Long Term Follow Up Study of the St. Jude Medical Trifecta™ Valve
Conditions: Aortic Valve Insufficiency, Aortic Valve Regurgitation, Aortic Valve Stenosis, Aortic Valve Incompetence
Sponsor: Abbott Medical Devices

 
Clinical Investigational Plan  
and Statistical Analysis Plan 
 
  
 
NCT Number: NCT01593917 
Trifecta™ Long Term Follow-Up Study 
Long Term Follow-Up Study of the St. Jude Medical Trifecta™ Valve 
Study Document No: SJM-CIP-100063, SJM Protocol: 1104 
Version A 
Date: 09 January 2012 
 
 
 
 
Sponsor:  
St. Jude Medical, Inc 
 
 
 
 
177 County Road B. East 
 
 
 
 
St Paul, MN  55117 
 
 
 
 

 
 
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Table of Contents 
 
PROTOCOL SUMMARY ...................................................................................... 4 
1.0 
Introduction ................................................................................................ 6 
1.1 
Valvular Disease Background .............................................................. 6 
1.2 
Trifecta™ Valve .................................................................................... 7 
2.0 
Study Design Overview .............................................................................. 7 
3.0 
Study Objectives and Endpoints ................................................................ 8 
3.1 
Study Objective .................................................................................... 8 
3.2 
Study Endpoints ................................................................................... 8 
3.2.1 
Primary Endpoint ....................................................................... 8 
3.2.2 
Secondary Endpoint: ................................................................. 8 
4.0 
Subject Population ..................................................................................... 8 
4.1 
Inclusion Criteria ................................................................................... 8 
4.2 
Exclusion Criteria.................................................................................. 8 
4.3 
Additional study data ............................................................................ 8 
4.4 
Sample Size and Study Duration .......................................................... 9 
4.5 
Method of Enrollment ........................................................................... 9 
5.0 
Confidentiality and Subject Informed Consent ........................................... 9 
and Research Authorization ................................................................................. 9 
6.0 
Study Procedures ...................................................................................... 9 
6.1 
Summary of Study Procedures ............................................................. 9 
7.0 
Echocardiography Core Laboratory Procedures ...................................... 10 
7.1 
Phone Assessment ............................................................................. 11 
7.2 
Study Termination .............................................................................. 11 
7.3 
Subject Withdrawal ............................................................................. 11 
7.4 
Lost to Follow-Up Procedures ............................................................ 11 
8.0 
Data Collection and Management ............................................................ 11 
9.0 
Serious Adverse Events (SAE) ................................................................ 12 
10.0 
Clinical Events Committee (CEC) ............................................................ 13 
11.0 
Data Analysis ........................................................................................... 13 
11.1 
Primary Endpoint ................................................................................ 13 
11.2 
Secondary Endpoints ......................................................................... 14 
11.3 
Additional Analysis ............................................................................. 14 
11.4 
Analysis of Scientific Soundness ........................................................ 14 
12.0 
Risk Analysis ........................................................................................... 15 
12.1 
Potential Benefits................................................................................ 15 
12.2 
Potential Risks .................................................................................... 15 
13.0 
Monitoring Procedures ............................................................................. 15 
13.1 
Study Monitors ................................................................................... 15 
13.2 
Monitoring Plan .................................................................................. 15 
13.3 
Compliance ........................................................................................ 15 
14.0 
Protocol Modifications .............................................................................. 16 

 
 
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14.1 
Amendments to the Protocol .............................................................. 16 
14.2 
Deviations from the Protocol .............................................................. 16 
15.0 
Records & Reports .................................................................................. 16 
15.1 
Study Sponsor .................................................................................... 16 
15.2 
Study Investigators ............................................................................. 16 
15.2.1 
Record Retention ..................................................................... 16 
16.0 
Regulatory Compliance ............................................................................ 17 
16.1 
Institutional Review Board (IRB)/ Ethics Committee (EC) Approval ... 17 
Appendix A:  Statistical Analysis Plan ........................................................... 18 
Appendix B:  Definitions ................................................................................ 21 
Appendix C:  References .............................................................................. 25 

 
 
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PROTOCOL SUMMARY 
 
Study Title: 
Long Term Follow Up Study of the St. Jude Medical 
Trifecta™ Valve  
 
Study Device: 
Trifecta™ Valve 
 
Study Purpose: 
To collect long term follow up study data of the Trifecta™ 
valve in subjects who had the Trifecta™ valve implanted 
during the IDE study. 
Study 
Objectives:  
Primary Objective: 
1. The primary objective is to collect long-term study data 
including long term valve-related events of the Trifecta™ 
valve.   
Study  
Endpoints:  
Primary Endpoint: 
1. Freedom from reoperation due to Structural Valve 
Deterioration (SVD) at year 10 post implant. 
 
Secondary Endpoint: 
1. Freedom from all-cause mortality; 
2. Freedom from valve related mortality; 
3. Freedom from SVD 
 
Study Design: 
This is a multi-center, prospective, non-randomized, post 
marketing study to collect long term follow up study data.  It 
will be conducted in the United States and Canada.  
Subjects enrolled in this clinical study received the Trifecta™ 
valve during the investigational study that was conducted to 
obtain FDA approval.   
   
In parallel to this study, a post-approval study (PAS) 
mandated by FDA is being conducted at 6 of the IDE sites in 
which follow-up data through 5 years post-implant is being 
collected. At the completion of the PAS study these sites and 
their participating subjects will be invited to participate in this 
long-term follow-up study.   
 
Subjects meeting the eligibility criteria and who have signed 
the Subject Informed Consent will undergo an NYHA 
functional classification assessment, a general clinical 
assessment and a transthoracic-echocardiogram (TTE) 

 
 
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based on their original Trifecta™ implant date at the 
following time points:  3 year, 5 year, 7 year and 10 year.  
The alternate years a phone follow-up will be completed.  
 
Study Population: Subjects previously implanted with a Trifecta™ prosthetic 
valve at the selected sites during the IDE clinical 
investigational study and who meet all eligibility criteria will 
be invited to participate.    
 
Sponsor: 
St. Jude Medical 
177 County Road B. East 
St Paul, MN 55117 
 

 
 
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1.0 
Introduction  
1.1 
Valvular Disease Background 
Valvular heart disease is responsible for nearly 93,000 valve related 
operations and 20,000 deaths each year in the United States.  It is also 
the contributing factor for another 42,000 deaths each year.  The majority 
of these cases involve disorders of the aortic valve (63%).i Specific aortic 
valvular disorders include: aortic stenosis, aortic regurgitation, or a 
combination of the two, with aortic stenosis being the leading indication for 
aortic valve replacement in adults. 
The most common cause of aortic stenosis in adults is an idiopathic 
degenerative calcification process that produces an immobilization of the 
aortic valve cusps.ii This disease progresses from the base of the cusps to 
the free edge, eventually causing a reduction in the effective valve area.  
Other causes include a congenital malformation (often a bicuspid valve) 
and rheumatic fever.  Classic symptoms of aortic stenosis include angina, 
syncope, dyspnea, heart murmur, fatigue, and heart failure. 
Common causes of aortic valve regurgitation include idiopathic aortic 
dilatation, 
congenital 
abnormalities 
(bicuspid 
valve), 
degenerative 
calcification, 
rheumatic 
fever, 
infective 
endocarditis, 
systemic 
hypertension, dissection of the ascending aorta, Marfan’s syndrome, and 
many others that occur much less frequently.iii  Symptoms of aortic 
regurgitation include angina, syncope, dyspnea, heart murmur, fatigue, 
and heart failure. 
Subjects with either aortic stenosis, regurgitation, or both may remain 
asymptomatic for many years however, after the onset of symptoms 
(angina, syncope, or dyspnea); the average survival is less than two to 
three years.ii Aortic valve replacement (AVR) appears to be the only 
effective treatment for these subjects.ii For certain subjects with severe 
aortic regurgitation who are not considered good surgical candidates, 
therapy with vasodilating agents may provide some benefit. ii 
Presently, there are two broad categories of aortic valve prostheses; 
mechanical and tissue (bioprosthesis).  The tilting-disc, and bileaflet are 
the two basic types of mechanical valve prostheses available today.  
There is a wide variety of bioprostheses available including:  autografts (a 
valve moved from one anatomical position to another within the same 
individual), homografts/allografts (human valves or tissue taken from 
cadavers), and heterografts/xenografts (valves or tissue taken from 
animals).  There are currently several different heterografts available.  

 
 
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Heterografts are primarily constructed from porcine aortic valves that have 
been preserved and sewn onto a frame (stented) or left intact (stentless).  
A stented bovine pericardial valve is another type of commonly accepted 
heterograft.iii,iv 
Each valve type, mechanical or tissue, has associated risks and benefits.  
Mechanical valves are associated with potential lifetime durability but 
require long-term anticoagulation therapy.  Tissue valves are reported to 
have reduced device durability, but typically do not require long-term 
anticoagulation therapy and are therefore associated with lower incidence 
of thromboembolic and hemorrhagic events.v,vi Implanting physicians must 
not only consider the various valve characteristics when deciding which 
aortic prosthesis to implant, but also various subject factors including, but 
not limited to, age, coexisting medical conditions, anticoagulation therapy 
tolerance, and cardiac physiology.ii,iii,iv  As a result, physicians frequently 
encounter a subject where the choice of valve type is unclear. 
1.2 
Trifecta™ Valve 
Trifecta™ valve sizes 19mm through 29mm were evaluated in the 
Trifecta™ IDE clinical study. 
 
The Trifecta™ valve was approved in the following geographies.  
• U.S. FDA approval April 20th, 2011 
• Health Canada approval October 18th, 2010 
2.0 
Study Design Overview 
This is a multi-center, prospective, non-randomized, post marketing study 
to collect long term follow up study data.  It will be conducted in the United 
States and Canada.  Subjects enrolled in this clinical study received the 
Trifecta™ valve during the IDE study that was conducted to obtain FDA 
approval.   
 
All previously available study data for all subjects from participating sites 
will be included in the data set for this study. This will include data 
collected during the IDE study as well as from the FDA-mandated post-
approval study, when available. 
 
Subjects meeting the eligibility criteria and who have signed the Subject 
Informed Consent will undergo an NYHA functional classification 
assessment, a general clinical assessment and a transthoracic-
echocardiogram (TTE) based on their Trifecta™ implant date at the 

 
 
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following time points:  3 year, 5 year, 7 year and 10 year.  The alternate 
years a phone follow-up will be completed.  
3.0 
Study Objectives and Endpoints 
3.1 
Study Objective  
The primary objective is to collect long-term study data including long term 
valve-related events of the Trifecta™ valve.   
3.2 
Study Endpoints 
3.2.1 Primary Endpoint 
Freedom from reoperation due to Structural Valve Deterioration (SVD) at 
year 10 post implant.   
3.2.2 Secondary Endpoint: 
1. Freedom from all-cause mortality; 
2. Freedom from valve related mortality; 
3. Freedom from SVD 
4.0 
Subject Population 
4.1 
Inclusion Criteria 
1. Patient currently has a Trifecta™ valve that was implanted at one of 
the U.S. or Canadian investigational sites during the Trifecta™ IDE 
study. 
2. Patient met eligibility criteria prior to enrollment in the Trifecta™ IDE 
study. 
3. Patient agrees to complete all required follow-up visits. 
4. Patient provided written informed consent prior to any study related 
procedure, as approved by the governing Institutional Review Board 
(IRB) or the Ethics Committee (EC) of the investigational site. 
4.2 
Exclusion Criteria 
1. Patient is currently participating or planning to participate in any other 
study unless approved by SJM. 
4.3 
Additional study data 
Data from the Trifecta™ IDE and PAS studies for all participating subjects 
will be included in the data sets for this study. See Analysis Population 
section of the Statistical Analysis Plan in Appendix B.  

 
 
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4.4 
Sample Size and Study Duration 
The long term follow-up study will enroll subjects who were previously 
implanted with the Trifecta™ valve in the IDE study and meet section 4.1 
criteria and will be followed for ten (10) years from their Trifecta™ implant 
procedure or until a final event, such as valve explant, death, or change in 
status (e.g. lost to follow-up or withdrawal from study).  
 
4.5 
Method of Enrollment 
Subjects are considered enrolled at the time the informed consent is 
signed.  
 
5.0 
Confidentiality and Subject Informed Consent  
and Research Authorization 
 
This study will be performed in accordance with applicable confidentiality, 
privacy and security, and data protection laws  
 
The Investigator, or an individual designated by the Investigator, must 
obtain written study-specific informed consent and research authorization 
(using the most recent IRB/REB approved document) from an eligible 
subject prior to commencing any study-related procedures.   
The process of obtaining informed consent must be consistent with the 
FDA published regulations, the Declaration of Helsinki and the reviewing 
IRB/EC. The subject or legal guardian must be given the opportunity to 
ask questions of, and receive satisfactory answers from, the investigator 
or study personnel prior to signing the consent document.  
Subjects will be asked to provide consent so that data can be gathered. 
After the subject signs the informed consent document, the original is to 
be filed in the subject’s medical record, a copy filed in the subject’s study 
binder, and a copy given to the subject. 
6.0 
Study Procedures 
6.1 
Summary of Study Procedures 
Subjects will begin follow up visits according to the anniversary date of 
their Trifecta™ valve implant.  However, prior to this visit, the patient must 
sign the informed consent.  

 
 
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Follow-up assessments will include the following (Refer to Table 7, 
Schedule of Assessments): 
• Transthoracic-echocardiogram (TTE) 
• NYHA functional classification assessment to be completed by a 
Study Investigator  
• General clinical assessment 
• Serious Adverse Event (SAE) Assessment 
 
Table 7: Schedule of Assessments 
 
Screening 
Year 2,4,6,8, and 9* 
(± 60 days) 
Year 3,5,7 and 10* 
 (± 60 days) 
Early 
Termination 
Informed Consent 
X 
 
 
 
Echocardiogram 
 
 
X 
X 
Clinical 
Assessment* 
 
 
X 
X 
NYHA 
 
 
X 
X 
Phone 
Assessment* 
 
X 
 
 
Serious Adverse 
Events 
X 
X 
X 
X 
*Subjects will continue the assessment schedule from the IDE study.   
7.0 
Echocardiography Core Laboratory Procedures 
Echocardiography examinations will be conducted at the 3, 5, 7 and 10 
year assessments.  Each site is responsible for performing the 
echocardiogram 
according 
to 
the 
Echocardiography 
Manual 
of 
Operations. Echocardiography examinations will be forwarded to the 
Echocardiography Core Laboratory for interpretation.   
The responsibility of the Echocardiography Core Laboratory is to complete 
the echocardiography data collection forms and submit these to the 
Sponsor. 

 
 
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The Echocardiography Core Laboratory will provide the study required 
interpretation and documentation of each follow-up echocardiogram 
submitted. 
SJM 
will 
use 
only 
the 
measurements 
from 
the 
Echocardiography Core Laboratory for analysis.  If the Core Laboratory 
determines the echocardiogram is unreadable, the subject may be asked 
to return for another echocardiogram. 
7.1 
Phone Assessment 
Phone follow up will be conducted at the 2, 4, 6, 8, and 9 year assessment 
schedule. This will consist of routine questions asking if any serious 
adverse events have occurred since the last assessment. 
7.2 
Study Termination 
Each subject will be followed through 10 years post implant or until time of 
death, explant, lost to follow up, withdrawal or study termination.  
7.3 
Subject Withdrawal 
Participation in this study is voluntary.  Subjects are free to withdraw from 
the study at any time without reason, however, subjects should be 
encouraged to complete the ten years of follow up.  .  
7.4 
Lost to Follow-Up Procedures 
Every effort should be made to obtain follow-up data.  Potential methods 
of subject tracking may include: 
• Attempting to contact the subject by multiple phone calls and letters 
documented at the site. 
• Mailing a registered letter to the subject’s last known address 
requesting that the subject contact the site. 
• Contacting individuals identified by the subject as alternative 
contacts. 
 
Subjects who cannot be located after at least three documented contact 
attempts will be reported as “lost to follow-up” by the study site, who must 
complete a Study Subject Status CRF and provide it to Sponsor. Subjects 
who are deemed lost to follow up may re-enroll in the study by signing the 
current IRB/EC approved informed consent.  
8.0 
Data Collection and Management 
To ensure data quality and completeness, all required data will be 
recorded on standardized specific CRFs, as provided by SJM.  

 
 
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The site will maintain the CRFs and documentation in the respective 
subject binders. 
The Investigator or his/her designee at each site is responsible for 
recording all data onto the CRFs.  The data on each CRF must be legibly 
written in indelible ink only.  If changes are required prior to submission to 
SJM, a single line must be drawn through the incorrect information, the 
correct information written in, and the changes initialed and dated.  The 
obscuring of any incorrect data (use of white-out, correction tape, or 
scribbling out) is strictly prohibited. 
If an error is discovered after submission of the CRF to SJM, notify SJM.  
SJM will generate a data clarification form (DCF) or query and send to the 
site for resolution. 
9.0 
Serious Adverse Events (SAE) 
Only serious adverse events are being collected for this study.   
A serious adverse event is any event on health or safety that is 
• Fatal or life threatening  
• Results in persistent or significant disability  
• Requires intervention to prevent permanent impairment/damage  
• Results in hospitalization or prolongation of hospitalization (> 24 
hours) 
 
All SAEs including those specified in Edmunds Criteriavii (1996) that occur 
throughout the conduct of the study will be reported on the Serious 
Adverse Event case report form. The Edmunds Criteria events include: 
• Structural Deterioration 
• Nonstructural Dysfunction 
• Embolism (Valve Related) 
• Valve Thrombosis 
• Major Bleeding Event 
• Endocarditis 
• Death (all cause mortality) 

 
 
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SJM will request that additional information such as operative notes, 
discharge summaries, histopathology reports, and a physician’s summary 
of the event, be provided to SJM as supporting documentation for any 
reported SAE. 
In the event of a subject death, an autopsy should be performed whenever 
possible and the Trifecta™ valve explanted and returned to SJM for 
evaluation.  If available, death summaries and autopsy reports should be 
provided to SJM. 
All SAEs, regardless of perceived causal relationship, should be 
communicated by study personnel to SJM within 48 hours of first learning 
of the event.  
It is the responsibility of the Principal Investigator to notify his/her IRB/EC 
of any SAEs, as required. SAEs will be reviewed by SJM personnel. All 
complaints/ Medical Device Report (MDR) will be reported to the 
appropriate regulatory body per geography requirements through the SJM 
Product Surveillance Department.  
Study specific Adverse Event definitions are located in Appendix C.  
10.0 Clinical Events Committee (CEC) 
An independent Clinical Events Committee (CEC) will be established prior 
to study enrollment.  The CEC will be comprised of two members from the 
original Trifecta™ IDE study Data Monitoring Committee which will provide 
continuity to the adjudication process.  These members are independent 
from the Sponsor, and the participating investigators in this long term 
follow up study.  The CEC consists of a cardiac surgeon and a 
cardiologist.  The cardiac surgeon will be serving as the chairperson. 
A CEC Charter will be developed and agreed upon by the Sponsor and 
both CEC members prior to the review of data.  The Charter will describe 
the functions of the CEC. 
The CEC will meet at a minimum, on a bi-annual basis.  However, the 
CEC may convene more often if deemed necessary by the committee 
and/or the Sponsor. 
11.0 Data Analysis 
11.1 Primary Endpoint 
Freedom from reoperation due to Structural Valve Deterioration (SVD) at 
year 10 post-implant.   

 
 
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11.2 Secondary Endpoints 
1. Freedom from all-cause mortality; 
2. Freedom from valve related mortality; 
3. Freedom from SVD. 
 
Additionally, NYHA, specific hemodynamic parameters (e.g. for calculating 
mean gradient, EOA) and confounding factors, including but not limited to 
demographic data, anticoagulation/antiplatelet therapy, beta blocker and 
calcium channel blocker use, and coexisting medical conditions will be 
collected, to the extent possible, to aid and support the interpretation of 
the analysis. 
11.3 Additional Analysis 
Summary information will be provided in graphical and/or tabular format.  
For continuous variables, summary statistics (N, mean, standard 
deviation, and percentiles) will be provided.  For categorical or ordinal 
variables, the number of subjects having each attribute and the 
percentage of total subjects used will be presented.  
 
The following analyses will be performed: 
1. Survival (Kaplan-Meier) analyses for all primary and secondary end 
point events occurring in the post-operative period. 
2. Number and linearized rates of subjects experiencing primary and 
secondary end point late events (>30 days post-implant). 
3. A summary of specific hemodynamic (mean gradient, effective orifice 
area) data 
4. NYHA functional classification assessment over time 
 
11.4 Analysis of Scientific Soundness 
The scientific soundness of the long term follow up study is established by 
the following characteristics: 
• Principal Investigators and appropriate research staff will be trained 
on the study protocol and methodologies. 
• The purpose of the study is defined. 
• Standard definitions are provided for study endpoints. 
• Uniform study procedures and echocardiographic methods will be 
used to ensure consistent measurement of study endpoints. 
• The long term follow up study will be conducted in a prospective 
manner allowing use of current diagnostic methodologies and 
treatment practices. 

 
 
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• The supporting statistical analysis methods are appropriate for the 
type of study endpoints and objectives. 
• An Echocardiography Core Laboratory will be used. 
• The conduct of the study will be monitored on an ongoing basis.  
Actions to secure and restore compliance will be implemented as 
appropriate. 
12.0 Risk Analysis 
12.1 Potential Benefits 
Potential benefits to the subjects participating in the study may include 
study-related 
assessments 
including 
annual 
transthoracic 
echocardiograms (TTE) and clinical assessments.  Future subjects 
participating in valve studies may benefit from the experience gained in 
this long term follow up study. 
12.2 Potential Risks 
It is expected that the procedures: (TTE, a clinical assessment and the 
determination of the NYHA functional classification) involve no additional 
known risks to the subject other than those commonly associated with the 
follow-up of subjects who have had a prosthetic heart valve implanted.   
13.0 Monitoring Procedures 
13.1 Study Monitors 
All sites will be monitored by Sponsor or Sponsor’s designee to ensure the 
long term follow up study is being conducted in accordance with the 
protocol, investigator agreement, applicable regulations, and SJM policies 
and procedures.  Only monitors qualified by training and experience who 
will be trained on the study protocol will be allowed to monitor.  The 
monitor’s qualifications and training on the protocol will be documented. 
13.2 Monitoring Plan 
Prior to initiating site monitoring activities, a  study specific Monitoring Plan 
will be created and revised by the Sponsor as needed over the course of 
the study. 
13.3 Compliance 
It is the responsibility of the Sponsor to promptly secure compliance from 
any site that is not complying with the requirements of this study protocol. 
If compliance is unable to be secured, SJM may terminate the 
Investigator’s participation in the study. 

 
 
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14.0 Protocol Modifications 
14.1 Amendments to the Protocol 
If a protocol amendment becomes necessary during the conduct of the 
study, SJM will submit the amendment to the site and to the respective 
IRB/EC, as necessary.   
14.2 Deviations from the Protocol 
Investigators are required to adhere to this protocol, the signed Study 
Agreement, applicable national or local laws and regulations, and any 
conditions required by the IRB or REB or appropriate applicable regulatory 
authorities. 
 
A deviation is used to describe situations in which this protocol was not 
followed.  All deviations must be reported to the Sponsor on the Protocol 
Deviation Case Report Form.  All deviations must be reported to the IRB 
or EC per their requirements.   
 
15.0 Records & Reports 
15.1 Study Sponsor 
The Sponsor is responsible for the study design, conduct, analysis, and 
reporting of the results from this study.  The Sponsor is also accountable 
for monitoring and performing those actions necessary to protect the rights 
of subjects and the scientific credibility of the manner in which this long 
term follow up study is conducted.  SJM reserves the right to obtain data 
clarification and/or additional medical documentation on subjects enrolled 
in this study at any time.  
 
15.2 Study Investigators 
The study Investigator is responsible for ensuring that the long term follow 
up study is conducted according to the Study Agreement and all 
amendments thereto, Protocol, any conditions of approval imposed by 
applicable regulatory authorities and/or the reviewing IRB/REBs and all 
applicable laws and regulations. 
15.2.1 Record Retention 
Subject study records, correspondence files, all supporting study 
documentation, and reports as described above must remain on file at the 
site for a minimum of two years after the termination of this study or per 
local laws.  All Study Investigators must contact SJM prior to destroying or 

 
 
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archiving off-site any records and reports pertaining to this study to ensure 
that they no longer need to be retained on-site. 
16.0 Regulatory Compliance 
The Principal Investigator and all research staff participating in this 
investigation are expected to adhere to the study agreement, the study 
protocol, the Declaration of Helsinki, 21 CFR parts 50, 54, and 56, 
applicable Canadian privacy, security and other Canadian laws applicable 
to the conducting of this study,  applicable U.S. Federal and State privacy 
and security laws. 
16.1 Institutional Review Board (IRB)/ Ethics Committee (EC) Approval 
A duly constituted IRB/EC representing the prospective study site must 
review and approve the subject informed consent and research 
authorization document, the study protocol, the prospective investigator’s 
participation in the study, and any other study related information to be 
provided to the subjects prior to subject enrollment.  Additionally, the 
Investigator must be aware of and adhere to all IRB/EC requirements such 
as, but not limited to:  the submission of progress reports, serious adverse 
events, and protocol deviations.  
 
 

 
 
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Appendix A:  Statistical Analysis Plan 
 
Summary 
 
The long term follow up data of the Trifecta™ valve will be collected for summary 
and analysis. 
 
In this long term follow up study, subjects who had the Trifecta™ valve implanted 
as part of the IDE study and enroll (refer to section 4.1) in this study will be 
followed for a minimum of:  
 
• Ten years post-implant or  
• Until time of death, explant, lost to follow-up, withdrawal or study 
termination.  
 
Additionally, all previously available study data (from Trifecta™ IDE and 
Trifecta™ post approval study (PAS)) for all subjects (who met eligibility criteria 
prior to enrollment in the Trifecta™ IDE study) from these participating sites will 
be included in the analysis datasets for this long term study.  This includes prior 
study data for subjects from these participating study sites who died, were 
explanted, or were lost to follow-up prior to this long term study as well as prior 
study data for subjects from these participating study sites who do not consent to 
participation in this long term study.  
 
The summary data of study primary and secondary endpoints will be provided 
based on CEC adjudication. 
 
In addition, NYHA functional classification and key specific hemodynamic data 
will also be provided.  
Study endpoints 
 
Primary endpoint 
1. Freedom from reoperation due to structural valve deterioration (SVD) 
at 10 years post implant. 
 
Secondary endpoints  
1. Freedom from all cause mortality;  
2. Freedom from valve related mortality;  
3. Freedom from SVD  
 
 

 
 
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Sample size  
 
Approximately 13 sites (among these, 6 sites originally from PAS) who 
participated in the Trifecta™ valve IDE study with approximately 650 active 
subjects at the end of the IDE study will be approached for participation in this 
study.   
 
Analysis Population 
 
Attempts will be made to approach all previous Trifecta™ IDE subjects at the 
sites participating in the long term follow up study (who were actively being 
followed and who met eligibility criteria prior to enrollment in the Trifecta™ IDE 
study) for participation in this study. 
 
In addition to the data collected during this long term follow up study, the study 
analysis datasets will include all previously available study data (from Trifecta™ 
IDE and Trifecta™ PAS) for all subjects (who met eligibility criteria prior to 
enrollment in the Trifecta™ IDE study) from sites participating in the long term 
follow up study and the PAS.  
Data Analysis and Reporting 
Data summary and analysis will be performed based on all available data. 
Statistical analysis software SAS version 9.2 (or newer if available) will be used 
for the analysis, except when otherwise specified.  
 
Valve Event Analysis 
 
Survival (Kaplan-Meier) Analysis for time-associated mortality, valve-related 
mortality, SVD, and reoperation due to SVD will be based on the time to the first 
occurrence of the adverse event for each subject.  Kaplan-Meier analysis will be 
performed to evaluate the freedom from adverse events data over time. Adverse 
events occurring in the postoperative period will be included in this analysis.  The 
time to event will be determined from the date of implant to the first occurrence of 
the event (for subjects experiencing the event) or to the last date of contact (for 
subjects not experiencing the event).  
 
 

 
 
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Late Serious Adverse Event (Linearized) Rate will be reported for serious 
adverse events when appropriate, as defined by the number of late events per 
100 late patient-years at risk: 
 
 
 
 
Late events are those that occur 31 or more days post-implant.  The late patient-
years for each subject are calculated from 31 days following implant to the last 
date of contact or adverse event as appropriate.  
 
Data Presentation 
 
Summary information will be provided in graphical and/or tabular format.  For 
continuous variables, summary statistics (N, mean, standard deviation, and 
percentiles) will be provided.  For categorical or ordinal variables, the number of 
subjects having each attribute and the percentage of total subjects used will be 
presented.  
 
The following data will be presented when necessary: 
1. Age at implant 
2. Gender 
3. Valve size 
4. Medical history 
 
The following analyses will be performed: 
1. Survival (Kaplan-Meier) analyses for all primary and secondary end point 
events occurring in the post-operative period. 
2. Number and linearized rates of subjects experiencing primary and 
secondary end point late events (>30 days post-implant). 
3. A summary of specific hemodynamic (mean gradient, effective orifice 
area) data 
4. NYHA functional classification assessment over time 
 
Ad hoc analyses may be performed as appropriate. 
 
 
%
100
*
year)
-
patient
 
(%/late
 
Rate
Linearized
years
patient
late
total
events
late
of
number
−
=

 
 
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Appendix B:  Definitions 
A. 
EDMUNDS CRITERIA AND SERIOUS ADVERSE EVENTSvii,viii ix,x 
 
 
Major Bleeding Event 
 
Any episode of major internal or external bleeding that causes death, 
hospitalization, operation, pericardiocentesis, or permanent injury (e.g., vision 
loss) or requires transfusion.  A bleeding event is reportable whether or not the 
subject is taking anticoagulation or antiplatelet drugs, since bleeding events can 
occur in subjects who are not receiving anticoagulants. 
 
Embolic stroke complicated by bleeding is classified as a neurological event 
under “embolism” and is not included as a separate bleeding event. 
 
Death 
 
Valve-related Mortality:  Death due to any of the following events involving the 
study valve: structural valvular deterioration, nonstructural dysfunction, valve 
thrombosis, embolism, bleeding event, endocarditis, or reoperation.  Sudden, 
unexplained deaths of subjects with an operated valve are included as valve 
related mortality. 
 
Sudden, unexpected, and unexplained deaths are sudden when they 
occur within one hour of an event of abrupt onset; unexpected if they 
occur in a previously well subject; and unexplained if no cause can be 
determined. 
 
Other cardiac Mortality:  Death resulting from cardiac causes, excluding 
valve-related mortality.  Examples include congestive heart failure, acute 
myocardial infarction, and documented fatal arrhythmias. 
 
Other cause Mortality:  Death due to any cause, excluding valve-related 
mortality or other cardiac mortality. 
 
Embolism 
Embolism is any embolic event that occurs in the absence of infection after the 
immediate perioperative period (when anesthesia-induced unconsciousness is 
completely reversed).  Only arterial emboli will be captured.  Pulmonary emboli, 
cardiac mural thromboemboli and atherosclerotic particle emboli are not to be 
reported.  Subsets of embolic events are: 
 
Neurologic Event: 

 
 
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Any new, temporary, or permanent focal or global neurological deficit.  
Psychomotor deficits determined by specialized testing are not considered 
neurologic events related to operated valves.  Types of neurologic events are: 
 
• Transient Ischemic Attack (TIA):  Fully reversible neurologic deficit 
that lasts less than or equal to 24 hours, and if an imaging study is 
performed, shows no evidence of infarction. 
• Reversible Ischemic Neurologic Deficit (RIND):  Fully reversible 
neurologic deficit that lasts more than 24 hours and less than or 
equal to three weeks. 
• Stroke or permanent neurologic event:  A neurologic deficit that 
lasts more than three weeks, causes death or lasts less than or 
equal to three weeks with a brain imaging study showing an 
infarction. 
 
Systemic Embolic Event: 
An operative, autopsy or clinically documented embolus that produced 
symptoms from complete or partial obstruction of a peripheral (non-cerebral) 
artery.  Systemic events should be classified as: 
• Minor:  symptoms resolve completely without medical or surgical 
intervention 
• Major:  permanent injury or medical/surgical intervention required 
• Fatal:  death results as a consequence of the embolism or from 
related adverse events (less than or equal to 30 days or during the 
same course of hospitalization) 
 
Endocarditis 
Valvular endocarditis is any infection involving an operated valve.  The diagnosis 
of operated valvular endocarditis is based on customary clinical criteria including 
an appropriate combination of positive blood cultures, clinical signs and/or 
histologic confirmation of endocarditis at reoperation or autopsy.  Morbidity 
associated with active infection, such as valve thrombosis, thrombotic embolus, 
bleeding event, or paravalvular leak, is included under this category and is not 
included in other areas of morbidity. 
 
Nonstructural Dysfunction 
Nonstructural dysfunction is any abnormality resulting in stenosis or regurgitation 
at the operated valve that is not intrinsic to the valve itself.  Nonstructural 
dysfunction refers to nonstructural problems that result in dysfunction of a study 
valve exclusive of thrombosis or infection diagnosed by reoperation, autopsy, or 
clinical investigation. 
 

 
 
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Examples of nonstructural dysfunction include:  entrapment by pannus, tissue, or 
suture; paravalvular leak, inappropriate sizing or positioning, residual leak or 
obstruction from valve implantation or repair, and clinically significant hemolytic 
anemia. 
 
Sudden or progressive dysfunction or deterioration of the study valve may be 
structural, nonstructural, or both as determined by reoperation, autopsy, or 
clinical investigation. 
 
Reoperation 
Reoperation is any operation that repairs, alters or replaces the study valve.  The 
reasons for reoperation are to be reported and may include reasons other than 
valve-related morbidity, such as recall, excessive noise, or incidental or 
prophylactic removal. 
 
Thrombolytic or catheter-aided therapy of valve-related morbidity is not 
considered reoperation; however, the morbid event that prompted the 
intervention should be reported. 
 
Structural Deterioration 
Structural valve deterioration is any change in function of a study valve resulting 
in an intrinsic abnormality of the valve that causes stenosis or regurgitation. 
 
Structural valvular deterioration includes study valve dysfunction or deterioration 
exclusive of infection or thrombosis as determined by reoperation, autopsy, or 
clinical investigation.  The term structural deterioration refers to changes intrinsic 
to the valve, such as wear, stent fracture, calcification, leaflet tear, stent creep, 
and suture line disruption of components (e.g., leaflets) of an operated valve. 
 
Valve Thrombosis 
Valve thrombosis is any thrombus, in the absence of infection, attached to or 
near the study valve that occludes part of the blood flow path or that interferes 
with function of the valve.  Valve thrombosis may be documented by operation, 
autopsy, or clinical investigation.  Valve thrombosis is categorized as follows: 
 
• Obstructive valve thrombosis:  The accumulation of thrombus on a 
replacement valve with (potentially) catastrophic hemodynamic or embolic 
consequences. 
• Non-obstructive valve thrombosis:  An incidental finding without 
(potentially) catastrophic hemodynamic consequences (e.g., thrombus on 
the outflow aspect of the bioprosthesis, etc.) 
 
 

 
 
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Serious Adverse Event 
A serious adverse event is any adverse event on health or safety, that is fatal or 
life threatening, results in persistent or significant disability, requires intervention 
to prevent permanent impairment/damage, or an event that results in 
hospitalization or prolongation of hospitalization (> 24 hours). 
 
 
B. 
OTHER STUDY RELATED DEFINITIONS 
 
New York Heart Association (NYHA) Functional Classification: 
 
Class I:  No limitations of physical activity.  Ordinary physical activity does not 
cause undue fatigue, palpitation, or dyspnea. 
 
Class II:  Slight limitation of physical activity.  They are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitation, or dyspnea. 
 
Class III:  Marked limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity causes fatigue, palpitation, or dyspnea. 
 
Class IV:  Unable to carry out any physical activity without discomfort.  
Symptoms of cardiac insufficiency at rest.  If any physical activity is undertaken, 
discomfort is increased. 
 

 
 
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Appendix C:  References 
                                                 
iAmerican Heart Association. Heart Disease and Stroke Statistics – 2005 Update. Dallas, Texas: 
American Heart Association 2005.   
 
iiBonow RO, Carabello B, de Leon AC Jr, et al.  ACC/AHA Guidelines for the Management of 
Patients with Valvular Heart Disease. J Am Coll Cardiol 1998;32:1486-588. 
 
iiiWerner JA, Crawford MH. Choosing a Prosthetic Heart Valve. Cardiol Clin. 1998;16:491-504. 
  
ivFann JI, Burdon TA.  Are the Indications for tissue valves different in 2001 and how do we 
communicate these changes to our cardiology colleagues?  Curr Opin Cardiol. 2001; 16:126-35  
 
vCartier PC, Metras J, Dumesnil JG, Pibarot P, Lemieux M.  Midterm Follow-up of  Unstented 
Biological Valves.  Seminars in Thoracic and Cardiovascular Surgery 1999;11:22-7. 
 
viFradet G, Bleese N, Busse E, Jamieson E, Raudkivi P, Goldstein J, Metras J.  the Mosaic Valve 
Clinical Performance at Seven Years:  Results from a Multicenter Prospective Clinical Trial.  J 
Heart Valve Dis 2004;13:239-47. 
 
viiEdmunds LH, Clark RE, Cohn LH, Grunkmeier GL, Miller DC, Weisel RD.  Guidelines for 
reporting morbidity and mortality after cardiac valvular operations. J Thorac Cardiovasc Surg 
1996;112:708-11. 
 
viiiBodnar E, Butchart EG, Bamford J, Besselaar AMPH, Grunkmeier GL, et al.  Proposal for 
reporting thrombosis, embolism, and bleeding after heart valve replacement.  J Heart Valve Dis 
1994;3:120-3. 
 
ixUS Food and Drug Administration, Division of Cardiovascular, Respiratory, and Neurological 
Devices, October 14, 1994.  Replacement Heart Valve Guidance Document.  
 
xInternational Standard ISO – 5840:2005