Retrospective Assessment of the Portico Transcatheter Aortic Valve for Valve-in-Valve Use
Conditions: Aortic Valve Stenosis, Aortic Valve Failure, Aortic Insufficiency, Aortic Stenosis
Sponsor: Abbott Medical Devices

 
 
 
 
 
 
 
 
 
 
 
 
 
Page 1 of 63 
 
Assessment of the PorticoTM Transcatheter Aortic Valve for Valve-in-Valve Use 
 
 
Version Number 
 
 
Date 
03June2021 
 
Planned Number of Sites and 
Region(s) 
 
Study Type 
Multicenter, international, single arm, retrospective, data-
collection study.  
Abbott Medical Expert 
 
 
 
 
 
 
Sponsor 
Abbott  
 
 
 
 
 
Study Monitor 
 
 
 
Electronic Data Capture 
Software 
 
Core Laboratories 
 
 
 
 
CIP Author of Current Version  
  
 
 
 
 
 
 

 
 
 
 
 
 
 
 
Page 2 of 63 
 
 
 
SITE PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
 
 
 
I have read and agree to adhere to the study plan and all regulatory requirements applicable in 
conducting this study. 
 
 
Site Principal Investigator 
 
Printed name: 
Signature: 
Date: 
 
 
 

 
 
 
 
 
 
 
 
Page 3 of 63 
 
Table of Contents 
 
COMPLIANCE STATEMENT:.............................................................................................................. 12 
 
INTRODUCTION .................................................................................................................................. 12 
 
Background and Justification for Study ....................................................................................... 12 
 
Rationale for Conducting this Study ............................................................................................ 14 
 
STUDY OVERVIEW ............................................................................................................................. 14 
 
Study Objective ........................................................................................................................... 14 
 
Exploratory Registry Arm ............................................................................................................ 14 
3.2.1 
Device(s) in this Study Description of the Devices .................................................................. 15 
3.2.2 
Indication for Use ..................................................................................................................... 16 
3.2.4 
Delivery Systems ..................................................................................................................... 17 
 
STUDY DESIGN .................................................................................................................................. 18 
 
Data-Collection Timepoints ......................................................................................................... 18 
 
Additional echocardiogram and data available ........................................................................... 20 
 
Measures Taken to Avoid Bias .................................................................................................... 20 
 
ENDPOINTS ........................................................................................................................................ 20 
 
Primary Safety Endpoint .............................................................................................................. 20 
 
Primary Performance Endpoint ................................................................................................... 20 
 
Descriptive Endpoints .................................................................................................................. 20 
 
SUBJECT SELECTION AND WITHDRAWAL ..................................................................................... 22 
 
Study Population ......................................................................................................................... 22 
 
Subject Recruitment and Screening ............................................................................................ 23 
 
Informed Consent ........................................................................................................................ 23 
 
Informed Consent and Enrollment of the Deceased ................................................................... 24 
 
ELIGIBILITY CRITERIA ....................................................................................................................... 24 
 
Inclusion Criteria .......................................................................................................................... 24 
 
Exclusion Criteria ......................................................................................................................... 25 
Exclusion criteria is from the time of the Portico ViV index procedure: ................................................... 25 
 
Exploratory Registry Arm Inclusion and Exclusion Criteria ......................................................... 25 
 
SUBJECT ENROLLMENT ................................................................................................................... 25 
 
Point of Enrollment ...................................................................................................................... 26 
 
Subject Lost to Follow-up and Withdrawal .................................................................................. 27 
 
Total Expected Study Duration .................................................................................................... 28 
 
DATA COLLECTION AND EVALUATION OF ENDPOINTS ............................................................... 28 
 
Baseline ....................................................................................................................................... 28 
 
Procedure .................................................................................................................................... 28 
 
Follow-up Data Collection ........................................................................................................... 29 

 
 
 
 
 
 
 
 
 
 
 
 
 
Page 4 of 63 
 
9.3.1 
Discharge (or up to 7 days post-procedure, whichever occurs first) ....................................... 29 
9.3.2 
30-Day Data Collection 
...................................................................................... 29 
9.3.3 
1-Year Data Collection 
 ................................................................................... 29 
9.3.4 
2-Year Data Collection 
 ................................................................................... 29 
9.3.5 
3-Year Data Collection 
 ................................................................................ 29 
9.3.6 
4-Year Data Collection 
 ............................................................................. 30 
9.3.7 
5-Year Data Collection 
 .............................................................................. 30 
 
Subject Study Completion ........................................................................................................... 32 
 
Description of Activities Performed by Sponsor Representatives ............................................... 32 
 
CORE LABORATORY .................................................................................................................... 32 
 
Echo Core Laboratory ................................................................................................................. 32 
 
SAFETY REPORTING .................................................................................................................... 33 
 
Adverse Events ........................................................................................................................... 33 
 
Serious Adverse Event (SAE) ..................................................................................................... 33 
 
Device Deficiency ........................................................................................................................ 33 
 
Device Relationship ..................................................................................................................... 34 
 
Unanticipated (Serious Adverse) Device Effect (USADE) .......................................................... 34 
 
Adverse Event and Device Deficiency/Device Malfunction Reporting ........................................ 34 
 
STATSTICAL CONSIDERATIONS ................................................................................................. 36 
 
Analysis Population ..................................................................................................................... 36 
 
Statistical Analyses...................................................................................................................... 36 
12.2.1 Primary Safety Endpoint Analyses .......................................................................................... 36 
12.2.2 Primary Performance Endpoint Analyses................................................................................ 36 
12.2.3 Descriptive Endpoints Analyses .............................................................................................. 36 
 
Sample Size Calculation ............................................................................................................. 36 
 
Timing of Analysis ....................................................................................................................... 36 
 
Subgroup Analysis....................................................................................................................... 36 
 
Pooling Strategy .......................................................................................................................... 37 
 
Procedures for Accounting for Missing Data ............................................................................... 37 
 
Planned Interim Analysis ............................................................................................................. 37 
 
Deviations from Statistical Plan ................................................................................................... 37 
 
Exploratory Registry Arm......................................................................................................... 37 
 
ACCESS TO SOURCE DATA AND DOCUMENTS ........................................................................ 37 
 
QUALITY ASSURANCE .................................................................................................................. 37 
 
Selection of Clinical Sites and Investigators ............................................................................... 37 
 
Study Finances and Agreements ................................................................................................ 37 
 
Protocol Amendments ................................................................................................................. 38 

 
 
 
 
 
 
 
 
Page 5 of 63 
 
 
Training ........................................................................................................................................ 38 
 
Monitoring .................................................................................................................................... 38 
 
Protocol Compliance and Deviations from the Protocol .............................................................. 39 
 
Quality Assurance and Audits ..................................................................................................... 39 
 
Study Committees ....................................................................................................................... 40 
14.8.1 Publication Committee............................................................................................................. 40 
14.8.2 Clinical Events Committee (CEC) ........................................................................................... 40 
 
DATA HANDLING AND RECORD KEEPING ................................................................................. 40 
 
Protection of Personally Identifiable Information ......................................................................... 41 
 
Data Management Plan ............................................................................................................... 41 
 
Document and Data Control ........................................................................................................ 41 
15.3.1 Recording Data ........................................................................................................................ 41 
 
Monitoring .................................................................................................................................... 41 
 
Source Records ........................................................................................................................... 41 
 
Records Retention ....................................................................................................................... 42 
 
ETHICAL CONSIDERATIONS ........................................................................................................ 42 
 
STUDY CONCLUSION ................................................................................................................... 42 
 
PUBLICATION POLICY .................................................................................................................. 42 
 
RISK AND BENEFITS ..................................................................................................................... 43 
 
Risks Associated with the Study ................................................................................................. 43 
 
Anticipated Benefits ..................................................................................................................... 43 
 
Risk-to-Benefit Rationale ............................................................................................................. 43 
 
STUDY CONDUCT COMPLIANCE ................................................................................................ 43 
 
SUSPENSION OR PREMATURE TERMINATION OF THE STUDY ............................................. 44 
 
Abbreviations ....................................................................................................................... 45 
 
Definitions ............................................................................................................................ 47 
 
NYHA Functional Classification ........................................................................................... 59 
 
Sample Informed Consent ................................................................................................... 60 
 
Explant, Return, and Analysis of Valve ............................................................................... 61 
 
Bibliography ......................................................................................................................... 63 
 
 
 
 
 
 

 
 
 
 
 
 
 
 
Page 6 of 63 
 
CIP Synopsis 
Title: 
Retrospective Assessment of the PorticoTM Transcatheter Aortic Valve for 
Valve-in-Valve Use  
Acronym/Short Title: 
Portico Valve-in-Valve Retrospective Registry 
Purpose: 
The purpose of this clinical study is to retrospectively evaluate the safety 
and performance of the PorticoTM transthoracic aortic valve for the 
treatment of a failed surgical aortic valve bioprosthesis, Valve-in-Valve 
(ViV), in patients who were considered to be at increased risk for redo 
surgical aortic valve replacement. Primary endpoints, descriptive 
endpoints, and designated events of interest will be defined and 
adjudicated per the Valve Academic Research Consortium-2 (VARC-2) 
and VARC-3 criteria1, 2.   
Endpoints: 
Primary Safety Endpoint: 
Composite of all-cause mortality, disabling stroke, life threatening bleeding 
requiring blood transfusion, acute kidney injury (AKI) requiring dialysis, 
and major vascular complications at 30 days. 
 
Primary Performance Endpoint:  
Composite of all-cause mortality or disabling stroke at 1 year. 
 
Descriptive Endpoints:  
1. Procedure success defined as:  
• 
Absence of procedural mortality AND  
• 
Successful access, delivery of the valve, and retrieval of the 
delivery system 
 
2. Evaluation of adverse event rates  
     At 30 days and one year:   
• 
All-cause mortality 
• 
Cardiovascular-related mortality 
• 
All Stroke (by severity)  
• 
Transient Ischemic Attacks (TIA) 
• 
Myocardial infarction (MI) 
• 
New pacemaker implant (PPI) 
• 
Coronary obstruction 
 
      At 30 days: 
• 
Minor, Major, and Life-threatening bleeding  
• 
Major vascular, major non-vascular access-related, or cardiac 
structure complication 
• 
Acute Kidney Injury (AKI) stages 1-4 
 
3. Evaluation of adverse event rates annually through 5 years: 
• 
All-cause mortality 
• 
Cardiovascular-related mortality 
• 
All Stroke (by severity) 
• 
TIA 

 
 
 
 
 
 
 
 
Page 7 of 63 
 
 
 
The following will be collected if standard of care or if available: 
 
4. Echocardiographic assessment of valve performance at discharge, 30 
days, 1 year, and annually through 5 years including: 
• 
Transvalvular mean gradient 
• 
Indexed Effective orifice area (iEOA) 
• 
Doppler velocity index (DVI) 
• 
Aortic Valve Area (AVA) 
• 
Non-structural valve dysfunction: 
o Prosthetic patient mismatch (PPM) per body mass index 
(BMI) 
o Degree of aortic valve regurgitation (transvalvular and 
paravalvular leak (PVL)) as none/trace, mild, mild-
moderate, moderate, moderate/severe, or severe per 
VARC-3; and per VARC-2 none/trace, mild, moderate, or 
severe). 
 
5. Valve Integrity at 1 year and annually through 5 years as assessed by:  
• 
Structural Valve Deterioration (SVD) (by hemodynamic valve 
deterioration (HVD) stages 1-3 per VARC-3) 
Confirmed intrinsic permanent changes to the prosthetic valve, 
including: 
o Wear and tear 
o Leaflet disruption 
o Flail leaflet 
o Leaflet fibrosis and/or calcification 
o Strut fracture or deformation 
 
• 
Non-structural Valve Dysfunction other than PVL and PPM (HVD 
stages 1-3 per VARC-3) 
Any abnormality not intrinsic to the prosthetic valve resulting in 
valve dysfunction other than PVL and PPM, including: 
o Leaflet entrapment by pannus or tissue 
o Inappropriate positioning or sizing 
o embolization 
 
• 
Clinically Significant Thrombosis  
Meeting either of the following criteria: 
o Clinical sequelae of thromboembolic event or worsening 
AS/transvalvular AR and HVD Stage 2-3 or confirmatory 
imaging of thrombosis 
Or 
o In the absence of clinical sequelae, both HVD Stage 3 and 
confirmatory imaging 
 
• 
Endocarditis (by HVD stages 1-3 per VARC-3) 
Meeting at least one of the following criteria: 

 
 
 
 
 
 
 
 
Page 10 of 63 
 
 
Inclusion Criteria 
1. Subject had a degenerated surgical aortic bioprosthetic valve with 
severe aortic stenosis, severe regurgitation, or a combination of at 
least moderate stenosis with at least moderate regurgitation per 
EAPCI-ESC-EACTS standardized criteria. 
2. Surgical bioprosthesis true inner diameter (true ID) was ≥ 19 mm 
and ≤ 27 mm and was confirmed by either CT or confirmed by the 
Valve in Valve Aortic App. Refer to the PCR website 
https://www.pcronline.com/PCR-Publications/PCR-mobile-
apps/Valve-in-Valve-Aortic-app Note: if CT was contraindicated 
and/or not possible to be obtained, a transesophageal 
echocardiogram (TEE) will be accepted for sizing.  
3. Prior to Portico ViV procedure, the patient was deemed at increased 
risk for surgery to replace the surgical aortic bioprosthetic valve.  
4. Subject provided written informed consent prior to performing data 
collection for study specific visits. For patients that are deceased at 
the time of enrollment, all institutional/local legal and regulatory 
requirements for consent must be met prior to enrollment and data 
collection. 
5. Subject is ≥ 18 years of age or legal age in host country at the time 
of consent.   
6. Prior to the Portico ViV index procedure, the subject had New York 
Heart Association (NYHA) class II, III, or IV. 
7. Subject had a minimum vessel diameter of 6.0 mm for Portico™ 
delivery system access or a minimum of 5.0 mm for the FlexNav™ 
delivery system. 
8. Subject had the Portico or FlexNav delivery system enter their 
vasculature with the intent of replacing a failed aortic bioprosthetic 
valve. 
 
Exclusion Criteria from the time of the Portico ViV index procedure: 
1. Subject had evidence of an acute MI, percutaneous intervention, or 
a peripheral intervention ≤30 days prior to Portico ViV index 
procedure (MI defined as: ST Segment Elevation as evidenced on 
12 Lead ECG). 
2. Subject had uncontrolled blood dyscrasias defined as: leukopenia 
(WBC<3,000 mm3), acute anemia (Hb <9 g/dL), or 
thrombocytopenia (platelet count <50,000 cells/mm³). 
3. Subject was considered hemodynamically unstable at the time of 
the ViV procedure (requiring inotropic support or mechanical heart 
assistance) 
4. Subject had severe ventricular dysfunction with left ventricular 
ejection fraction (LVEF) <20% as measured by resting 
echocardiogram. 
5. Subject had imaging evidence of intracardiac mass, thrombus or 
vegetation. 

 
 
 
 
 
 
 
 
Page 11 of 63 
 
6. Subject had an active peptic ulcer or has/had upper 
gastrointestinal (GI) bleeding ≤3 months prior to ViV index 
procedure.  
7. Subject had a documented history of a cerebrovascular accident 
(CVA) or a transient ischemic attack (TIA) ≤6 months prior to index 
procedure. 
8. Subject had renal insufficiency (serum creatinine >3.0 mg/dL 
(265.5µmol/L)) and/or end stage renal disease requiring chronic 
dialysis. 
9. Subject had active bacterial endocarditis or ongoing sepsis ≤ 6 
months prior to the index procedure. 
10. Surgical aortic bioprosthetic valve was unstable or rocking. 
11. Subject had a vascular condition (i.e. stenosis, tortuosity, or severe 
calcification) that made insertion and endovascular access to the 
aortic valve impossible. 
12. Subject was unable to tolerate antiplatelet or anticoagulant 
therapy. 
Data Collection 
Clinical and echocardiographic data will be collected, if available and 
standard of care (SOC), at baseline (pre-ViV implant), discharge, 30 days, 
1 year, and annually through 5 years post-ViV index procedure. 
Exploratory Registry 
Arm: 
In addition, an exploratory registry arm will collect data for patients that 
were treated for a failed surgical aortic bioprosthetic valve true ID size of 
<19 mm or >27 mm at the time of the Portico ViV procedure. There is no 
enrollment limit for this registry arm. Outcomes for the exploratory registry 
arm will be descriptive and the patient data collected from these subjects 
will not be included in the primary analysis. For this arm of the study, the 
same follow-up timepoints and data will be collected. 
All above inclusion and exclusion criteria apply, with the exception of the 
following: 
 
Inclusion Criteria #2: Surgical bioprosthesis true inner diameter (true ID) 
was ≥ 19 mm and ≤ 27 mm) and was confirmed by either CT or confirmed 
by the Valve in Valve V Aortic App. Refer to the PCR website 
https://www.pcronline.com/PCR-Publications/PCR-mobile-apps/Valve-in-
Valve-Aortic-app Note: if CT was contraindicated and/or not possible to be 
obtained, a transesophageal echocardiogram (TEE) will be accepted for 
sizing.  
 
 
 
 

 
 
 
 
 
 
 
 
Page 12 of 63 
 
 
COMPLIANCE STATEMENT: 
This clinical investigation will be conducted in accordance with this Clinical Investigation Plan, 
the Declaration of Helsinki, ISO 14155:2011 standard and the appropriate local legislation(s). 
The most stringent requirements, guidelines or regulations must always be followed. The 
conduct of the clinical investigation will be approved by the appropriate Ethics Committee (EC) 
of the respective clinical site and as specified by local regulations. 
 
INTRODUCTION 
 
This document is a study protocol for the PorticoTM Valve-in-Valve (ViV) retrospective data-
collection study. The objective of this study is to evaluate the safety and performance of the 
PorticoTM transcatheter aortic valve in the treatment of a failed surgical aortic valve prosthesis 
ViV.  
 
This clinical data-collection study will be conducted in accordance with this protocol. All parties 
involved in the conduct of this clinical study will be qualified by education, training, or 
experience to perform their tasks and this training will be documented appropriately.  
 
Background and Justification for Study 
Increased use of bioprosthetic valves, combined with increased life expectancy, is resulting in 
the need for treatment options for patients with failing bioprosthetic valves. Operative mortality 
for redo aortic valve surgery is generally low (2% to 7%) in suitable candidates. However, 
mortality risk can increase to more than 30%
n high
1,4 i
-surgical risk patients. Implantation of a 
transcatheter aortic valve in a failed surgical aortic bioprosthesis to achieve adequate valvular 
function for symptom relief represents a minimally invasive alternative to conventional redo 
surgery. 
The most common reasons for surgical bioprosthetic aortic valve replacement, or ViV treatment, 
is structural valve deterioration caused by 1) wear and tear, 2) calcific degeneration, 3) pannus, 
4) endocarditis, and 5) thrombus5. 
 
Two types of commercially available transcatheter heart valves (THVs) are currently approved 
for ViV in Europe and the United States: the balloon expandable Edwards Sapien XT and 
Sapien 3 THVs (Edwards Lifesciences, Irvine, CA) and the self-expanding Medtronic 
CoreValve, Evolut R, and Evolut Pro THV (Medtronic, Dublin, Ireland). 
 
Medtronic’s CoreValve was the first to obtain CE Mark and FDA approval in 2014 and 2015 
respectively for ViV with data from the Global ViV registry used to support the expanded 
indication. The Global Valve-in-Valve Registry6 was initiated in December 2010 and designed to 
collect retrospective and prospective data from centers worldwide that had ViV experience with 
either CoreValve or Edwards Sapien devices, used off-label at that time. A total of 202 patients 
with degenerated bioprosthetic valves from 38 centers across Europe, North America, Australia, 
New Zealand and the Middle East contributed data to the registry. Of these 202 patients (mean 
age 77.7±10.4 years; 52.5% men, 42% with stenosis as primary mode of failure), 124 
underwent Valve-in-Valve with a CoreValve THV and 78 with an Edwards SAPIEN THV. At 30 
days, 185 patients had survived, 17 patients died (8.4%). There were no differences between 
the CoreValve and Edwards SAPIEN patients with respect to mortality, major vascular 
complication, stroke, or need for a permanent pacemaker. At 30 days, mortality and stroke rate 
(8.4% and 2%, respectively) are comparable to the rates in other transcatheter aortic valve 
replacement cohorts. At 1 year, freedom from all-cause mortality was 85.8%. 

 
 
 
 
 
 
 
 
Page 13 of 63 
 
 
Edwards Lifesciences Sapien XT and Sapien 3 THVs are both currently approved for Valve-in-
Valve use. The Sapien XT valve received CE Mark and FDA approval in 2015 based on data 
from the PARTNER 2 ViV nested registry. The PARTNER 2 (Placement of Aortic Transcatheter 
Valves) trial was a prospective, multicenter study that enrolled patients with symptomatic aortic 
stenosis. The nested ViV registry included 100 patients with a degenerated surgical aortic 
bioprostheses who were at high risk of complications during reoperation and eligible to receive 
a 23mm or 26mm Sapien XT valve. Following enrollment of the 100 patients in the nested 
registry, additional patients were enrolled as part of a continued access registry. Data from the 
PARTNER 2 ViV nested registry and continued access registry were published5 and showed 
that in high-risk patients, ViV for treatment of bioprosthetic aortic valve failure is associated with 
relatively low mortality and complication rates, improved hemodynamics, and excellent 
functional and quality-of-life outcomes at 30 days and 1 year.   
 
Early in 2017, Edwards Lifesciences obtained FDA approval for the third-generation Sapien 3 
valve for ViV use based on unpublished real-world data collected from the Society of Thoracic 
Surgeons (STS)/American College of Cardiology (ACC) Transcatheter Valve Therapy (TVT) 
Registry. The STS/ACC TVT registry is a joint initiative of the STS and the ACC and is designed 
to provide important information on characteristics and outcomes of TAVR in contemporary U.S. 
clinical practice. Overall, 2,893 ViV procedures have been entered into the database from 2012 
to 2015. 
 
Given the growing body of competitive clinical data in support of ViV as a safe and effective 
alternative treatment option for patients with a failed surgical bioprosthetic valve, physicians 
have occasionally been using Portico in a ViV application at their own discretion in a commercial 
setting.  Abbott is interested in analyzing safety and performance of patients that have 
undergone a Portico TAVI ViV procedure. 
 
The Abbott (previously St. Jude Medical) family of CE Marked Portico transcatheter aortic 
valves (size range 23-29mm) is currently approved in Europe and Australia for treatment of 
patients with symptomatic, severe native aortic stenosis who are considered high or extreme 
surgical risk. First-in-human experiences of ViV with the Portico valve indicate the procedure is 
may be a safe and effective option for the treatment of a degenerated surgical bioprosthesis 
due to severe stenosis or severe central aortic regurgitation7, 8. 
 
A propensity-matched analysis from the ViV International Data (VIVID) registry which includes 
prospective data on patients who have undergone a commercial ViV procedure from 55 centers 
across Europe, the Americas, Australia, New Zealand demonstrated Valve-in-Valve with the 
Portico™ valve (n=54) is procedurally safe, associated with good clinical outcomes at 30 days 
and results in comparable hemodynamic performance at 1 year to ViV with CoreValve (n=102).9  
 
In a large nation-wide study recently published from France, 44,218 of patients were analyzed 
by propensity score matching from a hospital discharge database after undergoing TAVI for 
aortic stenosis or TAVI ViV for failed aortic bioprosthesis between 2010 and 2019.10 The mean 
follow-up was 516 days and 2,749 patients were analyzed in each arm. The combined endpoint 
of cardiovascular death, all-cause stroke or rehospitalization for heart failure was not different 
between the valve-in-valve TAVI and native TAVI groups (RR 1.03, 95% CI 0.94–1.13; p=1.00). 
The TAVI ViV patients had good short-term and long-term outcomes and there was no 

 
 
 
 
 
 
 
 
Page 20 of 63 
 
 
Additional echocardiogram and data available 
In the event that more than 1 echocardiogram or required data point is performed and available 
within a specific study data collection timepoint, the data closest to the study timepoints will be 
used for the primary analysis. However, all available data should be collected in additional 
applicable CRFs. Additional echocardiograms should be submitted to the echocardiogram core 
lab for analysis. 
 
Measures Taken to Avoid Bias 
In order to avoid bias, a Clinical Events Committee (CEC) will be used to review and adjudicate 
events of interest noted in the Safety Reporting and Committees section. The CEC adjudication 
(including relationship to procedure and device) will be used for the primary analysis. An 
Echocardiogram Core Lab will be used to assess echocardiographic data points. Echocardiogram 
assessments will be used for the primary analysis. Physicians and staff involved with the study 
CEC and core lab will not be participating as Primary Investigators in this study. All patients that 
underwent a Portico ViV procedure will be screened for eligibility and enrollment as study 
subjects, regardless of procedure success. All eligible subjects, regardless of their outcome or 
survival should be considered for screening and enrollment. 
 
 
ENDPOINTS 
 
Primary Safety Endpoint  
Composite of all-cause mortality, disabling stroke, life threatening bleeding requiring blood 
transfusion, acute kidney injury (AKI) requiring dialysis, and major vascular complications at 30 
days. 
 
Primary Performance Endpoint  
Composite of all-cause mortality or disabling stroke at 1 year. 
 
Descriptive Endpoints 
 
Descriptive Endpoints:  
 
1. Procedure success defined as:  
• 
Absence of procedural mortality AND  
• 
Successful access, delivery of the valve, and retrieval of the delivery system 
 
2. Evaluation of adverse event rates  
     At 30 days and one year:   
• 
All-cause mortality 
• 
Cardiovascular-related mortality 
• 
All Stroke (by severity)  
• 
Transient Ischemic Attacks (TIA) 
• 
Myocardial infarction (MI) 
• 
New pacemaker implant (PPI) 
• 
Coronary obstruction 

 
 
 
 
 
 
 
 
Page 21 of 63 
 
 
      At 30 days: 
• 
Minor, Major, and Life-threatening bleeding  
• 
Major vascular, major non-vascular access-related, or cardiac structure complication 
• 
Acute Kidney Injury (AKI) stages 1-4 
 
3. Evaluation of adverse event rates annually through 5 years: 
• 
All-cause mortality 
• 
Cardiovascular-related mortality 
• 
All Stroke (by severity) 
• 
TIA 
 
The following will be collected if standard of care or if available: 
 
4. Echocardiographic assessment of valve performance at discharge, 30 days, 1 year, and 
annually through 5 years including: 
• 
Transvalvular mean gradient 
• 
Indexed Effective orifice area (iEOA) 
• 
Doppler velocity index (DVI) 
• 
Aortic Valve Area (AVA) 
• 
Non-structural valve dysfunction: 
o Prosthetic patient mismatch (PPM) per body mass index (BMI) 
o Degree of aortic valve regurgitation (transvalvular and paravalvular leak (PVL)) as 
none/trace, mild, mild-moderate, moderate, moderate/severe, or severe per VARC-
3; and per VARC-2 none/trace, mild, moderate, or severe). 
 
5. Valve Integrity at 1 year and annually through 5 years as assessed by:  
• 
Structural Valve Deterioration (SVD) (by hemodynamic valve deterioration (HVD) stages 
1-3 per VARC-3) 
Confirmed intrinsic permanent changes to the prosthetic valve, including: 
o Wear and tear 
o Leaflet disruption 
o Flail leaflet 
o Leaflet fibrosis and/or calcification 
o Strut fracture or deformation 
 
• 
Non-structural Valve Dysfunction other than PVL and PPM (HVD stages 1-3 per VARC-3) 
Any abnormality not intrinsic to the prosthetic valve resulting in valve dysfunction other 
than PVL and PPM, including: 
o Leaflet entrapment by pannus or tissue 
o Inappropriate positioning or sizing 
o embolization 
 
• 
Clinically Significant Thrombosis  
Meeting either of the following criteria: 
o Clinical sequelae of thromboembolic event or worsening AS/transvalvular AR and 
HVD Stage 2-3 or confirmatory imaging of thrombosis 
Or 
o In the absence of clinical sequelae, both HVD Stage 3 and confirmatory imaging 

 
 
 
 
 
 
 
 
Page 22 of 63 
 
 
• 
Endocarditis (by HVD stages 1-3 per VARC-3) 
Meeting at least one of the following criteria: 
o Fulfilment of the Duke endocarditis criteria 
o Evidence of abscess, pus, or vegetation confirmed as secondary to infection by 
histological or microbiological studies during re-operation 
o Evidence of abscess, pus or vegetation confirmed on autopsy. 
 
The following definitions of HVD Stages (1-3) will be used when assessing valve integrity. 
• 
Stage 1 (Morphological Valve Deterioration): 
Evidence of SVD, non-structural valve dysfunction (other than paravalvular or PPM), 
thrombosis or endocarditis without significant hemodynamic changes. 
 
• 
Stage 2 (Moderate hemodynamic valve deterioration): 
Increase in mean transvalvular gradient ≥10 mmHg resulting in mean gradient ≥20 
mmHg with concomitant decrease in EOA ≥0.3 cm2 or ≥25% and/or decrease in 
Doppler velocity index ≥0.1 or ≥20% compared with echocardiographic assessment 
performed 1-3 months post-procedure, OR new occurrence or increase of ≥1 graded 
of intra-prosthetic AR resulting in ≥ moderate AR 
 
• 
Stage 3 (Severe hemodynamic valve deterioration): 
Increase in mean transvalvular gradient ≥20 mmHg resulting in mean gradient ≥30 
mmHg with concomitant decrease in EOA ≥0.6 cm2 or ≥50% and/or decrease in 
Doppler velocity index ≥0.2 or ≥40% compared with echocardiographic assessment 
performed 1-3 months post-procedure, OR new occurrence, or increase of ≥2 grades, 
of intra-prosthetic AR resulting in severe AR. 
 
• 
Any need for Portico TAVI re-intervention after implant through 5 years 
 
6. Clinical benefit endpoints defined as improvement from baseline to 30 days, 1 year, and 
annually through 5 years from index procedure, including: 
• 
New York Heart Association (NYHA) functional classification 
 
 
SUBJECT SELECTION AND WITHDRAWAL 
 
Study Population 
This study will enroll subjects of all genders from the general population of patients that have had 
a failed surgical bioprosthetic aortic valve procedure with a subsequent Portico™ ViV attempted 
implant. Patients must meet all general eligibility criteria and provide written informed consent 
prior to be being included in this retrospective data-collection study. 
 
For the exploratory registry arm, patients that had an inner aortic diameter <19 mm or >27 mm of 
the surgical aortic bioprosthetic valve will be included in this registry arm. Data collected in this 
registry arm will not be included in the primary analyses. 

 
 
 
 
 
 
 
 
Page 23 of 63 
 
 
Subject Recruitment and Screening 
A member of the site’s study team trained to the protocol must evaluate patients for the general 
study eligibility criteria, and if applicable, will enter the patients into a site-specific 
recruitment/screening log.  A patient who does not satisfy all general eligibility criteria prior to 
informed consent is considered a recruitment failure and should not be enrolled in the study. 
 
Sites will ask patients meeting general inclusion criteria and no general exclusion criteria to sign 
an Informed Consent Form (ICF) following the established Informed Consent process if they wish 
to participate in this data-collection study. Sites will enter these patients into the 
recruitment/screening log. Once a duly dated and signed ICF is obtained, sites will begin the 
protocol data collection assessments as part of the study screening process. 
 
Subjects who do not meet the study eligibility criteria are considered a screen failure and should 
not be enrolled in the study. The Principal Investigator or the delegated study personnel will 
record the screen failure in the hospital records and on a recruitment/screening log as required. 
 
Informed Consent 
Patients that have had a failed surgical aortic bioprosthetic valve and underwent a Portico ViV 
Implant procedure may be identified and screened as potential study subjects. Patients may be 
identified from their study site’s procedure records for potential study enrollment. Once identified, 
each patient must complete the informed consent process prior to study participation. 
 
The Principal Investigator or his/her authorized designee will conduct the Informed Consent 
process, as required by applicable regulations and the center’s local Ethics Committee (EC). This 
process will include a verbal discussion with the patient on all aspects of the study which are 
relevant to the patient’s decision to participate, such as details of data being collected, any 
potential benefits and potential risks of participation. During the discussion, the Principal 
Investigator or his/her authorized designee will avoid any improper influence on the patient and 
will respect the patient’s legal rights. The patient must be provided with the Informed Consent 
Form (ICF) written in a language that is understandable to the subject and has been approved by 
the center’s local EC. The patient must have adequate time to review, ask questions and consider 
participation. 
 
If the patient agrees to participate and signs the ICF, the ICF must be signed and dated by the 
subject and by the person who obtained the subject’s consent. The signed original form will be 
filed in the subject’s hospital or research charts, and a copy will be provided to the subject by the 
Investigator or his/her authorized designee. 
 
The Principal Investigator or his/her authorized designee will document the informed consent 
process in the subject’s hospital/clinic and/or research charts. The date of signature will be 
entered on an applicable Case Report Form (CRF). 
 
Failure to obtain the ICF from a subject prior to study enrollment should be reported to the 
Sponsor within 5 working days and to the study site’s EC according to their reporting 
requirements. 
 
If, during the study, new information becomes available that can significantly affect a subject's 
future health and medical care, the Principal Investigator or his/her authorized designee will 

 
 
 
 
 
 
 
 
Page 24 of 63 
 
provide this information to the subject. If relevant, the subject will be asked to confirm their 
continuing informed consent in writing. 
 
 
Informed Consent and Enrollment of the Deceased 
For patients that are deceased at enrollment time but underwent a previous Portico ViV procedure 
to replace a failed surgical bioprosthetic valve, all institutional/local legal and regulatory 
requirements must be met prior to enrollment and data collection.  
 
 
ELIGIBILITY CRITERIA 
 
Inclusion Criteria 
1. Subject had a degenerated surgical aortic bioprosthetic valve with severe aortic stenosis, 
severe regurgitation, or a combination of at least moderate stenosis with at least moderate 
regurgitation per EAPCI-ESC-EACTS standardized criteria. 
2. Surgical bioprosthesis true inner diameter (true ID) was ≥ 19 mm and ≤ 27 mm and was 
confirmed by either CT or confirmed by the Valve in Valve Aortic App. Refer to the PCR 
website https://www.pcronline.com/PCR-Publications/PCR-mobile-apps/Valve-in-Valve-
Aortic-app Note: if CT was contraindicated and/or not possible to be obtained, a 
transesophageal echocardiogram (TEE) will be accepted for sizing.  
3. Prior to Portico ViV procedure, the patient was deemed at increased risk for surgery to 
replace the surgical aortic bioprosthetic valve.  
4. Subject provided written informed consent prior to performing data collection for study 
specific visits. For patients that are deceased at the time of enrollment, all 
institutional/local legal and regulatory requirements for consent must be met prior to 
enrollment and data collection. 
5. Subject is ≥ 18 years of age or legal age in host country at the time of consent.   
6. Prior to the Portico ViV index procedure, the subject had New York Heart Association 
(NYHA) class II, III, or IV. 
7. Subject had a minimum vessel diameter of 6.0 mm for Portico™ delivery system access or 
a minimum of 5.0 mm for the FlexNav™ delivery system. 
8. Subject had the Portico or FlexNav delivery system enter their vasculature with the intent 
of replacing a failed aortic bioprosthetic valve. 
 

 
 
 
 
 
 
 
 
Page 25 of 63 
 
 
Exclusion Criteria 
Exclusion criteria is from the time of the Portico ViV index procedure: 
1. Subject had evidence of an acute MI, percutaneous intervention, or a peripheral 
intervention ≤30 days prior to Portico ViV index procedure (MI defined as: ST Segment 
Elevation as evidenced on 12 Lead ECG). 
2. Subject had uncontrolled blood dyscrasias defined as: leukopenia (WBC<3,000 mm3), 
acute anemia (Hb <9 g/dL), or thrombocytopenia (platelet count <50,000 cells/mm³). 
3. Subject was considered hemodynamically unstable at the time of the ViV procedure 
(requiring inotropic support or mechanical heart assistance) 
4. Subject had severe ventricular dysfunction with left ventricular ejection fraction (LVEF) 
<20% as measured by resting echocardiogram. 
5. Subject had imaging evidence of intracardiac mass, thrombus or vegetation. 
6. Subject had an active peptic ulcer or has/had upper gastrointestinal (GI) bleeding ≤3 
months prior to ViV index procedure.  
7. Subject had a documented history of a cerebrovascular accident (CVA) or a transient 
ischemic attack (TIA) ≤6 months prior to index procedure. 
8. Subject had renal insufficiency (serum creatinine >3.0 mg/dL (265.5µmol/L)) and/or end 
stage renal disease requiring chronic dialysis. 
9. Subject had active bacterial endocarditis or ongoing sepsis ≤ 6 months prior to the index 
procedure. 
10. Surgical aortic bioprosthetic valve was unstable or rocking. 
11. Subject had a vascular condition (i.e. stenosis, tortuosity, or severe calcification) that 
made insertion and endovascular access to the aortic valve impossible. 
12. Subject was unable to tolerate antiplatelet or anticoagulant therapy. 
 
 
Exploratory Registry Arm Inclusion and Exclusion Criteria 
For inclusion in the Exploratory Registry Arm, the eligibility required is the same as listed above, 
with the exception of the following: 
 
Inclusion Criteria #2:  
Surgical bioprosthesis true ID was ≥ 19 mm and ≤ 27 mm and was confirmed by either CT or 
confirmed by the ViV Aortic App. Refer to the PCR website https://www.pcronline.com/PCR-
Publications/PCR-mobile-apps/Valve-in-Valve-Aortic-app  
Note: if CT was contraindicated and/or not possible to be obtained, a transesophageal 
echocardiogram (TEE) will be accepted for sizing.  
 
SUBJECT ENROLLMENT 
Patients must first meet all inclusion criteria and none of the exclusion criteria. Patients must 
also have had the Portico™ or FlexNav™ delivery system enter their body with the intent to 
implant the Portico transcatheter aortic valve via ViV procedure. In order for patients to be 
enrolled as study subjects, the above must be met and the subject (or legally authorized 
representative/next of kin) must sign the approved study ICF and any required forms designated 
by the study site/local/national authorities, based on geographic regulations. Patients deceased 
at the time of study screening may be enrolled per local and national regulations. The 
enrollment process is outlined below in Figure 3. 

 
 
 
 
 
 
 
 
Page 27 of 63 
 
Notification of subject enrollment to the Sponsor is considered to have occurred once the 
patient met all eligibility criteria, the required consent process and forms were completed (with 
documentation of enrollment in the medical records), and when the screening/consent study 
database forms have been completed. 
 
 
Subject Lost to Follow-up and Withdrawal 
Subjects must be informed about their right to withdraw from the study at any time and for any 
reason without sanction, penalty or loss of benefits to which the subject is otherwise entitled. 
Withdrawal from the study will not jeopardize the subject’s future medical care or relationship 
with the study site Principal Investigator. Subjects will be requested to provide the reason for the 
request to withdraw from the study. The Principal Investigator must make all reasonable efforts 
to retain the subject in the study until completion of the study. 
 
A study subject that has been withdrawn from the study will not be replaced. All data collected 
up to the point of their study withdrawal will be reported and included in the data analysis as 
applicable. 
If a subject cannot be reached and review of their medical records does not provide sufficient 
information to assess the status and performance of their ViV, the site should make every effort 
to reach the subject and their local or referring physician. The efforts undertaken to contact the 
subject, referring physicians, including internists as well as cardiologists, family members, or 
other alternate contacts must be noted in the subject’s records. These efforts must include at 
least two attempts of telephone contact on separate dates, and a registered letter before 
considering the subject lost-to-follow-up.  
Reasons for early termination include, but are not limited to: 
1. Subject refuses to continue participating in the study, withdraws consent 
2. Subject is ‘lost to follow-up’: Site personnel should at all times make all reasonable 
efforts to locate and communicate with the subject in order to achieve subject 
compliance to the scheduled follow-up visits: 
• 
A subject will be considered ‘lost to follow-up’ after one missed visit, and a minimum 
of two phone calls from the investigational site to the subject or listed contact of the 
subject. These two phone calls need to be documented in the subject’s hospital 
records. 
• 
If these two attempted phone calls are unsuccessful, a letter should be sent to the 
subject’s last known address or general practitioner and a copy of this letter should 
be maintained in the subject’s hospital records. 
 
Note: If a subject missed one or more of the scheduled follow-up visits (inclusive of the assigned 
visit windows), this will be considered as a missed visit. The subject may therefore still return for 
subsequent follow-up visits and will not be withdrawn from the study. 
If a subject withdraws from the clinical study, the site will record the subject’s reasons for 
withdrawal, on a Withdrawal CRF. 
The status of the subject’s condition should be documented at the time of withdrawal on any 
ongoing adverse event forms.   

 
 
 
 
 
 
 
 
Page 28 of 63 
 
 
Total Expected Study Duration 
It is anticipated that all subject data would be collected from the Portico ViV procedure and 
through the following 5 years post-procedure.  
 
DATA COLLECTION AND EVALUATION OF ENDPOINTS 
The Principal Investigator is responsible for ensuring all study data is collected as required per 
the protocol scheduled time points. In addition to accessing the subject’s medical records, data 
collection may also occur remotely by phone contact, mail, in-person, or through email. The 
clinical study will be conducted in accordance with the protocol. All parties participating in the 
conduct of the study will be qualified by education, training and/or experience to perform their 
tasks. This training will be documented appropriately. The data collection elements required for 
each follow-up are listed below and in Table 3 below. 
 
Baseline 
The following baseline (pre-ViV implant procedure) data will be collected from medical records 
for all enrolled subjects: 
 
1. Medical History 
2. Demographics 
3. Cardiovascular medications 
4. New York Heart Association (NYHA) Classification (based on symptoms of any 
limitations) 
5. Echocardiography to include comprehensive transthoracic (TTE) or transesophageal 
(TEE) 2D echocardiogram, including, at minimum, assessment of aortic valve gradients 
(mean gradient, peak jet velocity, or doppler velocity index (DVI), aortic valve area 
(AVA), indexed effective orifice area (EOA), indices, degree of regurgitation, cardiac 
output and cardiac index, left ventricle systolic function (global and segmental).  
For all data-collection timepoints, echocardiogram reports may be acceptable if imaging 
study is not available to be submitted to Abbott. 
6. Lab Measurements per SOC (including CBC, Platelet count, BUN, creatinine and/or 
estimated GFR) 
7. Protocol deviations related to informed consent process or, inclusion/exclusion criteria (if 
applicable) 
 
Procedure 
The following data will be collected from the medical records of the ViV implant procedure: 
 
1. Vascular access, deployment, final valve placement, performance and closure data 
collection  
2. Other product utilization (e.g. introducer sheaths, guide wires, balloon catheters) 
3. Cardiac rhythm and any rhythm changes throughout the duration of the procedure 
4. Procedural information (e.g. number of valves used, cerebral protection device use, 
fluoroscopy time, balloon dilatation used, stent size, implant depth, final disposition of 
the subject, etc.) 
5. Adverse events and protocol deviations related to safety reporting (if applicable) 
 
All the required information must be recorded on the applicable CRF. 

 
 
 
 
 
 
 
 
Page 29 of 63 
 
 
Follow-up Data Collection 
9.3.1 
Discharge 
 
The discharge data-collection will be from hospital discharge or up to 7 days after the procedure, 
whichever occurs first. If the subject was discharged over the weekend, the data collection for 
discharge may be based on the last weekday prior to discharge. The discharge data will be 
collected from medical records and includes: 
1. Clinical assessment with physical exam 
2. Echocardiogram (within the first 48 hours post-procedure), including parameters noted 
above in Baseline. 
3. If applicable, reinterventions procedure details (eg. Surgery or TAVR) 
4. Adverse events and protocol deviations related to safety reporting (if applicable) 
9.3.2 
30-Day Data Collection 
 
The following data collection will occur at 30 days post index procedure: 
 
1. Clinical assessment with physical exam 
2. NYHA classification (based on symptoms of any limitations) 
3. Echocardiogram, including parameters noted above in Baseline. 
4. If applicable, reintervention procedure details 
5. Lab Measurements (CBC, Platelet count, and Creatinine)  
6. Cardiovascular medications 
7. Adverse events and protocol deviations related to safety reporting (if applicable) 
9.3.3 
1-Year Data Collection 
 
The following data collection will occur at 1 year post-index procedure: 
1. Clinical assessment with physical exam 
2. NYHA classification 
3. Echocardiogram, including parameters noted above in Baseline. 
4. If applicable, reintervention procedure details 
5. Cardiovascular medications 
6. Adverse events and protocol deviations related to safety reporting (if applicable) 
 
9.3.4 
2-Year Data Collection 
 
The following data collection will occur at 2 years post-index procedure: 
 
1. Clinical assessment with physical exam 
2. NYHA classification 
3. Echocardiogram, including parameters noted above in Baseline. 
4. If applicable, reintervention procedure details 
5. Cardiovascular medications 
6. Adverse events and protocol deviations related to safety reporting (if applicable) 
 
9.3.5 
3-Year Data Collection 
 
The following data collection will occur at 3 years post-index procedure: 
 

 
 
 
 
 
 
 
 
Page 30 of 63 
 
1. Clinical assessment with physical exam 
2. NYHA classification 
3. Echocardiogram, including parameters noted above in Baseline. 
4. If applicable, reintervention procedure details 
5. Cardiovascular medications 
6. Adverse events and protocol deviations related to safety reporting (if applicable) 
 
9.3.6 
4-Year Data Collection 
 
The following data collection will occur at 4 years post-index procedure: 
 
1. Clinical assessment with physical exam 
2. NYHA classification 
3. Echocardiogram, including parameters noted above in Baseline. 
4. If applicable, reintervention procedure details 
5. Cardiovascular medications 
6. Adverse events and protocol deviations related to safety reporting (if applicable) 
 
9.3.7 
5-Year Data Collection 
 
The following data collection will occur at 5 years post-index procedure: 
 
1. Clinical assessment with physical exam 
2. NYHA classification 
3. Echocardiogram, including parameters noted above in Baseline. 
4. If applicable, reintervention procedure details 
5. Cardiovascular medications 
6. Adverse events and protocol deviations related to safety reporting (if applicable) 
 
 

 
 
 
 
 
 
 
 
Page 32 of 63 
 
 
In the event that more than 1 echocardiogram or required data point is performed and available 
within a specific study data collection timepoint, the data closest to the study timepoints will be 
used for the primary analysis. However, all available data should be collected in additional 
applicable CRFs. Additional echocardiograms should be submitted to the echocardiogram core 
lab for analysis. Data may be collected based on availability from SOC and protocol deviations 
for out of window/missed visit or out of window/missed data will not be required. 
 
Subject Study Completion 
Subject participation in the study will conclude when: 
 
1. The subject completes the 5-year data collection time point. 
2. When consent is withdrawn (by the subject or legal authorized representative). 
3. When the subject is deceased at the time of enrollment or dies during the study, their 
study completion will occur after their last study follow-up was available, including details 
of what led up to death and the cause of death. 
4. When the subject is lost to follow-up, their study completion will occur after their last 
study follow-up.  
5. For subject’s where the Portico delivery system entered their body but was not 
successfully implanted, they will complete the study after 30 days from the attempted 
procedure.    
 
Upon completion of subject participation in this data-collection study, the subject will continue to 
receive follow-up as per standard of care. 
 
Description of Activities Performed by Sponsor Representatives 
Trained Sponsor personnel may provide guidance to ensure compliance to the protocol. If 
applicable, they may provide technical expertise and technical guidance related to the protocol.  
While Sponsor representatives may perform these activities, the Principal Investigator remains 
responsible for ensuring all study data is collected as required per the protocol. 
 
 CORE LABORATORY 
 Echo Core Laboratory 
Echocardiographic examinations will be forwarded to an independent Echocardiographic Core 
Laboratory for interpretation. It is the responsibility of each study site to perform the local 
interpretation of the echocardiogram for clinical assessment. The Echocardiographic Core 
Laboratory will not be responsible for notifying the site of any abnormal findings that are identified 
as part of participation in the study.  
 
The responsibility of the Echocardiographic Core Laboratory is to complete the data collection 
forms and provide the study required interpretation and documentation of each echocardiogram 
submitted to the Sponsor. Data obtained from the Core Laboratory evaluation will be used for 
study purposes only and not for clinical treatment of the subject.  

 
 
 
 
 
 
 
 
Page 33 of 63 
 
 SAFETY REPORTING 
To comply with worldwide standards and guidelines on clinical investigation adverse event 
reporting, the Sponsor has adopted uniform and worldwide applicable standard definitions and 
reporting timelines to be used and adhered to by the investigators.  
 Adverse Events 
An adverse event (AE) is any untoward medical occurrence, unintended disease or injury, or 
untoward clinical signs (including abnormal laboratory findings) in subjects, users or other 
persons, whether or not related to the medical device under investigation. 
 
As part of ISO14155 Section 3.2, the Adverse Event definition includes notes outlined below. 
 
Note 1: This definition includes events related to the medical device under investigation 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 medical 
devices under investigation. 
 Serious Adverse Event (SAE) 
If the AE meets any of the criteria below, it is regarded as a serious adverse event.  
 
1. Led to a death, 
2. Led to a serious deterioration in health of the subject, that either resulted in  
a. a life-threatening illness or injury, or 
b. a permanent impairment of a body structure or a body function, or 
c. in-patient hospitalization or prolongation of existing hospitalization, or 
d. medical or surgical intervention to prevent life threatening illness or injury or 
permanent impairment to a body structure or a body function. 
e. chronic disease  
3. Led to fetal distress, fetal death or a congenital abnormality or birth defect. 
 
Note: A planned hospitalization for a pre-existing condition, or a procedure required by the 
protocol without a serious deterioration in health, is not considered to be an SAE. 
 Device Deficiency  
During the clinical study, the Principal Investigator will be responsible for reporting all device 
deficiencies on the applicable case report forms (CRFs) in the electronic data capture system.  
 
A device deficiency is defined as an inadequacy of a medical device related to its identity, 
quality, durability, reliability, safety or performance, such as malfunction, misuse or use error 
and inadequate labeling. This includes the failure of the device to meet its performance 
specifications or otherwise perform as intended. Note: performance specifications include all 
claims made in the labeling of the device. 
 
A device malfunction is the failure of a device to meet its performance specifications or 
otherwise perform as intended, when used in accordance with the instructions for use or 
protocol. 

 
 
 
 
 
 
 
 
Page 34 of 63 
 
 Device Relationship 
Determination of whether there is a reasonable possibility that an investigational product or 
device under investigation caused or contributed to an AE is to be determined by the 
Investigator and recorded on the appropriate CRF form. Determination should be based on the 
assessment of temporal relationships, evidence of alternative etiology, medical/biologic 
plausibility and patient condition (pre-existing condition). 
 Unanticipated (Serious Adverse) Device Effect (USADE) 
Unanticipated serious adverse device effect (USADE) refers to any serious adverse effect on 
health or safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects. 
 Adverse Event and Device Deficiency/Device Malfunction Reporting  
Safety surveillance and reporting starts as soon as the patient met all enrollment requirements 
for the study. Adverse events will not be collected for screen failure subjects. Safety surveillance 
and reporting will continue until sites perform the last follow-up visit, the subject concludes 
participation in the clinical investigation, or the subject withdraws from the clinical investigation.  
Sites will collect all adverse event data, including deaths and device deficiency data throughout 
the period defined above and will report these events to the Sponsor on a CRF. Sites should 
update additional information regarding an adverse event on the appropriate CRF.  
 
Unchanged, chronic, non-worsening or pre-existing conditions are not AEs and should not be 
reported.  
 
The Sponsor will provide an offline form to allow the investigator to report SAEs in the event the 
entry cannot be made in the electronic data capture (EDC) system. This does not replace the 
EDC reporting system. Sites must still enter all information in the EDC system as soon as 
feasible. 
 
Non-cardiac related laboratory values collected in the study that are abnormal will not be 
considered AEs unless:  
1. the investigator determined that the value is clinically significant,  
2. the abnormal lab value required intervention, or  
3. the abnormal lab value required subject withdrawal from the clinical investigation. 
 
Clinical Site 
Reporting timelines 
All Sites 
Sites must report SAE and Device Deficiency/Device Malfunction events 
to the Sponsor no later than 3 calendar days from the day the site 
personnel became aware of the event or as per the investigative site’s 
local requirements, if the requirement is more stringent than those 
outlined. 
 
Note: SAEs that occur prior to the subject’s Portico ViV procedure are not 
required to be submitted/reported (refer to Table 3). 

 
 
 
 
 
 
 
 
Page 35 of 63 
 
 
Sites must record the date the site staff became aware that the event met the criteria of an SAE 
in the source document. The Investigator will further report the SAE to the local EC according to 
the institution’s EC reporting requirements. 
 
All data including deaths and device deficiency data will be collected throughout the clinical 
study and will be reported to the Sponsor through the Electronic Data Capture (EDC) system. 
The Principal Investigator will record all reportable adverse events and device deficiencies on 
the appropriate CRFs. The Principal Investigator will report the event to the EC per their 
reporting requirements.  
 
The List of Reportable Events include:  
 
1. Endpoint VARC-2 and VARC-3 events: 
 Death (all-cause and cardiovascular-related) 
 Myocardial Infarction 
 Major Vascular complications 
 Major non-vascular access-related complications 
 Stroke/TIA 
 Bleeding 
 Acute kidney Injury  
 New permanent pacemaker implantation 
 Coronary obstruction 
 Cardiac structural complication 
 Portico valve endocarditis 
 Portico valve thrombosis 
 Need for reintervention (conversion to surgery or repeat TAVR ViV) 
 Portico valve structural deterioration 
 
2. All non-serious device or procedure related Adverse Events.  
 
3. All Serious Adverse Events (SAEs) regardless of device or procedure relationship 
 
4. All Cardiovascular and Neurological events regardless of device or procedure relationship 
 
5. Device Deficiencies (DDs)/Device Malfunctions  
 
Sites must report SAEs and DDs to the Sponsor no later than 3 calendar days from the day the 
site personnel became aware of the event or as per the investigative site’s local requirements, if 
the requirement is more stringent than those outlined. 
 
Sites must record the date the study staff became aware that the event met the criteria of an 
SAE in the source document.  The Investigator will further report the SAE to the local EC 
according to the institution’s EC reporting requirements. 
 
11.6.1 Additional Considerations 
However, if the Portico delivery system entered the patient’s body but was not successfully 
implanted, the patient should continue to be followed-up until 30 days.   

 
 
 
 
 
 
 
 
Page 36 of 63 
 
 STATSTICAL CONSIDERATIONS 
The following section describes the statistical methods for the clinical investigation. A separate 
Statistical Analysis Plan will provide additional details on statistical analyses, including 
justification of clinical investigation design and analysis of descriptive endpoints.  
 Analysis Population 
Subjects who are enrolled in the study will be included in the analysis population. Subjects that 
are enrolled in the Exploratory Arm of the study will not be included in the primary arm of the 
study. 
 Statistical Analyses 
12.2.1 Primary Safety Endpoint Analyses 
The primary safety composite endpoint is all-cause mortality, disabling stroke, life threatening 
bleeding requiring transfusion, AKI requiring dialysis, and major vascular complications at 30 
days, as adjudicated by the CEC.  The proportion of subjects experiencing a primary safety 
endpoint will be estimated from the binomial model.  The 95% confidence intervals will be 
calculated using the exact Clopper–Pearson method.   
12.2.2 Primary Performance Endpoint Analyses 
The primary performance composite endpoint is all-cause mortality or disabling stroke at 1 year, 
adjudicated by the CEC.  The proportion of subjects experiencing a primary performance 
endpoint will be estimated using the Kaplan-Meier (KM) method, and the standard error of KM 
estimate will be calculated with Greenwood method.    
12.2.3 Descriptive Endpoints Analyses 
Descriptive endpoints are listed in Section 5.3. Study results will be summarized using 
descriptive statistics including mean, standard deviation, median and range for continuous data 
and count and percentage for categorical data.  
 Sample Size Calculation 
It is anticipated that up to 
subjects may be enrolled in the primary analysis population. 
Additional subjects that have undergone an attempted Portico ViV implant may be analyzed. 
The exploratory registry arm will have no limit on the number of enrolled subjects. 
 Timing of Analysis 
The analyses will be conducted on datasets locked after approximately 
 subjects 
completed their 1-year follow-up excepting deaths, withdrawals and loss to follow-up before 1-
year or crossed the 1-year visit window without a visit (missed visit). 
 Subgroup Analysis 
Subjects that were treated with adjunctive therapies during the ViV procedure (eg. snorkel, 
basilica, or chimney techniques), will be analyzed for study primary endpoints. 

 
 
 
 
 
 
 
 
Page 37 of 63 
 
 Pooling Strategy 
Additional information regarding the planned pooling strategy in this clinical study will be 
maintained in a separate Statistical Analysis Plan (SAP). 
 Procedures for Accounting for Missing Data 
This is a retrospective study collecting data that is available per the site standard of care (SOC) 
and the majority of subjects will be followed for at least 1 year. Therefore, there is no plan to 
impute missing data. 
 Planned Interim Analysis 
No interim analyses are planned for this clinical study. 
  Deviations from Statistical Plan 
The Sponsor will document any major changes to the statistical plan in an amendment to the 
statistical plan and any less significant changes to the planned analyses in the final report. 
  Exploratory Registry Arm 
Subjects enrolled that had a true inner surgical bioprosthetic aortic valve diameter of < 19 mm 
or > 27 mm will be included in a separate exploratory analysis. The data collected from these 
subjects will not be included in the primary analysis and will be analyzed using descriptive 
statistics. Data from this analysis may be used to explore future research, specifically on valve 
sizing and echocardiogram measurements (eg. PVL, TVL, etc.). 
 ACCESS TO SOURCE DATA AND DOCUMENTS 
The Investigator and study site institution will permit direct access to source data/documents for 
performing study-related monitoring, audits, EC review, and regulatory inspections or audits. 
 
Subjects (or legally authorized representatives) providing informed consent are agreeing to 
allow study monitors or regulatory authorities, including foreign countries, to review in 
confidence any records identifying the subjects in this study. This information may be shared 
with regulatory agencies; however, the Sponsor undertakes not to otherwise release the 
subject's personal and private information. 
 QUALITY ASSURANCE 
 Selection of Clinical Sites and Investigators 
The Sponsor will select Investigators qualified by training and experience to participate in the 
study. Sites will be selected based upon review of a recent site assessment, if applicable, and 
the qualifications of the investigators who will participate in the study. 
 Study Finances and Agreements 
Abbott will finance the study and will compensate investigational sites for participation in the 
study per the conditions of agreement between Abbott and the investigational site. 

 
 
 
 
 
 
 
 
Page 38 of 63 
 
 Protocol Amendments 
The Sponsor will provide approved protocol amendments to the Investigators prior to 
implementing the amendment. The Principal Investigator is responsible for notifying the EC or 
equivalent committee of the protocol amendment (administrative changes) or obtaining EC’s 
approval of the protocol amendment (changes in subject care or safety), according to the 
instructions provided by the Sponsor with the protocol amendment.   
 
Sites must provide documentation of acknowledgement and approval of the protocol 
amendment by the EC prior to implementation of the protocol amendment. Sites must also 
provide copies of this documentation to the Sponsor. 
 Training 
All Investigators and study personnel are required to attend Sponsor training sessions, which 
may be conducted at an Investigator's meeting, a site initiation visit, or other appropriate training 
sessions. Over-the-phone or self-training may take place as required. Training of Investigators 
and study personnel will include, but is not limited to, the protocol requirements, electronic case 
report form completion, and study personnel responsibilities. All Investigators and study 
personnel that are trained must sign a training log (or an equivalent) upon completion of the 
training. Prior to signing the training log, Investigators and study personnel must not perform 
any protocol related activities that are not considered standard of care at the site. 
 Monitoring 
Sponsor and/or designee will monitor the study over its duration according to the protocol 
specific monitoring plan which will include the planned extent of source data verification.  
 
Prior to initiating any procedure, the Sponsor monitor (or delegate) will ensure that the following 
criteria are met:  
 
 The investigator understands and accepts the obligation to conduct the study 
according to the protocol and applicable regulations and has signed the Clinical Trial 
Agreement. 
 
 The Investigator and his/her staff should have sufficient time and facilities to conduct 
the study and should have access to an adequate number of appropriate subjects to 
conduct the study.  
 
 
 Sites must have source documentation (including original medical records) to 
substantiate proper informed consent procedures, adherence to protocol procedures, 
adequate reporting and follow-up of adverse events, accuracy of data collected on 
case report forms, and device information.  
 
 The Investigator/site will permit access to such records and will maintain a 
monitoring visit sign-in log at the site. The Investigator will agree to dedicate an 
adequate amount of time to the monitoring process. The Investigator and/or research 
coordinator will be available for monitoring visits. It is expected that the Investigator 
will provide the monitor with a suitable working environment for review of study-
related documents. 

 
 
 
 
 
 
 
 
Page 39 of 63 
 
 Protocol Compliance and Deviations from the Protocol 
A protocol deviation must be reported for: 
 
 Any deviation to the informed consent process 
 Any deviation in the inclusion or exclusion criteria disqualifying patient eligibility 
 Any deviation in the safety reporting requirements outlined above in section 9. 
 
The Principal Investigator must maintain accurate, complete, and current records, including 
documents showing the date of and reason for each deviation from the protocol. Relevant 
information for each deviation will be documented as soon as possible on the applicable CRF.  
 
The Principal Investigator is required to adhere to local regulatory requirements for reporting 
deviations to their local EC.  
 
The Sponsor will not grant any waivers for protocol deviations. Sites must report the above 
noted deviations to the Sponsor using the Deviation CRF. The Sponsor will monitor the 
occurrence of protocol for evaluation of investigator compliance to the protocol and regulatory 
requirements and handle according to written procedures. Investigators will inform their EC or 
equivalent committee of all protocol deviations in accordance with their specific EC or equivalent 
committee reporting policies and procedures.  
 
In the event of repeated non-compliance, as determined by the Sponsor, a Sponsor’s monitor or 
company representative will attempt to secure compliance by one or more of the following (and 
not limited to):  
 
 Visiting the Investigator and/or delegate 
 Telephoning the Investigator and/or delegate 
 Corresponding with the Investigator and/or delegate 
 
Repeated non-compliance with the signed agreement, the protocol, or any other conditions of 
the study may result in further escalation in accordance with the Sponsor’s written procedures, 
including securing compliance or, at its sole discretion, the Sponsor may terminate the 
Investigator's participation in the study. 
 Quality Assurance and Audits 
A Sponsor representative or designee may request access to all study records, including source 
documentation, for inspection during a Quality Assurance audit.  
 
If an Investigator is contacted by a Regulatory Agency in relation to this study, the Investigator 
will notify Sponsor immediately. The Investigator and Research Coordinator must be available 
to respond to reasonable requests and audit queries made during the audit process. The 
Investigator must provide the Sponsor with copies of all correspondence that may affect the 
review of the current study (e.g., Form FDA 483, Inspectional Observations, Warning Letters, 
Inspection Reports, etc.). The Sponsor may provide any needed assistance in responding to 
regulatory audits.  
 
The Sponsor may also prepare an audit plan and conduct an audit. The designated Sponsor 
auditors will be different than those engaged in the site monitoring activities. The auditor shall 

 
 
 
 
 
 
 
 
Page 42 of 63 
 
consistent with, these source documents, and any discrepancies will be explained in writing. 
Anonymized source documents must be uploaded to the database on request of the Sponsor. 
The Principal Investigator will ensure accuracy, completeness, legibility, and timeliness of the 
data reported to the Sponsor on the CRFs and in all required reports. 
 Records Retention 
The Sponsor and the Principal Investigator will maintain the study documents as required. 
Measures will be taken to prevent accidental or premature destruction of these documents. The 
Principal Investigator or the Sponsor may transfer custody of records to another person/party 
and document the transfer at the investigational site or the Sponsor’s facility, as appropriate. 
 
These documents must be retained by the investigational site for a period of at least two years 
after the conclusion of the study and made available for monitoring or auditing by the Sponsor’s 
representative or representatives of the applicable regulatory agencies. 
 
All original source documents must be stored for the maximum time required by the regulations 
at the hospital, research institute, or practice in question. If original source documents can no 
longer be maintained at the site, the Principal investigator will notify the Sponsor.  
 ETHICAL CONSIDERATIONS 
The Principal Investigator at each investigational site will obtain EC approval for the protocol 
and ICF/other written information provided to the patient prior to consenting and enrolling 
patients in this study. The site must receive the approval letter prior to the start of this study and 
provide a copy to the Sponsor.  
 
Sites will submit any amendments to the protocol as well as associated ICF changes to the EC 
and written approval obtained prior to implementation, according to each institution’s EC 
requirements.  
 
No changes will be made to the protocol or ICF or other written information provided to the 
patient without appropriate approvals, including EC, the Sponsor, and the regulatory agencies 
(if applicable).  
 
Until the study is completed, the Investigator will advise his/her EC of the progress of this study, 
per EC requirements. Written approval must be obtained from the EC on an annual basis to 
continue the study, or according to each institution’s EC requirements.  

 
 
 
 
 
 
 
 
Page 44 of 63 
 
such information will be incorporated into the site informed consent, as applicable. If required, 
additional subject coverage or a study specific insurance will be provided by the Sponsor. 
 
Investigators are required to adhere to the protocol, signed investigator agreement and any 
conditions required by the EC. If a site has long-standing, open monitoring findings or 
challenges with compliance, the monitor or study management shall consider developing a 
corrective and preventative action plan. 
 SUSPENSION OR PREMATURE TERMINATION OF THE STUDY 
The Sponsor reserves the right to terminate the study at any stage, with appropriate written 
notice to the Investigators, local EC, and relevant regulatory authorities, if required.  
 
An Investigator, EC, or regulatory authority may suspend or prematurely terminate participation 
in a study at the investigational sites for which they are responsible. The Principal Investigators 
will follow the requirements specified in the Clinical Trial Agreement.  
 
If suspicion of an unacceptable risk to subjects arises during the study or when so instructed by 
the EC or regulatory authority, the Sponsor may suspend the study while the risk is assessed. 
The Sponsor will terminate the study if an unacceptable risk is confirmed. If the Sponsor 
completes an analysis of the reasons for the suspension, implements the necessary corrective 
actions, and decides to lift the temporary suspension, the Sponsor will inform the Principal 
Investigator, EC, or regulatory authority, where appropriate, of the rationale, providing them with 
the relevant data supporting this decision. Approval from the Ethics Committee or regulatory 
authority, where appropriate, will be obtained before the study resumes. If subjects have been 
informed of the suspension, the Principal Investigator or authorized designee will inform them of 
the reasons for resuming the study. 
 
If the Sponsor suspends or prematurely terminates the study at an individual investigational site 
in the interest of safety, the Sponsor will inform all other Principal Investigators. 
 
If suspension or premature termination occurs, the Sponsor will remain responsible for providing 
resources to fulfill the obligations from the protocol and existing agreements for following up the 
subjects enrolled in the study, and the Principal Investigator or authorized designee will 
promptly inform the enrolled subjects at his/her investigational site, if appropriate. 
 
 
 
 

 
 
 
 
 
 
 
 
Page 59 of 63 
 
 
 NYHA Functional Classification 
 
Class I 
Patient has cardiac disease but without resulting limitations of 
ordinary physical activity. Ordinary physical activity (eg, walking 
several blocks or climbing stairs) does not cause undue fatigue, 
palpitation, dyspnea, or anginal pain. Limiting symptoms may occur 
with marked exertion. 
 
Class II 
 
 Patient has cardiac disease resulting in slight limitation of ordinary 
physical activity. Patient is comfortable at rest. Ordinary physical 
activity such as walking more than 2 blocks or climbing more than 1 
flight of stairs results in limiting symptoms (eg, fatigue, palpitation, 
dyspnea, or anginal pain). 
 
Class III 
 
 Patient has cardiac disease resulting in marked limitation of physical 
activity. Patient is comfortable at rest. Less than ordinary physical 
activity (eg, walking 1 to 2 level blocks or climbing 1 flight of stairs) 
causes fatigue, palpitation, dyspnea, or anginal pain. 
 
Class IV 
Patient has dyspnea at rest that increases with any physical activity. 
Patient has cardiac disease resulting in inability to perform any 
physical activity without discomfort. Symptoms may be present even 
at rest. If any physical activity is undertaken, discomfort is increased. 
 
 
 

 
 
 
 
 
 
 
 
Page 60 of 63 
 

 
 
 
 
 
 
 
 
Page 61 of 63 
 

 
 
 
 
 
 
 
 
Page 62 of 63 
 

 
 
 
 
 
 
 
 
Page 63 of 63 
 
 Bibliography 
 
1 Kappetein A., et al. Updated standardized endpoint definitions for transcatheter aortic valve 
implantation: The Valve Academic Research Consortium-2 consensus document. J Thorac 
Cardiovasc Surg. 2013;145:6-23. 
 
2 Genereux P., et al. Valve Academic Research Consortium 3: updated endpoint definitions for 
aortic valve clinical research. European Heart Journal. 2021;00:1-33. 
 
3 Bortolotti U., et al. Results of reoperation for primary tissue failure of porcine bioprostheses. J 
Thorac Cardiovasc Surg 1985;90:564 –9. 
 
4 Jamieson W., et al. Re-operation for bioprosthetic aortic structural failure: risk assessment. 
Eur J Cardiothorac Surg 2003;24:873– 8. 
3 
5 J Webb J., et al. Transcatheter Aortic Valve Implantation Within Degenerated Aortic 
Surgical Bioprostheses: PARTNER 2 Valve-in-Valve Registry. J Am Coll Cardiol 2017;69:2253–
62). 
 
6 Dvir D., et al. Transcatheter Aortic Valve Replacement for Degenerative Bioprosthetic Surgical 
Valves: Results From the Global Valve-in-Valve Registry Circulation. 2012; 126:2335-2344. 
 
7 Jeger R. et al., First-in-man Portico® transcatheter aortic valve-in-valve implantation in a 
degenerated 19 mm Mitroflow® aortic pericardial heart valve. EuroIntervention. 2014.4(9):1368 
 
8 Kim W-K. et al., Transfemoral valve-in-valve implantation of a St. Jude Medical Portico in a 
failing trifecta bioprosthesis: a case report. Clin Res Cardiol. 2015. 104:363-365 
 
9 Dvir, D. et al. Trancatheter Aortic Valve Implantation in Failed Bioprosthetic Surgical Valves. 
JAMA 2014;312(2):162-170. 
 
10 Deharo P. et al. Valve-in-valve transcatheter aortic valve implantation after failed surgically 
implanted aortic bioprosthesis versus native transcatheter aortic valve implantation for aortic 
stenosis: data from a nationwide analysis. Archives of cardiovascular disease 2021;114:341-50.