Beating Heart Mitral Valve REPair With the HARPOON™ System: ReaL World Outcomes From a multICenter observATional European Registry
Phase: NA
Conditions: Severe Degenerative Mitral Regurgitation Due to Mid-segment Posterior Leaflet Prolapse
Sponsor: Edwards Lifesciences

 
 
 
 
Registry for the Harpoon Medical Device 
 
 
BeaƟng Heart Mitral Valve REPair with the HARPOON™ System: ReaL 
world outcomes from a multICenter observATional European registry 
(REPLICATE #2019-12)  
 
 
  
NCT04393779 
 
 
January 14, 2020 

EDWARDS LIFESCIENCES LLC 
CLINICAL INVESTIGATIONAL PLAN 
PROTOCOL NUMBER: 2019-12 
 
 
CONFIDENTIAL AND PROPRIETARY DATA: This document and the information contained herein may not be reproduced, used, or disclosed 
without written permission from Edwards Lifesciences LLC 
Revision A: 14 January 2020 
 
 
 
                    
                                                    
Beating Heart Mitral Valve REPair with the 
HARPOON™ System:  ReaL world outcomes from 
a multICenter observATional European registry 
(REPLICATE) 
 
CLINICAL INVESTIGATION PLAN (CIP) 
 
 
Protocol Number: 2019-12 
 
Version:  A  
Date:  14 January 2020 
 
 
Registry Sponsor: 
HARPOON Medical, an indirect wholly-owned subsidiary of Edwards Lifesciences Corporation  
Edwards Lifesciences  
One Edwards Way 
Irvine, CA 92614  
USA 
 
 
 
 
 

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1.0 PROTOCOL REVISION HISTORY 
Protocol Revision Number 
Protocol Revision Date 
A 
14 January 2020 
 
 
 

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2.0 PROTOCOL SIGNATURE PAGE 
Registry Title: 
HARPOON™ System:  ReaL world outcomes from a multICenter 
observATional European registry (REPLICATE) 
Protocol Number: 
2019-12 
Version: 
Rev. A 
Date: 
14 January 2020 
I have read this protocol and agree to participate in the clinical investigation sponsored by HARPOON 
Medical, an indirect wholly-owned subsidiary of Edwards Lifesciences Corporation.  I agree to conduct this 
investigation according to the requirements of the registry protocol and in accordance with the 
International Standard ISO 14155 (relevant sections), ethical principles that have their origins in the 
Declaration of Helsinki, applicable European or regional laws and regulations, and conditions imposed by 
the reviewing Ethics Committee.   
I agree to supervise all sub-investigators at my site as well and to ensure appropriate informed consent is 
obtained from all subjects prior to inclusion in this registry. This protocol contains confidential proprietary 
information with respect to Edwards Lifesciences’ products and clinical studies. I agree to hold this 
information in confidence and not to disclose it to any third parties as outlined in the clinical trial 
agreement, or until this information becomes a matter of public knowledge or until a formal agreement 
for that purpose is entered into by the parties. 
 
STATEMENT OF COMPLIANCE 
The Registry Protocol will be conducted in accordance with 
• 
Declaration of Helsinki (Rev. 2013)  
• 
ISO 14155: 2011 (Relevant sections) 
In addition, the Registry Protocol will comply with any applicable regional regulations. The clinical 
investigation shall not begin until the required approval/favourable opinion from the EC is obtained. 
 
 
 
INVESTIGATOR SIGNATURE 
 
DATE 
INVESTIGATOR NAME (PRINTED) 
 
 

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4.0 PROTOCOL SYNOPSIS 
Title: 
HARPOON™ System:  ReaL world outcomes from a multICenter 
observATional European registry (REPLICATE) 
Protocol Number: 
2019-12 
Sponsor 
HARPOONTM Medical, an indirect wholly owned subsidiary of Edwards 
Lifesciences Corporation 
Design: 
A single arm, prospective, multicenter, post-market, observational registry 
Objective: 
To collect data on the HARPOONTM Mitral Valve Repair System for use in 
patients with severe degenerative mitral regurgitation due to posterior 
leaflet prolapse. 
Device: 
HARPOONTM Beating Heart Mitral Valve Repair System 
Population: 
Patients who undergo mitral valve repair surgery with the HARPOONTM 
Beating Heart Mitral Valve Repair System as part of standard of care 
treatment for severe degenerative mitral regurgitation due to mid- segment 
posterior leaflet prolapse  
Enrollment: 
Approximately 150 implanted subjects, including up to 30 subjects enrolled 
after the HARPOON surgery (capped at 5 subjects per site) 
 
Definition of 
   Enrollment: 
A subject is considered enrolled upon providing a signed informed consent 
Registry Sites: 
Up to 50 sites in Europe 
Follow-up: 
Clinical and imaging assessments at baseline/pre-procedure, procedure, 
discharge, 30 days, 1-year and annually thereafter through 5 years post-
implant, per local standard of care 
Outcome Measures: Freedom from re-operation due to recurrent severe mitral regurgitation 
through 1-year post-implant  
 
 
 
 
Statistical Analysis: No planned statistical hypothesis testing will be performed within this 
REPLICATE Registry protocol.  Descriptive and summary statistical analysis will be 
provided for baseline/pre-procedure, procedure and outcome variables. 
 
 
 
 
 
 
 

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5.0 ABBREVIATIONS 
AE 
Adverse event 
CA 
Competent authority 
CE 
Conformité Européene 
CEC 
Clinical Events Committee 
CKD 
Chronic kidney disease 
CRF 
Case report form 
EC 
Ethics Committee 
ECL 
Echo Core Laboratory 
EDC 
Electronic data capture 
EFS 
Early Feasibility Study 
eCRF 
Electronic case report form 
ePTFE 
Expanded polytetrafluoroethylene 
GCP 
Good clinical practice 
ID 
Identity Number 
ISO 
International Organization for Standardization 
LTFU 
Lost to follow-up 
MDD 
Medical Device Directive 
MR 
Mitral Regurgitation 
MVRS 
Beating Heart Mitral Valve Repair System 
NYHA 
New York Heart Association 
OR 
Operating Room 
PA 
Pulmonary Artery 
PEC 
Patient Eligibility Committee 
SAE 
Serious Adverse Event 
SOC 
Standard of Care 
TOE 
Transoesophageal Echocardiogram 
TTE 
Transthoracic Echocardiogram 
USADE 
Unanticipated Serious Adverse Device Effect 
 
 
 
 
 

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Table of Contents 
 
Section 
Page 
1.0 
PROTOCOL REVISION HISTORY ............................................................................................... 2 
2.0 
PROTOCOL SIGNATURE PAGE ................................................................................................. 3 
3.0 
REGISTRY CONTACTS .............................................................................................................. 4 
3.1 SPONSOR AND REGISTRY CONTACTS ............................................................................................... 4 
3.2 REGISTRY OVERSIGHT ...................................................................................................................... 4 
3.3 CLINICAL SITES ................................................................................................................................. 4 
4.0 
PROTOCOL SYNOPSIS ............................................................................................................. 5 
5.0 
ABBREVIATIONS ..................................................................................................................... 6 
6.0 
INTRODUCTION AND BACKGROUND ....................................................................................... 9 
6.1 DEVICE DESCRIPTION ....................................................................................................................... 9 
6.2 PRIOR CLINICAL EXPERIENCE WITH THE HARPOON SYSTEM: EFS AND CE MARK TRIALS .................. 9 
7.0 
REGISTRY DESIGN ................................................................................................................ 10 
7.1 OBJECTIVE ...................................................................................................................................... 10 
7.2 DESIGN .......................................................................................................................................... 11 
7.3 OUTCOME MEASURES ................................................................................................................... 11 
7.4 NUMBER OF SUBJECTS ................................................................................................................... 11 
8.0 
REGISTRY POPULATION ........................................................................................................ 11 
8.1 SCREENING AND ENROLMENT ....................................................................................................... 11 
9.0 
REGISTRY PROCEDURES AND SCHEDULE OF ASSESSMENTS ................................................... 11 
9.1 SCHEDULE OF ASSESSMENTS ......................................................................................................... 11 
9.2 SCREENING EVALUATIONS AND PATIENT ELIGIBILITY COMMITTEE ................................................ 11 
9.3 BASELINE/PRE-PROCEDURE EVALUATIONS .................................................................................... 11 
9.4 TREATMENT/PROCEDURE ASSESSMENTS ...................................................................................... 12 
9.5 REGISTRY EXIT CRITERIA AND PROCEDURES .................................................................................. 13 
9.6 DEATH AND SURGICAL VALVE INTERVENTION ............................................................................... 14 
10.0 
STATISTICAL METHODS ........................................................................................................ 14 
11.0 
SAFETY REPORTING .............................................................................................................. 15 
11.1 DEFINITIONS OF DEVICE-RELATED ADVERSE EVENTS AND DEVICE DEFICIENCIES ........................... 15 
11.2 RELATEDNESS OF REPORTED EVENT............................................................................................... 17 
11.3 REPORTING ADVERSE EVENTS ........................................................................................................ 17 
12.0 
RISKS AND BENEFITS ............................................................................................................ 18 

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13.0 
REGISTRY CONDUCT AND DATA MANAGEMENT ................................................................... 18 
13.1 PROTOCOL DEVIATIONS ................................................................................................................. 18 
13.2 REGISTRY CONDUCT, TRAINING, AND CONFIDENTIALITY ............................................................... 18 
13.3 DOCUMENTATION REQUIREMENTS ............................................................................................... 19 
13.4 DATA MANAGEMENT..................................................................................................................... 19 
13.5 MONITORING ................................................................................................................................. 20 
13.6 DATA AND DOCUMENT RETENTION ............................................................................................... 20 
13.7 REGISTRY PROTOCOL AMENDMENTS ............................................................................................. 20 
13.8 REGISTRY COMPLETION OR TERMINATION .................................................................................... 20 
13.9 PUBLICATIONS ............................................................................................................................... 20 
14.0 
STATEMENTS OF COMPLIANCE AND CONFIDENTIALITY ......................................................... 21 
14.1 APPLICABLE REGULATIONS AND GUIDELINES ................................................................................ 21 
14.2 DATA PROTECTION AND PATIENT CONFIDENTIALITY ..................................................................... 21 
14.3 INVESTIGATOR RESPONSIBILITIES .................................................................................................. 21 
14.4 SPONSOR RESPONSIBILITIES .......................................................................................................... 21 
 
List of Tables 
TABLE 1 - DATA COLLECTION SCHEDULE .............................................................................................................. 13 
TABLE 2: ADVERSE EVENT DEFINITIONS (ISO 14155) ............................................................................................ 16 
 
Attachments 
ATTACHMENT A – SUGGESTED DEFINITIONS ..................................................................................... 23 
 
 
 

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6.0 INTRODUCTION AND BACKGROUND 
6.1 
DEVICE DESCRIPTION 
The HARPOON™ Beating Heart Mitral Valve Repair System, known hereafter as HARPOON System, is 
described in detail in the Instructions for Use (IFU).  The IFU will be provided to the sites and Ethics 
Committees (ECs), and a copy included in the Trial Master File and Investigator Site File. 
6.1.1 
REGULATORY STATUS 
The HARPOON System is CE-marked. Its use in this registry is consistent with the product’s labelling.  
6.1.2 
INDICATION FOR USE  
The HARPOON System is intended to reduce the degree of mitral regurgitation (MR) in patients with 
severe MR caused by mid-segment posterior leaflet prolapse as a result of degenerative mitral valve 
disease by delivering and anchoring Expanded polytetrafluoroethylene (ePTFE) chords to the prolapsed 
mitral valve leaflet in a beating heart.   
6.1.3 
TECHNICAL DESCRIPTION OF THE DEVICE 
The HARPOON System consists of two parts: 1) HARPOON Introducer and 2) HARPOON Delivery System. 
Both items are essential for proper delivery of ePTFE implants in the mitral valve leaflet to eliminate or 
reduce mitral valve regurgitation.  The HARPOON System is a Class III product following rule 8 of the Annex 
IX of the MDD 93/42/EEC (intended to be used to deliver an implant in direct contact with the heart).  For 
a detailed description of the HARPOON System, please refer to the HARPOON™ Beating Heart Mitral Valve 
Repair System Instructions for Use (IFU). 
6.2 
PRIOR CLINICAL EXPERIENCE WITH THE HARPOON SYSTEM: EFS AND CE MARK TRIALS 
Two (2) ongoing European clinical trials have assessed the safety and performance of the HARPOON 
System: the Early Feasibility Study (EFS) and the CE Marking Trial (CE Mark, conducted under two (2) 
clinical protocols):  
The purpose of the EFS trial is to assess the safety and performance of the HARPOON System (previously 
the Harpoon Medical TSD-5 Device). The early data collected from the trial were used to power and 
support the design of the study to support CE Mark of the HARPOON System. The purpose of the CE 
Marking trial is to assess the safety and performance of the HARPOON System in subjects with severe 
degenerative mitral regurgitation by implanting ePTFE chords in the posterior leaflet of the mitral valve 
via transapical access thereby obviating the need for open surgery and its risks. 
This clinical experience summary is based on clinical data as of 02 April 2019 for subjects enrolled from 16 
February 2015 (first enrolment in EFS) to 07 November 2017 (last enrolment in CE Mark).  
Sixty-five (65) subjects were enrolled at six (6) investigational sites between both studies. This includes 
thirteen (13) subjects enrolled in the EFS study and fifty-two (52) subjects in the CE Mark study. Of the 
enrolled population, sixty-two (62) subjects were implanted with the HARPOON System (thirteen (13) in 
the EFS trial and forty-nine (49) in the CE Mark Trial). Three patients left the operating room without the 
investigational device. One case was aborted before the Harpoon procedure and 2 cases were converted 
to standard of care (SOC) mitral valve surgery. Overall, follow-up compliance of 100% (56/56) of eligible 
subjects was achieved at the 1-year visit. Six (6) HARPOON System subjects were censored through 1-year 
including two (2) deaths and four (4) reoperations. Follow-up compliance of 98% (40/41) has been 
achieved so far at the 2-year visit; nine (9) subjects have yet to reach their 2-year follow-up window. 
Follow-up is currently ongoing. 

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6.2.1 
SAFETY ENDPOINTS 
One (1) early (1.6%) and two (2) late (2.0%/pt-yr) deaths have been reported. The CEC has adjudicated 
one (1) early death with primary cause of death as cardiac arrest, and not related to the study device. One 
of the two (2) late deaths was adjudicated as caused by aortic dissection and device related, and the 
second late death was a sudden death with unknown causality, and therefore was also counted as device 
related.  One (1) early (1.6%) and ten (10) late (10.1 %/pt-yr) reoperations have been reported, including 
nine (9) repairs and two (2) mitral valve replacements.   
There were no reports of unanticipated adverse device effects. 
6.2.2 
PRIMARY PERFORMANCE RESULTS 
In the EFS study, procedural success was defined as the subject leaving the operating room with at least 
one (1) ePTFE chord in place, having a discharge MR grade of ≤ mild and 30-Day MR grade ≤ mild, without 
a reoperation prior to 30 days. Procedural success was achieved in 84.6% (11/13) of the enrolled cohort. 
In the CE Mark study, procedural success was defined as the subject leaving the operating room with at 
least one (1) ePTFE chord in place, having a discharge MR grade of ≤ moderate and 30-Day MR grade ≤ 
moderate, without a reoperation prior to 30 days. Procedural success was achieved in 88.5% (46/52) of 
the enrolled cohort. 
6.2.3 
SECONDARY PERFORMANCE RESULTS 
6.2.3.1 
MITRAL REGURGITATION 
Severity of mitral regurgitation (MR) was evaluated by the Echo Core Lab at the baseline, discharge, 1-
month, 6-month, 1-year, and 2-year follow-up visits for the HARPOON System cohort. At 2-year follow up, 
65.8% (25/38) of patients had mitral regurgitation of mild or less, 26.3% (10/38) of patients had moderate 
MR and 7.9% (3/38) of patients had severe MR.  
Several subjects with moderate to severe mitral regurgitation underwent re-operations and were 
identified as having ruptured ePTFE chords.  An investigation was conducted to determine the root cause 
of ePTFE chord ruptures. The root cause of the chord ruptures was found to be over-tensioned chords. 
Findings confirmed that no material or device design changes were required.  As a result of this 
investigation, screening and procedural updates to the IFU, Training Program Materials, and Post Market 
Clinical Follow-up Study were made to mitigate future ePTFE chord ruptures. 
6.2.3.2 
NYHA FUNCTIONAL CLASS 
Performance was also assessed using NYHA functional classification change.  At 1 year of follow-up, 92.3% 
of subjects were in NYHA class I, 5.8% were in NYHA class II, and 1.9% were in NYHA class III, corresponding 
to an improvement (50%) or maintenance (48%) of NYHA class for 98% (51/52) of subjects. 
6.2.4 
SUMMARY 
The results of the EFS and CE Marking trials support the safety and performance of the HARPOON System.  
Patient follow-up is ongoing. 
7.0    REGISTRY DESIGN 
7.1 
OBJECTIVE 
The objective of this registry is to collect data on the HARPOONTM Mitral Valve Repair System for use 
in patients with severe degenerative mitral regurgitation due to posterior leaflet prolapse. 

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7.2 
DESIGN 
The design is a single arm, prospective, multicentre, post-market observational registry. 
7.3 
OUTCOME MEASURES 
The key outcome measure is freedom from re-operation due to recurrent severe mitral regurgitation 
through 1-year post-implant. 
7.4 
NUMBER OF SUBJECTS 
Approximately 150 implanted subjects, including up to 30 subjects enrolled after the HARPOON surgery 
(capped at 5 subjects per site) will be included in this registry. 
8.0    REGISTRY POPULATION 
The registry population will comprise of subjects (over 18 years of age) who undergo mitral valve repair 
surgery with the HARPOONTM Beating Heart Mitral Valve Repair System per the IFU as part of standard 
of care treatment for severe degenerative mitral regurgitation due to mid- segment posterior leaflet 
prolapse, and who are willing to participate in the registry and provide signed informed consent for the 
collection and use of their data.  
8.1 
SCREENING AND ENROLMENT 
Subjects who are clinically suitable for treatment with the HARPOON System, as per the IFU, will be 
evaluated for inclusion in the registry.   
Subjects who agree to participate must sign an Ethics Committee (EC)-approved informed consent and 
will be considered part of the enrolled population.   
As outlined in section 7.4, up to 30 subjects may be enrolled after undergoing the HARPOON surgery, 
capped at 5 subjects per site.   Subjects that have already been implanted with the HARPOON device will 
be asked to sign an EC-approved informed consent to enroll in the registry to allow collection of the data 
on their HARPOON surgery and data through 5 year follow-up.  
A subject is considered enrolled upon providing a signed informed consent. 
9.0 REGISTRY PROCEDURES AND SCHEDULE OF ASSESSMENTS 
9.1 
SCHEDULE OF ASSESSMENTS 
Clinical and echocardiographic data available from routine clinical assessments will be collected for the 
following time points:  Baseline/pre-procedure, Procedure, Discharge, 30 days, 1 year and annually 
through 5 years.  It is expected that the institutions' standard-of-care for the management of patients 
undergoing mitral valve repair surgery will be aligned and consistent with established guidelines and 
recommendations and may include the assessments described below.  
9.2 
SCREENING EVALUATIONS AND PATIENT ELIGIBILITY COMMITTEE 
All testing and assessment to determine if a patient is suitable for treatment with the HARPOON System 
is conducted within the standard-of care at the hospital.  
9.3 
BASELINE/PRE-PROCEDURE EVALUATIONS 
The following baseline and pre-procedure assessments, if conducted as part of the institution’s standard 
of care, will be recorded: 

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• 
Assessment of NYHA Heart Failure Class 
• 
3D Transoesophageal echocardiogram (TOE)  
• 
Assessment of Medical History 
9.4 
TREATMENT/PROCEDURE ASSESSMENTS 
9.4.1 
PROCEDURE OVERVIEW: 
The HARPOON System procedure will be conducted in accordance to the HARPOON System CE-Mark 
Instructions for Use.   
The registry investigator will be trained on device use through didactic, practicum training, and proctoring. 
Complete details on the preparation and use of the HARPOON System can be found in the Instructions for 
Use.  
9.4.2 
POST-PROCEDURE FOLLOW-UP ASSESSMENTS 
Post-procedure management: Standard hospital protocols for the management of subjects after mitral 
valve surgery shall be followed.   
Discharge assessment: All subjects shall be discharged from the hospital at the discretion of the attending 
cardiac surgeon.  Prior to discharge, all subjects shall undergo pre-discharge testing as per hospital 
standard of care, which may include a comprehensive pre-discharge TTE. 
Subject follow-up: Follow-up visits at 30 days, 1 year and annually through 5 years may be conducted in 
person (preferred) or via telephone interview, to minimize patient attrition, as per institution’s standard 
of care. It is important that follow-up visit schedule be maintained as closely as possible for all subjects. 
Edwards recognizes that subjects may not be able to complete all scheduled follow-up at precisely the 
date required, and therefore, a period of time in which each visit could be completed is indicated in Table 
1.  
In the event that study personnel learn of a subject’s hospitalization or re-operation outside the study 
center, the center should make every effort to obtain copies of reports or results based on tests (e.g., 
echocardiogram) and/or procedures performed on the study subject. 
The following assessments, if conducted as part of the institution’s standard of care, will be recorded 
through 5-year follow-up: 
• 
Transthoracic echocardiogram (TTE)  
• 
SAEs that results in a death, device-related events and device deficiencies/device malfunctions 
• 
Assessment of NYHA Heart Failure Class (at 1-year follow-up only) 
Table 1 summarizes the data that will be collected at each time point, per the local standard of care. 
 
 

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• 
Withdrawal 
o Subject Withdrawal: The subject may voluntarily withdraw from this registry at 
any time, without penalty or loss of benefits to which they are otherwise 
entitled. 
o Physician Withdrawal: The Investigator also has the right to withdraw a subject if 
s/he feels it is in the best interest of the subject. 
o Sponsor Withdrawal: The Sponsor may prematurely terminate the registry. 
Circumstances under which the Sponsor can suspend or stop this registry include, but 
are not limited to, low enrolment or new information regarding safety or device 
performance. 
• 
Death 
• 
Lost to follow-up 
o If a subject cannot be reached for at least two (2) consecutive  follow-up visits. 
For subjects who are lost-to-follow-up or withdraw early, Edwards may request the site to search death 
registries as available or applicable per GDPR requirements and may request the site to obtain the 
death certificate, if applicable. 
A subject who has been withdrawn from the registry will not be replaced. 
9.6 
DEATH AND SURGICAL VALVE INTERVENTION 
9.6.1 
DEATH 
In the event of subject death, every effort should be made to obtain a copy of a death summary/death 
certificate. Information on the cause of death will be determined by the investigator(s) and reported in 
the registry electronic data capture (EDC) system.   
9.6.2 
SURGICAL VALVE INTERVENTION 
In the event of device explant or surgical intervention, every effort should be made to obtain a copy of 
the procedure notes as well as any accompanying imaging data (i.e. CT, echo). Information on the cause 
of explant/surgical intervention will be determined by the investigator(s) and reported in the registry EDC 
system.  Subjects who have a surgical reintervention or whose device is explanted will be followed for 30 
days or until resolution of any adverse events related to the procedure, and then exited from the registry. 
Effort should also be made to return any explanted devices to the Sponsor for analysis by the Edwards 
Complaint Handling team. Return kits for explanted devices will be provided, upon request, by the 
Edwards Surgical Complaint Handling Department. 
10.0 STATISTICAL METHODS 
The analysis population will consist of the subjects who were enrolled and undergone a mitral valve repair 
surgery with the HARPOON System, regardless of procedure outcome.  The analysis population excludes 
any subjects who signed the registry consent but were exited from the study prior to the procedure. 
There is no planned statistical hypothesis testing within this REPLICATE Registry protocol.  Descriptive and 
summary statistical analysis will be provided for baseline/pre-procedure, procedure and outcome 
variables. 

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11.0 SAFETY REPORTING 
Safety event reporting to the sponsor is the Investigator’s responsibility and will start at the time of 
enrolment and will continue through the duration of the registry.  
The following critical safety events will be collected in this registry: 
• 
SAEs where the outcome is death, and  
• 
Device-related events/deficiencies.   
These events will be recorded in the EDC system by the Clinical Study Coordinator (or designated site 
personnel). If the EDC system is not accessible, the event should be reported to the sponsor by using the 
following e-mail address:   REPLICATE-Safety@edwards.com. Note: the event(s) will still need to be 
recorded in the EDC once the system is functional. 
All the information related to the reported events, such as an awareness date, start and stop dates, 
description of event, seriousness, action taken and outcome, and relatedness to the HARPOON System 
procedure and device, will be assessed and recorded in the EDC system in a timely manner by the site. 
Whether an event meets the definition of serious or device-related will be determined by the registry 
investigator using the ISO 14155 definitions (see Table 2).  Relatedness of the event to the HARPOON 
System device will be determined by the investigator by using the causality categories listed below.  
All relevant source documentation for reported events should be forwarded to Sponsor Safety 
Department via email  REPLICATE-Safety@edwards.com.  Source documentation must be redacted to 
remove identifiable references to the patient prior to submission to Sponsor.  
Sponsor’s Surgical Safety Team will review all reported events as per applicable regulatory requirements 
and Sponsor’s internal standard operating procedures, including vigilance assessment and reporting to 
Edwards Complaint Handling or Regulatory Affairs groups who performs appropriate reporting to 
Regulatory Authorities, if applicable and per national legislation. 
Local safety reporting to ethics committees will be completed, as required.  Events will be collected and 
reported through 5 years post-procedure. 
11.1 DEFINITIONS OF DEVICE-RELATED ADVERSE EVENTS AND DEVICE DEFICIENCIES 
Table 3 below includes all event definitions as per ISO14155.  Please note that for this registry, only the 
following events will be reported on the eCRFs: 
• 
Adverse device effect (ADE) 
• 
Serious adverse device effect (SADE) 
• 
Unanticipated serious adverse device effect (USADE) 
• 
SAE that results in a death 
• 
Device deficiency/device malfunction 
 
 

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11.3.3 VIGILANCE REPORTING  
Vigilance requirements apply and the site is required to report incidents and complaints as per the 
institution’s procedure.  
12.0 RISKS AND BENEFITS 
Patients participating in this registry will undergo mitral valve repair surgery with the HARPOON System 
as part of their standard-of-care treatment for severe degenerative mitral regurgitation due to mid- 
segment posterior leaflet prolapse.  There are potential risks related to the mitral valve repair surgery 
and the HARPOON System.  These risks as well as product handling and implant procedure guidance are 
provided in the IFU. 
No registry-specific procedures will be performed.  The risk to the patient participating in the registry is a 
potential loss of confidentiality (see Section 14.2 for more information). 
Information gained from this registry may be of benefit to other people with the same medical condition 
in the future.   
13.0 REGISTRY CONDUCT AND DATA MANAGEMENT 
13.1 PROTOCOL DEVIATIONS 
Each deviation from the protocol must be documented with the date and reason for the deviation and 
reported to Edwards as soon as possible, and to the EC per local guidelines and regulations. 
13.2 REGISTRY CONDUCT, TRAINING, AND CONFIDENTIALITY 
The registry will be conducted in accordance with the applicable regulations and guidelines as set forth in 
Section 14 of this protocol. The registry investigators are responsible for obtaining the appropriate 
regulatory approvals (ethics committee and, where applicable, Competent Authority approval) prior to 
initiation of the registry. The Investigator provides current copies of the registry protocol to all sub-
Investigators or other staff responsible for registry conduct. 
13.2.1 SITE INITIATION AND TRAINING 
Site staff will be trained and experienced to perform their delegated tasks. Training may be in person, 
webinar, read and acknowledge, or other methods as deemed appropriate.  
Training for each registry team member is documented on a Training Log. A Delegation of Authority Log 
is completed at each site for each staff individual designating which specific clinical registry related tasks 
may be performed. The delegated tasks will determine the training requirements for each member of the 
registry site staff.   
New registry team members may be trained by previously trained personnel on the registry protocol and 
procedures. 
Upon completion of site initiation, site will not be activated until the surgeons who will be using the 
HARPOON System have completed the required study-specific training.  Documentation of that training 
must be retained in the registry regulatory binder. 
13.2.2 HARPOON SYSTEM TRAINING 
Edwards has established a training program for the surgeons who will be using the Harpoon System. This 
training program is designed to provide the surgeons with the information and experience necessary to 

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control user-associated risks when the device is used in accordance with the IFU. Surgeons participating 
in the registry will be trained on device use through didactic, practicum training, and proctoring.  
13.2.3 SUBJECT AUTHORIZATION AND CONFIDENTIALITY 
Subject authorization and written informed consent must be obtained prior to the subject’s enrolment 
into the registry and in accordance with GCP, ISO 14155 (relevant sections), the Medical Devices Directive 
and all other applicable standards, regulations (local and national), guidelines and institutional policies. 
Subject confidentiality must be maintained in accordance with ISO 14155 (relevant sections), GCP, GDPR, 
the Medical Devices Directive and all other applicable standards, regulations (local and national), 
guidelines and institutional policies. 
13.2.4 INVESTIGATOR CONFIDENTIALITY 
Registry investigators must comply with the applicable provisions of the study agreement with regard to 
non-disclosure and confidentiality. 
13.3 DOCUMENTATION REQUIREMENTS 
13.3.1 SOURCE DOCUMENTS 
Clinical regulations require that Investigators maintain information in the subject’s medical records that 
corroborate data collected on the eCRF.  
To protect subject confidentiality, the subject’s name must not appear anywhere on the imaging media 
sent to registry Sponsor.  All other subject identifiers (i.e. medical record number, personal number) are 
to be obscured. Original copies of all data must be kept at the site. 
13.3.2 REGISTRY DOCUMENTS 
The registry Sponsor will provide pre-printed or electronic forms to each site for documentation of: 
• 
Investigator and site training to the protocol (Individual/Group Training Log) 
• 
Authorized registry site personnel (Individual/Group Delegation of Authority) 
• 
Subject consent and screening (Screening and Enrolment Log) 
During the course of the registry, all significant correspondence regarding the registry must be maintained 
in the regulatory binder provided by the registry Sponsor. Significant e-mail correspondence may be 
archived electronically on CD/DVD. The regulatory binder must be made available for possible audits. 
13.4 DATA MANAGEMENT 
This registry will use a secure, password protected electronic data capture (EDC) system accessible via the 
Internet.  A unique Subject ID will be assigned for each subject enrolled in the registry.  All pertinent data 
will be entered by the registry site into the eCRFs. 
  Data review by Edwards personnel (or designee) will occur remotely.  Data discrepancies will be queried 
and resolved through the EDC system. 
The site Principal Investigator or designee must ensure the accuracy and completeness of the recorded 
data and provide his/her electronic signature on the appropriate eCRFs at regular intervals during the 
conduct of the registry, as requested by Edwards.  If changes are made to previously signed-off data, a 
new electronic signature will be required to acknowledge/approve the changes. 

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13.5 MONITORING 
On-site monitoring will not be conducted by Edwards Lifesciences personnel (or designee) for data 
reported in this registry. 
13.6 DATA AND DOCUMENT RETENTION 
Registry-related correspondence, subject records, consent forms, and source documents are to be 
maintained on file by each participating site. The registry Sponsor requires that it be notified in writing if 
the Principal Investigator wishes to relinquish ownership of the data and information so that mutually 
agreed upon arrangements can be made for transfer of ownership to a qualified entity.  Records of each 
subject’s participation in the registry must be maintained for no less than a period of two (2) years (or per 
local requirements) after registry closure and submission of the final report to the EC, or longer, as 
dictated by local regulations. 
13.7 REGISTRY PROTOCOL AMENDMENTS 
Changes in the protocol affecting the registry outcome are made only by written amendment agreed upon 
by the registry Sponsor, the applicable regulatory agency, and if pertinent, the EC. As appropriate, the 
registry Sponsor will submit changes in the protocol and investigators will obtain EC re-approval. A report 
of withdrawal of EC approval must be submitted to the registry Sponsor within five (5) business days. Any 
major revisions to the protocol, must be approved by the Sponsor and the EC. 
13.8  REGISTRY COMPLETION OR TERMINATION 
A final clinical report shall be compiled once data collection is complete. Such reports include all 
information required and outlined in this protocol. The final report will be provided to the ethics 
committees and other regulatory agencies as per applicable laws. The final clinical report will be filed in 
the clinical registry master file. 
Edwards Lifesciences reserves the right to terminate the registry at any stage for scientific, 
administrative or regulatory reasons, and reasons related to protection of subjects.  Investigators, 
ECs/IRBs, and regulatory authorities, as applicable, will be notified in writing in the event of registry 
termination. 
13.9  PUBLICATIONS 
All information related to the registry is considered confidential and remains the sole property of Edwards 
Lifesciences. This includes but is not limited to the patent applications and the manufacturing process of 
HARPOON System. The investigator agrees to use this information only for purposes of this registry. 
Publication or presentation of the overall clinical registry results and/or site-specific results requires prior 
written approval of Edwards. If Edwards approves the publication or presentation of the overall clinical 
registry results and/or registry specific results, then Institutions and Investigators will comply with the 
Publication and Public Disclosure Section of the Clinical Trial Agreement. Edwards may provide statistical 
support for the publication process. 
 

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14.0 STATEMENTS OF COMPLIANCE AND CONFIDENTIALITY  
14.1 APPLICABLE REGULATIONS AND GUIDELINES 
This registry will be conducted in compliance in accordance with the ethical principles that have their 
origin in the Declaration of Helsinki as well as with the relevant sections of the ISO14155 and any regional 
or national regulations as appropriate.  
Principles protecting the rights, safety and well-being of human patients, shall prevail over interests of 
science and society, and shall be understood, observed, and applied at every step in the clinical registry.  
The registry shall not begin until the required approval/favourable opinion from the EC. Any additional 
requirements imposed by the EC shall be followed. 
14.2 DATA PROTECTION AND PATIENT CONFIDENTIALITY 
The Sponsor is dedicated to maintaining the confidentiality and privacy of patients who volunteer to 
participate in the registry. The Investigator is responsible for maintaining confidentiality throughout the 
clinical registry.  
All data used in the analysis and reporting of this evaluation will be without identifiable reference to the 
patient (patient identifiers include but are not limited to: patient’s name/initials, social security number 
or equivalent, and medical/hospital number). Authorized personnel assigned by the Sponsor will have 
access to the confidential files and will have the right to inspect and copy all records pertinent to this 
registry.  
With respect to data protection and patient confidentiality, Sponsor, Institution and all Registry Personnel 
will comply with applicable requirements (for example, the General Data Protection Regulation 2016/679 
(“GDPR”) for EU patients), including providing notice and obtaining patient consent regarding the 
processing of their personal data. 
14.3 INVESTIGATOR RESPONSIBILITIES 
The Investigator is responsible for ensuring that this clinical registry is conducted according to the Clinical 
Trial Agreement, clinical investigation plan (protocol), all conditions of regulatory and EC/IRB approval and 
applicable regulations. Written EC approval of the protocol and consent forms must be provided to the 
Sponsor prior to the enrolment of any subject in the clinical registry at each site.  
The Investigator is responsible for ensuring that informed consent is obtained from all subjects prior to 
any data being collected.  Safety reports to the local ethics committee (EC) will be submitted, as required.  
Subjects must be informed that their medical records will be subject to review by the Sponsor, its 
authorized designee or regulatory agencies.  Subjects will be informed that they are free to refuse 
participation in this clinical registry without loss of benefits to which they are otherwise entitled, and that 
if they choose to participate, they may withdraw at any time without prejudice to future care.  The 
informed consent will be provided by each site’s EC and consent must be obtained by the subject.  The 
original signed informed consent for each subject must be retained by the Investigator and is subject to 
review by the Sponsor.  A copy of the informed consent will be provided to the subject. 
14.4 SPONSOR RESPONSIBILITIES 
The Sponsor is responsible for ensuring that this registry will be conducted in compliance with all 
applicable local and European regulations. The Sponsor must ensure that EC approval is obtained and 
remains current. The Sponsor is responsible for the conduct and administration of this clinical registry. 

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These responsibilities include maintaining regular contact with each registry site to ensure compliance 
with this Clinical Investigational Plan and verify that data are reported in a timely manner. 
This registry does collect safety/adverse event information which will be reviewed by the Sponsor’s Safety 
Department along with relevant source documents provided by the sites. However, in addition to 
protocol-specified reporting, any complaint associated with an Edwards product will be forwarded to the 
Edwards Lifesciences complaint handling group.  The complaint handling procedure should be followed.   
 
 
 

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ATTACHMENT A – SUGGESTED DEFINITIONS 
Modified MVARC definition are suggested for the event reporting purpose. 
 
ACCESS SITE AND VASCULAR COMPLICATIONS 
I. Vascular complications 
A. Major access site vascular complications, including: 
• 
Aortic dissection or aortic rupture, or 
• 
Access site-related arterial or venous injury (dissection, stenosis, ischemia, arterial, or venous 
thrombosis including pulmonary emboli, perforation, rupture, arteriovenous fistula, 
pseudoaneurysm, hematoma, retroperitoneal hematoma, atrial septal defect), irreversible nerve 
injury, or compartment syndrome resulting in death; hemodynamic compromise; life-
threatening, extensive, or major bleeding (MVARC bleeding scale); visceral ischemia; or 
neurological impairment, or 
• 
Distal embolization (noncerebral) from a vascular source requiring surgery or resulting in 
amputation or irreversible end-organ damage, or 
• 
Unplanned endovascular or surgical interventions resulting in death; life-threatening, extensive, 
or major bleeding (MVARC bleeding scale); visceral ischemia; or neurological impairment 
B. Minor access site vascular complications, including: 
• 
Access site arterial or venous injury (dissection, stenosis, arterial, or venous thrombosis including 
pulmonary emboli, ischemia, perforation, rupture, arteriovenous fistula, pseudoaneurysm, 
hematoma, retroperitoneal hematoma, atrial septal defect) not resulting in death; life-
threatening, extensive, or major bleeding (MVARC scale); visceral ischemia; or neurological 
impairment, or 
• 
Distal embolization treated with embolectomy and/or thrombectomy not resulting in amputation 
or irreversible end-organ damage, or 
• 
Any unplanned endovascular stenting or unplanned surgical intervention not meeting the criteria 
for a major vascular complication, or 
• 
Vascular repair (via surgery, ultrasound-guided compression, transcatheter embolization, or 
stent-graft) 
II. Cardiac structural complications due to access-related issues 
A. Major cardiac structural complications, including cardiac perforation (including the left ventricle, left 
atrium, coronary sinus, right atrium, and right ventricle) or pseudoaneurysm resulting in death, life-
threatening bleeding, hemodynamic compromise, or tamponade, or requiring unplanned surgical or 
percutaneous intervention 
 
B. Minor cardiac structural complications, including cardiac perforation (including the left ventricle, left 
atrium, coronary sinus, right atrium, and right ventricle) or pseudoaneurysm not meeting major criteria 

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ACUTE KIDNEY INJURY 
Maximal change in sCr from baseline to 7 days post-procedure: 
• 
Stage 1: Increase in sCr to 150%–199% (1.50–1.99 x increase vs. baseline), increase of ≥0.3 
mg/dl (≥26.4 mmol/l) within 48 h, or urine output <0.5 ml/kg/h for ≥6 h but <12 h 
• 
Stage 2: Increase in sCr to 200%–299% (2.00–2.99 x increase vs. baseline) or urine output <0.5 
ml/kg/h for ≥12 h but <24 h 
• 
Stage 3:  Increase in sCr to ≥300% (>3.0 x increase vs. baseline), sCr of ≥4.0 mg/dl (≥354 
mmol/l) with an acute increase of ≥0.5 mg/dl (44 mmol/l), urine output <0.3 ml/kg/h for ≥24 
h, or anuria for ≥12 h; patients receiving renal replacement therapy are considered stage 3 
irrespective of other criteria 
 
ARRHYTHMIAS AND CONDUCTION SYSTEM DISTURBANCES 
For emerging mitral valve procedures in which the frequency of major arrhythmias and conduction system 
disturbances is unknown, continuous rhythm monitoring for at least 48 h in the post-procedural period is 
recommended to maximize the detection of arrhythmias and conduction system disturbances. 
Data elements to be collected for all patients should include: 
• 
Baseline conduction abnormalities, paroxysmal or permanent atrial fibrillation (or flutter), 
ventricular arrhythmias, and the presence of permanent pacemaker and implantable 
defibrillators. The type of permanent pacemaker should be recorded (e.g., single vs. dual 
chamber, biventricular). 
• 
Procedure-related new or worsened cardiac conduction disturbance (including first-, second- 
[Mobitz I or Mobitz II], or third-degree AV block; incomplete and complete right bundle branch 
block; intraventricular conduction delay; left bundle branch block; left anterior fascicular block; 
or left posterior fascicular block, including heart block) requiring a permanent pacemaker implant; 
each subclassified as persistent or transient 
• 
New-onset atrial fibrillation (or flutter) which lasts sufficiently long to be recorded on a 12-lead 
electrocardiogram, or at least 30 s on a rhythm strip. 
• 
New-onset ventricular tachycardia or fibrillation 
• 
Pacemaker or defibrillator lead dislodgement 
Arrhythmias and conduction system disturbances are subclassified according to: 
• 
The occurrence of hemodynamic instability 
• 
Need for therapy including electrical/pharmacological cardioversion or initiation of a new 
medication (oral anticoagulation, rhythm, or rate control therapy) 
• 
Need for new permanent pacemaker and/or defibrillator implantation, including the indication(s) 
and the number of days post-implant. For patients with defibrillators, the number of appropriate 
and inappropriate shocks should be recorded. 
ATRIAL FIBRILLATION (AF) – Heart Rhythm Society Guidelines 

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• 
Paroxysmal: Recurrent (≥ 2) atrial fibrillation episodes that terminate spontaneously within 7 
days. 
• 
Persistent: Atrial fibrillation that is sustained beyond 7 days, or lasting less than 7 days but 
necessitating pharmacologic or electrical cardioversion. 
• 
Longstanding Persistent AF: Continuous atrial fibrillation of greater than 1 year duration. 
• 
Permanent: Atrial fibrillation in which cardioversion has failed or not been attempted. 
 
BLEEDING 
• 
Minor 
Any overt*, actionable sign of hemorrhage (e.g., more bleeding than would be expected for a 
clinical circumstance, including bleeding found by imaging alone) that meets ≥1 of the following: 
requiring nonsurgical medical intervention by a health care professional; leading to 
hospitalization or increased level of care; prompting evaluation; or requires 1 or 2 U of whole 
blood or packed RBC transfusion and otherwise does not meet criteria for major, extensive, or 
life-threatening bleeding. 
• 
Major 
Overt bleeding either associated with a drop in the hemoglobin of ≥3.0 g/dl** or requiring 
transfusion of ≥3U of whole blood or packed RBCs AND does not meet criteria of life-threatening 
or extensive bleeding. 
• 
Extensive 
Overt source of bleeding with drop in hemoglobin of  ≥ 4 g/dl or whole blood or packed RBC 
transfusion  ≥ 4U within any 24-h period, or bleeding with drop in hemoglobin of  ≥ 6 g/dl or whole 
blood or packed RBC transfusion  ≥ 4 U (Overt bleeding plus hemoglobin drop ≥ 5 g/dl, cardiac 
tamponade, 
Bleeding 
requiring 
surgical 
intervention 
for 
control) 
excluding 
dental/nasal/skin/hemorrhoid)), OR Bleeding requiring IV vasoactive agents  within 30 days of the 
procedure. 
• 
Life-threatening 
Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial 
necessitating surgery or intervention, or intra- muscular with compartment syndrome OR 
bleeding causing hypovolemic shock or hypotension (systolic blood pressure <90 mm Hg lasting 
>30 min and not responding to volume resuscitation) or requiring signiﬁcant doses of 
vasopressors or surgery. 
• 
Fatal 
Bleeding adjudicated as being a proximate cause of death. Severe bleeding adjudicated as being 
a major contributing cause of a subsequent fatal complication, such as MI or cardiac arrest, is also 
considered fatal bleeding. 
*”Overt” bleeding is defined by any of the following criteria being met: Reoperation after closure of 
sternotomy for the purpose of controlling bleeding; chest tube output >2 l within any 24-h period, >350 
ml within the first post-operative hour, ≥250 ml within the second post-operative hour, or >150 ml within 

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the third post-operative hour; or visible bleeding from the vascular system either at or remote from the 
access/surgical site. 
**Adjusted for the number of units of blood transfused (1 U packed red blood cells or whole blood is 
equivalent to 1 g/dl hemoglobin). 
 
DEATH (ALL-CAUSE MORTALITY) 
A. Cardiovascular mortality 
Any of the following contributing conditions: 
• 
Heart failure (subclassified into left ventricular vs. right ventricular dysfunction) 
• 
Myocardial infarction 
• 
Major bleeding 
• 
Thromboembolism 
• 
Stroke 
• 
Arrhythmia and conduction system disturbance 
• 
Cardiovascular infection and sepsis (e.g., mediastinitis and endocarditis) 
• 
Tamponade 
• 
Sudden, unexpected death 
• 
Other cardiovascular 
• 
Device failure 
• 
Death of unknown cause (adjudicated as cardiovascular) 
B. Noncardiovascular mortality 
Any death in which the primary cause of death is clearly related to another condition: 
• 
Noncardiovascular infection and sepsis (e.g., pneumonia) 
• 
Renal failure 
• 
Liver failure 
• 
Cancer 
• 
Trauma 
• 
Homicide 
• 
Suicide 
• 
Other noncardiovascular 
 
 

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MAJOR DEVICE RELATED SERIOUS ADVERSE EVENT 
All Major Serious Adverse Events reported as device related, as defined by modified MVARC including: 
• 
Procedure or Device related Death 
• 
Device related Stroke 
• 
Device related Life-threatening bleeding (MVARC scale) 
• 
Major vascular or access (index procedure) complications caused by the device 
• 
Major cardiac structural complications related or caused by the device  
• 
Device related myocardial infarction or coronary ischemia requiring PCI or CABG 
• 
Device related severe hypotension, heart failure, or respiratory failure requiring intravenous 
pressors or invasive or mechanical heart failure, treatments such as ultrafiltration or 
hemodynamic assist devices, including intra-aortic balloon pumps or left ventricular or 
biventricular assist devices, or prolonged intubation for more than 48 h. 
• 
Any device-related dysfunction, migration, thrombosis, or other complication requiring surgery 
or repeat intervention including: 
 
Structural or Functional failure of the HARPOON device, introducer or artificial chords 
(ePTFE) requiring an intervention. 
 
Conversion to the Open Mitral Valve Surgery secondary to mitral valve apparatus damage 
or dysfunction, requiring surgical valve repair or replacement, or Secondary to procedural 
complications (such as cardiac perforation, removal of an embolized artificial chords, 
injury to Aortic valve and so on) 
 
Device malpositioning (Artificial chords malpositioning) requiring intervention. 
Permanent deployment of artificial chord(s) in a location other than intended or 
movement of the artificial chords during or post deployment which requires an 
intervention. 
 
Artificial Chord detachment (used with HARPOON device) which requires an intervention 
 
Device fracture: a break, tear, perforation, or other structural defect in the artificial 
chords (housing, leaflet, and so on) resulting in device failure, resulting in recurrent MR 
symptoms, or requiring reintervention. 
 
Damage to the native mitral valve apparatus (damage to native chordae tendinae, 
Leaflets, Papillary muscles or Mitral annulus) requiring an intervention or conversion to 
Open Mitral Valve Surgery. 
 
Symptomatic or requiring intervention Device Thrombosis (any thrombus attached or 
near the artificial HARPOON implanted chords) 
 
Interaction with non-mitral valve intracardiac structures which requires intervention and 
 
Endocarditis (as diagnosed by modified Duke endocarditis criteria or evidence of abscess, 
pus, or vegetation confirmed as secondary to infection by histological or bacteriological 
studies during an operation or autopsy) which required a surgical intervention. 

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 
Hemolysis (a presence of a leaflet perforation on transesophageal or transthoracic 
echocardiography plus anemia requiring transfusion plus increased haptoglobin and/or 
LDH levels; which lead to a surgical intervention. 
 
Other major device related SAEs. 
 
MYOCARDIAL INFARCTION 
MI After Transcatheter and Surgical Mitral Valve Replacement 
Periprocedural MI (≤48 h after the index procedure) 
• 
In patients with normal baseline CK-MB (or cTn): The peak CK-MB measured within 48 h of the 
procedure rises to ≥10 x of the local laboratory ULN plus new ST-segment elevation or depression 
of ≥1 mm in ≥2 contiguous leads (measured 80 ms after the J-point), or to ≥5 x ULN with new 
pathological Q waves in ≥2 contiguous leads or new persistent LBBB, OR in the absence of CK-MB 
measurements and a normal baseline cTn, a cTn (I or T) level measured within 48 h of the PCI rises 
to ≥70 x the local laboratory ULN plus new ST-segment elevation or depression of ≥1 mm in ≥2 
contiguous leads (measured 80 ms after the J-point), or ≥35 x ULN with new pathological Q waves 
in ≥2 contiguous leads or new persistent LBBB. 
• 
In patients with elevated baseline CK-MB (or cTn): The CK-MB (or cTn) rises by an absolute 
increment equal to those levels recommended above from the most recent pre-procedure level 
plus, new ECG changes as described. 
Spontaneous MI (>48 h after the index procedure) 
Detection of rise and/or fall of cardiac biomarkers (preferably cTn) with at least 1 value above the 99th 
percentile URL (or ULN in the absence of URL) together with at least 1 of the following: 
• 
Symptoms of ischemia 
• 
ECG changes indicative of new ischemia (new ST-segment or T-wave changes or new LBBB) or new 
pathological Q waves in ≥2 contiguous leads 
• 
Imaging evidence of a new loss of viable myocardium or new wall motion abnormality 
MI associated with sudden, unexpected cardiac death 
Sudden cardiac death or cardiac arrest, often with symptoms suggestive of myocardial ischemia, and 
accompanied by presumably new ST-segment elevation or new LBBB and/or evidence of fresh thrombus 
by coronary angiography and/or at autopsy, but death occurs before blood samples could be obtained or 
at a time before the appearance of cardiac biomarkers in the blood 
 
STROKE AND TIA 
Stroke is defined as a focal or global neurological deﬁcit lasting more than 24 h OR less than 24 h if 
available neuroimaging documents a new intracranial or subarachnoid hemorrhage (hemorrhagic stroke) 
or central nervous system infarction (ischemic stroke) OR the neurological deﬁcit results in death. 

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A disabling stroke includes any neurological deficit (for example partial visual field cut) with a modified 
Rankin scale score equal or more than 2 with an increase in equal 1 or more modified Rankin scale score 
category from individual’s pre-stroke baseline at 90 days after stroke onset. 
Stroke and Transient Ischemic Attack: Diagnosis and Classiﬁcation 
Diagnostic criteria 
• 
Acute episode of a focal or global neurological deﬁcit with at least 1 of the following: 
a. Change in the level of consciousness 
b. Hemiplegia, hemiparesis, numbness, or sensory loss affecting 1 side of the body 
c. Dysphasia or aphasia, hemianopia, amaurosis fugax, or other neurological signs or 
symptoms consistent with stroke 
• 
In addition, there is no other readily identiﬁable non-stroke cause for the clinical presentation 
(e.g., brain tumor, trauma, infection, hypoglycemia, peripheral lesion, pharmacological 
inﬂuences) as determined by or in conjunction with the designated neurologist.  
Patients with non-focal global encephalopathy will not be reported as having had a stroke 
without unequivocal evidence of cerebral infarction based upon neuroimaging studies (CT scan 
or cerebral MRI). 
The neurological event type classiﬁcation 
• 
Stroke: duration of a focal or global neurological deﬁcit ≥24 h OR <24 h if available neuroimaging 
documents a new intracranial or subarachnoid hemorrhage (hemorrhagic stroke) or central 
nervous system infarction (ischemic stroke) OR the neurological deﬁcit results in death 
• 
TIA: duration of a focal or global neurological deﬁcit <24 h and neuroimaging does not 
demonstrate a new hemorrhage or infarct 
Conﬁrmation of the diagnosis of stroke or TIA requires at least 1 of the following 
 
Neurologist or neurosurgical specialist, or 
 
Neuroimaging procedure (CT scan or brain MRI)  
Stroke/TIA etiology classiﬁcation 
• 
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: if there is insufﬁcient information to  allow categorization as ischemic or 
hemorrhagic 
Stroke severity is further classiﬁed as 
- 
Disabling stroke: an mRS score ≥2 at 90 days plus an increase in ≥1 mRS category from the pre-
stroke baseline 
- 
Nondisabling stroke: an mRS score <2 at 90 days or without an increase ≥1 mRS category from the 
pre-stroke baseline 

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PROTOCOL NUMBER: 2019-12 
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CONFIDENTIAL AND PROPRIETARY DATA: THIS DOCUMENT AND THE INFORMATION CONTAINED HEREIN MAY NOT BE REPRODUCED, USED, OR DISCLOSED WITHOUT 
WRITTEN PERMISSION FROM EDWARDS LIFESCIENCES LLC 
Revision A: 14 January 2020 
Reference:  
Clinical Trial Design Principles and Endpoint Definitions for Transcatheter Mitral Valve Repair and 
Replacement: Part 2; Endpoint Definitions A Consensus Document from the Mitral Valve Academic 
Research Consortium. 
Stone, Gregg W. M.D., Adams David H. M.D., et al. 
Journal of American College of Cardiology Vol 66, NO, 3, 2015 
ISSN 0735-1097