Medtronic Evolut™ EXPAND TAVR I Feasibility Study
Phase: NA
Conditions: Aortic Valve Stenosis
Sponsor: Medtronic Cardiovascular

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Clinical Investigation Plan
Clinical Investigation Plan 
Evolut™ EXPAND TAVR I Feasibility Study 
Study Product Name 
Evolut PRO+ TAVR System 
Sponsor/Local Sponsor 
Global Sponsor 
Medtronic, Inc 
Coronary and Structural Heart Clinical 
8200 Coral Sea St NE, MVS 66 
Mounds View, MN  55112 
United States 
Regional Sponsor: Europe and Israel 
Medtronic Bakken Research Center 
Coronary and Structural Heart 
Endepolsdomein 5 
6229 GW Maastricht 
The Netherlands 
Regional Sponsor: Australia  
Medtronic Australasia Pty Ltd 
2 Alma Road, Macquarie Park 
NSW 2113 
Australia 
Regional Sponsor: New Zealand 
Medtronic New Zealand Limited 
Level 3, Bldg 5, 666 Great South Road 
Penrose, Auckland 1051 
New Zealand 
Regional Sponsor: Canada 
Medtronic Canada ULC 
99 Hereford St., Brampton 
ON, L6Y 0R3  
Canada 
Document Version 
Revision D dated 09 Mar 2021 
Document Reference Number 
D00266108 
Lead Principal Investigator(s) 
Dr. Paul Sorajja 
Abbott Northwestern Hospital 
Minneapolis MN USA 
 
Dr. Josep Rodes-Cabau 
University Institute of Cardiology and Respirology of Quebec 
Quebec QC Canada 
Confidentiality Statement
The information contained in this document is confidential and the proprietary property of Medtronic. Any distribution, copying, or
disclosure without the prior written authorization of Medtronic is strictly prohibited. Persons to whom the information is disclosed must know 
that it is confidential and that it may not be further disclosed by them. 

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5.5.1 
Site Principal Investigator ................................................................................................... 22 
5.5.2 
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12.3.1 
Time Windows for Completion and Submission of eCRFs .................................................. 63 
12.3.2 
Data Review and Processing ............................................................................................... 63 
12.3.3 
Source Documents .............................................................................................................. 63 
12.3.4 
Direct Access to Source Data/Documents .......................................................................... 64 
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12.8.1 
Investigator Reports ............................................................................................................ 65 
12.8.2 
Sponsor Reports .................................................................................................................. 69 
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13.3.1 
Required Evaluations .......................................................................................................... 81 
13.3.2 
General Procedures ............................................................................................................ 81 
13.3.3 
Data Requirements ............................................................................................................. 82 
13.3.4 
Acquisition of Key Variables ................................................................................................ 84 
13.3.5 
Echocardiography Core Lab Analysis ................................................................................ 100 

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13.8.1 
Safety Endpoint Definitions70 ............................................................................................ 110 
13.8.2 
Other TAVR Related Complications70................................................................................ 113 
13.8.3 
Efficacy Endpoints ............................................................................................................. 115 
13.8.4 
Classification of Causal Relationships ............................................................................... 120 
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D00266108 
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This document is electronically controlled Medtronic Business Restricted   056-F275, vC Clinical Investigation Plan Template 
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Term 
Definition 
A 
Atrial (late diastolic mitral inflow velocity with atrial contraction) 
A’ 
A prime; mitral annular late diastolic velocity 
ACC 
American College of Cardiology 
ACCF 
American College of Cardiology Foundation 
ADE 
Adverse device effect 
AE 
Adverse event 
AHA 
American Heart Association 
AKI
Acute kidney injury
AS
Aortic stenosis 
AR 
Aortic regurgitation 
AV 
Atrial ventricular 
AVA 
Aortic valve area 
AVAI 
Aortic valve area index 
AVC 
Aortic valve closure 
BARC 
Bleeding Academic Research Consortium 
BMI 
Body mass index 
BSA 
Body surface area 
CABG 
Coronary artery bypass grafting 
EACTS 
European Association of Cardio Thoracic Surgery 
EQ-5D 
European Quality of Life – 5 Dimensions 
ESC 
European Society of Cardiology 
AVR 
Aortic valve replacement 
BAV 
Balloon aortic valvuloplasty 
BVD 
Bioprosthetic valve dysfunction 
BVF 
Bioprosthetic valve failure 
CEC 
Clinical Events Committee
CD 
Color Doppler 
CIP 
Clinical Investigational Plan 
COPD 
Chronic obstructive pulmonary disease 
CW 
Continuous wave 
CWD 
Continuous wave Doppler 
CVA 
Cerebral vascular accident 
DCS 
Delivery catheter system 
DICOM 
Digital Imaging and Communications in Medicine 
DTL 
Designated Task List 
DSMB 
Data Safety Monitoring Board 
DVI 
Doppler velocity index 

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D00266108 
Revision  D 
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This document is electronically controlled Medtronic Business Restricted   056-F275, vC Clinical Investigation Plan Template 
Term 
Definition 
E 
Early diastolic mitral inflow velocity 
e’ 
E prime; mitral annular early diastolic velocity
E:A ratio 
Ratio of early (E) to late (A) mitral inflow velocity 
E:e’ 
Ratio of early (E) mitral inflow velocity to early (e’) mitral annular velocity 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF
Electronic case report form 
EOAI 
Effective orifice area index 
ET 
Ejection time 
ETT 
Exercise tolerance test 
ERC 
Eligibility Review Committee 
ECL 
Echocardiography Core Laboratory 
HF 
Heart failure 
HREC 
Human Research Ethics Committee 
IB/RoPI 
Investigator Brochure/Report of Prior Investigations 
IDE 
Investigational Device Exemption 
IE 
Infective endocarditis 
IFU 
Instructions for Use 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FEV1 
Forced expiratory volume in one second 
FS 
Fractional shortening 
F/U 
Follow up 
LGE 
Late gadolinium enhancement 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GCMT 
Guideline compatible medical therapy 
GLS 
Global longitudinal strain 
GOLD
Global Initiative for Chronic Obstructive Lung Disease
HREC 
Human Research Ethics Committee 
ICH/GCP 
International Harmonized Committee/Good Clinical Practice 
IRB 
Institutional Review Board 
IRB/EC 
Institutional Review Board/Ethics Committee 
KCCQ 
Kansas City Cardiomyopathy Quality of Life 
Kg 
Kilograms 
LAVI 
Left atrial volume index 
LAX 
Long axis 
LS 
Loading system 
LV 
Left ventricle 
LVEDV 
Left ventricular end-diastolic volume 

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Term 
Definition 
LVESV 
Left ventricular end-systolic volume 
LVEF 
Left ventricular ejection fraction 
LVIDD 
Left ventricular internal dimension at end-diastole 
LVIDS 
Left ventricular internal dimension at end-systole 
LVM 
Left ventricular mass 
LVMI 
Left ventricular mass index 
LVOT 
Left ventricular outflow tract 
m-mode 
Motion mode
MDCT 
Multi-detector computed tomography
MdT 
Mitral E wave deceleration time 
MG 
Mean gradient 
MI 
Myocardial infarction 
μg 
microgram 
MR 
Mitral regurgitation 
MRI 
Magnetic resonance imaging 
mRS 
Modified Rankin Score 
NT-proBNP 
N-terminal pro B-type natriuretic peptide 
NYHA 
New York Heart Association 
PAR 
Paravalvular aortic regurgitation 
PI 
Principal investigator 
PISA 
Proximal isovelocity surface area 
PPI 
Permanent pacemaker implant 
PPM 
Patient-prosthesis mismatch 
PW 
Pulsed wave 
QoL 
Quality of Life 
RA 
Right atrium 
REB 
Research Ethics Board 
ROI 
Region of interest 
RF
Regurgitant fraction
RDC 
Remote data capture 
RVol 
Regurgitant volume 
RV 
Right ventricle 
RVOT 
Right ventricular outflow tract 
RVSP 
Right ventricular systolic pressure 
SAE 
Serious adverse event 
SADE 
Serious adverse device effect 
SAVR 
Surgical aortic valve replacement 
SAX 
Short axis 
SOP 
Standard operating procedure 
SoV 
Sinus of Valsalva 

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Term 
Definition 
STE 
Speckle tracking echocardiography 
TAPSE 
Tricuspid annular plane systolic excursion 
TAV 
Transcatheter aortic valve
TAVR 
Transcatheter aortic valve replacement 
TDI 
Tissue Doppler imaging 
TEE 
Transesophageal echocardiography 
TIA 
Transient ischemic attack 
TTE 
Transthoracic echocardiography 
TR 
Tricuspid regurgitation 
UADE 
Unanticipated adverse device effect 
USADE 
Unanticipated serious adverse device effect 
WBC 
White blood count 
WHO 
World Health Organization 
vMax 
Maximal velocity aortic valve 
VARC-2 
Valve Academic Research Consortium 
VTI 
Velocity time integral 
ZvA 
Valvulo-arterial impedance 
2-D 
Two dimensional 
6MWT 
Six-minute walk test 
 

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Study Type 
Prospective, interventional, premarket, feasibility 
Study Design 
Single arm, descriptive, multi-center  
Global Sponsor  
Medtronic, Inc. 
Coronary Structural Heart 
8200 Coral Sea St NE 
Mounds View, MN 55112 
Investigational Device  
The Medtronic Evolut PRO+ TAVR System 
Product Status 
Investigational 
Indication under investigation  
Severe, asymptomatic aortic stenosis 
Investigation Purpose 
Obtain safety and efficacy data to inform pivotal studies to support indication 
expansion to patients with severe asymptomatic aortic stenosis 
Primary Objectives 

Characterize the spectrum of cardiac function, degree of symptoms, and 
severity of aortic stenosis in the study population 

Estimate event rates for potential study endpoints to be evaluated in 
pivotal studies for the proposed patient population, and 

Evaluate the effect of TAVR on cardiac function, functional capacity, 
effort tolerance, and quality of life in the study population. 
Key Study Endpoints 
Safety 

All-cause mortality at 30 days and 6 months 

All stroke (disabling and non-disabling) at 30 days and 6 months 

Valve-related dysfunction requiring repeat procedure at 30 days and 6 
months 

New permanent pacemaker implant (PPI) at 30 days and 6 months 
Efficacy 

Cardiovascular and heart failure hospitalizations at 30 days and 6 months 

Heart failure events at 30 days and 6 months 

Change in KCCQ at 6 months 

Change in 6MWT at 6 months 

Change in cardiac function by echo (LVEF, Peak GLS, E:e’) at 6 months 
Number of Centers 
Up to 25 centers in the United States, Canada, Europe, Israel, Australia, and 
New Zealand 
Sample Size and Follow-up 
Duration 
Up to 75 patients with severe asymptomatic AS followed for five years 
Key Patient Selection Criteria 
 
Key inclusion criteria: 

Severe aortic stenosis, defined as:  
R
AVA < 1.0 cm2, or AVAI < 0.6 cm2/m2, and  
R
Mean gradient > 40 mmHg or Vmax > 4.0 m/sec

Subject denies symptoms attributable to aortic stenosis, including but not 
limited to: 
R
Dyspnea on rest or exertion 
R
Angina 
R
Syncope in the absence of another identifiable cause 
R
Fatigue 

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
LVEF >50% 
 
Key exclusion criteria: 

Age < 65 years 

Class I indication for SAVR 

Bicuspid, unicuspid, or quadricuspid aortic valve 

In need and suitable for coronary revascularization 

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3.1
Background 
Calcific aortic stenosis (AS) is the most prevalent valvular heart disease in developed countries, and its 
burden is expected to increase dramatically over the next 20 years with the aging of the population.1 In 
adults, AS is characterized by progressive thickening, calcification, and fibrosis of the valve leaflets 
leading to restricted leaflet motion and narrowing of the valve opening area, resulting in obstruction to 
left ventricular outflow.  The consequent increase in pressure afterload leads to an adaptive 
hypertrophic response of the left ventricle to normalize wall stress and maintain cardiac output.  In 
many patients, this compensatory mechanism cannot be maintained indefinitely, and ventricular 
function begins to decline, resulting in the development of symptoms, heart failure, and death because 
of inadequate cardiac output and elevated left ventricular filling pressure caused by diastolic 
dysfunction.2,3,4 This transition of ventricular adaption (compensation) to decompensation is driven by 
progressive myocyte death and fibrosis.  Therefore, it is important to consider AS a condition that 
affects both the valve and the myocardium.5,6 
The classic symptoms of AS include dyspnea, exertional angina, and syncope.  It is well accepted the 
onset of these symptoms is a marker of left ventricular decompensation, and once these symptoms 
develop, the cumulative mortality is high if AS is left untreated.7,8 In their seminal 1968 paper, Ross and 
Braunwald reported the average survival following onset of symptoms was five years for angina, three 
years for syncope, and two years for dyspnea.8  
Currently, there are no medications proven to attenuate or reverse the progression of AS, and aortic 
valve replacement (AVR), either surgical or transcatheter, is the only effective treatment for severe AS.  
Ideally, AVR should be performed when the risks of the disease process (heart failure, irreversible 
ventricular functional impairment) outweigh the risks of the intervention (complications of the implant 
procedure, long term device risks, and need for reintervention).2  However, determining the optimal 
timing for intervention remains one of the most challenging and important decisions in the management 
of AS. 9,10 
Contemporary guidelines make a Class I recommendation for AVR when AS is deemed severe and there 
are either symptoms of AS or objective evidence of left ventricular systolic dysfunction, where severe 
aortic stenosis is defined as an aortic valve area (AVA) ч 1.0 cm2 or a mean pressure gradient across the 
stenotic valve of > 40 mmHg, and left ventricular systolic dysfunction is defined by a left ventricular 
ejection fraction (LVEF) of < 50%.11,12,13  However, current guidelines are hesitant to recommend AVR for 
patients with AS outside of these criteria. 
The evaluation and treatment of AS has evolved considerably over the past decade in direct relationship 
to advancements in multimodality imaging,14,15,16,17,18 enhanced understanding of the natural history of 
AS19,20,21,22 and the transformative development of transcatheter aortic valve replacement 
(TAVR).23,24,25,26,27,28,29,30  These rapid advances have fueled a growing interest for the indications for AVR 
to evolve beyond the current measures defining the hemodynamic burden of AS in order to identify and 

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treat patients with AS who are at risk for adverse outcomes, but outside the current indications for 
intervention. 10,19,31,32,33,34,35,36,37
Severe Asymptomatic AS. The management of asymptomatic patients with severe AS, particularly the 
choice between early AVR and “watchful waiting”, remains controversial.32,33,36,38  Due to the high 
prevalence of AS in the elderly and ready access to echocardiography, severe AS is frequently diagnosed 
in asymptomatic patients.  For asymptomatic patients with severe AS, the guidelines make a Class I 
recommendation for AVR when the LVEF is reduced to < 50%.11,12  
Many patients with symptoms can remain undetected in clinical practice because they have 
unconsciously adapted by slowing their activity level to avoid symptoms.  Further, they may not 
recognize what represents important symptoms, or underestimate their severity and only report when 
they become extremely limiting.  Dyspnea, one of the most important prognostic symptoms in AS, may 
be particularly hard to detect, as patients may attribute their shortness of breath to poor stamina.39 
Studies have shown that roughly 50% of patients with severe AS report no symptoms on initial 
diagnosis.40,41,42 Among these patients, irreversible myocardial damage or sudden cardiac death can 
occur if symptoms are overlooked and treatment is deferred.  Therefore, for asymptomatic patients with 
ƐĞǀĞƌĞ^ĂŶĚ>s&шϱϬй͕ƚŚĞŐƵŝĚĞůŝŶĞƐƌĞĐŽŵŵĞŶĚĞǆĞƌĐŝƐĞƚŽůĞƌĂŶĐĞƚĞƐƚŝŶŐ;ddͿƚŽƵŶŵĂƐŬƚŚĞ
presence of AS-related symptoms.  If ETT reveals spontaneous symptoms clearly related to AS, the 
ESC/EACTS guidelines make a Class I recommendation for AVR, while the AHA/ACC guidelines make a 
Class IIa recommendation for AVR.11,12 Although the guidelines recommend ETT in these patients, it’s use 
is rather limited in routine practice, as a considerable number of elderly patients present with physical 
impairment that limit their ability to exercise.43,44 
For severe asymptomatic patients without a Class I or IIa indication for AVR, the guidelines recommend 
close follow-up for reassessment of symptoms and TTE every 6 to 12 months, and deferral of AVR until 
symptoms or signs of left ventricular systolic dysfunction, defined as LVEF <50%, develop.11,12 This 
strategy of “watchful waiting” is based on consensus opinion that the potential benefit of AVR to 
prevent sudden cardiac death may not be greater than the risk of dying during or within 30 days of the 
surgical AVR procedure.  This is supported by observational studies estimating the annual risk of sudden 
cardiac death in patients with severe, asymptomatic AS to be approximately 1%.45,46,47,48,49 
However, important issues have been identified regarding the strategy to “watch and wait” for 
symptoms or reduction in LVEF to <50% to determine the timing of intervention in these patients.  A 
2018 study by Wald et al50 observed that life-threatening decompensation is not uncommon in patients 
with known AS.  Among patients under watchful waiting who were admitted to the hospital for acute 
decompensated AS, 45% were in LV failure at the time of admission.  Inpatient mortality was high in this 
group (19%), exposing a shortcoming of a watchful waiting strategy in some patients with severe AS.  
Observational studies evaluating the outcomes of patients with severe asymptomatic aortic stenosis have 
been recently published.  In 2016, Généreux et al20 published a meta-analysis comparing a surgical AVR 
strategy to a conservative approach.  Their pooled analysis of four retrospective observational studies 

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indicated that patients with severe asymptomatic AS have an unadjusted ~3.5-fold higher rate of all-
cause death with a watchful-waiting strategy compared with AVR.  This suggests that early AVR might 
improve outcomes in patients with asymptomatic severe AS, but the authors note their findings should 
be considered hypothesis-generating.  In 2020, Pompeu et al38published a meta-analysis of seven studies 
comparing early AVR to clinical follow up.  A principal finding was the overall hazard ratio for death 
showed a statistically significant difference in mortality between the two groups, with a lower risk of 
dying in the “early AVR” group. 
Other studies have identified limitations of the LVEF <50% cut-point as the threshold for AVR in severe 
asymptomatic AS.  In their 2018 report of study of outcomes of patients with severe asymptomatic 
patients followed in dedicated heart valve clinics, Lancellotti et al51 noted that patients with LVEF 
between 50% and 59% had less favorable outcomes and more heart failure-related deaths than patients 
with an LVEF > 60%.  In their 2018 report of a study evaluating the temporal course of LVEF in patients 
with severe AS, Ito et al52 noted that 21% of patients had an LVEF < 50% at the time of initial diagnosis of 
severe AS.  Notably, in patients with severe AS and LVEF < 50%, the LVEF began to deteriorate and 
gradually worsened before AS became severe or AVA became <1.0 cm2.  The authors suggest the normal 
LVEF appears to >60% in patients with AS.  For patients with severe AS and LVEF <60%, mortality is worse 
even after AVR is performed.  These studies raise the question if the current threshold for AVR of LVEF < 
50% should be increased to <60% in these patients. 
Potential of TAVR in Expanded Indications. The rapid evolution of TAVR over the last 10 years has 
completely changed the landscape for decision-making regarding valve intervention in severe AS patients.  
Randomized trials have demonstrated similar or better outcomes compared to surgical AVR (SAVR) in 
patients with severe, symptomatic AS deemed at increased risk for operative mortality.23-28  Based on 
these studies, both the 2017 European and United States guidelines make a Class I indication for TAVR in 
patients with severe, symptomatic AS at high risk for SAVR, and a Class I or Class IIa for patients at 
intermediate risk for SAVR, respectively.11,12 
Advanced imaging, technological advances in delivery catheter systems and prosthesis design, and 
growing operator experience have led to improved procedural safety and transcatheter valve 
performance.  As a result, TAVR has recently been studied in patients with severe AS at low operative 
risk for SAVR.  In 2019, two randomized trials comparing TAVR to SAVR were published (one involving 
the Edwards balloon-expandable Sapien 3 system,29 and one involving the Medtronic Evolut R and PRO 
self-expanding systems.30  In younger and low risk patients, both trials showed TAVR had an early safety 
benefit (lower rates of mortality, disabling stroke, acute kidney injury, life-threatening bleed and new-
onset atrial fibrillation) over SAVR, significantly shorter length of hospital stay, faster recovery, and 
fewer rehospitalizations.  Importantly, the Medtronic Evolut R and PRO transcatheter valves 
demonstrated more complete relief of aortic valve obstruction compared to surgical bioprostheses in the 
form of larger effective orifice areas, lower prosthetic gradients, and a significantly lower incidence of 
patient-prosthesis mismatch.30 

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The current state of TAVR, with its procedural safety and hemodynamic performance benefits over SAVR, 
offers the potential to change the thresholds for AVR and extend the benefits of AVR to patients with AS 
who are at risk for adverse cardiac events, but outside the current indications for AVR.  When considering 
recent evidence on the prognosis of moderate symptomatic and severe asymptomatic AS, the need to 
reappraise the current indications for AVR becomes apparent.  As a result, clinical trials are underway to 
investigate the use of TAVR  in patients with severe, asymptomatic AS. 
The EARLY TAVR (Evaluation of Transcatheter Aortic Valve Replacement Compared to Surveillance for 
Patients with Asymptomatic Severe Aortic Stenosis, NCT030421040) is an ongoing randomized control 
trial to compare TAVR with “watchful waiting” in truly asymptomatic patients with severe AS.53 The 
EVoLVeD (Early Valve Replacement Guided by Biomarkers of LV Decompensation in Asymptomatic 
Patients with Severe AS, NCT03094143) TAVR study is an ongoing randomized clinical trial in which 
subjects are assessed for increased heart muscle strain that could lead to scarring using cardiac magnetic 
resonance imaging.  Subjects at risk for increased scarring are randomized to either routine clinical care 
or referral for AVR.54 
Medtronic is sponsoring this feasibility study to evaluate the safety and efficacy of the Medtronic Evolut 
PRO+ TAVR system in patients with severe asymptomatic aortic AS.  There are important differences in 
the inclusion/exclusion criteria for this study compared to the EARLY TAVR study.  The EARLY TAVR study 
requires ETT to establish the absence of symptoms.  While this is consistent with current guidelines, it is 
important to note that ETT is not feasible in a considerable number of elderly patients.  Therefore, this 
study will allow patients irrespective of the ability to perform ETT, provided they have additional 
markers of LV dysfunction that may prove to be more sensitive than LVEF for identification of LV 
dysfunction attributable to AS. 
3.2
Purpose 
The purpose of this study is to evaluate the safety and efficacy of the Medtronic Evolut PRO+ TAVR 
system in patients with severe asymptomatic AS.  Data will be used to inform the design of pivotal 
studies to support expansion of the current indication to include this patient population. 
 
 

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4.1
Primary Objectives
The primary objectives of this feasibility study are as follows: 
1. 
Characterize the spectrum of cardiac function, symptomology, and severity of aortic stenosis in 
the study population, 
2. 
Estimate event rates for potential safety and effectiveness endpoints to be evaluated in pivotal 
studies for the proposed patient population, and 
3. 
Evaluate the effect of TAVR on cardiac function, functional capacity, effort tolerance, and patient-
reported quality of life in the study population. 
4.2 
Endpoints and Outcome Measures 
4.2.1 Safety Endpoints
1.
All-cause and cardiovascular mortality at 30 days and 6 months
2. All stroke (disabling and non-disabling) at 30 days and 6 months 
3. Myocardial infarction (periprocedural and spontaneous) at 30 days and 6 months 
4. Acute kidney injury at 30 days and 6 months 
5. Major vascular complications at 30 days and 6 months 
6. Life-threatening bleed at 30 days and 6 months 
7. New permanent pacemaker implantation (PPI) at 30 days and 6 months 
8. New intraventricular conduction delays at 30 days and 6 months 
9. New-onset atrial fibrillation at 30 days and 6 months 
10.Valve-related dysfunction requiring repeat procedure at 30 days and 6 months 
4.2.2 Efficacy Endpoints 
1. Device success (VARC-2)63 
2. Cardiovascular and heart failure hospitalizations at 30 days and 6 months 
3. Heart failure events at 30 days and 6 months 
4. Hemodynamic performance metrics by Doppler echocardiography at discharge, 30 days, and 6 
months 
ͻ
Mean aortic gradient  
ͻ
Effective orifice area  
ͻ
Degree of total, para, and transvalvular prosthetic regurgitation   
ͻ
Incidence of moderate and severe patient-prosthesis mismatch (PPM)   
5. Change in New York Heart Association (NYHA) functional classification from baseline at 30 days and 
6 months 
6. Change in six-minute walk test (6MWT) from baseline at 6 months 
7. Change in Kansas City Cardiomyopathy (KCCQ) from baseline at 30 days and 6 months 

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8. Change in left ventricular ejection fraction (LVEF) from baseline at 6 months 
9. Change in peak global longitudinal strain (GLS) from baseline at 6 months 
10.Change in left ventricular filling pressure (E:e’) from baseline at 6 months 
11.Change in stroke volume index (SVI) from baseline at 6 months 
12.Change in NT-pro B-type natriuretic peptide (NT-proBNP) from baseline at 6 months 
4.2.3 Additional Outcome Measures
The following outcome measures will be also be evaluated: 
1.
All-cause and cardiovascular mortality annually through 5 years 
2.
All stroke (disabling and non-disabling) annually through 5 years 
3.
Cardiovascular and heart failure hospitalizations at annually through 5 years 
4.
Heart failure events at annually through 5 years 
5.
New York Heart Association (NYHA) functional classification at 30 days, 6 months, and annually 
through 5 years 
6.
Change in New York Heart Association (NYHA) functional classification from baseline annually 
through 5 years 
7.
Kansas City Cardiomyopathy (KCCQ) annually through 5 years 
8.
Hemodynamic performance metrics by Doppler echocardiography 
x
Mean aortic gradient annually through 5 years 
x
Effective orifice area annually through 5 years 
x
Degree of total, para, and transvalvular prosthetic regurgitation annually through 5 years 
x
Incidence of moderate and severe patient-prosthesis mismatch (PPM) annually through 5 
years 
9.
Prosthetic valve thrombosis 30 days, 6 months, and annually through 5 years 
10.
Prosthetic valve endocarditis at 30 days, 6 months, and annually through 5 years 
11.
Bioprosthetic valve dysfunction (BVD) at 30 days, 6 months, and annually through 5 years 
12.
Bioprosthetic valve failure (BVF) at 30 days, 6 months, and annually through 5 years 
13.
Valve-related dysfunction requiring repeat procedure annually through 5 years 
Definitions of endpoints and outcome measures are provided in Section 13.8.  
 

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This is a prospective, descriptive, interventional, multi-center, single-arm, pre-market, feasibility study.  
The study will involve up to 75 subjects with severe, asymptomatic AS implanted using the Medtronic 
Evolut PRO+ TAVR system among up to 25 centers in the United States, Canada, Europe, Israel, Australia, 
and New Zealand.  An initial analysis is anticipated when 50 to 75 subjects  have completed their 6 
month follow up exam.  The analysis will be descriptive; information on the data analyses are provided 
in Section 10. Study design and flow is outlined in Figure 1.  
 
 
 
 
 
Figure 1: Study Design and Flow 
 

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5.1
Number of Subjects, Duration, and Number of Investigational Devices 
This study will involve up to 75 subjects implanted with the study device among all active sites.  As not 
all patients consented for evaluation will go forward to implantation, the number of subjects consented 
for the study is expected to be higher (up to 150).  No site will implant more than 15 subjects without 
prior authorization from Medtronic in order to minimize bias. 
Subjects will be consented for follow-up through five years following implantation, and all implanted 
subjects will be followed per protocol through five years following implantation.  Subjects who exit from 
the study after implantation will not be replaced.  The enrollment period is estimated to be between 9 
and 20 months, and the estimated total study duration (first subject implanted to last subject 
completing his/her last follow-up exam) is estimated to be seven years. 
The number of investigational TAVR systems involved in this study is estimated to be between 75 and 
150 (inclusive of devices used during index implantation procedures, devices opened but not used, and 
devices shipped to sites as inventory for the study but not opened or used). 
5.2
Rationale 
The safety and effectiveness of the Medtronic self-expanding Evolut R and PRO TAVR systems have been 
established through rigorous clinical evaluation in patients with severe symptomatic AS.  However, 
contemporary evidence from scientific literature indicates patients with a degree of AS outside of the 
current TAVR indications are also at risk for serious adverse effects of AS.  The risk and benefits of TAVR 
in patients with severe asymptomatic AS has not been well studied in prospective clinical studies, 
although clinical trials have recently been initiated in AS patients using the balloon expandable TAVR 
system. 
This feasibility study is intended to obtain initial procedural safety and efficacy data on the use of the 
Medtronic self-expanding Evolut PRO+ TAVR system in this group of AS patients.  Data from this study 
will be used to inform the design of future pivotal studies to expand the current indications to include 
this population.  Specifically, the study objectives and associated endpoints are intended to fully 
characterize the spectrum of AS severity, LV function, and symptomology, provide information on event 
rates for pivotal sample size estimations, and refine the entrance criteria for future pivotal studies.  The 
single arm design and sample size of 75 subjects is consistent with the views and opinions of US FDA 
physicians regarding feasibility studies in the development of percutaneous heart valves55 and will 
provide adequate information to inform a pivotal study.  A comprehensive bench testing protocol has 
been completed on the Evolut PRO+ system and is generalizable to the study population.  The clinical 
study endpoints are relevant and consistent with the study objectives.  The design of this study is based 
on clinical evaluation and aligned with risk assessment results. 
5.3
Centers for Medicare Services Considerations (United States Centers only) 
This study protocol is designed to ensure all beneficiaries of the United States Centers for Medicare 
Services (CMS) are eligible for participation, and that the results are generalizable to all beneficiaries 

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with the degree of AS and symptomology under investigation.  Specifically, the inclusion/exclusion 
criteria require that the subjects to be ш 65 years of age, anatomically suited for the study TAVR system, 
and have a degree of AS that places them at risk for adverse cardiac events from their AS. 
An analysis of 2018 US claims data for claims with a diagnosis of nonrheumatic aortic stenosis found that 
88% of patients were age 65 or older, and Medicare was the primary payer in 84% of the claims, and 
secondary payer in 88% of the claims.56 Therefore, results from this study will be generalizable to the 
Medicare population. In addition, the inclusion and exclusion criteria ensure that traditionally 
underrepresented groups (e.g. minorities, women) will not be excluded from this study. Information on 
subject age, gender, and ethnicity will be collected in the study through electronic Case Report Forms 
(eCRFs). 
In addition, investigational sites are expected to retain participation of all enrolled subjects through 
their routine processes for arranging follow-up visits and encouraging subjects to attend visits and 
continue his/her participation.   Finally, the study report will include information (e.g. % of subjects by 
race, gender) on the level of representation of these traditionally underrepresented groups among the 
overall study population. 
5.4 Investigational Sites 
This study may be conducted at up to 25 sites in the United States, Canada, Europe, Israel, Australia, and 
New Zealand.  Investigative sites will meet the following criteria: 
1. The site will have extensive experience with TAVR and SAVR, including the following: 
x
/ŶƚĞƌǀĞŶƚŝŽŶĂůĂƌĚŝŽůŽŐŝƐƚǁŝƚŚшϮϬdsZƉƌŽĐĞĚƵƌĞƐŝŶƚŚĞƉƌŝŽƌǇĞĂƌ͕ŽƌшϰϬdsZƉƌŽĐĞĚƵƌĞƐ
in the prior two years. 
2. The site will have the presence or capacity of establishing an investigative team consisting of the 
following: 
x
Interventional Cardiologist with expertise in transcatheter aortic valve replacement 
x
Cardiothoracic Surgeon with expertise in aortic valve replacement 
x
Echocardiographer with expertise in evaluation of aortic stenosis and speckle-tracking 
echocardiography (STE), dobutamine stress echocardiography, and prosthetic valve evaluation 
x
Cardiovascular Imaging Specialist (either radiologist or cardiologist) with expertise in multi-
detector computed tomography (MDCT) for pre-TAVR procedure planning and cardiac MRI 
x
Exercise Testing physician with expertise in exercise tolerance testing 
x
Study Coordinator with experience in regulated medical device studies 
5.5
Site Study Team Members 
The following is a description of the key personnel who will form the investigative team at each site. 

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5.5.1 Site Principal Investigator 
Each site will have a Principal Investigator (PI) who is either an interventional cardiologist, cardiothoracic 
surgeon, or non-interventional cardiologist.  The PI has overall responsibility for the conduct of the study 
at the site, including protecting the rights, safety, and welfare of the study subjects at their site, the 
integrity of the study data generated by their site, and for ensuring the study is conducted in compliance 
with the Clinical Investigation Plan, all relevant regulatory requirements, and the IRB/EC requirements. 
The site PI may also serve as a member of the Heart Team. 
5.5.2 Heart Team 
Each site will utilize a local multi-disciplinary Heart Team to assess and document eligibility of the 
prospective subject for the study.  Local Heart Team members must be trained, delegated, and activated 
to participate in the clinical study.  At a minimum, the local Heart Team should include the following four 
members: 
1. A Cardiothoracic Surgeon 
2. An Interventional Cardiologist 
3. An Echocardiographer 
5.5.3 Echocardiographer 
Each site will have a designated cardiologist whose primary responsibilities are to confirm the 
prospective subjects meets the echocardiographic criteria for the study, to ensure the required 
echocardiograms are performed in accordance with the CIP, and reviewing and approving the site 
echocardiography eCRFs, if authorized by the PI.  Protocol-driven exams should be performed by 
designated individuals delegated by the site PI. The designated echocardiographer shall also serve as a 
member of the local Heart Team. 
5.5.4 Cardiovascular Imaging Physician
Each site will have a designated cardiovascular imaging specialist, whose responsibilities include 
ensuring the required pre-TAVR planning MDCT images are acquired per protocol, overseeing the 
acquisition of the protocol-required cardiac MRI images, analysis of the protocol-required MDCT and 
MRI exams, and reviewing and approving the site MDCT and MRI eCRFs, if authorized by the PI.  The 
Cardiovascular Imaging Specialist is either a radiologist or cardiologist with expertise in MDCT and 
Cardiac MRI. 
5.5.5 Exercise Testing Physician 
Each site will have designated physician whose responsibilities include overseeing the administration, 
interpretation, and reporting of protocol-required exercise tolerance, and reviewing and approving the 
site exercise testing eCRFs, if authorized by the PI. 

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5.5.6 Study Coordinator 
Each site will have a designated study coordinator whose responsibilities include coordination of study 
activities, follow-up evaluations, and maintaining the records defined in the CIP.  The study coordinator 
may conduct follow-up clinical evaluations if qualified per their scope of practice and authorized by the 
PI. 
5.6
Clinical Investigational Agreement and Financial Disclosure 
Medtronic contracts with participating institutions/investigators through a clinical investigational 
agreement that defines the scope and responsibilities and associated compensation related to carrying 
out the obligations under a clinical study sponsored by Medtronic. 
A Clinical Investigational Agreement shall be signed by the participating investigation site and/or the 
principal investigator at each investigation center per local legal requirements and returned to 
Medtronic prior to study center activation.  The investigator is required to indicate their approval of the 
CIP (and any subsequent amendments) by signing and dating the agreement.  All investigators will be 
asked to complete financial disclosure statements provided by Medtronic prior to their participation in 
the study. 
5.7
Curriculum Vitae 
Current, signed and dated curriculum vitae shall be obtained for all site study personnel, including their 
current position at the investigation site.  The signature on the curriculum vitae must be on or prior to 
the date of activation or delegation of any tasks. 
5.8
Study Site Training and Activation 
Prior to investigational center activation or subsequent involvement in study activities, Medtronic will 
provide training to the investigative team on the clinical investigation plan, relevant standards and 
regulations, informed consent, data collection and reporting tools, and the study methods, procedures, 
and requirements.  Training may be conducted via site initiation visits, investigator meetings, and/or 
other media sessions.  Medtronic will maintain documentation of these training sessions.  If new 
members join the study team, they will receive training on the applicable study requirements relevant 
to their role before contributing to the study.  Additionally, Medtronic representative(s) may be present 
at each site’s implant procedures as part of the ongoing training process. 
Prior to performing study related activities, all regulatory requirements shall be fulfilled, including but 
not limited to the following: 
x
IRB/EC approval (and voting list, as required by local law) of the current CIP and ICF 
x
Fully executed CTA 
x
Financial disclosure, as applicable 
x
CV of investigators and investigational site study team members as applicable 
x
Documentation of delegated tasks 

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x
Documentation of study training 
x
Additional requirements per local regulations, IRB/EC as applicable 
5.9
Eligibility Review Committees 
An Eligibility Review Committee (ERC) will be used to ensure subject selection is appropriate and 
consistent among study sites.  The role of the ERC will include the following:  
x
Confirmation that subjects have severe aortic stenosis per the relevant inclusion/exclusion criteria  
x
Confirmation that subjects symptoms have been adequately evaluated by the local Heart Team.  For 
subjects unable to undergo ETT, the ERC will confirm if the subject is asymptomatic for AS 
x
Confirmation that subjects have tricuspid aortic valves and are anatomically suitable for 
transfemoral TAVR with the study device 
The ERC may include representation from the following disciplines: interventional cardiology, cardiac 
surgery, echocardiography, and heart failure management.  A charter that describes the roles, 
responsibilities, and processes of the ERC will be approved by Medtronic prior to the start of enrollment. 
5.10 Echocardiography Core Lab 
An Echocardiography Core Lab (ECL) will be used to ensure consistency of evaluation and interpretation 
of the echocardiographic exams among the study sites.  The role of the ECL will include the following:  
x
Confirming all subjects meet echocardiographic criteria for severity of aortic stenosis and left 
ventricular function 
x
Evaluation of all protocol-driven echocardiograms 
x
Evaluation of unplanned echocardiograms as available 
Details on the echocardiography procedures are provided in Section 13.3. 
5.11 Clinical Events Committee 
A Clinical Events Committee (CEC) will be used to ensure consistent evaluation and adjudication of 
adverse events and safety-related endpoints.  Additional information on the composition, roles, and 
responsibilities of the CEC is provided in Section 7.7.  
5.12 Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will be used to monitor accruing data from study in order to 
protect the safety of the study subjects.  Additional information on the composition, roles, and 
responsibilities of the DSMB is provided in Section 7.8.  
5.13 Publication Committee 
A Publication Committee will provide direction and support in the development of clinical publications.  
The Publication Committee will consist of study investigators and Medtronic representatives.  The 
Publication Committee will be responsible to: 
x
Define the publication plan 

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Review, approve, and prioritize publication proposals 
x
Provide input on the scientific merit and clinical relevance of ancillary publications 
x
Identify the manuscript/abstract first author(s)/writer(s)/presenter(s) 
x
Review publications prior to submission 
 
 

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0HWKRGV
6.1
Study Population 
The study population includes males and females ш 65 years of age with severe, asymptomatic AS.  
Selection criteria are described in Section 6.2. 
6.2
Subject Selection Criteria  
6.2.1 Inclusion Criteria 
Prospective subjects must meet all of following inclusion criteria to be eligible for implantation: 
1. Severe aortic stenosis, defined as:  
x
sчϭ͘ϬĐŵ2, or s/чϬ͘ϲĐŵ2/m2, and  
x
Mean gradient шϰϬŵŵ,Ő or VmĂǆшϰ͘ϬŵͬƐĞĐ 
2. NYHA I 
3. Subject denies symptoms attributable to aortic stenosis, including but not limited to: 
ͻ Dyspnea on rest or exertion 
ͻ Angina 
ͻ Syncope in the absence of another identifiable cause 
ͻ Fatigue 
4. LVEF > 50% 
5. Anatomically suitable for transfemoral TAVR using the Medtronic Evolut PRO+ system 
6. The subject and treating physician agree the subject will return for all required follow-up visits 
6.2.2 Exclusion Criteria 
If any of the following exclusion criteria are present, the prospective subject is not eligible for 
implantation: 
1. Age < 65 years 
2. Class I indication for cardiac surgery 
3. Very severe aortic stenosis, defined as Vmax > 5m/sec, or mean gradient > 60 mmHg 
4. Bicuspid, unicuspid, or quadracuspid aortic valve 
5. Contraindication for placement of a bioprosthetic valve 
6. A known hypersensitivity or contraindication to any of the following that cannot be adequately pre-
medicated: 
x
Aspirin, heparin, or bivalirudin 
x
Ticlopidine and clopidogrel 
x
Nitinol (titanium or nickel) 
x
Contrast media 

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7. Blood dyscrasias as defined: leukopenia (WBC < 1000 mm3), thrombocytopenia (platelet count 
<50,000 cells/mm3), history of bleeding diathesis or coagulopathy, or hypercoagulable states 
8. Ongoing sepsis, including active endocarditis 
9. Any percutaneous coronary or peripheral interventional procedure within 30 days prior to date of 
qualifying echocardiogram 
10.In need of and suitable for coronary revascularization per Heart Team 
11.Chronic obstructive pulmonary disease (GOLD stage 3 or higher)57  
12.Placement of cardiac resynchronization device within 90 days of qualifying echocardiogram 
13.Symptomatic carotid or vertebral artery disease or successful treatment of carotid stenosis within 
70 days of qualifying echocardiogram 
14.Heart failure event or hospitalization within 14 days prior to qualifying echocardiogram 
15.Cardiogenic shock manifested by low cardiac output, vasopressor dependence, or mechanical 
hemodynamic support 
16.Recent (within 60 days of qualifying echocardiogram) cerebrovascular accident (CVA) or transient 
ischemic attack (TIA) 
17.Child-Pugh class C liver cirrhosis  
18.Gastrointestinal (GI) bleeding that would preclude anticoagulation 
19.Subject refuses a blood transfusion 
20.Severe dementia (resulting in either inability to provide informed consent for the study/procedure, 
prevents independent lifestyle outside of a chronic care facility, or will fundamentally complicate 
rehabilitation from the procedure or compliance with follow-up visits) 
21.Estimated life expectancy of less than 24 months due to associated non-cardiac co-morbid 
conditions 
22.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 
23.Currently participating in an investigational drug or another device trial or study (excluding 
registries) 
24.ǀŝĚĞŶĐĞŽĨĂŶĂĐƵƚĞŵǇŽĐĂƌĚŝĂůŝŶĨĂƌĐƚŝŽŶчϯϬĚĂǇƐďĞĨŽƌĞĚĂƚĞof qualifying echocardiogram58 
25.Advanced renal impairment (defined as GFR <30 mL/min) or need for renal replacement therapy 
26.Need for emergency surgery for any reason 
27.Subject is pregnant or breast feeding 
28.Subject is less than legal age of consent, unable to provide his/her own informed consent, legally 
incompetent, or otherwise vulnerable 
Anatomical exclusion criteria: 
29.Pre-existing prosthetic heart valve in any position 
30.Severe mitral regurgitation  
31.Severe tricuspid regurgitation  
32.Moderate or severe mitral stenosis  
33.Hypertrophic obstructive cardiomyopathy  
34.Significant aortopathy requiring ascending aortic replacement 

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35.Severe aortic regurgitation 
6.3
Informed Consent 
Prior to enrolling in the study, patients should be fully informed of the details of study participation as 
required by applicable regulations, the site’s IRB/EC, and by sponsor.  Informed consent must be 
obtained from each patient prior to conducting any protocol-induced activities beyond standard of care, 
by using the informed consent form (ICF) approved by that site’s IRB/EC, regulatory authorities as 
required and by Medtronic, Inc.  The ICF must be signed and dated by the patient and by the person 
obtaining the consent.  Any additional persons required by the site’s IRB/EC to sign the informed 
consent form must also comply. In the event the subject cannot read and/or write, a witnessed 
(impartial third party) ICF will be allowed, provided detailed documentation of the process is recorded in 
the subject’s case history and the witness signs and dates the ICF. 
If applicable, independent witness must be present throughout the entire informed consent process, 
and the written informed consent form and any other information related to the study must be read 
aloud and explained to the prospective subject. If applicable, witness shall also sign and personally date 
the consent form to attest that the information in the ICF was accurately explained and clearly 
understood by the subject, and that informed consent was freely given. 
Prior to the patient signing the ICF, the investigator or delegate will fully explain to the patient the 
nature of the research, study procedures, anticipated benefits, and potential risks of participation in the 
study.  The investigator or delegate will allow adequate time for the patient to read and review the 
consent form and to ask questions.  Signing the ICF serves to document the written and verbal 
information that the investigator or delegate provides to the patient, the patient’s understanding of the 
information, and his/her agreement to participate.  The investigator or 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 study records and a copy of 
the informed consent will be provided to the patient. If consent is obtained the same day the subject 
begins participating in study-related procedures, it must be documented in the subject’s case history 
that consent was obtained prior to participation in any study related procedures. It is best practice for 
the informed consent process to be documented in the subject’s case history, regardless of 
circumstance. 
Patients unable to provide his/her own informed consent, legally incompetent, or otherwise vulnerable 
are not allowed in the study.  Vulnerable subjects include individuals whose willingness to volunteer in a 
clinical investigation could be unduly influenced by the expectation, whether justified or not, of benefits 
associated with participation or of retaliatory response from senior members of a hierarchy in case of 
refusal to participate.   
6.4
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 revised information will be sent to the 

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investigator for approval by the IRB/EC (as applicable).  After approval by the IRB/EC, 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 authorized designee should inform 
the subject in a timely manner. 
6.5
Screening and Enrollment 
The process of patient screening and subject enrollment is as follows (Figure 2): 
1. Patients identified by or presented to the study site with AS will be screened by the investigative 
team for the subject selection criteria using available medical records, including relevant imaging 
studies previously performed for diagnostic purposes. 
2. If the patient is deemed a potential candidate, all aspects of the study will be explained to the 
patient.  The patient will then be invited to participate in the study.  If the patient agrees to 
participate, written informed consent will be obtained.  The date informed consent is signed is 
considered the point of enrollment, and the subject will be assigned a Subject ID number. 
3. The subject will undergo transthoracic echocardiography (TTE) to assess his/her degree of AS and 
cardiac function.  
4. If the site investigative team determines the subject meets AS criteria for severe asymptomatic AS, 
the qualifying echocardiogram will be submitted to the ECL for confirmation of severity of AS and 
other echocardiographic criteria. 
5. If the ECL confirms echocardiographic criteria are met1, the subject will undergo the following 
evaluations: 
x
Exercise tolerance testing (ETT), unless contra-indicated 
x
Multi-detector computed tomography (MDCT) 
x
Pulmonary function testing (simple spirometry with FEV1) 
x
Cardiac MRI 
x
Coronary arteriography if there is uncertainty regarding the status of coronary artery disease 
6. If the local Heart Team considers the subject suitable for implantation, the following information 
should be submitted to the ERC: 
x
Clinical assessments including medical history, co-morbidities, and symptomology 
x
TTE data on degree of AS and cardiac function 
x
MDCT data on anatomical suitability 
7. The ERC will review the submitted information and either confirm, disapprove, or defer eligibility for 
implantation.  Subjects confirmed eligible for implantation should undergo TAVR within 90 days of 
ERC approval.  Subjects disapproved should be exited from the study, and not be reconsidered for 
future participation without permission from Medtronic. 
1If a subject has balloon aortic valvuloplasty after their qualifying TTE, they must have repeat TTE to confirm he/she meets criteria for aortic 
stenosis prior to submission to the ERC. 

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Figure 2.  Flow diagram of the study entry process.  Patients should give written consent before undergoing any protocol-required testing.  
However, if any of protocol-required baseline/screening evaluations (e.g. echocardiography, ETT, MDCT, lab work) have been performed for 
diagnostic purposes or standard of care prior to consenting, they can be used as the protocol-required exams, provided they are within the 
protocol-required time windows and contain the necessary information. 
 

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6.6
Required Evaluations 
Protocol required evaluations should be performed at the study site.  The protocol required evaluations 
are as follows and summarized in Table 1.  Additional information on data collection requirements is 
provided in Section 6.13 through Section 6.18. As this is an interventional study, some or all of the 
required study procedures may be outside of standard of care for a given patient. 
Baseline (within 12 weeks prior to submission to the Eligibility Review Committee2) 
x
Clinical assessment and medical history, including NYHA classification 
x
Coronary arteriography (may be either selective or by computed tomography) 
x
Transthoracic echo (TTE) 
x
Exercise Tolerance Test (ETT)3 
x
Cardiac MRI 
x
Simple spirometry (timed vital capacity with FEV1) 
x
MDCT (peripheral vasculature and aortic annulus)  
x
12-lead ECG 
x
Complete blood count 
x
pro B-type natriuretic peptide (NT-proBNP) 
x
Heart Team assessment 
x
Six-minute walk test (6MWT) 
x
Modified Rankin Score 
x
Quality of Life Questionnaires: 
R Kansas City Cardiomyopathy Questionnaire (KCCQ) 
R European Quality of Life – 5 Dimensions (EQ-5D) 
x
Medications 
x
Adverse events 
Implant Procedure 
x
Pre-deployment hemodynamics (LV and aortic pressures) 
x
Aortography (final result) 
x
Adverse events and device deficiencies 
Discharge 
x
Clinical assessment (NYHA not assessed at discharge) 
x
12 lead ECG 
x
Medications 
x
TTE4 
x
Adverse events and device deficiencies 
 
30 days (between 30 to 45 days post implant) 
2Pre-implant MDCT and coronary arteriography should be performed within 365 days of submission to the eligibility review committee 
3Unless subject has contra-indication for ETT
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x
Clinical assessment, including NYHA classification 
x
12 lead ECG 
x
TTE 
x
Medications 
x
Adverse events and device deficiencies 
x
KCCQ 
6 Months (between 183 to 210 days post implant) 
x
Clinical assessment, including NYHA classification 
x
12 lead ECG 
x
TTE 
x
Medications 
x
pro B-type natriuretic peptide (NT-proBNP) 
x
Quality of Life Questionnaires: 
R Kansas City Cardiomyopathy Questionnaire (KCCQ) 
R European Quality of Life – 5 Dimensions (EQ-5D) 
x
Cardiac MRI 
x
Six-minute walk test (6MWT) 
x
Adverse events and device deficiencies 
1 Year (between 365 to 395 days post implant) 
x
Clinical assessment, including NYHA classification 
x
TTE 
x
Medications 
x
KCCQ 
x
Adverse events and device deficiencies 
2 Years (between 730 to 760 days post implant) 
x
Clinical assessment, including NYHA classification 
x
TTE 
x
Medications 
x
KCCQ 
x
Adverse events and device deficiencies 
3 Years (between 1095 to 1125 days post implant) 
x
Clinical assessment, including NYHA classification 
x
TTE 
x
Medications 
x
KCCQ 
x
Adverse events and device deficiencies 
4 Years (between 1460 to 1490 days post implant) 
x
Clinical assessment, including NYHA classification 
x
TTE 
x
Medications 

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x
KCCQ 
x
Adverse events and device deficiencies 
5 Years (between 1825 to 1855 days post implant) 
x
Clinical assessment, including NYHA classification 
x
TTE 
x
Medications 
x
KCCQ 
x
Adverse events and device deficiencies 
 
Other Evaluations  
x
Suspected stroke events should be confirmed by neurology consult and neuroimaging per site’s 
standard practice.  A Modified Rankin Score assessment should be conducted at 1 and 3 months 
following any confirmed stroke event. 
x
The investigative team should follow their standard practices for assessment of suspected 
myocardial infarction, acute kidney injury, neurological events, prosthetic valve endocarditis, 
prosthetic valve thrombosis, etc. 
x
Non-protocol echocardiograms (e.g. performed for suspicion of prosthetic valve dysfunction) should 
be submitted to the ECL for evaluation. 
Table 1.  Summary of required evaluations and visit schedule 
 
Baseline 
Implant 
Discharge 
30 Days 
6 Months 
Annual  
through 
5 Years 
1 month 
post 
stroke 
event 
3 months 
post 
stroke 
event 
Clinical assessment 
including NYHA 
95 
 
91 
9 
9 
9 
 
 
Transthoracic Echo 
9 
 
94 
9 
9 
9 
 
 
Multi-detector CT 
9 
 
 
 
 
 
 
 
12-lead ECG 
9 
 
9 
9 
9 
 
 
 
Coronary 
arteriography 
9 
 
 
 
 
 
 
 
Exercise Tolerance 
Test ( unless 
contraindicated) 
9
 
 
Cardiac MRI 
9 
 
 
 
9 
 
 
 
6-Minute Walk Test 
9 
 
 
 
9 
 
 
 
Spirometry 
9 
 
 
 
 
 
 
 
Complete Blood 
Count 
9 
 
 
 
 
 
 
 
Pro B-type natriuretic 
peptide 
9 
 
 
 
9 
 
 
 

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Heart Team 
Assessment 
9 
 
 
 
 
 
 
 
Aortography 
 
9 
 
 
 
 
 
 
Hemodynamics 
 
9 
 
 
 
 
 
 
Medications 
9 
 
9 
9 
9 
9 
 
 
KCCQ 
9 
 
 
9 
9 
9 
 
 
EQ-5D 
9 
 
 
 
9 
 
 
 
Modified Rankin Score 
9 
 
 
 
 
 
9 
9 
Adverse Events 
and/or device 
deficiencies2 
9 
9 
9 
9 
9 
9 
 
 
Notes 
1.
NYHA not required at discharge 
2.
Adverse events should be assessed and captured at each follow-up visit after time of informed consent. 
3.
Discharge TTE used for “Device Success” should be performed > 12 hours and < 7 days post implant 
4.
Clinical assessment and medical history required at baseline 
Visit Windows
Baseline 
Within 12 weeks prior to submission to ERC (except for MDCT and coronary arteriography) 
Discharge 
At the time of discharge from index TAVR procedure (at least 12 hours post-procedure) or within 7 days post implant, 
whichever comes first 
30 Days 
Between 30 and 45 days post implant 
6 Months 
Between 183 and 210 days post implant 
1 Year 
Between 365 and 395 days post implant 
2 Years 
Between 730 and 760 days post-implant 
3 Years 
Between 1095 to 1125 post-implant 
4 Years 
Between 1460 to 1490 days post-implant 
5 Years 
Between 1825 to 1855 days post-implant 
6.7
Subject Disposition 
Sites will maintain a log of subjects consented, the subject ID numbers assigned to them, and the dates 
of their implants (or attempted implants).  Subjects who are consented but are not taken to the 
procedure room for implantation should be exited from the study and need not be followed beyond the 
date of study exit. 
Subjects taken to the procedure room for implantation, and any of the following occurred: anesthesia 
administered, vascular line placed, TEE placed or any monitoring line placed, but do not receive a TAV 
for any reason should be followed for safety events for 30 days after the procedure or through the 
hospitalization, whichever is longer, and then exited from the study.  Subjects that have their TAV 
explanted should be followed for safety events for 30 days after the explant procedure, or through 
resolution of related adverse events, whichever is longer, then exited from the study. 
6.8
Missed Follow-Up Visits 
Every effort should be made to ensure subjects return to the clinic for all protocol required follow-up 
visits, tests, and assessments.  If the subject is unable to return for an in-person clinic visit, the 

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Investigator, or designee, should document in the subject record the reason the subject was unable to 
complete the visit and, if applicable, follow the requirements for deviation reporting as outlined in 
Section 6.10. 
The investigator should also make every effort to contact the subject within the visit window to collect 
the subject’s vital status as well as information related to potential adverse events, safety data, and 
hospitalizations. 
6.9
Unscheduled Follow-Up Visits 
If a subject returns to the study site or is contacted via telephone between their scheduled follow-up 
visits for an event potentially related to a study endpoint, the visit or telephone call will be treated as an 
unscheduled follow-up, and the assessments completed at this visit will be conducted at the discretion 
of the investigator per local standards of care and/or institutional policies and procedures. Relevant 
unscheduled visit data should be reported and imaging should be provided to the sponsor as needed. 
6.10 Protocol Deviations 
A protocol deviation is defined as an event where the clinical investigator or site personnel did not 
conduct the study according to the CIP or the Clinical Investigational Agreement.  Examples of CIP 
deviations include but are not limited to the following: 
x
Failure to obtain informed consent prior to participation 
x
Incorrect version of the informed consent form used 
x
Failure to obtain IRB/EC approval before the start of the study 
x
Implanted subject did not meet inclusion/exclusion criteria5 
x
Required testing and/or measurements not done or incorrectly done 
x
Subject does not attend follow-up visit or follow-up visit outside window 
x
Unauthorized use of investigational devices 
x
Adverse events not reported in the required time frame as required by regulation or as specified in 
the CIP 
x
Control of study devices not maintained 
x
Source data permanently missing 
x
Enrollment of patients during lapse of IRB/EC approval 
x
Enrollment limits exceeded  
Investigators should obtain prior approval from Medtronic before initiating any change or deviation 
from the CIP, except where necessary to protect the life or physical well-being of a subject in an 
emergency situation.  Such approval shall be documented in writing and maintained in the Investigator 
Site File.  Prior approval is generally not expected in situations where unforeseen circumstances are 
beyond the investigator’s control (e.g. subject did not attend scheduled follow-up visit). 
Subjects must meet all inclusion/exclusion criteria to be eligible for implantation.  However, it will not be considered a protocol deviation if 
study related testing (e.g. echo, MDCT, labs, coronary arteriography, Heart Team assessment, or ERC review) of a consented subject identifies 
implantation eligibility criteria that are not met. 

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Deviations will be reported to Medtronic regardless of whether medically justifiable, pre-approved by 
Medtronic, or taken to protect the subject in an emergency.  Study deviations should be reported to 
Medtronic via the Study Deviation eCRF. 
Investigators should report the following deviations to Medtronic, and if applicable their reviewing 
IRB/EC, within 5 working days (or earlier according to local requirements) of the occurrence of the 
deviations:  
x
Failure to obtain written informed consent 
x
Deviations to protect the life or physical well-being of a subject in an emergency 
In addition, Investigators are required to adhere to applicable local regulations and IRB/EC procedures 
for reporting deviations. Sponsor and investigator will follow requirements for reporting and handling 
serious breaches in Australia. Medtronic is responsible for analyzing deviations, assessing their 
significance, and identifying any corrective and/or preventive actions that may be warranted.  Repetitive 
or serious investigator compliance issues may represent a need to initiate a corrective action plan, which 
may include suspension of enrollment or the investigator’s or site’s participation in the study. 
6.11 Subject Withdrawal or Discontinuation 
All subjects will be encouraged to remain in the study through the last follow-up visit at five years.  
Subjects who discontinue participation prematurely will be included in the analysis of results (as 
appropriate) and will not be replaced in the enrollment of total study subjects.  If a subject is 
discontinued from the study early, the reason for discontinuation should be documented in the subject 
file and a Study Exit eCRF must be completed. 
The study site should make every effort to have all subjects complete the follow up visit schedule. When 
subjects are lost to follow-up the investigator will make efforts to confirm the vital status of the subject, 
as described in the informed consent.  A subject will not be considered lost to follow-up unless all efforts 
to obtain compliance are unsuccessful.  At a minimum, the efforts to obtain follow-up information must 
include 3 attempts to make contact via telephone and if contact via phone is not successful, a traceable 
letter from the investigator should be sent to the subject’s last known address.  The study site may also 
utilize a civil register for subject information, as applicable. 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 on the study eCRFs. 
If a subject discontinues the study at any time, is withdrawn from the study early, or completes all 
protocol required follow-up they should continue to be followed by the implanting site according to 
their routine clinical practice for patients with prosthetic aortic valves.  If for any reason this is not 
possible for a particular subject, or if a subject needs to change their follow-up site at any time point 
after conclusion of the study, investigators should refer subjects to a local site with appropriate training 
and experience in managing patients with prosthetic aortic valves. Study data will not be collected after 
a subject has ended their participation in the study. 

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6.12 Study Materials and Study-Specific Equipment 
Medtronic will control the supply of investigational devices and study materials (e.g. Investigator Site 
File, eCRF access).  Investigational devices will not be sent to the site until the site is activated.  
Medtronic will not provide any study specific equipment.  Equipment used for assessing study variables 
(e.g. echocardiographic systems, laboratory equipment) should be maintained per the site’s standard 
procedures. 
6.13 Pre-TAVR Multi-Detector Computed Tomography (MDCT) 
MDCT of the aortic root and peripheral vascular is required within 365 days of the qualifying 
echocardiogram to assess suitability for transfemoral TAVR with the study system.  Information 
regarding the required MDCT variables are provided in Section 13.1. 
6.14 Clinical Assessment 
Clinical assessment is required at each study interval.  Assessments should be performed at the study 
center by a member of the investigative team as delegated by the PI.  If the subject is unable to attend a 
follow-up visit, the clinical assessment can be performed by telephone, and this should be indicated on 
the eCRF and documented in the subject’s medical record at the site.  Information regarding the 
required variables and assessment procedures are provided in Section 13.2. 
6.15 Echocardiography 
Comprehensive transthoracic echocardiography (TTE) including speckle tracking (STE) is required at 
baseline, discharge, 30 days, 6 months, and annually through five years.  Protocol-required exams 
should be performed at the study center by designated members of the study team as delegated by the 
site PI.  All protocol-required exams will be sent to the ECL for central assessment.  In addition, 
unplanned echocardiograms (e.g. clinically indicated exams for change in symptoms or findings on 
physical exam) should be sent to the ECL if possible.  A listing of the required variables and details 
regarding their acquisition is provided in Section 13.3.  
6.16 Exercise Tolerance Testing (ETT) 
Subjects confirmed by the ECL to meet  severe asymptomatic AS criteria should undergo ETT unless 
contraindicated.  Examples of contraindications include an established indication for AVR, uncontrolled 
hypertension, symptomatic or hemodynamically significant arrhythmias, and inability to perform the 
test such as orthopedic limitations or global disabilities.59,60,61 The reason for not undergoing ETT should 
be documented in the study records. 
A symptom-limited exercise test with the goal of reaching 80% to 85% of the age-predicted maximum 
heart rate is recommended.  The recommended protocol is the modified-Bruce with treadmill, however 
the choice of the specific ETT protocol for each subject is per the clinical judgment of site study team. 

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Subjects who develop spontaneous AS-related symptoms or signs of AS (e.g. a drop or an insufficient 
rise in blood pressure, significant ventricular arrhythmias)39 may continue in the study as follows: At 
maximum, up to 30 subjects with a positive ETT will be included in the study.  Subjects with a positive 
ETT who are approved by the ERC may continue in the study until the 30-subject maximum is reached.  
Once the 30-subject maximum is reached, only subjects with a negative ETT may continue in the study.  
Details regarding the ETT methods and data requirements are provided in Section 13.4. 
6.17 Cardiac Magnetic Resonance Imaging (CMR) 
Subjects confirmed by the ECL to meet the severe asymptomatic AS criteria should undergo CMR unless 
contraindicated, and subjects implanted should have a CMR at the six-month follow-up.  CMR exams will 
be sent to the CMR core lab for central analysis.  Details on CMR methods and data requirements are 
provided in Section 13.5.  
6.18 Six Minute Walk Test (6MWT) 
Subjects confirmed by the ECL to meet the severe asymptomatic AS criteria should have a 6MWT unless 
contraindicated, and subjects implanted should have a 6MWT at the six-month follow-up.  Details on 
6MWT methods and data requirements are provided in Section 13.6.  
6.19 TAVR Implant Procedure 
The implantation procedure is performed according to the standard procedures of the implant team.  
For sites in the United States, the local heart team’s interventional cardiologist(s) and cardiac surgeon(s) 
must jointly participate in the intra-operative technical aspects of the TAVR procedure.  Procedural 
aspects specific to the Medtronic TAVR system should be performed according to the Instructions for 
Use (IFU).  Valve deployment in accordance with the cusp overlap technique62 is recommended for TAVR 
implant for all study subjects, as appropriate.  Transfemoral access is required for the TAVR implant.  
Information on TAVR implant data requirements is provided in Section 13.7.  
6.20 Post-Implant Antithrombotic and Medical Therapy 
Management of subject’s anti-thrombotic regimen will be per the discretion of the investigative team.   

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7.1
Definitions 
The definitions to be applied for the purposes of reporting adverse events are provided in Table 2. 
Table 2.  Adverse event definitions for reporting requirements 
Event Type 
Definition 
Device Deficiency 
(ISO 14155:2020 3.19) 
 
Inadequacy of a medical device with respect to its identity, quality, durability, reliability, 
usability, safety or performance.  
NOTE 1: Device deficiencies include malfunctions, use errors, and inadequacy in the information 
supplied by the manufacturer including labeling. 
NOTE 2: This definition includes device deficiencies related to the investigational medical device 
or the comparator
Adverse Event (AE)  
 
(ISO/FDIS 14155:2020 3.2) 
 
Untoward medical occurrence, unintended disease or injury, or untoward clinical signs 
(including abnormal laboratory findings) in subjects, users or other parties, whether or not 
related to the investigational medical device, and whether anticipated or unanticipated.  
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 the use of 
investigational medical devices or comparators. 
Serious Adverse Event (SAE)  
 
(ISO/FDIS 14155:2020 3.45) 
 
 
Adverse event that led to any of the following  
a) 
Death, 
b) 
Serious deterioration in the health of the subject, users, or other persons as defined by 
one or more of the following:   
1) 
a life-threatening illness or injury, or  
2) 
a permanent impairment of a body structure or a body function including 
chronic diseases, or 
3) 
in-patient or prolonged hospitalization, or  
4) 
medical or surgical intervention to prevent life-threatening illness or injury, or 
permanent impairment to a body structure or a body function, 
c) 
Foetal distress, foetal death, a congenital abnormality, or birth defect including physical 
or mental impairment.  
NOTE: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, 
without serious deterioration in health, is not considered a serious adverse event. 
Adverse Device Effect (ADE) 
or Device Related Adverse 
Event 
(ISO/FDIS 14155:2020 3.1) 
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. 
NOTE 3: This includes ‘comparator’ if the comparator is a medical device. 
Serious Adverse Device 
Effect (SADE) 
(ISO/FDIS 14155:2020 3.44) 
Adverse device effect that has resulted in any of the consequences characteristic of a Serious 
Adverse Event.  
Unanticipated Adverse 
Device Effect 
(UADE)
(21 CFR 812.3) 
Any serious adverse effect on health or safety of a patient, or any life-threatening problem or 
death caused by or associated with the device, if the effect, problem, or death has not been 
previously identified in nature, severity, or degree of incidence in the investigational plan or 
application, (including a supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects.  

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Unanticipated Serious 
Adverse Device Effect 
(USADE) 
(ISO/FDIS 14155:2020 3.51) 
Serious adverse device effect which by its nature, incidence, severity or outcome has not been 
identified in the current risk assessment  
NOTE: Anticipated serious adverse device effect (ASADE) is an effect which by its nature, 
incidence, severity or outcome has been identified in the risk assessment. 
Serious Health Threat 
(ISO 14155:2020 3.46)  
A signal from any adverse event or device deficiency that indicates an imminent risk of death or 
a serious deterioration in the health in subjects, users or other persons, and that requires 
prompt remedial action for other subjects, users or other persons. 
 
NOTE: This would include events that are of significant and unexpected nature such that they 
become alarming as a potential serious health hazard or possibility of multiple deaths occurring 
at short intervals. 
 
Additional Event Types 
Definition 
Significant Safety Issue (SSI) 
(NHMRC Safety monitoring 
and reporting in clinical trials 
involving therapeutic goods 
November 2016) 
(Australia ONLY) 
A safety issue that could adversely affect the safety of participants or materially impact on the 
continued ethical acceptability or conduct of the trial.
Urgent Safety Measure 
(USM) 
(NHMRC Safety monitoring 
and reporting in clinical trials 
involving therapeutic goods 
November 2016) 
(Australia ONLY) 
A measure required to be taken in order to eliminate an immediate hazard to a participant’s 
health or safety. 
Note: This type of significant safety issue can be instigated by either the investigator or sponsor 
and can be implemented before seeking approval from HRECs or institutions. 
Notes:
x
The interpretation of Seriousness will exclude certain interventions considered standard of care during 
hospitalization (e.g. IV hydration, certain medications delivered intravenously due to available 
intravenous access or NPO (nothing by mouth) status, and the delivery of electrolytes to maintain 
electrolyte balance or to address mild electrolyte depletion). Any nonoral medication or fluid delivery 
used to treat an acute physical decompensation/deterioration episode or to otherwise resuscitate a 
subject will be considered serious by definition in that it prevents a permanent impairment of a body 
structure or deterioration of the health of a subject. 
x
Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without serious 
deterioration in health, is not considered a serious adverse event. 
x
Hospitalization requires admission for at least 24 hours. 
x
Ballooning as needed during the implant procedure is standard practice and should not be considered a 
reintervention. 
 
7.2
Evaluation and Documentation of Adverse Events and Device Deficiencies 
Investigators are required to evaluate and document in the subject’s medical records all adverse events 
(AE) and device deficiencies (per the definitions in Table 2) observed in study subjects from the time 

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they are enrolled until they are exited from the study.  All AEs should be followed through their 
resolution. 
All AEs that occur during the study need to be reported to Medtronic via the AE eCRF.  Documented pre-
existing conditions are not considered to be reportable unless there is a change in the nature or severity 
of the condition.  Pre-existing events should be reported as AE in the situation where a new treatment 
has to be started or an existing treatment has to be changed to treat the adverse event and the event is 
accompanied with signs and symptoms.  In addition, after the subject has completed his/her 6-month 
follow-up visit, only SAE, device-related AEs, and device deficiencies need to be reported to Medtronic. 
Unavoidable events are conditions which do not fulfill the definition of an Adverse Event, meaning those 
medical occurrences, clinical signs (including toward abnormal laboratory findings), diseases or injuries 
that are not untoward in nature; specifically, those resulting from the intended injury such as the index 
TAVR procedure.  The events listed in Table 3 are expected for patients undergoing TAVR, and do not 
need to be reported as AE, unless they occur outside of the stated timeframe, are otherwise considered 
to be an AE according to the treating investigator, or are suspected or confirmed to be device-related. 
 
Table 3.  Non-reportable medical occurrences associated with the index implant procedure 
Event 
Timeframe (hours) from 
the Index Procedure 
Short transient episode of arrhythmia (including ventricular fibrillation) during index 
procedure 
0 
Confusion, anxiety and/or disorientation (other than TIA/stroke) starting within 48 hours 
with or without medical intervention 
120 (5 days) 
Temporary change in mental status (other than TIA/stroke) not requiring additional medical 
interventions or new medical assessments (e.g. CT) 
72 
Dizziness and/or lightheadedness with or without treatment  
24 
Headache with or without treatment 
72 
Sleep problems or insomnia with or without treatment 
120 (5 days) 
Mild dyspnea or cough with or without treatment 
72 
Oxygen supply after extubation/“forced breathing therapy”  
48  
Diarrhea with or without treatment  
48  
Obstipation/Constipation with or without treatment  
72  
Anesthesia-related nausea and/or vomiting with or without treatment  
24  
Low-grade fever (<101.3°F or <38.5°C) without confirmed infection  
48  
Low body temperature  
6  
Pain (eg, back, shoulder) related to laying on the procedure table with or without treatment  
72  
Incisional pain (pain at access site) with or without standard treatment and patient not 
returning to clinic to have additional treatment  
No time limit  
Pain in throat and/or trachea due to intubation  
72  

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Mild to moderate bruising or ecchymosis  
168 (7 days)  
Atelectasis/Pleural Effusion not requiring punctuation  
168 (7 days)  
Edema resulting in weight increase up to 4 kg/9lbs from baseline  
168 (7 days)  
For all reportable AEs, investigators should assess and document the following information on the 
Adverse Event eCRF: 
x
Date of onset and first observation/awareness of the event 
x
Description of the event 
x
Seriousness of the event 
x
Causal relationship of the event to the TAV 
x
Causal relationship of the event to the DCS or LS 
x
Causal relationship of the event to the TAVR implant procedure 
x
Treatment required 
x
Outcome or status of the event 
x
Date of resolution 
For all deaths, investigators should assess and document the following information on the Death eCRF: 
x
Date of death 
x
Primary death category 
x
Causal relationship of the event to the TAV 
x
Causal relationship of the event to the DCS or LS 
x
Causal relationship of the event to the implant procedure 
In addition, for all endpoint-related adverse events and deaths, sites should submit relevant, de-
identified source documents to Medtronic for the Clinical Events Committee (CEC) members to use in 
their adjudication of the event.  The CEC may request source documentation on additional events, at 
their discretion and according to the CEC Charter. 
Definitions of safety endpoints and guidelines for accessing causal relationships are provided in Section 
13.8. 
7.3
Anticipated Adverse Events 
Adverse events that are anticipated (foreseeable) for subjects participating in this study are described in 
Section 8.1 and in the Investigator’s Brochure/ROPI. 
7.4
Adverse Event Reporting Requirements for Clinical Sites 
Adverse events and device deficiencies that occur during this study are required to be reported to 
Medtronic via the AE or device deficiency eCRF, as soon as possible after the event occurs, but no later 
than the timeframes listed in Table 4 or local requirements, whichever is more stringent. 
Table 4.  Required timeframes for adverse event reporting to Medtronic 

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Event Type 
Timeframe for Reporting 
Adverse Event (AE) 
No later than 10 working days of the investigator’s / site’s first knowledge of the event 
Serious Adverse Event (SAE) 
Immediately, but no later than 72 hours of the investigator’s / site’s first knowledge of 
the event 
Adverse Device Effect (ADE) or 
Device Related Adverse Event 
Immediately, but no later than 72 hours of the investigator’s / site’s first knowledge of 
the event 
Serious Adverse Device Effect 
(SADE) 
Immediately, but no later than 72 hours of the investigator’s / site’s first knowledge of 
the event 
Unanticipated Adverse Device 
Effect (UADE) 
Immediately, but no later than 72 hours of the investigator’s / site’s first knowledge of 
the event 
Unanticipated Serious Adverse 
Device Effect (USADE) 
Immediately, but no later than 72 hours of the investigator’s / site’s first knowledge of 
the event 
Device Deficiency 
No later than 72 hours of the investigator’s / site’s first knowledge of the event 
Device Deficiency that might 
have led to a SADE 
Immediately, but no later than 72 hours of the investigator’s / site’s first knowledge of 
the event 
Serious Health Threat  
Immediately, but no later than 72 hours of the investigator’s / site’s first knowledge of the 
event 
Additional Event Types 
Timeframe for Reporting 
Mandatory Problem Reporting 
Incident  
(Canada ONLY)
No later than 72 hours of the investigator’s / site’s first knowledge of the event, to Health 
Canada and Medtronic 
All SAEs and DDs with potential 
SADE 
(Australia ONLY) 
Without unjustified delay to Medtronic
 (NHMRC Safety monitoring and reporting in clinical trials involving therapeutic goods 
November 2016 section C.2.b) 
Significant Safety Issues  
(Australia ONLY) 
x
Urgent Safety Measures (USMs): Within 24 hours to Medtronic 
(NHMRC Safety monitoring and reporting in clinical trials involving therapeutic goods 
November 2016 section C.2.c) 
x
All significant safety issues: Without undue delay and no later than 72 hours of 
the principal investigator becoming aware of the event to HREC and Institution 
(NHMRC Safety monitoring and reporting in clinical trials involving therapeutic goods 
November 2016 section C.2.g) 
Unanticipated Serious Adverse 
Device Effect (USADE) 
(Australia ONLY) 
Report to their HREC and  institution without undue delay and no later than 72 hours of 
the Principal Investigator becoming aware of the event. 
(NHMRC Safety monitoring and reporting in clinical trials involving therapeutic goods 
November 2016 section C.2.g) 
In addition, Investigators are obligated to report adverse events in accordance with the requirements of 
their reviewing IRB/EC and local regulations. 
The Sponsor is obligated to report adverse events and device deficiencies that occur during this study to 
the Regulatory Authorities and IRB/EC as per local requirements.  The applicable timeframes are 
described in the Safety Plan associated with this study. 

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7.5
Documentation and Reporting of Device Deficiencies 
Device deficiency information will be collected throughout the study and reported to Medtronic.  Device 
deficiencies that led to an AE are reported on the AE eCRF.  Device deficiencies that did not lead to an 
AE should be reported on a Device Deficiency eCRF (one for each Device deficiency). 
Device deficiencies that did not lead to an adverse event but might have led to a SADE if: 
x
a suitable action had not been taken, or  
x
an intervention had not been made, or  
x
circumstances had been less fortunate,  
Device deficiency information should be reported to Medtronic via the Device Deficiency eCRF as soon 
as possible but no later than 72 hours after the investigator first learns of the event.  
7.6
Emergency Contact Details for Reporting SAE, SADE, UADE, and Device Deficiencies 
Investigators should contact their Medtronic clinical study manager or site manager if they have any 
questions regarding reportable AEs. Medtronic will provide and maintain a listing of current contact 
details for each site.  
7.7
Clinical Events Committee 
A Clinical Events Committee (CEC) will provide independent medical review and adjudication of adverse 
event data used in the safety assessment of the investigational device.  The CEC will adjudicate, at 
minimum, all deaths and safety endpoint-related adverse events and TAVR related complications 
reported by the investigators, and may leverage core lab-reported data for events where echo imaging 
is used in the adjudication.  The CEC will follow the VARC II63 recommendations where relative for 
classifying adverse events related to clinical safety endpoints.  The analysis of the study safety data will 
be based on CEC adjudicated events.  Definitions of safety endpoints and other TAVR related 
complications are provided in Section 13.8. 
The committee will consist of at least 3 independent experts (non-Medtronic employed physicians that 
are not participating investigators for the study) with expertise relevant to the study.  This may include 
experience in the areas of: 
x
Interventional cardiology 
x
Cardiology 
x
Neurology 
x
Cardiac surgery 
A CEC charter will be approved by Medtronic and the CEC prior to the first subject enrollment. 

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7.8
Data Safety Monitoring Board 
A Data Safety Monitoring Board (DSMB) will assess interim study data and provide recommendations to 
Medtronic regarding study conduct, should they identify any issues that may affect the safety of the 
study subjects.  DSMB members will be free from bias towards the study and will be independent from 
both the study and investigators and Medtronic.  The DSMB will consist of a minimum of 4 members:  
x
a non-interventional cardiologist with expertise in the management of aortic stenosis  
x
an interventional cardiologist with expertise in TAVR 
x
a cardiothoracic surgeon with expertise in aortic valve replacement 
x
a statistician 
A DSMB charter will be approved by Medtronic and the DSMB members prior to the first subject 
enrollment.  The DSMB will meet (via teleconference or in person) prior to the first subject enrollment 
to establish procedures for safety data review, chairman appointment, and guidelines for study 
recommendations.  The DSMB will meet on a periodic basis to perform a comprehensive data review, 
including at a minimum, all SAEs and deaths, and will meet more frequently when needed.  Safety-
related endpoints may also be reviewed at these meetings.  DSMB meetings may consist of both open 
and closed sessions.  Medtronic personnel may facilitate the DSMB meeting but will not have voting 
privileges. 
Following each meeting, the DSMB will report to Medtronic in writing and may recommend changes in 
the conduct of the study.  The DSMB recommendations may include recommendations on study status 
such as continuing the study without modifications, continuing the study with modifications, stopping or 
suspending enrollment, or recommendations regarding study 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 study within 5 working days 
after making that determination and no later than 15 working days after Medtronic first receives notice 
of the effect.  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 study.  All data presented at the meetings will be 
considered confidential.  
7.9
Product Complaint Reporting
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 immediately and via the regular channels for market-released 
products.  The reporting of product complaints by the clinical team must be done according to the local 
Standard Operating Procedures.  Medtronic will notify the regulatory authorities as applicable for the 
following incidents immediately upon learning of them and is not limited to adverse events and device 
deficiencies only: 

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Any malfunction or deterioration in the characteristics and/or performance of a device, as well as 
any inadequacy in the labeling or instructions for use which led or might have led to the death or 
serious deterioration in the state of health of a patient, user, or other person. 
x
Any technical or medical reason resulting in withdrawal of a device from the market by the 
manufacturer. 
x
Any serious deterioration in the state of health, including: 
 Life-threatening illness or injury 
 Permanent impairment of a body function or permanent damage to a body structure 
 A condition necessitating medical or surgical intervention to prevent permanent impairment of a 
body function or permanent damage to a body structure 
 

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8.1
Potential Risks
As with any TAVR procedure, there are risks associated with participation in this study.  However, the 
risks to a patient for participation in this study are not materially different than those a patient would 
incur if they underwent TAVR outside of this study. 
TAVR has been associated with serious complications, including death. In addition, complications may 
occur at varying intervals necessitating re-intervention or surgical replacement of the TAV.  Known 
(anticipated) complications that may result from TAVR include but are not limited to the following: 
x
Allergic reaction to anti-platelet agents, contrast medium, or anesthesia 
x
Anemia 
x
Bowel ischemia 
x
Cardiac arrest 
x
Cardiac tamponade 
x
Cardiovascular injury (including rupture, perforation, tissue erosion, or dissection of vessels, 
ascending aorta trauma, ventricle myocardium, or valvular structure that may require intervention) 
x
Coronary occlusion, obstruction, or vessel spasm (including acute coronary closure) 
x
Exposure to radiation through fluoroscopy and angiography 
x
Major or minor bleeding that may require transfusion or intervention (including life-threatening or 
disabling bleeding) 
x
Mitral valve regurgitation or injury 
x
Myocardial infarction 
x
Myocardial ischemia 
x
Pericardial effusion 
x
Peripheral ischemia 
x
Pleural effusion 
x
Stroke (ischemic or hemorrhagic), transient ischemic attack (TIA), encephalopathy, or other 
neurological deficits 
Known complications that are associated with the TAV include but are not limited to the following: 
x
Ancillary device embolization 
x
Delivery catheter system malfunction resulting in the need for additional re-crossing of the aortic 
valve and prolonged procedural time 
x
Hemolysis 
x
Hypertension 
x
Prosthetic valve dysfunction, which could lead to urgent need for balloon valvuloplasty or 
Percutaneous Coronary Intervention (PCI), including but not limited to: 
 Fracture 
 Bending (out-of-round) configuration of the valve frame 
 Calcification 
 Pannus 
 Wear, tear, prolapse, or retraction in the valve leaflet 

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 Poor valve coaptation 

Suture breaks or disruption 

Leak 

Mal-sizing (prosthesis-patient mismatch) 

Malposition (either too high or too low) 

Valve regurgitation (paravalvular or transvalvular) 

Valve stenosis 
x
Tissue erosion 
x
Valve migration/embolization 
Known complications that could result from either the TAVR procedure or the TAV include but are not 
limited to the following: 
x
Abnormal lab values (including electrolyte imbalance) 
x
Angina 
x
Cardiac arrhythmias 
x
Disturbances in the electrical system of the heart that may result in the permanent placement of a 
device (pacemaker): 
 Atrio-ventricular node block 
 Bundle branch block 
 Asystole 
x
Dyspnea 
x
Fever 
x
Hypotension 
x
Individual organ, for example, cardiac, respiratory, or renal (including acute kidney failure), 
insufficiency or failure 
x
Infection (including septicemia or endocarditis) 
x
Inflammation 
x
Multi-organ failure or low cardiac output 
x
Pulmonary edema 
x
Permanent disability 
x
Syncope 
x
Thrombosis (including valve thrombosis) 
x
Valvular access site or access related complications including but not limited to: 
 Dissection 
 Perforation 
 Pain 
 Bleeding 
 Hematoma 
 Pseudoaneurysm 
 Irreversible nerve injury 
 Compartment syndrome 
 Arteriovenous fistula 
 Stenosis 
 

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Known risks associated with participation in this study include but are not limited to the following: 
x
Minor pain, bruising, presyncope, or syncope (fainting) during blood draws 
x
Excessive bleeding, infection, blood clots, or inflammation of the vein during blood draws 
x
Anxiety 
x
Skin irritation from ECG electrodes 
x
Chest pain 
x
Arrhythmia 
x
Dizziness 
x
Nausea 
x
Fatigue 
x
Allergic reaction to contrast medium 
x
Changes in taste 
x
Headache 
 
Each of these complications has the potential to be life-threatening, and some could lead to the need for 
open heart surgery. 
8.2
Risk Analysis and Minimization
Medtronic has determined this to be a significant risk clinical study.  In the United States, Medtronic will 
obtain an Investigational Device Exemption (IDE) from the United States Food and Drug Administration.  
Medtronic will obtain approval from country-specific authorities in Canada, Europe, Israel, Australia, and 
New Zealand. 
Risk Analysis procedures were completed in accordance with ISO 14971:2012, and the results are 
provided in the Investigator Brochure/Report of Prior Investigations. 
The following measures will be implemented to minimize risks to the study subjects: 
x
Implanting physicians will have considerable experience with TAVR 
x
Study sites will have significant experience with surgical SAVR and TAVR 
x
Patients will undergo thorough imaging assessment during their pre-implant screening 
x
Patients will be rigorously followed over the course of the study 
x
An independent DSMB will review interim results in order to advise Medtronic regarding study 
conduct, should safety concerns be identified. 
8.3
Potential Benefits 
The primary potential benefit to subjects participating in the study is restored function of their aortic 
valve, specifically relief of obstruction of their stenotic aortic valve.  In patients with severe, 
symptomatic aortic stenosis, TAVR has been demonstrated to improve symptoms and survival.  
However, the benefits with TAVR have not been confirmed in clinical trials for patients with severe, 
asymptomatic AS. 

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8.4 
Risk-Benefit Rationale 
Study subjects will be exposed to the procedural and device risks associated with TAVR, as well as the 
study specific risks listed in Section 8.1. However, evidence from the scientific literature indicates 
patients with the degree of AS in this study are also exposed to the serious risks associated with their 
disease, including heart failure, irreversible ventricular functional impairment, and death.  Further, 
recent evidence indicates the risks of the disease for the subjects in this study are similar to those with 
for which TAVR has been shown to be effective in improving symptoms and survival. 
The known benefits of TAVR in patients with severe symptomatic AS are expected to be conferred to the 
study subjects with severe asymptomatic AS, and it is believed that the benefits of the relief of 
obstruction will outweigh the risks of intervention. Therefore, the risk/benefit ratio for the study 
subjects is justified. 
 

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9.1
General  
The investigational device in this study is the Medtronic Evolut PRO+ System.  The Medtronic Evolut 
PRO+ System (Figure 3) is a recapturable transcatheter aortic valve replacement (TAVR) 
implantation system comprised of the following three components: 
1. Medtronic Evolut PRO+ TAV 
2. Medtronic Evolut PRO+ DCS  
3. Medtronic Evolut PRO+ LS 
 
Figure 3.  The Evolut PRO+ TAVR system; Evolut PRO+ Transcatheter Aortic Valve (top); Evolut PRO+ Loading System (middle); Evolut PRO+ 
Delivery Catheter System (bottom). 
There are no anticipated changes to any of the system components during this investigation.  A listing of 
the system components is provided in Table 5. 

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Table 5. Evolut PRO+ System Components
Component 
US Model Number 
OUS Model Number 
Size (mm) 
Aortic Annulus 
Diameter (mm) 
Medtronic Evolut PRO+ TAV 
EVPROPLUS-23US-C 
EVPROPLUS-23-C 
23 
18 – 20  
EVPROPLUS-26US-C 
EVPROPLUS-26-C 
26 
20 – 23 
EVPROPLUS-29US-C 
EVPROPLUS-29-C 
29 
23 – 26 
EVPROPLUS-34US-C 
EVPROPLUS-34-C 
34 
26 - 30 
Medtronic Evolut PRO+ DCS 
D-EVPROP2329US-C 
D-EVPROP23-29GC 
Used with 23, 
26, and 29 mm 
TAVs 
Not applicable 
D-EVPROP34US-C 
D-EVPROP34GC 
Used with 
34mm TAV 
Not applicable 
Medtronic Evolut PRO+ LS 
L-EVPROP2329US-C 
L-EVPROP23-29GC 
Used with 
23,26, and 29 
mm TAVs 
Not applicable 
L-EVPROP34US-C 
L-EVPROP34GC 
Used with 34 
mm TAV 
Not applicable 
9.2
Medtronic Evolut PRO+ Transcatheter Aortic Valve (TAV) Prosthesis 
The Medtronic Evolut PRO+ TAV is available in 4 sizes (23, 26, 29, 34mm), covering an aortic annulus 
diameter of 18 to 30 mm.  The TAV is comprised of 3 leaflets, a sealing skirt, and outer tissue wrap 
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 AOA, 
a compound derived from oleic acid, a naturally occurring long-chain fatty acid. 
9.3
Medtronic Evolut PRO+ Delivery Catheter System 
The Evolut PRO+ catheter facilitates the placement of the bioprosthesis 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 the bioprosthesis to be partially or fully recaptured 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.  A PRO+ 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 catheter 

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is compatible with an 18 Fr (6.0 mm) introducer sheath for the 23, 26, and 29 mm TAVs and a 22 Fr (7.3 
mm) introducer sheath for the 34 mm TAV. 
The DCS consists of a catheter with an integrated handle to assist 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 
deployment knob turns to deploy the bioprosthesis.  Arrows on the deployment knob indicate the 
direction of rotation required to deploy the bioprosthesis.  If desired, the deployment knob can be 
turned in the opposite direction to partially or fully recapture the bioprosthesis if the radiopaque 
capsule marker band has not yet reached the distal end of the radiopaque paddle attachment.  Once the 
radiopaque capsule marker band reaches the distal end of the radiopaque paddle attachment, it is at 
the point of no recapture.  The deployment knob also features a trigger, which can be engaged to make 
macro adjustments to the capsule position.  A blue hand rest connects to the deployment knob.  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. 
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 to these features, the 
device packaging is swiveled and secured to facilitate the bioprosthesis loading procedure. 
9.4
Medtronic Evolut PRO+ Loading System 
The Evolut PRO+ LS compresses the bioprosthesis into the catheter.  Note: verify the correct delivery 
system and loading system are used for the Evolut PRO+ 34 mm valve.  This loading system is designed 
for compatibility with this specific TAV and delivery system.  
9.5
Packaging 
Examples of the Instructions for Use (IFU) and package labeling (English versions) will be provided under 
separate cover.  Devices will be labeled as investigational (i.e. “Exclusively for clinical investigation”).  
IFU and labeling will be provided in local languages. Labeling will be in accordance with country 
regulation in each geography. 
9.6
Intended Population 
The intended population for this study includes males and females ш than 65 years of age with severe, 
asymptomatic aortic stenosis. 
9.7
Product Use 
The Evolut PRO+ TAV treats aortic stenosis by displacing and functionally replacing the dysfunctional 
native valve with a bioprosthetic valve delivered on a catheter while the heart is still beating.  Its 
intended performance is to relieve aortic valve stenosis without inducing significant regurgitation, 

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thereby restoring effective aortic valve function. The Evolut PRO+ device shall be used in compliance 
with applicable national regulations. 
9.8
Product Training Requirements 
There are no training requirements specific to this study. Study trained, delegated, and activated 
implanters will have experience with the TAVR procedure as noted in Section 5.4. 
9.9
Product Receipt, Tracking, Storage, and Accountability 
All components of the Evolut PRO+ TAVR system are not approved for use outside of patients in this 
study and therefore are considered investigational devices.  As such, they should be stored as labeled 
and in a secure location.  The method of storage should prevent the use of these investigational devices 
for applications other than mentioned in this CIP.  The investigator shall maintain adequate records of 
the receipt and disposition of all investigational devices. 
Centers are required to maintain investigational device records that contain the following information: 
x
Investigational device name 
x
TAV serial number 
x
Lot number (for delivery and loading systems only) 
x
Date of receipt of device 
x
Name of person receiving the device 
x
Name of person using the device 
x
Date of implant or use 
x
ID number of subject receiving or using the device 
x
Disposition (implanted, disposed of, or returned to Medtronic) 
For devices that are returned to Medtronic or disposed of, centers are required to document the 
following information: 
x
The device serial numbers 
x
Lot numbers (for delivery systems only) 
x
The quantity and reason for the device being returned to Medtronic or disposed of
x
Name of the person who returned or disposed of each device 
x
Date of shipment back to Medtronic 
At the study closeout visit, the investigator must return to Medtronic any unused devices and a copy of 
the completed device inventory.  The investigator’s copy of the device reconciliation records must 
document any unused devices that have been returned to Medtronic as well as all product usage 
including opened but non-implanted devices. Country specific regulations will also be followed. 
9.10 Product Return 
In the event of a device malfunction of the Evolut PRO+ system prior to implant, or in the event a TAV is 
explanted after implant (due to reintervention or autopsy), the TAV and/or affected components of the 
Evolut PRO+ system should be sent to Medtronic at the following address: 

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Medtronic, Inc.  
Attn: Explant Lab [PCR#] 
1851 E. Deere Avenue 
Santa Ana, CA  92705-5720 
Study sites shall notify the sponsor at the time of TAV explant.  Additional details surrounding the device 
return process are contained within the Medtronic explant kit that will be provided upon notification of 
a device malfunction or explant.  Explanted TAVs returned to Medtronic will be evaluated by a Pathology 
Core lab. 
 

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10.1 General Aspects of Analysis 
Data analysis will be performed by Medtronic clinical personnel per departmental SOP and according to 
the Statistical Analysis Plan developed for this study.  As this is a descriptive study, there are no 
prospectively developed study hypotheses or powered clinical endpoints.  There will be two analysis 
sets: 1) the Attempted Implant set, and 2) the Implanted set: 
Attempted Implant. The attempted implant data set will include all subjects with an attempted implant, 
where an attempted implant 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. Day 0 is the date of first attempted procedure. 
Implanted. The implanted data set includes of all subjects with an attempted implant where the study 
device is implanted, defined as when the TAV is fully released from the DCS. Day 0 is the date of first 
attempted procedure. 
Information on the analysis data sets specific to the study endpoints and outcome measures are 
provided in Section 10.4.  Data from all geographies and active centers will be included in the analyses; 
there are no planned poolability analyses (e.g. by gender, race, geography). 
Baseline demographic and clinical variables will be summarized for attempted implant analysis set. The 
subjects’ baseline characteristics will be summarized with standard descriptive summary statistics, 
including counts and percentages for categorical variables, and mean, standard deviation, median, first 
and third quartiles, minimums and maximums for continuous variables. 
Subject disposition will be illustrated in a flow diagram.  Subject visits will be tabulated and compliance 
to visit schedule and visit windows will be summarized, and attrition will be identified and summarized. 
Every effort will be undertaken to minimize missing data.  Missing (accidentally, due to withdrawal, 
missing follow-up or loss to follow-up, etc.), unused and spurious data will remain identifiable in the 
database.  Data from subjects that cannot be analyzed for a specific variable will be displayed as missing 
All analyses will be based on available data and missing data will not be imputed.  Subgroup analyses 
may be performed (but are not limited to) include the following subject groups: 
1. Baseline Peak GLS > median value and < median value  
2. Baseline NO-proBNP > median value and < median value 
Subgroup analyses will be performed at minimum for the following key study endpoints at 30 days and 6 
months, where applicable: all-cause mortality, stroke, valve-related dysfunction requiring repeat 
procedure, new PPI, cardiovascular and heart failure hospitalizations, heart failure events, change in 
KCCQ, change in 6MWT, and change in cardiac function by echo. 

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10.2 Analysis Execution 
Analyses are planned when all implanted subjects have completed his/her six-month follow-up, and 
when all implanted subjects have completed his/her five-year follow-up.  A final report will be prepared 
once all implanted subjects have completed his/her five-year follow-up and all data collection has 
ended.  See section 10.3 for additional analyses. 
10.3 Interim Analysis 
An initial analysis is planned when the first 50 implanted subjects have completed his/her six-month 
follow-up; however initial analyses may be performed earlier if enrollment is slower than expected 
Initial analyses will assess all safety and efficacy endpoints based on available data. 
There are no formal interim analyses planned for purposes of “early-win” assessment, futility, or sample 
size confirmation. 
10.4 Safety Endpoints 
Safety endpoints include: 
1. All-cause and cardiovascular mortality at 30 days and 6 months 
2. All stroke (disabling and non-disabling) at 30 days and 6 months 
3. Myocardial infarction (periprocedural and spontaneous) at 30 days and 6 months 
4. Acute kidney injury at 30 days and 6 months 
5. Major vascular complications at 30 days and 6 months 
6. Life-threatening bleed at 30 days and 6 months 
7. New permanent pacemaker implantation (PPI) at 30 days and 6 months 
8. New intraventricular conduction delays at 30 days and 6 months 
9. New-onset atrial fibrillation at 30 days and 6 months 
10.Valve-related dysfunction requiring repeat procedure at 30 days and 6 months 
Analysis for the safety endpoints will be based on the “Attempted Implant” data set.  For each time-
related event, Kaplan-Meier rates (cumulative incidence) and 95% two-sided confidence intervals at 30 
days and 6 months will be calculated.  Safety endpoints will be based on CEC adjudicated events. 
10.5 Efficacy Endpoints 
Efficacy endpoints include: 
1. Device success (VARC-2) 
2. Cardiovascular and heart failure hospitalizations at 30 days and 6 months 
3. Heart failure events at 30 days and 6 months 
4. Hemodynamic performance metrics by Doppler echocardiography at discharge, 30 days, and 6 
months 

Mean aortic gradient  

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Effective orifice area  

Degree of total, para, and transvalvular prosthetic regurgitation   

Incidence of moderate and severe patient-prosthesis mismatch (PPM)   
5. Change from baseline in New York Heart Association (NYHA) functional classification at 30 days and 
6 months 
6. Change in six-minute walk test (6MWT) from baseline at 6 months 
7. Change in Kansas City Cardiomyopathy (KCCQ) from baseline at 30 days and 6 months 
8. Change in left ventricular ejection fraction (LVEF) from baseline at 6 months 
9. Change in peak global longitudinal strain (GLS) from baseline at 6 months 
10.Change in left ventricular filling pressure (E:e’) from baseline at 6 months 
11.Change in stroke volume index (SVI) from baseline at 6 months 
12.Change in NT-pro B-type natriuretic peptide (NT-proBNP) from baseline at 6 months 
Analyses of the efficacy endpoints will be descriptive. The attempted implant set will be used for safety 
and quality of life outcomes. However, the efficacy endpoints involving echocardiographic variables will 
be analyzed for the implanted set. Continuous variables will be summarized as the number of subjects, 
mean, standard deviation, median, first and third quartiles, minimums, and maximums. Categorical 
variables will be summarized as counts and percentages. For each time-related event, Kaplan-Meier 
rates (cumulative incidence) and 95% two-sided confidence intervals will be calculated.  Efficacy 
endpoints involving echocardiographic variables will be based on ECL reported data. 
10.6 Additional Outcome Measures 
The following outcome measures will be also be evaluated: 
1. All-cause and cardiovascular mortality annually through 5 years 
2. All stroke (disabling and non-disabling) annually through 5 years 
3. Cardiovascular and heart failure hospitalizations at annually through 5 years 
4. Heart failure events at annually through 5 years 
5. New York Heart Association (NYHA) functional classification at 30 days, 6 months, and annually 
through 5 years 
6. Change in New York Heart Association (NYHA) functional classification from baseline annually 
through 5 years 
7. Kansas City Cardiomyopathy (KCCQ) annually through 5 years 
8. Hemodynamic performance metrics by Doppler echocardiography 
x
Mean aortic gradient annually through 5 years 
x
Effective orifice area annually through 5 years 
x
Degree of total, para, and transvalvular prosthetic regurgitation annually through 5 years 
x
Incidence of moderate and severe patient-prosthesis mismatch (PPM) annually through 5 
years 
9. Prosthetic valve thrombosis 30 days, 6 months, and annually through 5 years 
10.Prosthetic valve endocarditis at 30 days, 6 months, and annually through 5 years 

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11.Bioprosthetic valve dysfunction (BVD) at 30 days, 6 months, and annually through 5 years 
12.Bioprosthetic valve failure (BVF) at 30 days, 6 months, and annually through 5 years 
13.Valve-related dysfunction requiring repeat procedure annually through 5 years 
Analyses of the additional outcome measures will be descriptive. The attempted implant set will be used 
for safety and quality of life outcomes. However, the outcomes involving echocardiographic variables 
will be analyzed for the implanted set. Continuous variables will be summarized as the number of 
subjects, mean, standard deviation, median, first and third quartiles, minimums, and maximums. 
Categorical variables will be summarized as counts and percentages. For each time-related event, 
Kaplan-Meier rates (cumulative incidence) and 95% two-sided confidence intervals will be calculated. 
10.7 Sample Size Determination 
As this is a descriptive study, the sample size of 75 subjects was not determined by statistical sample size 
methods.  However, a sample size of 75 subjects is adequate to accomplish the study objectives and for 
an assessment of the procedural safety and efficacy of the study device in the study population. 
10.8 Minimization of Bias 
The study methods include the following measures to minimize potential sources of bias: 
x
An Eligibility Review Committee (ERC) will confirm each subject’s eligibility for the study. 
x
An external, independent Clinical Events Committee (CEC) will adjudicate all deaths and safety-
related endpoint events.  Safety endpoint results will be based on CEC adjudications. 
x
Sites will follow a standardized protocol for acquisition of echocardiographic endpoint data. 
x
Echocardiographic endpoint results will be based on Echocardiography Core Lab assessments. 
x
A statistical analysis plan (SAP) will be developed prior to analyzing data. The plan will document all 
pre-specified analyses and analysis methods. 
In summary, potential sources of bias that may be encountered in this study have been considered and 
minimized by careful study design. 
 
 

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11.1 Statement(s) of Compliance 
The Evolut™  EXPAND TAVR I Feasibility Study will be conducted in compliance with the current version 
of the Declaration of Helsinki, the International Conference on Harmonization (ICH) Good Clinical 
Practice (GCP) R2 guidelines, the study protocol, the Sponsor’s standard operating procedures and/or 
guidelines, and in accordance with federal, national and local laws, regulations, standards, and 
requirements of the countries/geographies where the study is being conducted.  
These include but are not limited to the following: 
x
In the United States, the study will be conducted under a US FDA Investigational Device 
Exemption (IDE) in compliance with 21 CFR Parts 11, 50, 54, 56 and 812, and ISO 14155:2020 
(except for Adverse Event reporting after 6-month visit as noted in section 7.2)   
x
In the EMEA region the study will be conducted in compliance with ISO 14155:2020 (except for 
Adverse Event reporting after 6-month visit as noted in section 7.2). The laws and regulations of 
the countries in which the study is conducted, included data protection laws, must be followed.   
x
In Canada, SOR/98-282, Section 79-88 will be followed.  The study will be conducted in 
compliance with ISO 14155:2020 (except for Adverse Event reporting after 6-month visit as 
noted in section 7.2 
x
In Australia, New Zealand the study will be conducted in compliance with local regulations and 
ISO 14155:2020 (except for Adverse Event reporting after 6-month visit as noted in section 7.2)  
In addition, the study will be conducted in compliance with 21 CFR Part 11 and 54 in all participating 
geographies. 
11.2 Institutional Review Boards and Ethics Committees 
The study will be conducted in accordance with the requirements of local Institutional Review Boards 
and Ethics Committees.  The responsible Institutional Review Board (IRB) or Ethics Committee (EC) at 
each investigational site must approve the study protocol and informed consent form.  Study activities 
will not commence prior to receipt of documentation of IRB/EC approval by the site and Medtronic.  The 
Investigator and study staff must comply with the requirements of their IRB/EC, including any additional 
requirements imposed by the IRB/EC after initial approval. 
Prior to enrolling subjects, each investigation site’s IRB/EC will be required to approve the current CIP, 
the Informed Consent form, and any other written information to be provided to the subjects.  Study 
sites in the United States must also utilize IRB approved Health Insurance Portability and Accountability 
Act (HIPAA) Authorization. 
IRB/EC 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 

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needs to be accompanied by an IRB/EC 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/EC. If 
they are members of the IRB/EC, 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/EC approval once the investigation site has started enrollment.  If any action is taken by an IRB/EC 
with respect to the investigation, that information will be forwarded to Medtronic by the respective 
investigator. 
11.3 Regulatory Submission 
Each site must fulfill all local regulatory requirements prior to enrolling subjects.  Each study site must 
have written documentation of site/investigator readiness, including but not limited to IRB/EC approval 
of the current version of the CIP, Informed Consent form, a signed Clinical Investigational Agreement, 
current investigator curriculum vitae, and documentation of training.  The principal investigators and 
their institutions shall agree to this CIP and any amendments and indicate their approval by signing and 
dating the Clinical Investigational Agreement. Each center is required to have documented approval 
from their local Regulatory Authority prior to their first subject enrollment.   
If a regulatory authority imposes any additional requirements (e.g. safety reports, progress reports etc.), 
Medtronic will prepare the required documents and send them to the respective authority. 
Any revisions or amendments to the CIP, Investigator Brochure, Reports of Prior Investigations, 
Informed Consent documents or any other documents submitted to Regulatory Authorities will be 
notified to all affected Regulatory Authorities.  A final report will be submitted to all Regulatory 
Authorities upon study closure. 
 

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12.1 Monitoring 
Investigational sites will be monitored to ensure compliance with the study protocol, adherence to 
applicable regulations, and accuracy of study data. Monitoring visits may be conducted both on site and 
remotely, primarily to ensure the safety and well-being of the subjects is preserved, as well as to  assess 
study site progress periodically, the investigator’s adherence to the CIP, regulatory compliance, 
maintenance of records and reports, and review and verification of source documents against subject 
CRFs in accordance to the study-specific monitoring plan. Frequency of monitoring visits may be based 
upon subject enrollment, study compliance, number of adverse events, number of deviations, 
observations from previous monitoring visits and any suspected inconsistency in data that requires 
investigation. Regulatory documents will be reviewed at each study site. Monitoring visits will also be 
used to verify that data submitted on case report forms are complete and accurate with respect to the 
subject clinical records and to verify device accountability. Sites should provide appropriate access to 
the source data. For countries where local law allows this should also include remote access to the EMR. 
Site personnel will complete eCRFs following each subject visit. Study data submitted will be reviewed 
against subject charts and other sources containing original records of subject data.  
The progress of the study will be monitored by: 
x
On-site and remote review, as deemed appropriate by Medtronic and as described in the 
Monitoring Plan. 
x
Remote source data verification will be done where local country regulations allow 
x
Telephone communications between the site personnel (e.g., investigator, study coordinator) and 
study monitors 
x
Review of eCRFs and the associated clinical records 
x
Review of regulatory documents 
Monitoring and monitoring oversight will be provided by the global sponsor (8200 Coral Sea St NE, 
Mounds View, MN 55112). Representatives of the global sponsor (contractors and designees) may also 
act as study monitors. 
12.2 Study Closure 
Upon completion of the study, Site Closeout Visits will be conducted, as outlined in the Monitoring Plan. 
After the study has been completed, medical care will be provided to the subjects upon the discretion of 
the treating physician. 
12.3 Data Management 
Study sites will assign a unique ID number to each subject.  Records of the subject/subject ID 
relationship will be maintained by the study site.  Individual subject medical information obtained as a 
result of this study will be considered confidential. 

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This study will utilize an internet based Remote Data Capture (RDC) system that is the property of 
Medtronic.  Required data will be recorded on electronic case report forms (eCRFs) by authorized site 
personnel as indicated on the Delegation Task List (DTL).  Study personnel delegated for eCRF 
completion and/or approval per the DTL will be trained on the use of the RDC system and thereafter 
provided with a username and password to access the system.  The eCRFs must be completed or 
updated to reflect the latest observations on the subjects participating in the study.  The investigator (or 
approved sub-investigator) will electronically sign the appropriate pages of each eCRF. 
Data from the echocardiography core lab will be entered into the RDC system by core lab personnel per 
their procedures established for the study.  The echocardiography core lab cardiologist (or designee) will 
approve core lab eCRFs. 
The RDC system maintains an audit trail of entries, changes, and corrections in eCRFs.  If a person only 
authorized to complete eCRFs makes changes to an already signed eCRF, the investigator shall re-
approve this eCRF. 
All study-related documents must be retained until notified by Medtronic that retention is no longer 
required.  Medtronic will inform the investigator/institution when these documents are no longer 
required to be retained.  
No study document or image should be destroyed without prior written agreement between Medtronic 
and the investigator.  Should the investigator wish to assign the study records to another party or move 
them to another location, advance written notice must be given to Medtronic. 
12.3.1 Time Windows for Completion and Submission of eCRFs 
The Device Use Notification eCRF should be completed as soon as possible after device use.  As a best 
practice, study sites should strive to complete and approve all other eCRFs within 2 weeks of the 
applicable follow-up visit. 
12.3.2 Data Review and Processing 
Medtronic will be responsible for the processing and quality control of the data.  Data review, database 
cleaning and issuing and resolving data queries will be done according to Medtronic internal SOPs and 
the Data Management Plan for this study.  The study database will be developed and validated per the 
Data Management Plan and will employ validation programs (e.g. range and logic checks) on entered 
data to identify possible data entry errors and to facilitate data validation.  The study database will 
maintain an audit trail of all changes made to the eCRFs. 
12.3.3 Source Documents 
Entered data must be traceable to source documents.  Source documentation is defined as the first time 
the data appear and may include all clinical records, hospital records, procedural reports, autopsy 
reports, and any other material that contains original information used for study data collection or 

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adverse event reporting.  Identified discrepancies between source documents and the eCRFs will be 
resolved through the on-line query resolution process per the Data Management plan. 
The eCRFs may not serve as source documents.  Source documentation for data elements not routinely 
captured in medical records (e.g. echocardiography variables, MDCT variables, implant procedural 
variables, exercise testing variables, Heart Team assessment, Modified Rankin Score) may vary from 
center to center: the site may use technical worksheets if identified as source documents. 
Source documents must be retained by the investigational site for a period of two years after study 
conclusion (or longer as required by local law) and made available for monitoring or auditing by the 
sponsor’s representative or representatives of the US FDA and other applicable regulatory agencies or 
IRB/EC. 
The Investigator must ensure the availability of source documents from which the information on the 
eCRFs was derived.  Where printouts of electronic medical records, are provided as source documents, 
or where copies of source documents are retained as source documents, they should be signed and 
dated by a member of the investigation site team indicating they are a true reproduction of the original 
source document. 
In addition, the medical records of study subjects should be marked or flagged in such a way to indicate 
their participation in the study. 
12.3.4 Direct Access to Source Data/Documents
Medtronic may conduct audits at participating study sites. The purpose of an audit is to verify the 
performance of the monitoring process and the study conduct, independently of the personnel directly 
involved in the study. Regulatory bodies, such as the US FDA, may also perform inspections at 
participating study sites. The investigator and/or institution shall permit Medtronic, IRB/ECs and 
regulatory bodies direct access to source data and documents during monitoring, audits and regulatory 
inspections. 
12.4 Confidentiality 
All information and data sent to parties involved in study conduct concerning subjects or their 
participation in this study will be considered confidential.  Study sites will assign a unique subject ID 
number (SID) to each subject.  The SID is to be recorded on all study documents to link them to the 
subject’s medical records at the site.  To maintain confidentiality, the subjects’ name or any other 
personal identifiers should not be recorded on any study document other than the informed consent 
form.  In the event a subject’s name is included for any reason, it will be masked as applicable.  In the 
event of inability to mask the identification (e.g., digital media), it will be handled in a confidential 
manner by the authorized personnel.  Access to subject confidential information will be confined to 
authorized personnel only; specifically, members of the sponsor clinical study team, the ECL, and the 
CEC.  The sponsor will maintain a list of all authorized personnel with access to subject confidential 
information. 

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12.5 Liability 
Medtronic, Inc. (including all wholly owned subsidiaries) 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 Study Insurance 
statement/certificate will be provided to the EC if required. 
12.6 CIP Amendments 
The investigator may propose any appropriate modification(s) of the CIP 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 amendment to the CIP, including a justification for the amendment, to all 
affected regulatory agencies and to the investigators to obtain approval from their IRB/EC.  The 
investigator will only implement the amendment after approval of the IRB/EC, regulatory agencies, and 
Medtronic, as applicable.   Furthermore, the Principal investigators shall sign any approved amendment 
for agreement. 
12.7 Record Retention 
The investigator must retain the Investigator Site File, source documents, and the records listed in 
Section 12.8 until informed by Medtronic they no longer need to be retained.  At a minimum, the 
investigator must retain records for at least 2 years, or longer as in accordance with local law, after the 
last approval of a marketing application and until there are no pending or contemplated marketing 
applications, or at least two years have elapsed since the formal discontinuation of clinical development 
of the investigational devices.  The investigator should take measures to prevent accidental or early 
destruction of the study related materials. 
12.8 Reporting Requirements 
12.8.1 Investigator Reports 
The Investigator is responsible for the preparation, review, and signature (as applicable), and retention 
of the following records: 
x
All essential correspondence that pertains to the investigation 
x
Device use/disposition records 
x
Records of each subject’s case history and exposure to the device.  Case histories include the 
approved eCRFs and supporting data (source documentation), including, for example: 
-
Signed and dated consent forms 
-
Medical records, including, for example, progress notes of the physicians, the subject’s hospital 
chart(s) and the nurses’ notes 
-
All adverse event/device deficiency information  

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A record of the exposure of each subject to the investigational device (e.g., date of implant 
procedure and follow-up assessment dates) 
x
Documentation of any deviation from the CIP, including the date and the rationale for such 
deviation 
x
Signed Clinical Investigational Agreement, signed and dated curriculum vitae of the PI, sub-
investigator(s) and key members, signed Delegated Task List 
x
The approved CIP, Patient Information/Informed Consent Form, Investigator Brochure or Report of 
Prior Investigations, and any amendments 
x
Insurance certificate, where applicable 
x
IRB/EC Approval documentation and voting list 
x
Regulatory authority notification and approval documentation 
x
List of sponsor contacts and monitoring contact list 
x
List of investigation sites 
x
Training records 
x
Disclosure of conflict of interest 
x
Lab certificate/lab normal ranges 
x
Subject ID and enrollment log 
x
Sponsor’s statistical analyses and clinical investigation report 
x
Shipping records of investigational devices 
x
Investigational device Product Accountability Log(s) 
x
Any other records that US FDA or local regulatory agencies require to be maintained 
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 in Table 6 - Table 
9 for their respective geographies.  These are also subject to inspection by government agencies and 
must be retained.  Reports will be submitted to regulatory authorities per local reporting 
requirements/regulations.  Requirements for reporting Adverse Events to Medtronic are described in 
Table 4. 
 
 

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Table 6.  Investigator records and reporting responsibilities applicable to the United States 
Report
Submit To
Description/Constraints
Withdrawal of IRB 
approval (either 
suspension or 
termination) 
Sponsor
An investigator shall report to the sponsor, within 5 working days, a withdrawal of 
approval by the reviewing IRB of the investigator's part of an investigation.  (21 
CFR 812.150(a)(2)).
Progress report 
Sponsor and IRB
The investigator must submit this report to the sponsor and IRB at regular 
intervals, but in no event less than yearly. (21 CFR 812.150 (3)).  
Study deviations 
Sponsor and IRB
Notice of deviations from the CIP to protect the life or physical well-being of a 
subject in an emergency shall be given as soon as possible, but no later than 5 
working days after the emergency occurred. (21 CFR 812.150(a)(4))
Failure to obtain IC 
prior to 
investigational 
device use
Sponsor and IRBs
If an investigator uses a device without obtaining informed consent, the 
investigator shall report such use within 5 working days after device use. (21 CFR 
812.150(a)(5))
Final investigator 
report
Sponsor, IRB s and 
Relevant 
Authorities
This report must be submitted within 3 months of study completion or 
termination of the investigation or the investigator’s part of the investigation. (21 
CFR 812.150(a)(6))
Other
IRB and US FDA
An investigator shall, upon request by a reviewing IRB, US FDA or any other 
regulatory agency, provide accurate, complete, and current information about 
any aspect of the investigation. (21 CFR 812.150(a)(7))
Table 7.  Investigator reports applicable to Europe and Israel 
Report 
Submit To
Description/Constraints 
Withdrawal of EC 
approval 
Sponsor and 
Relevant 
Authorities
The investigator must report a withdrawal of approval by the reviewing EC of the 
investigator’s part of the investigation within 5 working days of the date of 
withdrawal. (Medtronic Requirement)
Progress Report 
Sponsor and EC
Provide if required by local law or EC. 
(ISO/FDIS 14155:2020)
Study Deviations 
Sponsor, EC and 
Relevant 
Authorities
Any deviation from the CIP shall be recorded together with an explanation for the 
deviation.  Deviations shall be reported to the sponsor who is responsible for 
analyzing them and assessing their significance.  
Note: When relevant, ECs, competent authorities or the appropriate regulatory 
bodies should be informed. (ISO/FDIS 14155:2020)
Notice of deviations from the CIP to protect the life or physical well-being of a 
subject in an emergency shall be given as soon as possible, but no later than 5 
working days after the emergency occurred. Except in such emergency, prior 
approval is required for changes in the plan or deviations.  (Medtronic 
Requirement)
Final Report
EC and Relevant 
Authorities
This report must be submitted within 3 months of study completion or termination. 
(Medtronic Requirement)
Failure to obtain IC 
Sponsor and 
Relevant 
Authorities 
IC shall be obtained in writing and documented before a subject is enrolled into the 
clinical investigation.  (ISO/FDIS 14155:2020) 

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Table 8.  Investigator reports applicable to Canada 
Report 
Submit To
Description/Constraints 
Withdrawal 
of REB 
approval 
Sponsor
The investigator must report a withdrawal of approval by the reviewing REB of the 
investigator’s part of the investigation within 5 working days of the date of withdrawal. 
(Medtronic Requirement)
Study 
Deviations  
Sponsor and 
REB
Any deviation from the clinical investigational plan shall be recorded together with the 
explanation of the deviation.
Notice of deviations from the CIP to protect the life or physical well-being of a subject in an 
emergency shall be given as soon as possible, but no later than 5 working days after the 
emergency occurred.  (Medtronic Requirement)
Final Report 
REB, Relevant 
Authorities
This report must be submitted within 3 months of study completion or termination of the 
investigation or the investigator’s part of the investigation. (Medtronic Requirement)
Mandatory 
Problem 
Reporting 
Incident
Health Canada, 
Sponsor, REB 
as applicable 
Report the incident to Medtronic and Health Canada no later than 72 hours of the 
investigator’s / site’s first knowledge of the event. Submit to Ethics Board per local 
requirement.   
Table 9.  Investigator reports applicable to Australia and New Zealand 
Report 
Submit To 
Description/Constraints 
Study 
Deviation 
Sponsor, EC, 
other relevant 
authorities 
Any deviation from the clinical investigational plan shall be recorded together with the 
explanation of the deviation 
Notice of deviations from the CIP to protect the life or physical well-being of a subject in 
an emergency shall be given as soon as possible, but no later than 5 working days or 
earlier when required due to local requirements, after the emergency occurred.  
(Medtronic Requirement) 
Australia: Report any suspected breaches to the sponsor and confirmed serious breaches 
to their institution (research governance office) within 72 hours of being aware or notified 
of the same; provide any follow up information as required and work with the institution 
or sponsor, as appropriate, to implement any corrective and preventative actions. 
Withdrawal 
of EC 
approval 
Sponsor and 
applicable 
authorities per 
local 
requirements 
The investigator must report a withdrawal of approval by the reviewing EC of the 
investigator’s part of the investigation within 5 working days of the date of withdrawal. 
(Medtronic Requirement) 
USADEs for 
Australia and 
international 
/ Annual 
Safety 
Report/ 
updated IB/ 
approved 
Product 
Information 
HREC 
Australia: Per EC requirements, but at least annually, the investigator must provide to 
HREC responsible for study; 
x Updated Investigator Brochure or IF, if appropriate ((NHMRC Safety monitoring and 
reporting in clinical trials involving therapeutic goods November 2016 section C.1.h) 
x Annual Safety Report including; - a summary of the evolving safety profile of the trial, a 
brief description and analysis of new/relevant findings, implications of safety data to 
the risk-benefit ratio for the trial, a description of any measures taken or proposed to 
minimize risks 
(NHMRC Safety Monitoring and Reporting in Clinical Trials involving Therapeutic Goods 
November 2016 section C.1.i) 
Other 
information  
HREC 
Any additional reports required per local requirements and EC must be provided 
Australia: 
Upon request, supply Medtronic, with any additional information related to the safety 
reporting (NHMRC Safety monitoring and reporting in clinical trials involving therapeutic 
goods November 2016, section C.2(f)  

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12.8.2 Sponsor Reports 
The Sponsor will maintain the following records, including but not limited to: 
x
All essential correspondence related to the clinical study 
x
Signed Clinical Investigational Agreement 
x
Signed and dated current curriculum vitae for each Investigator 
x
Records of device shipment and disposition (shipping receipts, material destruct records, etc.) 
x
Investigational Device Accountability Log(s) 
x
Adverse event and device deficiency information  
x
Device complaint documentation 
x
All data forms, prepared and signed by the Investigators, and received source documentation and 
core lab reports 
x
CIP, investigator brochure or report of prior investigations and subsequent amendments 
x
Site monitoring reports 
x
Financial disclosure information 
x
Study training records for site participants and internal study staff members 
x
Contact lists of all participating investigators/investigative sites, Ethics Board information, study 
monitors and Sponsor staff members; Sponsor will maintain these lists and provide updates to the 
necessary parties.  
x
Sample of device labeling attached to investigational device 
x
Insurance certificates 
x
Ethics Committee approval documentation and voting list 
x
Regulatory authority notification and approval documentation 
x
Lab certificates /Lab normal ranges 
x
Statistical analyses 
x
Clinical investigation report 
x
Any other records that US FDA or local regulatory agencies require to be maintained 
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 10 - Table 13.  
 
 

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Table 10: Sponsor records and reporting responsibilities applicable to the United States 
Report 
Submit To 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, IRB, 
and Relevant 
authorities
Provide prompt notification of termination or suspension and reason(s). 
(ISO/FDIS 14155:2020), (MHLW Ordinance 36, Article 32) 
Unanticipated 
Adverse Device Effect 
Investigators, IRB, US 
FDA, and relevant 
authorities
Notification within ten working days after the sponsor first receives notice 
of the effect.  (21 CFR 812.150(b)(1))
Withdrawal of IRB 
approval 
Investigators, IRB, US 
FDA, and relevant 
authorities
Notification within five working days after receipt of the withdrawal of 
approval.  (21 CFR 812.150(b)(2))  
Withdrawal of US 
FDA approval 
Investigators, IRB, 
and relevant 
authorities
Notification within five working days after receipt of notice of the 
withdrawal of approval.  (21 CFR 812.150(b)(3))
Investigator List 
US FDA
Submit at 6-month intervals, a current list of the names and addresses of all 
investigators participating in the investigation.  (21 CFR 812.150(b)(4))
Progress Reports 
IRB and US FDA
Progress reports will be submitted at least annually.  (21 CFR 
812.150(b)(4)(5), 812.36(f)  
Recall and device 
disposition 
Investigators, IRB, 
relevant authorities, 
and US FDA
Notification within 30 working days after the request is made and will 
include the reasons for any request that an investigator return, repair, or 
otherwise dispose of any devices.  (21 CFR 812.150(b)(6))
Failure to obtain 
informed consent  
US FDA
Investigator’s report will be submitted to US FDA within five working days of 
notification. (21 CFR 812.150(b)(8))
Final Report 
Investigators, IRB, 
Regulatory 
authorities upon 
request, and US FDA
Medtronic will notify US FDA within 30 working days of the completion or 
termination of the investigation.  A final report will be submitted to the US 
FDA, investigators, and IRBs within six months after completion or 
termination of this study. (21 CFR 812.150(b)(7))
Study deviation 
Investigators
Ensure that all deviations from the CIP are reviewed with the appropriate 
clinical investigator(s), are reported on the case report forms and the final 
report of the clinical investigation.  
Site specific study deviations will be submitted to investigators quarterly.  
(ISO/FDIS 14155:2020)
 

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Table 11: Sponsor records and reporting responsibilities applicable to Europe and Israel 
Report 
Submit To 
Description/Constraints 
Unanticipated 
Serious Adverse 
Device Effects 
(USADE) 
EC, 
Investigators, 
Relevant 
Authorities 
Medtronic will notify investigators and EC in all geographies as soon as possible, but 
not later than 10 working days after the sponsor first learns of the effect.  
For reporting to Regulatory authorities, all UADEs are classified as SADEs and should 
follow the applicable reporting requirements. (ISO/FDIS 14155:2020) and Note for 
Guidance on Clinical Safety Data Management: Definitions and Standards for 
Expedited Reporting (CPMP/ICH/377/95 3.A.1).  Reporting timeframe as per local 
Regulatory authority. (ISO/FDIS 14155:2020 3.42) 
Serious Adverse 
Event (SAE) 
EC, Relevant 
Authorities 
Submit to EC per local reporting requirement.  Submit to Regulatory Authorities per 
local reporting requirement.  Reports will be in compliance with the laws and 
regulations of the countries in which the study is conducted, including data protection 
laws. 
Serious Adverse 
Device Effects 
(SADE) 
EC, Relevant 
Authorities 
Submit to EC per local requirement (ISO/FDIS 14155:2020).  Submit to regulatory 
authorities as per local requirements. 
Device Deficiency 
that might have 
led to a SADE 
EC, Relevant 
Authorities 
Submit to EC per local requirement.  Submit to regulatory authorities as per local 
requirements. (ISO/FDIS 14155:2020) 
Premature 
termination or 
suspension of the 
clinical 
investigation 
Investigators, 
EC, Relevant 
Authorities 
Provide prompt notification of termination or suspension and reason(s). (ISO/FDIS 
14155:2020)  
Withdrawal of EC 
approval 
Investigators, 
EC, Relevant 
Authorities 
Investigators and ECs will be notified only if required by local laws or by the EC. 
Withdrawal of 
Regulatory 
Authority 
approval 
Investigators, 
EC, Relevant 
Authorities 
Investigators and ECs will be notified only if required by local laws or by the EC. 
Progress Reports 
EC, Relevant 
Authorities 
This will be submitted to the EC and/or Regulatory Authorities only if required.  
Final Report 
Investigators, 
EC, and 
Relevant 
Authorities 
(upon request)
The investigator shall have the opportunity to review and comment on the final 
report.  If a clinical investigator does not agree with the final report, his/her comments 
shall be communicated to the other investigator(s).  The coordinating investigator 
shall sign the report (ISO/FDIS 14155:2020)
Study deviation  
Investigators
Ensure that all deviations from the CIP are reviewed with the appropriate clinical 
investigator(s), are reported on the case report forms and the final report of the 
clinical investigation.
Site specific study deviations will be submitted to investigators periodically. (ISO/FDIS 
14155:2020)
Significant new 
information 
EC and 
Relevant 
Authorities
Ensure that the ECs and Regulatory Authorities are informed of significant new 
information about the clinical investigation (ISO/FDIS 14155:2020)

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Table 12: Sponsor records and reporting responsibilities applicable to Canada 
Report 
Submit To 
Description/Constraints 
Unanticipated 
Serious Adverse 
Device Effects 
(USADE) 
REB, 
Investigators, 
Health Canada 
Medtronic will notify investigators and Ethics Boards in all geographies as soon as possible, but 
not later than 10 working days after the sponsor first learns of the effect.  
Preliminary and final reporting to the Canadian Ministry of Health of events occurring inside 
(always) or outside Canada (in case of corrective actions) that is related to a failure of the 
device or a deterioration in its effectiveness, or any inadequacy in its labeling or its directions 
for use and has led to the death or a serious deterioration in the state of health of a patient, 
user or other person or could do so were it to recur. Report a) within 10 days after awareness, 
if incident has led to death or a serious deterioration in the state of health of a patient, user or 
other person b) within 30 days, if incident has not led to death or a serious deterioration in the 
state of health of a patient, user or other person, but could do so were it to recur c) as soon as 
possible, if incident occurred outside of Canada and is related to a corrective action. (Canada 
Medical Device Regulations, SOR/98-282; Mandatory Problem Reporting 59(1) , 59(2), 60 (1)) 
Serious Adverse 
Device Effects 
(SADE) 
REB, Health 
Canada 
Submit to Ethics Boards per local requirement (ISO 14155:2020) 
Preliminary and final reporting to the Canadian Ministry of Health of events occurring inside 
(always) or outside Canada (in case of corrective actions) that is related to a failure of the 
device or a deterioration in its effectiveness, or any inadequacy in its labeling or its directions 
for use and has led to the death or a serious deterioration in the state of health of a patient, 
user or other person or could do so were it to recur. Report a) within 10 days after awareness, 
if incident has led to death or a serious deterioration in the state of health of a patient, user or 
other person b) within 30 days, if incident has not led to death or a serious deterioration in the 
state of health of a patient, user or other person, but could do so were it to recur c) as soon as 
possible, if incident occurred outside of Canada and is related to a corrective action. (Canada 
Medical Device Regulations, SOR/98-282; Mandatory Problem Reporting 59(1) , 59(2), 60 (1)) 
Device Deficiency 
that might have 
led to a SADE 
REB, 
Investigators, 
Health Canada 
Submit to Ethics Board per local requirement.  Submit to regulatory authority as per local 
requirement.  
Premature 
termination or 
suspension of 
the clinical 
investigation 
Investigators, 
REB, Health 
Canada 
Provide prompt notification of termination or suspension and reason(s). (ISO/FDIS 14155:2020) 
Recall and device 
disposition 
Investigators, 
Head of 
Institution, REB, 
Health Canada 
Notification within 30 working days of the request and will include the reasons for any request 
that an investigator return, repair, or otherwise dispose of any devices. (Medical Devices 
Regulation Mandatory Problem Reporting 63 – 65.1) 
Final Report 
Investigators, 
REB, and Health 
Canada 
The investigator shall have the opportunity to review and comment on the final report.  If a 
clinical investigator does not agree with the final report, his/her comments shall be 
communicated to the other investigator(s).  The principal clinical investigator in each center 
shall sign the report. (ISO/FDIS 14155:2020) 
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the appropriate clinical 
investigator(s), are reported on the case report forms and the final report of the clinical 
investigation.   
Site specific study deviations will be submitted to investigators quarterly. (ISO/FDIS 
14155:2020) 
Significant new 
information 
REB and Health 
Canada 
Ensure that the Ethics Boards and Regulatory Authorities are informed of significant new 
information about the clinical investigation (ISO/FDIS 14155:2020) 

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Table 13: Sponsor records and reporting responsibilities applicable to Australia and New Zealand 
Report 
Submit To 
Description/Constraints 
Premature 
termination or 
suspension of the 
clinical investigation 
Investigators, 
Ethics 
Committee, and 
relevant 
authorities 
Provide prompt notification of termination or suspension and reason(s). (ISO 
14155:2020) 
Australia:  
Temporary halt due to safety reasons along with its scope or an early termination 
of a trial for safety reasons must be notified to Therapeutic Goods Authority (TGA), 
HREC and investigators along with reasons, measures and further action planned 
without undue delay and no later than 15 calendar days of the sponsor’s decision.  
(Safety Monitoring and reporting in clinical trials involving therapeutic goods by 
NHMRC Nov 2016, Table 1) 
Notification of an 
amendment 
Investigators, 
Ethics 
Committee, 
relevant 
authorities 
Australia: Notification of an amendment due to SSI, without undue delay and no 
later than 15 calendar days  
Note: TGA should receive notification that a SSI has occurred but the amendment 
revising trial documentation should be submitted to the HREC only 
(Safety Monitoring and reporting in clinical trials involving therapeutic goods by 
NHMRC Nov 2016, Table 1) 
Urgent Safety 
Measure(s) 
Investigators, 
Ethics 
committee, 
relevant 
authorities 
Australia: Urgent Safety Measure (USMs) be reported within 24 hours (where 
possible) and in any case, no later than 72 hours of the measure being taken to 
TGA, HREC and Australian investigators with reasons for the urgent safety 
measure, measures taken and further actions planned. 
(Safety Monitoring and reporting in clinical trials involving therapeutic goods by 
NHMRC  Nov 2016, Table 1) 
USADE  
TGA, Australia 
Fatal or life-threatening Australian USADE: No later than 7 calendar days after 
being made aware of the case with any follow up information within a further 8 
calendar days to TGA 
Other Australian USADEs: No later than 15 calendar days after being made aware 
of the case to TGA 
(Safety Monitoring and reporting in clinical trials involving therapeutic goods by 
NHMRC  Nov 2016, Table 1) 
Recall and device 
disposition 
Investigators, 
Ethics 
Committee, 
relevant 
authorities 
Notification as per local requirements 
Study deviation  
Investigators 
Ensure that all deviations from the CIP are reviewed with the appropriate clinical 
investigator(s), are reported on the case report forms and the final report of the 
clinical investigation. 
Site specific study deviations will be submitted to investigators periodically. (ISO 
14155:2020)  
Australia: Reporting of serious breaches should be reported to the reviewing HREC 
and PI within 7 calendar days of confirming a serious breach has occurred and 
provide follow-up reports when required  
(NHMRC Reporting of Serious Breaches of Good Clinical Practice (GCP) or the 
Protocol for Trials Involving Therapeutic Goods 2018) 
Action with respect 
to safety that has 
been taken by 
another country’s 
regulatory agency 
TGA, Australia 
Without undue delay and no later than 72 hours of the trial sponsor becoming 
aware of the action  
(Australian clinical trial handbook version 2.3) 

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Report 
Submit To 
Description/Constraints 
(relevant to an 
ongoing clinical trial 
in Australia) 
USADEs, Annual 
Safety Report/ 
updated IB/ 
approved PI 
 
Investigator and 
HREC 
Australia: 
Per EC requirements, but at least annually, the sponsor will ensure investigator will 
provide to HREC responsible for study; 
x an Annual Safety Report (including a summary of the evolving safety profile 
of the trial, a brief description and analysis of new/relevant findings, 
implications of safety data to the risk-benefit ratio for the trial, a description of 
any measures taken or proposed to minimize risks  
x an updated Investigator Brochure, or current, approved Product Information 
(PI), if appropriate (e.g. in a study for a product approved in Australia or where 
an Investigator Brochure is no longer maintained) 
(NHMRC Safety monitoring and reporting in clinical trials involving therapeutic 
goods November 2016 section C.1.i) 
Annual Safety 
Reports and other 
single adverse 
events reports 
TGA, Australia 
To be submitted upon request by TGA 
12.9 Publication and Use of Information 
Medtronic is committed to the dissemination of the study results.  A Publication Plan will be 
implemented and followed.  At the conclusion of the study, a multisite abstract reporting the primary 
results will be prepared by the Principal Investigators (in collaboration with others including but not 
limited to the echocardiography core lab physicians, and the CEC/DSMB).  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 study 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 endpoint results, active participation of all participating 
investigators, CEC/DSMB committee members, and core laboratory personnel will be solicited for data 
analysis and abstract and manuscript preparation.  Submission of all abstracts and publications 
regarding the study results requires approval by the Principal Investigators after review by the 
Publications Committee.  A separate Publication Plan will provide detailed information about the 
publication committee, authorship, publication proposals, and requests for data. 
The results of the study will be made public within 12 months of the study’s primary completion point, 
defined as the date the final subject has completed his/her five-year follow-up.  Final results will be 
reported in a publicly accessibly manner; either in a peer-reviewed scientific journal (in print or on-line), 
in an on-line publicly accessible registry dedicated to the dissemination of clinical trial information such 
as ClinicalTrials.gov, or in journals willing to publish in abbreviated format (e.g., for studies with negative 
or incomplete results).

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12.10  Suspension or Early Termination 
Medtronic may decide to suspend or prematurely terminate the study (e.g. if information becomes 
available that the risk to study subjects is higher than initially indicated.  If the study is terminated 
prematurely or suspended, Medtronic shall promptly inform the clinical investigators and regulatory 
authorities of the termination or suspension and the reason(s) for this.  The investigator shall then 
promptly inform the reviewing IRB/EC.  Medtronic will, as soon as possible, provide a written statement 
to the investigators to enable prompt notification of the IRB/ECs.  If study enrollment is terminated 
early, follow-up visits will continue for all enrolled subjects. 
12.11  Role of Sponsor Representatives 
Representatives from Medtronic may participate in confirmation of MDCT anatomical measurements 
prior to implant of each subject.  In addition, representatives from Medtronic may provide technical 
support during the implant procedures to the implanting physicians and study site staff relative to the 
use of the investigational devices.  A list of sponsor personnel (including monitors, safety 
representatives, and the medical expert) and their contact details will be maintained in a separate 
document and provided to the study centers. 
12.12  Additional Contact Information 
The following contact information will be provided to the clinical sites in a separate document: 
x
Additional relevant sponsor contact information, including email and telephone number 
x
The name, address, and telephone number of the monitor 
x
The name, title, address, and telephone numbers of the study Principal Investigators 
x
The name, title, address, and telephone number of the sponsor’s medical expert for the study. 
12.13  Consent Materials 
A sample informed consent form for the study will be provided under separate cover. 
12.14 Investigator’s Brochure and Report of Prior Investigations 
An Investigator Brochure/Report of Prior Investigations (IB/RoPI) will be provided under separate cover 
to the sites and regulatory agencies.  Medtronic will update the IB/RoPI in accordance with ISO/FDIS 
14155:2020; and provide those updates to sites and regulatory agencies.  For geographies under 
ISO/FDIS 14155:2020, documentation of receipt of the IB/RoPI by each site’s Ethics Board is required for 
all versions of the IB/RoPI.  
12.15  Contact Information: Other Institutions, Core Labs, and Committees 
Information and contact details for the ECL, CEC, DSMB, ERC, and Explant Core Lab each of will be 
maintained in a separate document and provided to the study sites.  A definitive list of all participating 
parties will be provided in clinical reports.  In addition, a list of the names and addresses of participating 
institutions will maintained and provided to the sites. 

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12.16 Institutional Review Board/Ethics Committee Information 
Information on each participating Institutional Review Board/Ethics Committee will be maintained in a 
separate document.  A definitive list of all participating IRB/ECs will be maintained and provided in 
clinical reports. 
 

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13.1 Appendix I: MDCT Procedures: Pre-TAVR Planning 
MDCT is required to confirm anatomical suitability for transfemoral TAVR with the Evolut PRO+ system.  
The MDCT exam should be performed at the study center, but exams performed for diagnostic purposes 
outside the study center and prior to consent can be used, provided they are within 365 days of the 
qualifying echocardiogram, and contain the protocol-required data as determined by a designated study 
Cardiovascular Imaging physician. 
Technical Aspects.  Technical aspects of the exam are per the site’s standard routine for clinical TAVR 
cases; however, the following are recommended parameters: 

Detector collimation 0.4-0.625 mm. 

^ůŝĐĞƚŚŝĐŬŶĞƐƐчϭ͘Ϭŵŵ͘ 

Coverage area from superior to the aortic arch to inferior to the cardiac apex. 

Slice overlap of 0.4 mm (will result in isotropic voxels with a 20 cm field of view) 
Required Variables. The following variables are required to confirm anatomical suitability for 
implantation and TAV size selection (Figure 4). 

Annulus perimeter (measured at systole if retrospective gating is used) 

Sinus of Valsalva (SoV)diameters (measured at diastole) 
-
Right coronary sinus diameter 
-
Left coronary sinus diameter 
-
Non coronary sinus diameter 
-
Mean sinus diameter (mean of the three coronary sinus diameters) 

SoV heights (measured at diastole) 
-
Right coronary SoV height 
-
Left coronary SoV height 
-
Non coronary SoV height 
-
Mean SoV height (mean of the three SoV heights) 

Mean diameter of left iliofemoral artery 

Mean diameter of right iliofemoral artery 
These variables should be documented in the MDCT report for the subject’s medical record or on an 
alternative source document to be maintained in the subject’s study files (e.g. a report from dedicated 
off-line cardiac image analysis system such as 3mensio, Vital Images, etc). 
In addition, calcium volumes should be determined in the following 3 regions: 1) the basal annular plane 
to the top of the aortic valve leaflets, 2) the basal annular plane to 5 mm below the basal annular plane, 
and 3) 5 mm below the basal annular plane to 10 mm below the annular plane (Figure 5).  These 
measurements are intended for exploratory analyses and are not required.  If performed, patient-
specific calcium threshold detection is recommended; however, determination of the calcium threshold 
detection should be per the site’s standard practice. 
 

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Figure 4. (A)  Annular perimeter measured from a reformatted double-oblique axial image at aortic annulus level.  Measurement is 
recommended at systole if retrospective gating was used, although measurement at diastole is also acceptable; (B) SoV diameter is measured 
at diastole from the double oblique axial image where the widest portion of the three sinuses is visible.  A diameter from each commissure is 
measured through the site of the root to the opposite sinus.  The mean of the three SoV diameters is reported on the eCRF; (C, D, & E) 
Measurement of the left, non, and right coronary SoV heights, respectively.  SoV heights measured at diastole from double oblique axial image 
located 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.  SoV height is measured from the aortic annular plane to the sinotubular junction. 
 
  
Figure 5.  Stretched view of the aortic root showing the 3 regions for calcium volume measurements. 
 

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13.2 Appendix II: Clinical Assessment 
Clinical assessment by a delegated member of the study team is required at each study interval. 
Baseline. The baseline clinical assessment can be conducted on an outpatient, clinic, or inpatient basis, 
and should include the following: 
x
History and physical, with special emphasis for symptoms of aortic stenosis, coronary heart disease, 
chronic obstructive lung disease, and cerebrovascular disease 
x
New York Heart Association Functional (NYHA) functional class assessment 
x
Modified Rankin Score assessment 
x
Complete blood count 
x
pro B-type natriuretic peptide (NT-proBNP) 
x
Simple spirometry (e.g. timed vital capacity and FEV1) 
Blood pressure should be taken with the subject sitting in a chair after resting for 5-10 minutes.  The 
subject’s weight and height can be taken with shoes off or on.  The subject’s height at baseline will be 
used for calculation of BSA and BMI at all subsequent follow-up exams, but weight must be taken at 
each visit.  Findings of the baseline assessment must be documented in the subject’s medical record or 
study records. 
Post-Implant. Post-implant follow-up exams should also be conducted by a delegated member of the 
study team, and can be performed on either an outpatient, clinic, or inpatient basis.  If the subject is 
unable to attend a visit, a telephone follow-up can be performed, but should be documented on the 
eCRF.  Post-implant clinical evaluation should include the following: 
x
A physical exam (including blood pressure and weight) and interview, with special emphasis for 
symptoms of aortic stenosis, coronary heart disease, neurological events, and pulmonary symptoms.  
If suspicion of a neurological event is raised, a neurologist should be consulted to see if further 
evaluation for a stroke is warranted. 
x
NYHA functional class assessment (except at discharge) 
x
Assessment for any adverse events and device deficiencies since last follow-up, and follow-up of any 
unresolved adverse events previously identified. 
The findings of post-implant clinical assessment must be documented in the subject’s medical records or 
study records, and should include the presence or absence of any symptoms, NHYA functional class, 
prescribed medications, description of any new adverse events and device deficiencies since last follow-
up (or absence of new adverse events), and follow up any unresolved adverse events previously 
identified. 
Information and definitions for ACCF/AHA Heart Failure stages64, NYHA functional classifications, and 
Modified Rankin Score65 are provided in Table 14, Figure 6, Table 15, and Table 16. 
 

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Table 14. ACCF/AHA heart failure stages 
Stage 
Description 
A 
At high risk for HF but without structural heart disease or symptoms of HF 
B 
Structural heart disease but without signs or symptoms of HF 
C 
Structural heart disease with prior or current symptoms of HF 
D 
Refractory HF requiring specialized interventions 
Figure 6.  Stages in the development of heart failure.  Adapted from Hunt et al.64 
Table 15. NYHA classification 
Class 
Description 
Class I 
Patient is without limitations of physical activity.  Ordinary physical activity does not cause undue fatigue, 
palpitations, or dyspnea. 
Class II 
Patient has slight limitations of physical activity.  Is comfortable at rest.  Ordinary physical activity results in 
fatigue, palpitations, or dyspnea. 
Class III 
Patient has marked limitations of physical activity.  Is comfortable at rest. Less than ordinary activity causes 
fatigue, palpitations, or dyspnea. 
Class IV 
Patient has inability to carry on any physical activity without discomfort.  Heart failure symptoms are present 
even at rest or with minimal exertion. 
Table 16. Modified Rankin score 
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 

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13.3 Appendix III: Echocardiography Procedures 
13.3.1 Required Evaluations 
Comprehensive transthoracic echocardiography is required at the following intervals: 
x
Baseline  
x
Discharge 
 
x
30 Days 
x
6 Months 
x
Annually through 5 years 
 
13.3.2 General Procedures 
x
Protocol-driven exams should be performed by designated individuals delegated by the site PI 
x
Subject’s blood pressure and weight should be recorded at each visit.  Blood pressure should be 
taken with the subject sitting in a chair after resting for 5-10 minutes.  Subject’s weight can be taken 
with shoes off or on.6
x
The subject’s ID number and exam interval should be annotated on the image. 
x
A simultaneous ECG with a clearly defined R-wave should be displayed on all clips 
x
Digital cine clips should be a minimum of two cardiac cycles 
x
To minimize inter-vendor and inter-software variation in GLS measurements, serial assessments 
should be performed using the same vendor’s equipment and software to the extent practical. 
x
Color Doppler images for assessment of prosthetic regurgitation should be obtained at a minimum 
frame rate of 20 Hz through optimization of sector width and depth settings. 
x
Still frames of measured variables should be captured.  In addition, still frames of spectral Doppler 
tracings without the measurements should be captured to facilitate analysis by the Echo Core Lab.  
Still frames of spectral and tissue Doppler tracings should contain a minimum of 3 cardiac cycles for 
subjects in sinus rhythm, and a minimum of 5 cardiac cycles for subjects in atrial fibrillation (two 
sequential frames per variable may be necessary). 
x
Spectral and tissue Doppler waveforms should be recorded at a minimum sweep speed of 50 
mm/sec. 
x
Exams will be transmitted to the Echo Core Lab via web-based picture archiving and communication 
system.  Details of the image transmission process for each site will be established during site 
initiation process. 
 
 
Weight can be taken from the clinical assessment exam.  Blood pressure should be taken within 5-10 minutes before or after the echo exam. 

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13.3.3 Data Requirements 
Sites should acquire the necessary views and Doppler recordings to assess the following variables.  
Procedures for acquiring key variables are described in Section 13.3.4. 
x
Height (cm) and weight (kg) 
x
Heart rate (HR) 
x
Blood pressure (BP) 
x
Left ventricular outflow tract (LVOT) diameter in mid systole 
x
Max aortic or prosthetic valve velocity (vMax) by CW Doppler 
x
Aortic or prosthetic valve velocity time integral (VTI) by CW Doppler 
x
Mean gradient across aortic or prosthetic aortic valve (MG) by CW Doppler 
x
LVOT VTI by PW Doppler 
x
Systolic ejection time (ET) 
x
Aortic valve area (AVA) by continuity equation with VTI7 
x
Aortic valve area index (AVAI) by continuity equation with VTI 
x
Grade of native aortic regurgitation (baseline only) 
x
Grade of prosthetic paravalvular regurgitation (post-implant only) 
x
Grade of prosthetic transvalvular regurgitation (post-implant only) 
x
Grade of total prosthetic regurgitation (post-implant only) 
x
Right ventricular outflow tract (RVOT) diameter (post-implant; if AR > mild by visual estimate 
x
RVOT VTI (post-implant; if aortic regurgitation > mild by visual estimate) 
x
Grade of mitral regurgitation (MR) 
x
Grade of tricuspid regurgitation (TR) 
x
Max TR jet velocity (if TR is present) 
x
Left ventricular internal dimension at end diastole (LVIDD)
x
Left ventricular internal dimension at end systole (LVIDS) 
x
Interventricular septal thickness at end diastole (IVS) 
x
Left ventricular posterior wall thickness at end diastole (LVPW) 
x
Left ventricular end diastolic volume by modified Simpson’s rule (LVEDV) 
x
Left ventricular end systolic volume by modified Simpson’s rule (LVESV) 
x
Left atrial volume at end systole by bi-plane Simpson’s rule (LAV) 
x
Mitral inflow early (E) velocity
x
Mitral inflow atrial (A) velocity 
x
Mitral inflow E wave deceleration time (MdT) 
x
Mitral annular early (e’) diastolic velocity; lateral 
x
Mitral annular late (a’) diastolic velocity; lateral 
x
Mitral annular early (e’) diastolic velocity; medial 
x
Mitral annular late (a’) diastolic velocity; medial 
AVA and AVAI should be based on the LVOT diameter, LVOT VTI, aortic valve VTI, height and weight reported on the eCRF

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x
Grade of diastolic dysfunction 
x
Pattern of LV geometry
x
Peak average left ventricular global longitudinal strain (GLS) at end systole (aortic valve closure) 
x
Vendor, model, and software version of echocardiography system 
x
Tricuspid annular plane systolic excursion (TAPSE) 
x
Basal right ventricular linear dimension at end diastole (RVD) 
x
Right ventricular area at end diastole (RVAD) 
x
Right ventricular area at end systole (RVAS) 
Information on variables that will be derived by the central database from these measurements is 
provided in Section 13.3.5. 
 

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13.3.4 Acquisition of Key Variables 
13.3.4.1 LVOT Diameter 
The LVOT diameter is measured in the parasternal long-axis view, with the optimal imaging plane 
through the long axis of the aorta (anterior and posterior walls of the aortic root parallel with the 
maximal aortic diameter).66 
LVOT diameter is measured in mid-systole at the level of the aortic annulus at the base of the aortic 
valve cusps, with a line drown from where the anterior aortic cusp meets the ventricular septum to 
where the posterior aortic cusp meets the anterior mitral leaflet perpendicular to the anterior aortic 
wall (Figure 7, A and B).67,68,69,70,71,72 Post-implant, LVOT diameter is measured in the parasternal long-
axis view in mid-systole, from the outer edge to outer edge of the inflow aspect of the stent (Figure 7, C 
and D).73,74 
 
Figure 7. (A) and (B) Examples of measurement of pre-implant LVOT diameter.  LVOT diameter is measured at the level of the aortic annulus, 
with a line drawn from where the anterior aortic cusp meets the ventricular septum to where the posterior aortic cusp meets the anterior 
mitral leaflet perpendicular to the anterior aortic wall; (C) and (D) Post TAV implantation, LVOT diameter measurement is from outer edge to 
outer edge of the inflow aspect of the stent. 

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13.3.4.2 LVOT Velocity 
LVOT velocity is recorded with PW Doppler from the apical position, in either the apical long-axis view or 
the anteriorly angulated four-chamber view (“5-chamber view”).  For pre-implant exams, the PW sample 
volume should be positioned just proximal to the aortic valve, with care to avoid the zone of pre-valve 
acceleration (usually 0.5 to 1.0 cm proximal to the cusps, (Figure 8, A and B).75,76The recommended 
procedure is to initially place the sample volume within the aortic valve leaflets, and then gradually 
move it apically until a clear spectral waveform is observed with a well-defined peak and minimal 
spectral broadening.   Post TAVR, the sample volume should be placed proximal to the inflow aspect of 
the stent (Figure 8, C).77,78.  The VTI is measured by tracing the modal velocity (middle of the dense 
signal). 
 
 
Figure 8. (A) Sample volume placement just proximal to zone of pre-valve acceleration (illustration by Mayo Clinic); (B) Example of pre-stenotic 
acceleration at the aortic annulus and LVOT near the annulus; (C) Correct sample volume placement just proximal to inflow of stent.  Full-
screen imaging of stent is helpful to verify positioning of sample volume proximal to the stent before switching to Doppler mode. (D) 
Measurement of LVOT VTI and ejection time. 

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13.3.4.3 Aortic Valve Velocities 
To avoid underestimation of the aortic valve gradient (native or prosthetic), the aortic valve velocity 
should be interrogated with CW Doppler from the apical, suprasternal notch, right supraclavicular, and 
right parasternal windows.79  The window 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 9).76 
 
Figure 9. (A) Aortic valve velocities interrogated from multiple transducer positions (illustration by Mayo Clinic); (B) CW Doppler of severe aortic 
stenosis showing tracing of the velocity curve for mean gradient and VTI, and max velocity. American Society of Echocardiography 2017 30372-
392DOI: (10.1016/j.echo.2017.02.009) Copyright © 2017 The Authors 
13.3.4.4 Left-Ventricle and Left Atrium: Volumes, Ejection Fraction, and Dimensions 
Left Ventricle. Standard 2-D views of the left ventricle should be obtained from parasternal and apical 
transducer positions for quantitative assessment of left ventricular volumes and ejection fraction, and 
visual assessment of regional wall motion. 
Specifically, for LV volumes and ejection fraction, two orthogonal views (apical four-chamber and apical 
two-chamber) should be recording at equal depth settings for quantification using the modified 
Simpson’s rule (biplane method of disks, (Figure 10, A).  Image acquisition should aim to maximize LV 
areas, while avoiding foreshortening of the LV.  Acquiring LV views at reduced depth to focus on the LV 
cavity can reduce likelihood of foreshortening and minimize errors in endocardial border tracings.80  Use 
of contrast agents to improve endocardial delineation when segments are poorly visualized is per 
discretion of the study echocardiographer and institutional procedures.  LV volumes should be traced at 
the actual endocardial border (between the compacted and non-compacted myocardium rather than at 
the blood-tissue interface).  Trabeculations and papillary muscles should be included as part of the LV 

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cavity, not part of the LV wall.72  At the mitral valve level, the contour is closed by connecting the two 
opposite sections of the mitral ring with a straight line.  LV length is defined as the distance between the 
middle of this line and the most distant point of the LV contour.80 
M-mode recordings of the LV should also be obtained.  Dimensions of the left ventricle should be 
obtained by either 2-D linear measurements or 2-D guided m-mode in the parasternal long-axis view, 
perpendicular to the LV long axis, and measured at the level of the mitral valve leaflet tips Figure 10, B 
and C). 
 
 
 
 
A 
B 
C 
Figure 10. (A) Still frames of two orthogonal planes at end systole and diastole to calculate LV volumes and ejection fraction by modified 
Simpson; (B) measurement of LV end-diastolic diameter by 2-D guided m-mode; (C) Measurement of LV linear dimensions by 2-D, 
electronic calipers should be positioned on the interface between myocardial wall and cavity and the interface between wall and 
pericardium (orange arrow). [Journal of the American Society of Echocardiography 2015 281-39.e14DOI: (10.1016/j.echo.2014.10.003)  
Copyright © 2015 American Society of Echocardiography] 

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Left Atrium. Two-dimensional images should be obtained from the apical four-chamber and apical two-
chamber views to enable quantification of left atrial volume by the bi-plane Simpson’s method.  The 
views should be adjusted to optimize left atrial size.  Image optimization should include avoiding 
foreshortening and optimizing focus depth and gain. 
Left atrial measurements are taken at ventricular end systole, with the left atrium at its maximal size just 
prior to mitral valve opening.  The chamber area is traced at the blood tissue interface, starting at the 
lateral mitral annulus and finishing at the medial annulus.  The length of the left atrium is measured 
parallel to the long axis of the left atrium (Figure 11 A).  The left atrial appendage, pulmonary vein 
orifices, and any atrial septal aneurysm should be excluded from the area measurement.80 
 
 
Figure 11. Still frame of apical 4 and 2 chamber views demonstrating bi-plane Simpson’s method for quantification of LA volume.  [Journal of 
the American Society of Echocardiography 2015 281-39.e14DOI: (10.1016/j.echo.2014.10.003)  Copyright © 2015 American Society of 
Echocardiography] 
 

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13.3.4.5 Peak Left Ventricular Global Longitudinal Strain (GLS) 
Speckle tracking echocardiography (STE) for measurement of peak left ventricular GLS should be 
performed at each study interval.  Serial exams for each subject should be performed using the same 
vendor’s equipment and software to the extent practical.  The following is intended to provide a 
standardized approach for image acquisition and minimize sources of variability. 
Optimal Image Acquisition (Figure 12) 
x
Electrocardiographic (ECG) gating.  An optimal ECG signal with prominent P, R, and T waves and 
minimal heart rate variability should be present across 3 cardiac cycles in patients with normal sinus 
rhythm.  Clips for GLS should include 3 cardiac cycles. 
x
Frame rate.  Images for STE should be maintained at a frame rate of 40 to 90 frames per second 
through optimization of image depth and sector width.  Images for GLS should be acquired at the 
same depth and section width. 
x
Image quality.  Images should be acquired using optimal gain settings and breath-hold techniques to 
delineate endocardial and epicardial borders throughout the cardiac cycle and to avoid artifact 
related to excess noise, rib or lung movements, and translational motion of the heart.  Images 
should be “on-axis”, with image width and depth focused on the LV.  It is essential to avoid 
foreshortening in the apical views.  Also, there should be a space of at least 5 mm between the 
epicardium in diastole and the sector width.72 
x
Required views.  The following views are required for GLS: 1) apical 2 chamber, 2) apical 3 chamber 
(apical LAX), and 3) apical 4 chamber.  It is recommended the images for GLS analysis be acquired at 
the beginning or end of the apical section of the exam; this allows the operator to see the apical 
images in a row and facilitates selection of images with similar heart rates. 
 
 
Figure 12.  Example of optimal apical 2,3, and 4 chamber images for GLS analysis.  Endocardial borders are visualized over the cardiac 
cycle, apex not foreshortened, frame rate is 50 fps, and depth and sector width the same in all three.
 

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Image Analysis and Post-Processing 
Contemporary echocardiography systems perform automated analysis of GLS once the required apical 
views have been selected, however the automated analysis for each of the views should be visually 
assessed for the following and corrected if indicated. 
Region of interest (Figure 13).  The auto-generated region of interest (ROI) for each view should be 
visually assessed for adequacy of tracking.  The ROI should encompass the myocardium form the 
subendocardial border to the subepicardium border81, and should be at least 85% to 90% of the 
thickness of the myocardium.72  If the auto-generated ROI is inadequate, it should be adjusted manually 
or semi-automatically using the “3 point” method available on contemporary systems.  The redrawn ROI 
should be visually assessed, and the endocardial borders and ROI width adjusted as needed.  The ROI 
should include the endocardium and myocardium within the lines, excluding the pericardium, 
trabeculation, and papillary muscles. 
 
Figure 13.  Three-point method for defining start and end points for ROI.  For the apical 2-chamber view, the first point is on the basal posterior 
wall at the mitral annulus, the second point is at the basal anterior wall at the mitral annulus, and the third point is at the apex.  For the apical 
3-chamber view, one point is placed at the basal posterior wall at the mitral annulus (ventricular side), one point is placed at the apex, and one 
point is placed at the base of the anterior septum just proximal to the LVOT.  For the apical 4-chamber view, the first point is placed on the 
basal inferoseptum at the mitral annulus (ventricular side), the second point is placed at the basal anterolateral wall at the mitral annulus 
(ventricular side), and the third point is at the apex. 
Event timing.  The apical 3 chamber view should be reviewed frame by frame to ensure the reference 
point for defining aortic valve closure (AVC) is correct.  AVC should be corrected manually in indicated. 
Review of Strain Curves.  The resulting strain curves and bulls-eye plot should be reviewed by possible 
errors in tracking and the affected analyses corrected as indicated.  The final peak average LV GLS should 
be reported on the eCRF. 
 

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13.3.4.6 Left Ventricular Diastolic Function 
A spectral Doppler recording of mitral inflow should be obtained with PW Doppler in the apical 4-
chamber view, using a 1 to 2 mm sample volume placed between the mitral leaflet tips (Figure 14, A). 
The following variables should be measured: 
x
Mitral inflow “A” velocity 
x
Mitral inflow “E” velocity 
x
Mitral inflow E-wave deceleration time (MdT) 
Mitral annular velocities should be recorded from the lateral and medial (septal) aspects of the mitral 
annulus using tissue Doppler imaging (TDI) in the apical 4-chamber view (Figure 14, C).  Minimal 
angulation (<20 degrees) should be present between the ultrasound beam and the plane of cardiac 
motion. The following variables should be measured: 
ͻ 
Mitral annular tissue Doppler early diastolic velocity (e’); medial and lateral 
ͻ 
Mitral annular tissue Doppler late diastolic velocity (a’); septal and lateral 
 
Figure 14. (A) Apical 4 chamber with sample volume placement between mitral leaflet tips during diastole; (B) Doppler gains and wall filters 
optimized to clearly show onset and cessation of mitral inflow; (C) A 2 to 5 mm sample volume should be positioned at or 1 cm within the 
septal and lateral insertion sites of the mitral leaflets and adjusted as necessary to cover the longitudinal excursion of the mitral annulus in both 
systole and diastole.
 

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13.3.4.7 Prosthetic Aortic Regurgitation 
An integrated approach using color flow, pulsed-wave (PW), and continuous-wave (CW) Doppler is used 
to assess the severity of transvalvular and paravalvular aortic regurgitation (AR).  Color flow Doppler 
imaging should be performed from the parasternal long and short-axis views, and the apical 5-chamber 
and apical 3 chamber views (Figure 15).  The entire valve should be scanned, from the aortic to the 
ventricular end of the TAV to identify the number, location, and direction of regurgitant jets, which can 
be multiple and eccentric.  In the short axis view, color imaging should be performed at multiple planes 
(sweeping from level of the leaflets to below the skirt and frame to assess paravalvular regurgitation), 
and at the coaptation point of the leaflets for transvalvular (central) regurgitation (Figure 16).82 
 
 
Figure 15.  Standard views showing detection of paravalvular regurgitation.  Color coding delineates the regions around the valve that can be 
visualized from the parasternal and apical views.  With ultrasound plane rotation, tilting upwards or sideways, a more complete interrogation of 
the valve can be accomplished.  Apical views are important in that some jets may not be detected in the parasternal views because of 
shadowing from the prosthesis.  [Journal of the American Society of Echocardiography 2019 32431-475DOI: (10.1016/j.echo.2019.01.003, 
Copyright © 2019 American Society of Echocardiography] 
 

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Figure 16.  Imaging planes for detection for paravalvular and transvalvular regurgitation.  Thorough imaging of the entire valve is needed to 
identify the origin and vena contracta of regurgitant jets, which may be multiple and not be all at the same level.  A sweep of the aortic root 
from the parasternal SAX view is recommended. [Journal of the American Society of Echocardiography2019 32431-475DOI: 
(10.1016/j.echo.2019.01.003, Copyright © 2019 American Society of Echocardiography] 
 

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If prosthetic AR is seen by color Doppler, a CW spectral Doppler recording of the regurgitant signal 
should be obtained for measurement of pressure half-time and assessment of jet density (Figure 17, A).  
In addition, a PW spectral Doppler recording from the proximal descending or abdominal aorta should 
be recorded to assess the degree of flow reversal (Figure 17, B). 
 
 
Figure 17.(A) CW Doppler spectral recording of AR regurgitant signal and measurement of pressure half-time; (B) PW Doppler spectral 
recording from abdominal aorta showing flow reversal. 
If AR appears more than mild by visual assessment, and if image quality is technically adequate, the 
RVOT and LVOT diameters and VTIs can be measured to calculate regurgitant volume and fraction 
(Figure 18). 
 
 
Figure 18.  Example of quantification of aortic regurgitant fraction and volume to complement other assessments.  Stroke volume is calculated 
at the RVOT and LVOT. 
 

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Grading of Prosthetic Regurgitation.  The degree of transvalvular, paravalvular, and total (transvalvular 
plus paravalvular) AR should be graded as none, mild, moderate, or severe based on overall 
comprehensive evaluation the echocardiographic findings in Table 17, Figure 19.82 The category of 
“trace” can be used if regurgitation is barely detectable. The following caveats are noted in the ASE 2019 
Guidelines for the evaluation of valvular regurgitation after percutaneous valve replacement. 
1. Central AR jets will occur at the level of leaflet coaptation whereas PVR will be seen at the proximal 
(ventricular) edge of the valve.  The jet must enter the LV to be considered true regurgitation, thus 
imaging just below the edge of the stent will confirm the presence of true PVR; however, the vena 
contracta of the jet should be measured at its narrowest region. 
2. Color flow around the TAV within the sinuses of Valsalva but above the annular valve skirt should 
not be mistaken for PVR.  Flow in the sinuses has low velocity and does not connect with the LVOT in 
diastole.  Scanning through the long axis of the valve is useful in distinguishing color flow in the 
sinuses from PVR. 
3. Small jets of regurgitation are typically isolated to open stent cells and not at the “nodes” of the 
stent frame.  It is important not to include the stented frame in the measurement of circumferential 
extent of the regurgitation but to integrate only the regurgitant jets when determining the 
circumferential extent. 
Table 17. Evaluation of severity of prosthetic aortic regurgitation post TAVR 
 
Mild 
Moderate 
Severe 
Structural Parameters 
 
Position of prosthesis 
Usually normal 
Variable 
Frequently abnormal 
Stent and leaflet morphology 
Usually normal 
Variable 
Frequently abnormal 
Doppler Parameters
 
Proximal flow convergence (CD) 
Absent 
May be present 
Often present 
AR velocity waveform density (CWD) 
Soft 
Dense 
Dense 
Diastolic flow reversal in proximal aorta 
Brief, early diastolic 
May be holodiastolic 
Holodiastolic (end-diastolic 
velocity ш 20 cm/sec) 
Diastolic flow reversal in abdominal 
aorta 
Absent 
Absent 
Present 
Vena contracta width (cm) (CD) 
< 0.3 
0.3 – 0.6 
> 0.6 
Vena contracta area (cm2) * (2D, CD) 
< 0.10 
0.10 – 0.29 
ш 0.30 
Circumferential extent of PVR (%Ϳ๥ړ 
<10 
10-29 
ш 30 
Jet deceleration rate (PHT, ms)# (CWD) 
Variable 
Usually > 500 
Variable 
Steep 
Regurgitant volume (mL)
<30
30-59
>60
Regurgitant fraction (%)
<30 
30-49 
ш50 
EROA (cm2)##
<0.10
0.10 – 0.29
ш0.30
CD, Color Doppler; CWD, continuous wave Doppler; PVR, paravalvular regurgitation; PHT, pressure half-time 
*Vena contracta area is measured by planimetry of the vena contracta of the jet(s) on the 2-D color Doppler images in the short-axis view 
جCircumferential extent of PVR best not to be used alone, but in combination with vena contracta width or area 
#Influenced by LV and aortic compliance 
##ERO is infrequently used in A 
 

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Figure 19.  Suggested algorithm to guide integration of multiple parameters of AR severity after TAVR.  Good-quality echocardiography imaging 
and complete data acquistion are assumed.  [Journal of the American Society of Echocardiography2019 32431-475DOI: 
(10.1016/j.echo.2019.01.003, Copyright © 2019 American Society of Echocardiography] 

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13.3.4.8 Mitral Regurgitation 
Color flow Doppler imaging of the left atrium should be performed from the parasternal long-axis view, 
and from the apical 4, 2, and long axis views. 
Mitral regurgitant (MR) jets should be recorded with CW Doppler using a velocity scale that allows 
assessment of the density, shape, duration, and peak velocity of the MR jet.  If 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.  A spectral Doppler recording of mitral 
inflow should be recorded to assess the early filling velocity (E) and the A wave inflow pattern.  If image 
quality is technically adequate, quantitative assessment of the mitral regurgitant orifice area using PISA, 
or derivation of regurgitant volume and regurgitant fraction (stroke volume method) can be performed.  
Grading of the severity of mitral regurgitation should be integrative using the parameters in Table 18.83 
Table 18. Parameters for grading the severity of mitral regurgitation 
Parameter 
Mild 
Moderate 
Severe 
Structural 
 
   MV Morphology 
None or mild leaflet 
abnormality (e.g., mild 
thickening, calcifications or 
prolapse, mild tenting
Moderate leaflet abnormality 
or moderate tenting 
Severe valve lesions (primary: flail 
leaflet, ruptured papillary muscle, 
severe retraction, large perforation; 
secondary: severe tenting, poor 
leaflet coaptation 
   LA and LV Size† 
Usually normal 
Normal or mildly dilated 
Dilated‡ 
Qualitative Doppler 
 
   Color flow jet area§ 
Small, central, narrow, often
Variable
Large central jet (>50% of LA) or 
eccentric wall-impinging jet of 
variable size 
Flow convergencek
Not visible, transient or 
small 
Intermediate in size and 
duration 
Large throughout systole 
   CWD jet 
Faint/partial/parabolic 
Dense but partial or parabolic 
Holosystolic/dense/triangular 
Semi-quantitative 
 
   Vena contracta width (cm) 
<0.3 
Intermediate 
ш0.7 (>0.8 for biplane) 
   Pulmonary vein flow 
Systolic dominance (may be 
blunted in LV dysfunction or 
AF)  
Normal or systolic blunting 
Minimal to no systolic flow systolic 
flow reversal 
Mitral inflow
A-wave dominant 
Variable
E-wave dominant (>1.2 m/sec) 
Quantitative 
 
   EROA, 2D PISA (cm2) 
<0.20 
0.20-0.39 
ш0.40 
(may be lower in secondary MR with 
elliptical ROA) 
   RVol (mL) 
< 30 
30-44 
шϲϬ 
   RF (%) 
< 30 
30-49 
ш 50 
EROA, Effective regurgitant orifice area; RVol, Regurgitant volume; RF, Regurgitant fraction; PISA, Proximal isovelocity surface area 
Bolded qualitative and semiquantitative signs are considered specific for their MR grade. 
†This pertains mostly to patients with primary MR. 
‡LV and LA can be within the ‘‘normal’’ range for patients with acute severe MR or with chronic severe MR who have small body size, particularly women, or with small LV size preceding the 
occurrence of MR. 
§With Nyquist limit 50-70 cm/sec. 
K Small flow convergence is usually <0.3 cm, and large is ı 1 cm at a Nyquist limit of 30-40 cm/sec. 
 
 

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13.3.4.9 Tricuspid Regurgitation and Estimated RVSP 
Color flow imaging of the right atrium should be performed from the apical 4-chamber view, the 
parasternal long-axis view of the RVOT, and the parasternal short-axis view at the level of the aortic 
valve. 
Tricuspid regurgitant (TR) jets should be recorded with CW Doppler using a velocity scale that allows 
assessment of the density, shape, duration, and peak velocity of the TR jet.  If severity appears mild or 
greater by visual assessment, hepatic vein and tricuspid inflow velocities should be recorded with PW 
Doppler to assess systolic flow reversal and tricuspid inflow pattern, respectively.  If image quality is 
technically adequate, quantitative assessment of the regurgitant orifice area using PISA, or derivation of 
regurgitant volume (stroke volume method) can be performed.  Grading of the severity of tricuspid 
regurgitation should be integrative using the parameters in Table 19.83 
Table 19. Parameters for grading the severity of tricuspid regurgitation 
Parameter 
Mild 
Moderate 
Severe 
Structural 
 
   TV Morphology 
Normal or mildly abnormal 
leaflets 
Moderately abnormal leaflets 
Severe valve lesions (e.g., flail leaflet, 
severe retraction, large perforation 
   RV and RA Size† 
Usually normal 
Normal or mildly dilated 
Usually dilated‡ 
Qualitative Doppler 
 
   Color flow jet area 
Small, narrow, central 
Moderate central 
Large central jet or eccentric 
wall-impinging jet of variable size 
   Flow convergence 
Not visible, transient or 
small 
Intermediate in size and 
duration 
Large throughout systole 
   CWD jet 
Faint/partial/parabolic 
Dense, parabolic or 
triangular 
Dense, often triangular 
Semi-quantitative 
 
   Color flow jet area (cm2)†
Not defined 
Not defined 
> 10 
Vena contracta width (cm)
<0.3
0.3-0.69 
ш 0.7 
   PISA radius (cm) ‡ 
ч0.5 
0.6-0.9 
> 0.9 
   Hepatic vein flow§ 
Systolic dominance 
Systolic blunting 
Systolic flow reversal 
   Tricuspid inflow§ 
A-wave dominant 
Variable 
E-wave >1.0 m/sec 
Quantitative 
 
   EROA, 2D PISA (cm2) 
<0.20 
0.20-0.39 
шϬ͘ϰϬ 
RVol (mL)
<30 
30-44 
шϰϱ
RA, Right atrium; RV, Right ventricle; EROA, Effective regurgitant orifice area; RVol, Regurgitant volume; PISA, Proximal isovelocity surface area 
Bolded signs are considered specific for their TR grade. 
*RV and RA size can be within the ‘‘normal’’ range in patients with acute severe TR 
†With Nyquist limit >50-70 cm/sec. 
‡With baseline Nyquist limit shift of 28 cm/sec. 
§Signs are nonspecific and are influenced by many other factors (RV diastolic function, atrial fibrillation, RA pressure). 
 

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13.3.4.10 Right Ventricular Function 
The right ventricle (RV) should be imaged from the apical four-chamber, RV-focused apical 4-chamber, 
left parasternal long- and short-axis, left parasternal RV inflow, and subcostal views.  In most cases, 
visualization of the entire RV free wall is better in the RV-focused view (transducer angled medially) than 
the standard 4-chamber view.  Therefore, the RV-focused view is recommended for measurements.80 
The following measurements should be obtained to evaluate RV function (Figure 20): 
x
Basal RV internal dimension at end-diastole 
x
RV internal area at end-diastole 
x
RV internal area at end-systole 
x
Tricuspid annular plane systolic excursion (TAPSE) 
 
Figure 20. (A) Measurement of basal RV linear dimension; maximal transversal dimension in the basal 1/3 of RV inflow at end-diastole (RV-
focused view); (B) TAPSE by m-mode, measured between end-diastole and peak systole.  Proper alignment of m-mode cursor with the direction 
of RV longitudinal excursion should be achieved from the apical approach; (C) Example of measurement of RV areas: manual tracing of RV 
endocardial border from the lateral tricuspid annulus along the free wall to the apex and back to medial tricuspid annulus, along the 
interventricular septum at end-diastole and at end-systole.  Trabeculations, papillary muscles and moderator band are included in the cavity 
area. [Journal of the American Society of Echocardiography 2015 281-39.e14DOI: (10.1016/j.echo.2014.10.003)  Copyright © 2015 American 
Society of Echocardiography] 
 
 

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13.3.5 Echocardiography Core Lab Analysis 
Protocol-required and endpoint or event related (as applicable) echocardiograms will be sent to the ECL 
for assessment: the data generated by the ECL will be the primary data used for analysis and reporting.  
Received echocardiograms will be logged in and analyzed by the ECL according to their procedures 
determined for this study.  Qualitive assessment of valvular regurgitation and quantitative analysis of 
variables related to hemodynamic valve performance, cardiac function and cardiac dimensions will be 
performed according to the methods described in Section 13.3.2. 
The ECL will report the following variables: 
x
Height (cm) and weight (kg) 
x
Heart rate (HR) 
x
Left ventricular outflow tract (LVOT) diameter in mid systole 
x
Max aortic or prosthetic valve velocity (vMax) by CW Doppler 
x
Aortic or prosthetic valve velocity time integral (VTI) by CW Doppler 
x
Mean gradient across aortic or prosthetic aortic valve (MG) by CW Doppler 
x
LVOT VTI by PW Doppler 
x
Systolic ejection time (ET) 
x
Grade of native aortic regurgitation (baseline only) 
x
Grade of prosthetic paravalvular regurgitation (post-implant only) 
x
Grade of prosthetic transvalvular regurgitation (post-implant only) 
x
Right ventricular outflow tract (RVOT) diameter (post-implant; if AR > mild by visual estimate 
x
RVOT VTI (post-implant; if aortic regurgitation > mild by visual estimate) 
x
Grade of prosthetic total (transvalvular plus paravalvular) regurgitation (post-implant only) 
x
Grade of mitral regurgitation (MR) 
x
Grade of tricuspid regurgitation (TR) 
x
Max TR jet velocity (if TR is present) 
x
Left ventricular internal dimension at end diastole (LVIDD) 
x
Left ventricular internal dimension at end systole (LVIDS) 
x
Interventricular septal thickness at end diastole (IVS) 
x
Left ventricular posterior wall thickness at end diastole (LVPW) 
x
Left ventricular end diastolic volume by modified Simpson’s rule (LVEDV) 
x
Left ventricular end systolic volume by modified Simpson’s rule (LVESV) 
x
Left atrial volume at end systole by bi-plane Simpson’s rule (LAV) 
x
Left atrial internal linear dimension at end systole (LA) 
x
Mitral inflow early (E) velocity 
x
Mitral inflow atrial (A) velocity 
x
Mitral inflow E wave deceleration time (MdT) 
x
Mitral annular early (e’) diastolic velocity; lateral 
x
Mitral annular late (a’) diastolic velocity; lateral 
x
Mitral annular early (e’) diastolic velocity; medial 

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x
Mitral annular late (a’) diastolic velocity; medial 
x
Grade of diastolic dysfunction
x
Pattern of LV geometry 
x
Peak average left ventricular global longitudinal strain (GLS) measured at end systole (aortic valve 
closure) 
x
Vendor, model, and software version of echocardiography system 
x
Tricuspid annular plane systolic excursion (TAPSE) 
x
Basal right ventricular linear dimension at end diastole (RVD) 
x
Right ventricular area at end diastole (RVAD) 
x
Right ventricular area at end systole (RVAS) 
In addition, the following variables will be derived by the central database from the appropriate 
measurements reported by both the site and ECL. 
x
Body Surface Area (BSA) in m2 
BSA = 0.007184 x height 0.725 x weight 0.425 
Where: BSA is the body surface area in cm2, height is in cm, and weight is in kg8 
x
Body Mass Index (BMI) in kg/cm 
BMI =weight in kg/height in cm 
x
Aortic Valve Area (AVA) in cm2 
AVA = LVOT diameter in cm2 x 0.785 x (LVOT VTI/aortic valve VTI) 
Where: LVOT VTI is the velocity time integral of the left ventricular outflow tract in cm, and aortic 
valve VTI is the velocity time integral of the native aortic valve in cm 
x
Aortic Valve Area Index (AVAI) in cm2/m2 
AVAI = AVA/BSA 
Where: AVA is the native aortic valve area in cm2, and BSA is the body surface area in m2 
x
Effective Orifice Area (EOA) in cm2 
EOA = LVOT diameter2 x 0.785 x (LVOT VTI/Aortic valve VTI) 
Where: LVOT VTI is the velocity time integral of the left ventricular outflow tract in cm, and aortic 
valve VTI is the velocity time integral of the aortic prosthesis in cm 
x
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 
x
Doppler Velocity Index (DVI) 
DVI= LVOT VTI/Aortic valve VTI 
Where: LVOT VTI is the velocity time integral of the left ventricular outflow tract in cm, and aortic 
valve VTI is the time velocity integral of the prosthetic aortic valve in cm 
 
 
Height will be pulled from the site baseline eCRF, and weight will be pulled from the site eCRF for the visit

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x
Estimated Right Ventricular Systolic Pressure (RVSP) in mmHg 
RVSP = (4 x MVTR jet2) + 10 
Where: MV TR jet is the max velocity of the tricuspid regurgitant jet, and 10 = the assumed mean 
right atrial pressure in mmHg 
x
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 
x
Cardiac Index (CI) in l/min/m2 
CI=CO/BSA 
Where CO is the cardiac output in l/min and BSA is Body Surface Area in cm2 
x
Stroke Volume (SV) in ml/beat 
SV = LVOT diameter2 x 0.785 x LVOT VTI 
Where: LVOT VTI is the velocity time integral from the left ventricular outflow tract in cm 
x
Stroke Volume Index (SVI) in ml/beat/m2 
SVI=SV/BSA 
Where SV is stroke volume in ml/beat and BSA is Body Surface Area in m2
x
Stroke Volume RVOT (SV RVOT) in ml/beat 
SV RVOT = RVOT diameter x RVOT VTI 
Where RVOT diameter is the right ventricular outflow tract diameter in cm and RVOT VTI is the 
right ventricular velocity time integral 
x
Aortic Regurgitant Volume (ARVol) in ml/beat 
RV = SV – SV RVOT 
Where: SV = LVOT diameter2 x 0.785 x LVOT VTI, and SV RVOT = RVOT diameter2 x 0.785 x RVOT VTI 
x
Aortic Regurgitant Fraction (ARF) in % 
ARF = ARVol/SV 
Where ARVol is the aortic regurgitant volume in ml and SV is the stroke volume in ml 
x
Left Atrial Volume Index (LAVI) 
LAVI = LAV/BSA,  
Where LAV is left atrial volume (biplane Simpson’s) at end systole in ml, and BSA is body surface 
area in m2
x
Aortic transvalvular flow rate (AFR) in ml/second 
AFR = SV/ET 
Where SV is the stroke volume in ml/beat and ET is systolic ejection time in milliseconds 
x
Valvulo-arterial impedance (Zva) 
Zva=(MG + SAP)/SVI 
Where MG is mean aortic gradient in mmHg, SAP is systolic blood pressure in mmHg9, and SVI is 
stroke volume index in ml/beat/m2 body surface area
Systolic blood pressure will be pulled from the site eCRF

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E:e’ 
Mitral inflow early (E) velocity/(mitral annular early (e’) diastolic velocity; lateral + mitral annular 
early (e’) diastolic velocity; medial)/2 
x
E:A Ratio 
Mitral inflow early (E) velocity/ mitral inflow atrial (A) velocity 
x
Left ventricular ejection fraction (LVEF) by modified-Simpson’s rule 
LVEF=[(LVEDV-LVESV)/LVEDV] x 100 
Where LVEDV is left ventricular end-diastolic volume in ml and LVESV is left ventricular end systolic 
volume 
x
Fractional Shortening (FS) in % 
FS = [(LVIDD - LVIDS)/LVIDD] x 100 
Where: LVIDD is left ventricular internal dimension at end diastole in cm, and LVIDS is left 
ventricular internal dimension at end systole in cm 
x
Relative wall thickness (RWT) 
RWT = (IVS + LVPW)/LVIDD 
Where IVS is interventricular septal thickness at end-diastole in cm, LVPW is left ventricular 
posterior wall thickness at end-diastole in cm, and LVIDD is left ventricular internal dimension at 
end-diastole in cm 
x
Left Ventricular Mass (LVM) in grams 
LVM = 0.83 x [(LVIDD + LVPW + IVS)3 - (LVIDD)3] +0.6 
Where: LVIDD is the left ventricular internal dimension at end diastole 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. 
x
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 
x
Right Ventricular Fractional Area Change (RVFAC) in % 
RVFAC = [(RVAD-RAS)/RVAD} x 100 
Where RVAD is right ventricular area at end diastole and RVAS is right ventricular area at end-
systole 
 

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13.4 Appendix IV: Exercise Tolerance Testing Procedures 
Subjects confirmed by the ECL to meet the AS criteria should undergo ETT unless contraindicated.  A 
symptom-limited exercise test with the goal of reaching 80% to 85% of the age-predicted maximum 
heart rate is recommended.  The recommended protocol is the modified-Bruce with treadmill, however 
the choice of the specific ETT protocol for each subject is per the clinical judgment of site study team. 
During the test, subjects should be questioned for symptoms every 2 min, and blood pressure and a 12-
lead ECG are recorded at baseline, at the end of each stage, and at peak exercise.  The test should be 
stopped prematurely for symptoms (significant breathlessness) or any chest constriction or dizziness), 
progressive ventricular ectopy >3 beats, new atrial fibrillation, a sustained fall in systolic blood pressure 
>10 mm Hg from the previous stage or more than 2 mm ST segment depression.39  Significant 
breathlessness can be differentiated clinically from physiological breathlessness by the presence of 
distress, the inability to speak, facial pallor and sometimes associated ventricular ectopy or a fall in 
blood pressure.84 
The following information should be recorded: reason(s) for stopping (symptom, fall in blood pressure, 
ventricular ectopy, ST segment depression and fatigue with physiological breathlessness), exercise time, 
exercise capacity in metabolic equivalents (METs), maximum rise in systolic blood pressure and 
maximum fall from peak and ST segment depression in millimeters, and percentage of target heart rate 
achieved. 
METs should be calculated from the speed and gradient of the treadmill by the machine’s software using 
the formula (METS=[(speed × 0.1)+(gradient/100×1.8×speed)+ 3.5]/3.5), where speed is measured in 
meters/minute and grade as a percentage.  One MET is usually defined as the energy expended at rest, 
which is equal to a body oxygen consumption of nearly 3.5 mL per kilogram of body weight for an 
average adult.85  
A positive ETT is defined by the development of significant symptoms, a sustained fall in systolic blood 
pressure >10 mm Hg below baseline or more than 2 mm ST segment depression, a sustained 
tachyarrhythmia, or test limiting dyspnea or fatigue before reaching 60% age and gender adjusted 
predicted MET capacity.  At maximum, up to 30 subjects with a positive ETT will be included in the 
study.  Subjects with a positive ETT may continue in the study until the 30-subject maximum is reached. 
Once the 30-subject maximum is reached, only subjects with a negative ETT may continue in the study. 
 
 

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13.5 Appendix V: Cardiac Magnetic Resonance Imaging (CMR) Procedures 
Subjects confirmed by the ECL to meet the AS criteria should undergo CMR with late gadolinium 
enhancement (LGE) unless contraindicated, and subjects implanted should have a CMR at the six-month 
follow-up.  CMR exams can be performed with either 1.5 Tesla or 3 Tesla.  Details of the acquisition 
protocol will be provided under separate cover.  CMR exams will be sent to a core CMR lab for 
centralized analysis.  The following variables will be reported: 
x
Left ventricular end-diastolic volume 
x
Left ventricular end-systolic volume 
x
Left ventricular end-diastolic volume index 
x
Left ventricular end-systolic volume index 
x
Left ventricular ejection fraction 
x
Stroke volume 
x
Stroke volume index 
x
Left ventricular mass 
x
Left ventricular mass index 
x
Maximum left ventricular wall thickness 
x
Left ventricular mass/left ventricular volume 
x
Longitudinal systolic function 
x
Left atrial volume index 
x
Presence of infarct on LGE 
x
Infarct LGE mass 
x
Presence of midwall LGE 
x
Midwall LGE mass 
x
Aortic regurgitant volume (post implant only) 
x
Aortic regurgitant fraction (post implant only) 
 
 

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13.6 Appendix VI: Six Minute Walk Test (6MWT) Procedures
Subjects confirmed by the ECL to meet the AS criteria should have a 6MWT unless contraindicated, and 
subjects implanted should have a 6MWT at the six-month follow-up.  The 6MWT test is administered 
per the site’s standard procedure, although the following recommendations are intended to standard 
the test across sites and minimize sources of variability.86 
Technical Aspects. The 6MWT should be performed indoors, along a long, flat, straight,enclosed 
corridor with a hard surface that is seldom traveled.  The walking course should be 30 meters in length, 
and the course marked every 3 meters.  Turnaround points should be marked (e.g. with an orange traffic 
cone).  A starting line, which marks the beginning and end of each 60-meter lap, should be marked on 
the floor using brightly colored tape.  A stopwatch and means to record the number of laps should be in 
place (e.g. lap counter or worksheet). 
Patient Preparation. Subjects should wear comfortable clothing and appropriate walking shoes; and 
should not have exercised vigorously within 2 hours of beginning thetest.   A light meal is acceptable 
before early morning or early afternoon tests.  Patients should use their usual walking aids during the 
test(cane, walker, etc. 
Test Procedures 
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 subject should sit at rest in a chair, located near thestarting position, for at least 10 minutes 
before the test starts.  
4. Set the timer to 6 minutes and lap counter to zero (if used).   
5. 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.   Remember that the object is to walk AS FAR AS POSSIBLE for 6 minutes, but don't run or 
jog.  
6. Position the patient at the starting line.  As soon as the subject starts to walk, start the timer.  Do 
not walk with the subject. 
Use an even tone of voice when using standard phrases of encouragement. For example, after each 
minute tell the subject "You are doing well and have X minutes to go”.  Do not use other words of 
encouragement (or body language tospeed up). 

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If the subject stops walking during the test and needs to rest, do not stop the timer.  The subject 
should be told to rest, “but continue walking whenever you feel able." If the patient stops before 
the 6 minutes are up and refuses to continue (or you decide that they should not continue), bring a 
chair over for the patient to sit on, discontinuethe 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, tell the subject "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, mark 
the spot where they stopped walking. 
7. Record the number of laps from the counter (or tick marks on the worksheet).  
8. Record the additional distance covered (the number of meters in the final partial lap) using the 
markers on the wall as distanceguides.  Calculate the totaldistance walked, rounding to thenearest 
meter, and record on the worksheet.  
 

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13.7 Appendix VII: TAVR Implant Procedure 
The implantation procedure is performed according to the standard procedures of the implanting 
physicians.  Valve deployment in accordance with the cusp overlap technique62 is recommended for 
TAVR implant for all study subjects, as appropriate.  Transfemoral access is required for the TAVR 
implant. For sites in the United States, the local heart team’s interventional cardiologist(s) and cardiac 
surgeon(s) must jointly participate in the intra-operative technical aspects of the TAVR procedure.  
Procedural aspects specific to the Medtronic TAVR system should be performed according to the 
Instructions for Use.  TAV size selection should be based on MDCT measurements and the dimensional 
criteria shown in Figure 21. 
 
Figure 21.  TAV sizing matrix showing the anatomical dimensional criteria for each TAV size. 
The following variables will be collected regarding the TAVR implantation procedure: 
x
Name of the primary operator 
x
Anesthesia type (general or local) 
x
Pre-implant pressures (LV systolic and end-diastolic, aortic systolic and diastolic) 
x
Pre-implant mean aortic gradient (simultaneous recording or LV and central aortic pressures) 
x
Pre-deployment BAV (yes/no) 
x
Use of rapid or controlled pacing during BAV and deployment (yes/no) 

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x
Size of TAV implanted 
x
Post-implant dilation (yes/no)
x
Implantation of TAV within the desired location (yes/no) 
x
Post-implant grade of prosthetic regurgitation by angiography (final result) 
x
More than one TAV implanted (yes/no) 
x
Patency of coronary arteries post-implant (yes/no) 
x
Occurrence of adverse events 
x
If TAV implantation not attempted, reason why 
Criteria for grading prosthetic regurgitation by aortography87 
Grade 1+, mild: A small amount of contrast material enters the left ventricle in diastole; it is essentially 
cleared with each beat and never fills the ventricular chamber. 
Grade 2+, moderate: More contrast material enters with each diastole and faint opacification of the 
entire chamber occurs. 
Grade 3+, moderately severe: The left ventricle chamber is well opacified and equal in density with the 
ascending aorta. 
Grade 4+, severe: Complete, dense opacification of the left ventricle chamber in one beat and the left 
ventricle appears more densely opacified than the ascending aorta. 
 
 

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13.8 Appendix VIII: Definitions of Endpoints and Outcome Measures 
Definitions of safety endpoints, TAVR related complications, and efficacy endpoints are provided in 
Sections 13.8.1, 13.8.2, and 13.8.3, respectively.  The CEC will code safety endpoints according to these 
definitions. 
13.8.1 Safety Endpoint Definitions63
Mortality 
Cardiovascular: Any of the following: 
1)
Death due to proximate cardiac cause (eg, myocardial infarction, cardiac tamponade, worsening heart failure) 
2)
Death caused by non-coronary vascular conditions such as neurological events, pulmonary embolism, ruptured aortic 
aneurysm, dissecting aneurysm, or other vascular disease 
3)
All procedure-related deaths, including those related to a complication of the procedure or treatment for a complication of 
the procedure 
4)
All valve-related deaths including structural or nonstructural valve dysfunction or other valve-related adverse events 
5)
Sudden or unwitnessed death 
6)
Death of unknown cause 
Non-cardiovascular: Any death in which the primary cause of death is clearly related to another condition (e.g., trauma, cancer, 
suicide). 
Myocardial Infarction 
Periprocedural MI (<72 h after the index procedure): 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, new pathological Q-waves in at least 2 contiguous leads, imaging evidence of new loss of viable myocardium or new 
wall motion abnormality) AND Elevated cardiac biomarkers (preferable CK-MB) within 72 h after the index procedure, 
consisting of at least 1 sample post procedure with a peak value exceeding 15x as the upper reference limit 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 h after the index procedure): Any of the following criteria: 
1)
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least 1 value above the 99th percentile 
URL, together with the evidence of myocardial ischemia with at least 1 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 2 contiguous leads 

Imaging evidence of a new loss of viable myocardium or new 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 
Stroke and TIA 
Diagnostic Criteria: Acute episode of a focal or global neurological deficit with at least 1 of the following:  

change in the level of consciousness

hemiplegia, hemiparesis 

numbness or sensory loss affecting 1 side of the body 

dysphasia or aphasia 

hemianopia 

amaurosis fugax 

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1.
other neurological signs or symptoms consistent with stroke 
Stroke: duration of a focal or global neurological deficit ı24 h; OR <24 h if available neuroimaging documents a new 
hemorrhage or infarct; OR the neurological deficit results in death 
TIA: duration of a focal or global neurological deficit <24 h, any variable neuroimaging does not demonstrate a new 
hemorrhage or infarct 
2) No other readily identifiable non-stroke cause for the clinical presentation (e.g. brain tumor, trauma, infection, 
hypoglycemia, peripheral lesion, pharmacological influences), to be determined by or in conjunction with the designated 
neurologist 
3) Confirmation of the diagnosis by at least 1 of the following: 
ͻ
Neurologist or neurosurgical specialist, OR 
ͻ
Neuroimaging procedure (CT scan or brain MRI), but stroke may be diagnosed on clinical grounds alone 
Stroke Definitions 
Disabling stroke: mRS of 2 or more at 90 days and an increase in at least 1 mRS category from an individual’s pre-stroke 
baseline 
Non-disabling stroke: mRS of <2 at 90 days or one that does not result in an increase in at least 1 mRS category from an 
individual’s pre-stroke baseline 
Stroke Classifications
Ischemic: an acute episode of focal cerebral, spinal, or retinal dysfunction caused by infarction of the central nervous system 
tissue 
Hemorrhagic: an acute episode of focal or global cerebral or spinal dysfunction caused by intraparenchymal, intraventricular, or 
subarachnoid hemorrhage 
Undetermined: insufficient information to allow categorization as ischemic or hemorrhagic 
Bleeding Complications 
Life-threatening or disabling bleeding: Fatal bleeding (BARC type 5) OR, bleeding in a critical organ, such as intracranial, 
intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC 
type 3b and 3c) OR, bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or surgery (BARC type 
3b) OR, oǀĞƌƚƐŽƵƌĐĞŽĨďůĞĞĚŝŶŐǁŝƚŚĚƌŽƉŝŶŚĞŵŽŐůŽďŝŶшϱŐͬĚ>ŽƌǁŚŽůĞďůŽŽĚŽƌƉĂĐŬĞĚƌĞĚďůŽŽĚĐĞůůƐ;ZƐͿƚƌĂŶƐĨƵƐŝŽŶ
шϰƵŶŝƚƐ10 (BARC type 3b)88 
Major Bleeding: Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0 g/dL or requiring 
transfusion of 2 or 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: Any bleeding worthy of clinical mention (eg, access site hematoma) that does not qualify as life-threatening, 
disabling, or major. 
Acute Kidney Injury (up to 7 days post procedure) 
Stage 1: Increase in serum creatinine to 150%-199% (1.5-1.99 x increase compared with baseline) OR, ŝŶĐƌĞĂƐĞŽĨшϬ͘ϯŵŐͬĚ>
;шϮϲ͘ϰŵŵŽůͬ>ͿOR, Urine output <0.5 mL/kg/h for >6 but <12 h 
Stage 2: Increase in serum creatinine to 200%-299% (2.0%-2.99% increase compared with baseline) OR, Urine output <0.5 
mL/kg/h for >12 but <24 h 
Stage 3: /ŶĐƌĞĂƐĞŝŶƐĞƌƵŵĐƌĞĂƚŝŶŝŶĞƚŽшϯϬϬй;хϯǆŝŶĐƌĞĂƐĞĐŽŵƉĂƌĞĚǁŝƚŚďĂƐĞůŝŶĞͿOR, ƐĞƌƵŵĐƌĞĂƚŝŶŝŶĞŽĨшϰ͘ϬŵŐͬĚ>
;шϯϱϰŵŵŽůͬ>ͿǁŝƚŚĂŶĂĐƵƚĞŝŶĐƌĞĂƐĞŽĨĂƚůĞĂƐƚϬ͘ϱŵŐͬĚ>;ϰϰŵŵŽůͬ>ͿOR, uƌŝŶĞŽƵƚƉƵƚфϬ͘ϯŵůͬŬŐͬŚĨŽƌшϮϰŚOR, anuria for 
шϭϮŚ 
 
Given one unit of packed RBC typically will raise hemoglobin concentration by 1 g/dL, an estimated decrease in hemoglobin will be 
calculated.  A bleeding complication has to be the result of overt bleeding and cannot be adjudicated based on blood transfusions alone.

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Vascular Access Site and Access Related Complications 
Major vascular complication:  
1)
Any aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new apical aneurysm/pseudoaneurysm OR, 
2)
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, 
3)
Distal embolization (noncerebral) from a vascular source requiring surgery or resulting in amputation or irreversible end-organ damage 
OR, 
4)
Use of unplanned endovascular or surgical intervention associated with death, major bleeding, visceral ischemia or neurological 
impairment OR, 
5)
Any new ipsilateral lower extremity ischemia documented by patient symptoms, physical exam, and/or decreased or absent blood flow 
on lower extremity angiogram OR, 
6)
Surgery for access site-related nerve injury OR, 
7)
Permanent access-site related nerve injury 
Minor vascular complication 
1)
Access site or access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula, pseudoaneurysms, 
hematomas, percutaneous closure device failure) not leading to death, life-threatening or major bleeding11, visceral ischemia, or 
neurological impairment OR, 
2)
Distal embolization treated with embolectomy and/or thrombectomy and not resulting in amputation or irreversible end-organ damage 
OR, 
3)
Any unplanned endovascular stenting or unplanned surgical intervention not meeting the criteria for a major vascular complication OR, 
4)
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) 
Valve Dysfunction Requiring Repeat Procedure: Any valve dysfunction that requires repeat procedure (e.g. balloon 
valvuloplasty, TAVR, snare repositioning, placement of vascular plug paravalvular leak, or surgical AVR) 
 
11 Refer to bleeding definitions 

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13.8.2 Other TAVR Related Complications63 
Conversion to open surgery:  Conversion to open sternotomy during the TAVR procedure secondary to any procedure-related 
complications. 
Unplanned use of cardiopulmonary bypass: Unplanned use of CPB for hemodynamic support at any time during the TAVI 
procedure. 
Coronary artery obstruction: Angiographic or echocardiographic evidence of a new, partial or complete, obstruction of a 
coronary ostium, either by the TAV prosthesis itself, the native leaflets, calcifications, or dissection, occurring during or after the 
TAVR procedure. 
Ventricular septal perforation: Angiographic or echocardiographic evidence of a new septal perforation during or after the 
TAVR procedure  
Mitral valve apparatus damage or dysfunction: Angiographic or echocardiographic evidence of new damage (chordae, 
papillary muscle, or leaflet) to the mitral valve apparatus or dysfunction (e.g. restrictions due to the TAV of the mitral valve 
during or after the TAVR procedure. 
Cardiac tamponade: Evidence of new pericardial effusion associated with hemodynamic instability and clearly related to the 
TAVI procedure. 
Prosthetic valve thrombosis: 
1.  Clinical: 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 which is associated with any of the following clinical 
sequelae: 
x
Thromboembolic complications including 
R
Any ischemic stroke 
R
Any peripheral embolic event 
R
ST segment elevation or Non-ST elevation myocardial infarction 
R
Hemodynamic impairment associated with a worsening of heart failure 
Note: 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 be reported as valve thrombosis  
2.  Sub-Clinical: Any thrombus not caused by infection attached to or near the trial valve that occludes part of the blood flow 
path or interferes with valve function, without evident clinical sequelae, causing a hemodynamic impediment meeting the 
following criteria: 
x
Increase in aortic regurgitation to moderate to severe. 
x
An increase by more than 50% of discharge mean aortic valve gradient (with the post discharge mean gradient being 
> 20 mmHg) or a decrease in the Doppler Velocity Index (DVI) by more than 50% 
Valve migration: After initial correct positioning, any observed movement (upward or downward) of the TAV within the aortic 
annulus from its initial position, with or without consequences. 
Valve embolization: The TAV moves during or after deployment such that it loses contact within the aortic annulus. 
Ectopic valve deployment:  Permanent deployment of the TAV in a location other than the aortic root. 
TAV in TAV deployment: Additional valve prosthesis is implanted within a previously implanted TAV because of sub-optimal 
device position and/or function, during or after the index procedure. 
Hemolysis: Red cell destruction confirmed by lab data; Minor hemolysis: No intervention required; Major hemolysis: Requires 
intervention (e.g. iron supplements, transfusion, invasive intervention). 
 

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Prosthetic Valve Endocarditis:  Any of the following; 
1)
Fulfillment of the following Duke criteria for definite endocarditis:  
x
Histologic and/or microbiologic evidence of infection at surgery or autopsy, or 
x
2 major criteria, or 
x
1 major criteria or 3 minor criteria, or  
x
5 minor criteria 
Major Criteria: 
x
Blood cultures positive for Infective Endocarditis (IE) 

Typical microorganisms consistent with IE isolated from two separate blood cultures, as noted below 
x Viridans streptococci, Streptococcus bovis, Staphylcoccus aureus, or HACEK group 
x Community-acquired enterococci in the presence of a primary focus 

Microorganisms consistent with IE isolated from persistently positive blood cultures defined as: 
x At least two positive cultures or blood samples obtained >12 hours apart, or 
x All of three, or a majority of four or more separate cultures of blood, the first and last sample obtained > 
one hour apart 

Single blood culture positive for Coxiella burnetti or an antiphase I IG antibody titer >1:800 
x
Evidence of endocardial involvement 

Positive results of echocardiography for IE defined as: 
x Oscillating intracardiac mass on a valve or supporting structures in the path of regurgitant jets or on 
implanted material in the absence of an anatomic explanation, or 
x Abscess, or 
x New partial dehiscence of a valvular prosthesis 

New valvular regurgitation (worsening or changing or pre-existing murmur not sufficient) 
Minor Criteria: 
 
x
Predisposition: predisposing heart condition or intravenous drug use 
x
Fever:  temperature >38මC 
x
Vascular phenomena: major arterial emboli, septic pulmonary infarcts, mycotic aneurysm, intracranial 
hemorrhage, conjunctival hemorrhages, and Janeway’s lesions 
x
Immunological phenomena: glomerulonephritis, Osler’s nodes, Roth’s spots, and rheumatoid factor 
x
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 infectious endocarditis. 
x
Echocardiographic findings: consistent with IE but do not meet a major criterion as noted above 
If only 1 major and 1-2 minor criteria are fulfilled, or if only 3-4 minor criteria are fulfilled, the event will be coded as 
“possible endocarditis” 
2)
Evidence of abscess, paravalvular leak, pus, or vegetation confirmed as secondary to infection by histological or 
bacteriological studies during a re-operation 
3)
Findings of abscess, pus, or vegetation involving the TAV or surgical bioprosthesis at autopsy 
 

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13.8.3 Efficacy Endpoints 
Cardiovascular Hospitalization: includes hospitalizations for heart failure, unstable angina, myocardial 
infarction, cardiogenic shock, conduction disturbances and arrythmias, or other hospitalizations directly 
related to complications of the implant procedure or device (Figure 22), defined as follows; 
Heart Failure89 
A hospitalization that meets all of the following criteria: 
1.
The patient is admitted to the hospital with a primary diagnosis of heart failure (HF) 
2.
The patient’s length of stay extends for at least 24 hours (or a change in calendar date if hospital admission and discharge 
times are unavailable) 
3.
The patient exhibits documented new or worsening symptoms due to HF on presentation, including at least one of the 
following: 

Dyspnea 

Decreased exercise tolerance 

Fatigue 

Other symptoms of worsened end-organ perfusion (decreased blood supply to the vital organs (kidney, liver, lungs, 
heart, and brain)) or volume overload (excessive accumulation of intravascular fluid resulting from compromised 
regulatory mechanisms) 
4.
The patient has evidence of new or worsening HF, consisting of at least two physical examination findings or one physical 
examination finding and at least one laboratory criterion, including: 

Physical Examination findings, including new or worsening: 
-
Peripheral edema 
-
Increasing abdominal distention or ascites (in the absence of primary hepatic disease) 
-
Pulmonary rales/crackles/crepitations 
-
Increased jugular venous pressure and/or hepatojugular reflux 
-
S3 gallop 
-
Clinically significant or rapid weight gain thought to be related to fluid retention 

Laboratory evidence of new or worsening HF, if obtained within 24 hours of presentation, including: 
-
Increased B-type natriuretic peptide (BNP) / N-terminal pro-BNP (NT-proBNP) concentrations consistent with 
decompensation of heart failure (such as BNP > 500 pg/mL or NT-proBNP > 2,000 pg/mL).  In patients with 
chronically elevated natriuretic peptides, a significant increase should be noted above baseline. 
-
Radiological evidence of pulmonary congestion 
-
Non-invasive diagnostic evidence of clinically significant elevated left- or right-sided ventricular filling pressure or 
low cardiac output.  For example, echocardiographic criteria could include:  septal or lateral E/e’ > 15 or > 12, 
respectively;  D-dominant pulmonary venous inflow pattern; plethoric inferior vena cava with minimal collapse 
on inspiration; or decreased left ventricular outflow tract (LVOT) minute stroke distance (time velocity integral 
[TVI]), OR 
-
Invasive diagnostic evidence with right heart catheterization showing a pulmonary capillary wedge pressure 
(pulmonary artery occlusion pressure) > 18 mmHg, central venous pressure > 12 mmHg, or a cardiac index < 2.2 
L/min/m2 
5.
The patient receives at least one of the following treatments specifically for HF: 

Significant augmentation in oral diuretic therapy (e.g., doubling of loop diuretic dose, initiation of maintenance loop 
diuretic therapy, initiation of combination diuretic therapy)  

Combination diuretic therapy could include a thiazide-type diuretic (e.g. hydrochlorothiazide, metolazone, 
chlorothiazide) plus a loop diuretic, or mineral-corticoid receptor antagonist (MRA) (e.g., spironolactone or 
eplerenone) plus a loop diuretic. 

Initiation of intravenous diuretic (even a single dose) or vasoactive agent (e.g., inotrope, vasopressor, vasodilator)  

Mechanical or surgical intervention, including: 
-
Mechanical circulatory support (e.g., intra-aortic balloon pump, ventricular assist device, extracorporeal 
membrane oxygenation, total artificial heart) 
-
Mechanical fluid removal (e.g. ultrafiltration, hemofiltration, dialysis) 
 
 

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Unstable Angina89 
1.
Ischemic discomfort (angina, or symptoms thought to be equivalent) > 10 minutes in duration occurring at rest, or in an 
accelerating pattern with frequent episodes associated with progressively decreased exercise capacity, AND 
2.
Prompting an unscheduled hospitalization within 24 hours of the most recent symptoms.  Hospitalization is defined as an 
admission to an inpatient unit or a visit to an emergency department that results in at least a 24 hour stay (or a change in 
calendar date if the hospital admission or discharge times are not available), AND 
3.
At least one of the following: 
x
New or worsening ST or T wave changes on resting ECG (in absence of confounders, such as LBBB or LVH) 
-
Transient ST elevation (duration < 20 minutes) 
-
New ST elevation at the J point in two contiguous leads with the cut-points:   
-
0.1 mV in all leads other than leads V2-V3 where the following cut-points apply:  > 0.2 mV in men > 40 years (> 
0.25 mV in men < 40 years) or > 0.15 mV in women.  
-
ST depression and T-wave changes 
-
New horizontal or down-sloping ST depression > 0.05 mV in two contiguous leads and/or new T-wave inversion > 
0.3 mV in two contiguous leads with prominent R wave or R/S ratio > 1. 
x
Definite evidence of inducible myocardial ischemia as demonstrated by:  
-
an early positive exercise stress test, defined as ST elevation or > 2 mm ST depression prior to 5 mets, OR  
-
stress echocardiography (reversible wall motion abnormality) OR, 
-
myocardial scintigraphy (reversible perfusion defect), OR 
-
MRI (myocardial perfusion deficit under pharmacologic stress) AND believed to be responsible for the myocardial 
ischemic symptoms/signs. 
x
Angiographic evidence of new or worse > 70% lesion (> 50% for left main lesion) and/or thrombus in an epicardial 
coronary artery that is believed to be responsible for the myocardial ischemic symptoms/signs. 
x
Need for coronary revascularization procedure (PCI or CABG) for the presumed culprit lesion(s).  This criterion would 
be fulfilled if revascularization was undertaken during the unscheduled hospitalization, or subsequent to transfer to 
another institution without interceding home discharge AND,  
4.
Negative cardiac biomarkers and no evidence of acute MI  
General Considerations 
ƐĐĂůĂƚŝŽŶŽĨƉŚĂƌŵĂĐŽƚŚĞƌĂƉǇĨŽƌŝƐĐŚĞŵŝĂ͕ƐƵĐŚĂƐ/sŶŝƚƌĂƚĞƐŽƌŝŶĐƌĞĂƐŝŶŐĚŽƐĂŐĞƐŽĨɴ-blockers, should be considered 
supportive but not diagnostic of unstable angina.  However, a typical presentation and admission to the hospital with escalation 
of pharmacotherapy, without any of the additional findings listed under category 3, would be insufficient to support 
classification as hospitalization for unstable angina. 
If subjects are admitted with suspected unstable angina, and subsequent testing reveals a non-cardiac or non-ischemic etiology, 
this event should not be recorded as hospitalization for unstable angina.  Potential ischemic events meeting the criteria for MI 
should not be adjudicated as unstable angina. 
Planned hospitalization or rehospitalization for performance of an elective revascularization in patients who do not fulfill the 
criteria for unstable angina should not be considered a hospitalization for unstable angina.  For example,  

Hospitalization of a patient with stable exertional angina for coronary angiography and PCI that is prompted by a positive 
outpatient stress test should not be considered hospitalization for unstable angina. 

Rehospitalization of a patient meeting the criteria for unstable angina who was stabilized, discharged, and subsequently 
readmitted for revascularization, does not constitute a second hospitalization for unstable angina. 

A patient who undergoes an elective catheterization where incidental coronary artery disease is found and who 
subsequently undergoes coronary revascularization will not be considered as meeting the hospitalization for unstable 
angina endpoint. 
Myocardial Infarction89 
Hospitalization for primary diagnosis of myocardial infarction (MI); includes peri-procedural or spontaneous MI as defined in 
Section 13.8.1. 

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Cardiogenic Shock89 
Sustained (>30 min) episode of hypoperfusion evidenced by systolic blood pressure <90 mm Hg and/or, if available, cardiac 
index <2.2 L/min per square meter determined to be secondary to cardiac dysfunction and/or the requirement for parenteral 
inotropic or vasopressor agents or mechanical support (e.g., IABP, extracorporeal circulation, VADs) to maintain blood pressure 
and cardiac index above those specified levels.  
Note: Transient episodes of hypotension reversed with IV fluid or atropine do not constitute cardiogenic shock. The 
hemodynamic compromise (with or without extraordinary supportive therapy) must persist for at least 30 min. 
Conduction Disturbances and Arrhythmias89 
Hospitalization for new or worsening of any of the following new or worsening conduction disturbances or arrhythmias: 
x
First-degree atrioventricular (AV) block 
x
Second-degree AV block (Mobitz I or Mobitz II) 
x
Third-degree AV block 
x
Incomplete right bundle branch block 
x
Right bundle branch block 
x
Intraventricular conduction delay 
x
Left bundle branch block 
x
Left anterior or posterior fascicular block 
x
Atrial fibrillation (or flutter), defined as any arrhythmia within hospitalization that has the ECG characteristics of atrial 
fibrillation (or flutter) and lasts sufficiently long to be recorded on a 12-lead ECG or at least 30 seconds on a rhythm strip 
Other Procedural or Device Related 
Includes any other hospitalization where the primary cause was directly related to complications of the implant procedure or 
device.  
 
 
Figure 22.  Diagram of categorization of hospitalizations. 
 

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Heart Failure Events89: Includes hospitalization for heart failure (per previous definition) AND urgent 
outpatient visits, defined as an event that meets all of the following criteria: 
1) The patient has an urgent, unscheduled office/practice or emergency department visit for a primary diagnosis of HF, but 
does not meet the criteria for a HF hospitalization 
2) The patient exhibits documented new or worsening symptoms due to HF on presentation, including at least one of the 
following: 
ͻ
Dyspnea 
ͻ
Decreased exercise tolerance 
ͻ
Fatigue 
ͻ
Other symptoms of worsened end-organ perfusion (decreased blood supply to the vital organs (kidney, liver, lungs, 
heart, and brain)) or volume overload (excessive accumulation of intravascular fluid resulting from compromised 
regulatory mechanisms) 
3) The patient has evidence of new or worsening HF, consisting of at least two physical examination findings or one physical 
examination finding and at least one laboratory criterion, including: 

Physical Examination findings, including new or worsening: 
-
Peripheral edema 
-
Increasing abdominal distention or ascites (in the absence of primary hepatic disease) 
-
Pulmonary rales/crackles/crepitations 
-
Increased jugular venous pressure and/or hepatojugular reflux 
-
S3 gallop 
-
Clinically significant or rapid weight gain thought to be related to fluid retention 
ͻ
Laboratory evidence of new or worsening HF, if obtained within 24 hours of presentation, including: 
-
Increased B-type natriuretic peptide (BNP) / N-terminal pro-BNP (NT-proBNP) concentrations consistent with 
decompensation of heart failure (such as BNP > 500 pg/mL or NT-proBNP > 2,000 pg/mL).  In patients with 
chronically elevated natriuretic peptides, a significant increase should be noted above baseline. 
-
Radiological evidence of pulmonary congestion 
-
Non-invasive diagnostic evidence of clinically significant elevated left- or right-sided ventricular filling pressure or 
low cardiac output.  For example, echocardiographic criteria could include:  septal or lateral E/e’ > 15 or > 12, 
respectively; D-dominant pulmonary venous inflow pattern; plethoric inferior vena cava with minimal collapse 
on inspiration; or decreased left ventricular outflow tract (LVOT) minute stroke distance (time velocity integral 
[TVI]) 
OR 
ͻ
Invasive diagnostic evidence with right heart catheterization showing a pulmonary capillary wedge pressure 
(pulmonary artery occlusion pressure) > 18 mmHg, central venous pressure > 12 mmHg, or a cardiac index < 2.2 
L/min/m2 
4) The patient receives at least one of the following treatments specifically for HF: 
ͻ
Initiation of intravenous diuretic or vasoactive agent (e.g. inotrope, vasopressor, or vasodilator) 
Note that signification augmentation of oral diuretic therapy will not be sufficient to fulfill the urgent HF visit criteria 
ͻ
Mechanical or surgical intervention, including: 
-
Mechanical circulatory support (e.g. intra-aortic balloon pump, ventricular assist device, extracorporeal 
membrane oxygenation, total artificial heart) 
-
Mechanical fluid removal (e.g. ultrafiltration, hemofiltration, dialysis 
Note that clinic visits for scheduled administration of HF therapies or procedures (e.g. intravenous diuretics, intravenous 
vasoactive agents, or mechanical fluid removal) do not qualify as non-hospitalized HF events.

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Device Success63 
All of the following: 

Absence of procedural mortality, AND 

Correct positioning of a single prosthetic heart valve into the proper anatomical location, AND 

Absence of patient prosthesis-mismatch and mean aortic valve gradient < 20 mmHg (or peak velocity < 3 m/sec), AND 

Absence of moderate or severe prosthetic valve regurgitation. 
Bioprosthetic Valve Dysfunction (BVD)63: Any of the following 

Stenosis: moderate/severe; any of the following: 
-
Peak aortic velocity > 4 m/s OR mean aortic gradient > 40 mmHg, AND EOA < 0.8 cm2 
-
Peak aortic velocity > 4 m/s OR mean aortic gradient > 40 mmHg, AND EOA ш 0.8 cm2, AND DVI < 0.25 
-
Peak aortic velocity ч 4 m/s and mean aortic gradient ч 40 mmHg, AND EOA < 0.8 cm2, AND DVI < 0.25 

Paravalvular regurgitation: moderate 

Paravalvular regurgitation: severe 

Transvalvular regurgitation: moderate 

Transvalvular regurgitation: severe 

Total regurgitation: moderate 

Total regurgitation: severe 
Notes: 
 
1.
For subjects with BSA < 1.6 m2, the EOA criteria for significant (moderate or severe) stenosis is < 0.6 cm2 
2.
For subjects with LVOT diameter > 2.5 cm, the DVI criteria for significant (moderate or severe) stenosis is < 0.2 
3.
Reporting of prosthetic valve dysfunction will be based on core lab results. 
4.
Bioprosthetic valve dysfunction events are not reported as adverse events, unless the dysfunction is accompanied with 
clinical sequelae at the time of event detection, and the clinical sequelae are chronologically and physiologically associated 
with the dysfunction.  However, prosthetic dysfunctions that are associated with adverse events, and that meet the 
definition of a serious adverse event, should be reported as such. 
Patient-Prosthesis Mismatch (PPM) 63 
For subjects with BMI < 30 kg/cm2 
x
Moderate PPM: EOAI = 0.85 – 0.65 
x
Severe PPM: EOAI < 0.65 
For subjects with BMI ш 30 kg/cm2 
x
Moderate PPM12: EOAI = 0.70 – 0.60 
x
Severe PPM: EOAI < 0.60 
Bioprosthetic Valve Failure (BVF) 90: Any of the following:
x
Autopsy findings of bioprosthetic valve dysfunction, likely related to the cause of death, or valve-related death (i.e. any 
death caused by bioprosthetic valve dysfunction or sudden unexplained death following diagnosis of bioprosthetic valve 
dysfunction) 
x
Repeat intervention (i.e. valve-in-valve TAVI, paravalvular leak closure or SAVR following confirmed diagnosis of 
bioprosthetic valve dysfunction) 
x
Severe bioprosthetic valve dysfunction 
12 Original VARC-2 definition lists 0.90-0.60 as moderate PPM range, this definition has been updated to reflect corrected range of 0.70-0.60 for 
moderate PPM 

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13.8.4 Classification of Causal Relationships
The following definitions are intended as guidelines for classifying causal relationships between the 
event and the TAV, the catheter delivery system, the loading system, and the TAVR implant procedure. 
Causal relationships between event and the TAV 
Not related to the TAV 
The relationship to TAV can be excluded when: 
x
the event is not a known side effect of the TAV or product category the device belongs to 
or of similar devices; 
x
The event has no temporal relationship with the TAV 
x
The event does not follow a known response pattern to the TAV and is biologically 
implausible;  
x
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at the same 
time. 
Unlikely to be related to the 
TAV 
The relationship with the TAV seems not relevant and/or the event can be reasonably explained 
by another cause, but additional information may be obtained. 
Possibly related to the TAV 
The relationship with the TAV is weak but cannot be ruled out completely. Alternative causes 
are also possible (e.g. an underlying or concurrent illness/ clinical condition or/and an effect of 
another device, drug or treatment).  Cases were relatedness cannot be assessed or no 
information has been obtained should also be classified as possible. 
Probably related to the TAV 
The relationship with TAV seems relevant and/or the event cannot reasonably be explained by 
another cause, but additional information may be obtained. 
Causal relationship 
“Related” to the TAV 
The event is associated with the TAV beyond reasonable doubt when:  
x
the event is a known side effect of the TAV or product category the device belongs to or of 
similar devices; 
x
the event has a temporal relationship with investigational device use/application or 
procedures; 
x
the event involves a body-site or organ that  
-
the TAV is applied to;  
-
the TAV of has an effect on; 
x
the event follows a known response pattern to the TAV; 
x
other possible causes (eg an underlying or concurrent illness/clinical condition or an effect 
of another device, drug, or treatment) have been adequately ruled out 
x
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the same time. 
Timeframe for assessing implant procedure relationships begin when subject is being prepared for the TAVR or implant (or re-implant) 
procedure. 
 

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Causal relationships between event and the TAVR delivery system 
Not related to the TAVR 
delivery system 
The relationship with the TAVR delivery system can be excluded when:  
x
the event is not a known side effect of the TAVR delivery system product category the 
device belongs to or of similar devices; 
x
The event has no temporal relationship with the use of the TAVR delivery system 
x
The event does not follow a known response pattern to the TAVR delivery system and is 
biologically implausible;  
x
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at the same 
time 
Unlikely to be related to the 
TAVR delivery system 
The relationship with the TAVR delivery system seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
Possibly related to the TAVR 
delivery system 
The relationship with the TAVR delivery system is weak but cannot be ruled out completely. 
Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment). Cases were relatedness cannot be 
assessed or no information has been obtained should also be classified as possible. 
Probably related to the 
TAVR delivery system 
The relationship with the TAVR delivery system seems relevant and/or the event cannot be 
reasonably explained by another cause, but additional information may be obtained. 
Causal relationship 
“Related” to the TAVR 
delivery system 
The event is associated with the TAVR delivery system reasonable beyond doubt when: 
x
the event is a known side effect of the product category the device belongs to or of similar 
devices; 
x
the event has a temporal relationship with the TAVR delivery system use/application; 
x
the event involves a body-site or organ that  
-
the TAVR delivery system is applied to;  
-
the TAVR delivery system has an effect on; 
x
the event follows a known response pattern to the TAVR delivery system; 
x
other possible causes (eg an underlying or concurrent illness/clinical condition or an effect 
of another device, drug, or treatment) have been adequately ruled out 
x
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the same time. 
 

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Causal relationships between event and the loading system 
Not related to the loading 
system 
The relationship with the loading system can be excluded when:  
x
the event is not a known side effect of the loading system product category the device 
belongs to or of similar devices; 
x
The event has no temporal relationship with the use of the loading system 
x
The event does not follow a known response pattern to the loading system and is 
biologically implausible;  
x
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at the same 
time 
Unlikely to be related to the 
loading system 
The relationship with the system seems not relevant and/or the event can be reasonably 
explained by another cause, but additional information may be obtained. 
Possibly related to the 
loading system 
The relationship with the loading system is weak but cannot be ruled out completely. 
Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment). Cases were relatedness cannot be 
assessed or no information has been obtained should also be classified as possible. 
Probably related to the 
loading system 
The relationship with the loading system seems relevant and/or the event cannot be reasonably 
explained by another cause, but additional information may be obtained. 
Causal relationship 
“Related” to the loading 
system 
The event is associated with the loading system reasonable beyond doubt when: 
x
the event is a known side effect of the product category the device belongs to or of similar 
devices; 
x
the event has a temporal relationship with the Loading system use/application; 
x
the event involves a body-site or organ that  
-
the Loading system is applied to;  
-
the Loading system has an effect on; 
x
the event follows a known response pattern to the Loading system; 
x
other possible causes (eg an underlying or concurrent illness/clinical condition or an effect 
of another device, drug, or treatment) have been adequately ruled out 
x
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the same time. 
 

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Causal relationships between event and the TAVR implant procedure 
Not related to the TAVR 
implant procedure 
The relationship with the TAVR or SAVR implant procedure can be excluded when:  
x
the event is not a known side effect of the TAV implant procedure; 
x
The event has no temporal relationship with the TAVR implant relationship 
x
The event does not follow a known response pattern to the TAVR implant procedure and is 
biologically implausible;  
x
The event involves a body-site or an organ not expected 
In order to establish non-relatedness, not all the criteria listed above might be met at the same 
time. 
Unlikely to be related to the 
TAVR implant procedure 
The relationship with the TAVR implant procedure seems not relevant and/or the event can be 
reasonably explained by another cause, but additional information may be obtained. 
Possibly related to the TAVR 
implant procedure 
The relationship with the TAVR implant procedure is weak but cannot be ruled out completely.  
Alternative causes are also possible (e.g. an underlying or concurrent illness/ clinical condition 
or/and an effect of another device, drug or treatment). Cases were relatedness cannot be 
assessed or no information has been obtained should also be classified as possible. 
Probably related to the 
TAVR implant procedure 
The relationship with TAVR implant procedure seems relevant and/or the event cannot be 
reasonably explained by another cause, but additional information may be obtained. 
Causal relationship 
“Related” to the TAVR 
implant procedure 
The event is associated with the TAVR implant procedure beyond reasonable doubt when:  
x
the event is a known side effect of the TAVR implant procedure; 
x
the event has a temporal relationship with the TAVR implant procedure; 
x
the event involves a body-site or organ that  
-
the TAVR is applied to;  
-
the TAVR implant procedure has an effect on; 
x
the event follows a known response pattern to the TAVR implant procedure; 
x
other possible causes (eg an underlying or concurrent illness/clinical condition or an effect 
of another device, drug, or treatment) have been adequately ruled out 
x
harm to the subject is due to error in use 
In order to establish relatedness, not all the criteria listed above might be met at the same time. 
Note: 
Procedure related events refers to the procedure related to the initial application of the investigational medical device only and therefore not 
to any other procedures or treatments applied later throughout the clinical investigation, for instance to treat (serious) adverse events. 
 
 

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 9HUVLRQ+LVWRU\
Version 
Summary of changes
Justification of 
changes 
Potential impact 
of the change on 
performance, 
effectiveness, or 
safety or other 
endpoints 
Identification of 
the affected 
study 
documents 
Author(s)/Title
Revision 
A 
Not Applicable, New 
Document 
Not Applicable, 
New Document 
Not Applicable, 
New Document 
Not Applicable, 
New Document 
Charles Boldt 
Sr Clinical Program Mgr 
Maggie Haltvick 
Sr Clinical Research 
Specialist 
Leah Crocker 
Clinical Research 
Specialist 
Hang Nguyen 
Sr Clinical Research Mgr 
Bibi Waterval 
Associate Clinical 
Research Specialist  
Revision 
B 
Study name change to 
“Evolut™ EXPAND 
TAVR I Feasibility 
Study” (was 
previously Evolut™ 
System EXPAND I 
Feasibility Study).  
Administrative change 
only 
N/A - 
Administrative 
Change only 
N/A - 
Administrative 
Change only 
Study name 
change to be 
updated in 
affected study 
documents, as 
applicable 
Charles Boldt 
Sr Clinical Program Mgr 
Maggie Haltvick 
Sr Clinical Research 
Specialist 
Leah Crocker 
Clinical Research 
Specialist 
Hang Nguyen 
Sr Clinical Research Mgr 
Bibi Waterval 
Associate Clinical 
Research Specialist  

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Form 
D00266108 
Revision  D 
Page 125 of 135 
This document is electronically controlled Medtronic Business Restricted   056-F275, vC Clinical Investigation Plan Template 
Version 
Summary of changes 
Justification of 
changes 
Potential impact 
of the change on 
performance, 
effectiveness, or 
safety or other 
endpoints 
Identification of 
the affected 
study 
documents 
Author(s)/Title 
Revision 
C 
Study follow-up 
period extended 
through 5 years, and 
total study duration 
extended to 7 years 
 
Inclusion criteria #5 
added to Cohort B to 
align with Cohort A 
inclusion criteria 
(anatomical suitability 
for transfemoral 
TAVR) 
 
Additional clarifying 
language regarding 
procedures for 
subjects lost to 
follow-up  added to 
section 6.11 
 
Removed 
requirement for CEC 
to adjudicate 
additional outcome 
measures from 
section 7.7 
 
Clarified procedures 
for collecting calcium 
volume 
measurements in 
section 13.1 
 
Removed 
requirement to 
document in eCRF 
whether shoes were 
on or off for height 
and weight 
measurements 
throughout 
 
Clerical changes 
throughout 
Study duration 
updated based on 
FDA feedback 
 
Additional changes 
made to ensure 
alignment 
throughout the CIP 
and correction of 
clerical issues 
Endpoints updated 
to reflect 5 year 
follow up 
Updates to be 
reflected in 
applicable study 
documents 
Charles Boldt 
Sr Clinical Program Mgr 
Maggie Haltvick 
Sr Clinical Research 
Specialist 
Leah Crocker 
Clinical Research 
Specialist 
Hang Nguyen 
Sr Clinical Research Mgr 
Bibi Waterval 
Associate Clinical 
Research Specialist 

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D00266108 
Revision  D 
Page 126 of 135 
This document is electronically controlled Medtronic Business Restricted   056-F275, vC Clinical Investigation Plan Template 
Revision 
D 
Entire document 
updated throughout 
to reflect removal of 
Cohort A (Moderate 
Symptomatic AS) 
 
Sections 4.2.3 and 
10.6: Clarified that 
incidence of PPM will 
also be evaluated 
annually through 5 
years 
 
Section 5.3: Added 
clarification on plan 
for the retention and 
reporting of 
traditionally 
underrepresented  
populations in this 
study 
 
Sections 5.4, 5.5.2, 
and 6.20 Removal of 
Heart Failure 
Specialist Role (note 
that section 5.5.4 was 
removed entirely due 
to this change) 
 
Section 5.9: Noted 
confirmation of AS 
will be made per 
relevant 
inclusion/exclusion 
criteria 
 
Section 6.2.1: Added 
inclusion criteria #6 
“The subject and 
treating physician 
agree the subject will 
return for all required 
follow-up visits” 
 
Section 6.7: Clarified 
that subjects who 
have their TAV 
explanted will be 
followed for 30 days 
post explant, or 
through resolution of 
related adverse 
events, whichever is 
Removal of Cohort 
A (Moderate 
Symptomatic AS) 
agreed upon with 
internal 
stakeholders and 
applicable 
regulatory bodies 
 
Sections 4.2.3 and 
10.6: Clarified that 
incidence of PPM 
will also be 
evaluated annual 
through 5 years, to 
align with all 
additional outcome 
measures 
 
Section 5.3: 
Language added 
clarifying retention 
and reporting of 
traditionally 
underrepresented 
patient populations 
based on CMS 
feedback  
 
Sections 5.4, 5.5.2, 
and 6.20 Removal 
of Heart Failure 
Specialist Role, as 
this role is not 
required following 
removal of Cohort A 
(Moderate 
Symptomatic AS) 
 
Section 5.9: 
Clarification 
provided to specify 
the criteria ERC will 
use to confirm AS 
diagnosis 
 
Section 6.2.1: 
Added inclusion 
criteria #6 “The 
subject and treating 
physician agree the 
subject will return 
for all required 
follow-up visits” to 
align inclusion 
Removal of Cohort 
A: No negative 
impact on 
performance.  
Data will not be 
collected on 
Moderate, 
Symptomatic AS 
subjects to 
support safety, 
efficacy, or other 
endpoints. 
 
Sections 4.2.3 and 
10.6: No negative 
impact on 
performance, 
effectiveness, 
safety, or 
endpoints.  
 
Section 5.3: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints.  
 
Section 5.4, 5.5.2, 
and 6.20 (removal 
of Heart Failure 
Specialist): No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints.  
 
Section 5.9: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints. 
 
Section 6.2.1: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints.  
 
Section 6.7: 
No negative 
impact on 
Updates to be 
reflected in 
applicable study 
documents.   
Charles Boldt 
Sr Clinical Program Mgr 
 
Maggie Haltvick 
Sr Clinical Research 
Specialist 
 
Leah Crocker 
Clinical Research 
Specialist 
 
Hang Nguyen 
Sr Clinical Research Mgr 
 
Bibi Waterval 
Associate Clinical 
Research Specialist 

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Revision  D 
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This document is electronically controlled Medtronic Business Restricted   056-F275, vC Clinical Investigation Plan Template 
longest, then exited 
from the study.   
 
Section 6.9: Added 
entire section to 
clarify when and how 
unscheduled visits 
would occur and how 
data and imaging 
would be entered. 
 
Section 6.16: Clarified 
that up to 30 subjects 
with a positive ETT 
who are approved by 
the ERC may move 
forward in the study  
 
Section 7.1, Table 2: 
Clarified event 
definitions to align 
with  ISO14155:2020. 
Further defined 
additional Australian 
safety definitions for 
SSI and USM 
 
Section 7.4, Tables 4, 
9, and 13: 
Updated to further 
define Australian 
safety reporting 
requirements  
 
Section 7.7: 
Clarification provided 
on CEC membership 
and events 
adjudicated 
 
Section 10.1: 
Clarification provided 
on subgroup analysis 
 
Section 11.1 and 
Table 11: Updated 
EMEA compliance to 
reference applicable 
laws and regulations 
of the countries in 
which the study will 
be conducted.  
Clarified current 
version of Declaration 
criteria between 
both study cohorts. 
 
Section 6.7: 
Following subjects 
who have their TAV 
explanted will be 
followed for 30 post 
explant, or through 
resolution of 
related adverse 
events, whichever 
is longest, will allow 
collection of 
relevant subject AE 
data to ensure 
adequate reporting 
prior to study exit. 
 
Section 6.9: 
Language added 
regarding 
unscheduled visit 
data will provide 
clarity around 
unscheduled visit 
procedures and 
data. 
 
Section 6.16: 
Additional language 
added to clarify 
how subjects with a 
positive ETT may 
move forward in 
the study. 
 
Section 7.1, Table 2 
and Section 7.4 
Tables 4, 9, and 13: 
Alignment with 
ISO14155:2020, 
Australian safety 
reporting 
requirements per 
NHMRC Safety 
monitoring and 
reporting in clinical 
trials involving 
therapeutic goods 
November 2016, 
and internal 
Medtronic 
documentation 
requirements. 
performance, 
effectiveness, 
safety, or 
endpoints. 
 
Section 6.9: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints. 
Unscheduled data 
collected following 
subject adverse 
events may 
provide additional 
clarity around 
endpoint-related 
events. 
 
Section 6.16: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints. 
 
Section 7.1, Table 
2 and Section 7.4, 
Table 4: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints.  
Clarification of 
NHMRC Safety 
monitoring and 
reporting in clinical 
trials involving 
therapeutic goods 
November 2016 
requirements. 
 
Section 7.7: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints 
 
Section 10.1: No 
negative impact on 
performance, 
effectiveness, 

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of Helsinki will be 
followed. 
 
Section 12.8.1, Table 
9: Investigator 
reporting 
requirements 
updated 
 
Section 12.8.2, Table 
13: Australia and New 
Zealand sponsor 
reporting 
requirements 
updated 
 
Section 13.3.5: Added 
language to clarify 
that endpoint and 
event-related 
echocardiograms will 
be sent to the echo 
core lab for 
assessment. 
 
Section 13.8.2: 
Updated definitions 
of Other TAVR 
Related Complications 
(ventricular septal 
perforation and 
prosthetic valve 
thrombosis) 
 
Clerical updates 
completed 
throughout 
document. 
 
 
 
Section 7.7: 
Clarification 
provided on CEC 
membership and 
events adjudicated 
to align with current 
CIP template 
 
Section 10.1: 
Clarification on 
subgroup analysis 
provided to align 
with SAP and define 
subset of endpoints 
to focus. 
 
Section 11.1 and 
Table 11: Updated 
EMEA compliance 
to reference 
applicable laws and 
regulations of the 
countries in which 
the study will be 
conducted, to 
ensure compliance 
with local 
regulations. 
Clarified current 
version of 
Declaration of 
Helsinki will be 
followed. 
 
Section 12.8.1, 
Table 9: Investigator 
reporting 
requirements 
updated to align 
with current 
requirements 
 
Section 12.8.2, 
Table 13: Australia 
and New Zealand 
sponsor reporting 
requirements 
updated to align 
with current 
requirements 
 
Section 13.3.5: 
Language added will 
clarify that the echo 
safety, or 
endpoints 
 
 
Section 11.1 and 
Table 11: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints. Event 
reporting to occur 
per CIP and local 
laws and 
regulations. 
 
Section 12.8.1, 
Table 9: No 
negative impact on 
performance, 
effectiveness,  
safety, or 
endpoints. 
Reporting to occur 
per CIP and local 
laws and 
regulations 
 
Section 12.8.2, 
Table 13: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints. 
Reporting to occur 
per CIP and local 
laws and 
regulations 
 
Section 13.3.5: No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints. Echo 
core lab 
assessment of  
event-related and 
endpoint 
echocardiograms  
may provide 
additional clarity 
around endpoint-
related events. 

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Version 
Summary of changes 
Justification of 
changes 
Potential impact 
of the change on 
performance, 
effectiveness, or 
safety or other 
endpoints 
Identification of 
the affected 
study 
documents 
Author(s)/Title 
core lab will also 
assess endpoint and 
event-related 
echocardiograms. 
 
Section 13.8.2: 
Updated definitions 
of Other TAVR 
Related 
Complications 
(ventricular septal 
perforation and 
prosthetic valve 
thrombosis) for 
alignment with CEC 
charter and code 
list. 
 
Additional clerical 
changes made to 
ensure alignment 
throughout the CIP 
and correction of 
clerical issues  
 
Section 13.8.2; No 
negative impact on 
performance, 
effectiveness, 
safety, or 
endpoints. 
Updated 
definitions of 
ventricular septal 
performance and 
prosthetic valve 
thrombosis will 
align with the CEC 
code list to 
provide 
consistency in 
adjudication of 
these events. 
 
Clerical changes 
throughout have 
no negative impact 
on performance, 
effectiveness, 
safety, or 
endpoints. 
Medtronic approvals are maintained in an electronic document control system. 

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