. J Am Coll Cardiol. 2012 Oct 9;60(15):1438-54. doi: 10.1016/j.jacc.2012.09.001” 
 
 
 
 
 

 
 
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R.8 
Electrocardiogram (ECG) Submission 
The standard 12 lead ECG will be utilized as a diagnostic and prognostic tool in patients 
participating in this study.   
Acquisition: 
1. Standard 12-lead ECGs must be obtained (with the exception of implant procedure) 
2. ECG should be conducted with the subject at rest 
3. ECGs should be provided on a single page printout (i.e. lead strips are not acceptable) using 
standard amplification of 1mV/cm and paper speed of 25mm/sec (50mm/sec is strongly 
discouraged) 
4. Visible lead annotation 
5. More than 1 normal beat per lead. No average ECGs 
6. ECG without Pace-Maker beats is preferred 
Labeling: 
7. Protect subject confidentiality.  Effectively block out any subject confidential information 
recorded on the ECG  
8. ECG labels are to be placed on top of the tracing, being careful not to obstruct any of the 
lead recordings 
9. Labels with Study name will be provided by Medtronic and shall be filled out completely, 
including 
a) Site number 
b) Subject identification number 
c) ECG date and time  
d) Applicable visit/interval (i.e. screening, Discharge) 
10. Incomplete labeling will result in the generation of a data clarification query and untimely 
interpretation of the tracing 
Submission: 
11. Original ECGs are strongly encouraged but high quality photocopies with good visible 
gridline are accepted 
12. Submission of all ECGs within appropriate timeframe is imperative 
13. Upload all ECGs to InteleGRID (secure electronic system used for transferring images) 
 

 
 
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Computed Tomography (CT) Angiography Acquisition 
Guidelines 
Background 
Cardiac Multislice Computed Tomographic Angiography (Cardiac MSCT Angiography) is intended 
to evaluate aortic valve anatomy, aortic root dimensions for device sizing, and assessment of 
peripheral vessel dimensions and anatomy.  This appendix is meant as a guideline to help with the 
proper acquisition of the images necessary for assessment of the above mentioned items.  The 
primary objective should be to acquire the highest resolution images and perform the correct 
measurements, as specified below, by tailoring the acquisition to your particular hardware and 
experience.   
Equipment Requirements 
 
Multi-detector CT scanner (64-slice minimum) with ECG-gating capability 
o 
The scans acquired and submitted for analysis of the aortic root MUST be ECG-
gated 
o 
Non-gated scans in areas with cardiac motion lead to measurement inaccuracy and 
therefore incomplete information for device selection 
o 
Peripheral vessel image acquisition may be non-gated 
 
Ability to electronically transfer the imaging data via secure network (InteleGRID) 
Scans Acquired 
 
Chest Topogram 
 
ECG-gated contrast enhanced aortic root* 
 
Non ECG-gated contrast enhanced peripheral vessels* 
*Sub-millimeter slice thickness is required 
Scanning Procedures 
The scan protocol is similar to a CT coronary angiogram. The aim is to get adequate contrast in 
the region of interest which includes: endo-luminal surface for visualization of left heart, aorta, and 
peripheral access vessels (i.e., femorals and subclavians, when necessary). Temporal resolution 
should be optimized to reduce motion artifact. Spatial resolution should be as high as possible 
(goal is smallest isotropic voxel size). 
Step 1: Patient preparation 
 
Administer medication per institution standard practice for CT scanning (suggest avoid 
sublingual nitrate, avoid or caution with B-blockers) 
 
Attach ECG electrodes for gating of scan (suggest:  avoiding large respiratory muscles as 
these may introduce ECG-artifact). Verify quality and stability of ECG tracing on scanner 
console during an inspiratory breath hold 
 
Prepare large intravenous line (i.e., 18 or 20 gauge) for administration of contrast media 
 
Instruct patient to lie still during scan, even if they experience warmth or tingling due to the 
injection of contrast 
 
Instruct patient in practice breath-hold at end-inspiration for 10-15 seconds (duration 
required will depend on specific scanner performance). Assess heart rate variability during 
breath-hold. If heart rate is >65 bpm or unstable, consider cautious titration of beta-blockers 

 
 
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Step 2: Chest Topogram 
 
Acquire a chest topogram for use in planning the following imaging protocol 
 
Figure CTA-1:  Example image of chest topogram 
Step 3: ECG-gated contrast enhanced scan of aortic root 
The aim of this scan is to assess the aortic root and valve anatomy. Ensure the required scan 
parameters are used; these are listed below in Table 1. The following parameters are crucial to the 
optimum required scan: 
 
The recommended coverage area is from superior to the aortic arch to inferior to the 
cardiac apex. The minimum required coverage area is from 50mm above the aortic 
annulus to the inferior border of the heart.  Coverage less than this will not allow for proper 
assessment of the patients anatomic suitability 
 
The scan requires dynamic 4D acquisition using retrospective ECG-gating 
 
The required detector collimation is 0.4-0.625mm 
 
The required slice thickness is ≤ 0.8mm 
 
The recommended slice overlap is 0.4mm 
Contrast Enhanced Scan Execution 
 
Prepare iodinated contrast injection apparatus (recommendations in scan parameters are 
provided in Table 1) 
 
Set up scan parameters per the table below  
 
Instruct patient to lie still during scan, even if they experience warmth or tingling due to the 
injection of contrast 
 
Initiate contrast injection 
 
When contrast reaches threshold at bolus-tracking location, instruct patient to hold breath 
at end-inspiration, then initiate main scan protocol 
 
At completion of scan verify scan is of adequate quality 
 
Record amount of contrast given.  Note: this is not on the CRF, but is recommended in 
this patient population 
 
Record heart rate average and range.  Note: this is not on the CRF, but is recommended 
for explanation of image quality issues 

 
 
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Post-processing 
 
Verify heart rate ECG triggers are at consistent place in cardiac cycle, edit if necessary. 
Additional editing/removal of arrhythmias may be performed 
 
Reconstruct at multiple phases (10 increments of 10%), with ≤0.8mm slice thickness.  If 
the system has the capability, also reconstruct a “best systolic” and “best diastolic” phase. 
If image quality of the aortic root is not good in the end systolic phase the phase with the 
best image quality may be selected instead 
Table 1. Recommended Scan Parameters 
 
Recommended Parameters 
IV injection with iodine 
contrast 
80-100 (320mg/ml or higher), modify per patient as appropriate 
Injection rate 
4-6 mL/sec 
Bolus tracking, delay 
Delay time calculated using protocol for current scanner (bolus tracking or 
similar) with peak of contrast concentration in the ascending aorta during 
acquisition.  Bolus tracking is the preferred method.   
ECG Leads 
Required 
ECG-gating 
Retrospective (Prospective may be used in centers with much experience of 
the technique and in patients with stable heart rate) 
Scan direction 
Cranial-caudal 
Scan coverage 
From above the aortic arch to past the cardiac apex 
Detector collimation 
0.4 – 0.625 mm 
Pitch 
0.2–0.43 adapted to the heart rate 
Dose modulation 
Modulation and full current between 30 and 80% of the cardiac cycle (or no 
modulation i.e. full dose throughout) 
Slice thickness 
0.8mm 
Slice overlap 
0.4mm 
Reconstruction kernel 
Medium Smooth 
Post-processing 
Use single segmental reconstruction algorithm that minimizes motion artifact. 
Reconstruct at multiple phases (10 minimum, 20 preferred, increments of 5-
10%).  Reconstructed slice thickness  0.75-1mm. 
 

 
 
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Step 4: Non ECG-gated contrast enhanced scan of vessels  
The aim of this scan is to assess the peripheral access vessels and abdominal aorta for suitability 
for the procedure. 
 
 
Standard radiology CT angiography protocol should be used. 
 
Can be non ECG-gated 
 
Contrast Volume: 40-50 cc, Injection rate: 4 cc/sec.  Modify per patient as necessary to 
acquire good quality images 
 
Delay time calculated using protocol for current scanner (bolus tracking, etc) with peak of 
contrast concentration in the abdominal aorta and iliac arteries 
 
Suggested coverage areas:  
o 
Femoral access only screening: abdominal aorta above celiac artery and down to 
the femoral head.  Use this option there if you are confident that femoral access will 
be suitable for this patient 
o 
Subclavian access only screening: above the subclavian arteries and down to mid-
thorax.  Use this option if prior information (i.e., CT scan) exists which demonstrates 
that femoral access will not be possible in this patient 
o 
Combined access screening: above the subclavian arteries and down to the femoral 
head.  This is the recommended option.  An additional option for subclavian 
screening is to include the subclavian vessels in the ECG-gated portion and use 
femoral only screening for the rest of the vessels 
 
Source data reconstructed using sub-millimeter slice thickness 
Aortic Root and Peripheral Vessel Measurements 
CT measurements are conducted in different parts of the cardiac cycle to correlate most closely 
with corresponding echo measurements 
 
Systole for aortic annulus measurements 
 
Diastole for sinus of Valsalva diameters, sinus of Valsalva heights, maximum ascending 
aorta diameter, and aortic root angulation 
 
Table 2: Required CT Measurements 
 
•
Aortic annulus measurements (Systole)
–
Major aortic annulus diameter.
–
Orthogonal minor aortic annulus diameter.
–
Annulus perimeter.
•
Additional aortic root measurements (Diastole)
–
Maximum ascending aorta diameter at 40mm above 
annulus. 
–
Sinus of Valsalva diameters.
–
Sinus of Valsalva heights.
–
Aortic root angulation.
Measured on 
ECG-gated 
images of the 
chest.
Measured on 
Non ECG-
gated images 
of the 
vasculature.
•
Vessel measurements
–
Minimum and perpendicular abdominal aorta diameter.
–
Right and left common and external illiac artery min and 
perpendicular diameter at minimum diameter along path.
–
Right and left femoral artery min and perpendicular 
diameter at minimum diameter along path.
–
If non-iliofemoral access is planned: right and left 
subclavian artery min and perpendicular diameter at 
minimum diameter along path.

 
 
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Proper Aortic Annulus Measurements 
The aortic annulus is not co-planar with the planes of the body (i.e., axial, sagittal, or coronal). 
Therefore, multi-planar reformatting of the CT images to create a double-oblique axial image is 
required for annulus measurements. This reformatting is critical; if the plane is not correctly 
aligned, it may be going through the sinuses or the LVOT.  This can lead to improper device 
selection. 
The methods described here for measurement of the aortic annulus (virtual basal ring) are similar 
to those reported in Schultz et al. EuroIntervention Supplement (2010) Volume 6 (Supplement G) 
G6-G13.   
Step 1: Reformatting of Images 
 
Center image cross-hairs on aortic root in all windows where it is visible.  Lock cross-hairs 
so they remain orthogonal for all steps 
 
In the coronal window, rotate cross-hairs (horizontal line) counter-clockwise to align with 
virtual basal plane, as shown in Figure CTA-2 (upper left panel) 
 
In the sagittal window, the horizontal line has to be rotated clockwise or counter-clockwise 
to align with virtual basal plane, as shown in Figure CTA-2 (lower left panel) 
 
On the newly defined double-oblique axial image, scroll up and down through the aortic 
root until the most caudal attachment points of the three native leaflets come into view 
(indicated by arrowheads in Figure CTA-3 below). If one of the leaflets comes into view at 
a more cranial or caudal slice, adjust the coronal or sagittal cross-hairs until all three 
leaflets come into view on the same axial slice 
 
 
Figure CTA-2:  Example images in original orientation (axial, coronal and sagittal).  Red curved arrow and line indicate 
adjustment of coronal and sagittal planes to align with aortic basal annulus. 
 
Sagittal 
Coronal 
Axial 

 
 
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Figure CTA-3:  Example images of reformatted oblique coronal (upper left), oblique sagittal (lower left), double oblique 
axial (upper right) and 3D reconstruction lower right. Yellow arrowheads indicate most caudal attachment of three 
leaflets of aortic valve. 
 
 
For confirmation of the correct aortic annulus plane, scroll through the double oblique axial 
images starting in the mid sinus and ending at the level of the aortic annulus.  The sinuses 
should appear to be relatively the same size at the level of the mid-sinus and the leaflets 
should all disappear equally at the level of the annulus 
Step 2: Aortic Root Measurements 
Aortic Annulus Measurements 
 
Choose the cleanest systolic images for the aortic annulus measurements 
 
Aortic annulus measurements should be completed on the properly reformatted double-
oblique axial image at aortic annulus level 
 
Trace the perimeter of the basal annulus (Figure CTA-4, left).  Place cross-hairs at center 
of basal annulus, create major diameter through the center, create minor diameter defined 
as perpendicular to major and through center (Figure CTA-4, right).  Record perimeter, 
major and minor diameter measurements on the screening worksheet 
    
Figure CTA-4:  Example of perimeter measurement (left) and major and minor diameter measurements (right). 
 
 
Oblique 
Coronal 
Oblique 
Sagittal 
Double-oblique axial 

 
 
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Additional Aortic Root Measurements 
 
Choose the best diastolic images for measurement of sinus of Valsalva diameters, sinus 
of Valsalva heights, maximum ascending aorta diameter (40 mm from annulus), and aortic 
root angulation.  Sinus of Valsalva diameters, heights, and maximum ascending aorta 
diameter should be completed on reformatted images using the same reformatting 
technique as used for the aortic annulus measurements 
Sinus of Valsalva Diameters 
 
Select the double oblique axial image where the widest portion of the three sinuses is 
visible 
 
Measure a diameter from each commissure through the center of the root to the opposite 
sinus.  Complete for all three sinuses (Figure CTA-5) 
 
Figure CTA-5:  Example of sinus of Valsalva diameters. 
 

 
 
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Sinus of Valsalva Heights 
 
The sinotubular junction is typically not co-planar with the aortic annulus.  Therefore, a 
sinus of Valsalva height must be measured for each of the three sinuses.  This height is 
defined as the distance between the aortic annular plane and the tallest point in the sinus 
 
Choose the double oblique axial image so that it is located at the level of the aortic 
annulus.  The reformatting line representing the double oblique axial image should now be 
visible in the oblique coronal and oblique sagittal images at the level of the aortic annulus 
 
For the left coronary and non-coronary heights, use the oblique coronal image.  For the 
right coronary height, use the oblique sagittal image 
 
To complete the measurement, scroll through the oblique coronal or sagittal image 
(depending on which sinus you are measuring) and locate the heights location of the 
sinotubular junction.  On that image, measure the distance along the path of the aortic root 
from the aortic annular plane, marked by the reformatting line, to the sinotubular junction 
(Figure CTA-6). 
 
 
Figure CTA-6:  Example of sinus of Valsalva heights. 
 

 
 
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Maximum Ascending Aorta Diameter 
 
Choose the double oblique axial image so that it is located at the level of the aortic 
annulus.  The reformatting line representing the double oblique axial image should now be 
visible in the oblique coronal and oblique sagittal images at the level of the aortic annulus 
 
Choose the oblique coronal image that is in the center of the aortic root 
 
Measure a distance of 40mm from the line representing the aortic annular plane 
 
Center the images at this level, and reformat the images so that the double oblique is 
perpendicular to the ascending aorta at this level (Figure CTA-7) 
 
Measure the maximum diameter at this level (Figure CTA-7) 
 
 
 
Figure CTA-7:  Oblique coronal with measurement of 40mm above the aortic annulus (left) and double-oblique 
reformatted to be perpendicular to that location (right).   
 

 
 
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Aortic Root Angulation 
 
The aortic root angle measured in this study is the angle between the aortic annulus and 
the true axial plane of the patient 
 
To measure, use the standard coronal diastolic image, before any reformatting 
 
Scroll to the middle of the aortic root in these images (Figure CTA-8) 
 
Use the angle tool to draw a line first across the aortic annulus and second horizontal to 
the coronal image, which represents the axial plane of the patient.  Start the angle 
measurement in the upper left of the patient, so that the angle is to the lower right of the 
patient (Figure CTA-8) 
 
 
Figure CTA-8:  Aortic root angulation measurement on the standard coronal image.  Use the angle tool beginning at 
point 1, with point 2 on the lower right of the patient, and the final point on the lower left of the patient.  The first line, 
between points 1 and 2 should be along the aortic annulus.  The second line, between points 2 and 3, should be 
horizontal in the coronal image, which represents the axial plane of the patient. 

 
 
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Step 3:  Access Vessel Measurements 
Peripheral vessel measurements are made on non-gated CT and measured on images 
perpendicular to the vessel.  The intent of these measurements is to determine the minimum 
diameters for the potential access routes.  All vessel measurements should be completed on 
images that are perpendicular to the vessels of interest.  
Minimum Abdominal Aortic Diameter 
 
Use a stretched vessel view to locate the minimum luminal abdominal aortic diameter 
 
Measure the minimum lumen diameter and a perpendicular diameter on the image 
orthogonal to the vessel at the minimum location (Figure CTA-9) 
 
Figure CTA-9:  Example of minimum abdominal aortic diameter.  Stretched vessel (left), with the pink line at the location 
of the minimum luminal abdominal diameter.  Orthogonal image (right), showing the minimum luminal diameter and the 
perpendicular diameter. 
Peripheral Vessel Measurements 
 
These techniques are to be used for measurements on the following arteries: 
o 
Right and left femorals 
o 
Right and left common and external iliacs 
o 
If non-femoral access is planned – right and left subclavians 
 
Use a stretched vessel view to locate the minimum luminal diameter 
 
Measure the minimum lumen diameter and a perpendicular diameter on the image 
orthogonal to the vessel at the minimum location (Figure CTA-10) 
 
Figure CTA-10:  Example of the peripheral vessels and measurements for the right (left) and left (right) iliac arteries. 
 
 

 
 
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Additional CT Measurements 
 
In the case of a thoracic aortic aneurysm, measure the maximum diameter in the 
aneurysm. 
 
To determine the maximum location, use similar methods to the other vessel 
measurements (stretched vessel view) 
 
Complete the measurement on the orthogonal images and report the maximum diameter 
Prepare data for submission  
 
Data should be stored in DICOM 3.0 format 
 
If possible, de-identify all images prior to uploading 
 
Burn images to DICOM DVD/CD or upload to internal electronic records system 
 
Ensure all required images are included on DVD/CD or internal electronic records system 
for upload: 
o 
ECG-gated contrast enhanced aortic root.  Upload on 4 time-points: 30% & 40% 
(systole) and 60% & 70% (diastole).  If the system has “best-systolic” and “best-
diastolic,” only upload those 2 phases.   
o 
Non ECG-gated contrast enhanced peripheral vessels – upload entire set. 
o 
Screenshots of all measurements 
 
Upload all images to InteleGRID (secure electronic system used for transferring images) 
 
 

 
 
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R.10 
Interactive Voice/Web Response System (IXRS) 
Medtronic will utilize an Interactive Voice/Web Response (IXRS) System to manage subject 
screen failures and randomization into the Medtronic CoreValve™SURTAVI Trial. 
The IXRS system will assign patients a Screening ID to be used for all patients that sign the 
Informed Consent Form and are considered for possible enrollment by the Heart Team. If a patient 
is screened and does not meet eligibility criteria, the IXRS system will capture the reason for 
screen failure and disposition of the patient (if known). 
Upon meeting eligibility criteria, the IXRS system will randomize the patient and assign a Subject 
ID to be used in the Oracle Clinical Database upon enrollment.   
The IXRS system will assign subjects within one of four groups:  
 
TAVI with planned PCI 
 
TAVI without planned PCI 
 
SAVR with planned CABG 
 
SAVR without planned CABG 
Users can sign in to the Medtronic CoreValve™SURTAVI Trial study web site by using the URL 
below and use the sign in box labeled "IVRS/IWRS Login": 
 www.bracketglobal.com/client-login 
The first time a user accesses the study website, they will be prompted to update their password. 
The password must be at least 8 characters in length and contain at least 1 capital letter and 1 
number or symbol. 
Remember that the User ID and Password are private and should not be shared with other 
individuals. 
For technical questions, contact UBC Technical Support at 888-794-0122 or at 
support@bracketglobal.com 
 
 

 
 
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Explanted Device/Pathology and Return Procedures 
In the event of a device malfunction of the investigational device prior to or during implant, or in the 
event that a TAV device is explanted after implant (due to reintervention or autopsy), the TAV 
device and/or affected device components should be returned to Medtronic. 
SHIPPING INSTRUCTIONS 
 System Malfunction (TAV Device, Delivery Catheter System (DCS) and/or 
Compression Loading System (CLS/LS) Before or During Procedure 
1. Always retain original product packaging until the procedure is completed. 
2. Place product back into original packaging if it was not clinically used (i.e. in contact with 
blood or body fluids) 
3. If clinically used, use heart valve return kit to ship the valve or CLS/LS. Use a DCS return 
kit for the DCS, if applicable. 
Explant of CoreValve at Reoperation 
1. Photograph the TAV in situ (if possible). 
2. If possible, indicate with a suture on the frame, the relation of the TAV device to the 
midpoint of the mitral valve. 
3. Following explantation, rinse blood from the lumen with a physiologic solution (e.g. 
Ringer’s lactate solution). 
4. Do not disturb or alter the valve leaflets in any way (as possible). 
5. Remove all packaging material and forms from kit. Temperature indicator should remain in 
box unless it has been activated. If it has been activated, discard noting that the kit is still 
usable. 
6. Immerse the TAV and any surrounding tissue in the solution provided in the explant kit. 
7. Place the jar into the yellow absorbent pouch and close, then into the zip lock bag and 
seal. 
Explant of CoreValve at Autopsy 
1. Remove all packaging material and forms from kit.  
2. If possible, leave aortic root intact with an ample margin between the valve and 
descending aorta. 
3. Whole hearts should be immersion fixed in formalin in the local autopsy suite or pathology 
lab for at least 24-48 hours prior to shipping. Note: hospitals or contract pathology labs 
should have formalin available for use. 
4. Use the plastic container provided in the return kit for fixing the heart. 
5. Before shipping, remove most of the formalin from the container and wrap the heart in the 
cloth specimen bag that is provided, which has been thoroughly soaked in formalin.  Place 
the heart and specimen bag back into the container. 
6. Label the outside of the container (lid and container) with the TAV device serial number, 
patient ID, center name and study name.   
7. Seal the container tightly and wrap the container-lid interface with parafilm (if available). 
 

 
 
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All Explants/Returns 
1. Complete the Product Experience Report (PER) form and email a copy to 
rs.structuralheartfieldassurance@medtronic.com to receive a PE number. 
a. If an adverse event form has already been reported for this event and a PE number 
has already been issued via the AE, use the PE number from the AE 
correspondence.  In this instance, sending the PER to field assurance to receive a 
PCR number is not required. 
2. Note the PE number on the Product Experience Report and place the completed form and 
autopsy heart in the box.  
3. Using the pre-paid/pre-printed form, ship by Federal Express or other overnight carrier if a 
form is not provided for your convenience. For further assistance, call the number below.  
If a return kit is required, contact Customer Service: 
1-800-556-4247 
All return product should be sent to:  
Medtronic, Inc. 
Attn: Explant Lab/ [PE #] 
1851 E. Deere Ave. 
Santa Ana, CA 92705-5720 
USA 
1-800-854-3570 
 

 
 
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Economic and Quality of Life Data Collection 
 R.12.1 
Health Economic Data Collection 
Throughout this trial, resource utilization data will be collected by the research coordinator along 
with clinical data using case report forms.   
Prior to enrollment in the study, patients will be asked to provide the information and permission to 
obtain such billing records for the length of their follow-up period.  All related data will be kept in a 
secure and confidential database.  
R.12.2 
Quality of Life Data Collection 
The QoL questionnaires will be administered to all subjects in languages where translation is 
available. It is not a deviation if a subject does not complete a Quality of Life Questionnaire 
because a translation is not available in the subject’s language. 
All QoL assessments will be by written, self-administered questionnaires. Ample, uninterrupted 
time should be provided for the subject to complete the questionnaires. Every effort should be 
made to have the subject complete the questionnaire him or herself.  If the subject is unable to 
complete the questionnaires, the caregiver may complete the questionnaires on their behalf. 
R.12.2.1 Schedule of Assessments 
Questionnaires are to be administered, per protocol: 
 
Baseline 
 
30 days 
 
3 months 
 
6 months 
 
12 months 
 
18 months 
 
24 months 
 
3 years 
 
4 years 
 
5 years 
Baseline Assessment: 
Questionnaires may be administered any time after the subject has provided informed consent but 
should be collected prior to informing the subject of their treatment assignment. 
3 month Assessment: 
Questionnaire(s) should be administered via telephone. 
 
EQ-5D – collected in all participating geographies 
 
SF-36 – collected is limited to subjects in: 
o 
Canada 
o 
Denmark 
o 
Netherlands 
o 
United Kingdom 
o 
United States 
 
 

 
 
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R.12.2.2 Questionnaires 
Kansas City Cardiomyopathy Questionnaire (KCCQ) 
The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a validated self-administered 23-item 
questionnaire that quantifies physical limitations, symptoms, self-efficacy, social interference and 
quality of life.  
SF-36 
QualityMetric’s SF-36v2® Health Survey is a multi-purpose short-form that measures functional 
health and well-being from the patient’s point of view. 
EuroQoL EQ-5D 
The EQ-5D is a measure of self-reported health outcomes that is applicable to a wide range of 
health conditions and treatments. It consists of two parts: a descriptive system (Part I) and a visual 
analogue scale (VAS) (Part II). Part I of the scale consists of 5 single-item dimensions including: 
mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has a 
3 point response scale designed to indicate the level of the problem. Part II uses a vertical 
graduated VAS (thermometer) to measure health status, ranging from worst imaginable health 
state to best imaginable health state. 
 

 
 
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Pacing Guidelines 
Recommendations for pacing pre-, peri- and post-operatively are provided below (see also 
respective investigational device Instructions For Use).  These are recommendations and final 
decisions should be made via clinical presentation and physician discretion.  Programmed settings 
for temporary and permanent pacing are per subject condition and physician discretion.   
Pre-operative Recommendations 
 
Ensure subject is informed about the placement of temporary pacing wires during the 
procedure and any additional associated risks. 
 
Ensure subject is informed about the potential for the placement of a permanent pacemaker 
and any additional associated risks. 
 
Obtain a baseline 12-lead ECG and assess for subject’s conduction status 
 
Subjects with a pre-existing permanent pacemaker only: Conduct a full interrogation and 
AV conduction assessment. Print a copy of the interrogation and save the data on a diskette.  
Label the diskette with labels provided by Medtronic, including center name, subject ID, date 
and time of visit/interrogation and type of visit. Retain the printout and diskette in the subject’s 
file for source verification.   
o Recommended AV conduction assessment:   
 
Conduct an atrial threshold test with a long AV delay (e.g. 350ms) in DDD mode. 
 
If the subject’s ventricular rhythm doesn't come through within the 350 ms, the 
subject would be considered dependent on ventricular pacing. 
Peri-operative Recommendations 
 
Prior to beginning the respective investigational device implant, place a temporary 4-5 Fr. 
balloon-tip pacing wire in a stable location within the right ventricular (a screw-tip wire may be 
used for more secure placement for subjects at high-risk for dislodgement, if necessary and 
experienced with implantation technique).   
o Whenever possible, use the upper torso venous system (e.g., jugular, sub-clavian) for 
temporary pacing wire access due to the recommendation to leave this system in for at 
least 48 hours post-procedure. 
o Use fluoroscopy to guide wire placement and stability. 
o Confirm sensing and capture 
o Program the backup pacing rate to minimize ventricular pacing (e.g. 30-40 bpm).  If heart 
block develops, adjustment the rate accordingly. 
 
Rapid pacing during balloon valvuloplasty 
o Conduct a rapid pacing test prior to balloon valvuloplasty.   
 
Successful test is defined as 1-to-1 pacing capture with an immediate drop in 
pressure and elimination of the systolic-diastolic waveform. 
Post-operative Recommendations 
 
All subjects should stay on telemetry until discharge 
 
Maintain temporary pacing until at least 48 hours post-implant 
o Ensure a clean, sterile environment is maintained 
 
After 48 hours, obtain ECG and assess subject rhythm and conduction 
o Based on assessment, and with the consult of an electrophysiologist as needed, take one 
of the following actions: 
 
Discontinue temporary pacing 
 
Continue temporary pacing for another 24 hours (longer if needed) to make further 
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 
Place a permanent pacemaker according to ACC/AHA/HRS Guidelines for Device-
Based Therapy of Cardiac Rhythm Abnormalities1(Class I or IIa for Acquired 
Atrioventricular Block in Adults or Permanent Pacing in Chronic Bifascicular Block) 
 Prior to the permanent pacemaker implantation, document the reason for the 
placement of the permanent pacemaker via a 12-lead ECG. 
 
For complete heart block, review subject medications.  Consider withholding some 
medications to assess for subject’s intrinsic rate and conduction.  If heart block persists off 
medications, a permanent pacemaker should be considered. 
 
If a permanent pacemaker is required, a dual chamber system is recommended to optimize 
subject hemodynamics. 
o Recommended AV conduction assessment:   
 
Conduct an atrial threshold test with a long AV delay 350ms) in DDD mode.   
 
If the subject’s ventricular rhythm doesn't come through within the 350 ms, the 
subject would be considered dependent on ventricular pacing. 
                                                    
 
1  ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities: J Am Coll Cardiol 2008; 51:2085–105; 
Circulation 2008;117:2820–40
 

 
 
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ACC/AHA/HRS 2008 Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities 
Recommendations for Acquired Atrioventricular Block in Adults 
Class I Permanent pacemaker implantation is indicated for: 
 
Third-degree and advanced second-degree atrioventricular (AV) block at any anatomic level 
associated with bradycardia with symptoms (including heart failure) or ventricular arrhythmias 
presumed to be due to AV block. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level associated with 
arrhythmias and other medical conditions that require drug therapy that results in 
symptomatic bradycardia. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level in awake, 
symptom-free patients in sinus rhythm, with documented periods of asystole greater than or 
equal to 3.0 seconds or any escape rate less than 40 bpm, or with an escape rhythm that is 
below the AV node. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level in awake, 
symptom-free patients with atrial fibrillation and bradycardia with 1 or more pauses of at least 
5 seconds or longer. (LOE: C)  
 
Third-degree and advanced second-degree AV block at any anatomic level after catheter 
ablation of the AV junction. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level associated with 
postoperative AV block that is not expected to resolve after cardiac surgery. (LOE: C) 
 
Third-degree and advanced second-degree AV block at any anatomic level associated with 
neuromuscular diseases with AV block, such as myotonic muscular dystrophy, Kearns-Sayre 
syndrome, Erb dystrophy (limb-girdle muscular dystrophy), and peroneal muscular atrophy, 
with or without symptoms. (LOE: B) 
 
Second-degree AV block with associated symptomatic bradycardia regardless of type or site 
of block. (LOE: B) 
 
Asymptomatic persistent third-degree AV block at any anatomic site with average awake 
ventricular rates of 40 bpm or faster if cardiomegaly or left ventricular (LV) dysfunction is 
present or if the site of block is below the AV node. (LOE: B) 
 
Second- or third-degree AV block during exercise in the absence of myocardial ischemia. 
(LOE: C)  
Class IIa Permanent pacemaker implantation is reasonable for: 
 
Persistent third-degree AV block with an escape rate greater than 40 bpm in asymptomatic 
adult patients without cardiomegaly. (LOE: C) 
 
Asymptomatic second-degree AV block at intra or infra-His levels found at 
electrophysiological study. (LOE: B) 
 
First- or second-degree AV block with symptoms similar to those of pacemaker syndrome or 
hemodynamic compromise. (LOE: B) 
 
Asymptomatic type II second-degree AV block with a narrow QRS. When type II second-
degree AV block occurs with a wide QRS, including isolated right bundle-branch block, 
pacing becomes a Class I recommendation (see Section 2.1.3, “Chronic Bifascicular Block,” 
in the full-text guidelines). (LOE: B) 
 

 
 
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Recommendations for Permanent Pacing in Chronic Bifascicular Block 
Class I Permanent pacemaker implantation is indicated for: 
1. Advanced second-degree AV block or intermittent third-degree AV block. (LOE: B) 
2. Type II second-degree AV block. (LOE: B) 
3. Alternating bundle-branch block. (LOE: C) 
 
Class IIa Permanent pacemaker implantation is reasonable for: 
 
Syncope not demonstrated to be due to AV block when other likely causes have been 
excluded, specifically ventricular tachycardia (VT). (LOE: B) 
 
Incidental finding at electrophysiological study of a markedly prolonged HV interval (greater 
than or equal to 100 milliseconds) in asymptomatic patients. (LOE: B) 
 
Incidental finding at electrophysiological study of pacing-induced infra-His block that is not 
physiological. (LOE: B) 
 
 

 
 
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Six Minute Walk Test Instructions 
American Thoracic Society 
ATS Statement: Guidelines for the Six-Minute Walk Test  
THIS OFFICIAL STATEMENT OF THE AMERICAN THORACIC SOCIETY WAS APPROVED BY 
THE ATS BOARD OF DIRECTORS MARCH 2002  
CONTENTS  
Purpose and Scope  
Background  
Indications and Limitations  
Contraindications  
Safety Issues  
Technical Aspects of the 6-Minute Walk Test  
Required Equipment  
Patient Preparation  
Measurements  
Quality Assurance  
Interpretation  
References  
PURPOSE AND SCOPE  
This statement provides practical guidelines for the 6-minute walk test (6MWT). Specifically, it 
reviews indications, details factors that influence results, presents a brief step-by-step protocol, 
outlines safety measures, describes proper patient preparation and procedures, and offers 
guidelines for clinical interpretation of results. These recommendations are not intended to limit the 
use of alternative protocols for research studies. We do not discuss the general topic of clinical 
exercise testing.  
As with other American Thoracic Society statements on pulmonary function testing, these 
guidelines come out of a consensus conference. Drafts were prepared by two members (P.L.E. and 
R.J.Z.) and were based on a comprehensive Medline literature search from 1970 through 2001, 
augmented by suggestions from other committee members. Each draft responded to comments 
from the working committee. The guidelines follow previously published methods as closely as 
possible and provide a rationale for each specific recommendation. The final recommendations 
represent a consensus of the committee. The committee recommends that these guidelines be 
reviewed in five years and in the meantime encourages further research in areas of controversy.  
BACKGROUND  
There are several modalities available for the objective evaluation of functional exercise capacity. 
Some provide a very complete assessment of all systems involved in exercise performance (high 
tech), whereas others provide basic information but are low tech and are simpler to perform. The 
modality used should be chosen based on the clinical question to be addressed and on available 
resources. The most popular clinical exercise tests in order of increasing complexity are stair 
climbing, a 6MWT, a shuttle-walk test, detection of exercise-induced asthma, a cardiac stress test 
(e.g., Bruce protocol), and a cardiopulmonary exercise test (1, 2). Other professional organizations 
have published standards for cardiac stress testing (3, 4).  
Assessment of functional capacity has traditionally been done by merely asking patients the 
following: "How many flights of stairs can you climb or how many blocks can you walk?" However, 
patients vary in their recollection and may report overestimations or underestimations of their true 
functional capacity. Objective measurements are usually better than self-reports. In the early 1960s, 
Balke developed a simple test to evaluate the functional capacity by measuring the distance walked 
during a defined period of time (5). A 12-minute field performance test was then developed to 
evaluate the level of physical fitness of healthy individuals (6). The walking test was also adapted to 
assess disability in patients with chronic bronchitis (7). In an attempt to accommodate patients with 
respiratory disease for whom walking 12 minutes was too exhausting, a 6-minute walk was found to 
perform as well as the 12-minute walk (8). A recent review of functional walking tests concluded that 

 
 
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"the 6MWT is easy to administer, better tolerated, and more reflective of activities of daily living than 
the other walk tests" (9).  
The 6MWT is a practical simple test that requires a 100-ft hallway but no exercise equipment or 
advanced training for technicians. Walking is an activity performed daily by all but the most severely 
impaired patients. This test measures the distance that a patient can quickly walk on a flat, hard 
surface in a period of 6 minutes (the 6MWD). It evaluates the global and integrated responses of all 
the systems involved during exercise, including the pulmonary and cardiovascular systems, 
systemic circulation, peripheral circulation, blood, neuromuscular units, and muscle metabolism. It 
does not provide specific information on the function of each of the different organs and systems 
involved in exercise or the mechanism of exercise limitation, as is possible with maximal 
cardiopulmonary exercise testing. The self-paced 6MWT assesses the submaximal level of 
functional capacity. Most patients do not achieve maximal exercise capacity during the 6MWT; 
instead, they choose their own intensity of exercise and are allowed to stop and rest during the test. 
However, because most activities of daily living are performed at submaximal levels of exertion, the 
6MWD may better reflect the functional exercise level for daily physical activities.  
INDICATIONS AND LIMITATIONS  
The strongest indication for the 6MWT is for measuring the response to medical interventions in 
patients with moderate to severe heart or lung disease. The 6MWT has also been used as a one-
time measure of functional status of patients, as well as a predictor of morbidity and mortality (see 
Table 1 for a list of these indications). The fact that investigators have used the 6MWT in these 
settings does not prove that the test is clinically useful (or the best test) for determining functional 
capacity or changes in functional capacity due to an intervention in patients with these diseases. 
Further studies are necessary to determine the utility of the 6MWT in various clinical situations.  
TABLE 1. Indications for the Six-Minute Walk Test  
Pretreatment and post treatment comparisons 
Lung transplantation (9, 10) 
Lung resection (11) 
Lung volume reduction surgery (12, 13) 
Pulmonary rehabilitation (14, 15) 
COPD (16–18) 
Pulmonary hypertension 
Heart failure (19, 20) 
Functional status (single measurement) 
COPD (21, 22) 
Cystic fibrosis (23, 24) 
Heart failure (25–27) 
Peripheral vascular disease (28, 29) 
Fibromyalgia (30) 
Older patients (31) 
Predictor of morbidity and mortality 
Heart failure (32, 33) 
COPD (34, 35) 
Primary pulmonary hypertension (10, 36) 
Definition of abbreviation: COPD = chronic obstructive pulmonary disease. 
Formal cardiopulmonary exercise testing provides a global assessment of the exercise response, 
an objective determination of functional capacity and impairment, determination of the appropriate 
intensity needed to perform prolonged exercise, quantification of factors limiting exercise, and a 
definition of the underlying pathophysiologic mechanisms such as the contribution of different organ 
systems involved in exercise. The 6MWT does not determine peak oxygen uptake, diagnose the 
cause of dyspnea on exertion, or evaluate the causes or mechanisms of exercise limitation (1, 2). 
The information provided by a 6MWT should be considered complementary to cardiopulmonary 
exercise testing, not a replacement for it. Despite the difference between these two functional tests, 
some good correlations between them have been reported. For example, a significant correlation (r 
= 0.73) between 6MWD and peak oxygen uptake has been reported for patients with end-stage 
lung diseases (36).  

 
 
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In some clinical situations, the 6MWT provides information that may be a better index of the 
patient's ability to perform daily activities than is peak oxygen uptake; for example, 6MWD 
correlates better with formal measures of quality of life (37). Changes in 6MWD after therapeutic 
interventions correlate with subjective improvement in dyspnea (38, 39). The reproducibility of the 
6MWD (with a coefficient of variation of approximately 8%) appears to be better than the 
reproducibility of 1-second forced expiratory volume in patients with chronic obstructive pulmonary 
disease (COPD) (8, 39–42). Questionnaire indices of functional status have a larger short-term 
variability (22–33%) than does the 6MWD (37).  
The shuttle-walking test is similar to the 6MWT, but it uses an audio signal from a tape cassette to 
direct the walking pace of the patient back and forth on a 10-m course (43–45). The walking speed 
is increased every minute, and the test ends when the patient cannot reach the turnaround point 
within the required time. The exercise performed is similar to a symptom-limited, maximal, 
incremental treadmill test. An advantage of the shuttle walking test is that it has a better correlation 
with peak oxygen uptake than the 6MWD (46, 47). Disadvantages include less validation, less 
widespread use, and more potential for cardiovascular problems.  
CONTRAINDICATIONS  
Absolute contraindications for the 6MWT include the following: unstable angina during the previous 
month and myocardial infarction during the previous month. Relative contraindications include a 
resting heart rate of more than 120, a systolic blood pressure of more than 180 mm Hg, and a 
diastolic blood pressure of more than 100 mm Hg.  
Patients with any of these findings should be referred to the physician ordering or supervising the 
test for individual clinical assessment and a decision about the conduct of the test. The results from 
a resting electrocardiogram done during the previous 6 months should also be reviewed before 
testing. Stable exertional angina is not an absolute contraindication for a 6MWT, but patients with 
these symptoms should perform the test after using their antiangina medication, and rescue nitrate 
medication should be readily available.  
Rationale 
Patients with the previously mentioned risk factors may be at increased risk for arrhythmias or 
cardiovascular collapse during testing. However, each patient determines the intensity of their 
exercise, and the test (without electrocardiogram monitoring) has been performed in thousands 
of older persons (31, 48) and thousands of patients with heart failure or cardiomyopathy (32, 49, 
50) without serious adverse events. The contraindications listed previously here were used by 
study investigators based on their impressions of the general safety of the 6MWT and their 
desire to be prudent, but it is unknown whether adverse events would occur if such patients 
performed a 6MWT; they are, therefore, listed as relative contraindications.  
SAFETY ISSUES  
1. Testing should be performed in a location where a rapid, appropriate response to an 
emergency is possible. The appropriate location of a crash cart should be determined by the 
physician supervising the facility.  
2. Supplies that must be available include oxygen, sublingual nitroglycerine, aspirin, and 
albuterol (metered dose inhaler or nebulizer). A telephone or other means should be in place 
to enable a call for help.  
3. The technician should be certified in cardiopulmonary resuscitation with a minimum of Basic 
Life Support by an American Health Association–approved cardiopulmonary resuscitation 
course. Advanced cardiac life support certification is desirable. Training, experience, and 
certification in related health care fields (registered nurse, registered respiratory therapist, 
certified pulmonary function technician, etc.) are also desirable. A certified individual should 
be readily available to respond if needed.  
4. Physicians are not required to be present during all tests. The physician ordering the test or a 
supervising laboratory physician may decide whether physician attendance at a specific test is 
required.  

 
 
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5. If a patient is on chronic oxygen therapy, oxygen should be given at their standard rate or as 
directed by a physician or a protocol.  
Reasons for immediately stopping a 6MWT include the following: (1) chest pain, (2) intolerable 
dyspnea, (3) leg cramps, (4) staggering, (5) diaphoresis, and (6) pale or ashen appearance.  
Technicians must be trained to recognize these problems and the appropriate responses. If a test is 
stopped for any of these reasons, the patient should sit or lie supine as appropriate depending on 
the severity or the event and the technician's assessment of the severity of the event and the risk of 
syncope. The following should be obtained based on the judgment of the technician: blood 
pressure, pulse rate, oxygen saturation, and a physician evaluation. Oxygen should be 
administered as appropriate.  
TECHNICAL ASPECTS OF THE 6MWT  
Location 
The 6MWT should be performed indoors, along a long, flat, straight, enclosed corridor with a hard 
surface that is seldom traveled. If the weather is comfortable, the test may be performed outdoors. 
The walking course must be 30 m in length. A 100-ft hallway is, therefore, required. The length of 
the corridor should be marked every 3 m. The turnaround points should be marked with a cone 
(such as an orange traffic cone). A starting line, which marks the beginning and end of each 60-m 
lap, should be marked on the floor using brightly colored tape.  
Rationale 
A shorter corridor requires patients to take more time to reverse directions more often, reducing 
the 6MWD. Most studies have used a 30-m corridor (51), but some have used 20- or 50-m 
corridors (52, 53). A recent multicenter study found no significant effect of the length of straight 
courses ranging from 50 to 164 ft, but patients walked farther on continuous (oval) tracks (mean 
92 ft farther) (54).  
The use of a treadmill to determine the 6MWD might save space and allow constant monitoring 
during the exercise, but the use of a treadmill for 6-minute walk testing is not recommended. 
Patients are unable to pace themselves on a treadmill. In one study of patients with severe lung 
disease, the mean distance walked on the treadmill during 6 minutes (with the speed adjusted 
by the patients) was shorter by a mean of 14% when compared with the standard 6MWD using 
a 100-ft hallway (55). The range of differences was wide, with patients walking between 400–
1,300 ft on the treadmill who walked 1,200 ft in the hallway. Treadmill test results, therefore, are 
not interchangeable with corridor tests.  
REQUIRED EQUIPMENT  
1. Countdown timer (or stopwatch)  
2. Mechanical lap counter  
3. Two small cones to mark the turnaround points  
4. A chair that can be easily moved along the walking course  
5. Worksheets on a clipboard  
6. A source of oxygen  
7. Sphygmomanometer  
8. Telephone  
9. Automated electronic defibrillator  

 
 
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PATIENT PREPARATION  
6. Comfortable clothing should be worn.  
7. Appropriate shoes for walking should be worn.  
8. Patients should use their usual walking aids during the test (cane, walker, etc.).  
9. The patient's usual medical regimen should be continued.  
10. A light meal is acceptable before early morning or early afternoon tests.  
11. Patients should not have exercised vigorously within 2 hours of beginning the test.  
MEASUREMENTS  
1. Repeat testing should be performed about the same time of day to minimize intraday 
variability.  
2. A "warm-up" period before the test should not be performed.  
3. The patient should sit at rest in a chair, located near the starting position, for at least 10 
minutes before the test starts. During this time, check for contraindications, measure pulse 
and blood pressure, and make sure that clothing and shoes are appropriate. Complete the 
first portion of the worksheet (see the APPENDIX).  
4. Pulse oximetry is optional. If it is performed, measure and record baseline heart rate and 
oxygen saturation (SpO2) and follow manufacturer's instructions to maximize the signal and 
to minimize motion artifact (56). Make sure the readings are stable before recording. Note 
pulse regularity and whether the oximeter signal quality is acceptable.  
The rationale for measuring oxygen saturation is that although the distance is the primary 
outcome measure, improvement during serial evaluations may be manifest either by an 
increased distance or by reduced symptoms with the same distance walked (38). The SpO2 
should not be used for constant monitoring during the exercise. The technician must not 
walk with the patient to observe the SpO2. If worn during the walk, the pulse oximeter must 
be lightweight (less than 2 pounds), battery powered, and held in place (perhaps by a 
"fanny pack") so that the patient does not have to hold or stabilize it and so that stride is not 
affected. Many pulse oximeters have considerable motion artifact that prevents accurate 
readings during the walk (57).  
5. Have the patient stand and rate
 their baseline dyspnea and overall
 fatigue using the Borg scale
 
(see Table 2 for the Borg scale
 and instructions [58]).
  
6. Set
 the lap counter to zero and the timer to 6 minutes. Assemble
 all necessary equipment (lap 
counter, timer, clipboard, Borg
 Scale, worksheet) and move to the starting point.
  
7. Instruct
 the patient as follows:
  
"The object of this test is to walk as far as possible for 6 minutes. You will walk back 
and forth in this hallway. Six minutes is a long time to walk, so you will be exerting 
yourself. You will probably get out of breath or become exhausted. You are permitted to 
slow down, to stop, and to rest as necessary. You may lean against the wall while 
resting, but resume walking as soon as you are able.  
You will be walking back and forth around the cones. You should pivot briskly around the 
cones and continue back the other way without hesitation. Now I'm going to show you. 
Please watch the way I turn without hesitation."  
Demonstrate by walking one lap yourself. Walk and pivot around a cone briskly.  
"Are you ready to do that? I am going to use this counter to keep track of the number of 
laps you complete. I will click it each time you turn around at this starting line. Remember 
that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or jog.  
Start now or whenever you are ready."  
 
 

 
 
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TABLE 2. The Borg scale 
0 
Nothing at all 
0.5 
Very, very slight (just noticeable) 
1 
Very slight 
2 
Slight (light) 
3 
Moderate 
4 
Somewhat severe 
5 
Severe (heavy) 
6 
 
7 
Very severe 
8 
 
9 
 
10 
Very, very severe (maximal) 
 
This Borg scale should be printed on heavy paper (11 inches high and perhaps laminated) in 
20-point type size. At the beginning of the 6-minute exercise, show the scale to the patient and 
ask the patient this: "Please grade your level of shortness of breath using this scale." Then ask 
this: 
"Please 
grade 
your 
level 
of 
fatigue 
using 
this 
scale." 
At the end of the exercise, remind the patient of the breathing number that they chose before 
the exercise and ask the patient to grade their breathing level again. Then ask the patient to 
grade their level of fatigue, after reminding them of their grade before the exercise. 
8. Position the patient at the starting line. You should also stand near the starting line during 
the test. Do not walk with the patient. As soon as the patient starts to walk, start the timer  
9. Do not talk to anyone during the walk. Use an even tone of voice when using the standard 
phrases of encouragement. Watch the patient. Do not get distracted and lose count of the 
laps. Each time the participant returns to the starting line, click the lap counter once (or 
mark the lap on the worksheet). Let the participant see you do it. Exaggerate the click using 
body language, like using a stopwatch at a race.  
After the first minute, tell the patient the following (in even tones): "You are doing well. You 
have 5 minutes to go."  
When the timer shows 4 minutes remaining, tell the patient the following: "Keep up the 
good work. You have 4 minutes to go."  
When the timer shows 3 minutes remaining, tell the patient the following: "You are doing 
well. You are halfway done."  
When the timer shows 2 minutes remaining, tell the patient the following: "Keep up the 
good work. You have only 2 minutes left."  
When the timer shows only 1 minute remaining, tell the patient: "You are doing well. You 
have only 1 minute to go."  
Do not use other words of encouragement (or body language to speed up).  
If the patient stops walking during the test and needs a rest, say this: "You can lean against 
the wall if you would like; then continue walking whenever you feel able." Do not stop the 
timer. If the patient stops before the 6 minutes are up and refuses to continue (or you 
decide that they should not continue), wheel the chair over for the patient to sit on, 
discontinue the walk, and note on the worksheet the distance, the time stopped, and the 
reason for stopping prematurely.  
When the timer is 15 seconds from completion, say this: "In a moment I'm going to tell you 
to stop. When I do, just stop right where you are and I will come to you."  
When the timer rings (or buzzes), say this: "Stop!" Walk over to the patient. Consider taking 
the chair if they look exhausted. Mark the spot where they stopped by placing a bean bag 
or a piece of tape on the floor.  
10. Post-test: Record the postwalk Borg dyspnea and fatigue levels and ask this: "What, if 
anything, kept you from walking farther?"  

 
 
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11. If using a pulse oximeter, measure SpO2 and pulse rate from the oximeter and then remove 
the sensor.  
12. Record the number of laps from the counter (or tick marks on the worksheet).  
13. Record the additional distance covered (the number of meters in the final partial lap) using 
the markers on the wall as distance guides. Calculate the total distance walked, rounding to 
the nearest meter, and record it on the worksheet.  
14. Congratulate the patient on good effort and offer a drink of water.  
QUALITY ASSURANCE  
Sources of Variability 
There are many sources of 6MWD variability (see Table 3). The sources of variability caused by the 
test procedure itself should be controlled as much as possible. This is done by following the 
standards found in this document and by using a quality-assurance program.  
TABLE 3. 6MWD Sources of Variability  
Factors reducing the 6MWD 
Shorter height 
Older age 
Higher body weight 
Female sex 
Impaired cognition 
A shorter corridor (more turns) 
Pulmonary disease (COPD, asthma, cystic fibrosis, interstitial lung disease) 
Cardiovascular disease (angina, MI, CHF, stroke, TIA, PVD, AAI) 
Musculoskeletal disorders (arthritis, ankle, knee, or hip injuries, muscle wasting, etc.) 
Factors increasing the 6MWD 
Taller height (longer legs) 
Male sex 
High motivation 
A patient who was previously performed the test 
Medication for a disabling disease taken just before the test 
Oxygen supplementation in patients with exercise induced hypoxemia 
 
Definition of abbreviations: COPD = chronic obstructive pulmonary disease; 6MWD = 6-minute walking distance.  
 
Practice Tests 
A practice test is not needed in most clinical settings but should be considered. If a practice test is 
done, wait for at least 1 hour before the second test and report the highest 6MWD as the patient's 
6MWD baseline.  
Rationale 
The 6MWD is only slightly higher for a second 6MWT performed a day later. The mean 
reported increase ranges from 0 to 17% (23, 27, 40, 41, 54, 59). A multicenter study of 470 
highly motivated patients with severe COPD performed two 6MWTs 1 day apart, and on 
average, the 6MWD was only 66 ft (5.8%) higher on the second day (54).  
Performance (without an intervention) usually reaches a plateau after two tests done within a 
week (8, 60). The training effect may be due to improved coordination, finding optimal stride 
length, and overcoming anxiety. The possibility of a practice or training effect from tests 
repeated after more than a month has not been studied or reported; however, it is likely that the 
effect of training wears off (does not persist) after a few weeks.  

 
 
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Technician Training and Experience 
Technicians who perform 6MWTs should be trained using the standard protocol and then 
supervised for several tests before performing them alone. They should also have completed 
cardiopulmonary resuscitation training.  
Rationale 
One multicenter study of older people found that after correction for many other factors, two of 
the technicians had mean 6MWDs that were approximately 7% lower than the other two sites 
(31).  
Encouragement 
Only the standardized phrases for encouragement (as specified previously here) must be used 
during the test.  
Rationale 
Encouragement significantly increases the distance walked (42). Reproducibility for tests with 
and without encouragement is similar. Some studies have used encouragement every 30 
seconds, every minute, or every 2 minutes. We have chosen every minute and standard 
phrases. Some studies (53) have instructed patients to walk as fast as possible. Although larger 
mean 6MWDs may be obtained thereby, we recommend that such phrases not be used, as they 
emphasize initial speed at the expense of earlier fatigue and possible excessive cardiac stress 
in some patients with heart disease.  
Supplemental Oxygen 
If oxygen supplementation is needed during the walks and serial tests are planned (after an 
intervention other than oxygen therapy), then during all walks by that patient oxygen should be 
delivered in the same way with the same flow. If the flow must be increased during subsequent 
visits due to worsening gas exchange, this should be noted on the worksheet and considered 
during interpretation of the change noted in 6MWD. The type of oxygen delivery device should also 
be noted on the report: for instance, the patient carried liquid oxygen or pushed or pulled an oxygen 
tank, the delivery was pulsed or continuous, or a technician walked behind the patient with the 
oxygen source (not recommended). Measurements of pulse and SpO2 should be made after waiting 
at least 10 minutes after any change in oxygen delivery.  
Rationale 
For patients with COPD or interstitial lung disease, oxygen supplementation increases the 
6MWD (17, 59, 61). Carrying a portable gas container (but not using it for supplemental 
oxygen) reduced the mean 6MWD by 14% in one study of patients with severe respiratory 
disability, but using the container to deliver supplemental oxygen during the exercise increased 
the mean 6MWD by 20–36% (59).  
Medications 
The type of medication, dose, and number of hours taken before the test should be noted.  
Rationale 
Significant improvement in the distance walked, or the dyspnea scale, after administration of 
bronchodilators has been demonstrated in patients with COPD (62, 63), as well as 
cardiovascular medications in patients with heart failure (19).  
INTERPRETATION  
Most 6MWTs will be done before and after intervention, and the primary question to be answered 
after both tests have been completed is whether the patient has experienced a clinically significant 
improvement. With a good quality-assurance program, with patients tested by the same technician, 
and after one or two practice tests, short-term reproducibility of the 6MWD is excellent (36). It is not 
known whether it is best for clinical purposes to express change in 6MWD as (1) an absolute value, 
(2) a percentage change, or (3) a change in the percentage of predicted value. Until further 
research is available, we recommend that change in 6MWD be expressed as an absolute value 
(e.g., the patient walked 50 m farther).  
A statistically significant mean increase in 6MWD in a group of study participants is often much less 
than a clinically significant increase in an individual patient. In one study of 112 patients (half of 
them women) with stable, severe COPD, the smallest difference in 6MWD that was associated with 
a noticeable clinical difference in the patients' perception of exercise performance was a mean of 54 

 
 
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m (95% confidence interval, 37–71 m) (64). This study suggests that for individual patients with 
COPD, an improvement of more than 70 m in the 6MWD after an intervention is necessary to be 
95% confident that the improvement was significant. In an observational study of 45 older patients 
with heart failure, the smallest difference in 6MWD that was associated with a noticeable difference 
in their global rating of worsening was a mean of 43 m (20). The 6MWD was more responsive to 
deterioration than to improvement in heart failure symptoms.  
Reported Mean Changes in 6MWD After Interventions 
Supplemental oxygen (6 L/min) during exercise in patients with COPD or interstitial lung disease 
increased mean 6MWD by approximately 83 m (36%) in one study (59). Patients taking an inhaled 
corticosteroid experienced a mean 33 m (8%) increase in 6MWD in an international COPD study 
(16). Patients with COPD in a study of the effects of exercise and diaphragmatic strength training 
experienced a mean increase in 6MWD of 50 m (20%) (65). Lung volume reduction surgery in 
patients with very severe COPD has been reported to increase 6MWD by a mean of 55 m (20%) 
(13).  
Cardiac rehabilitation in patients referred with various heart diseases increased 6MWD by a mean 
of 170 m (15%) in a recent study (66). In 25 older patients with heart failure, an angiotensin-
converting enzyme inhibitor medication (50 mg captopril per day) improved 6MWD a mean of 64 m 
(39%) compared with a mean increase of only 8% in those receiving a placebo (19).  
Interpreting Single Measurements of Functional Status 
Optimal reference equations from healthy population-based samples using standardized 6MWT 
methods are not yet available. In one study, the median 6MWD was approximately 580 m for 117 
healthy men and 500 m for 173 healthy women (48). A mean 6MWD of 630 m was reported by 
another study of 51 healthy older adults (53). Differences in the population sampled, type and 
frequency of encouragement, corridor length, and number of practice tests may account for reported 
differences in mean 6MWD in healthy persons. Age, height, weight, and sex independently affect 
the 6MWD in healthy adults; therefore, these factors should be taken into consideration when 
interpreting the results of single measurements made to determine functional status. We encourage 
investigators to publish reference equations for healthy persons using the previously mentioned 
standardized procedures.  
A low 6MWD is nonspecific and nondiagnostic. When the 6MWD is reduced, a thorough search for 
the cause of the impairment is warranted. The following tests may then be helpful: pulmonary 
function, cardiac function, ankle–arm index, muscle strength, nutritional status, orthopedic function, 
and cognitive function.  
Conclusions 
The 6MWT is a useful measure of functional capacity targeted at people with at least moderately 
severe impairment. The test has been widely used for preoperative and postoperative evaluation 
and for measuring the response to therapeutic interventions for pulmonary and cardiac disease. 
These guidelines provide a standardized approach to performing the 6MWT. The committee hopes 
that these guidelines will encourage further research into the 6MWT and allow direct comparisons 
among different studies.  
 
 

 
 
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APPENDIX  
The following elements should be present on the 6MWT worksheet and report: 
Lap counter:  __ __ __ __ __  __ __ __ __ __  __ __ __ __ __  
Patient name: ____________________      Patient ID# ___________  
Walk # ______    Tech ID: _________ Date: __________  
Gender: M F  Age: ____  Race: ____  Height: ___ft ____in, ____ meters  
Weight: ______ lbs, _____kg      Blood pressure: _____ / _____  
Medications taken before the test (dose and time): __________________  
Supplemental oxygen during the test: No  Yes, flow ______ L/min, type _____ 
 
Baseline 
End of Test 
 Time 
___:___ 
___:___ 
 Heart Rate 
_____ 
_____ 
 Dyspnea 
_____ 
_____ (Borg scale) 
 Fatigue 
_____ 
_____ (Borg scale) 
 SpO2 
_____ % 
_____ % 
Stopped or paused before 6 minutes? No  Yes, reason: _______________  
Other symptoms at end of exercise: angina  dizziness  hip, leg, or calf pain  
Number of laps: ____ (x60 meters) + final partial lap: _____ meters =  
Total distance walked in 6 minutes: ______ meters  
Predicted distance: _____ meters    Percent predicted: _____%  
 
Tech comments:  
 Interpretation (including comparison with a preintervention 6MWD): 
 
 

 
 
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Acknowledgments  
This statement was developed by the ATS Committee on Proficiency Standards for Clinical 
Pulmonary Function Laboratories.  
Members of the committee are:  
ROBERT O. CRAPO, M.D., Chair *  
RICHARD CASABURI, PH.D, M.D.  
ALLAN L. COATES, M.D.  
PAUL L. ENRIGHT, M.D.*  
NEIL R. MACINTYRE, M.D.  
ROY T. MCKAY, PH.D.  
DOUGLAS JOHNSON, M.D.  
JACK S. WANGER, M.S.  
R. JORGE ZEBALLOS, M.D.*  
Ad Hoc Committee members are:  
VERA BITTNER, M.D.  
CARL MOTTRAM, R.R.T.  
*Writing Committee Members  
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28.  Montogomery PS, Gardner AW. The clinical utility of a six-minute walk test in peripheral arterial 
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disease: conclusions from a random control trial. Respir Med 1991;85(Suppl B):17–21.  
39.  Niederman MS, Clemente PH, Fein AM, Feinsilver SH, Robinson DA, Ilowite JS, Bernstein MG. 
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40.  Noseda A, Carpiaux J, Prigogine T, Schmerber J. Lung function, maximum and submaximum exercise 
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2016–2020.  
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J. A shuttle walk test for assessment of functional capacity in chronic heart failure. Am Heart J 
1999;138:292–298.  
48.  Enright PL, Sherrill DL. Reference equations for the six-minute walk in healthy adults. Am J Respir Crit 
Care Med 1998;158:1384–1387.  

 
 
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49.  Barst RJ, Rubin LJ, McGoon MD, Caldwell EJ. Long WA, Levy PS. Survival in primary pulmonary 
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50.  Miyamoto S, Nagaya N, Satoh T, Kyotani S, Sakamaki F, Fujita M, Nakanishi N, Miyatake K. Clinical 
correlates and prognostic significance of six-minute walk test in patients with primary pulmonary 
hypertension. Am J Respir Crit Care Med 2000;161:487–492.  
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walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J 1985; 
132:919–923.  
52.  Lipkin DP, Scrivin AJ, Crake T, Poole-Wilson PA. Six minute walking test for assessing exercise 
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53.  Troosters T, Gosselink R, Decramer M. Six minute walking distance in healthy elderly subjects. Eur 
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54.  Weiss RA, et al. Six minute walk test in severe COPD: reliability and effect of walking course layout and 
length. Paper presented at ACCP Conference; September 2000; San Francisco.  
55.  Stevens D, Elpern E, Sharma K, Szidon P, Ankin M, Kesten S. Comparison of hallway and treadmill six-
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56.  Jensen LA, Onyskiw JE, Prasad NGN. Meta-analysis of arterial oxygen saturation monitoring by pulse 
oximetry in adults. Heart Lung 1998; 27:387–408.  
57.  Barthelemy JC, Geyssant A, Riffat J, Antoniadis A, Berruyer J, LaCour JR. Accuracy of pulse oximetry 
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59.  Leach RM, Davidson AC, Chinn S, Twort CHC, Cameron IR, Batemen NT. Portable liquid oxygen and 
exercise ability in severe respiratory disability. Thorax 1992;47:781–789.  
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airways disease. Thorax 1979;34:254–258.  
61.  Roberts CM, Bell J, Wedzicha JA. Comparison of the efficacy of a demand oxygen delivery system with 
continuous low flow oxygen in subjects with stable COPD and severe oxygen desaturation on walking. 
Thorax 1996;51:831–834.  
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Bronchodilator reversibility, exercise performance and breathlessness in stable chronic obstructive 
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63.  Grove A, Lipworth BJ, Reid P, Smith RP, Lamage L, Ingram CG, Jenkins RJ, Winter JH, Dhillon DP. 
Effects of regular salmeterol on lung function and exercise capacity in patients with COPD. Thorax 
1996;51:689–693.  
64.  Redelmeier DA, Bayoumi AM, Goldstein RS, Guyatt GH. Interpreting small differences in functional 
status: The six minute walk test in chronic lung disease patients. Am J Respir Crit Care Med 
1997;155:1278–1282.  
65.  Weiner P, Magadle R, Berar-Yanay N, Davidovich A, Weiner M. The cumulative effect of long-acting 
bronchodilators, exercise, and inspiratory muscle training on the perception of dyspnea in patients with 
advanced COPD. Chest 2000;118:672–678.  
66.  Bittner V, Sanderson B, Breland J, Adams C, Schuman C. Assessing functional capacity as an outcome 
in cardiac rehabilitation: role of the 6 minute walk test. Clinical Exercise Physiology 2000. 
 

 
 
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R.15 
National Institute of Health Stroke Scale (NIHSS) 
Administer stroke scale items in the order listed. Record performance in each category after each 
subscale exam. Do not go back and change scores. Follow directions provided for each exam 
technique. Scores should reflect what the patient does, not what the clinician thinks the patient 
can do. The clinician should record answers while administering the exam and work quickly. 
Except where indicated, the patient should not be coached (i.e., repeated requests to patient to 
make a special effort). 
 
 Instructions  
Scale Definition  
Score  
1a. Level of Consciousness: The investigator 
must choose a response if a full evaluation is 
prevented by such obstacles as an endotracheal 
tube, 
language 
barrier, 
orotracheal 
trauma/bandages. A 3 is scored only if the 
patient makes no movement (other than reflexive 
posturing) in response to noxious stimulation.  
0 = Alert; keenly responsive.  
1 = Not alert; but arousable by minor 
stimulation to obey, answer, or 
respond.  
2 = Not alert; requires repeated 
stimulation to attend, or is obtunded 
and requires strong or painful 
stimulation to make movements (not 
stereotyped).  
3 = Responds only with reflex motor or 
autonomic effects or totally 
unresponsive, flaccid, and areflexic.  
______  
1b. LOC Questions: The patient is asked the 
month and his/her age. The answer must be 
correct - there is no partial credit for being close. 
Aphasic and stuporous patients who do not 
comprehend the questions will score 2. Patients 
unable to speak because of endotracheal 
intubation, orotracheal trauma, severe dysarthria 
from any cause, language barrier, or any other 
problem not secondary to aphasia are given a 1. 
It is important that only the initial answer be 
graded and that the examiner not "help" the 
patient with verbal or non-verbal cues.  
0 = Answers both questions correctly.  
1 = Answers one question correctly.  
2 = Answers neither question correctly.  
______  
1c. LOC Commands: The patient is asked to 
open and close the eyes and then to grip and 
release the non-paretic hand. Substitute another 
one step command if the hands cannot be used. 
Credit is given if an unequivocal attempt is made 
but not completed due to weakness. If the patient 
does not respond to command, the task should 
be demonstrated to him or her (pantomime), and 
the result scored (i.e., follows none, one or two 
commands). Patients with trauma, amputation, or 
other physical impediments should be given 
suitable one-step commands. Only the first 
attempt is scored.  
0 = Performs both tasks correctly.  
1 = Performs one task correctly.  
2 = Performs neither task correctly.  
______  
 
 

 
 
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2. Best Gaze: Only horizontal eye movements 
will 
be 
tested. 
Voluntary 
or 
reflexive 
(oculocephalic) eye movements will be scored, 
but caloric testing is not done. If the patient has a 
conjugate deviation of the eyes that can be 
overcome by voluntary or reflexive activity, the 
score will be 1. If a patient has an isolated 
peripheral nerve paresis (CN III, IV or VI), score 
a 1. Gaze is testable in all aphasic patients. 
Patients with ocular trauma, bandages, pre-
existing blindness, or other disorder of visual 
acuity or fields should be tested with reflexive 
movements, and a choice made 
by the 
investigator. Establishing eye contact and then 
moving about the patient from side to side will 
occasionally clarify the presence of a partial gaze 
palsy.  
0 = Normal.  
1 = Partial gaze palsy; gaze is abnormal 
in one or both eyes, but forced 
deviation or total gaze paresis is not 
present.  
2 = Forced deviation, or total gaze 
paresis not overcome by the 
oculocephalic maneuver.  
______  
3. Visual: Visual fields (upper and lower 
quadrants) are tested by confrontation, using 
finger counting or visual threat, as appropriate. 
Patients may be encouraged, but if they look at 
the side of the moving fingers appropriately, this 
can be scored as normal. If there is unilateral 
blindness or enucleation, visual fields in the 
remaining eye are scored. Score 1 only if a clear-
cut asymmetry, including quadrantanopia, is 
found. If patient is blind from any cause, score 3. 
Double simultaneous stimulation is performed at 
this point. If there is extinction, patient receives a 
1, and the results are used to respond to item 11. 
0 = No visual loss.  
1 = Partial hemianopia.  
2 = Complete hemianopia.  
3 = Bilateral hemianopia (blind including 
cortical blindness).  
______  
4. Facial Palsy: Ask – or use pantomime to 
encourage – the patient to show teeth or raise 
eyebrows and close eyes. Score symmetry of 
grimace in response to noxious stimuli in the 
poorly responsive or non-comprehending patient. 
If facial trauma/bandages, orotracheal tube, tape 
or other physical barriers obscure the face, these 
should be removed to the extent possible.  
0 = Normal symmetrical movements.  
1 = Minor paralysis (flattened nasolabial 
fold, asymmetry on smiling).  
2 = Partial paralysis (total or near-total 
paralysis of lower face).  
3 = Complete paralysis of one or both 
sides (absence of facial movement in 
the upper and lower face).  
______  
5. Motor Arm: The limb is placed in the 
appropriate position: extend the arms (palms 
down) 90 degrees (if sitting) or 45 degrees (if 
supine). Drift is scored if the arm falls before 10 
seconds. The aphasic patient is encouraged 
using urgency in the voice and pantomime, but 
not noxious stimulation. Each limb is tested in 
turn, beginning with the non-paretic arm. Only in 
the case of amputation or joint fusion at the 
shoulder, the examiner should record the score 
as untestable (UN), and clearly write the 
explanation for this choice.  
0 = No drift; limb holds 90 (or 45) 
degrees for full 10 seconds.  
1 = Drift; limb holds 90 (or 45) degrees, 
but drifts down before full 10 seconds; 
does not hit bed or other support.  
2 = Some effort against gravity; limb 
cannot get to or maintain (if cued) 90 
(or 45) degrees, drifts down to bed, 
but has some effort against gravity.  
3 = No effort against gravity; limb falls.  
4 = No movement.  
UN = Amputation or joint fusion, explain: 
_____________________  
5a. Left Arm  
5b. Right Arm  
______  
______  
 
 

 
 
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6. Motor Leg: The limb is placed in the 
appropriate position: hold the leg at 30 degrees 
(always tested supine). Drift is scored if the leg 
falls before 5 seconds. The aphasic patient is 
encouraged using urgency in the voice and 
pantomime, but not noxious stimulation. Each 
limb is tested in turn, beginning with the non-
paretic leg. Only in the case of amputation or 
joint fusion at the hip, the examiner should record 
the score as untestable (UN), and clearly write 
the explanation for this choice.  
0 = No drift; leg holds 30-degree 
position for full 5 seconds.  
1 = Drift; leg falls by the end of the 5-
second period but does not hit bed.  
2 = Some effort against gravity; leg 
falls to bed by 5 seconds, but has 
some effort against gravity.  
3 = No effort against gravity; leg falls to 
bed immediately.  
4 = No movement.  
UN = Amputation or joint fusion, explain: 
________________  
6a. Left Leg  
6b. Right 
______  
______  
7. Limb Ataxia: This item is aimed at finding 
evidence of a unilateral cerebellar lesion. Test 
with eyes open. In case of visual defect, ensure 
testing is done in intact visual field. The finger-
nose-finger and heel-shin tests are performed on 
both sides, and ataxia is scored only if present 
out of proportion to weakness. Ataxia is absent in 
the patient who cannot understand or is 
paralyzed. Only in the case of amputation or joint 
fusion, the examiner should record the score as 
untestable (UN), and clearly write the explanation 
for this choice. In case of blindness, test by 
having the patient touch nose from extended arm 
position.  
0 = Absent.  
1 = Present in one limb.  
2 = Present in two limbs.  
UN = Amputation or joint fusion, explain: 
________________  
______  
8. Sensory: Sensation or grimace to pinprick 
when tested, or withdrawal from noxious stimulus 
in the obtunded or aphasic patient. Only sensory 
loss attributed to stroke is scored as abnormal 
and the examiner should test as many body 
areas (arms [not hands], legs, trunk, face) as 
needed to accurately check for hemisensory loss. 
A score of 2, “severe or total sensory loss,” 
should only be given when a severe or total loss 
of sensation can be clearly demonstrated. 
Stuporous and aphasic patients will, therefore, 
probably score 1 or 0. The patient with brainstem 
stroke who has bilateral loss of sensation is 
scored 2. If the patient does not respond and is 
quadriplegic, score 2. Patients in a coma (item 
1a=3) are automatically given a 2 on this item.  
0 = Normal; no sensory loss.  
1 = Mild-to-moderate sensory loss; 
patient feels pinprick is less sharp or 
is dull on the affected side; or there is 
a loss of superficial pain with pinprick, 
but patient is aware of being touched.  
2 = Severe to total sensory loss; patient 
is not aware of being touched in the 
face, arm, and leg.  
______  
 
 

 
 
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9. Best Language: A great deal of information 
about comprehension will be obtained during the 
preceding sections of the examination. For this 
scale item, the patient is asked to describe what 
is happening in the attached picture, to name the 
items on the attached naming sheet and to read 
from 
the 
attached 
list 
of 
sentences. 
Comprehension is judged from responses here, 
as well as to all of the commands in the 
preceding general neurological exam. If visual 
loss interferes with the tests, ask the patient to 
identify objects placed in the hand, repeat, and 
produce speech. The intubated patient should be 
asked to write. The patient in a coma (item 1a=3) 
will automatically score 3 on this item. The 
examiner must choose a score for the patient 
with stupor or limited cooperation, but a score of 
3 should be used only if the patient is mute and 
follows no one-step commands.  
0 = No aphasia; normal.  
1 = Mild-to-moderate aphasia; some 
obvious loss of fluency or facility of 
comprehension, without significant 
limitation on ideas expressed or form 
of expression. Reduction of speech 
and/or comprehension, however, 
makes conversation about provided 
materials difficult or impossible. For 
example, in conversation about 
provided materials, examiner can 
identify picture or naming card content 
from patient’s response.  
2 = Severe aphasia; all communication is 
through fragmentary expression; great 
need for inference, questioning, and 
guessing by the listener. Range of 
information that can be exchanged is 
limited; listener carries burden of 
communication. Examiner cannot 
identify materials provided from 
patient response.  
3 = Mute, global aphasia; no usable 
speech or auditory comprehension.  
______  
10. Dysarthria: If patient is thought to be normal, 
an adequate sample of speech must be obtained 
by asking patient to read or repeat words from 
the attached list. If the patient has severe 
aphasia, the clarity of articulation of spontaneous 
speech can be rated. Only if the patient is 
intubated or has other physical barriers to 
producing speech, the examiner should record 
the score as untestable (UN), and clearly write an 
explanation for this choice. Do not tell the patient 
why he or she is being tested.  
0 = Normal.  
1 = Mild-to-moderate dysarthria; patient 
slurs at least some words and, at 
worst, can be understood with some 
difficulty.  
2 = Severe dysarthria; patient's speech 
is so slurred as to be unintelligible in 
the absence of or out of proportion to 
any dysphasia, or is mute/anarthric.  
UN = Intubated or other physical barrier, 
explain:________________________  
______  
11. 
Extinction 
and 
Inattention 
(formerly 
Neglect): 
Sufficient 
information 
to 
identify 
neglect may be obtained during the prior testing. 
If the patient has a severe visual loss preventing 
visual double simultaneous stimulation, and the 
cutaneous stimuli are normal, the score is 
normal. If the patient has aphasia but does 
appear to attend to both sides, the score is 
normal. The presence of visual spatial neglect or 
anosagnosia may also be taken as evidence of 
abnormality. Since the abnormality is scored only 
if present, the item is never untestable.  
0 = No abnormality.  
1 = Visual, tactile, auditory, spatial, or 
personal inattention or extinction to 
bilateral simultaneous stimulation in 
one of the sensory modalities.  
2 = Profound hemi-inattention or 
extinction to more than one 
modality; does not recognize own 
hand or orients to only one side of 
space.  
______  
 
 
 

 
 
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Modified Rankin Scale (mRS) Instructions  
Instructions:  
 
The mRS is to be determined after the NIHSS has been determined and graded and by the 
same rater.  
 
The determination of the scale should be made from 5 to 0, i.e., the order presented.  
 
The purpose of the mRS is to record whether the patient is dead, severely, moderately, or 
slightly disabled and if not dead or disabled, whether the patient is performing all usual 
activities without symptoms or not. Because subjects and family members may understate 
the severity of disability, it is important for the rating clinician to understand that the mRS is 
a clinical scale and not a patient-reported outcome. The rater may ask questions but must 
assess the disability whether or not in agreement with the subject or family.  
 
5 Severe disability; someone needs to be available at all times; care may be provided by either a 
trained or an untrained caregiver.  
Question: Does the person require constant care?  
4 Moderately severe disability; need for assistance with some basic ADL, but not requiring 
constant care.  
Question: Is assistance essential for eating, using the toilet, daily hygiene, or walking?  
3 Moderate disability; need for assistance with some instrumental ADL but not basic ADL.  
Question: Is assistance essential for preparing a simple meal, doing household chores, looking 
after money, shopping, or traveling locally?  
2 Slight disability; limitations in participation in usual social roles, but independent for ADL.  
Questions:  
 
Has there been a change in the person’s ability to work or look after others if these were 
roles before stroke?  
 
Has there been a change in the person’s ability to participate in previous social and 
leisure activities?  
 
Has the person had problems with relationships or become isolated?  
 
Do any of the following interfere with the subject's ability to perform all usual activities: 
difficulty reading or writing, difficulty speaking or finding the right word, problems with 
balance or coordination, visual problems, numbness (face, arms, legs, hands, feet), loss 
of movement (face, arms, legs, hands, feet), difficulty with swallowing, or other symptom 
resulting from stroke?  
1 No significant disability; symptoms present but not other limitations.  
Question: Does the subject have any symptoms that do not interfere with the performance of all 
usual activities?  
0 No symptoms at all; no limitations and no symptoms.  
Note:  The above questions are a modification of the questions from Wilson, et. al, Stroke. 2002:33:2243-2246 and are 
modified here for the use in percutaneous heart valve trials for the FDA Division of CV Devices.  
 

 
 
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Mini Mental State Exam (MMSE-2:SV) 
Mini Mental Status Exam1:  The MMSE-2 Standard Version should be used.    
 
Procedure: 
Administer the MMSE-2 exam utilizing the standardized worksheets provided. 
 
http://www.minimental.com/ 

 
 
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Additional Neurological Assessments 
Visual Field Testing 
Visual fields, (upper and lower quadrants) are tested by confrontation, using finger counting or 
visual threat as appropriate. 
Visual fields may be impaired by lesions anywhere in the neural visual pathways, from the optic 
nerves to the occipital lobes. 
• 
Individual eyes: 
In direct confrontation, examiner should sit directly in front of the patient, at the same level 
and approximately one meter apart. Ask the patient to cover one eye and maintain a fixed 
gaze on the examiners eye or nose. The examiner brings a small target (e.g. a match or a 
finger) from the periphery of the subject’s visual field into each of the 4 visual quadrants 
and requests that the patient indicate when they first visualize the object. Wiggling the 
target assists in the patients separating and defining it.  
Repeat the testing for the other eye.  
Any abnormalities in target detection should prompt detailed testing with more precise 
instruments.  
• 
Bilateral eyes:  
In the same position, and with the patients fixed gaze on the examiners nose or eyes, use 
finger counting or visual threat to identify any asymmetry in the visual field.  
Gait Assessment 
Not tested as part of the NIH Stroke Scale.  
Ask the patient to walk down a straight hallway under observation, if ambulatory.  
Note any apparent abnormalities of gait. (Ataxic, lateralized hemi-paretic, ‘shuffling’ or ‘small-
step’ or other abnormality).  
Hand Function 
• 
Motor assessment  
The extensors are weaker than the flexors in the upper extremities. Consequently, following 
a neurological event, the arm eventually assumes a flexed position. Therefore the biceps 
will be stronger than the triceps, the wrist and finger flexors stronger than the extensors. 
For this reason it is not a good idea to monitor for stroke progression by testing grip 
strength. Test finger extensor strength instead. 
Muscle power is classically graded on a scale of 0 – 5, with 0 being no power and 5 being 
normal power. For the purposes of documenting subtleties in potential deficits, power in 
finger muscle groups should be documented on a 0 – 10 scale as follows.  
Grade 0 
 
No muscle contraction  
Grade 2 
 
Muscle contraction without joint movement 
Grade 4 
 
Partial movement with gravity eliminated 
Grade 6 
 
Movement against gravity 
Grade 8 
 
Movement against some resistance 
Grade 10   
Normal strength 
(Use odd numbers to document when physical findings fall between grades). 
 
 

 
 
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• 
Finger Abductors 
Instruct the patient to “Spread your fingers apart, push your index finger towards the other 
hand. Don’t let me push it back”.  Push on the finger at the Proximal Interphalangeal (PIP) 
joint level.  
• 
Finger Adductors 
Ask patient to ‘grip a sheet of paper’ between their fingers. Try to pull the sheet away from 
them.  
• 
Finger Extensors 
Instruct the patient to “Keep your fingers out straight, and don’t let me bend them”. This is a 
test of extension at the metacarpophalangeal (MCP) joints. It is important to support the 
palm and apply pressure to the PIP joints, testing extension at only one set of joints, 
because extension at the PIP joints is performed by the small hand muscles.  
• 
Sensory Assessment 
In a seated position, ask the patient to place both hands on their lap with palms facing 
down. Instruct them to close their eyes, and using their index finger point to the position 
touched by the examiner on fingers of the opposite hand. Repeat for both hands. 
This should be documented as: ‘normal sensation’ or ‘can feel but unable to localize’ or ‘no 
sensation’ for each hand. 
Writing Evaluation 
Ask the patient to write two sentences about a particular subject. (e.g. their hometown). There is 
no time limit, and patient can be given time prior to neurological examination as necessary.  
Note the subject’s ‘use of paper’, including the position of writing. Also, note whether the written 
subject is appropriate to that asked, and the correctness of the grammar, spelling and syntax 
used.  
Document as ‘fail’ or ‘pass’ or ‘subject unable to attempt test’ if patient is unable.  
Drawing Assessment 
The ‘clock-drawing’ test is used for screening for cognitive impairment and dementia, and as a 
measure of spatial dysfunction and neglect. Doing the test requires verbal understanding, 
memory and spatially coded knowledge in addition to constructive skills.  
Constructional apraxia may occur with lesions in either the left or right parietal lobe, although it is 
more frequent after right parietal damage (visually dominant).  
Clock drawing has been used as a diagnostic measure of unilateral spatial neglect, with neglect 
patients omitting numbers on one half, with or without transposition of the numbers from the 
neglect side to the other, or demonstrating inattention to parts of the spatial layout of numbers.  
The test has a high correlation with the MMSE and other tests of cognitive dysfunction.  
 
Ask patient to draw the face of a clock and put the numbers in the correct position.  
 
Then ask patient to draw in the hands at a particular time (e.g., "twenty minutes after 
eight").  
 
There is no time limit. 
One point will be assigned for each of the following items completed (draws closed circle, 
includes all 12 correct numbers, places numbers in correct positions, places hands in correct 
positions) for a total of four points. 
 

 
 
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Medtronic CoreValve™ Clinical Assessment Guidelines 
Clinical Assessments will be collected to help assess the overall heath and frailty1 of study 
participants at the time of screening. These assessments include measures of nutrition, strength 
and balance, independence in average daily living, mental status, and medical comorbidities.   
The following are guidelines provided for administering the strength and balance examination. 
 
5-Meter Gait Speed: The Gait Test measures, in seconds, the time a person takes walk 5meters. 
Procedure: 
 
Accompany the patient to the designated area, which should be well-lit, unobstructed, and 
contain clearly indicated markings at 0 and 5 meters 
 
Position the patient with his/her feet behind and just touching the 0-meter start line 
 
Instruct the patient to “Walk at your comfortable pace” until a few steps past the 5-meter 
mark (the patient should not start to slow down before the 5-meter mark) 
 
Begin each trial on the word “Go” 
 
Start the timer with the first footfall after the 0-meter line 
 
Stop the timer with the first footfall after the 5-meter line 
 
Repeat 3 times, allowing sufficient time for recuperation between trials 
Note: Patient may use a walking aid (cane, walker). If the patient is receiving an IV drip, he/she 
should perform the test without the IV only if it can be interrupted temporarily without any potential 
risk to the patient, if not, then the patient may perform the test pushing the IV pole. 
 
Grip strength test2: The grip strength test is used to determine the strength in each of the 
participant’s hands. 
Procedure: 
 
Equipment: Hand Dynamometer 
 
Illustrate the use of the instrument to the participant prior to testing. 
 
The participant should be in a seated position. 
 
Ask the participant to squeeze the dynamometer with as much force as possible, being 
careful to squeeze only once for each measurement. 
 
Three trials should be made for the right hand followed by three trials for left hand with a 
pause of about 10-20 seconds between each trial to avoid the effects of muscle fatigue. 
 
The highest reading for each hand should be reported on the case report form. 
 
 
1 
 Fried
 LP et al, (2001). Frailty in older adults: Evidence for a phenotype. Journal of Gerontology: Medical Science , 56A 
(3), M146-M156. 
2 
 Luna-Heredia E, Martin-Pena G, Ruiz-Galiana J. Handgrip dynamometry in healthy adults. Clinical Nutrition 2005; 
24:250-258 
 

 
 
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Katz Index of Independence in Activities of Daily Living 
 
Activities 
Points (1 or 0) 
Independence 
(1 POINT) 
NO supervision, direction or 
personal assistance 
 
Dependence 
(0 Points) 
WITH supervision, direction, 
personal assistance or total 
assistance 
BATHING 
 
 
 
Points: __________ 
(1 POINT) Bathes self 
completely or needs help in 
bathing only a single part of 
the body such as the back, 
genital area or disabled 
extremity. 
(0 POINTS) Needs help with 
bathing more than one part of 
the body, getting in or out of 
the tub or shower. Requires 
total bathing. 
DRESSING 
 
 
 
Points: __________ 
(1 POINT) Gets clothes from 
closets and drawers and puts 
on clothes and outer garments 
complete with fasteners. May 
have help tying shoes. 
0 POINTS) Needs help with 
dressing self or needs to be 
completely dressed. 
TOILETING 
 
 
Points: ___________ 
(1 POINT) Goes to toilet, gets 
on and off, arranges clothes, 
cleans genital area without 
help 
(0 POINTS) Needs help 
transferring to the toilet, 
cleaning self or uses bedpan 
or commode. 
TRANSFERRING 
 
 
Points: ___________ 
(1 POINT) Moves in and out of 
bed or chair unassisted. 
Mechanical transferring aides 
are acceptable. 
(0 POINTS) Needs help in 
moving from bed to chair or 
requires a complete transfer. 
CONTINENCE 
 
Points: ___________ 
(1 POINT) Exercises complete 
self-control over urination and 
defecation. 
(0 POINTS) Is partially or 
totally incontinent of bowel or 
bladder. 
FEEDING 
 
 
Points: ____________ 
(1 POINT) Gets food from 
plate into mouth without help. 
Preparation of food may be 
done by another person. 
(0 POINTS) Needs partial or 
total help with feeding or 
requires parenteral feeding. 
 
 
TOTAL POINTS = _________    
6 = High (patient independent) 
0 = Low (patient very dependent) 
 
Slightly adapted from Katz S., Down, T.D., Cash, H.R. et al. (1970) 
Progress in the Development of the Index of ADL. Gerontologist 
10:20-30. Copyright The Gerontological Society of America 
 

 
 
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Investigator Brochure / Report of Prior Investigations for the 
Investigational Devices 
The geography-specific Investigator Brochure for the Medtronic CoreValve™ System will be 
provided separately, as applicable.

 
 
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Investigational Devices Instructions For Use 
The geography-specific Instructions For Use for the Medtronic CoreValve™ System will be 
provided under separate cover. 
 

 
 
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Radiation Exposure and Data Collection 
The SURTAVI protocol requires several tests and procedures that expose subjects to radiation 
(angiograms, arteriograms and fluoroscopy).  These tests and procedures are essential to 
appropriate patient selection and proper deployment of the study valves. 
Procedure 
Interval 
Multi-slice Computed Tomorgraphy (MSCT) Angiogram 
Screening 
Coronary arteriogram 
Screening 
Index Procedure – TAVI only 
Aorotogram 
Index Procedure – TAVI only 
The following describes radiation exposure data collection requirements as well as parameters for 
additional subject follow-up. 
Follow-up and Data Collection 
Data regarding subject radiation exposure will be collected at all protocol intervals where radiation 
test or procedures are required.   
 
Screening 
 
Index-Procedure (TAVI only) 
o 
Percutaneous Coronary Intervention (PCI) – if staged approach 
 
Reintervention (Valve related) 
 
NOTE: Based on the protocol design, imaging required at screening may have been completed prior to the 
subject signing the informed consent form and data related to radiation exposure during the 
acquisition of the images may not be available.  Radiation exposure data missing from the 
subject record will not be considered a protocol deviation. 
Substantial Radiation Dose Level 
For purposes of SURTAVI, substantial radiation dose level (SRDL) is defined as meeting/exceeding 
one of the following: 
Dose Metric 
SRDL 
Total air kerma at IRP (K a,r) 
3 Gy 
Kerma-area product (Pka) 
250 Gy·cm2 
Fluoroscopy Time 
60 min 
 
In cases where SRDL is met or exceeded additional steps should be taken. 
 
Document the radiation dose the subject was exposed to in the medical record 
 
Include an explanation regarding the medical necessity 
 
Describe the planned follow-up 
 
Notify the subject and caregiver, if applicable 
o 
Instruct subject (and caregiver) to perform visual skin assessments at least once per 
week between in-clinic visits 
o 
If a hand-sized read area or rash is noted, contact the Investigator immediately to 
schedule a follow-up visit 
 
 
 

 
 
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To ensure signs and symptoms of radiation exposure are identified as soon as possible, subjects 
should have a routine visual skin assessment at the following protocol intervals: 
 
Baseline 
 
Immediate Post-Procedure – within 48 hours of TAVI 
 
Discharge 
 
30-days 
 
Additional follow-up should be scheduled at the Investigators discretion based on progression of 
symptoms, as applicable. 
 
If skin changes are noted at any interval additional follow-up should be scheduled with a 
dermatologist, or physician with the appropriate training and expertise for diagnosis and treatment.  
Long-term follow-up should be conducted in accordance with local standard of care. 
 
Skin assessment findings should be noted in the patient medical record and applicable adverse 
events should be reported. 
Threshold for Radiation Dose Exposure 
Chronology and Severity of Tissue Reactions From Single-Delivery Radiation Dose  
Single site 
(Gy) acute 
skin dose 
Prompt 
(<2 weeks) 
Early
(2–8 weeks) 
Mid term
(6–52 weeks) 
Long term
(<40 weeks) 
 
No observable 
effects expected 
 
 
 
2-5 
Transient erythema 
Epilation 
Recovery from hair 
loss 
None expected 
5-10 
Transient erythema 
Erythema, 
epilation 
Recovery; high 
doses cause 
prolonged erythema 
and permanent 
partial epilation 
Recovery; higher dose 
cause dermal 
atrophy/induration 
10-15 
Transient erythema  
Erythema, 
epilation; dry/moist 
desquamation  
Prolonged erythema 
permanent epilation  
Telangiectasia; dermal 
atrophy/induration  
>15 
Transient erythema; 
Very high dose 
causes moist 
desquamation 
edema/ulceration  
Erythema, 
epilation  
Dermal atrophy with 
secondary 
ulceration; 
atrophy/induration; 
High dose dermal 
necrosis surgical 
repair likely  
Telangietasia; dermal 
Late skin breakdown  
Modified: Balter S. Fluoroscopically guided interventional procedure: A review of radiation effects on skin and hair. 
NCRP SC 2–3, Feb 2010.  
List of Abbreviations 
 
 
 
Abbreviation 
Term 
Gy 
Gray 
IRP 
Interventional reference point 
KAP 
Kerma area product 
PSD 
Peak skin dose 
SDRL 
Substantial radiation dose level 

 
 
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References 
Balter, S. Moses, J. Managing Patient Dose in Interventional Cardiology.  Catheterization and Cardiovascular 
Interventions 2007; 70:244–249 
Chambers, et al. Radiation Safety Program for the Cardiac Catheterization Laboratory. Catheterization and 
Cardiovascular Interventions 2011; 77:546–556 
Hirshfield, et al. ACCF/AHA/HRS/SCAI Clinical Competence Statement on Physician Knowledge to Optimize 
Patient Safety and Image Quality in Fluoroscopically Guided Invasive Cardiovascular Procedures: A Report of 
the American College of Cardiology Foundation/American Heart Association/American College of Physicians 
Task Force on Clinical Competence and Training Circulation 2005, 111:511-532 
 

 
 
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SURTAVI Risk Model 
Risk assessment is essential in the strategy to approach patients with valvular heart disease in 
general and AS in particular. Various risk models primarily focusing on short-term mortality have 
been validated for AS patients (30-38). Some were initially derived from a broader patient 
population undergoing any type of cardiac surgery, others were more explicitly tailored to patients 
with AS. Most notably, contemporary scoring models tend to be consistent in lower risk patients 
but diverge with increasing risk profile. This can be partly explained by the fact that these models 
were extracted from large databases where the average patient risk is fairly low. Therefore such 
models are less well validated for higher risk patients and expectedly perform less well in the 
“outlier” population currently considered for TAVI (39).  
An in-depth reappraisal of existing scoring models reveals some concordant risk factors  (e.g. age, 
gender) but also established risk factors that are clearly missing (e.g. mediastinal radiation, 
porcelain aorta and frailty) (40-42). Furthermore definitions of individual components are not 
uniform and do not correspond to current suggested guidelines/definitions by respective 
professional societies.  
R.24.1  
SURTAVI Risk Model Rationale 
1.   Joint database 
Following the initial report by the Bern, Rotterdam collaboration (28) including 1122 patients 
with severe AS, four academic institutions in Bern, Rotterdam, Bad Nauheim and Munich have 
created a joint database on all consecutive patients with severe AS treated with either TAVI or 
SAVR between January 2006 and December 2009. 
Preliminary analysis on 3688 patients has been performed, including 789 TAVI and 2899 
SAVR patients.  
The pre-specified primary outcome was all cause mortality at 1 year. Patients were actively 
followed up after the index procedure and their vital status confirmed by outpatient clinic visit, 
telephone contact, review of medical records or national civil registries. 
2.   Statistical methods 
The propensity scores of SAVR patients were estimated using a probit model with all baseline 
characteristics as described above as independent variables. The propensity score is the 
probability that a patient would have been treated with SAVR given that patient's observed 
baseline characteristics. To ensure the quality of the matching using propensity scores the 
common support assumption was applied, using the Epanechnikov kernel probability density 
estimates. The IPT weighted multivariable analysis was used. The IPT weighted analyses 
used the inverse of the propensity score as weights in SAVR patients and the inverse of 1 
minus the propensity score in TAVI patients. All analyses were based on logistic regression 
models on the 1 year mortality and were performed in the overall dataset and stratified 
according to presence or absence of sufficient overlap of propensity scores (propensity score 
<0.675 versus ≥0.675). 
3.   Type of patient (patient selection) 
Preliminary analysis demonstrated a pre-dominance of patients with age >80 years old, and a 
logistic EuroSCORE <20% in the TAVI cohort (figure “scatterplot”). However, the majority of 
patients in the entire study population are between 65-and 83-years-old (figure “age 
distribution”).  
 

 
 
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Survival curves of the general Dutch 
population 
(derived 
from 
death 
register); and patients undergoing an 
AVR 
(derived 
from 
meta-analysis 
data), or an AVR with the additional 
risk 
factor 
of 
coronary 
sclerosis 
(derived from meta-analysis data). 
 
The range of both the EuroSCORE and STS 
score in a patient with 2 risk factors. The lower 
boundary indicates a score with risk factors that 
have little influence on the score, while the upper 
boundary indicates a score with risk factors that 
influence the score significantly 
 
 
 
 
 
 
 
 
 
 
 
 
As it is well-known that both the STS score and EuroSCORE are suboptimal in operative risk 
assessment, these models are only used for descriptive purposes (39). Age is the predominant 
predictor of mortality in general, and after valve surgery in particular. Furthermore, the impact of 
other risk factors appears to be accentuated in an older age population.  
 
 
The distribution of age in patients treated for 
aortic stenosis. The color indicates the 
percentage of patients treated with TAVI in the 
corresponding age group 
A scatterplot showing the age and corresponding 
EuroSCORE of patients treated for aortic stenosis. 
Indicated by colours are the treatment arms surgical 
aortic valve replacement and transcatheter aortic 
valve implantation. A previous commonly used 
EuroSCORE cut-off value of 20% is indicated in the 
graphic to show that many patients with lower scores 
are already treated by TAVI, but in lower ages this 
treatment 
remains 
limited 
due 
to 
the 
low 
EuroSCORE. 

 
 
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Therefore, we opt for a risk assessment based on age in combination with encoded co-morbidities 
selected from a pre-specified listing. Patients at intermediate risk are defined as age 70-74 years 
with 2 or 3 co-morbidities (cohort 1); age 75-79 years with 1 or 2 co-morbidities (cohort 2); and 
patients ≥80 years of age with ≤1 co-morbidities (cohort 3). 
In-depth analysis and translation of the risk profile mentioned above to the STS score (table STS 
below):  
 
Cohort 1: range of 0.9% to 10.2% in males, and 1.4% to 14.8% in females 
 
Cohort 2: range of 1.2% to 8.5% in males, and 1.8% to 12.4% in females 
 
Cohort 3*: range of 1.7% to 8.9% in males, and 2.6% to 12.7% in females 
 
 
STS score: ranges of scores are displayed as: score with least influential risk factors – score with most influential risk 
factors. *Upper age limit 91 years old 
 
In-depth analysis and translation of the risk profile mentioned above to the logistic EuroSCORE 
(Table EuroSCORE below):  
 
Cohort 1: range of 9.1% to 42.3% in males, and 12.2% to 50.5% in females 
 
Cohort 2: range of 7.2% to 32.1% in males, and 9.8% to 39.6% in females 
 
Cohort 3*: range of 6.6% to 27.8% in males, and 9.0% to 34.9% in females 
 
 
Euroscore: ranges of scores are displayed as: score with least influential risk factors – score with most influential risk 
factors. *Upper age limit 91 years old 
 
4.   Comparative patient outcome 
One-year mortality amounts to 30% in the overall high-risk matched population with a logistic 
EuroSCORE of 15.8%. The hazard ratio of propensity matched patients between SAVR and 
TAVI is 0.97. This suggests equipoise for both treatment strategies and is the legitimation for a 
randomized trial in this intermediate risk AS population. 
 

 
 
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R.24.2  
SURTAVI co-morbidity list  
 
Methodology for identifying enlisted co-morbidities: 
We first identified those components recurring in the previously published scoring models and 
looked for updated definitions by international professional societies. We then added missing risk 
factors, identified in the literature, which we felt, were essential. In addition, there exists an ‘open 
box’ to capture less prevalent and unanticipated risk factors (e.g. liver failure, mediastinal 
radiation, porcelain aorta, etc.) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The above risk factors will guide the Heart Team in the selection of the treatment options but will 
not dictate patient allocation. The final decision treatment will be done by the local Heart Team.   
1. Significant concomitant Coronary Artery Disease: defined as ≥70% stenosis by invasive 
coronary angiography because the combination of revascularization and aortic valve 
replacement reduces the rates of perioperative MI, perioperative mortality, late mortality and 
morbidity when compared with patients not undergoing simultaneous revascularization 
(ACC/AHA/ESC class IC recommendation)(6, 43, 44). Previous CABG or PCI is not 
considered to have considerable impact on short term outcome.  
2. Frailty: in the absence of a generally accepted consensus definition Frailty is defined as 
suggested by Lee and co-workers by the presence of any 1 of the following(40):  
o 
Katz score(independence in Activities of Daily Living);  
o 
Ambulation (walking aid/assist?);  
o 
Diagnosis of (pre-)dementia. 
3. Left Ventricular dysfunction: defined as EF < 35%, with respect to the pivotal position of this 
particular threshold in the heart failure population (45). 
70 yrs of age 
and 2 or 3 risk factors 
75 yrs of age 
and 1 or 2 risk factors 
80 yrs of age 
And 0 or 1 risk factors 
Risk factors: 
 
 
Coronary artery disease requiring revascularization 
 
Frailty  
 
Left Ventricular dysfunction (EF <35%) 
 
Neurological dysfunction (with functional impairment) 
 
Pulmonary disease (Gold stage II)  
 
Peripheral vascular disease  
 
Renal disease (KDOQI Stage III) 
 
Redo cardiac surgery 
 
Pulmonary hypertension (syst PAP 60 mmHg at most recent measurement) 
 
Diabetes (R/ oral meds or insulin) 
 
‘Open Box’ capturing less prevalent risk factors (e.g. liver failure, mediastinal 
radiation, porcelain aorta, etc.) 

 
 
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4. Neurological dysfunction: Cerebro-Vascular Disease, documented by any one of the 
following: CVA (symptoms lasting >24 hours or imaging of an acute clinically relevant brain 
lesion in patients with rapidly vanishing symptoms); TIA (brief episode of neurological 
dysfunction caused by a focal disturbance of brain or retinal ischemia, with clinical 
symptoms with recovery within 24 hrs and without evidence of infarction); Non-invasive 
carotid test with > 60% diameter occlusion or prior carotid surgery or symptomatic carotid 
stenosis > 50%(46-49). Does not include neurological disease processes such as metabolic 
and/or anoxic ischemic encephalopathy. 
5. Pulmonary disease: COPD Gold Stage II: moderate COPD with worsening airflow limitation 
(FEV1/FVC <70%; 50% ≥ FEV1 <80% predicted), with shortness of breath typically 
developing on exertion(50). 
6. Peripheral vascular disease: adapted from the STS risk model: Claudication, either with 
exertion or at rest; Amputation for arterial vascular insufficiency; Vascular reconstruction, 
bypass surgery, or percutaneous intervention to the extremities; Documented aortic 
aneurysm with or without repair; Positive non-invasive 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) 
7.  Renal disease: at least moderate chronic kidney disease with GFR < 60 mL/min according 
to the National Kidney Foundation kidney disease outcome quality initiative advisory 
board(51). 
8. Redo cardiac surgery 
9. Pulmonary hypertension (> 60mmHg at most recent measurement) 
10. Diabetes Mellitus on oral or insulin therapy. 
11. OPEN BOX: e.g., extensive mediastinal radiation, chest wall deformity, Liver Failure Child-C 
 
 
 
 

 
 
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Patients available for screening 
 
All patients 
 
 
 
SAVR patients 
 
0
1
2
3
4
≥5
Total cases
<60
107
85
17
11
1
1
222
60‐64
47
37
15
8
0
0
107
65‐69
57
53
24
10
5
0
149
70‐74
60
66
47
10
5
4
192
75‐79
64
89
38
20
5
2
218
≥80
46
53
43
35
6
11
194
1082
SAVR
668/1082 61.7%
Random ‐‐> TAVI / SAVR
283/1082 26.2%
Too high risk
131/1082 12.1%
Comorbidities (n)
Age (yrs)
 
0
1
2
3
4
≥5
Total cases
<60
106
84
17
11
0
0
218
60‐64
47
37
14
6
0
0
104
65‐69
57
52
23
8
3
0
143
70‐74
59
65
44
5
4
0
177
75‐79
60
83
33
14
1
0
191
≥80
36
32
15
3
0
0
86
919
SAVR
649/919 70.6%
Random ‐‐> TAVI / SAVR
233/919 25.4%
Too high risk
37/919
4.0%
Comorbidities (n)
Age (yrs)

 
 
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TAVI patients 
 
 
 
 
 
 
 
0
1
2
3
4
≥5
Total Cases
≤ 60
1
1
0
0
1
1
4
60‐64
0
0
1
2
0
0
3
65‐69
0
1
1
2
2
0
6
70‐74
1
1
3
5
1
4
15
75‐79
4
6
5
6
4
2
27
≥ 80
10
21
28
32
6
11
108
163
SAVR
19/163 
11.7%
Random ‐‐> TAVI / SAVR
50/163
30.7%
Too high risk
94/163 
57.7%
Age (yrs)
Comorbidities (n)
Distribution of age and comorbidities in patients with severe aortic stenosis in the Rotterdam practice. In each age 
group, patients are divided by the total number of comorbidities as previously defined. 
Indicated in green are the patients that are too low risk for randomization (62%). Indicated by orange are patients 
that will be randomized in SURTAVI (26%). In blue are patients too high risk for randomization (12%). Therefore, it 
is estimated that every 1 in 4 patients meets the inclusion criteria for screening. 

 
 
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STS versus Euro Score 
This table illustrates the relative impact of common co-morbidities in STS score (vertical axis) and 
Euroscore (horizontal axis) risk model. This present panel relates specifically of a male patient of 
70 years old with 0, 1 or 2 risk factors.  
The black line separates the score values of the two respective models: below the line relates to 
STS score, above to Euroscore. 
The empty boxes indicate that the specific risk factor is not accounted for in the risk model, e.g. 
diabetes in Euroscore. 
If this patient has no co-morbidity he would have an STS score of 0.9 and a Euroscore of 3 (see 
first square in upper left corner). 
If this patient has a poor LVEF combined with peripheral vascular disease he would have a STS 
score of 1.5 and Euroscore of 15.5 
Redo surgery is displayed as “first reoperation / second reoperation”, and COPD as “moderate / 
severe”. Values indicated as “score - score” correspond to the range of scores possible when 
combining all 4 risk factors (for instance ‘moderate COPD + 1st redo’ - ‘severe COPD + 2nd redo’) 
DM = diabetes mellitus; PVD = peripheral vascular disease; CVD = cerebrovascular disease; 
LVEF = left ventricular ejection fraction; CAD = coronary artery disease; NYHA = New York Heart 
Association; COPD = chronic obstructive pulmonary disease; PH = pulmonary hypertension 
 

 
 
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R.25 
CMS Considerations for Coverage and Reimbursement – US 
ONLY 
The SURTAVI protocol outlines the minimum requirements for trial participation, patient screening 
by the local Heart Team, and conduct of the TAVI procedure. 
Within the United States, sites and Investigators should adhere to the following additional CMS 
requirements for coverage and reimbursementi, as applicable to the Medicare patient population 
enrolled in the study: 
Section C.4.2.1 Heart Team Composition 
Local Heart Teams should be comprised of a multidisciplinary team qualified by education and 
experience to determine appropriate patient treatment. 
 
Minimum Membership  
 
Interventional Cardiologist - ≥ 1 representative is required 
 
Cardiac Surgeon - ≥ 2 representatives are required 
 
Recommended Membership  
Additional members of the Heart Team should be included based on current standard practices 
and patient specific considerations, including but not limited to: 
 
Echocardiographer 
 
Anesthesiologist 
 
Cardiologist (general or referring physician) 
 
Geriatrician 
 
Neurologist or stroke specialist 
 
Radiologist or imaging specialist 
 
Heart Failure specialist 
 
Intesivist 
 
Nurse 
 
Social Worker 
 
Section C.4.6.1 TAVI 
TAVI Procedure 
 
Joint Participation 
o 
The heart team’s interventional cardiologist(s) and cardiac surgeon(s) must jointly 
participate in the intra-operative technical aspects of the TAVI procedure 
 
                                                    
 
i  
http://www.cms.gov/medicare-coverage-database/details/nca-decision-
memo.aspx?NCAId=257&ver=4&NcaName=Transcatheter+Aortic+Valve+Replacement+(TAVR)&bc=ACAAAAAAIAA
A&  

 
 
 
 
CardioVascular Structural Heart Clinical Department 
 
 
SURTAVI 
 
STATISTICAL ANALYSIS PLAN 
 
 
Revision 1A 
 
16-May-2012 
 
 
 
 
 
 
SUrgical Replacement and Transcatheter Aortic Valve Implantation 
Version 4.0, 10-May-2012 
Prepared by: 
Sharla Chenoweth, MS 
Sr. Principal Statistician 
 
Bayesian Design by: 
Andrew S Mugglin, PHD 
Paradigm Biostatistics, LLC 
 
 
 
 
 
 

 
 
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Table of Contents 
A 
PURPOSE OF SAP ............................................................................................ 4 
B 
RATIONALE FOR STUDY DESIGN................................................................... 4 
C 
STATISTICAL METHODS AND ANALYSIS ...................................................... 4 
C.1 
Statistical considerations and analysis ................................................................................ 4 
C.2 
Description of Baseline Variables ........................................................................................ 4 
C.3 
Analysis Populations ........................................................................................................... 5 
 Screening population ................................................................................................. 5 
C.3.1
 Randomized population............................................................................................. 5 
C.3.2
C.4 
Primary analysis .................................................................................................................. 5 
 Hypothesis of non-inferiority ...................................................................................... 5 
C.4.1
 Randomization, Sample Size, and Analysis Plan ..................................................... 5 
C.4.2
C.5 
Predictions ........................................................................................................................... 7 
 Prior Distributions for Transition Probabilities ........................................................... 9 
C.5.1
C.6 
Operating Characteristics .................................................................................................. 11 
C.7 
Simulation Details and Design Sensitivity ......................................................................... 11 
 LTFU/Data Missingness .......................................................................................... 12 
C.7.1
 Control Arm Event Rate .......................................................................................... 12 
C.7.2
 Rate of Enrollment ................................................................................................... 13 
C.7.3
 Temporal Correlation ............................................................................................... 13 
C.7.4
 Type I Errors ............................................................................................................ 16 
C.7.5
C.8 
Missing Data and Planned Sensitivity Analyses (Primary Objective) ................................ 16 
C.9 
Description of performed analysis, per population ............................................................ 17 
 Analysis of screening population ............................................................................. 17 
C.9.1
 Analysis of mITT population .................................................................................... 17 
C.9.2
 Analysis of implanted population ............................................................................. 17 
C.9.3
C.10 Secondary Endpoints ........................................................................................................ 18 
C.11 Analysis Methods for Secondary Objectives ..................................................................... 21 
 
Discrete (Dichotomous) Data:  Bayesian Version of a Comparison of 
C.11.1
Proportions .............................................................................................................. 21 
 
Discrete (Polytomous) Data:  Bayesian Version of a Comparison of Proportions21 
C.11.2
 
Discrete (Dichotomous) Data:  Bayesian Comparison of Proportions (with 
C.11.3
Predictions) ............................................................................................................. 21 
 
Continuous Data:  Bayesian version of a t-test. ................................................. 22 
C.11.4

 
 
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Continuous Data (Distribution-free, Superiority):  Bayesian Version of a 
C.11.5
Wilcoxon Rank-Sum Test ........................................................................................ 22 
C.12 Multiplicity Considerations ................................................................................................. 23 
 
Ordered List of Secondary Objectives to be Tested To Support Labeling Claims23 
C.12.1
C.13 Heterogeneity/Poolability ................................................................................................... 24 
 
Geography Poolability Analysis .......................................................................... 25 
C.13.1
 
Site Poolability Analysis ...................................................................................... 25 
C.13.2
C.14 Pre-Defined Subgroups ..................................................................................................... 26 
 
Health-Related Quality of Life (HRQoL) and Treatment Costs ........................... 26 
C.14.1
 
Quality of Life ...................................................................................................... 26 
C.14.2
C.15 Economic Outcomes/Cost-Effectiveness .......................................................................... 27 
C.16 Use of Data for CE Mark ................................................................................................... 27 
D 
REVISION PROCESS ...................................................................................... 27 
E 
DISTRIBUTION ................................................................................................ 27 
 
 
 
 

 
 
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A PURPOSE OF SAP 
This Statistical Analysis Plan has been designed to document, before data are 
analyzed, the rationale for the study design, and the planned analyses that will be 
included in study reports. The design and analyses are consistent with the objectives 
of the Clinical Investigational Plan (CIP). 
B RATIONALE FOR STUDY DESIGN 
The purpose of this study is to evaluate the safety and efficacy of the Medtronic CoreValve® 
System in the treatment of symptomatic severe aortic stenosis in subjects who have a predicted 
intermediate (STS 4-10) for aortic valve surgery. Intermediate risk surgical subjects will be 
randomized to receive either transcatheter aortic valve implant (TAVI) with the Medtronic 
CoreValve® System (MCS) or surgical aortic valve replacement (SAVR) in a 1:1 ratio. 
This statistical analysis plan is developed based on the Clinical Investigational Plan Version 
4.0. 
C STATISTICAL METHODS AND ANALYSIS 
The SURTAVI study is a multicenter, multinational, prospective, adaptive, 1:1 randomized study 
designed to demonstrate non-inferiority (to within a relative margin of 20%) of TAVI to SAVR 
with the Medtronic CoreValve® System, as measured by a composite of all-cause death and 
major stroke incidence at 24 months.  The study is designed to adaptively determine sample 
size.  Once the sample size (N) becomes known, study success will be evaluated at an interim 
analysis that is timed to occur 12 months later (with the expectation that all subjects will have at 
least 12 months of follow-up); if necessary, study success will again be evaluated when all 
subjects have reached 24 months.   
A study report will be prepared for submission to FDA at the time study success criteria have 
been met, for the purpose of seeking marketing approval.  After all subjects have completed all 
protocol-specified follow-up, a final clinical report including updated long-term safety data will 
be prepared and submitted. 
Any deviations from this section and/or the Statistical Analysis Plan will be described and 
justified in the Final Report, as appropriate. 
C.1 Statistical considerations and analysis 
This section describes the statistical considerations and analysis plans for the SURTAVI trial.  
The statistical analysis will be performed by the statistics department of Medtronic. As primary 
analysis, all randomized subjects will be analyzed following the modified intention to treat 
(mITT) approach; i.e., analyses will be conducted on the cohort of subjects who undergo an 
attempted study treatment, analyzed according to the randomized assignment.  A secondary 
analysis of key objectives will be performed according to the therapy actually received. All 
follow-up periods are defined as the number of days after the procedure date. 
C.2 Description of Baseline Variables 
Baseline demographic and clinical variables will be summarized for each of the treatment 
groups for the randomized, modified intent-to-treat (mITT), and implanted populations (as-
treated). All continuous variables will be summarized as means, medians, standard deviations 
and interquartile ranges and compared between treatment groups using a Bayesian analog of a 
two-sample t-test or the non-parametric Wilcoxon rank-sum test.  Categorical variables will be 
summarized as frequencies and percentages and compared between treatment groups using a 
Bayesian version of a comparison of proportions. 

 
 
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C.3 Analysis Populations 
 
Screening population 
C.3.1
All patients with symptomatic severe AS  that provide informed consent will be considered 
screened and all available data will be entered into the EDC system.  
 
Randomized population 
C.3.2
If the patient signs informed consent, meets all inclusion and none of the exclusion criteria, and 
Heart Team determines the patient is suitable for randomization in the trial, the patient is added 
to the randomized population once the treatment assignment is made. Within the randomized 
population three subpopulations are distinguished: 
 
The intention to treat (ITT) population, - Patients are reported according to the 
randomized assignment, SAVR or TAVI, regardless of what, if any, therapy was 
actually received.  
 
The modified intention to treat (mITT) population – Patients who undergo an attempted 
study treatment are reported according to the randomized assignment, SAVR or TAVI, 
regardless of what, if any, therapy was actually received.  A procedure attempt is 
defined as when the subject is brought into the procedure room and any of the 
following have occurred: anesthesia administered, vascular line placed, TEE placed or 
any monitoring line placed. 
 
The implanted population: This population includes the mITT patients who are actually 
implanted with either the CoreValve device or a surgical valve.  Depending on context, 
subjects may be analyzed according to randomized treatment assignment or treatment 
actually received. 
The primary objective and most secondary objectives will be evaluated using the mITT 
population. 
C.4 Primary analysis 
The primary endpoint of all-cause mortality or major stroke at 24 months will be evaluated using 
the relative risk of the TAVI rate and the SAVR rate for all-cause mortality or major stroke 
during a fixed follow-up of 24 months’ time. The hypothesis test is designed to show non-
inferiority of TAVI to SAVR for the primary endpoint.  
 
Hypothesis of non-inferiority 
C.4.1
The primary objective is to establish that TAVI is non-inferior to SAVR for the primary endpoint.  
The hypothesis of interest is: 
H: πT / πc < 1 + δ 
where πT and πC denote binary rates of all-cause mortality or major stroke during a fixed follow-
up of 24 months for the treatment (TAVI) and control (SAVR) groups, for a population with an 
STS score in the range 4-10.  This study is designed using Bayesian statistical techniques.  
TAVI will be declared to be non-inferior to SAVR if it can be established that the posterior 
probability Pr(Hδ=0.20 | data) > Ψ, where Ψ is a pre-specified threshold value.  If, in addition, it 
can be shown that Pr(Hδ=0 | data) > Ψ, TAVI will be declared to be superior to SAVR.  The value 
chosen for Ψ is described below. 
 
 
Randomization, Sample Size, and Analysis Plan 
C.4.2
Randomization will follow a 1:1 (treatment:control) allocation ratio and be stratified by site and 
need for revascularization, using a blocked randomization scheme with blocks of randomly 
varying sizes.  This study is designed to adaptively determine the proper sample size.  Possible 
sample sizes are 1000, 1500, 2000, 2500, 3000, and 3700 (maximum).  Once the final sample 

 
 
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size has been determined, an interim analysis (timed to occur 12 months later) will be 
conducted for the purpose of possibly passing the primary objective early.  If the criterion for 
passing the primary objective is not met at that time, follow-up will continue until all subjects 
have reached 24 months, and a final analysis will occur. 
C.4.2.1 
Determination of Sample Size 
The sample size is guided by a standard frequentist non-inferiority power analysis.  Under the 
assumptions of πT = πC = 0.25, δ=0.2, 1:1 randomization, α= 0.05, and power = 80%, the 
method of Farrington and Manning1 as implemented in PASS 20052 indicates that the required 
sample size for a single-look analysis is 2240. To allow for up to 6% dropout, 2383 subjects 
must be accrued.  Furthermore, to compensate for power lost in a two-look group sequential 
analysis plan using Pocock-type alpha spending, the sample size would have to be increased 
by about 12.5%3,4.  This leads to an estimated sample size of 2680.   
The assumed values πT = πC = 0.25 are based on the PARTNER Cohort A results5, the Kaplan-
Meier estimate at one-year follow-up for SAVR was 28.0%. This trial however had a higher-risk 
population than SURTAVI. Therefore, the PARTNER A rate is adjusted downwards and a two-
year follow-up period instead of a one-year follow-up period is used. The resulting 25% should 
be a conservative estimation of the 24 month SURTAVI rate.  Uncertainty in these event rates 
motivates the use of a design where the sample size can be determined adaptively.  If πT = πC = 
0.30, calculations similar to the above yield a required sample size of 2088; while if πT = πC = 
0.20, a size of 3574 is required.  Of course, if πT ≠ πC, more or fewer subjects may be required.   
This uncertainty motivates an adaptive design with possible sample sizes of 1000, 1500, 2000, 
2500, 3000, 3700.  It is intended that the design will achieve at least 80% power for πT = πC = 
0.25 and πT = πC = 0.30 and at least 75% power for πT = πC = 0.20, while allowing early stopping 
of subject accrual (for either evidence of efficacy or futility) and an interim analysis for a 
possible "early win."   
This study is designed using Bayesian statistical techniques.  The sample size determination 
algorithm is as follows.  At a pre-defined analysis time (e.g., when N=Ni subjects have been 
accrued;  Ni = 1000, 1500, 2000, 2500, or 3000), two predictive probabilities are calculated: 
• 
PPwin = Pr(Eventual Win | Data, N=Ni is the final sample size) 
• 
PPfut = Pr(Eventual Win | Data, N=3700 is the final sample size) 
If PPwin exceeds a suitably high threshold Wi, subject accrual will stop because final success 
looks probable.  On the other hand, if PPfut is less than a suitably low threshold Fi, subject 
accrual will stop and futility will be declared.  If neither of these conditions obtains, enrollment 
will continue to the next larger sample size.  These analyses are termed "Sample Size Looks."  
Thresholds Wi and Fi are listed in Table 1.  Further detail on the calculation of these predictive 
probabilities is given in Section A.1.5 Predictions. 
                                                     
 
1 Farrington, C. P. and Manning, G. 1990. 'Test Statistics and Sample Size Formulae for Comparative Binomial Trials with 
Null 
2 Hintze, J. (2004). NCSS and PASS, Number Cruncher Statistical Systems. Kaysville UT. www.ncss.com 
3 Hintze, J. (2004). NCSS and PASS, Number Cruncher Statistical Systems. Kaysville UT. www.ncss.com 
4 Jennison C and Turnbull BW, Group Sequential Methods with Applications to Clinical Trials.  Boca Raton:  Chapman & 
Hall, 2000, p 27 
5 Smith C, etal for PARTNER Trial Investigators, Transcatheter versus Surgical Aortic-Valve Replacement in High-Risk 
Patients, N Engl J Med 2011; 364:2187-98 

 
 
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Table 1:  Thresholds for stopping enrollment for reasons of futility or probable eventual 
success for each of the 5 interim sample size determination analyses 
Sample Size 
Determination 
Analysis 
(i) 
Sample Size  
 
 
(Ni) 
Threshold for  
Stopping for Futility 
(Fi) 
Threshold for Stopping 
for Likely Future Win 
(Wi) 
1 
1000 
0.05 
0.85 
2 
1500 
0.05 
0.85 
3 
2000 
0.10 
0.85 
4 
2500 
0.10 
0.85 
5 
3000 
0.10 
0.85 
Once subject accrual has stopped, an interim analysis (timed to occur 12 months after the last 
subject is accrued) for the purpose of declaring an early win will occur.  At this analysis, If 
P(Hδ=0.20 | data) > Ψ, non-inferiority will be declared at this time, and a regulatory submission 
will follow.  On the other hand, if P(Hδ=0.20 | data) ≤ Ψ, all subjects will be followed to 24 months, 
when a final analysis will occur.  At the final analysis, the standard for trial success will again be 
P(Hδ=0.20 | data) > Ψ.  These two analyses are termed "Win Looks." 
If, at the first (interim) "Win Look," non-inferiority is established, a test of superiority will 
immediately follow.  If P(Hδ=0 | data) > Ψ, superiority will be claimed at this time.  However, if 
P(Hδ=0 | data) ≤ Ψ, subjects will continue to be followed and analyzed according to the same 
analysis plan.  At the final "Win" analysis, if P(Hδ=0 | data) > Ψ, a delayed determination of 
superiority will be claimed.   
The statistical approach for these analyses is Bayesian. The prior distributions for πT and πC in 
these calculations are Beta(1,1).  The threshold Ψ is designated to be 0.972; this value is 
selected by trial-and-error to achieve a type I error (under simulation) of at most 0.05.  
C.5 Predictions 
Outcomes at 24-month are binary and are denoted "E" (for having experienced an Event) or "N" 
(for not having experienced an event).  Predicted values of 24-month outcomes for those 
subjects who have not yet yielded 24-month outcomes will be based on intermediate outcomes 
observed at 1 month, 6 months, 12 months, and 18 months.  These intermediate outcomes are:   
• 
"E" -- subject has had a known primary event (death or major stroke) at the time point 
in question 
• 
"P" -- subject is known to have had a "possible primary event" at the time point in 
question.  "Possible primary events" are adverse events that may later be determined 
to be Major Strokes.  This determination takes 90 days, by definition.  For example, a 
subject may have a stroke at month 5 which cannot be known to be a Major Stroke 
until Month 8.  At Month 6, such a subject is in the "P" state.   
• 
"N" -- subject has not had a primary event or a "possible primary event" at the time 
point in question. 
Subjects without 24-month outcome data will thus be considered to be in one of 26 states (13 
for each treatment group).  The 13 states are: 
• 
no interim data 
• 
E or P or N at 1 month, no subsequent data 
• 
E or P or N at 6 months, no subsequent data 
• 
E or P or N at 12 months, no subsequent data 
• 
E or P or N at 18 months, no subsequent data 
Subjects in the "E" state at an interim analysis can be imputed to be "E" at 24 months, with 
certainty.  For each of the remaining 18 states (9 for each treatment group), the probability of 
becoming an "E" at 24 months is modeled via a Beta(a,b) prior distribution which is updated to 

 
 
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a Beta(a+X, b+Y) distribution, based on the number X and Y of subjects who went on from that 
state to become 24-month "E" and "N" subjects, respectively.  For example, if, in the treatment 
group at an interim analysis time point, it is known that 10 of 30 subjects had previously gone 
from the "N at 18 months" state to the "E at 24 months" state, then the transition probability 
from the 18-month "N" state to the 24-month "E" state will be modeled as Beta(a+10, b+20).  At 
an interim analysis time point, any treatment-group subjects residing in the "N-at-18-month-but-
without-24-month-data" state will have their 24-month outcome predicted on the basis of this 
Beta(a+10, b+20) distribution.  Similar statements can be made about each of the possible 
transitions.  As data are accrued in this study, the Beta distributions used for prediction are 
updated accordingly.  Figure 1 graphically depicts the various possible states and transitions 
from them to the final state, for a generic treatment group.   For clarity, the lines connecting the 
interim "E" state to the 24-month "E" state have been omitted.  The numerical example above 
would apply to transition #9 in the Figure 1. 
Figure 1 Graphical depiction of transitions from interim states (E = Event, P = Possible 
Event, N = No Event, Start) to 24-month outcome.  Each transition is assigned 
a separate Beta(a,b) prior distribution which is updated as data are gathered.   
 
By predicting 24-month outcomes for each of these states, and combining with the data from 
subjects with known 24-month outcomes, a posterior probability of non-inferiority is 
calculated; it is based on observed 24-month data and also a predictive model that employs 
interim outcomes and the relationship between those interim outcomes and their corresponding 
final outcomes that is learned during the current trial.  This is accomplished in Monte Carlo 
fashion.  With any one imputation of incomplete data, we calculate the posterior probability 
Pr(Hδ=δ* | Observed 24-month Data, Imputed 24-month Data), and store it.  By iterating this 
process and averaging these posterior probabilities, we are essentially integrating them over 
the predictive distribution of imputed data.  This resulting quantity we have denoted as Pr(Hδ=δ* | 
Data).  The model is very similar to that employed in Lipscomb et al.6   The chief differences 
are that this model incorporates interim outcomes at other time points (e.g., 1 month, 6 months,  
                                                     
 
6  Lipscomb B, Ma G, Berry D, “Bayesian predictions of final outcomes: regulatory approval of a spinal 
implant,”  Clinical Trials, Vol. 2, No. 4, 325-333 (2005) 
E = Event 
P = Possible Event 
N = No Event 
Start 
1 
Month 
6 
Month 
12 
Month 
18 
Month 
24 
Month 
E 
P 
N 
E 
P 
N 
E 
P 
N 
E 
P 
N 
E 
N 
 
 
 
 
 
 
 
 
 
#1 
#2 
#3 
#7 
#9 
#4 
#6 
#8 
#5 

 
 
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18 months rather than just 12 months), and the model also considers trichotomous rather than 
dichotomous interim states.  
The predictive probability of eventual trial success can be calculated in a similar manner.  
With any one imputation of incomplete data, we calculate the posterior probability Pr(Hδ=δ* | 
Observed 24-month Data, Imputed 24-month Data) and record whether this value exceeds the 
threshold Ψ.  By iterating this process and reporting the proportion of times that Ψ is exceeded, 
we obtain an estimate of the predictive probability of eventual trial success (meaning a trial that 
results in a conclusion of non-inferiority).  
In this trial, predictive probabilities of eventual success are used in the determination of sample 
size (i.e., analyses in the adaptive portion of the trial, or “Sample Size Looks”).  Posterior 
probabilities are used for the determination of non-inferiority (i.e., analyses in the evaluation 
portion of the trial, or “Win Looks”). 
 
Prior Distributions for Transition Probabilities 
C.5.1
The transitions of Figure 1 are assigned individual Beta(a,b) prior distributions.  For “sample 
size looks,” the values of a and b are tabulated in Table 2 and graphically depicted in Figure 2 
(for the treatment group) and Figure 3 (for the control group).  These values represent the trial 
sponsor’s knowledge and belief about the relationship of the various interim states to the final 
state.  At the times when sample size decisions must be made, the number of subjects who 
have completed 24 months (and thus provide information on the transition probabilities) will 
generally be insufficient to make good sample size decisions without including some additional 
information.  Therefore, in all Sample Size Looks, the transitions are given informative priors, as 
tabulated in Table 2.  However, for all Win Looks, only flat priors (a = b = 1) for the transitions 
will be used. 
Table 2.  Parameters for Prior Distributions of the Transition Probabilities used in the 
determination of sample size.  For all "Win" analyses, a and b are set to 1. 
 
Treatment Group 
Control Group 
a 
b 
a 
b 
Transition #1 (Start to E24) 
21.117 
61.695 
21.117 
61.695 
Transition #2 (P1 to E24) 
32.699 
28.496 
30.703 
25.998 
Transition #3 (N1 to E24) 
22.633 
91.792 
21.206 
83.650 
Transition #4 (P6 to E24) 
33.675 
32.662 
31.623 
29.835 
Transition #5 (N6 to E24) 
23.027 
129.623 
21.583 
118.269 
Transition #6 (P12 to E24) 
34.933 
37.780 
32.827 
34.574 
Transition #7 (N12 to E24) 
23.853 
212.300 
22.370 
194.040 
Transition #8 (P18 to E24) 
46.744 
50.190 
44.237 
46.438 
Transition #9 (N18 to E24) 
26.346 
528.664 
24.725 
484.423 

 
 
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Figure 2:  Prior Distributions of the Transition Probabilities used in the determination of 
sample size (Treatment Group) 
 
Figure 3:  Prior Distributions of the Transition Probabilities used in the determination of 
sample size (Control Group) 
 
0.0
0.2
0.4
0.6
0.8
1.0
Transition 1: No D
 Beta( 21.117 ,  61.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 2: P1 to
 Beta( 32.699 ,  28.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 3: N1 to
 Beta( 22.633 ,  91
0.0
0.2
0.4
0.6
0.8
1.0
Transition 4: P6 to
 Beta( 33.675 ,  32.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 5: N6 to
 Beta( 23.027 ,  129
0.0
0.2
0.4
0.6
0.8
1.0
Transition 6: P12 t
 Beta( 34.933 ,  37
0.0
0.2
0.4
0.6
0.8
1.0
Transition 7: N12 t
 Beta( 23.853 ,  212
0.0
0.2
0.4
0.6
0.8
1.0
Transition 8: P18 t
 Beta( 46.744 ,  50.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 9: N18 t
 Beta( 26.346 ,  52
Treatment Group
0.0
0.2
0.4
0.6
0.8
1.0
Transition 1: No D
 Beta( 21.117 ,  61.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 2: P1 to
 Beta( 30.703 ,  25.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 3: N1 to
 Beta( 21.206 ,  83.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 4: P6 to
 Beta( 31.623 ,  29.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 5: N6 to
 Beta( 21.583 ,  118
0.0
0.2
0.4
0.6
0.8
1.0
Transition 6: P12 t
 Beta( 32.827 ,  34.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 7: N12 t
 Beta( 22.37 ,  194.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 8: P18 t
 Beta( 44.237 ,  46.
0.0
0.2
0.4
0.6
0.8
1.0
Transition 9: N18 t
 Beta( 24.725 ,  484
Control Group

 
 
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C.6 Operating Characteristics 
The design described above has been subjected to intensive simulations in order to evaluate its 
anticipated performance in practice.  In the simulation, the proportion of simulated trials that 
result in a declaration of non-inferiority is the estimated power when πT / πC < 1.2 and the 
estimated type I error rate when πT / πC ≥ 1.2.     The estimated operating characteristics are 
based on 10000 simulated trials per scenario, with predictions (for each transition at each 
interim analysis of each of the 10000 trials) based on 5000 draws from the relevant transition 
probability distribution.   
Table 3 displays the operating characteristics and summarizes the performance of the adaptive 
sample size determination algorithm under various assumed values of πC and πT/πC.  The 
column “Overall Power” is the proportion of trials that resulted in a declaration of non-inferiority 
(NI).  The column "Early Win, Late Win" indicates at which of the two "win analyses" the "win" 
occurred;  i.e., a trial that passed the primary objective at the interim "win" analysis would 
appear as an "Early Win" in the upper number, while a trial that did not pass until the final 
analysis would appear in the lower number as a "late win."  The column “Average N” shows the 
average sample size attained for that row.  The probability of attaining any of the allowed 
sample sizes (1000, 1500, 2000, 2500, 3000, 3700) is then displayed;  the upper number 
indicates the proportion that stopped at that size because the results were promising, while the 
lower number indicates the proportion that stopped at that size for futility.  The last column 
shows the proportion of trials that went to the maximum sample size of 3700.   
Table 3: Operating characteristics of the design when πC = 0.25, from a simulation of 
10,000 simulated trials per line.  Interpretations of column headings are given in 
the narrative  
πC = 0.25 
Probability of Achieving Sample Size N 
πT/πC 
Power 
Early 
Win, 
Late 
Win 
Average 
N 
N=1000 
(Promise, 
Futile) 
N=1500 
(Promise, 
Futile) 
N=2000 
(Promise, 
Futile) 
N=2500 
(Promise, 
Futile) 
N=3000 
(Promise, 
Futile) 
N=3700 
1.3 
0.001 
0.001 
2854.9 
0.000 
0.000 
0.001 
0.004 
0.002 
0.147 
0.000 
0.000 
0.000 
0.004 
0.483 
0.360 
1.2 
0.041 
0.031 
3112.3 
0.000 
0.000 
0.008 
0.031 
0.019 
0.379 
0.010 
0.000 
0.000 
0.001 
0.256 
0.306 
1.1 
0.373 
0.307 
3205.2 
0.000 
0.004 
0.040 
0.127 
0.089 
0.517 
0.066 
0.000 
0.000 
0.000 
0.093 
0.129 
1.0 
0.858 
0.781 
2917.7 
0.001 
0.021 
0.146 
0.259 
0.180 
0.342 
0.077 
0.000 
0.000 
0.000 
0.025 
0.026 
0.9 
0.989 
0.965 
2446.4 
0.004 
0.080 
0.331 
0.323 
0.156 
0.099 
0.024 
0.000 
0.000 
0.000 
0.004 
0.002 
In Table 3, the type I error rate (when πT/πC = 1.2) is 0.041.  In this scenario, the trial went to its 
maximum size of N=3700 37.9% of the time, often stopping enrollment sooner for futility (0.001 
+ 0.256 + 0.306 = 0.563), and only rarely stopping enrollment early for promising trend (0.008 + 
0.031 + 0.019 = 0.058).  Those trials that either stopped early for promising trend or went to the 
maximum of 3700 were tested for an "early win" twelve months after enrollment stop, with 3.1% 
(of the 10,000) winning early and an additional 1.0% winning at the final analysis (for a total 
type 1 error rate of 0.041).  When πT/πC = 1.0, the estimated power is 85.8%; the trial stopped 
enrolling for promising trend at N=2000 14.6% percent of the time, at N=2500 25.9% of the 
time, and at N=3000 18% of the time;  the maximum of N=3700 occurred 34.2% of the time.   
The proportion of trials that passed at the interim "win" analysis was 78.1%, while an additional 
7.7% passed the primary objective at the final "win" analysis.  The average of the sample sizes 
(across the 10,000 simulated trials) was 2917.7 subjects. 
C.7 Simulation Details and Design Sensitivity 
In order to generate data for the operating characteristics simulations described above, several 
additional assumptions about the data mechanism had to be made.  These assumptions are 

 
 
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intrinsic to the generation of artificial data in the simulation exercise but are not part of the 
analysis that is conducted on any data (real or simulated).  This section describes these 
assumptions and also the sensitivity of the design to these assumptions. 
 
LTFU/Data Missingness 
C.7.1
Simulations were conducted under the assumption of 6% missingness over the 24-month study 
period.  With each simulated trial, each subject was designated to be "lost" with probability 
0.06; thus the exact number of subjects lost from one simulated trial to the next varied, though it 
was always approximately 6%.  Furthermore, those subjects designated to "drop" were 
assumed to have dropped out uniformly in time, so that each of these subjects was dropped by 
18 months with probability 18/24, each of those was in turn dropped by 12 months with 
probability 12/18, and so on.  Marginally, the probability of being lost at 12 months was thus 
0.06 × 18/24 × 12/18  = 0.03, and similar statements can be made about each time point.  
Dropout was thus uniform in time over the 24-month study period.  Artificial patients, once lost, 
did not return to the analysis for subsequent visits. 
 
Control Arm Event Rate 
C.7.2
A stated assumption made in the operating characteristics as displayed in Table 3 is that the 
control arm event rate is πC = 0.25.  Alternative scenarios were simulated in which the control 
arm event rate was instead 30% and 20%.  The results of these simulations are provided below 
in Table 4.  It is evident that the type I error is < 0.05.  Power is > 95% when πT/πC = 1.0 and πC = 
0.30 and > 75% when πT/πC = 1.0 and πC = 0.20.  Average sample size is smaller when πC = 0.30. 
Table 4:  Operating characteristics of the design under differing control arm event rate 
assumptions.  10,000 simulated trials per line, with predictions based on 5000 
imputations. Column interpretations are the same as in Table 3 
πC = 0.30 
Probability of Achieving Sample Size N 
πT/πC 
Power 
Early 
Win, 
Late 
Win 
Average 
N 
N=1000 
(Promise, 
Futile) 
N=1500 
(Promise, 
Futile) 
N=2000 
(Promise, 
Futile) 
N=2500 
(Promise, 
Futile) 
N=3000 
(Promise, 
Futile) 
N=3700 
1.3 
0.001 
0.001 
2809.9 
0.000 
0.000 
0.001 
0.004 
0.001 
0.120 
0.000 
0.000 
0.000 
0.009 
0.525 
0.341 
1.2 
0.040 
0.032 
3106.2 
0.000 
0.000 
0.009 
0.026 
0.019 
0.378 
0.008 
0.000 
0.000 
0.002 
0.268 
0.298 
1.1 
0.443 
0.368 
3170.1 
0.001 
0.005 
0.054 
0.143 
0.104 
0.497 
0.075 
0.000 
0.000 
0.000 
0.086 
0.110 
1.0 
0.915 
0.852 
2763.0 
0.004 
0.039 
0.196 
0.292 
0.181 
0.256 
0.063 
0.000 
0.000 
0.000 
0.016 
0.016 
0.9 
0.997 
0.972 
2249.5 
0.013 
0.147 
0.391 
0.294 
0.106 
0.048 
0.025 
0.000 
0.000 
0.000 
0.002 
0.001 
πC = 0.20 
Probability of Achieving Sample Size N 
πT/C 
Power 
Early 
Win, 
Late 
Win 
Average 
N 
N=1000 
(Promise, 
Futile) 
N=1500 
(Promise, 
Futile) 
N=2000 
(Promise, 
Futile) 
N=2500 
(Promise, 
Futile) 
N=3000 
(Promise, 
Futile) 
N=3700 
1.3 
0.002 
0.001 
2913.4 
0.000 
0.000 
0.001 
0.005 
0.003 
0.185 
0.000 
0.000 
0.000 
0.001 
0.422 
0.382 
1.2 
0.039 
0.032 
3141.4 
0.000 
0.000 
0.007 
0.030 
0.017 
0.402 
0.007 
0.000 
0.000 
0.000 
0.234 
0.309 
1.1 
0.308 
0.251 
3250.4 
0.000 
0.002 
0.031 
0.098 
0.074 
0.544 
0.057 
0.000 
0.000 
0.000 
0.097 
0.154 
1.0 
0.769 
0.685 
3056.8 
0.000 
0.007 
0.104 
0.222 
0.164 
0.428 
0.084 
0.000 
0.000 
0.000 
0.033 
0.041 
0.9 
0.972 
0.934 
2678.8 
0.000 
0.032 
0.236 
0.334 
0.191 
0.193 
0.039 
0.000 
0.000 
0.000 
0.007 
0.006 

 
 
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Rate of Enrollment 
C.7.3
The speed at which subjects are recruited into the trial is another important assumption 
embedded within the simulations to determine operating characteristics.  It is anticipated that 
this study will enroll approximately 100 subjects per month, after a ramp-up period of about 12 
months.  Specifically, the monthly accrual in the simulation is 8, 16, 24, 32, 40, 48, 56, 64, 72, 
80, 88, 100 for the first 12 months, and 100/month thereafter until accrual is complete.  This is 
the accrual rate used in the generation of Table 3 and Table 4.  Table 5 illustrates how the 
study design performs if enrollment is faster or slower than this expectation. 
The slow speed assumes that 50 subjects are accrued per month and that the ramp-up period 
takes 15 months.  (Monthly accrual = 3, 6, 9, 12, 15, 18, 22, 25, 28, 31, 34, 38, 42, 46, 50 for 
the first 15 months, and 50/month thereafter.)  The fast speed assumes 120 subjects are 
accrued per month and ramp-up is completed in only 8 months (15, 30, 45, 60, 75, 90, 105, 
120, and 120/month thereafter).  
The results in Table 5 demonstrate that type I error is controlled at < 0.05 as the rate of 
enrollment varies.  Power is in the range 84% - 89% for the cases where πT/πC = 1.0, though it is 
evident that sample size tends to be much smaller when the enrollment is slow.   
Table 5: Operating charactersistics of the design under differing assumptions about 
accrual rate.  10,000 simulated trials per line, with predictions based on 5000 
imputations. Column meanings are the same as in Table 3 
πC = 0.25, Slow Enrollment 
Probability of Achieving Sample Size N 
πT/πC 
Power 
Early 
Win, 
Late 
Win 
Average 
N 
N=1000 
(Promise, 
Futile) 
N=1500 
(Promise, 
Futile) 
N=2000 
(Promise, 
Futile) 
N=2500 
(Promise, 
Futile) 
N=3000 
(Promise, 
Futile) 
N=370
0 
1.3 
0.002 
0.001 
2026.2 
0.001 
0.002 
0.001 
0.000 
0.000 
0.024 
0.000 
0.000 
0.275 
0.501 
0.144 
0.052 
1.2 
0.045 
0.038 
2439.8 
0.004 
0.017 
0.013 
0.006 
0.005 
0.165 
0.007 
0.000 
0.116 
0.353 
0.198 
0.122 
1.1 
0.373 
0.334 
2765.4 
0.014 
0.077 
0.070 
0.061 
0.053 
0.366 
0.039 
0.000 
0.040 
0.138 
0.098 
0.083 
1.0 
0.845 
0.803 
2399.8 
0.050 
0.224 
0.192 
0.145 
0.105 
0.216 
0.042 
0.000 
0.010 
0.026 
0.019 
0.013 
0.9 
0.984 
0.963 
1800.0 
0.134 
0.433 
0.242 
0.108 
0.049 
0.028 
0.021 
0.000 
0.001 
0.002 
0.001 
0.000 
πC = 0.25, Fast Enrollment 
Probability of Achieving Sample Size N 
πT/πC 
Power 
Early 
Win, 
Late 
Win 
Average 
N 
N=1000 
(Promise, 
Futile) 
N=1500 
(Promise, 
Futile) 
N=2000 
(Promise, 
Futile) 
N=2500 
(Promise, 
Futile) 
N=3000 
(Promise, 
Futile) 
N=370
0 
1.3 
0.001 
0.000 
3291.2 
0.000 
0.000 
0.000 
0.000 
0.006 
0.417 
0.000 
0.000 
0.000 
0.000 
0.001 
0.576 
1.2 
0.042 
0.032 
3457.0 
0.000 
0.000 
0.001 
0.005 
0.041 
0.659 
0.009 
0.000 
0.000 
0.000 
0.000 
0.294 
1.1 
0.384 
0.305 
3469.7 
0.000 
0.001 
0.008 
0.034 
0.146 
0.709 
0.079 
0.000 
0.000 
0.000 
0.000 
0.102 
1.0 
0.888 
0.803 
3169.0 
0.000 
0.009 
0.052 
0.167 
0.294 
0.454 
0.086 
0.000 
0.000 
0.000 
0.000 
0.024 
0.9 
0.994 
0.964 
2725.5 
0.001 
0.033 
0.184 
0.328 
0.272 
0.179 
0.030 
0.000 
0.000 
0.000 
0.000 
0.003 
 
Temporal Correlation 
C.7.4
For simulation, patient-level data with realistic temporal correlation had to be generated.  For 
each treatment group, a "skeleton" of probabilities for the various state transitions was 
constructed, as shown below in Table 6.   For example, a subject in the Treatment group could 

 
 
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become an "E" at 1 month with probability 0.05, a "P" at 1 month with probability 0.06, and an 
"N" at 1 month with probability 1 –  0.05 – 0.06 = 0.89.  If a subject is "E" at 1 month (denoted 
"E1" in the table), that subject becomes an "E" at 6 months with probability 1 (since subjects 
who have had an event by 1 month necessarily will have had that event by 6 months.  If a 
subject is "P" at 1 month, that subject becomes an "E" at 6 months with probability 0.45, a "P" 
at 6 months with probability 0.05, and an N at 6 months with probability 0.50. Taken as a whole, 
the treatment "skeleton" of probabilities implies a 24-month marginal event rate of 26.9%, while 
the control "skeleton" of probabilities implies a 24-month marginal event rate of 26.3%; the 
serial correlation implied by the skeleton is the sponsor's best estimate of what will actually 
occur in the trial.  (Shaded cells in the table are uniquely determined by the immediately 
preceding cells, a consequence of the fact that probabilities conditioned on the same event 
must sum to one.)   
Table 6:  Probability "Skeletons" for State Transitions used in Generating Temporally 
Correlated Data 
State 
Transition  
Probability 
State 
Transition  
Probability 
Treatment 
Group 
Control 
Group 
Treatment 
Group 
Control 
Group 
Start → E1 
0.05 
0.06 
N6 → E12 
0.05 
0.05 
Start → P1 
0.06 
0.02 
N6 → P12 
0.02 
0.02 
Start → N1 
0.89 
0.92 
N6 → N12 
0.93 
0.93 
E1 → E6 
1.00 
1.00 
E12 → E18 
1.00 
1.00 
P1 → E6 
0.45 
0.45 
P12 → E18 
0.45 
0.45 
P1 → P6 
0.05 
0.05 
P12 → P18  
0.05 
0.05 
P1 → N6 
0.50 
0.50 
P12 → N18 
0.50 
0.50 
N1 → E6 
0.05 
0.05 
N12 → E18 
0.05 
0.05 
N1 → P6 
0.02 
0.02 
N12 → P18 
0.02 
0.02 
N1 → N6 
0.93 
0.93 
N12 → N18 
0.93 
0.93 
E6 → E12 
1.00 
1.00 
E18 → E24 
1.00 
1.00 
P6 → E12  
0.45 
0.45 
P18 → E24 
0.50 
0.50 
P6 → P12 
0.05 
0.05 
P18 → N24 
0.50 
0.50 
P6 → N12  
0.50 
0.50 
N18 → E24 
0.05 
0.05 
N18 → N24 
0.95 
0.95 
In the course of simulating multiple data scenarios, it is necessary to generate data with specific 
24-month target event rates for both the Treatment and Control groups.  To do this, the 
"skeleton" values of Table 6 are adjusted as follows.  First, the probabilities in all unshaded 
cells that are not already 1.00 by construction are transformed to the logit scale; then a 
common value ε is added to each logit-transformed probability before transforming the sum 
back to the probability scale.  By algebraically expressing the 24-month event rate in terms of 
the foregoing modified skeletal probabilities and subsequently solving for ε, a suitable 
adjustment to the skeletal state transition probabilities is found that sets the 24-month event 
rate equal to the desired target value π (e.g., π = 0.25) while approximately maintaining the 
serial correlation of the original skeleton.  This is accomplished separately for the two treatment 
groups. 
This mechanism of generating temporally correlated data represents the sponsor's best 
knowledge and belief about the data that will actually arise in the prospective clinical trial.  All 
operating characteristics in Table 3, Table 4, and Table 5 are generated with this method.   
This mechanism only applies to the generation of artificial data in the simulation; it is not used 
at all in the analysis of data (real or simulated).  If this data generation model does not 
adequately reflect the true pattern of serial correlation, the analysis model will nonetheless be 
tasked with recognizing this and causing the design to respond appropriately.  In order to 
evaluate the robustness of the analysis model and sampling plan to the pattern of serial 
correlation, a simulation was conducted wherein the study design was presented with data 

 
 
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simulated at the extremes of complete temporal correlation and complete temporal 
independence. 
"Complete Temporal Correlation" is a scenario in which knowing the 1-month outcome for a 
subject is the same as knowing the 24-month outcome.  This is accomplished by setting all 
interim outcomes (e.g., 1-month, 6-month, etc.) to be equal to the 24-month "E" or "N" 
outcomes (except for those patients lost to follow-up in the simulation).  The study design is 
expected to react appropriately and much sooner when presented with this pattern of data.  
"Complete Temporal Independence" is a scenario where knowing the interim outcomes for a 
subject gives no information about what that subject will be at 24 months.  To accomplish this, 
no patient can be an "E" prior to 24 months (else there would be serial correlation), and subject 
outcomes at interim time points are set to be "P" or "N" with probability P(E24), independently 
at each time point.  
Table 7 displays operating characteristics generated under the Complete Temporal Correlation 
and Complete Temporal Independence patterns.   As expected, the design reacts quicker (i.e., 
with smaller sample size) when the data are completely correlated.  While neither scenario is 
particularly realistic, it is important that the observed Type I errors are < 0.05 in both cases. 
Table 7: Operating charactersistics of the design under alternative assumptions about 
temporal correlation.  10,000 simulated trials per line, with predictions based on 
5000 imputations. Column meanings are the same as in Table 2 
Complete Temporal Correlation 
πC = 0.25, Expected Enrollment 
Rate 
Probability of Achieving Sample Size N 
πT/πC 
Power 
Early 
Win, 
Late 
Win 
Average 
N 
N=1000 
(Promise, 
Futile) 
N=1500 
(Promise, 
Futile) 
N=2000 
(Promise, 
Futile) 
N=2500 
(Promise, 
Futile) 
N=3000 
(Promise, 
Futile) 
N=3700 
1.3 
0.002 
0.002 
2723.8 
0.001 
0.000 
0.001 
0.000 
0.000 
0.048 
0.000 
0.000 
0.000 
0.008 
0.598 
0.343 
1.2 
0.046 
0.044 
3040.2 
0.006 
0.009 
0.013 
0.006 
0.004 
0.307 
0.002 
0.000 
0.000 
0.001 
0.267 
0.388 
1.1 
0.401 
0.391 
3052.9 
0.040 
0.071 
0.076 
0.051 
0.051 
0.524 
0.010 
0.000 
0.000 
0.000 
0.052 
0.136 
1.0 
0.895 
0.872 
2226.3 
0.162 
0.225 
0.194 
0.115 
0.084 
0.203 
0.023 
0.000 
0.000 
0.000 
0.004 
0.012 
0.9 
0.996 
0.966 
1485.8 
0.416 
0.344 
0.151 
0.052 
0.022 
0.015 
0.031 
0.000 
0.000 
0.000 
0.000 
0.000 
Complete Temporal 
Independence 
πC = 0.25, Expected Enrollment 
Rate 
Probability of Achieving Sample Size N 
πT/πC 
Power 
Early 
Win, 
Late 
Win 
Average 
N 
N=1000 
(Promise, 
Futile) 
N=1500 
(Promise, 
Futile) 
N=2000 
(Promise, 
Futile) 
N=2500 
(Promise, 
Futile) 
N=3000 
(Promise, 
Futile) 
N=3700 
1.3 
0.002 
0.002 
3012.9 
0.000 
0.000 
0.000 
0.021 
0.012 
0.277 
0.000 
0.000 
0.000 
0.001 
0.339 
0.350 
1.2 
0.047 
0.036 
3187.5 
0.000 
0.000 
0.004 
0.067 
0.048 
0.455 
0.011 
0.000 
0.000 
0.000 
0.188 
0.238 
1.1 
0.362 
0.251 
3201.1 
0.000 
0.000 
0.024 
0.167 
0.121 
0.498 
0.111 
0.000 
0.000 
0.000 
0.079 
0.111 
1.0 
0.818 
0.657 
2995.5 
0.000 
0.000 
0.093 
0.289 
0.197 
0.357 
0.161 
0.000 
0.000 
0.000 
0.031 
0.032 
0.9 
0.970 
0.867 
2621.9 
0.000 
0.011 
0.263 
0.385 
0.184 
0.142 
0.104 
0.000 
0.000 
0.000 
0.008 
0.006 

 
 
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Type I Errors 
C.7.5
To study all combinations of enrollment rate, control success rate, and serial correlation would 
require 3 × 3 × 3 = 27 tables similar to Table 3.  Rather than present all of these, Table 8 
provides a comprehensive summary of all type I error rates observed through repeated trial 
simulations under the varying conditions described above.  Each cell is based on 10,000 
simulated clinical trials, with predictions based on 5,000 draws from each of the predictive 
model transition distributions.  Under all scenarios, type I error is controlled.  There is no 
evidence that type I error exceeds 0.05.  Even the few scenarios with observed type I error 
greater than 0.05 (e.g., the maximum of 0.0527) could easily result from a simulation of size 
10,000 with underlying true rate = 0.05:  a 95% probability interval calculated as 0.05 ± 1.96 
√(0.05× 0.95 / 10000) would range from 0.0457 to 0.0543, so a value as high as 0.0527 is 
entirely expected and constitutes no evidence of a type I error inflation.   
Table 8:  Simulated Type I error rates given varied correlation structures, accrual rates, 
and control event rates.  10,000 simulated trials per line, with predictions based 
on 5,000 imputations 
 
Control Event Rate 
0.20 
0.25 
0.30 
Complete 
Temporal 
Correlation 
Enrollment Rate 
Slow 
0.0477 
0.0438 
0.0505 
Expected 
0.0412 
0.0486 
0.0516 
Fast 
0.0431 
0.0527 
0.0518 
Expected 
Temporal 
Correlation 
Slow 
0.0434 
0.0459 
0.0441 
Expected 
0.0414 
0.0413 
0.0418 
Fast 
0.0396 
0.0391 
0.0417 
Complete 
Temporal 
Independence 
Slow 
0.0474 
0.0473 
0.0478 
Expected 
0.0434 
0.0485 
0.0503 
Fast 
0.0505 
0.0483 
0.0456 
C.8 Missing Data and Planned Sensitivity Analyses (Primary Objective) 
Every effort will be undertaken to minimize missing data.  However, some missingness is 
inevitable, and the study is designed with the expectation that there may be up to 6% missing 
primary data at 24 months.   The reasons for missing data will be described in detail and 
evaluated for assessment of possible bias.  The distribution of prognostic factors between 
patients with data and those without data will be examined to evaluate any potential sources of 
bias.  
By design, the analysis of the primary objective (at both interim time points) will predict 24-
month outcomes for any subjects without measured 24-month outcomes, based on transitions 
from interim states and the experience of those who went on from those states to provide 
complete 24-month data.  This is true whether the missing 24-month outcomes are due to being 
enrolled later in the trial (as happens for many subjects at the interim "win" analyses) or some 
other cause, such as loss to follow-up (which will likely apply at both the interim and final "win" 
analyses).  Several additional analyses are planned to be conducted (at the conclusion of the 
trial) that will explore the sensitivity of the main conclusions to the predictions for subjects 
whose missing 24-month outcomes cannot be explained by simply being enrolled late (i.e., 
subjects who are known to be lost to follow-up or whose 24-month visit window has closed 
without a measured outcome).  In these analyses and for such subjects, 24-month outcomes 
will be imputed according to the model described below.  
As with the primary analysis, any such subject will be viewed as belonging to one of several 
interim states.  These are the same states used in the primary analysis (e.g., "E" or "P" or "N" 
at 6 months, etc.)  
For each of these states, the probability of becoming a composite success at 24 months will be 
modeled via a logistic formulation.  Based on the number of subjects who went on from that 
state to become 24-month "E" and "N" subjects, respectively, a logistic regression of the 
following form will be fit: 

 
 
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logit( p ) = β0 
where the parameter β0 will be assigned a vague N(0,102) distribution.  The posterior 
distribution for β0 will then be shifted by a biasing constant γ and will be back-transformed to the 
probability scale as: 
p* = logit–1(β0 + γ) 
The 24-month outcome for any subject belonging to this state but lost thereafter will be imputed 
based on this distribution of p*.  The case γ = 0 contains no bias and corresponds essentially to 
the primary analysis.   
By varying γ, the impact of a biasing influence on the study results can be examined.  The 
values γ = +∞ and γ = –∞ correspond to setting all such observations to be "E" or "N."  The 
impact of various values of γ (including +∞ and –∞) will be examined and presented in a 
sensitivity analysis, representing both positive and negative biases for the two groups.   
Further analyses will explore the sensitivity of efficacy to the imputation model.  Specifically, 
one analysis will present posterior probabilities of non-inferiority/superiority without the use of 
prediction (i.e., completers only).  Another will present the results of a tipping point analysis.   
C.9 Description of performed analysis, per population 
 
Analysis of screening population 
C.9.1
For the screening population only descriptive statistical analysis will be performed, on variables 
that are captured in the EDC system. 
 
Analysis of mITT population 
C.9.2
For the patients in the randomized population the primary analysis of the primary endpoint and 
inferential statistics for the following secondary endpoints will be performed on an m ITT basis: 
• 
Major adverse cardiovascular and cerebrovascular events (MACCE) 
• 
Individual MACCE components 
• 
Major adverse events (MAE)  
• 
Conduction disturbance requiring permanent pacemaker implantation 
• 
NYHA 
• 
Six-minute walk test 
• 
Ratio of days alive out of hospital versus total days alive 
• 
Quality of life 
• 
Echocardiographic assessment of valve performance  
• 
Aortic valve disease-related hospitalizations 
• 
Cardiovascular deaths and valve-related deaths 
• 
Strokes and TIAs 
• 
Peri-procedural neurological injury 
• 
Index procedure-related MAEs 
• 
Length of index procedure hospital stay 
• 
Device success 
• 
Procedure success 
 
Analysis of implanted population 
C.9.3
The implanted population will be used for analyzing the secondary endpoint of prosthetic valve 
dysfunction.  An additional analysis of the primary endpoint and of the secondary endpoint of 
echocardiographic assessment of valve performance will also be performed on the implanted 
population. 

 
 
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C.10 Secondary Endpoints 
The following secondary endpoints will be compared between MCS TAVI and SAVR subject 
cohorts using the appropriate Bayesian version of analysis for comparing proportions and 
continuous variables as described below: 
1. Incidence of Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  
MACCE is defined as a composite of: 
• 
All-cause death 
• 
Myocardial infarction (MI) 
• 
All stroke, and 
• 
Reintervention (defined as any cardiac surgery or percutaneous reintervention 
catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously 
implanted valve) 
MACCE-incidence estimates will be provided for the two treatment groups at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  The 
statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
Additionally, incidence of MACCE will be compared at 30 days or hosital disharge, whichever 
is later.  The statistical method will be the Bayesian version of a comparison of proportions. 
2. The occurrence of individual MACCE components at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
MACCE components will be summarized and their incidence estimates provided at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  The 
statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
3. Major Adverse Events (MAE) at 30 days, 6 months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years. 
MAE events will be summarized and the incidence of MAEs will be provided at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years The 
statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
4. Conduction disturbance requiring permanent pacemaker implantation at 30 days, 6 months, 
12 months, 18 months, 24 months, and annually thereafter up to 5 years. 
The incidence of conduction disturbance requiring permanent pacemaker implantation will be 
provided at 30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up 
to 5 years, separately for new onset and pre-existing conduction disturbance.  The statistical 
method will be the Bayesian version of a comparison of proportions (with predictions). 
5. Change in NYHA class from baseline at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
For each subject with paired data, the number of classes changed from baseline (-3, -2, -1, 0, 
1, 2, or 3) will be calculated at 30 days, 6 months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years. The endpoint will be evaluated using a Bayesian version of 
a t-test (or Wilcoxon test, as appropriate). 
6. Change in distance walked during 6-minute walk test (6MWT) from baseline to 30 days, 
baseline to 12 months, and baseline to 24 months. 
All subjects who are able to perform the six-minute walk evaluation; and those subjects who 
are unable to perform the walk evaluation due to heart failure symptoms at the time of the 
follow-up visit will be included in the analysis. 
The endpoint will be evaluated using a Bayesian version of a t-test (or Wilcoxon test, as 
appropriate). 

 
 
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7. Ratio of days alive out of hospital versus total days alive assessed at 12 months and 24 
months follow-up.  
The proportion of post randomization days alive out of hospital against total days alive will be 
compared between groups at 12 and 24 months.  The numerator will be the number of days 
alive out of hospital, and the denominator will be the number of days alive as of the follow-up 
visit date.  All hospitalizations will be included in this analysis, including hospitalization for 
device implant.   
The endpoint will be evaluated using a Bayesian version of a t-test (or Wilcoxon test, as 
appropriate). 
8. Quality of Life (QoL) change from baseline at 30 days, 3 months, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
The Kansas City Cardiomyopathy Questionnaire (KCCQ), SF-36, and EuroQoL will be 
assessed at baseline, 30 days, 6 months, 12 months, 18 months, 24 months, and annually 
thereafter up to 5 years.  SF-36 and EuroQoL will also be assessed at 3 months.  All subjects 
completing the questionnaires will be evaluated and the reasons for missing data will be 
provided. 
The endpoint will be evaluated using a Bayesian version of a t-test (or Wilcoxon test, as 
appropriate). 
9. Echocardiographic assessment of prosthetic valve performance at discharge, 6 months, 12 
months, 24 months, and annually thereafter up to 5 years using the following measures: 
• 
transvalvular mean gradient 
• 
effective orifice area 
• 
degree of prosthetic aortic valve regurgitation (transvalvular and paravalvular) 
The four echocardiographic measurements will be evaluated at discharge, 6 months, 12 
months, 24 months, and annually thereafter up to 5 years.  All randomized subjects 
undergoing echocardiography procedures will be evaluated.   
Continuous measures will be evaluated using a Bayesian version of a two-sample t-test or the 
Wilcoxon rank-sum test, as appropriate.  Categorical variables will be evaluated using 
Bayesian version of a comparison of polytomous outcomes.   
10. Aortic valve disease related hospitalizations  
The number of subjects re-hospitalized after the initial index procedure will be compared at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.   
Incidence of re-hospitalization will be provided at 30 days, 6 months, 12 months, 18 months, 
24 months, and annually thereafter up to 5 years.  The statistical method will be the Bayesian 
version of a comparison of proportions (with predictions).   
11. Cardiovascular deaths and valve-related deaths 
The number of cardiovascular deaths and valve-related deaths at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years.  Incidences will be 
compared between groups.  The statistical method will be the Bayesian version of a 
comparison of proportions (with predictions). 
12. Strokes and TIAs 
The number of subjects with strokes (of any severity) and TIAs at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years. A separate analysis will 
be performed for each of the following: 
• 
a composite of all strokes and TIAs 
• 
major strokes only 
• 
minor strokes only 
• 
TIAs only  

 
 
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The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
13. Peri-procedural Neurological Injury (Stroke, TIA, Encephalopathy) 
For each treatment group, the proportion of subjects with a neurologic injury (stroke, TIA, or 
encephalopathy) at discharge or at 7 days post-index procedure (whichever occurs first) will 
be calculated. The numerator will be the number of subjects with a neurologic injury (stroke, 
TIA, or encephalopathy) at discharge or at 7 days post-index procedure (whichever occurs 
first), and the denominator will be the number of subjects in that treatment group. Results will 
also be presented separately for major stroke, minor stroke, TIA, and encephalopathy.  
Proportions will be compared between groups using Bayesian version of a comparison of 
proportions. 
14. Index procedure related MAEs 
Index procedure-related MAE events will be summarized and event rates will be provided at 
30 days.  The numerator will be the number of procedure-related MAE events experienced by 
the end of the follow-up visit, and the denominator will be the number of subjects evaluated at 
the follow-up visit plus the number of subjects not evaluated but who experienced a 
procedure-related MAE event prior to the end of the follow-up visit window. 
The endpoint is descriptive and no statistical hypothesis test will be performed. 
15. Length of index procedure hospital stay 
The length of TAVI or SAVR hospital stay will be summarized for all subjects undergoing a 
study procedure. 
Descriptive statistics will be provided.  The endpoint is descriptive and no statistical 
hypothesis test will be performed. 
 
The following secondary endpoints will be assessed for the MCS TAVI cohort subjects only: 
16. Device success defined as follows: 
• 
successful vascular access, delivery and deployment of the device, and successful 
retrieval of the delivery system, 
• 
correct position of the device in the proper anatomical location (placement in the 
annulus with no impedance on device function), 
• 
Intended performance of the prosthetic valve (aortic valve area > 1.2 cm2 (by 
echocardiography using the continuity equation) and mean aortic valve gradient < 20 
mmHg or peak velocity < 3 m/sec, without moderate or severe prosthetic valve AR) 
o 
assessed acutely in a resting state, either within 24-48 hours after the index 
procedure or before hospital discharge 
• 
Only one valve implanted in the proper anatomical location 
Device success, as defined above, will be calculated for all subjects undergoing the TAVI 
procedure.   
The endpoint is descriptive and no statistical hypothesis test will be performed. 
17. Procedural success, defined as device success and absence of in-hospital MACCE. 
Procedure success, as defined above, will be calculated for all randomized subjects 
undergoing the TAVI procedure.   
The endpoint is descriptive and no statistical hypothesis test will be performed. 
18. Evidence of prosthetic valve dysfunction at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 

 
 
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The number of subjects with evidence of prosthetic valve dysfunction will be evaluated at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.   
Point estimates and 95% BCIs for each time point will be presented using methods described 
below in the Bayesian version of a comparison of proportions (with predictions); only analyses 
relevant to a single cohort will be used. 
C.11 Analysis Methods for Secondary Objectives 
As indicated below, flat or diffuse prior distributions have been identified for all secondary 
objective analyses.   
 Discrete (Dichotomous) Data:  Bayesian Version of a Comparison of Proportions 
C.11.1
Given proportions pt and pc for a dichotomous outcome, let each be assigned a flat Beta(1, 1) 
prior.  Then the posterior distributions for pt and pc follow Beta(1+Yt,1+Nt–Yt) and 
Beta(1+Yc,1+Nc–Yc) distributions, respectively, where Yt and Yc represent the number of 
“successes” and Nt and Nc represent the number of “tries” (e.g., subjects) in their respective 
treatment groups.  The distribution of the difference pt – pc can be easily estimated by drawing 
a large number of observations (e.g., 100,000) from each Beta posterior, and subtracting.  
The posterior probability P(pt / pc < θ | data) is estimated as the proportion of these 
observations where the ratio is less than θ.  A 95% equal-tail Bayesian credible interval can 
be calculated from the 2.5th and 97.5th percentiles of the sampled distribution of pt / pc.  
Similarly, the posterior probability P(pt – pc < δ | data) is estimated as the proportion of these 
observations where the difference is less than δ.  A 95% equal-tail Bayesian credible interval 
can be calculated from the 2.5th and 97.5th percentiles of the sampled distribution of pt – pc or 
pt / pc, , as appropriate.   Credible intervals for pt and pc can be individually calculated as the 
2.5th and 97.5th percentiles from their respective (beta) posterior distributions.  
 Discrete (Polytomous) Data:  Bayesian Version of a Comparison of Proportions 
C.11.2
Given the vectors pt and pc of k-variate proportions for a polytomous outcome, let each be 
assigned a flat Dirichlet(1) prior.  The Dirichlet distribution is the multidimensional analog of 
the Beta distribution.  After observing multinomial count data Yt and Yc, the posterior 
distributions of pt and pc follow Dirichlet(1+Yt) and Dirichlet(1+Yc) distributions, respectively.  
The distribution of the difference pt – pc (or ratio) can be easily estimated by drawing a large 
number of observations (e.g., 100,000) from each Dirichlet posterior, and subtracting (or 
dividing).  The marginal posterior probability Pr(pt
(i) – pc
(i) >  δ | data) for the ith  component of 
(pt – pc) is estimated as the proportion of these observations where the difference exceeds δ.  
A 95% Bayesian equal-tail credible interval can be calculated from the 2.5th and 97.5th 
percentiles of the sampled distribution of pt
(i) – pc
(i).  Posterior probabilities of ratios are 
similarly calculated from the sampled distribution of pt
(i) / pc
(i). 
 Discrete (Dichotomous) Data:  Bayesian Comparison of Proportions (with 
C.11.3
Predictions) 
The analysis above under “Bayesian Version of a Comparison of Proportions” applies only to 
subjects with observed data at the time point of interest (e.g., the 24-month visit).  A 
modification is required in order to take into account subjects with partial follow-up, as will be 
the case if non-inferiority is demonstrated for the primary objective at the interim analysis time 
point.  
The modeling is analogous to the predictions in the Primary Objective. Subjects without 
outcome data for the time point of interest T0 will be considered to be in intermediate states 
that are analogous to those used in the primary objecive.  If T0 = 24 months, subjects without 
24-month outcome data will be considered to be in one of 26 states (13 for each treatment 
group).  The 13 states are: 
• 
no interim data 
• 
E or P or N at 1 month, no subsequent data 
• 
E or P or N at 6 months, no subsequent data 

 
 
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• 
E or P or N at 12 months, no subsequent data 
• 
E or P or N at 18 months, no subsequent data 
If T0 is later (e.g., 3 years), there is one more set of 3 interim states (E or P or N at 24 
months).  If the time point of interest is sooner (e.g., 12 months), only the first few bullets 
above (measured at time points prior to T0) would apply.   
As with the primary objective analysis, subjects in the "E" state at interim time points can be 
imputed to be "E" at T0, with certainty.  For each of the remaining interim states (separately by 
treatment group), the probability of becoming an "E" at 24 months is modeled via a Beta(1,1) 
prior distribution which is updated to a Beta(1+X, 1+Y) distribution, based on the number X 
and Y of subjects who went on from that state to become 24-month "E" and "N" subjects, 
respectively.  
Predicting 2-year outcomes for each of these states, and combining with the data from 
subjects with known 2-year outcomes, a posterior probability of non-inferiority (or superiority) 
is calculated; it is based on observed 2-year data and also a predictive model that employs 
interim outcomes and the relationship between those interim outcomes and their 
corresponding final outcomes that is learned during the current trial.   
Inference proceeds from a sampled version of the posterior distribution of [pt – pc] or [pt / pc], 
as appropriate, that incorporates both the observed and predicted values at T0.  With any one 
imputation of incomplete data, we draw and store a sample from the posterior distribution [pt – 
pc | Observed 2-year data, Imputed 2-year data].  By iterating this process we create a 
sampled version of the [pt – pc] posterior distribution that accounts for uncertainty in the 
prediction.  The probability of superiority is then estimated by the proportion of these stored 
values wherein pt > pc.  By identifying the 2.5th and 97.5th percentiles of the combined stored 
samples, a 95% credible interval that accounts for uncertainty in the predicted values is 
obtained.  Analogous techniques are used if the quantity of interest is the ratio pt / pc. 
In this analysis, all prior distributions (i.e., those for pt and pc as well as for all transition 
probability distributions) and Beta(1,1). 
 Continuous Data:  Bayesian version of a t-test. 
C.11.4
Assuming that the quantity of interest Y follows a N(μ,σ2) distribution, and placing a uniform 
prior distribution on (μ, log(σ)), the posterior distribution of μ has the form27  
1
~
−










−
nt
Y
n
s
y
µ
 
Employing this for both μt and μc, the distribution of (μt - μc) can be estimated in Monte Carlo 
fashion by drawing a large number of observations (e.g., 25000) from a tn-1 distribution for n = 
nt and n = nc, back-transforming these observations to the μt- and μc-scales, and subtracting.  
The posterior probability P(μt – μc > δ | data) is estimated as the proportion of observed 
values of (μt – μc) that exceed δ.  A 95% equal-tail Bayesian credible interval can be 
calculated from the 2.5th and 97.5th percentiles of the sampled distribution of μt – μc.    
 Continuous Data (Distribution-free, Superiority):  Bayesian Version of a Wilcoxon 
C.11.5
Rank-Sum Test 
For this test, data are ranked.  Analogous to the Wilcoxon Rank-Sum test, observations in 
each group are replaced by their ranks in the combined order statistic.  Then the two groups 
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been shown that conducting a two-sample t-test on rank-transformed data is approximately 
equivalent to the Wilcoxon Rank-Sum test7,8. 
Non-inferiority can be evaluated by first subtracting a margin (δ) from each observation in one 
treatment group prior to the rank transformation.  
C.12 Multiplicity Considerations 
It is recognized that with a multiplicity of tests comes an inflation in the chance of a false 
finding of superiority or non-inferiority.  Therefore, for the purpose of seeking approved 
labeling claims on designated secondary objectives, the following standard will be used.  If 
the primary objective demonstrates non-inferiority, claims will be sought at the same time for 
the subset of secondary objectives enumerated below.  These will be tested via a hierarchical 
testing procedure in the order specified below:  objectives are tested in order and continue so 
long as all previous objectives have met their designated success criterion.  Once one 
objective fails to meet its success criterion, tests further down the list do not occur. 
For those objectives in the list that test non-inferiority, if non-inferiority is established using 
this procedure, a test of superiority will also be conducted.  Such superiority testing is not part 
of the hierarchical testing procedure;  it is not necessary for superiority to be established on a 
non-inferiority objective in order to "pass" the stated objectives further down the list. 
Since, for all secondary objectives, the prior distributions are flat or nearly flat, virtually all 
information in the model is contained within the likelihood.  Therefore, a rule that determines 
P(H | data ) > θ must induce a “critical value” in the data space that is approximately equal to 
the critical value defined by a (1–θ)-level significance test in the setting of a standard 
frequentist hypothesis test, and the type 1 error of each secondary objective analysis must 
therefore approximate the quantity 1 – θ.    This is consistent with the statement of Gelman et 
al. that "[i]n various simple one-sided hypothesis tests, conventional p-values may correspond 
with posterior probabilities, under noninformative prior distributions"9 and the statement of 
Albert that "a Bayesian probability of a hypothesis is equal to the p-value for one-sided testing 
problems when a vague prior distribution is placed on the parameter"10.  It follows that 
frequentist methods that control type 1 errors among multiple objectives must apply, at least 
approximately, to posterior probabilities in an analogous fashion.    
For the purposes of seeking claims, these objectives will only be evaluated once, at the same 
time as non-inferiority of the primary objective is established.   
The remaining secondary objectives may be of interest for scientific or financial reasons but 
will not be the basis for supporting labeling claims. 
 Ordered List of Secondary Objectives to be Tested To Support Labeling Claims 
C.12.1
1. Change in transvalvular mean gradient from baseline to 12 months: MCS TAVI vs. SAVR 
(secondary objective #9). The hypothesis of interest is  
H: µ MCS TAVI > µ SAVR –15 
where µ MCS TAVI and µ SAVR denote the mean improvements in mean gradient from baseline to 
12 months, measured in mmHg.  The posterior probability P(H | data) will be calculated and 
compared to a threshold of 0.95.   
                                                     
 
7  Berry D & Lindgren B, Statistics:  Theory and Methods, 2ed. Belmont, CA:  Duxbury, 1996, p 505. 
8  Conover WJ & Iman RL, "Rank transformations as a bridge between parametric and nonparameteric 
statistics," American Statistician 35 (1981), 124-129. 
9 Gelman A, Carlin JB, Stern HS, Rubin DB, Bayesian Data Analysis, 1st ed.  London:  Chapman & Hall, 
1995, p. 69. 
10 Albert J, Bayesian Computation with R, 1st ed.  New York: Springer, 2007. 

 
 
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2. Change in effective orifice area from baseline to 12 months: MCS TAVI vs. SAVR (secondary 
objective #9).  The hypothesis of interest is  
H: µ MCS TAVI > µ SAVR – 0.375 
where µ MCS TAVI and µ SAVR denote the mean improvements in effective orifice area from 
baseline to 12 months, measured in cm2.  The posterior probability P(H | data) will be 
calculated and compared to a threshold of 0.95.   
3. Change in NYHA classification from baseline to 12 months: MCS TAVI vs. SAVR (secondary 
objective #5).  The hypothesis of interest is  
H: µ MCS TAVI > µ SAVR – 0.375 
where µ MCS TAVI and µ SAVR denote the mean number of classification improvements in NYHA 
from baseline to 12 months.  The posterior probability P(H | data) will be calculated and 
compared to a threshold of 0.95.   
4. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 12 
months: MCS TAVI vs. SAVR (secondary objective #8).  The hypothesis of interest is  
H: µ MCS TAVI > µ SAVR -5 
where µ MCS TAVI and µ SAVR denote the mean improvements in the KCCQ score from baseline 
to 12 months.  The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.95.   
5. TAVI with the Medtronic CoreValve® System is superior to SAVR in binary rate of MACCE at 
30 days or hospital discharge, whichever is longer (secondary objective #1).  The hypothesis 
of interest is  
H: π MCS TAVI < π SAVR 
where π MCS TAVI and π SAVR denote the binary rate of MACCE at 30 days or hospital discharge 
(if longer).  The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.95.   
6. Change in SF-36 Physical Summary Scale from baseline to 30 days: TAVI vs. SAVR 
(secondary objective #8).  The hypothesis of interest is  
H: µ MCS TAVI > µ SAVR 
where µ MCS TAVI and µ SAVR denote the mean improvements in the SF-36 Physical Summary 
Scale from baseline to 30 days.  The posterior probability P(H | data) will be calculated and 
compared to a threshold of 0.975.   
Other than the hierarchical testing procedure described above, no further multiplicity 
adjustments will be made in the analyses of the secondary endpoints.  Summary data from 
other secondary objectives, such as device success and procedural success from secondary 
objectives #16 and #17, respectively, may be provided in the device labeling.  However, no 
claims of statistical significance or other statistical inference will be made.   
C.13 Heterogeneity/Poolability 
A poolability analysis among investigational centers, access site (ilio-femoral or non-ilio-
femoral), need for revascularization, and primary baseline demographics will be performed for 
the primary endpoint. In particular, the primary endpoint and key secondary endpoints such as 
MACCE and MAE incidence will be examined for differences in outcome between genders, 
need for revascularization, and between access sites.  Additionally, tests for these outcomes 
will be performed to evaluate potential interactions between treatment and gender and between 
treatments and need for revascularization and between treatment and access site. 
 

 
 
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 Geography Poolability Analysis 
C.13.1
C.13.1.1 Primary Endpoint by Geography 
The interaction between geography (Europe and North America) and treatment on the 
probability of death or major stroke will be compared using a logistic regression model. This 
analysis will be performed on the modified intent-to-treat (mITT) population, for subjects whose 
status at 24 months is known. If the resulting p-value is ≤ 0.15, further exploratory analysis will 
attempt to identify covariates that may explain treatment effect differences between the regions. 
Otherwise, the data will be considered to be poolable across geographies. 
C.13.1.2 Univariate Covariate Analysis 
If in the analysis of primary endpoint by geography, the resulting p-value is ≤ 0.15 then the 
following baseline characteristics will be examined individually as potential predictors of death 
or major stroke using logistic regression models: 
• 
Gender 
• 
Age 
• 
Baseline NYHA 
• 
STS score 
• 
Baseline LVEF 
• 
Hypertension 
• 
Diabetes 
• 
Coronary artery disease 
• 
Prior stroke 
• 
Prior MI 
• 
Prior PI 
C.13.1.3 Multivariate Analysis 
If in the analysis of primary endpoint by geography, the resulting p-value ≤ 0.15 then the 
covariates with p-value ≤ 0.20 from the Univariate Covariate Analysis will be included along with 
geography in a logistic regression model. If this multivariate regression does not result in a 
significant (p-value ≤ 0.15) geography by treatment interaction after adjustment for these 
baseline factors, then outcome results will again be considered poolable across geographies. If 
geography by treatment interaction is still significant (p-value ≤ 0.15) after adjustment for these 
factors, results will be presented by geography and the clinical significance of these differences 
will be assessed. 
If it is determined that data is not poolable by geography, then a random-effects model for the 
primary endpoint that includes geography as a random effect will be provided. 
 Site Poolability Analysis 
C.13.2
If the geographic regions Europe and North America are considered to be poolable, then the 
Site Poolability Analysis will be p North America performed on all sites, for patients with an STS 
score between 4-10. The geographic region (Europe, Unites States,) is not taken into account.  
Should, however, the geographic regions Europe and North America not be considered to be 
poolable, then for both of these regions a separate poolabillity analysis will take place. Per 
region the STS 4-10 population will be analyzed.  
C.13.2.1 Pooling of Small Sites 
With up to 75 sites expected to participate in the study, this leads to an average of 33 subjects 
per site. 
Sites should contribute both at least 5 treatment and at least 5 control subjects to the mITT 
population. If this is not the case, the site is considered a “small site”; small sites will be ordered 
by the date of first enrollment in the mITT population. Starting with the first “small site”, a 
pseudo-site will be created by adding subjects from successive “small sites”. Once the number 

 
 
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of subjects (treatment and control subject together) reaches or exceeds the size of the median 
enrollment (treatment and control subject together) of the “large sites”, then a second pseudo-
site will be created, beginning with the next site not already included in the first pseudo-site. 
Additional pseudo-sites, if needed, would be created in the same manner. 
If the geographic regions Europe and North America are considered to be poolable then the 
pseudo-sites can consist of small sites of both geographics regions. If however the regions are 
not considered to be poolable, then specific Europe pseudo-sites and North America pseudo-
sites need to be created. A separate site poolability analysis will be performed for Europe sites 
and for North American sites. 
C.13.2.2 Primary Endpoint by Site 
The interaction between site or pseudosite and treatment on the probability of death or major 
stroke will be compared using a logistic regression model. This analysis will be performed on 
the mITT population for subjects whose status at 24 months is known. If the resulting p-value is 
≤ 0.15, further exploratory analysis will attempt to identify covariates that may explain treatment 
effect differences among the sites, beginning in the next section. Otherwise, the data will be 
considered to be poolable across study sites. 
C.13.2.3 Multivariate Analysis 
If in the analysis for Primary Endpoint by Site, the resulting p-value ≤ 0.15 then the covariates 
with p-value ≤ 0.20 from Univariate Covariate Analysis will be included along with site in a 
logistic regression model. If this multivariate regression does not result in a significant (p-value 
≤ 0.15) site by treatment interaction after adjustment for these baseline factors, then outcome 
results will again be considered poolable across study sites. If site by treatment interaction is 
still significant (p-value ≤ 0.15) after adjustment for these factors, results will be presented by 
site and the clinical significance of these differences will be assessed. 
C.14 Pre-Defined Subgroups 
The following sub-groups will be analyzed for publication purposes: 
 
Diabetes Mellitus (yes, no) 
 
Age (<70 years of age, 70-74 years of age, 75-79 years of age and >=80 years of age) 
 
Sex (male, female) 
 
Presence of co-morbidities 
 
Need for coronary revascularization 
A test for interaction between the treatment effect (SAVR versus TAVI) and the subgroup 
variable will be performed. 
These comparisons are not powered, and will be for exploratory purposes only, not to be used 
to support labeling claims.  
 
Health-Related Quality of Life (HRQoL) and Treatment Costs 
C.14.1
Health-related quality of life (HRQoL) and treatment costs will be assessed alongside the core 
clinical trial to evaluate the impact of the TAVI and SAVR strategies on a range of relevant 
quality of life (QoL) domains and also to evaluate the cost-effectiveness of the two treatment 
strategies. 
 Quality of Life 
C.14.2
Health Related Quality of Life (HRQoL) and functional status will be assessed using a 
combination of generic and disease-specific measures selected to cover a broad range of 
health domains that may be affected by severe aortic stenosis disease, its treatment, and its 
complications: the Medical Outcomes Study 36-item Short Form (SF-36), the Kansas City 
Cardiomyopathy Questionnaire (KCCQ), and the EuroQoL Five Dimensions (EQ-5D). All 
subjects will complete standardized, written questionnaires at baseline (prior to subject being 
informed of randomization), 30 days, 6 months, 12 months, 18 months, 24 months and annually 

 
 
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thereafter up to 5 years.  At 3 months subjects will also be contacted via telephone to complete 
the EQ-5D, in select geographies SF-36 will also be collected Economic Outcomes/Cost-
Effectiveness. 
C.15 Economic Outcomes/Cost-Effectiveness 
Data on resource utilization will be collected for the index hospitalization and through long-term 
follow-up for all enrolled subjects.  These resource items will include number and duration in-
patient stays in hospital by type of unit (e.g. intensive care, high-dependency care and standard 
ward care); number of clinic visits (by type of physician); and details of the main procedure 
undertaken.  As part of the trial analysis, resource use estimates will be presented by 
randomized group (e.g. mean per patient plus standard deviation).  This data, together with the 
EQ-5D data will provide an important input into cost effectiveness analysis.  However, as such 
analysis is likely to be based on a modeling framework, to include evidence from a number of 
sources (e.g. a meta-analysis of other TAVI trials) and to vary according to the jurisdiction of 
interest, it is appropriate to detail the methods in separate protocols and analysis plans.  
C.16 Use of Data for CE Mark 
Data from the MCS TAVI arm may be utilized to seek CE Mark approval for the Intermediate 
Risk indication prior to study completion.  This is expected to include the experience of 
approximately the first 150 TAVI subjects out to 1 year.  This analysis will not impact the Type I 
error rate of this study as there will not be an early analysis of control (randomized) data, and 
no decisions to alter the pivotal trial are allowed based on this analysis.  This data will not be 
made public and a limited number of personnel will have access to the results. 
D REVISION PROCESS 
The study statistician will be responsible for the execution of this statistical analysis plan, 
including any revisions and obtaining of appropriate approvals. 
E DISTRIBUTION 
The study statistician will be responsible for execution of this statistical analysis plan and 
distribution of revisions to the appropriate clinical staff. 

 
 
 
 
Coronary and Structural Heart Clinical Department 
 
 
SURTAVI 
 
STATISTICAL ANALYSIS PLAN 
 
 
Revision 6  
31-May-2016 
 
 
 
 
 
 
SUrgical Replacement and Transcatheter Aortic Valve Implantation 
Version 12.0, 31-May-2016 
Prepared by: 
Yanping Chang, MS 
Sr. Principal Statistician 
 
Bayesian Design by: 
Andrew S Mugglin, PhD 
Paradigm Biostatistics, LLC 
 
Anna McGlothlin, PhD 
Berry Consultants, LLC   
 
 
 
 
 
 
 

 
 
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Table of Contents 
A 
PURPOSE OF SAP ............................................................................................ 4 
B 
RATIONALE FOR STUDY DESIGN................................................................... 4 
C 
STATISTICAL METHODS AND ANALYSIS ...................................................... 4 
C.1 
Statistical considerations and analysis ................................................................................ 4 
C.2 
Description of Baseline Variables ........................................................................................ 4 
C.3 
Analysis Populations ........................................................................................................... 5 
 Screening population ................................................................................................. 5 
C.3.1
 Randomized population............................................................................................. 5 
C.3.2
C.4 
Primary analysis .................................................................................................................. 5 
 Hypothesis of non-inferiority ...................................................................................... 5 
C.4.1
 Randomization, Sample Size, and Analysis Plan ..................................................... 6 
C.4.2
C.5 
Predictions ........................................................................................................................... 8 
 Prior Distributions for Transition Probabilities ......................................................... 10 
C.5.1
C.6 
Operating Characteristics .................................................................................................. 12 
C.7 
Simulation Details and Design Sensitivity ......................................................................... 13 
 LTFU/Data Missingness .......................................................................................... 13 
C.7.1
 Control Arm Event Rate .......................................................................................... 14 
C.7.2
 Rate of Accrual ........................................................................................................ 14 
C.7.3
 Temporal Correlation ............................................................................................... 17 
C.7.4
 Type I Errors ............................................................................................................ 19 
C.7.5
C.8 
Missing Data and Planned Sensitivity Analyses (Primary Objective) ................................ 21 
C.9 
Description of Performed Analysis, per Population ........................................................... 22 
 Analysis of screening population ............................................................................. 22 
C.9.1
 Analysis of ITT and mITT Populations .................................................................... 22 
C.9.2
 Analysis of implanted population ............................................................................. 22 
C.9.3
C.10 Secondary Endpoints ........................................................................................................ 22 
C.11 Analysis Methods for Secondary Objectives ..................................................................... 27 
 
Discrete (Dichotomous) Data:  Bayesian Version of a Comparison of 
C.11.1
Proportions .............................................................................................................. 27 
 
Discrete (Polytomous) Data:  Bayesian Version of a Comparison of Proportions27 
C.11.2
 
Discrete (Dichotomous) Data:  Bayesian Comparison of Proportions (with 
C.11.3
Predictions) ............................................................................................................. 28 
 
Continuous Data:  Bayesian version of a t-test. ................................................. 28 
C.11.4

 
 
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Continuous Data (Distribution-free, Superiority):  Bayesian Version of a 
C.11.5
Wilcoxon Rank-Sum Test ........................................................................................ 29 
C.12 Multiplicity Considerations ................................................................................................. 29 
 
Ordered List of Secondary Objectives to be Tested To Support Labeling Claims30 
C.12.1
C.13 Heterogeneity/Poolability ................................................................................................... 33 
 
Geography Poolability Analysis .......................................................................... 34 
C.13.1
 
Site Poolability Analysis ...................................................................................... 35 
C.13.2
C.14 Additional Analysis ............................................................................................................ 35 
 
Pre-Defined Subgroups ...................................................................................... 35 
C.14.1
 
Analysis of VARC Endpoints and Definitions...................................................... 36 
C.14.2
 
Health-Related Quality of Life (HRQoL) and Treatment Costs ........................... 36 
C.14.3
 
Quality of Life ...................................................................................................... 36 
C.14.4
C.15 Economic Outcomes/Cost-Effectiveness .......................................................................... 36 
C.16 Use of Data for CE Mark ................................................................................................... 37 
D 
REVISION PROCESS ...................................................................................... 38 
E 
DISTRIBUTION ................................................................................................ 38 
F 
REVISION HISTORY ........................................................................................ 39 
G 
APPENDIX ....................................................................................................... 41 
G.1 
Sample Size Determination Algorithm ............................................................................... 41 
G.2 
Reasonableness of Priors ................................................................................................. 41 
G.3 
Derivation of the Informative Priors ................................................................................... 42 
G.4 
Justifying the Skeletons ..................................................................................................... 44 
G.5 
Appropriateness of Imputing Missing Data ........................................................................ 45 
G.6 
Type I Errors for the Primary Endpoint Superiority Testing ............................................... 45 
 
 
 
 

 
 
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A PURPOSE OF SAP 
This Statistical Analysis Plan has been designed to document, before data are analyzed, the 
rationale for the study design, and the planned analyses that will be included in study reports. 
The design and analyses are consistent with the objectives of the Clinical Investigational Plan 
(CIP). 
B RATIONALE FOR STUDY DESIGN 
The purpose of this trial is to evaluate the safety and efficacy of transcatheter aortic valve 
implantation (TAVI) in the treatment of symptomatic severe aortic stenosis (AS) in subjects who 
are determined by the Heart Team to be at intermediate surgical risk. Subjects will be 
randomized to receive either transcatheter aortic valve implant (TAVI)   or surgical aortic valve 
replacement (SAVR) in a 1:1 ratio. 
This statistical analysis plan is developed based on the Clinical Investigational Plan (CIP) 
Version 12.0.    
C STATISTICAL METHODS AND ANALYSIS 
The SURTAVI trial is a multicenter, multinational, prospective, adaptive, 1:1 randomized study 
designed to demonstrate non-inferiority (to within an absolute margin of 0.07) of TAVI to SAVR, 
as measured by a composite of all-cause death or disabling stroke incidence at 24 months.      
Study success will be evaluated at an interim analysis that is timed to occur when 1400 
subjects who undergo an attempted study treatment have reached 12 months; if necessary, 
study success will again be evaluated when all subjects have reached 24 months.   
A study report will be prepared for submission to FDA at the time study success criteria have 
been met, for the purpose of seeking marketing approval.  After all subjects have completed all 
protocol-specified follow-up, a final clinical report including updated long-term safety data will 
be prepared and submitted. 
Roll-in subjects (refer to CIP section C.4.4) will not be included in the primary or secondary 
analysis; however, the data will be summarized separately with descriptive statistics. 
Any deviations from this section and/or the Statistical Analysis Plan will be described and 
justified in the Final Report, as appropriate. 
C.1 Statistical considerations and analysis 
This section describes the statistical considerations and analysis plans for the SURTAVI trial.  
The statistical analysis will be performed by the statistics department of Medtronic. As primary 
analysis, all randomized subjects will be analyzed following the modified intention to treat 
(mITT) approach; ie., analyses will be conducted on the cohort of subjects who undergo an 
attempted study treatment, analyzed according to the randomized assignment.  A secondary 
analysis of key objectives will be performed according to the therapy actually received. All 
follow-up periods are defined as the number of days after the procedure date. 
C.2 Description of Baseline Variables 
Baseline demographic and clinical variables will be summarized for each of the treatment 
groups for the intention-to-treat (ITT), modified intent-to-treat (mITT), and implanted 
populations. All continuous variables will be summarized as means, medians, standard 
deviations, interquartile ranges, minima and maxima and compared between treatment groups 
using a Bayesian analog of a two-sample t-test or the non-parametric Wilcoxon rank-sum test.  
Categorical variables will be summarized as frequencies and percentages and compared 
between treatment groups using a Bayesian version of a comparison of proportions. 

 
 
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C.3 Analysis Populations 
 
Screening population 
C.3.1
All patients with symptomatic severe AS  who provide informed consent will be considered 
screened and all available data will be entered into the Electronic Data Capture (EDC) system.  
 
Randomized population 
C.3.2
If the patient signs informed consent, meets all inclusion and none of the exclusion criteria, and 
the Heart Team determines the patient is suitable for randomization in the trial, then the subject 
is reviewed by the SURTAVI Screening Committee.  If the subject is approved by the Screening 
Committee and the subject is enrolled/randomized to either TAVI or SAVR the subject is added 
to the randomized population. Within the randomized population three subpopulations are 
distinguished: 
 
The intention-to-treat (ITT) population: Subjects are reported according to the 
randomized assignment, SAVR or TAVI, regardless of what, if any, therapy was 
actually received.  
 
The modified intention-to-treat (mITT) population: Randomized subjects in whom a 
procedure is attempted. Patients who undergo an attempted trial treatment are reported 
according to the randomized assignment, SAVR or TAVI, regardless of what, if any, 
therapy was actually received. A procedure attempt is defined as when the subject is 
brought into the procedure room and any of the following have occurred: anesthesia 
administered, vascular line placed, TEE placed or any monitoring line placed. In the 
database, attempted procedure is defined by a non-missing procedure date. 
 
The implanted population: This population includes the mITT subjects who are actually 
implanted with either the TAVI device or a surgical valve.  Depending on context, 
subjects may be analyzed according to randomized treatment assignment or treatment 
actually received. 
The primary analysis for the primary objective and most secondary objectives will use the mITT 
population.   At the conclusion of the trial, an analysis using the ITT population will also be 
presented.  
C.4 Primary analysis 
The primary endpoint of all-cause mortality or disabling stroke at 24 months will be evaluated 
using the absolute difference of the TAVI rate and the SAVR rate for all-cause mortality or 
disabling stroke during a fixed follow-up of 24 months’ time. The hypothesis test is designed to 
show non-inferiority of TAVI to SAVR for the primary endpoint.  
 
Hypothesis of non-inferiority 
C.4.1
The primary objective is to establish that TAVI is non-inferior to SAVR for the primary endpoint.  
The hypothesis of interest is: 
𝐻𝐴: 𝜋𝑇 < 𝜋𝐶+ 𝛿 
  
where T and C denote binary rates of all-cause mortality or disabling stroke during a fixed 
follow-up of 24 months for the treatment (TAVI) and control (SAVR) groups, and 𝛿= 0.07.  This 
study is designed using Bayesian statistical techniques.  TAVI will be declared to be non-
inferior to SAVR if it can be established that the posterior probability Pr(H A,δ=0.07 | data) > Ψ, 
where Ψ is a pre-specified threshold value.  If, in addition, it can be shown that Pr(𝐻𝐴: 𝜋𝑇 <
𝜋𝐶+ 0 | data) > ΨSUP, TAVI will be declared to be superior to SAVR.  The values chosen for Ψ 
and ΨSUP are described below. 

 
 
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C.4.1.1 
Non-inferiority Margin 
The δ =0.07 non-inferiority margin is considered clinically relevant and is consistent with the 
FDA Draft Guidance for Industry Non-inferiority Clinical Trials (March 2010). As stated in the 
guidance, M1 is the entire effect of the active control assumed to be present in the non-
inferiority study; M2 is the largest clinically acceptable difference (degree of inferiority) of the 
test drug (or investigational device) compared to active control. Active control is SAVR in the 
study. 
Medical management and SAVR historical data1 are summarized in the following table. The 
estimated SAVR 2 year all-cause mortality or stroke rate in high risk population is 38.8% (using 
the higher upper bound of Partner A2 and Pivotal High Risk3). The historical SAVR treatment 
effect over standard therapy (M1) can be calculated as 19.1% (=57.9%-38.8%). To preserve 
50% M1, a NI margin of 7% is specified based on clinical judgment.  
Table 1:  Medical Management and SAVR Data from Literature 
Study 
 24 Month All-cause Mortality or 
Stroke/Major Stroke* Kaplan-Meier Rate 
  
95% Exact 
Confidence Interval 
Medical Management Data 
Partner B 
68.0% (117/179) 
(57.9%, 72.3%) 
SAVR Data 
Partner A 
34.2% (104/313) 
(28.0%, 38.8%) 
Pivotal High Risk 
32.5% (113/359) 
(26.7%, 36.6%) 
*24 month all-cause mortality or stroke for Partner A and B studies; 24 month all-cause 
mortality or major stroke for Pivotal High Risk study 
 
 
 
Randomization, Sample Size, and Analysis Plan 
C.4.2
Randomization will follow a 1:1 (treatment:control) allocation ratio and be stratified by site and 
need for revascularization, using a blocked randomization scheme with blocks of randomly 
varying sizes.  The sample size for the mITT population is 1600 subjects.   
 
C.4.2.1 
  Sample Size Justification 
Although the pre-specified analysis methods are Bayesian, the sample size is guided by a 
standard frequentist non-inferiority power analysis.  Under the assumptions of T = C = 0.17, 
non-inferiority margin δ=0.07, 1:1 randomization, α= 0.05, and power = 95%, the method of 
Farrington and Manning4 as implemented in PASS 20085 indicates that the required  sample 
size for a single-look analysis is 1258. To allow for up to 6% dropout, 1339 subjects must be 
accrued.  Furthermore, to compensate for power lost in a two-look group sequential analysis 
plan using Pocock-type alpha spending, the sample size would have to be increased by about 
                                                     
 
1 Raj R. Makkar, Gregory P. Fontana, et al. Transcatheter Aortic-Valve Replacement for Inoperable Severe Aortic 
Stenosis, N Engl J Med 2012; 366:1696-1704 
2 Kodali SK, Williams MR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement, N 
Engl J Med 2012; 366:1686-1695 
3 Michael J. Reardon, David H. Adams, et al. 2-Year outcomes in patients undergoing surgical or self-expanding 
transcatheter aortic valve placement, JACC 2015; 66:113-21 
4 Farrington, C. P. and Manning, G. 1990. 'Test Statistics and Sample Size Formulae for Comparative Binomial 
Trials with Null 
5 Hintze, J. (2004). NCSS and PASS, Number Cruncher Statistical Systems. Kaysville UT. www.ncss.com 

 
 
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12.5%6.  This leads to an estimated sample size of 1531. Thus a sample size of 1600 mITT 
subjects should provide ample power for establishing non-inferiority in the primary hypothesis 
test. 
The assumed values T = C = 0.17 are based on the data published by Iturra et al.7 and 
CoreValve US Pivotal High Risk study results. As reported in the Iturra paper, the incidence of 
all-cause mortality at 30 days was 2.8% and the late all-cause mortality Kaplan-Meier rate at 24 
months was 12.1%. The overall 24-month all-cause mortality rate was approximately 15%. STS 
score reported in the Iturra paper (5.6 ± 1.1, n=502) was similar to the STS score for subjects 
currently enrolled in the SURTAVI study (5.6 ± 1.4, n=654) 8, and it is believed that the 24-
month all-cause mortality rate in SURTAVI will be approximately 15% at 24 months. The major 
stroke rate was 3.2% for subjects who survived to 1 year in the CoreValve Pivotal High Risk 
study.  The High Risk study enrolled a higher-risk population than SURTAVI, therefore, the 
major stroke rate in the High Risk study is adjusted downward, and it is believed the disabling 
stroke rate at 24 months would be approximately 2% in the SURTAVI study. Overall, the 
estimation of all-cause mortality or disabling stroke rate is 17% at 24 months.     
C.4.2.2 
  Analysis Plan 
The sample size look analysis (timed when 1400 subjects had entered the mITT population) 
occurred prior to the change of margin; the conclusion of this analysis was that 1400 would be 
inadequate to establish non-inferiority (using δ = 0.05) and that subject accrual should continue 
(refer to Appendix G.1 for sample size determination algorithm).  With the re-design 
accompanying the change of margin, an interim analysis (timed to occur when 1400 mITT 
subjects have reached 12 months) for the purpose of declaring an early win will occur and all 
enrolled mITT subjects will be included in the analysis. At this analysis, if P(Hδ=0.07 | data) > Ψ, 
non-inferiority will be declared at this time, and a regulatory submission will follow.  On the other 
hand, if P(Hδ=0.07 | data) ≤ Ψ, all mITT subjects will be followed to 24 months, when a final 
analysis will occur.  At the final analysis, the standard for trial success will again be P(Hδ=0.07 | 
data) > Ψ.   These two analyses are termed “Win Looks”. 
 If, at the early interim “Win Look,”, non-inferiority is established, a test of superiority will 
immediately follow.  If P(Hδ=0 | data) > ΨSUP, superiority will be established at this time.  
However, if P(Hδ=0 | data) ≤ ΨSUP, subjects will continue to be followed and analyzed according 
to the same analysis plan (i.e., with one more possible “Win” analysis when all mITT subjects 
have reached 24 months).  At the final “Win”  analysis, if P(Hδ=0 | data) > ΨSUP, a delayed 
determination of superiority will be made.   
The statistical approach for these analyses is Bayesian. The prior distributions for T and C in 
these calculations are Beta(1,1).  The threshold Ψ is designated to be 0.971 for non-inferiority 
testing and ΨSUP =0.989 for superiority testing; these values were selected by trial-and-error to 
achieve a type I error (under extensive simulation) of at most 0.05 for non-inferiority testing and 
at most 0.025 for superiority testing under the design with δ = 0.05 margin . These same 
thresholds are retained in the current study design. Control of type I error using these 
thresholds is described in detail in “Type I Errors” (Section C.7.5). Of note, establishing P(Hδ=0 | 
data) > ΨSUP means that superiority has been established to a standard equivalent to a nominal 
significance level of 0.025 (1-sided), but this does not automatically mean that a labeling claim 
of superiority is supported.  See “Multiplicity Considerations” (Section C.12) for additional 
requirements regarding labeling claims on secondary objectives.   
                                                     
 
6 Jennison C and Turnbull BW, Group Sequential Methods with Applications to Clinical Trials.  Boca Raton:  
Chapman & Hall, 2000, p 27 
7 Iturra SA, Suri RM, Greason KL, et al. The Journal of thoracic and cardiovascular surgery 2014;147:127-132.  
 
8 Medtronic CoreValve SURTAVI Trial 2014 FDA Annual Progress Report.  
 

 
 
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C.5 Predictions 
Outcomes at 24-month are binary and are denoted "E" (for having experienced an Event) or "N" 
(for not having experienced an event).  Predicted values of 24-month outcomes for those 
subjects who have not yet yielded 24-month outcomes will be based on intermediate outcomes 
observed at 1 month, 6 months, 12 months, and 18 months.  These intermediate outcomes are:   
• 
"E" -- subject has had a known primary event (death or disabling stroke) at the time 
point in question 
• 
"P" -- subject is known to have had a "possible primary event" at the time point in 
question.  "Possible primary events" are adverse events that may later be determined 
to be Disabling Strokes.  This determination takes 90 days, by definition.  For 
example, a subject may have a stroke at month 5 which cannot be known to be a 
Disabling Stroke until Month 8.  At Month 6, such a subject is in the "P" state.   
• 
"N" -- subject has not had a primary event or a "possible primary event" at the time 
point in question. 
Subjects without 24-month outcome data will thus be considered to be in one of 26 states (13 
for each treatment group).  The 13 states are: 
• 
no interim data 
• 
E or P or N at 1 month, no subsequent data 
• 
E or P or N at 6 months, no subsequent data 
• 
E or P or N at 12 months, no subsequent data 
• 
E or P or N at 18 months, no subsequent data 
Subjects in the "E" state at an interim analysis can be imputed to be "E" at 24 months, with 
certainty.  For each of the remaining 18 states (9 for each treatment group), the probability of 
becoming an "E" at 24 months is modeled via a Beta(a,b) prior distribution which is updated to 
a Beta(a+X, b+Y) distribution, based on the number X and Y of subjects who went on from that 
state to become 24-month "E" and "N" subjects, respectively.  For example, if, in the treatment 
group at an interim analysis time point, it is known that 10 of 30 subjects had previously gone 
from the "N at 18 months" state to the "E at 24 months" state, then the transition probability 
from the 18-month "N" state to the 24-month "E" state will be modeled as Beta(a+10, b+20).  At 
an interim analysis time point, any treatment-group subjects residing in the "N-at-18-month-but-
without-24-month-data" state will have their 24-month outcome predicted on the basis of this 
Beta(a+10, b+20) distribution.  Similar statements can be made about each of the possible 
transitions.  As data are accrued in this study, the Beta distributions used for prediction are 
updated accordingly.  Figure 1 graphically depicts the various possible states and transitions 
from them to the final state, for a generic treatment group.   For clarity, the lines connecting the 
interim "E" state to the 24-month "E" state have been omitted.  The numerical example above 
would apply to transition #9 in the Figure 1. 

 
 
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Figure 1 Graphical depiction of transitions from interim states (E = Event, P = Possible 
Event, N = No Event, Start) to 24-month outcome.  Each transition is assigned 
a separate Beta(a,b) prior distribution which is updated as data are gathered.   
 
By predicting 24-month outcomes for each of these states, and combining with the data from 
subjects with known 24-month outcomes, a posterior probability of non-inferiority is 
calculated; it is based on observed 24-month data and also a predictive model that employs 
interim outcomes and the relationship between those interim outcomes and their corresponding 
final outcomes that is learned during the current trial.  This is accomplished in Monte Carlo 
fashion.  With any one imputation of incomplete data, we calculate the posterior probability 
Pr(Hδ=δ* | Observed 24-month Data, Imputed 24-month Data), and store it.  By iterating this 
process and averaging these posterior probabilities, we are essentially integrating them over 
the predictive distribution of imputed data.  This resulting quantity we have denoted as Pr(Hδ=δ* | 
Data).  The model is very similar to that employed in Lipscomb et al.9   The chief differences are 
that this model incorporates interim outcomes at other time points (eg., 1 month, 6 months,  18 
months rather than just 12 months), and the model also considers trichotomous rather than 
dichotomous interim states.  
The predictive probability of eventual trial success can be calculated in a similar manner.  
With any one imputation of incomplete data, we calculate the posterior probability Pr(Hδ=δ* | 
Observed 24-month Data, Imputed 24-month Data) and record whether this value exceeds the 
threshold Ψ.  By iterating this process and reporting the proportion of times that Ψ is exceeded, 
we obtain an estimate of the predictive probability of eventual trial success (meaning a trial that 
results in a conclusion of non-inferiority with the designated sample size).  
In this trial, predictive probabilities of eventual success are used in the 1400-subject sample 
size analysis.  Posterior probabilities are used for the determination of non-inferiority (ie., 
analyses in the evaluation portion of the trial or “Win Looks”). 
In any analysis conducted for the purpose of determining whether the primary endpoint has 
passed (ie, any “Win” analysis), no subject can be a "P" at 24 months. Whether a stroke 
                                                     
 
9  Lipscomb B, Ma G, Berry D, “Bayesian predictions of final outcomes: regulatory approval of a spinal 
implant,”  Clinical Trials, Vol. 2, No. 4, 325-333 (2005) 
E = Event 
P = Possible Event 
N = No Event 
Start 
1 
Month 
6 
Month 
12 
Month 
18 
Month 
24 
Month 
E 
P 
N 
E 
P 
N 
E 
P 
N 
E 
P 
N 
E 
N 
 
 
 
 
 
 
 
 
 
#1 
#2 
#3 
#7 
#9 
#4 
#6 
#8 
#5 

 
 
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qualifies as a disabling stroke (primary endpoint) is accomplished via the Modified Rankin 
Score (mRS), which may take up to 3 months after the stroke's onset to determine, but all P's at 
24 months will be converted to E's or N's.  If at the precise time of a Win analysis there are any 
subjects who are still "P" at 24 months, Medtronic will wait until all such determinations and 
conversions are made before submitting the results, and thus there can be no P's at 24 months.   
Sample Size Determination analysis is similar but with one small difference. If, at the precise 
time of a Sample Size Determination analysis, there are any subjects who are still "P" at 24 
months, Medtronic may proceed with the Sample Size Determination analysis, treating each P 
in the TAVI or SAVR group as an E or an N in four separate analyses:  
 
each P in the SAVR group as an N and each P in the TAVI group as an E  
 
each P in the SAVR group as an N and each P in the TAVI group as an N  
 
each P in the SAVR group as an E and each P in the TAVI group as an E  
 
each P in the SAVR group as an E and each P in the TAVI group as an N 
If the results of these analyses all imply the same decision about whether to stop enrolling, 
Medtronic will follow that decision. If the results imply differing decisions about whether to stop 
enrolling, no decision will be made until all 24-month P's have been resolved and converted to 
E's or N's. 
 
Prior Distributions for Transition Probabilities 
C.5.1
The transitions of Figure 1 are assigned individual Beta(a,b) prior distributions.  For the 1400 
sample size look analysis, the values of a and b are tabulated in Table 2 and graphically 
depicted in Figure 2 (for the treatment group) and Figure 3 (for the control group).  These 
values represent the trial sponsor’s knowledge and belief about the relationship of the various 
interim states to the final state.  At the times when sample size decisions must be made, the 
number of subjects who have completed 24 months (and thus provide information on the 
transition probabilities) will generally be insufficient to make good sample size decisions without 
including some additional information.  Therefore, in the 1400 Sample Size Look analysis, the 
transitions are given informative priors, as tabulated in Table 2 and displayed graphically in 
Figure 2 and Figure 3 (further rationale for the choice of these prior distributions is given in 
Appendix G.1 and G.2). However, for all Win Looks, only flat priors (a = b = 1) for the transitions 
will be used. 
Table 2.  Parameters for Prior Distributions of the Transition Probabilities used in the 
determination of sample size.  For all "Win" analyses, a and b are set to 1. 
 
Treatment Group 
Control Group 
a 
b 
A 
b 
Transition #1 (Start to E24) 
7.35 
41.65 
7.35 
41.651 
Transition #2 (P1 to E24) 
8.538 
21.273 
8.554 
23.942 
Transition #3 (N1 to E24) 
7.639 
50.038 
7.745 
53.642 
Transition #4 (P6 to E24) 
8.736 
24.537 
8.735 
27.49 
Transition #5 (N6 to E24) 
7.739 
67.557 
7.819 
76.512 
Transition #6 (P12 to E24) 
8.983 
28.795 
8.961 
32.089 
Transition #7 (N12 to E24) 
7.89 
101.736 
7.959 
114.768 
Transition #8 (P18 to E24) 
9.491 
34.896 
9.416 
38.505 
Transition #9 (N18 to E24) 
8.218 
197.452 
8.263 
221.227 

 
 
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Figure 2:  Prior Distributions of the Transition Probabilities used in the determination of 
sample size (Treatment Group) 
 
 
0.0
0.2
0.4
0.6
0.8
1.0
Transition 1: No Data to E24 
 Beta( 7.35 ,  41.65 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 2: P1 to E24 
 Beta( 8.538 ,  21.273 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 3: N1 to E24 
 Beta( 7.639 ,  50.038 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 4: P6 to E24 
 Beta( 8.736 ,  24.537 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 5: N6 to E24 
 Beta( 7.739 ,  67.557 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 6: P12 to E24 
 Beta( 8.983 ,  28.795 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 7: N12 to E24 
 Beta( 7.89 ,  101.736 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 8: P18 to E24 
 Beta( 9.491 ,  34.896 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 9: N18 to E24 
 Beta( 8.218 ,  197.452 )
Treatment Group

 
 
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Figure 3:  Prior Distributions of the Transition Probabilities used in the determination of 
sample size (Control Group) 
 
C.6 Operating Characteristics 
The design described above has been subjected to intensive simulations in order to evaluate its 
anticipated performance in practice. In this section, we summarize the simulations of the  
design, which has one sample size look analysis (using δ = 0.05) when 1400 subjects had 
entered the mITT population, one “Early Win” analysis (using δ = 0.07) when 1400 mITT 
subjects have reached 12 months, and a final analysis (using δ = 0.07) when the maximum 
sample size N=1600 mITT subjects have reached 24 months.   
In the simulation, the proportion of simulated trials that result in a declaration of non-inferiority is 
the estimated power when T - C < 0.07 and the estimated type I error rate when T - C ≥ 
0.07.     The estimated operating characteristics are based on 10000 simulated trials per 
scenario, with predictions (for each transition at each interim analysis of each of the 10000 
trials) based on 5000 draws from the relevant transition probability distribution.   
Table 3 displays the operating characteristics and summarizes the performance of the adaptive 
sample size determination algorithm under various assumed values of πC and difference of πT-
πC.  The column “Overall Power” is the proportion of trials that resulted in a declaration of non-
inferiority (NI).  The column "Early Win, Late Win" indicates at which of the two "win analyses" 
the "win" occurred;  ie., a trial that passed the primary objective at the interim "win" analysis 
would appear as an "Early Win" in the upper number, while a trial that did not pass until the final 
analysis would appear in the lower number as a "late win."  The column “Average N” shows the 
average sample size attained for that row.  The probability of attaining any of the allowed 
sample sizes (1400, 1600) is then displayed;  the upper number indicates the proportion that 
stopped at that size because the results were promising, while the lower number indicates the 
proportion that stopped at that size for futility.  The last column shows the proportion of trials 
that went to the maximum sample size of 1600.   
0.0
0.2
0.4
0.6
0.8
1.0
Transition 1: No Data to E24 
 Beta( 7.35 ,  41.651 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 2: P1 to E24 
 Beta( 8.554 ,  23.942 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 3: N1 to E24 
 Beta( 7.745 ,  53.642 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 4: P6 to E24 
 Beta( 8.735 ,  27.49 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 5: N6 to E24 
 Beta( 7.819 ,  76.512 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 6: P12 to E24 
 Beta( 8.961 ,  32.089 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 7: N12 to E24 
 Beta( 7.959 ,  114.768 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 8: P18 to E24 
 Beta( 9.416 ,  38.505 )
0.0
0.2
0.4
0.6
0.8
1.0
Transition 9: N18 to E24 
 Beta( 8.263 ,  221.227 )
Control Group

 
 
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Table 3: Operating characteristics of the design when πC = 0.17, from a simulation of 
10,000 simulated trials per line.  Interpretations of column headings are given in 
the narrative  
πC = 0.17 
Probability of Achieving Sample Size N 
Diff (πT-πC) 
Power 
Early Win, Late 
Win 
Average N 
N=1400 
(Promise, 
Futile)  
N=1600 
-0.025 
0.9954 
0.9909 
1446.8  
0.7615 
0.2342 
0.0045  
0.0043 
0 
0.9402 
0.8896 
1509.1  
0.4146 
0.5453 
0.0506  
0.0401 
0.025 
0.6410 
0.5338 
1536.1  
0.1425 
0.6807 
0.1072  
0.1768 
0.05 
0.1974 
0.1505  
1506.5  
0.0268 
0.5326 
0.0469  
0.4406 
0.07 
0.0409  
0.0329 
1465.0 
0.0050 
0.3250 
0.0080 
0.6700 
0.075 
0.0218 
0.0158  
1454.3 
0.0033 
0.2714 
0.0060  
0.7253 
 
In Table 3, the type I error rate (when πT-πC = 0.07) is 0.0409.  In this scenario, the trial went to 
its maximum size of N=1600 32.50% of the time, often stopping accrual sooner for futility ( 
0.6700), and only rarely stopping accrual early for promising trend (0.0050).  Those trials that 
either stopped early for promising trend or went to the maximum of 1600 were tested for an 
"early win" twelve months after accrual stops, with 3.29% (of the 10,000) winning early and an 
additional 0.80% winning at the final analysis (for a total type 1 error rate of 0.0409).  When πT-
πC = 0, the estimated power is 94.02%; the trial stopped accruing for promising trend at N=1400 
41.46% of the time; the maximum of N=1600 occurred 54.53% of the time.   The proportion of 
trials that passed at the interim "win" analysis was 88.96%, while an additional 5.06% passed 
the primary objective at the final "win" analysis.  The average of the sample sizes (across the 
10,000 simulated trials) was 1509.1 subjects, which is an average of some trials that stop 
accrual at N=1400 and some that stop at N=1600. 
C.7 Simulation Details and Design Sensitivity 
In order to generate data for the operating characteristics simulations described above, several 
additional assumptions about the data mechanism had to be made.  These assumptions are 
intrinsic to the generation of artificial data in the simulation exercise but are not part of the 
analysis that is conducted on any data (real or simulated).  This section describes these 
assumptions and also the sensitivity of the design to these assumptions. 
 
LTFU/Data Missingness 
C.7.1
Simulations were conducted under the assumption of 6% missingness over the 24-month study 
period.  With each simulated trial, each subject was designated to be "lost" with probability 
0.06; thus the exact number of subjects lost from one simulated trial to the next varied, though it 
was always approximately 6%.  Furthermore, those subjects designated to "drop" were 
assumed to have dropped out uniformly in time, so that each of these subjects was dropped by 
18 months with probability 18/24, each of those was in turn dropped by 12 months with 
probability 12/18, and so on.  Marginally, the probability of being lost at 12 months was thus 
0.06 × 18/24 × 12/18  = 0.03, and similar statements can be made about each time point.  
Dropout was thus uniform in time over the 24-month study period.  Artificial subjects, once lost, 
did not return to the analysis for subsequent visits. 

 
 
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Control Arm Event Rate 
C.7.2
A stated assumption made in the operating characteristics as displayed in Table 3 is that the 
control arm event rate is πC = 0.17.  Alternative scenarios were simulated in which the control 
arm event rate was instead 12% and 22%.  The results of these simulations are provided below 
in Table 4.  It is evident that the type I error is < 0.05.  Power is > 95% when T - C = 0 and C 
= 0.12 and > 80% when T - C = 0 and C = 0.22.    
Table 4:  Operating characteristics of the design under differing control arm event rate 
assumptions.  10,000 simulated trials per line, with predictions based on 5000 
imputations. Column interpretations are the same as in Table 3 
πC = 0.12 
Probability of Achieving Sample Size N 
Diff (πT-πC) 
Power 
Early Win, Late 
Win 
Average N 
N=1400 
(Promise, 
Futile)  
N=1600 
-0.025 
0.9994 
0.9989 
1424.8 
0.8753 
0.1241 
0.0005 
0.0006 
0 
0.9778 
0.9549 
1493.2 
0.5177 
0.4660 
0.0229 
0.0163 
0.025 
0.7455 
0.6417 
1540.1 
0.1713 
0.7004 
0.1038 
0.1283 
0.05 
0.2443 
0.1857 
1512.9 
0.0284 
0.5467 
0.0586 
0.4069 
0.07 
0.0407 
0.0311 
1463.3 
0.0055 
0.3164 
0.0096 
0.6781 
0.075 
0.0243 
0.0192 
1454.1 
0.0028 
0.2707 
0.0051 
0.7265 
πC = 0.22 
Probability of Achieving Sample Size N 
Diff (πT-πC) 
Power 
Early Win, Late 
Win 
Average N 
N=1400 
(Promise, 
Futile)  
N=1600 
-0.025 
0.9872 
0.9752 
1464.4 
0.6670 
0.3222 
0.0120 
0.0108 
0 
0.8971 
0.8277 
1517.7 
0.3519 
0.5883 
0.0694 
0.0598 
0.025 
0.4702 
0.4702 
1535.7 
0.1188 
0.6783 
0.1071 
0.2029 
0.05 
0.1861 
0.1424 
1503.6 
0.0260 
0.5182 
0.0437 
0.4558 
0.07 
0.0388 
0.0305 
1463.2 
0.0053 
0.3160 
0.0083 
0.6787 
0.075 
0.0270 
0.0204 
1454.7 
0.0044 
0.2737 
0.0066 
0.7219 
 
 
Rate of Accrual 
C.7.3
The speed at which subjects are recruited into the trial is another important assumption 
embedded within the simulations to determine operating characteristics.  SURTAVI started to 
enroll subjects in June 2012. The enrollment was slow in the first 2 years. Therefore, in 
simulation of operating characteristics, the monthly accrual totals over the first 21 months were 
set to approximate the actual number of monthly implants, as follows:  7 in the first month, 2 in 
the second month, followed by 4, 7, 17, 21, 24, 31, 29, 28, 32, 32, 31, 34, 44, 42, 40, 39, 33, 
36, 43. Beginning in Month 22, the assumed accrual is 45 subjects per month for the duration of 
the trial. This is the accrual rate used in the generation of Table 3 and Table 4.  

 
 
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Table 5 illustrates how the study design performs if accrual is faster or slower than this 
expectation. The slow speed assumes that 30 subjects are accrued per month after the first 22 
months of accrual, and the fast speed assumes a steady set of 60 subjects per month (after the 
first 22 months).   
The results in Table 5 demonstrate that type I error is controlled at < 0.05 as the rate of accrual 
varies.  Power is approximately 94% for the cases where πT-πC = 0, and type 1 error is < 0.05, 
though sample size tends to be smaller when accrual is slow.   
Table 5: Operating characteristics of the design under differing assumptions about 
accrual rate.  10,000 simulated trials per line, with predictions based on 5000 
imputations. Column meanings are the same as in Table 3 
πC = 0.17, slow accrual 
Probability of Achieving Sample Size N 
Diff (πT-πC) 
Power 
Early Win, Late 
Win 
Average N 
N=1400 
(Promise, 
Futile)  
N=16000 
-0.025 
0.9981 
0.9971 
1427.0 
0.8631 
0.1351 
0.0010 
0.0018 
0 
0.9435 
0.9086 
1493.8 
0.4944 
0.4692 
0.0349 
0.0364 
0.025 
0.6473 
0.5666 
1527.6 
0.1467 
0.6381 
0.0807 
0.2152 
0.05 
0.2042 
0.1671 
1481.1 
0.0228 
0.4054 
0.0371 
0.5718 
0.07 
0.0407 
0.0320 
1436.7 
0.0024 
0.1834 
0.0087 
0.8142 
0.075 
0.0263 
0.0210 
1428.0 
0.0017 
0.1401 
0.0053 
0.8582 
πC = 0.17, fast accrual 
Probability of Achieving Sample Size N 
Diff (πT-πC) 
Power 
Early Win, Late 
Win 
Average N 
N=1400 
(Promise, 
Futile)  
N=1600 
-0.025 
0.9926 
0.9844 
1468.3 
0.6518 
0.3413 
0.0082 
0.0069 
0 
0.9363 
0.8616 
1523.2 
0.3472 
0.6159 
0.0747 
0.0369 
0.025 
0.6488 
0.5078 
1545.2 
0.1349 
0.7258 
0.1410 
0.1393 
0.05 
0.2173 
0.1529 
1528.1 
0.0365 
0.6407 
0.0644 
0.3228 
0.07 
0.0437 
0.0317 
1493.6 
0.0097 
0.4679 
0.0120 
0.5224 
0.075 
0.0299 
0.0229 
1485.7 
0.0068 
0.4286 
0.0070 
0.5646 
 
C.7.3.1 
Subject Follow-up for ‘Early Win’ Analysis 
The Early Win analysis occurs when 1400 mITT subject have reached 12 months, assuming 
that accrual did not stop for futility.    Thus it is expected that approximately 1400 subjects will 
have 12 month follow-up at this analysis, except for perhaps 3% lost-to-follow-up during this 12 
months, and perhaps a little variability due to the follow-up visit window.  The number of 
subjects who have reached 24 months as of this analysis varies primarily with accrual rate.  
The table below displays the probable counts of 24-month observations at the early win 
analysis  .   

 
 
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Table 6: Probable counts of subjects with 24-month outcomes at the Early Win analysis, 
for various accrual rates   
Accrual Rate 
Expected 
Slow 
Fast 
808   
978   
639   
 
The percentage of subjects with 12-month and 24-month observations will depend on whether 
the trial stopped accrual at N=1400 or continued to N=1600, which in turn   depends on factors 
such as the event rates and the treatment effect size .   Tthe expected counts of subjects 
accrued and subjects with 12- and 24-month outcomes at the Early Win analysis are shown in 
Table 7.  
Table 7: Expected counts and proportions of subjects with 24-month outcomes, for 
various accrual rates and treatment effect sizes, as assessed by simulation.   
 
πC 
πt – πC 
N Accrued 
N at 
12 Month 
N at 
24 Month 
% at 24 
Month 
Slow Accrual  
0.12 
-0.025 
1409.9 
1358.0 
976.5 
69.3% 
0.000 
1473.5 
1358.0 
976.7 
66.6% 
0.025 
1556.4 
1358.1 
976.6 
62.9% 
0.050 
1589.9 
1358.1 
976.4 
61.5% 
0.070 
1597.5 
1357.8 
975.3 
61.1% 
0.075 
1598.2 
1358.1 
975.5 
61.0% 
0.17 
-0.025 
1427.1 
1358.0 
976.9 
68.6% 
0.000 
1497.4 
1358.0 
976.6 
65.5% 
0.025 
1562.6 
1358.0 
976.3 
62.7% 
0.050 
1589.4 
1358.1 
976.4 
61.5% 
0.070 
1597.4 
1358.1 
975.6 
61.1% 
0.075 
1597.6 
1358.0 
976.1 
61.1% 
0.22 
-0.025 
1442.1 
1358.0 
976.6 
67.9% 
0.000 
1510.8 
1358.0 
976.1 
64.9% 
0.025 
1563.4 
1358.1 
976.7 
62.6% 
0.050 
1590.4 
1358.1 
976.1 
61.4% 
0.070 
1597.4 
1358.1 
976.1 
61.1% 
0.075 
1597.9 
1357.8 
976.0 
61.1% 
Expected Accrual 
0.12 
-0.025 
1424.8 
1358.0 
807.5 
56.8% 
0.000 
1494.7 
1358.1 
807.3 
54.2% 
0.025 
1560.7 
1358.0 
807.3 
51.9% 
0.050 
1590.4 
1358.0 
807.0 
50.8% 
0.070 
1596.6 
1357.9 
806.9 
50.6% 
0.075 
1598.0 
1358.0 
806.9 
50.5% 
0.17 
-0.025 
1447.0 
1358.0 
807.4 
56.0% 
0.000 
1513.6 
1358.0 
807.6 
53.6% 
0.025 
1565.4 
1357.9 
807.2 
51.7% 
0.050 
1590.4 
1357.9 
806.9 
50.8% 
0.070 
1597.0 
1358.1 
806.1 
50.5% 
0.075 
1597.6 
1357.8 
805.8 
50.4% 
0.22 
-0.025 
1465.1 
1358.0 
807.7 
55.3% 
0.000 
1525.1 
1358.0 
807.2 
53.1% 
0.025 
1570.2 
1358.0 
807.2 
51.5% 
0.050 
1590.4 
1357.9 
807.1 
50.8% 
0.070 
1596.7 
1358.0 
806.3 
50.5% 
0.075 
1596.8 
1358.1 
806.0 
50.5% 

 
 
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πC 
πt – πC 
N Accrued 
N at 
12 Month 
N at 
24 Month 
% at 24 
Month 
Fast Accrual 
0.12 
-0.025 
1445.4 
1358.0 
638.3 
44.3% 
0.000 
1510.9 
1357.9 
637.8 
42.4% 
0.025 
1566.5 
1358.0 
638.6 
40.9% 
0.050 
1590.1 
1357.9 
637.9 
40.2% 
0.070 
1597.3 
1357.8 
636.7 
39.9% 
0.075 
1597.3 
1358.0 
636.6 
39.9% 
0.17 
-0.025 
1468.7 
1358.1 
638.0 
43.6% 
0.000 
1527.9 
1358.0 
638.5 
42.0% 
0.025 
1568.7 
1358.1 
637.2 
40.7% 
0.050 
1589.2 
1358.0 
638.2 
40.2% 
0.070 
1595.9 
1358.2 
637.0 
39.9% 
0.075 
1596.9 
1358.1 
637.3 
39.9% 
0.22 
-0.025 
1486.8 
1357.9 
638.4 
43.1% 
0.000 
1538.3 
1358.0 
638.4 
41.7% 
0.025 
1571.6 
1358.0 
638.7 
40.7% 
0.050 
1590.3 
1358.0 
637.9 
40.1% 
0.070 
1596.2 
1358.0 
637.4 
39.9% 
0.075 
1596.8 
1358.1 
636.8 
39.9% 
 
 
Temporal Correlation 
C.7.4
For simulation, patient-level data with realistic temporal correlation had to be generated.  For 
each treatment group, a "skeleton" of probabilities for the various state transitions was 
constructed, as shown below in Table 8.   For example, a subject in the Treatment group could 
become an "E" at 1 month with probability 0.02, a "P" at 1 month with probability 0.03, and an 
"N" at 1 month with probability 1 –  0.02 – 0.03 = 0.95.  If a subject is "E" at 1 month (denoted 
"E1" in the table), that subject becomes an "E" at 6 months with probability 1 (since subjects 
who have had an event by 1 month necessarily will have had that event by 6 months.  If a 
subject is "P" at 1 month, that subject becomes an "E" at 6 months with probability 0.25, a "P" 
at 6 months with probability 0.01, and an N at 6 months with probability 0.74. Taken as a whole, 
the treatment "skeleton" of probabilities implies a 24-month marginal event rate of 18.7%, while 
the control "skeleton" of probabilities implies a 24-month marginal event rate of 20.7%; the 
serial correlation implied by the skeleton is the sponsor's best estimate of what will actually 
occur in the trial.  (Shaded cells in the table are uniquely determined by the immediately 
preceding cells, a consequence of the fact that probabilities conditioned on the same event 
must sum to one.)   
Table 8:  Probability "Skeletons" for State Transitions used in Generating Temporally 
Correlated Data 
Status 
TAVI 
SAVR 
Status 
TAVI 
SAVR 
Treated  1 Month 
6 Month  12 Month 
P(E1) 
0.02 
0.03 
P(E12 | N6) 
0.04 
0.04 
P(P1) 
0.03 
0.05 
P(P12 | N6) 
0.01 
0.01 
P(N1) 
0.95 
0.92 
P(N12 | N6) 
0.95 
0.95 
1 Month  6 Month 
12 Month  18 Month 
P(E6 | E1) 
1.00 
1.00 
P(E18 | E12) 
1.00 
1.00 
P(E6 | P1) 
0.25 
0.25 
P(E18 | P12) 
0.25 
0.25 
P(P6 | P1) 
0.01 
0.01 
P(P18 | P 12) 
0.01 
0.01 
P(N6 | P1) 
0.74 
0.74 
P(N18 | P12) 
0.74 
0.74 
P(E6 | N1) 
0.04 
0.05 
P(E18 | N12) 
0.04 
0.04 
P(P6 | N1) 
0.01 
0.01 
P(P18 | N12) 
0.01 
0.01 
P(N6 | N1) 
0.95 
0.94 
P(N18 | N12) 
0.95 
0.95 

 
 
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Status 
TAVI 
SAVR 
Status 
TAVI 
SAVR 
6 Month  12 Month 
18 Month  24 Month 
P(E12 | E6) 
1.00 
1.00 
P(E24 | E18) 
1.00 
1.00 
P(E12 | P6) 
0.25 
0.25 
P(E24 | P18) 
0.26 
0.26 
P(P12 | P6) 
0.01 
0.01 
P(N24 | P18) 
0.74 
0.74 
P(N12 | P6) 
0.74 
0.74 
P(E24 | N18) 
0.05 
0.05 
 
 
 
P(N24 | N18) 
0.95 
0.95 
Estimated probability of subject’s status at a specified follow-up given the subject’s status at previous 
follow-up visit  
E=Event experienced (either death or major stroke) 
P=Potential major stroke experienced (severity not known until 90 day MRS) 
N=No event experience 
 
In the course of simulating multiple data scenarios, it is necessary to generate data with specific 
24-month target event rates for both the Treatment and Control groups.  To do this, the 
"skeleton" values of Table 8 are adjusted as follows.  First, the probabilities in all unshaded 
cells that are not already 1.00 by construction are transformed to the logit scale; then a 
common value ε is added to each logit-transformed probability before transforming the sum 
back to the probability scale.  By algebraically expressing the 24-month event rate in terms of 
the foregoing modified skeletal probabilities and subsequently solving for ε, a suitable 
adjustment to the skeletal state transition probabilities is found that sets the 24-month event 
rate equal to the desired target value π (eg., π = 0.17) while approximately maintaining the 
serial correlation of the original skeleton.  This is accomplished separately for the two treatment 
groups. 
This mechanism of generating temporally correlated data represents the sponsor's best 
knowledge and belief about the data that will actually arise in the prospective clinical trial.  All 
operating characteristics in Table 3, Table 4, and Table 5 are generated with this method.   
This mechanism only applies to the generation of artificial data in the simulation; it is not used 
at all in the analysis of data (real or simulated).  If this data generation model does not 
adequately reflect the true pattern of serial correlation, the analysis model will nonetheless be 
tasked with recognizing this and causing the design to respond appropriately.  In order to 
evaluate the robustness of the analysis model and sampling plan to the pattern of serial 
correlation, a simulation was conducted wherein the study design was presented with data 
simulated at the extremes of complete temporal correlation and complete temporal 
independence. 
"Complete Temporal Correlation" is a scenario in which knowing the 1-month outcome for a 
subject is the same as knowing the 24-month outcome.  This is accomplished by setting all 
interim outcomes (eg., 1-month, 6-month, etc.) to be equal to the 24-month "E" or "N" outcomes 
(except for those patients lost to follow-up in the simulation).  The study design is expected to 
react appropriately and much sooner when presented with this pattern of data.  "Complete 
Temporal Independence" is a scenario where knowing the interim outcomes for a subject gives 
no information about what that subject will be at 24 months.  To accomplish this, no patient can 
be an "E" prior to 24 months (else there would be serial correlation), and subject outcomes at 
interim time points are set to be "P" or "N" with probability P(E24), independently at each time 
point.  
Table 9 displays operating characteristics generated under the Complete Temporal Correlation 
and Complete Temporal Independence patterns.   As expected, the design reacts quicker (ie., 
with smaller sample size and higher chance of early win) when the data are completely 
correlated.  While neither scenario is particularly realistic, it is important that the observed Type 
I errors are < 0.05 in both cases and the powers are acceptable. 
 

 
 
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Table 9: Operating characteristics of the design under alternative assumptions about 
temporal correlation.  10,000 simulated trials per line, with predictions based on 
5000 imputations. Column meanings are the same as in Table 3 
Complete Temporal Correlation 
πC = 0.17, Expected Accrual Rate 
Probability of Achieving Sample Size N 
Diff (πT-πC) 
Power 
Early Win, Late 
Win 
Average N 
N=1400 
(Promise, 
Futile)  
N=1600 
-0.025 
0.9990 
0.9989 
1416.7 
0.9157 
0.0836 
0.0001 
0.0007 
0 
0.9589 
0.9575 
1487.7 
0.5413 
0.4383 
0.0014 
0.0204 
0.025 
0.6496 
0.6404 
1539.2 
0.1274 
0.6958 
0.0092 
0.1768 
0.05 
0.1826 
0.1757 
1487.9 
0.0102 
0.4394 
0.0069 
0.5504 
0.07 
0.0278 
0.0266 
1434.1 
0.0010 
0.1704 
0.0012 
0.8286 
0.075 
0.0145 
0.0134 
1425.9 
0.0002 
0.1294 
0.0011 
0.8704 
Complete Temporal Independence 
πC = 0.17, Expected Accrual Rate 
Probability of Achieving Sample Size N 
Diff (πT-πC) 
Power 
Early Win, Late 
Win 
Average N 
N=1400 
(Promise, 
Futile)  
N=1600 
-0.025 
0.9914 
0.9701 
1469.8 
0.6431 
0.3488 
0.0213 
0.0081 
0 
0.9283 
0.8048 
1512.9 
0.3905 
0.5646 
0.1235 
0.0449 
0.025 
0.6446 
0.4591 
1534.0 
0.1878 
0.6698 
0.1855 
0.1424 
0.05 
0.2230 
0.1530 
1521.0 
0.0719 
0.6048 
0.0700 
0.3233 
0.07 
0.0516 
0.0384 
1494.9 
0.0248 
0.4744 
0.0132 
0.5008 
0.075 
0.0391 
0.0301 
1487.6 
0.0213 
0.4381 
0.0090 
0.5406 
 
 
Type I Errors 
C.7.5
To study all combinations of accrual rate, control success rate, and serial correlation would 
require 3 × 3 × 3 = 27 tables similar to Table 3.  Rather than present all of these, we instead 
provide a comprehensive summary of all type I error rates observed through repeated trial 
simulations under the varying conditions described above. For reference, Table 10 shows the 
type I error rates for the previous trial design (non-inferiority margin δ = 0.05, sample size of 
either N=1400, N=1700, N=2000, and Early Win analysis 12 months after stopping accrual). 
Each cell is based on 10,000 simulated clinical trials, with predictions based on 5,000 draws 
from each of the predictive model transition distributions.  Under all scenarios, type I error is 
controlled.  There is no evidence that type I error exceeds 0.05.  Even the few scenarios with 
observed type I error greater than 0.05 (eg., the maximum of 0.0524) could easily result from a 
simulation of size 10,000 with underlying true rate = 0.05:  a 95% probability interval calculated 
as 0.05 ± 1.96 √(0.05× 0.95 / 10000) would range from 0.0457 to 0.0543, so a value as high as 
0.0524 is entirely expected and constitutes no evidence of a type I error inflation.   
Similarly, Table 11 shows the type I error rate for the same design, but changing only the non-
inferiority margin from δ = 0.05 to δ = 0.07. This table was produced under the assumption that 

 
 
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the underlying true treatment rate is 0.07 higher than the control rate. The type I error rate 
remains in a similar range to the previous design, though the error rate is occasionally above 
0.05 for the scenario of complete temporal independence, especially combined with the fast 
accrual profile. However, the assumption of complete temporal independence (with all events 
happening between 18 and 24 months) is not realistic, and the fast accrual scenario is faster 
than the known accrual rate that has been observed in the ongoing trial. 
Finally, Table 12 shows the type I error rate for the current design which uses δ = 0.05 for the, 
sample size analysis at N=1400 enrolled, δ = 0.07 for the Early Win interim analysis when 1400 
mITT subjects have reached 12 months, and the final Win analysis when N=1600 have reached 
24 months. Again, the implausible scenario of complete temporal independence combined with 
fast accrual shows the highest type I error rates. For the expected temporal correlation profile, 
type I error rates remain well below the nominal rate of 0.05. 
Type I error rates for the superiority testing are described in Appendix G.5. 
 
Table 10:  Simulated Type I error rates for the previous trial design with non-inferiority 
margin 0.05, given varied correlation structures, accrual rates, and control 
event rates.  10,000 simulated trials per line, with predictions based on 5,000 
imputations 
 
Control Event Rate 
0.12 
0.17 
0.22 
Complete 
Temporal 
Correlation 
Accrual Rate 
Slow 
0.0364 
0.0349 
0.0370 
Expected 
0.0313 
0.0331 
0.0356 
Fast 
0.0338 
0.0309 
0.0325 
Expected 
Temporal 
Correlation 
Slow 
0.0469 
0.0424 
0.0419 
Expected 
0.0442 
0.0433 
0.0475  
Fast 
0.0421 
0.0488 
0.0411 
Complete 
Temporal 
Independence 
Slow 
0.0507 
0.0483 
0.0455 
Expected 
0.0506 
0.0476 
0.0524 
Fast 
0.0520 
0.0501 
0.0498 
 
Table 11:  Simulated Type I error rates for the previous trial design with non-inferiority 
margin 0.07, given varied correlation structures, accrual rates, and control 
event rates.  10,000 simulated trials per line, with predictions based on 5,000 
imputations 
 
Control Event Rate 
0.12 
0.17 
0.22 
Complete 
Temporal 
Correlation 
Accrual Rate 
Slow 
0.0370 
0.0363 
0.0406 
Expected 
0.0354 
0.0335 
0.0340 
Fast 
0.0330 
0.0274 
0.0332 
Expected 
Temporal 
Correlation 
Slow 
0.0418 
0.0401 
0.0420 
Expected 
0.0409 
0.0413 
0.0436 
Fast 
0.0447 
0.0430 
0.0430 
Complete 
Temporal 
Independence 
Slow 
0.0451 
0.0502 
0.0475 
Expected 
0.0531 
0.0530 
0.0502 
Fast 
0.0555 
0.0552 
0.0537 
 

 
 
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Table 12:  Simulated Type I error rates for the current trial design (with non-inferiority 
margin δ = 0.07 for “Win” analyses but δ = 0.05 for the sample size 
assessment at N=1400), given varied correlation structures, accrual rates, 
and control event rates.  10,000 simulated trials per line, with predictions 
based on 5,000 imputations 
 
Control Event Rate 
0.12 
0.17 
0.22 
Complete 
Temporal 
Correlation 
Accrual Rate 
Slow 
0.0259 
0.0304 
0.0302 
Expected 
0.0275 
0.0278 
0.0295 
Fast 
0.0305 
0.0298 
0.0292 
Expected 
Temporal 
Correlation 
Slow 
0.0396 
0.0407 
0.0381 
Expected 
0.0407 
0.0409 
0.0388 
Fast 
0.0441 
0.0437 
0.0461 
Complete 
Temporal 
Independence 
Slow 
0.0453 
0.0488 
0.0447 
Expected 
0.0546 
0.0516 
0.0534 
Fast 
0.0618 
0.0638 
0.0621 
 
C.8 Missing Data and Planned Sensitivity Analyses (Primary Objective) 
Every effort will be undertaken to minimize missing data.  However, some missingness is 
inevitable, and the study is designed with the expectation that there may be up to 6% missing 
primary data at 24 months.   The reasons for missing data will be described in detail and 
evaluated for assessment of possible bias.  The distribution of prognostic factors between 
patients with data and those without data will be examined to evaluate any potential sources of 
bias.  
By design, the analysis of the primary objective (at both interim time points) will predict 24-
month outcomes for any subjects without measured 24-month outcomes, based on transitions 
from interim states and the experience of those who went on from those states to provide 
complete 24-month data.  This is true whether the missing 24-month outcomes are due to being 
accrued later in the trial (as happens for many subjects at the interim "win" analyses) or some 
other cause, such as loss to follow-up (which will likely apply at both the interim and final "win" 
analyses).  Several additional analyses are planned to be conducted (at the conclusion of the 
trial) that will explore the sensitivity of the main conclusions to the predictions for subjects 
whose missing 24-month outcomes cannot be explained by simply being accrued late (ie., 
subjects who are known to be lost to follow-up or whose 24-month visit window has closed 
without a measured outcome).  In these analyses and for such subjects, 24-month outcomes 
will be imputed according to the model described below.  
As with the primary analysis, any such subject will be viewed as belonging to one of several 
interim states.  These are the same states used in the primary analysis (eg., "E" or "P" or "N" at 
6 months, etc.)  
For each of these states, the probability of becoming a composite success at 24 months will be 
modeled via a logistic formulation.  Based on the number of subjects who went on from that 
state to become 24-month "E" and "N" subjects, respectively, a logistic regression of the 
following form will be fit: 
logit( p ) = β0 
where the parameter β0 will be assigned a vague N(0,102) distribution.  The posterior 
distribution for β0 will then be shifted by a biasing constant γ and will be back-transformed to the 
probability scale as: 
p* = logit–1(β0 + γ) 

 
 
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The 24-month outcome for any subject belonging to this state but lost thereafter will be imputed 
based on this distribution of p*.  The case γ = 0 contains no bias and corresponds essentially to 
the primary analysis.   
By varying γ, the impact of a biasing influence on the study results can be examined.  The 
values γ = +∞ and γ = –∞ correspond to setting all such observations to be "E" or "N."  The 
impact of various values of γ (including +∞ and –∞) will be examined and presented in a 
sensitivity analysis, representing both positive and negative biases for the two groups.   
Further analyses will explore the sensitivity of efficacy to the imputation model.  Specifically, 
one analysis will present posterior probabilities of non-inferiority/superiority without the use of 
prediction (ie., completers only).  Another will present the results of a tipping point analysis.   
C.9 Description of Performed Analysis, per Population 
 
Analysis of screening population 
C.9.1
For the screening population only descriptive statistical analysis will be performed, on variables 
that are captured in the EDC system. 
 
Analysis of ITT and mITT Populations 
C.9.2
For the subjects in the randomized population the primary analysis of the primary endpoint and 
inferential statistics for the following secondary endpoints will be performed on the ITT and 
mITT populations: 
• 
Major adverse cardiovascular and cerebrovascular events (MACCE) 
• 
Individual MACCE components 
• 
Major adverse events (MAE)  
• 
Conduction disturbance requiring permanent pacemaker implantation 
• 
NYHA 
• 
Six-minute walk test 
• 
Ratio of days alive out of hospital versus total days alive 
• 
Quality of life 
• 
Echocardiographic assessment of valve performance  
• 
Aortic valve disease-related hospitalizations 
• 
Cardiovascular deaths and valve-related deaths 
• 
Strokes and TIAs 
• 
Peri-procedural neurological injury 
• 
Index procedure-related MAEs 
• 
Length of index procedure hospital stay 
• 
Device success 
• 
Procedure success 
 
Analysis of implanted population 
C.9.3
The endpoints listed in C.9.2 will also be performed on the implanted population.  Additionally, 
the implanted population will be used for analyzing the primary endpoint,  secondary endpoint 
of prosthetic valve dysfunction, and echocardiographic assessment of valve performance.   . 
C.10 Secondary Endpoints 
The following secondary endpoints will be compared between TAVI and SAVR subject cohorts 
using the appropriate Bayesian version of analysis for comparing proportions and continuous 
variables as described below: 
1. Incidence of Major Adverse Cardiovascular and Cerebrovascular Events (MACCE) at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  
MACCE is defined as a composite of: 

 
 
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 
All-cause death 
 
Myocardial infarction (MI) 
 
All stroke, and 
 
Reintervention (defined as any cardiac surgery or percutaneous reintervention 
catheter procedure that repairs, otherwise alters or adjusts, or replaces a previously 
implanted valve) 
MACCE-incidence estimates will be provided for the two treatment groups at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  The 
statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
Additionally, incidence of MACCE will be compared at 30 days or hospital discharge, 
whichever is later.  The statistical method will be the Bayesian version of a comparison of 
proportions   
2. The occurrence of individual MACCE components at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
MACCE components will be summarized and their incidence estimates provided at 30 days, 6 
months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  The 
statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
3. Major Adverse Events (MAE) and individual components of MAE at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years. 
Major adverse event (MAE) includes:  
 
MACCE  
 
Acute kidney Injury  
 
Cardiac tamponade  
 
Prosthetic valve dysfunction – including moderate or severe aortic regurgitation  
 
Cardiogenic shock  
 
Prosthetic valve endocarditis  
 
Life-threatening, disabling or major bleeding  
 
Major vascular complication  
 
Cardiac perforation  
 
Valve malpositioning  
MAE events and individual components of MAE will be summarized and the incidence of 
MAEs will be provided at 30 days, 6 months, 12 months, 18 months, 24 months, and annually 
thereafter up to 5 years The statistical method will be the Bayesian version of a comparison of 
proportions (with predictions). 
Additionally, incidence of major vascular complications and incidence of major or life-
threatening bleeding events at 30 days or hospital discharge, whichever is longer, will also be 
compared using the Bayesian version of a comparison of proportions. 
4. Incidence of Early safety at 30 days defined as a composite of: 
 
All-cause mortality 
 
All stroke (disabling and non-disabling) 
 
Life-threatening bleeding 
 
Acute kidney injury—Stage 2 or 3 (including renal replacement therapy)  
 
Coronary artery obstruction requiring intervention 
 
Major vascular complication 
 
Valve-related dysfunction requiring repeat procedure (BAV, TAVI, or SAVR) 
 
All-cause death 
Early safety composite endpoint-incidence estimates will be provided for the two treatment 
groups at 30 days.  The statistical method will be the Bayesian version of a comparison of 
proportions. 

 
 
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5. Incidence of Clinical Efficacy (after 30 days) at 6 months, 12 months, 18 months, 24 months 
and annually thereafter up to 5 years. Clinical efficacy defined as a composite of: 
 
All-cause mortality 
 
All stroke (disabling and non-disabling) 
 
Requiring hospitalizations for valve-related symptoms or worsening congestive heart 
failure 
 
NYHA class III or IV 
 
Valve-related dysfunction (mean aortic valve gradient ≥20 mmHg, EOA ≤0.9-1.1 cm2 
and/or DVI<0. 35m/s, AND/OR moderate or severe prosthetic valve regurgitation*) 
Clinical efficacy estimates will be provided for the two treatment groups at 6 months, 12 
months, 18 months, 24 months and annually thereafter up to 5 years.  The statistical method 
will be the Bayesian version of a comparison of proportions (with predictions). 
*Refers to VARC-2 definitions 
6. Incidence of Time-Related Safety at 30 days, 6 months, 12 months, 18 months, 24 months 
and annually thereafter up to 5 years. Time-Related Safety defined as a composite of: 
 
Structural valve deterioration: 
o 
Valve-related dysfunction (mean aortic valve gradient ≥20 mmHg, EOA ≤0.9-
1.1 cm2 and/or DVI<0.35m/s, AND/OR moderate or severe prosthetic valve 
regurgitation*) 
o 
Requiring repeat procedure (TAVI or SAVR) 
 
Prosthetic valve endocarditis 
 
Prosthetic valve thrombosis 
 
Thromboembolic events (e.g. stroke) 
 
VARC bleeding, unless clearly unrelated to valve therapy (e.g. trauma) 
Time related safety composite endpoint-incidence estimates will be provided for the two 
treatment groups at 30 days, 6 months, 12 months, 18 months, 24 months and annually 
thereafter up to 5 years.  The statistical method will be the Bayesian version of a comparison 
of proportions (with predictions). 
*Refers to VARC-2 definitions 
7. Conduction disturbance requiring permanent pacemaker implantation at 30 days, 6 months, 
12 months, 18 months, 24 months, and annually thereafter up to 5 years. 
The incidence of conduction disturbance requiring permanent pacemaker implantation will be 
provided at 30 days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up 
to 5 years, separately for new onset and pre-existing conduction disturbance.  The statistical 
method will be the Bayesian version of a comparison of proportions (with predictions). 
8. Change in NYHA class from baseline at 30 days, 6 months, 12 months, 18 months, 24 
months, and annually thereafter up to 5 years. 
NYHA classifications will be summarized with frequencies and percentages at baseline, 30 
days, 6 months, 12 months, 18 months, 24 months, and annually through five years. Change 
in NYHA classification from baseline will be summarized both with frequencies and 
percentages and as continuous data at 30 days, 6 months, 12 months, 18 months, 24 months 
and annually through five years. 
For each subject with paired data, the number of classes changed from baseline (-3, -2, -1, 0, 
1, 2, or 3) will be calculated at 30 days, 6 months, 12 months, 18 months, 24 months, and 
annually thereafter up to 5 years. For each treatment group, a Bayesian version of a paired t-
test will be performed to evaluate change from baseline at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually through five years.  The endpoint will be evaluated between 
groups using a Bayesian version of a t-test. 
9. Change in distance walked during 6-minute walk test (6MWT) from baseline to 30 days, 
baseline to 12 months, and baseline to 24 months. 
All subjects who are able to perform the six-minute walk evaluation  at the time of the follow-
up visit will be included in the analysis. 

 
 
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The endpoint will be evaluated using a Bayesian version of a t-test. 
10. Ratio of days alive out of hospital versus total days alive assessed at 12 months and 24 
months follow-up.  
The proportion of post-procedure days alive out of hospital against total days alive will be 
compared between groups at 12 and 24 months.  The numerator will be the number of days 
alive out of hospital, and the denominator will be the number of post-procedure days alive as 
of the last follow-up  date.  All hospitalizations will be included in this analysis, including 
hospitalization for device implant.   
In addition, days alive out of hospital will be compared between groups at 12 months and 24 
months.  
The endpoint will be evaluated using a Bayesian version of a t-test. 
11. Quality of Life (QoL) change from baseline at 30 days, 3 months, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
The Kansas City Cardiomyopathy Questionnaire (KCCQ), SF-36, and EuroQoL will be 
assessed at baseline, 30 days, 6 months, 12 months, 18 months, 24 months, and annually 
thereafter up to 5 years.  SF-36 and EuroQoL will also be assessed at 3 months.  All subjects 
completing the questionnaires will be evaluated and the reasons for missing data will be 
provided. 
The endpoint will be evaluated using a Bayesian version of a t-test. 
12. Echocardiographic assessment of prosthetic valve performance at discharge, 6 months, 12 
months, 24 months, and annually thereafter up to 5 years using the following measures: 
 
transvalvular mean gradient 
 
effective orifice area 
 
degree of prosthetic aortic valve regurgitation (including transvalvular and 
paravalvular) 
The four echocardiographic measurements will be evaluated at discharge, 6 months, 12 
months, 24 months, and annually thereafter up to 5 years.  All implanted subjects undergoing 
echocardiography procedures will be evaluated.   
Continuous measures will be evaluated using a Bayesian version of a two-sample t-test.  
Categorical variables will be evaluated using Bayesian version of a comparison of polytomous 
outcomes.   
Additionally, incidence of moderate/severe aortic insufficiency at discharge will be compared 
between groups using the Bayesian version of a comparison of proportions. 
 
13. Aortic valve disease related hospitalizations  
The number of subjects re-hospitalized after the initial index procedure will be compared at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.   
Incidence of recurrent hospitalization will be provided at 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years.  The statistical method will be the 
Bayesian version of a comparison of proportions (with predictions).   
14. Cardiovascular deaths and valve-related deaths 
The number of subjects experiencing cardiovascular deaths and valve-related deaths at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.  
Incidences will be compared between groups.  The statistical method will be the Bayesian 
version of a comparison of proportions (with predictions). 
15. Strokes and TIAs 
The number of subjects with strokes (of any severity) and TIAs at 30 days, 6 months, 12 
months, 18 months, 24 months, and annually thereafter up to 5 years. A separate analysis will 
be performed for each of the following: 

 
 
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 
a composite of all strokes and TIAs 
 
disabling strokes only 
 
non-disabling strokes only 
 
TIAs only  
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
Additionally, incidence of all strokes at 30 days or hospital discharge, whichever is longer, will 
be compared between groups using the Bayesian version of a comparison of proportions. 
16. Peri-procedural Neurological Injury (Stroke, TIA, Encephalopathy) 
For each treatment group, the proportion of subjects with a neurologic injury (stroke, TIA, or 
encephalopathy) at discharge or at 7 days post-index procedure (whichever occurs first) will 
be calculated. The numerator will be the number of subjects with a neurologic injury (stroke, 
TIA, or encephalopathy) at discharge or at 7 days post-index procedure (whichever occurs 
first), and the denominator will be the number of subjects in that treatment group. Results will 
also be presented separately for disabling stroke, non-disabling stroke, TIA, and 
encephalopathy.  Proportions will be compared between groups using Bayesian version of a 
comparison of proportions. 
17. Index procedure related MAEs 
Index procedure-related MAE events will be summarized and event rates will be provided at 
30 days.  The numerator will be the number of procedure-related MAE events experienced by 
the end of the 30-day follow-up visit, and the denominator will be the number of subjects 
evaluated at the 30-day follow-up visit (or a later follow-up) plus the number of subjects not 
evaluated but who experienced a procedure-related MAE event prior to the end of the follow-
up visit window. 
Additionally, the percentage of subjects with a procedure-related MAE will be calculated in the 
same way, but allowing no more than one MAE per subject. The endpoint is descriptive and 
no statistical hypothesis test will be performed.   
18. Length of index procedure hospital stay 
The length of TAVI or SAVR hospital stay will be summarized for all subjects undergoing a 
study procedure. 
The endpoint will be evaluated between groups using a Bayesian version of a t-test. 
19. Presence of atrial fibrillation at post-procedure, discharge, 30 days, 6 months, 12 months, 18 
months, 24 months, and annually thereafter up to 5 years. 
The statistical method will be the Bayesian version of a comparison of proportions (with 
predictions). 
The following secondary endpoints will be assessed for the TAVI cohort subjects only: 
20. Device success defined as follows: 
 
Absence of procedural mortality AND 
 
Correct positioning of a single prosthetic heart valve into the proper anatomical 
location AND 
 
Intended performance of the prosthetic heart valve (no prosthesis-patient mismatch 
and mean aortic valve gradient <20 mmHg or peak velocity <3 m/s, AND no 
moderate or severe prosthetic valve regurgitation*) 
o 
assessed acutely in a resting state, either within 24-48 hours after the index 
procedure or before hospital discharge 
*Refers to VARC-2 definitions 
Device success, as defined above, will be calculated for all subjects undergoing the TAVI 
procedure.   
The endpoint is descriptive and no statistical hypothesis test will be performed. 

 
 
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21. Procedural success, defined as device success and absence of in-hospital MACCE. 
Procedural success, as defined above, will be calculated for all randomized subjects 
undergoing the TAVI procedure.   
The endpoint is descriptive and no statistical hypothesis test will be performed. 
22. Evidence of prosthetic valve dysfunction at 30 days, 6 months, 12 months, 24 months, and 
annually thereafter up to 5 years. 
The number of subjects with evidence of prosthetic valve dysfunction will be evaluated at 30 
days, 6 months, 12 months, 18 months, 24 months, and annually thereafter up to 5 years.   
Point estimates and 95% BCIs for each time point will be presented using methods described 
below in the Bayesian version of a comparison of proportions (with predictions).   
23. Resheath and Recapture (combined) success rate.  
The success rate will be analyzed for all subjects in whom the resheath or recapture feature is 
attempted. The number and percentage of successful resheath or recapture attempts 
combined will be calculated. Separate resheathing and recapturing success rates will also be 
calculated.  
The endpoint is descriptive and no statistical hypothesis test will be performed.  
Resheath and recapture success, as defined above, will be calculated for all subjects 
undergoing the TAVI procedure with Evolut R. 
C.11 Analysis Methods for Secondary Objectives 
As indicated below, flat or diffuse prior distributions have been identified for all secondary 
objective analyses.   
 Discrete (Dichotomous) Data:  Bayesian Version of a Comparison of Proportions 
C.11.1
Given proportions pt and pc for a dichotomous outcome, let each be assigned a flat Beta(1, 1) 
prior.  Then the posterior distributions for pt and pc follow Beta(1+Yt,1+Nt–Yt) and 
Beta(1+Yc,1+Nc–Yc) distributions, respectively, where Yt and Yc represent the number of 
“successes” and Nt and Nc represent the number of “tries” (e.g., subjects) in their respective 
treatment groups.  The distribution of the difference pt – pc can be easily estimated by drawing 
a large number of observations (e.g., 100,000) from each Beta posterior, and subtracting.  
The posterior probability P(pt / pc < θ | data) is estimated as the proportion of these 
observations where the ratio is less than θ.     Similarly, the posterior probability P(pt – pc < δ | 
data) is estimated as the proportion of these observations where the difference is less than δ.  
A 95% equal-tail Bayesian credible interval can be calculated from the 2.5th and 97.5th 
percentiles of the sampled distribution of pt – pc or pt / pc, , as appropriate.   Credible intervals 
for pt and pc can be individually calculated as the 2.5th and 97.5th percentiles from their 
respective (beta) posterior distributions.  
 Discrete (Polytomous) Data:  Bayesian Version of a Comparison of Proportions 
C.11.2
Given the vectors pt and pc of k-variate proportions for a polytomous outcome, let each be 
assigned a flat Dirichlet(1) prior.  The Dirichlet distribution is the multidimensional analog of 
the Beta distribution.  After observing multinomial count data Yt and Yc, the posterior 
distributions of pt and pc follow Dirichlet(1+Yt) and Dirichlet(1+Yc) distributions, respectively.  
The distribution of the difference pt – pc (or ratio) can be easily estimated by drawing a large 
number of observations (eg, 100,000) from each Dirichlet posterior, and subtracting (or 
dividing).  The marginal posterior probability Pr(pt
(i) – pc
(i) >  δ | data) for the ith  component of 
(pt – pc) is estimated as the proportion of these observations where the difference exceeds δ.  
A 95% Bayesian equal-tail credible interval can be calculated from the 2.5th and 97.5th 
percentiles of the sampled distribution of pt
(i) – pc
(i).  Posterior probabilities of ratios are 
similarly calculated from the sampled distribution of pt
(i) / pc
(i). 

 
 
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 Discrete (Dichotomous) Data:  Bayesian Comparison of Proportions (with 
C.11.3
Predictions) 
The analysis above under “Bayesian Version of a Comparison of Proportions” applies only to 
subjects with observed data at the time point of interest (eg, the 24-month visit).  A 
modification is required in order to take into account subjects with partial follow-up, as will be 
the case if non-inferiority is demonstrated for the primary objective at the interim analysis time 
point.  
The modeling is analogous to the predictions in the Primary Objective. Subjects without 
outcome data for the time point of interest T0 will be considered to be in intermediate states 
that are analogous to those used in the primary objective.  If T0 = 24 months, subjects without 
24-month outcome data will be considered to be in one of 26 states (13 for each treatment 
group).  The 13 states are: 
• 
no interim data 
• 
E or P or N at 1 month, no subsequent data 
• 
E or P or N at 6 months, no subsequent data 
• 
E or P or N at 12 months, no subsequent data 
• 
E or P or N at 18 months, no subsequent data 
If T0 is later (eg, 3 years), there is one more set of 3 interim states (E or P or N at 24 months).  
If the time point of interest is sooner (eg, 12 months), only the first few bullets above 
(measured at time points prior to T0) would apply.   
As with the primary objective analysis, subjects in the "E" state at interim time points can be 
imputed to be "E" at T0, with certainty.  For each of the remaining interim states (separately by 
treatment group), the probability of becoming an "E" at 24 months is modeled via a Beta(1,1) 
prior distribution which is updated to a Beta(1+X, 1+Y) distribution, based on the number X 
and Y of subjects who went on from that state to become 24-month "E" and "N" subjects, 
respectively.  
Predicting 2-year outcomes for each of these states, and combining with the data from 
subjects with known 2-year outcomes, a posterior probability of non-inferiority (or superiority) 
is calculated; it is based on observed 2-year data and also a predictive model that employs 
interim outcomes and the relationship between those interim outcomes and their 
corresponding final outcomes that is learned during the current trial.   
Inference proceeds from a sampled version of the posterior distribution of [pt – pc] or [pt / pc], 
as appropriate, that incorporates both the observed and predicted values at T0.  With any one 
imputation of incomplete data, we draw and store a sample from the posterior distribution [pt – 
pc | Observed 2-year data, Imputed 2-year data].  By iterating this process we create a 
sampled version of the [pt – pc] posterior distribution that accounts for uncertainty in the 
prediction.  The probability of superiority is then estimated by the proportion of these stored 
values wherein pt > pc.  By identifying the 2.5th and 97.5th percentiles of the combined stored 
samples, a 95% credible interval that accounts for uncertainty in the predicted values is 
obtained.  Analogous techniques are used if the quantity of interest is the ratio pt / pc. 
In this analysis, all prior distributions (i.e., those for pt and pc as well as for all transition 
probability distributions) are Beta(1,1). 
 Continuous Data:  Bayesian version of a t-test. 
C.11.4
Assuming that the quantity of interest Y follows a N(μ,σ2) distribution, and placing a uniform 
prior distribution on (μ, log(σ)), the posterior distribution of μ has the form27  
1
~












nt
Y
n
s
y

 

 
 
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Employing this for both μt and μc, the distribution of (μt - μc) can be estimated in Monte Carlo 
fashion by drawing a large number of observations (eg, 25000) from a tn-1 distribution for n = 
nt and n = nc, back-transforming these observations to the μt- and μc-scales, and subtracting.  
The posterior probability P(μt – μc > δ | data) is estimated as the proportion of observed 
values of (μt – μc) that exceed δ.  A 95% equal-tail Bayesian credible interval can be 
calculated from the 2.5th and 97.5th percentiles of the sampled distribution of μt – μc. Credible 
intervals for μt and μc can be individually calculated as the 2.5th and 97.5th percentiles from 
their respective (scaled t) posterior distributions.   
 Continuous Data (Distribution-free, Superiority):  Bayesian Version of a Wilcoxon 
C.11.5
Rank-Sum Test 
For this test, data are ranked.  Analogous to the Wilcoxon Rank-Sum test, observations in 
each group are replaced by their ranks in the combined order statistic.  Then the two groups 
of rank-transformed data are compared via the Bayesian version of a t-test, above.  It has 
been shown that conducting a two-sample t-test on rank-transformed data is approximately 
equivalent to the Wilcoxon Rank-Sum test10,11. 
Non-inferiority can be evaluated by first subtracting a margin (δ) from each observation in one 
treatment group prior to the rank transformation.  
C.12 Multiplicity Considerations 
It is recognized that with a multiplicity of tests comes an inflation in the chance of a false 
finding of superiority or non-inferiority. Therefore, for the purpose of seeking approved 
labeling claims on designated secondary objectives, the following standard will be used:  If 
the primary objective demonstrates non-inferiority, claims will be sought for selected 
secondary non-inferiority and superiority objectives and for superiority on the primary 
objective metric. These will be tested via a hierarchical (sequential) testing order that 
preserves the overall study-wise type I error rate at the level of 0.05, while requiring all non-
inferiority tests to meet a nominal type I error rate of 0.05 and all superiority tests to meet a 
nominal type I error rate of 0.025.  The testing order is specified below. The following 
objectives are tested in order, and testing continues if and only if all previous objectives have 
met their designated success criterion.      
1. Primary endpoint (non-inferiority)  
2. Transvalvular mean gradient at 12 months (non-inferiority) 
3. Effective orifice area at 12 months (non-inferiority) 
4. Change in NYHA classification from baseline to 12 months (non-inferiority) 
5. Change in KCCQ score from baseline to 30 days (non-inferiority)  
 
All of the above are non-inferiority tests and are tested with a type I error standard of 0.05.  If 
all of the above tests meet their success criterion, the type I error rate of 0.05 that is passed 
on from the above tests will be split equally (using a Bonferroni justification) between the 
following parallel subfamilies, so that each subfamily is tested using a type I error rate of 
0.025: 
                                                     
 
10  
Berry D & Lindgren B, Statistics:  Theory and Methods, 2ed. Belmont, CA:  Duxbury, 1996, p 
505. 
11  Conover WJ & Iman RL, "Rank transformations as a bridge between parametric and nonparameteric 
statistics," American Statistician 35 (1981), 124-129. 

 
 
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Subfamily #1:  Primary endpoint (superiority) 
Subfamily #2:  Secondary (superiority) objectives #5–#18 as enumerated below, tested in 
ordered sequence such that all α is passed on to subsequent tests if a test criterion is 
met, while all testing stops if a test criterion is not met.  This procedure controls the type I 
error rate of this subfamily at the level 0.025. 
It is not necessary to “pass” all objectives in one subfamily in order to test the objective(s) in 
the other subfamily.  
Since, for all secondary objectives, the prior distributions are flat or nearly flat, virtually all 
information in the model is contained within the likelihood.  Therefore, a rule that determines 
P(H | data ) > θ must induce a “critical value” in the data space that is approximately equal to 
the critical value defined by a (1–θ)-level significance test in the setting of a standard 
frequentist hypothesis test, and the type 1 error of each secondary objective analysis must 
therefore approximate the quantity 1 – θ.    This is consistent with the statement of Gelman et 
al. that "[i]n various simple one-sided hypothesis tests, conventional p-values may correspond 
with posterior probabilities, under noninformative prior distributions"12 and the statement of 
Albert that "a Bayesian probability of a hypothesis is equal to the p-value for one-sided testing 
problems when a vague prior distribution is placed on the parameter"13.  It follows that 
frequentist methods that control type 1 errors among multiple objectives must apply, at least 
approximately, to posterior probabilities in an analogous fashion.    
For the purposes of seeking claims, these objectives will only be evaluated once, at the same 
time as non-inferiority of the primary objective is established.  The only exception to this is the 
primary endpoint superiority test, which carries the possibility of a delayed determination of 
superiority (as described in Section 4.2.1 and Appendix G.5 of this SAP document) and may 
thus meet its success criterion at a different time. 
 
The remaining secondary objectives may be of interest for scientific or financial reasons but 
will not be the basis for supporting labeling claims; they are thus outside of the hierarchical 
testing procedure. Similarly, for those objectives that test non-inferiority, if non-inferiority is 
established, a test of superiority will also be conducted, but unless specifically itemized in the 
list, such superiority testing is not part of the hierarchical testing procedure; these superiority 
tests may be of interest for scientific or financial reasons but will not be the basis for 
supporting labeling claims. 
 
 Ordered List of Secondary Objectives to be Tested To Support Labeling Claims 
C.12.1
1. Transvalvular mean gradient at 12 months (non-inferiority):   TAVI vs. SAVR (secondary 
objective #12). The hypothesis of interest is  
H: µ   TAVI < µ SAVR +5 
where µ   TAVI and µ SAVR denote the average mean gradient at 12 months, measured in mmHg.  
This objective will be evaluated using a Bayesian version of a two-sample t-test (see Section 
C.11). The posterior probability P(H | data) will be calculated and compared to a threshold of 
0.95.  
Rationale for Delta:  A difference less that 5 mmHg for mean gradient is not considered 
clinically relevant for the SURTAVI   Steering Committee.  
                                                     
 
12 Gelman A, Carlin JB, Stern HS, Rubin DB, Bayesian Data Analysis, 1st ed.  London:  Chapman & Hall, 
1995, p. 69. 
13 Albert J, Bayesian Computation with R, 1st ed.  New York: Springer, 2007. 

 
 
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2. Effective orifice area at 12 months (non-inferiority):   TAVI vs. SAVR (secondary objective 
#12).  The hypothesis of interest is  
H: µ   TAVI > µ SAVR – 0.1 
where µ   TAVI and µ SAVR denote the mean effective orifice area at 12 months, measured in 
cm2.  This objective will be evaluated using a Bayesian version of a two-sample t-test (see 
Section C.11). The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.95.   
Rationale for Delta:  A difference less that 0.1 cm2 for effective orifice area is not considered 
clinically relevant for the SURTAVI   Steering Committee. 
3. Change in NYHA classification from baseline to 12 months (non-inferiority):   TAVI vs. SAVR 
(secondary objective #8).  The hypothesis of interest is  
H: µ   TAVI > µ SAVR – 0.375 
where µ   TAVI and µ SAVR denote the mean number of classification improvements in NYHA 
from baseline to 12 months.  For subjects with NYHA categories at both baseline and 12 
month visit, the NYHA classification improvements will be calculated as NYHAbaseline – 
NYHA12month. The objective will be evaluated using a Bayesian version of a two-sample t-test 
(see Section C.11). The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.95.    
Rationale for Delta:  A difference less than 0.375 for NYHA classification is not considered 
clinically relevant for the SURTAVI   Steering Committee. 
4. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 30 
days (non-inferiority):   TAVI vs. SAVR (secondary objective #11).  The hypothesis of interest 
is  
H: µ   TAVI > µ SAVR -5 
where µ   TAVI and µ SAVR denote the mean improvements in the KCCQ score from baseline to 
30 days.  For subjects with KCCQ score at both baseline and 30 days, the improvement in 
KCCQ will be calculated as KCCQ30day – KCCQ baseline. The objective will be evaluated using a 
Bayesian version of a two-sample t-test (see Section C.11). The posterior probability P(H | 
data) will be calculated and compared to a threshold of 0.95.   
Rationale for Delta:  A 5 point improvement or decrease in KCCQ is the minimum difference 
that is clinically relevant. (Spertus J, et al, "Monitoring clinical changes in patients with heart 
failure: A comparison of methods," American Heart Journal 2005;150:710-715.) 
5. Length of index procedure hospital stay after   TAVI vs. SAVR (secondary objective #18).  
The hypothesis of interest is  
H: µ   TAVI < µ SAVR 
where µ   TAVI and µ SAVR denote the mean length of index hospital stay. The objective will be 
evaluated using a Bayesian version of a two-sample t-test (see Section C.11). The posterior 
probability P(H | data) will be calculated and compared to a threshold of 0.975. 
6. Transvalvular mean gradient at 12 months (superiority):   TAVI vs. SAVR (secondary 
objective #12). The hypothesis of interest is  
H: µ   TAVI < µ SAVR  
where µ   TAVI and µ SAVR denote the average mean gradient at 12 months, measured in mmHg.  
This objective will be evaluated using a Bayesian version of a two-sample t-test (see Section 
C.11). The posterior probability P(H | data) will be calculated and compared to a threshold of 
0.975.  
7.  Effective orifice area at 12 months (superiority):   TAVI vs. SAVR (secondary objective #12).  
The hypothesis of interest is  
H: µ   TAVI > µ SAVR   

 
 
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where µ   TAVI and µ SAVR denote the mean effective orifice area at 12 months, measured in 
cm2.  This objective will be evaluated using a Bayesian version of a two-sample t-test (see 
Section C.11). The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975.   
 
8. Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score from baseline to 30 
days (superiority):   TAVI vs. SAVR (secondary objective #11).  The hypothesis of interest is  
H: µ   TAVI > µ SAVR  
where µ   TAVI and µ SAVR denote the mean improvements in the KCCQ score from baseline to 
30 days.  For subjects with KCCQ score at both baseline and 30 days, the improvement in 
KCCQ will be calculated as KCCQ30day – KCCQ baseline. The objective will be evaluated using a 
Bayesian version of a two-sample t-test (see Section C.11). The posterior probability P(H | 
data) will be calculated and compared to a threshold of 0.975.   
 
9. Days alive out of the hospital at 12 months after   TAVI vs. SAVR (secondary objective #10).  
The hypothesis of interest is  
H: µ   TAVI > µ SAVR 
where µ   TAVI and µ SAVR denote the mean number of days alive out of the hospital at 12 
months.  The objective will be evaluated using a Bayesian version of a two-sample t-test (see 
Section C.11). The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975. 
10. Days alive out of the hospital at 24 months after   TAVI vs. SAVR (secondary objective #10).  
The hypothesis of interest is  
H: µ   TAVI > µ SAVR 
where µ   TAVI and µ SAVR denote the mean number of days alive out of the hospital at 24 
months.  The objective will be evaluated using a Bayesian version of a two-sample t-test (see 
Section C.11). The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975. 
11. Change in SF-36 Physical Summary Scale from baseline to 3 months: TAVI vs. SAVR 
(secondary objective #11).  The hypothesis of interest is  
H: µ   TAVI > µ SAVR 
 
where µ   TAVI and µ SAVR denote the mean improvements in the SF-36 Physical Summary 
Scale from baseline to 3 months.  The objective will be evaluated using a Bayesian version of 
a two-sample t-test (see Section C.11). The posterior probability P(H | data) will be calculated 
and compared to a threshold of 0.975.   
12. Change in EQ-5D from baseline to 3 months: TAVI vs. SAVR (secondary objective #11).  The 
hypothesis of interest is  
H: µ   TAVI > µ SAVR 
 
where µ   TAVI and µ SAVR denote the mean improvements in the EQ-5D from baseline to 3 
months.  The objective will be evaluated using a Bayesian version of a two-sample t-test (see 
Section C.11). The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975.   
13. Incidence of MACCE at 30 days or hospital discharge, whichever is longer: TAVI vs. SAVR 
(secondary objective #1).  The hypothesis of interest is  
H:    TAVI <  SAVR 
 
where    TAVI and  SAVR denote the binary rate of MACCE at 30 days or hospital discharge (if 
longer).  The posterior probability P(H | data) will be calculated and compared to a threshold 

 
 
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of 0.975.  The statistical method will be the Bayesian version of a comparison of proportions 
(see Section C.11).   
 
14. Incidence of major vascular complication at 30 days or hospital discharge, whichever is 
longer: TAVI vs. SAVR (secondary objective #3).  The hypothesis of interest is 
H:    TAVI <  SAVR 
where    TAVI and  SAVR denote the binary rate of major vascular complications at 30 days or 
hospital discharge (if longer).  The posterior probability P(H | data) will be calculated and 
compared to a threshold of 0.975. The statistical method will be the Bayesian version of a 
comparison of proportions (see Section C.11).   
15. Incidence of major or life-threatening bleeding events at 30 days or hospital discharge, 
whichever is longer: TAVI vs. SAVR (secondary objective #3).  The hypothesis of interest is 
H:    TAVI <  SAVR 
where    TAVI and  SAVR denote the binary rate of major or life-threatening bleeding events at 
30 days or hospital discharge (if longer).  The posterior probability P(H | data) will be 
calculated and compared to a threshold of 0.975. The statistical method will be the Bayesian 
version of a comparison of proportions (see Section C.11).   
16. Incidence of all strokes at 30 days or hospital discharge, whichever is longer: TAVI vs. SAVR 
(secondary objective #15).  The hypothesis of interest is 
H:    TAVI <  SAVR 
where    TAVI and  SAVR denote the binary rate of all strokes at 30 days or hospital discharge 
(if longer).  The posterior probability P(H | data) will be calculated and compared to a 
threshold of 0.975. The statistical method will be the Bayesian version of a comparison of 
proportions (see Section C.11).   
17. Incidence of moderate/severe aortic insufficiency after  TAVI vs. SAVR (secondary objective 
#12).  The hypothesis of interest is 
H:    TAVI <  SAVR 
where    TAVI and  SAVR denote the proportion of subjects with moderate/severe aortic 
insufficiency at the discharge echo.  The posterior probability P(H | data) will be calculated 
and compared to a threshold of 0.975. The statistical method will be the Bayesian version of a 
comparison of proportions (see Section C.11).   
18. New pacemaker implant rate for TAVI at 30 days or hospital discharge, whichever is longer 
(secondary objective #7).  The hypothesis of interest is 
H:    TAVI < 30% 
where    TAVI denote the binary rate of new pacemaker implants for TAVI at 30 days or 
hospital discharge (if longer).  The posterior probability P(H | data) will be calculated and 
compared to a threshold of 0.975. The statistical method will be the Bayesian version of a 
comparison of proportions (see Section C.11).   
Other than the hierarchical testing procedure described above, no further multiplicity 
adjustments will be made in the analyses of the secondary endpoints.  Summary data from 
other secondary objectives, such as device success and procedural success from secondary 
objectives #20 and #21, respectively, may be provided in the device labeling.  However, no 
claims of statistical significance or other statistical inference will be made.   
C.13 Heterogeneity/Poolability 
A poolability analysis among investigational centers, access site (iliofemoral or non-iliofemoral), 
need for revascularization, and primary baseline demographics will be performed for the 

 
 
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primary endpoint. In particular, the primary endpoint and key secondary endpoints such as 
MACCE and MAE incidence will be examined for differences in outcome between genders, 
need for revascularization, and between access sites.  Additionally, tests for these outcomes 
will be performed to evaluate potential interactions between treatment and gender and between 
treatments and need for revascularization and between treatment and access site. 
 Geography Poolability Analysis 
C.13.1
Poolability analyses may be conducted either with frequentist or Bayesian statistical methods.  
The analysis descriptions below are written with the language of frequentist methods.  If 
Bayesian methods are used, analogous models will be employed, with non-informative prior 
distributions, and statements below such as "significant at the 0.15 level" can be understood to 
mean if the 85% equal-tailed Bayesian credible interval (BCI) for the parameter of interest 
excludes 0." 
C.13.1.1 Primary Endpoint by Geography 
The interaction between geography (Europe and North America) and treatment on the 
probability of death or disabling stroke will be compared using a logistic regression model. This 
analysis will be performed on the modified intent-to-treat (mITT) population, for subjects whose 
status at 24 months is known. If the resulting test is significant at the 0.15 level, further 
exploratory analysis will attempt to identify covariates that may explain treatment effect 
differences between the regions. Otherwise, the data will be considered to be poolable across 
geographies. 
C.13.1.2 Univariate Covariate Analysis 
If in the analysis of primary endpoint by geography, the resulting p-value is ≤ 0.15 then the 
following baseline characteristics will be examined individually as potential predictors of death 
or disabling stroke using logistic regression models: 
 
Gender 
 
Age 
 
Baseline NYHA 
 
STS score 
 
Baseline LVEF 
 
Hypertension 
 
Diabetes 
 
Coronary artery disease 
 
Prior stroke 
 
Prior MI 
 
Prior PI 
C.13.1.3 Multivariate Analysis 
If in the analysis of primary endpoint by geography, with a 0.15 significant level, and the 
covariates with a 0.20 significant level from the Univariate Covariate Analysis will be included 
along with geography in a logistic regression model. If this multivariate regression does not 
result in a significant (level 0.15) geography by treatment interaction after adjustment for these 
baseline factors, then outcome results will again be considered poolable across geographies. If 
geography by treatment interaction is still significant (level 0.15) after adjustment for these 
factors, results will be presented by geography and the clinical significance of these differences 
will be assessed. 
If it is determined the data is not poolable across geographies, then a random-effects model for 
the primary endpoint that includes geography as a random effect will be provided. 

 
 
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 Site Poolability Analysis 
C.13.2
If the geographic regions Europe and North America are considered to be poolable, then the 
Site Poolability Analysis will be performed on all sites, for subjects. The geographic regions 
(Europe, United States, Canada ) is not taken into account.  
Should, however, the geographic regions Europe and North America not be considered to be 
poolable, then for both of these regions a separate poolability analysis will take place.  
C.13.2.1 Pooling of Small Sites 
  
Sites should contribute both at least 5 treatment and at least 5 control subjects to the mITT 
population. If this is not the case, the site is considered a “small site”; small sites will be ordered 
by the date of first enrollment in the mITT population. Starting with the first “small site”, a 
pseudo-site will be created by adding subjects from successive “small sites”. Once the number 
of subjects (treatment and control subject together) reaches or exceeds the size of the median 
enrollment (treatment and control subject together) of the “large sites”, then a second pseudo-
site will be created, beginning with the next site not already included in the first pseudo-site. 
Additional pseudo-sites, if needed, would be created in the same manner. 
If the geographic regions Europe and North America are considered to be poolable then the 
pseudo-sites can consist of small sites of both geographic regions. If however the regions are 
not considered to be poolable, then specific Europe pseudo-sites and North America pseudo-
sites need to be created. A separate site poolability analysis will be performed for Europe sites 
and for North American sites. 
C.13.2.2 Primary Endpoint by Site 
The interaction between site or pseudosite and treatment on the probability of death or 
disabling stroke will be compared using a logistic regression model. This analysis will be 
performed on the mITT population for subjects whose status at 24 months is known. If the 
resulting test is significant at the 0.15 level, further exploratory analysis will be conducted.  One 
analysis will implement a random-effects model for the primary endpoint that includes site as a 
random effect.  Another analysis will attempt to identify covariates that may explain treatment 
effect differences among the sites, beginning in the next section. Otherwise, the data will be 
considered to be poolable across study sites. 
C.13.2.3 Multivariate Analysis 
If in the analysis for Primary Endpoint by Site, the resulting test is significant at the 0.15 level 
then the covariates significant at the 0.20 level from Univariate Covariate Analysis will be 
included along with site in a logistic regression model. If this multivariate regression does not 
result in a significant (level 0.15) site by treatment interaction after adjustment for these 
baseline factors, then outcome results will again be considered poolable across study sites. If 
site by treatment interaction is still significant (level 0.15) after adjustment for these factors, 
results will be presented by site and the clinical significance of these differences will be 
assessed. 
C.14 Additional Analysis 
 Pre-Defined Subgroups 
C.14.1
The following sub-groups will be analyzed for publication purposes: 
 
Diabetes Mellitus (yes, no) 
 
Age ([< 65 years of age (i.e. Medicare population), 65-70 years of age, 70-74 years of 
age, 75-79 years of age and ≥80 years of age) 
 
Gender (male, female) 
 
STS score 
 
Presence of co-morbidities 

 
 
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 
Need for coronary revascularization 
A test for interaction between the treatment effect (SAVR versus TAVI) and the subgroup 
variable will be performed. 
These comparisons are not powered, and will be for exploratory purposes only, not to be used 
to support labeling claims.  
 Analysis of VARC Endpoints and Definitions 
C.14.2
C.14.2.1 Endpoints:   
Device success will be calculated per the definition outlined in the SURTAVI protocol Section 
O.2 Definitions of Terms as well as using the VARC-I definition, as appropriate. 
C.14.2.2 Definitions 
Events with definitions modified in revisions to VARC will be analyzed per both the definition 
outlined in the SURTAVI protocol Section O.2 Definitions of Terms and VARC-I definitions.  
Applicable terms include: 
 
Acute Kidney Injury 
 
Bleeding 
 
Death  
 
Device Migration/ Valve Embolism 
 
Device Malplacement 
 
Myocardial Infarction 
 
Prosthetic Valve Dysfunction 
 
Stroke and TIA 
 
Vascular Complications 
 Health-Related Quality of Life (HRQoL) and Treatment Costs 
C.14.3
Health-related quality of life (HRQoL) and treatment costs will be assessed alongside the core 
clinical trial to evaluate the impact of the TAVI and SAVR strategies on a range of relevant 
quality of life (QoL) domains and also to evaluate the cost-effectiveness of the two treatment 
strategies. 
 Quality of Life 
C.14.4
Health Related Quality of Life (HRQoL) and functional status will be assessed using a 
combination of generic and disease-specific measures selected to cover a broad range of 
health domains that may be affected by severe aortic stenosis disease, its treatment, and its 
complications: the Medical Outcomes Study 36-item Short Form (SF-36), the Kansas City 
Cardiomyopathy Questionnaire (KCCQ), and the EuroQoL Five Dimensions (EQ-5D). All 
subjects will complete standardized, written questionnaires at baseline (prior to subject being 
informed of randomization), 30 days, 6 months, 12 months, 18 months, 24 months and annually 
thereafter up to 5 years.  At 3 months subjects will also be contacted via telephone to complete 
the EQ-5D, in select geographies SF-36 will also be collected Economic Outcomes/Cost-
Effectiveness. 
C.15 Economic Outcomes/Cost-Effectiveness 
Data on resource utilization will be collected for the index hospitalization and through long-term 
follow-up for all enrolled subjects.  These resource items will include number and duration in-
patient stays in hospital by type of unit (eg, intensive care, high-dependency care and standard 
ward care); number of clinic visits (by type of physician); and details of the main procedure 
undertaken.  As part of the trial analysis, resource use estimates will be presented by 
randomized group (eg, mean per subject plus standard deviation).  These data, together with 
the EQ-5D data will provide an important input into cost effectiveness analysis.  However, as 
such analysis is likely to be based on a modeling framework, to include evidence from a 
number of sources (eg, a meta-analysis of other TAVI trials) and to vary according to the 

 
 
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jurisdiction of interest, it is appropriate to detail the methods in separate protocols and analysis 
plans.  
C.16 Use of Data for CE Mark 
Data from the TAVI arm may be utilized to seek CE Mark approval for the Intermediate Risk 
indication prior to study completion.  This is expected to include the experience of 
approximately the first 100 TAVI subjects out to 30 days.  This analysis will not impact the Type 
I error rate of this study as there will not be an early analysis of control (randomized) data, and 
no decisions to alter the pivotal trial are allowed based on this analysis.  This data will not be 
made public and a limited number of personnel will have access to the results. 
 
 

 
 
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D REVISION PROCESS 
The study statistician will be responsible for the execution of this statistical analysis plan, 
including any revisions and obtaining of appropriate approvals. 
E DISTRIBUTION 
The study statistician will be responsible for execution of this statistical analysis plan and 
distribution of revisions to the appropriate clinical staff. 
 
 

 
 
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F REVISION HISTORY 
Version 
Date 
Author 
Summary of Changes 
1.0 
16-May-2012 
Sharla Chenoweth 
Initial Release 
2.0 
26-Aug-2012 
Sharla Chenoweth 
Incorporate recommended changes from 
FDA:  perform analysis on ITT, mITT, and 
implanted populations 
Incorporate Medtronic responses to FDA 
regarding justification  
3.0 
27-Nov-2012 
Sharla Chenoweth 
Incorporate recommended changes from 
FDA 
Update secondary endpoints to correspond 
to VARC II definitions 
4.0 
25-Feb-2015 
  
Yanping Chang 
Incorporate study re-design changes: 
 
Modify non-inferiority to absolute 5% 
 
Adjust assumed event rate to 17% 
 
Adjust final sample size to N=2000 
 
Modify Sample Size Looks to 
N=1400 and 1700 
 
Add #24 secondary endpoint resheath and 
recapture (combined) success rate 
 
Modify the hypothesis testing from 
superiority to non-inferiority for #3 
hierarchical testing NYHA change from 
baseline to 12 months   
 
Version control (footer) corrected to internal 
document control requirements 
5.0 
28-OCT-2015 
Yanping Chang 
Incorporate recommendations from FDA: 
 
Add primary endpoint superiority testing 
threshold and type I error rate table for the 
primary endpoint superiority testing 
 
All OC tables for non-inferiority testing of the 
primary objective have been updated 
because of the re-run of the simulation to 
incorporate superiority testing at the level 
0.025 (Ψsup = 0.989). 
 
Add more scenarios treating P as an N or an 
E for sample size determination analyses   
 
Modify hierarchical testing procedure by 
adding the primary endpoint superiority 
testing and the superiority testing for the 
following secondary endpoints to the testing 
order:   
 
Transvalvular mean gradient at 12 
months 
 
Effective orifice area at 12 months 
 
Change in Kansas City 
Cardiomyopathy Questionnaire 
(KCCQ) score from baseline to 30 
days   
6.0 
31-May-2016 
 
Incorporate study design changes: 
 
Modify non-inferiority margin to 

 
 
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absolute δ =0.07 
 
Adjust maximum sample size to 
N=1600. This trial was previously 
designed using a non-inferiority 
margin (δ) of 0.05, and an adaptive 
analysis plan wherein the sample 
size was chosen from possible 
values of 1400, 1700, and 2000, 
based on evidence available at 
interim analyses.  After the 1400-
subject sample size interim analysis, 
the margin was changed to δ = 0.07.  
The resulting increase in study 
power obviated the need for 
adaptively determining sample size, 
and the accrued sample size at the 
time of this change (approximately 
1600 mITT subjects) was 
determined to sufficiently power the 
study. 
 
Modify the previous study design. 
Current design has one sample size 
look analysis (using δ = 0.05) when 
1400 subjects have entered the 
mITT population, one “Early Win” 
analysis (using δ = 0.07) when 1400 
mITT subjects have reached 12 
months, and a final analysis (using δ 
= 0.07) when all mITT subjects have 
reached 24 months.   
 
 
 
 

 
 
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G APPENDIX 
G.1 Sample Size Determination Algorithm 
The sample size determination algorithm is as follows.  At a pre-defined analysis time (eg., 
when N=Ni subjects have been accrued;  Ni =1400 , or 1700 for the previous design), two 
predictive probabilities are calculated: 
• 
PPwin = Pr(Eventual Win | Data, N=Ni is the final sample size) 
• 
PPfut = Pr(Eventual Win | Data, N=2000 is the final sample size) 
Although the current design has a maximum sample size of N=1600, the predictive probability 
calculation retains N=2000 from the previous design. 
If PPwin exceeds a suitably high threshold Wi, subject accrual will stop because final success 
looks probable.  On the other hand, if PPfut is less than a suitably low threshold Fi, subject 
accrual will stop and futility will be declared.  If neither of these conditions obtains, accrual will 
continue to the next larger sample size.  These analyses are termed "Sample Size Looks."  
Thresholds Wi and Fi are listed in Table 13 (Note that the second row, N=1700 is no longer 
applicable for the current design)Error! Reference source not found..  Further detail on the 
calculation of these predictive probabilities is given in Section C.5 Predictions. 
Table 13:  Thresholds for stopping accrual for reasons of futility or probable eventual 
success for each of the 2 interim sample size determination analyses 
Sample Size 
Determination 
Analysis 
(i) 
Sample Size  
 
 
(Ni) 
Threshold for  
Stopping for Futility 
(Fi) 
Threshold for Stopping 
for Likely Future Win 
(Wi) 
1 
1400 
0.05 
0.80 
2 
1700 
0.10 
0.80 
 
 
For all Sample Size Looks, informative priors for the transitions are tabulated in Table 2 and 
displayed graphically in Figures 2 and 3. Further rationale for the choice of these prior 
distributions is given in appendix G.2 and G.3. Appendix G.4 provides skeletons justification 
and Appendix G.5 summarizes the appropriateness of imputing missing data in the analysis. 
 
G.2 Reasonableness of Priors 
Consider the following desirable features: 
 
Transition #1 represents the probability of a subject having an event somewhere 
between initial implant and 24 months, and this is expected to be approximately 17%, 
with some uncertainty over the range 7%-23%.     The   estimated   24 month SURTAVI 
rate is 17%. Uncertainty in this rate is exactly the motivation for using an adaptive study 
design.  This expected value and uncertainty are both captured nicely in this 
distribution.   
 
Transition #9 is fairly narrow, with dominant support centered close to 5% and ranging 
up to 10%.  This represents the belief that if a subject is event-free at 18 months, the 
likelihood of that subject having an event prior to 24 months is low. 
 
Transitions 1, 3, 5, 7 represent a progression of the notion in transition #9.  The 
distribution of Transition #7 is somewhat wider and shifted somewhat higher than that 
of Transition #9, reflecting the fact that subjects who are event-free at 12 months have 

 
 
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more time to have an event than does a subject who is event-free at 18 months.  
Similar statements can be made about Transitions 5, 3, and 1. 
 
Transitions 2, 4, 6, and 8 all address the probability that a subject with a "Possible 
Event" at some time point will end up in the "Event" state at 24 months.  It is expected 
that "possible events" will be classified as disabling strokes with probability about 0.25, 
and all of these distributions are centered at approximately 0.25, with some spread in 
support ranging from about 10% to 40%, with slightly more precision in the later 
transitions (e.g., Transition #8) than the earlier ones (e.g., Transition #2).  Even if a 
subject in a "Possible Event" state has that possible event classified as "not a disabling 
stroke", it is still possible that such a subject will end up as an "Event" at 24 months 
because of a subsequent stroke or death, and thus the mean of the Transition #2 
distribution is slightly higher than the mean of Transition #8, reflecting the increased 
time in which such a subsequent event could occur. 
It is also important to recognize that, during the course of the trial, these priors are modified by 
the accruing data via Bayes' theorem, and thus at later analyses, when substantial 24-month 
data are available, the impact of these priors is diminished.  Most importantly, all decisions for a 
"Win" will not use these informative distributions, but rather will use flat priors. 
G.3 Derivation of the Informative Priors 
To understand the derivation of the prior distributions assigned to the model transition 
probabilities, it is helpful first to consider how subjects traverse the study period.  In Figure 1, 
consider that a subject begins in the "Start" state and moves to one of the states (gray circles 
E, P, or N) at 1 month, and then again to a state (gray circle E, P, or N) at 6 months, and again 
at 12 and 18 months, and finally ending in either the E or N state at 24 months.  Suppose that 
each one of these "state transitions" has a known probability of occurrence.  These "state 
transitions" arise from consecutive time points and are generally not the transitions that are part 
of the analysis model ; the "model transitions" are generally from non-consecutive time points, 
such as P(E24|P1) or P(E24|N6), which are indicated as the curved lines in Figure 1.  However, 
probability values for the state transitions uniquely determine the probability values of the model 
transitions, and by understanding or making sensible assumptions about the state transitions, 
sensible model transitions will result.   It is generally easier to think about state transitions than 
model transitions, and that was the approach taken here. 
The consecutive-visit state transitions is exactly the process that is used to generate artificial 
data for the simulation.  Section C.7 Simulation Details and Design Sensitivity describe the 
mechanism for generating artificial data with sensible temporal correlation.  This starts with a 
"skeleton" of state transition probabilities (see Table 8).  Consider that a subject must traverse 
the study period by following a particular path, such as Non-Event at 1, 6, and 12 months and 
then a Possible Event at 18 and finally an Event at 24 months.  The probability of a randomly 
chosen subject following this particular path would be  
P(N1) × P(N6|N1) × P(N12|N6) × P(P18|N12) × P(E24|P18). 
By summing such probabilities over all possible paths, these transition probabilities induce 
marginal probabilities at each time point (such as P(E1), P(E6), P(E12), P(E18), and P(E24)).  
Similarly, these skeletal probabilities also induce probabilities for the model transitions (e.g., 
P(E24|P1) or P(E24|N12)).   
The process of generating data for the simulation entailed starting with the skeleton of 
probabilities and adjusting it to achieve specific target values of P(E24).  This process is 
described in Section C.7.4 Temporal Correlation.  For example, if the target value of P(E24) in 
the treatment group is to be 0.20, then the value ε = 0.07012076 is applied to the skeleton 
probabilities for the treatment group to result in a transformed vector of "state transition" 
probabilities as shown in Table 14Error! Reference source not found..  These state transition 
probabilities induce the values for marginal probabilities and model transition probabilities also 
shown in Table 14Error! Reference source not found..   

 
 
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Table 14.  Induced Probabilities when the Target Value P(E24) = 0.20 
State 
Transitions 
(Consecutive 
Time Points) 
P(E1) 
P(P1) 
P(N1) 
P(E6|E1) 
P(E6|P1) 
P(P6|P1) 
0.0214 
0.0321 
0.9465 
1.0000 
0.2634 
0.0107 
P(N6|P1) 
P(E6|N1) 
P(P6|N1) 
P(N6|N1) 
P(E12|E6) 
P(E12|P6) 
0.7259 
0.0428 
0.0107 
0.9465 
1.0000 
0.2634 
P(P12|P6) 
P(N12|P6) 
P(E12|N6) 
P(P12|N6) 
P(N12|N6) 
P(E18|E12) 
0.0107 
0.7259 
0.0428 
0.0107 
0.9465 
1.0000 
P(E18|P12) 
P(P18|P12) 
P(N18|P12) 
P(E18|N12) 
P(P18|N12) 
P(N18|N12) 
0.2634 
0.0107 
0.7259 
0.0428 
0.0107 
0.9465 
P(E24|E18) 
P(E24|P18) 
P(N24|P18) 
P(E24|N18) 
P(N24|N18) 
 
1.0000 
0.2737 
0.7263 
0.0534 
0.9466 
 
Marginal 
Probabilities 
P(E1) 
P(P1) 
P(N1) 
P(E6) 
P(P6) 
P(N6) 
0.0214 
0.0321 
0.9465 
0.0704 
0.0105 
0.9191 
P(E12) 
P(P12) 
P(N12) 
P(E18) 
P(P18) 
P(N18) 
0.1125 
0.0100 
0.8776 
0.1526 
0.0095 
0.8379 
P(E24) 
P(N24) 
 
 
 
 
0.2000 
0.8000 
 
 
 
 
Model 
Transitions 
#1 
#2 
#3 
#4 
#5 
#6 
0.2000 
0.3666 
0.1762 
0.3365 
0.1372 
0.3051 
#7 
#8 
#9 
 
 
 
0.0963 
0.2737 
0.0534 
 
 
 
 
The target values of most interest in our simulation range from a low of 0.07 to a high of 0.23.  
By iterating this process over target values ranging from 0.07 to 0.23, a vector of model 
transition probabilities is created for each of the model transitions, and the means and 
variances of these vectors are used to create Beta prior distributions that match those means 
and variances.  As an example, consider P(E24|P18), which is Model Transition #8 and also 
happens to be one of the State Transitions.  As the target value of P(E24) varies from 0.07 to 
0.23, this transition takes on the probabilities shown in Table 15.  The mean and standard 
deviation of these 16 values are 0.2138192 and 0.06058585, respectively, and a Beta 
distribution that matches that mean and standard deviation is Beta(9.491, 34.896), which is 
thus the specified prior distribution for Transition #8 (treatment group), as shown in Figure 2.   
Table 15.  Induced Probabilities of P(E24|P18) [Transition #8] as the Target P(E24) is 
varied from 0.07 to 0.23 
Target P(E24) 
0.07 
0.08 
0.09 
0.10 
0.11 
0.12 
0.13 
0.14 
P(E24|P18) 
0.1119 
0.1262 
0.1401 
0.1537 
0.1669 
0.1799 
0.1925 
0.2049 
Target P(E24) 
0.15 
0.16 
0.17 
0.18 
0.19 
0.20 
0.21 
0.22 
P(E24|P18) 
0.2169 
0.2288 
0.2404 
0.2517 
0.2628 
0.2737 
0.2844 
0.2949 
Target P(E24) 
0.23 
P(E24|P18) 
0.3052 
 
It is not a theoretical requirement that the prior distributions be consistent with the data that will 
be presented to the model during simulation (or during the actual trial).  For trial design, 
however, it seems most logical to tune the model to perform well for the data that are actually 
expected to arise, and these priors are specifically chosen to do that.  It is recognized that the 
actual data may or may not be consistent with the assumptions used in creating these priors,  
and for that reason the protocol includes a study of sensitivity to this temporal correlation (by 
examining the impact of total temporal correlation and total temporal independence in Section 
C.7.4 Temporal Correlation).   The design is quite robust, as seen in Table 4. 

 
 
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G.4 Justifying the Skeletons 
This section describes the rationale for the probability skeletons shown in Table 8. 
Data published by Iturra et al.14 and CoreValve US Pivotal High Risk study results are 
presented in Figure 4.  
Figure 4: Mortality or Major Stroke rate from Literature and CoreValve US Pivotal High 
Risk Study 
 
As reported in the Iturra paper, the incidence of all-cause mortality at 30 day was 2.8% and late 
all-cause mortality Kaplan-Meier rate at 24 months was 12.1%. The major stroke rate was 3.2% 
for subjects who survived to 1 year in the CoreValve Pivotal High Risk study. The High Risk 
study had a higher-risk population than SURTAVI, therefore, the major stroke rate in the High 
Risk study is adjusted downwards and a two-year follow-up period instead of a one-year follow-
up period is used. Overall, the estimation of the 24 months all-cause mortality or disabling 
stroke rate range of 17%-21% should be a close estimation of the 2 year rate in SURTAVI. 
A set of inclusion and exclusion criteria were developed to identify subjects at intermediate risk 
for SAVR from the High Risk cohort. A total of 444 subjects from this US Pivotal Trial met these 
criteria, and received an attempted procedure, and are presented as the intermediate risk (IR) 
cohort. Table 16 summarizes the all-cause mortality and all stroke rate for those subjects.  
Table 16.  All-Cause Mortality and All Stroke Data for IR Cohort of the High Risk Study  
 
IR TAVI 
N=239 
IR SAVR 
N=205 
 
# Subjects 
with Events 
Binomial  
% 
Kaplan-Meier 
% 
# Subjects 
with Events 
Binomial  
% 
Kaplan-Meier 
% 
All-Cause Mortality 
30 Day 
5 
2.1 
2.1 
8 
3.9 
3.9 
1 Year 
26 
10.9 
11.0 
27 
13.2 
13.3 
All Stroke 
30 Day 
9 
3.8 
3.8 
12 
5.9 
5.9 
                                                     
 
14 Iturra SA, Suri RM, Greason KL, et al. The Journal of thoracic and cardiovascular surgery 2014;147:127-132.  
 
2.8% 
12.1% 
3.2% 
0.0%
2.0%
4.0%
6.0%
8.0%
10.0%
12.0%
14.0%
16.0%
18.0%
20.0%
All-cause Mortality or Major 
Stroke (%) 
Major stroke without
mortality (incidence, IR HR)
Late mortality at 2 years (KM,
Iturra et al)
30-day mortality (incidence,
Iturra et al)
Iturra et 

 
 
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1 Year 
14 
5.9 
6.0 
22 
10.7 
11.4 
The skeleton in Table 8 was developed to have a probability for all-cause mortality or disabling 
stroke at 24 months to be between 18%-21% for each treatment arm.  As shown in the Table 
16, the SAVR cohort is expected to have a slightly higher all-cause mortality rate and all stroke 
rate at 1 month than TAVI    The probability of a stroke being classified as disabling in literature 
is a wide range of approximately 40%-70%, however, it was observed to be 11.4% (95% CI 
3.2%-26.7%)  in this IR cohort. Therefore   the estimated probability of 25% is chosen.  After 6 
months, it is assumed that the rate of all-cause death and disabling stroke will be similar and 
remain constant for each treatment arm.   
G.5 Appropriateness of Imputing Missing Data 
The appropriateness of predicting/imputing missing data is justifiable on the basis of several 
important considerations: 
1. The FDA guidance on Bayesian statistics discusses the use of predicting/imputing missing 
data.  See "Guidance for the Use of Bayesian Statistics in Medical Device Clinical Trials," 
Sections 5.4 "Predictive Probabilities" and Section 5.5 "Interim Analyses." 
2. There is precedent.  For example, the INTERFIX PMA documentation that is referenced in 
the FDA guidance:  Summary of Safety and Effectiveness for PMA P970015 at 
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfTopic/pma/pma.cfm?num=p970015.  
As an example from the field of cardiology, see Wilber et al., "Comparison of Antiarrhythmic 
Drug Therapy and Radiofrequency Catheter Ablation in Patients With Paroxysmal Atrial 
Fibrillation:  A Randomized Controlled Trial,"  JAMA, January 27, 2010—Vol 303, No. 4, pp 
333-340, and especially the statistical methods in the third column of page 335. 
3. At any analysis (interim or final, sample size or "win" determination), ignoring subjects with 
incomplete follow-up leads to biased estimates of the event rate.  Consider two hypothetical 
subjects (A and B), one of which (A) will be LTFU at 11 months and the other (B) at 13 
months, so neither will finish the trial.  .  Now suppose each die at 12 months.  We will know 
about B's death but not about A's death, so a simple proportion of events at 24 months will 
include B in the numerator, but whether or not to include A in the denominator is disputable.  
To include A in the denominator as a non-death when there has only been 11 months of 
known follow-up is to assume that A will not have an event in the remaining 13 months, 
which in this case is patently false and would lead to an underestimate of the true event 
rate.  To exclude A and any other subjects with only 11 months of follow-up would lead to 
an over-estimate of the true event rate.  Either way, the event rate estimate is biased.  The 
only sensible approach is to somehow account for partial follow-up by giving "partial credit" 
to these patients.  Survival analysis techniques with explicit censoring mechanisms do this 
automatically and explicitly, and this is non-controversial.  But that is not the only way to 
accomplish this goal.  Important considerations in why the proposed method was chosen 
over survival analysis are (a) the fact that outcomes known at interim time points are not 
binary (event/no event) but rather ternary (event, possible disabling stroke, no event), (b) 
the fact that the focus of interest is an event rate at a specific time point (24 months), while 
most survival analysis techniques tend to compare hazards over all follow-up time, and (c) 
the fact that Bayesian survival analysis methods are generally more computationally 
burdensome than binomial and betabinomial calculations, a non-trivial consideration when 
faced with the task of extensive simulation. 
4. The partial follow-up and interim outcomes are part of the body of evidence.  Outcomes at 
interim time points such as 12 months are important in their own right and also predictive of 
the 24-month outcomes.  The quality of the prediction is learned in this very trial, so to 
analyze completers only is to ignore important evidence in the decision process. 
G.6 Type I Errors for the Primary Endpoint Superiority Testing 
There are three possible time points where testing primary endpoint superiority could occur:  
 
Simultaneous to demonstrating non-inferiority at the first (interim) “Win Look.” 

 
 
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 
Simultaneous to demonstrating non-inferiority at the final “Win Look,” in the event that 
non-inferiority is not established at the first (interim) Win Look. 
 
All mITT subjects have reached 24 months, in the event that non-inferiority but not 
superiority ise established at the first (interim) Win Look.  (SAP Section C.4.2.1 terms 
this a “delayed determination of superiority.” 
Simulations were conducted to assess the type I error rate for the primary endpoint superiority 
testing under the previous trial design, and it was found that, in order to control the type I error 
rate at ≤ 0.025, the posterior threshold ΨSUP for declaring superiority must be higher than the 
posterior threshold Ψ used for the primary endpoint non-inferiority testing. The threshold value 
ΨSUP is designated to be 0.989 in order to control type I error at a level ≤ 0.025 for superiority. 
The current design retains the same threshold. Table 17 summarizes all type I errors observed 
through repeated trial simulations under the varying conditions of accrual rate, control success 
rate, and serial correlation that were described in the SAP section C.7.  As with the simulations 
assessing non-inferiority, each cell of the table is based on 10,000 simulated clinical trials, with 
predictions based on 5,000 draws from each of the predictive model transition distributions.  
Under all scenarios, type I error is controlled at ≤ 0.025.  There is no evidence that the type I 
error exceeds 0.025.  Even in the scenario with observed type I error greater than 0.025 (eg., 
0.0275) could easily result from a simulation of size 10,000 with underlying true rate = 0.025:  a 
95% probability interval calculated as 0.025 ± 1.96 √(0.025× 0.975 / 10000) would range from 
0.0219 to 0.0281, so a value as high as 0.0275 is entirely expected and constitutes no evidence 
of a type I error inflation.   
Table 17:  Simulated Type I error rates given varied correlation structures, accrual rates, 
and control event rates.  10,000 simulated trials per cell, with predictions based 
on 5,000 imputations for the primary endpoint superiority testing 
 
Control Event Rate 
0.12 
0.17 
0.22 
Complete 
Temporal 
Correlation 
Accrual Rate 
Slow 
0.0118 
0.0123 
0.0118 
Expected 
0.0154 
0.0135 
0.0124 
Fast 
0.0110 
0.0133 
0.0108 
Expected 
Temporal 
Correlation 
Slow 
0.0149 
0.0120 
0.0147 
Expected 
0.0164 
0.0163 
0.0200 
Fast 
0.0175 
0.0176 
0.0173 
Complete 
Temporal 
Independence 
Slow 
0.0172 
0.0188 
0.0169 
Expected 
0.0206 
0.0202 
0.0215 
Fast 
0.0252 
0.0275 
0.0258 
 

SURTAVI SAP summary of changes 
 
Design Element 
V1 (CIP V4) 
V2 (CIP V5) 
V3 (CIP V6) 
V4 (CIP V10) 
V5 (CIP V11) 
V6 (CIP V12) 
Noninferiority (NI) 
margin 
20% relative NI 
margin  
  HA: πT / πc < 1 
+ 0.2 
 
No Change 
No Change 
5% absolute NI 
margin 
𝐻𝐻𝐴𝐴: 𝜋𝜋𝑇𝑇 < 𝜋𝜋𝐶𝐶
+ 0.05 
No Change 
7% absolute NI 
margin 
𝐻𝐻𝐴𝐴: 𝜋𝜋𝑇𝑇 < 𝜋𝜋𝐶𝐶
+ 0.07 
Design 
Bayesian 
Adaptive with 
one early win 
analysis 
with prediction 
of missing 
outcomes 
No Change 
No Change 
Bayesian, 
Adaptive 
• Maximum 
N=2000 
• Early Win 
Analysis (12 
months after 
enrollment 
stop) 
• Final Analysis 
(all subjects 
through 24 
months) 
No Change 
Bayesian 
 
• Maximum 
N≈1600 
• Early Win 
Analysis (12 
months after 
N=1400 
accrued) 
• Final Analysis 
(all subjects 
through 24 
months; 
N≈1600) 
 
Assumed 2 yr event rate 
25% 
No Change 
No Change 
17% 
No change 
No Change 
Sample size 
3700 
No Change 
No Change 
2000 
No Change 
 
Sample size looks 
first look at 
1000 then at 
1500, 2000, 
2500 and 3000 
patients 
First look at 
1500 then  
2000, 2500, 
3000 patients 
No Change 
First look at 
1400 patients, 
then 1700 
No Change 
1400 patients 
with 12 month 
follow-up; Final 
all patients 
through 24 
months  
Secondary endpoint 
18  
19 (added AF) 
22 (added three 
VARC II 
composite 
endpoints) 
No Change 
No Change 
No Change 

 
Hierarchical testing 
6 endpoints 
 
• MGV 
• EOA 
• NYHA 
• KCCQ 
•  MACCE 
•  SF-36 
8 
 
Added: 
• Length of stay  
• Major bleeding 
at 30 days) 
 
15 
 
Added: 
• Days alive out 
of hospital at 1 
year 
• Days alive out 
of hospital at 2 
year 
• EQ-5D 
• Major vascular 
complication  
• All stroke 
• Moderate/seve
re AR 
•  PPI 
Modified: 
• Major bleeding 
to major or 
life-
threatening 
bleeding. 
 
15 
 
Modified NYHA 
from superiority 
to NI testing 
 
18 
Added 
superiority 
testing for 
• MGV 
• EOA 
• KCCQ 
 
No Change 
Other 
 
ITT, IMP for 
primary and 
most secondary 
endpoints 
 
Inclusion 
criteria changed 
from STS 4-8% 
to 30-day 
predictive 
mortality risk  
[3, 15)% 
Added primary 
endpoint 
superiority 
testing 
threshold