A Prospective, Single-Arm, Multi-Center Study in Collaboration With INTERMACS to Evaluate the Thoracotomy Implant Technique of the HeartWare™ HVAD™ System in Patients With Advanced Heart Failure
Phase: NA
Conditions: Left Sided Heart Failure
Sponsor: Medtronic Cardiac Rhythm and Heart Failure

A Prospective, Single Arm, Multi-Center Clinical Study in Collaboration 
with the InterAgency Registry for Mechanically Assisted Circulatory 
Support (INTERMACS®) to Evaluate the Thoracotomy Implant Technique 
of the HeartWare HVAD® System in Patients with Advanced Heart Failure
NCT Number: NCT02268942
Document Name and Date: Clinical Study Protocol, 24 October 2018

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CLINICAL STUDY PROTOCOL 
 
A Prospective, Single Arm, Multi-Center Clinical Study in Collaboration 
with the InterAgency Registry for Mechanically Assisted Circulatory Support 
(INTERMACS®) to Evaluate the Thoracotomy Implant Technique of the 
HeartWare HVAD® System in Patients with Advanced Heart Failure 
 
 
 
Investigational Product: 
HeartWare® Ventricular Assist Device System (HVAD®) 
Protocol Number: 
HW006 
Version Number: 
7.3 
IDE Number: 
G130279 (through PMA approval; 10 Jul 2018) 
PMA Number: 
100047 
Date: 
24 October 2018 
 
 
 
 
 
 
This protocol contains confidential information which is the property of Medtronic / 
HeartWare for use by the principal investigators, designated representatives and applicable 
ethics committee/institutional review board and regulatory authorities participating in this 
clinical investigation.  It should be held confidential and maintained in a secure location. It 
should not be copied or made available for review by any person or firm without the prior 
written consent of Medtronic / HeartWare. 

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1. 
ADMINISTRATIVE INFORMATION 
1.1 
Contacts 
Medical, Clinical and Operational Support 
Sponsor Name: 
Medtronic / HeartWare 
 
Cardiac Rhythm and Heart Failure 
 
Mechanical Circulatory Support 
Sponsor Contact:  
Sonali Dewan, Sr Prin Regulatory Affairs Specialist 
 
Sponsor Telephone Number: 
1 305 364 1579 
Manufacturer and Sponsor Address: 
14400 NW 60th Avenue 
Miami Lakes, FL 33014 
USA 
1.2 
Administrative Information 
Protocol Number: 
HW006 
Revision Number: 
7.3 
Protocol Date: 
24 Oct 2018 
Investigational Product: 
HeartWare® Ventricular Assist Device System (HVAD) 
 
1.3 
Amendment History 
 
Date 
Amendment Number 
Amendment Type 
18 November 2013 
1.0 
Original Protocol 
04 February 2014 
2.0 
Revised Submission 
07 April 2014 
3.0 
Revised Submission 
07 May 2014 
4.0 
Revised Submission 
11 Aug 2014 
5.0 
Revised Submission 
15 Sep 2014 
6.0 
Revised Submission 
3 Feb 2015 
7.0 
Revised Submission 
06 July 2015 
7.1 
Revised Submission 
10 Feb 2016 
7.2 
           Revised Submission 
24 Oct 2018  
7.3 
Revised Submission 

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e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
e-signature  
 
1.4 
Sponsor Approval 
Representatives of Medtronic HeartWare 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this Protocol and all applicable local laws and regulations, including, 
without limitation, data privacy laws and regulations.  
 
SIGNATURES 
Sponsor 
Signatory: 
 
Signature: 
Date: 
 
Name & Title 
 
 
        _______________________________________________       ________________ 
  
__ 
 
Thomas Vassiliades Jr., M.D., 
Chief Medical Officer, Mechanical Circulatory Support 
Name & Title 
 
 
 
Jeff Cerkvenik, 
Distinguished Statistician 
Name & Title 
 
 
Theresa McGovern, 
Senior Regulatory Affairs Director 
 
Name & Title 
 
 
Alejandra Ochoa, 
Clinical Research Specialist  
 
 
Name & Title 
 
Arundhati Datye, M.D., 
Medical Safety Advisor/Strategist 
 
 
Name & Title 
______________________________________________     __________________ 
 
Dana Chesness, 
 
Principal Clinical Quality Specialist Compliance  
 
 
Name & Title 
 
 
Taryn Randall, 
Senior Clinical Monitoring Manager 

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1.5 
Investigator Agreement 
I will provide copies of the clinical study protocol and all pertinent information to all individuals 
responsible to me who assist in the conduct of the study. I will discuss this material with them to 
ensure they are fully informed regarding the products and the conduct of the study. 
I also understand that this study will not be initiated without approval of the appropriate 
IRB/CREB and that all administrative requirements of the governing body of the institution will 
be complied with fully. 
I will use only the informed consent forms approved by the Sponsor, INTERMACS® and the 
Institutional Review Board (IRB)/Clinical Research Ethics Board (CREB), or its representative. 
I will obtain written informed consent from all participating subjects according to the 
INTERMACS® protocol defined process using the approved INTERMACS® protocol, informed 
consent and health privacy documents, and will fulfill all responsibilities for submitting pertinent 
information to the IRB/CREB. In addition, I will obtain a HeartWare specific written informed 
consent from subjects who will receive a HeartWare® HVAD via a thoracotomy procedure. 
I also agree to record all information or data in the INTERMACS® registry in accordance with the 
INTERMACS® protocol and procedures, in particular, I agree to report without unjustified delay, 
all Adverse Events (AEs) and Serious Adverse Events (SAEs). 
I further agree that HeartWare, INTERMACS and/or designee will have access to any original 
source documents from which electronic case report form (eCRF) information may have been 
generated and for which consent has been given. 
I also agree to have control over all clinical supplies (including products) provided by HeartWare 
and/or designee and collect, account and handle all clinical specimens in accordance with the 
protocol. 
I further agree not to originate or use the name of HeartWare Inc. and/or HVAD, or any of its 
employees, in any publicity, news release or other public announcement, written or oral, whether 
to the public, press or otherwise, relating to this protocol, to any amendment hereto, or to the 
performance hereunder, without the prior written consent of HeartWare Inc. 
I herewith declare that I agree with the protocol described in detail in this document and agree to 
conduct the study in accordance with the protocol and in compliance with Good Clinical Practice, 
and all applicable regulatory requirements. 
 
Investigator Name (print) 
  
 
 
 
Investigator Signature 
 
Date 
  
 
Name of Facility 
  
 
Location of Facility (City)    
 

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Table of Contents 
1. 
ADMINISTRATIVE INFORMATION 
2 
1.1 
Contacts ............................................................................................................... 2 
1.2 
Administrative Information ................................................................................. 2 
1.3 
Amendment History ............................................................................................. 2 
1.4 
Sponsor Approval ................................................................................................ 3 
1.5 
Investigator Agreement ........................................................................................ 4 
2. 
STUDY SUMMARY 
8 
3. 
STUDY REFERENCE INFORMATION 
12 
3.1 
List of Abbreviations ......................................................................................... 12 
4. 
INTRODUCTION 
16 
4.1 
Background and Rationale ................................................................................. 16 
4.2 
Previous Patient Experience .............................................................................. 18 
4.2.1 
International Bridge to Transplant Study ........................................................... 18 
4.2.2 
ReVOLVE ................................................................................................... 19 
4.2.3 
US Bridge to Transplant Trial...................................................................... 22 
4.3 
Name and Intended Use ..................................................................................... 24 
5. 
DEVICE DESCRIPTION 
25 
5.1 
HeartWare® Ventricular Assist System ............................................................. 25 
5.2 
HeartWare® Controller ....................................................................................... 26 
5.3 
HeartWare® Monitor .......................................................................................... 26 
5.4 
HeartWare® Controller Power Sources .............................................................. 27 
5.5 
HeartWare® Battery Charger .............................................................................. 27 
5.6 
Equipment for Implant ....................................................................................... 28 
5.7 
Principles of Operation ...................................................................................... 29 
5.7.1 
Blood Flow Characteristics .......................................................................... 30 
5.7.2 
Physiological Control Algorithms ............................................................... 30 
5.7.3 
Flow Estimation ........................................................................................... 30 
5.7.4 
Ventricular Suction Detection Alarm .......................................................... 30 
6. 
STUDY OBJECTIVES AND ENDPOINT MEASURES 
33 
6.1 
Study Objectives ................................................................................................ 33 
6.2 
Estimated Period of Study ................................................................................. 33 
6.2.1 
Time Schedule ................................................................................................... 33 
6.2.2 
End of Study ...................................................................................................... 33 
6.3 
Primary Endpoint ............................................................................................... 33 
6.4 
Secondary Endpoint ........................................................................................... 34 
 
 

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7. 
STUDY DESIGN 
35 
7.1 
Number of Clinical Sites and Subjects .............................................................. 35 
7.2 
Subject Participation and Study Duration .......................................................... 35 
8. 
PATIENT POPULATION, SELECTION AND WITHDRAWAL 
37 
8.1 
Characterization of Study Population ................................................................ 37 
8.2 
Inclusion Criteria ............................................................................................... 37 
8.3 
Exclusion Criteria .............................................................................................. 37 
9. 
STUDY COURSE AND PROCEDURES 
38 
9.1 
Enrollment ......................................................................................................... 38 
9.2 
Assessments ....................................................................................................... 38 
9.2.1 
Baseline / Pre-Implant information .................................................................... 38 
9.2.2 
Implant Information ........................................................................................... 38 
9.2.3 
Follow-up Assessments ..................................................................................... 38 
9.2.4 
Re-hospitalizations ............................................................................................. 39 
9.2.5 
Outcomes ........................................................................................................... 39 
9.2.6 
Adverse Events .................................................................................................. 39 
9.2.7 
Device Related Adverse Events and Device Malfunctions ............................... 40 
10. 
SURGICAL IMPLANT PROCEDURE 
41 
10.1 
Pre-Implant Device Management ...................................................................... 41 
10.2 
Implant Procedure .............................................................................................. 41 
10.3 
Postoperative Patient Management .................................................................... 41 
11. 
STATISTICAL CONSIDERATIONS 
42 
11.1 
Study Endpoints and Hypotheses....................................................................... 42 
11.1.1 
Analysis Populations .......................................................................................... 42 
11.1.2 
Primary Endpoint ............................................................................................... 42 
11.1.3 
Secondary Endpoint ........................................................................................... 42 
 
 
11.2 
Sample Size Justification ................................................................................... 44 
11.3 
Site Poolability ................................................................................................... 45 
11.4 
Handling of Missing Outcomes ......................................................................... 45 
11.5 
Early Submission ............................................................................................... 46 
12. 
RISK AND BENEFIT ANALYSIS 
47 
12.1 
Potential Benefits ............................................................................................... 47 
12.2 
Risk Analysis ..................................................................................................... 48 
13. 
INVESTIGATOR RESPONSIBILITY 
50 
13.1 
Institutional Review Board (IRB)/Research Ethics Board (CREB) Approval .. 50 
13.2 
Informed Consent .............................................................................................. 50 

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13.3 
Subject Data Protection ..................................................................................... 51 
13.4 
Investigator Agreement ...................................................................................... 51 
13.5 
Financial Disclosure .......................................................................................... 51 
13.6 
Protocol Deviations and Medical Emergencies ................................................. 52 
13.7 
Device Accountability ....................................................................................... 52 
14. 
MONITORING AND QUALITY CONTROL 
53 
14.1 
Site Training ...................................................................................................... 53 
14.2 
Monitoring of the Study ..................................................................................... 53 
14.3 
Independent Data Review and Event Adjudication ........................................... 53 
14.3.1 
HeartWare DSMB .............................................................................................. 53 
14.3.2 
INTERMACS® Observational Study Monitoring Board (OSMB ..................... 54 
14.4 
Progress Reports to Regulatory Agencies ......................................................... 54 
15. 
RECORDS AND REPORTS 
54 
15.1 
Case Report Forms ............................................................................................. 54 
15.2 
Data Review ....................................................................................................... 54 
15.3 
Record Retention ............................................................................................... 54 
15.4 
Study Insurance .................................................................................................. 54 
16. 
APPENDICES 
55 
16.1 
Appendix A – INTERMACS® Protocol ............................................................. 55 
 
 
 
 
16.4 
Appendix D – INTERMACS® Adverse Event Definitions ............................. 160 
17. 
REFERENCES 
174 

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2. 
STUDY SUMMARY 
 
Name of Sponsor(s): 
Medtronic / HeartWare (hereafter referred to as HeartWare) 
Title of protocol: 
A Prospective, Single Arm, Multi-Center Clinical Study in Collaboration with the InterAgency Registry for 
Mechanically Assisted Circulatory Support (INTERMACS®) to Evaluate the Thoracotomy Implant Technique 
of the HeartWare HVAD® System in Patients with Advanced Heart Failure 
Study Number: HW006 
Number of Subjects: 
145 subjects implanted via thoracotomy with the HeartWare HVAD® 
System.  It is anticipated that each site will enroll at least 1 subject. 
No site will implant more than 20 patients into the study without prior 
written approval from HeartWare. 
Number of Sites: 
Up to 30 Sites in the US and 1 site in Canada 
Study Design: 
This is a multi-center, prospective, single arm study that will evaluate the thoracotomy implant technique in up to 145 
subjects implanted via thoracotomy with the HeartWare HVAD® System and enrolled in the InterAgency Registry for 
Mechanically Assisted Circulatory Support (INTERMACS®) protocol and database. 
All participating centers will be current enrolled INTERMACS® sites in good standing and will follow the 
INTERMACS® protocol and procedures. 
Primary Endpoint: 
The primary endpoint is success at 6 months defined as all enrolled and implanted subjects: 
• 
Alive on the originally implanted device at 6 months, and the subject has not had a stroke with a modified 
Rankin Scale ≥ 4 (assessed ≥3 months post stroke event); or 
• 
Transplanted by Month 6, and the subject has not had a stroke with a modified Rankin Scale ≥ 4 (assessed ≥3 
months post stroke event); or 
• 
Explanted for recovery by Month 6, and the subject has not had a stroke with a modified Rankin Scale ≥ 4 
(assessed ≥3 months post stroke event). 
All subjects with stroke events from implant to Month 6 will be required to remain in follow-up until the post-stroke 
mRS measure (≥3 months post stroke event) is obtained, even if this occurs after the 6-month visit. If a stroke subject is 
alive at 6 months, but dies before the post-stroke mRS is obtained, the subject will be considered a failure with regard to 
the primary endpoint. 
Secondary Endpoint: 
The secondary endpoint is an improvement in the mean length of initial hospital stay (initial recovery and step 
down unit) for all enrolled and implanted subjects. The mean length of initial hospital stay is estimated to be 
26.1 days for median sternotomy subjects. 

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Safety Assessments: 
Safety assessments will be collected according to the INTERMACS® protocol and procedure, as summarized in Section 
9. 
Device:   HeartWare® System 
The HeartWare® System is an implantable ventricular assist device, with the following major components: Implantable 
Centrifugal Rotary Blood Pump (HVAD® Pump) with Inflow and Outflow Conduits, Controller and Power Sources, 
Monitor, Power Sources, Battery Charger, Surgical Tools and Carrying Case. 
Intended Use: 
The HeartWare® HVAD is intended for use as a bridge to cardiac transplantation in patients who are at risk of death 
from refractory end-stage left ventricular heart failure. 
The HeartWare® HVAD is designed for in-hospital and out-of-hospital settings, including transportation via fixed wing 
aircraft or helicopter. 
The HeartWare® HVAD is contraindicated in patients who cannot tolerate anticoagulation therapy. 
Period of Evaluation: 
Subjects will be followed according to the INTERMACS® protocol and standard of care at the enrolling institution. 
Data recorded in the INTERMACS® database to the primary endpoint at 6 months post implant of the HeartWare® 
HVAD will be evaluated. 
• 
Subjects who have been transplanted prior to month 6 will be considered complete at the primary endpoint time- 
point. 
• 
Subjects, who have a device exchange prior to month 6, will be evaluated according to the original implant date. 
• 
Subjects who remain on device support after the primary endpoint time-point, either the original device or 
exchange device, will be followed according to the INTERMACS® protocol until transplant, or until 2.5 years 
post implant of the original device. A subject’s study participation is considered complete at either the time of 
induction of anesthesia for transplant, or at the 2.5 year post implant visit. 
• 
Subjects who have been explanted for recovery prior to month 6 will be followed until their next scheduled 
follow-up visit according to the INTERMACS® protocol, at which time their participation in the study is 
considered complete. 
• 
The per-protocol analysis population will include those thoracotomy subjects with the outflow in the ascending 
aorta only.  As a result, enrollment may exceed sample size requirements. 
• 
The per-protocol analysis population will include those thoracotomy subjects with the procedure performed on- 
pump only.  As a result, enrollment may exceed sample size requirements. 
Subject data will be evaluated for a maximum of 2.5 years. 
Estimated start date: 
October 2014 
Estimated end date:   October 2018 

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Background: 
Heart failure is a progressive disease for which there are numerous therapies to reduce symptoms; however, presently 
there is no cure and a more definitive therapy is not on the horizon. Cardiac transplantation is currently the most 
effective therapy for advanced heart failure. However, the lack of available donor organs restricts the use of heart 
transplantation to fewer than 2,500 patients per year in the United States1. In 2012, 2169 heart transplants were 
performed at approximately 125 heart transplant centers in the United States (United Network for Organ Sharing 
website accessed February 23, 2013)1. Currently there are more than 3400 patients on the UNOS heart transplant list, 
with 68% of those having a waiting time to transplant of longer than six months1. 
Clinical studies have shown a survival and quality of life benefit for patients supported by a left ventricular assist device 
(LVAD) when compared to those receiving medical therapy 2, 3. Approximately 35% of the patients who receive heart 
transplants are bridged with ventricular assist devices4. 
The US bridge-to-transplant trial (i.e. ADVANCE) was a multi-center, prospective, clinical trial designed to evaluate 
the safety and efficacy of the HeartWare® System in heart failure patients listed for cardiac transplantation 5. The trial 
was conducted between 18 August 2008 and 25 February 2010 with a total enrollment of 160, including 140 implants at 
30 sites. The implant procedure chosen for placement of the HVAD® Pump in this trial was via a median sternotomy5, 
and the current Instructions for Use (IFU) and patient materials reference this implant method and describe the 
associated risks. 
Since the HVAD® Pump is small and designed to be placed within the pericardial space alternative implant procedures 
have been developed. Surgeons in Europe, Canada, and the United States and throughout the world have successfully 
implanted the HVAD® Pump using both thoracotomy and sternotomy approaches 6-8. It is believed that the addition of 
the thoracotomy implant procedure will provide clinicians an additional option to optimize results and expand the 
potential patient population. There is a growing trend toward the use of less invasive non-sternotomy incisions in all 
fields of cardiac surgery. While a median sternotomy provides the best access to the heart and great vessels, the same 
exposure could be accomplished with several smaller thoracotomy incisions. The potential benefit to the subject 
participating in this study is the implantation of a blood pump using a technique that is less obtrusive and that may be 
more comfortable. Morbidity rates and time of recovery may also be positively affected. The thoracotomy technique for 
implant may provide benefits not currently available with existing technology such as less tissue trauma and shorter 
hospital stays. 
Main Criteria for Inclusion: 
1. 
Must be ≥19 years of age at time of informed consent to participate in the INTERMACS® registry. 
2. 
Subject receives a HeartWare® HVAD (The device should be the subject’s first VAD implant). 
3. 
Subject signed an INTERMACS® informed consent if required by local IRB/CREB policy. 
4. Subject signed a HeartWare® informed consent 
Main Criteria for Exclusion: 
The INTERMACS® protocol has no exclusion for age, gender, race, ethnicity, or any other demographic limit. The 
following are exclusions currently described by the INTERMACS® protocol: 
1. Subject is incarcerated (prisoner). 
2. Subject did not sign the informed consent at sites where waiver of consent was not granted. 
In addition, for this study, the following exclusion criteria will be applied after enrollment into the INTERMACS® 
protocol: 
3. Body Surface Area (BSA) < 1.2 m2. 
4. Prior cardiac transplant or cardiomyoplasty. 
5. Subject is receiving a BiVAD. 
6. Subject is receiving the device as an RVAD. 
7. Subject data is generated from non- INTERMACS® centers. 
8. Pediatric subjects (< 19 years of age). 
9. Subjects who receive a temporary LVAD (e.g., ECMO, TandemHeart, Impella, etc.) 
10. Subjects whose device strategy is listed as “Destination Therapy” at the time of implant. 
11. Severe Right Heart failure, defined as mean central venous or right arterial pressure > 20 mmHg on multiple 
inotropes, or right ventricular ejection fraction (RVEF) <15% with clinical signs of severe right heart failure 

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(e.g. ascites, treatment with diuretics and two inotropic drugs). 
12. ≥ 2+ Aortic insufficiency or mechanical aortic valve 
13. Planned concomitant procedure (e.g. valve repair or replacement, CABG, septal defect repair). 
14. Known LV thrombus 
Study Procedures: 
All participating centers will follow the INTERMACS® protocol and procedures. A summary of the INTERMACS® 
protocol and procedures can be found in Section 9. 
Main Criteria for Evaluation and Analyses: 
The primary endpoint is success at 6 months compared to a pre-specified performance goal. 
The secondary endpoint is an improvement in the mean length of initial hospital stay. 
Additional observational endpoints will also be assessed at 6 months. Statistical tests will not be conducted. 
Sample Size Justification and Statistical Considerations: 
Primary Endpoint: 
Success at 6 months for thoracotomy is estimated to be 86% compared to a performance goal of 77.5%. Using an exact 
binomial test, with a one-sided alpha of 0.05, and 80% Power, a sample size of 145 implanted subjects is required. 
Secondary Endpoint: 
The mean length of initial hospital stay is estimated to be 26.1 days with a standard deviation of 22.8 days and a median 
of 20 days based on data from the BTT CAP population (N=242). Using a one sample t-test, with a one-sided alpha of 
0.05, a sample of 145 implanted subjects with an average value of 21.3 days or less will result in Power greater than 
80%. 
Due to the skewed nature of this data, a non-parametric test (one-sample Sign test with a one-sided alpha of 0.05) to 
assess a reduction in median days (from the estimated 20 days) will also be conducted for support. 

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3. 
STUDY REFERENCE INFORMATION 
3.1 
List of Abbreviations 
ACE 
Angiotensin-converting enzyme 
AC or DC 
Alternating-Current or Direct-Current 
ACC 
American College of Cardiology 
ADE 
Adverse Device Effect 
AE 
Adverse Event 
AHA 
American Heart Association 
AI 
Aortic insufficiency 
ALT 
Alanine Aminotransferase 
ARB 
Angiotensin Receptor Blocker 
AR 
Aortic regurgitation 
ASD 
Atrial septal defect 
AST 
Aspartate Aminotransferase 
ASA 
Acetylsalicylic Acid 
BiVAD 
Biventricular Assist Device 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BPM 
Beats Per Minute 
BSA 
Body Surface Area (m2) 
BTT 
Bridge to Transplantation 
BUN 
Blood Urea Nitrogen 
cc 
Cubic Centimeter (equal to a milliliter) 
CABG 
Coronary artery bypass graft 
CFR 
Code of Federal Regulations 
CHF 
Chronic Heart Failure 
CK 
Creatine Kinase 
CK- MB 
Creatine Kinase MB Isoenzyme 
CMS 
Centers for Medicare and Medicaid Services 
COPD 
Chronic Obstructive Pulmonary Disease 
CREB 
Clinical Research Ethics Board 
CRF 
Case Report Form 
CRO 
Clinical Research Organization 
CRP 
C- Reactive Protein 
CRT 
Cardiac Resynchronization Therapy 
CSS 
Clinical Summary Score of KCCQ 
Abbreviation 
Definition 

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Definition 
 
 
CT 
Computed Tomography 
CVA 
Cerebral Vascular Accident (stroke) 
CVP 
Central Venous Pressure 
dL 
Deciliter 
Dy 
Day / Days 
eCRF 
Electronic Case Report Form 
ECG 
Electrocardiogram 
ECMO 
Extracorporeal Membrane Oxygenation 
EDC 
Electronic Data Capture 
EEG 
Electro Encephalogram 
EuroQol 
European Quality of Life (EQ-5D) 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FEV1 
Forced expiratory volume in one second 
GCP 
Good Clinical Practice 
g 
Gram 
HCT 
Hematocrit 
HEPA 
High-Efficiency Particulate Arresting 
HF 
Heart Failure 
Hgb 
Hemoglobin 
hr 
Hour 
IABP 
Intra-Aortic Balloon Pump 
ICD 
Implantable Cardiac Defibrillator 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
ICU 
Intensive Care Unit 
INR 
International Normalized Ratio 
INTERMACS 
InterAgency Registry for Mechanical Assisted Circulatory Support 
IRB 
Institutional Review Board 
ISHLT 
International Society for Heart and Lung Transplantation 
ITT 
Intent to Treat 
JCAHO 
Joint Commission on the Accreditation of Healthcare Organizations 
KCCQ 
Kansas City Cardiomyopathy Questionnaire (tool) 
Kg 
Kilogram 
LCD 
Liquid Crystal Display 
LDH 
Lactate Dehydrogenase 
LED 
Light Emitting Diode 
Li-Ion 
Lithium ion 

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Abbreviation 
Definition 
 
 
L/min 
Liters per minute 
LLT 
Left lateral thoracotomy 
LOS 
Length of Stay 
LV 
Left Ventricle 
LVAD 
Left Ventricular Assist Device 
LVEDD 
Left Ventricular End- diastolic Diameter 
LVEDV 
Left Ventricular End- diastolic Volume 
LVEF 
Left Ventricular Ejection Fraction 
LVESD 
Left Ventricular End- systolic Diameter 
LVESV 
Left Ventricular Endiastolic Volume 
MAP 
Mean Arterial Pressure 
MCS 
Mechanical Circulatory Support 
MCSD 
Mechanical Circulatory Support Device 
M 
Meter 
Mg 
Milligram 
MI 
Myocardial Infarction 
mL 
Milliliter 
Mm 
Millimeter 
MR 
Mitral regurgitation 
N or n 
Number of Patients 
NIHSS 
National Institutes of Health Stroke Scale 
NYHA 
New York Heart Association (heart failure classification) 
NP 
Nurse Practitioner 
OMM 
Optimal Medical Management 
OR 
Operating Room 
OPC 
Objective Performance Criteria 
OSS 
Overall Clinical Summary Score of KCCQ 
PA 
Physician Assistant 
PCWP 
Pulmonary Capillary Wedge Pressure 
PFO 
Patent Foramen Ovale 
PI 
Principal Investigator 
PRBC 
Packed Red Blood Cells 
Pt (or Pts) 
Patient (or Patients) 
PTT 
Partial Thromboplastin Time (activated = aPTT) 
PVO2 
Pulmonary Venous Oxygen Tension 
PVR 
Pulmonary Vascular Resistance 
QoL 
Quality of Life 
RAP 
Right Arterial Pressure 

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Abbreviation 
Definition 
 
 
RGA 
Returned Goods Authorization 
RHC 
Right Heart Catheterization 
RPM 
Rotations per Minute 
RV 
Right Ventricle 
RVAD 
Right Ventricular Assist Device 
RVEF 
Right Ventricular Ejection Fraction 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
SE 
Standard Error 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SVO2 
Mixed Venous Oxygen Saturation 
TE 
Thromboembolic Event 
TEE 
Transesophageal Echocardiogram 
TIA 
Transient Ischemic Attack 
TVR 
Tricuspid Valve Replace/Repair 
TX 
Transplant 
UADE 
Unanticipated Adverse Device Event 
USB 
Universal Serial Bus 
VAD 
Ventricular Assist Device 
VO2 max 
Maximal Rate of Oxygen Consumption 
VSD 
Ventricular septal defect 
WBC 
White Blood Cell 
Wk 
Week 
Yr 
Year 

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4. 
INTRODUCTION 
4.1 
Background and Rationale 
Heart failure is a progressive disease for which there are numerous therapies to reduce symptoms; 
however, presently there is no cure and a more definitive therapy is not on the horizon. Cardiac 
transplantation is currently the most effective therapy for advanced heart failure. However, the 
lack of available donor organs restricts the use of heart transplantation to fewer than 2,500 
patients per year in the United States1.  In 2012, 2169 heart transplants were performed at 
approximately 125 heart transplant centers in the United States (United Network for Organ 
Sharing website accessed February 23, 2013)1. Currently there are more than 3400 patients on the 
UNOS heart transplant list, with 68% of those having a waiting time to transplant of longer than 
six months1. 
Clinical studies have shown a survival and quality of life benefit for patients supported by a left 
ventricular assist device (LVAD) when compared to those receiving medical therapy2, 3. 
Approximately 35% of the patients who receive heart transplants are bridged with ventricular 
assist devices4. 
The US bridge-to-transplant trial (i.e. ADVANCE) was a multi-center, prospective, clinical trial 
designed to evaluate the safety and efficacy of the HeartWare® System in heart failure patients 
listed for cardiac transplantation 5. The trial was conducted between 18 August 2008 and 25 
February 2010 with a total enrollment of 160, including 140 implants at 30 sites. The implant 
procedure chosen for placement of the HVAD® Pump in this trial was via a median sternotomy5, 
and the current Instructions for Use (IFU) and patient materials reference this implant method and 
describe the associated risks. 
Since the HVAD® Pump is small and designed to be placed within the pericardial space 
alternative implant procedures have been developed. Surgeons in Europe, Canada, and the United 
States and throughout the world have successfully implanted the HVAD® Pump using both 
thoracotomy and sternotomy approaches6-8. It is believed that the addition of the thoracotomy 
implant procedure will provide clinicians an additional option to optimize results and expand the 
potential patient population. There is a growing trend toward the use of less invasive non- 
sternotomy incisions in all fields of cardiac surgery. While a median sternotomy provides the best 
access to the heart and great vessels, the same exposure could be accomplished with several 
smaller thoracotomy incisions. The potential benefit to the subject participating in this study is the 
implantation of a blood pump using a technique that is less obtrusive and that may be more 
comfortable. Morbidity rates and time of recovery may also be positively affected. The 
thoracotomy technique for implant may provide benefits not currently available with existing 
technology such as less tissue trauma and shorter hospital stays. 
The thoracotomy procedure most often includes a small hemi-sternotomy for placement of the 
outflow graft in the ascending aorta, although the descending aorta may be selected in some cases. 
While most cases have been done on CPB, many cases in Europe no longer use CPB. For this 
study it is recommended that cases be done on cardiopulmonary bypass and that the outflow be 

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attached to the ascending aorta. An artist’s depiction of the thoracotomy procedure is shown in 
the figure below: 
 
 
 
 
And an actual photograph of the thoracotomy opening is shown in the second figure: The sewing 
ring can be seen through the surgical opening. 

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4.2 
Previous Patient Experience 
4.2.1 
International Bridge to Transplant Study 
Between March 2006 and June 2009 the HeartWare® HVAD was evaluated as a bridge to cardiac 
transplantation at five centers in Europe and Australia. Fifty patients were enrolled in the trial 
with the last patient reaching the 180 day endpoint on June 2, 2009. This summary covers the 
period from March 3, 2006 through June 2, 2009. The pump was implanted in the pericardial 
space in all patients using a midline sternotomy and cardiopulmonary bypass. There were 43 
males and 7 females ranging in age from 20 to 75 years (mean 48.6 ± 13.6) of which 40% had 
ischemic disease. BSA ranged from 1.40 to 2.56 m2 (mean 1.9 ± 0.23). The total duration of 
support was 47.8 patient years.  The mean duration of support was 349 ± 223 days with 20 
patients supported > 1 year and 3 patients supported > 2 years. The most common significant 
adverse events were: 

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Update as of October 25, 2013, 45 patients reached endpoint, 29 patients were transplanted, four 
were weaned from support after recovery, 11 died on support and 6 remain supported. Twenty 
eight patients were supported longer than one year and 13 greater than two years. Six patients 
remain well on support with five patients on support greater than five years. Kaplan Meier 
actuarial survival for the 50 patients in the trial is shown below. 
4.2.2 
ReVOLVE 
The ReVOLVE registry was an investigator-initiated registry of commercial implants performed 
between February of 2009 and November 2012.  Patients receiving the HeartWare® HVAD 
System for labeled indications only are included in this report. Data was collected at nine centers 
in Europe (7) and Australia (2). The ReVOLVE registry was not sponsored by HeartWare, 
although HeartWare provided support and assisted in the analysis of the data. While the data was 
not monitored on-site, steps were taken to verify the accuracy through telephone and email 
communications with the users at each participating center.  The total number of on-label subjects 
85% 
78% 
70% 

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enrolled for which adverse event data was collected was 254.  Mean age of patients was 52.5 + 
12.0 years, and females accounted for 23% of the total patient population.  Mean BSA was 1.93 + 
0.23 m2. The diagnosis or type of cardiomyopathy at baseline includes idiopathic 
cardiomyopathies in 65% of patients, while ischemic cardiomyopathies accounted for only 27%. 
The mean duration of support was of 363 + 280 days (median 299.5 days). Fifty-six of the 254 
patients were transplanted, three recovered myocardial function and had the device removed, 43 
died on support and 152 patients remained on the device. Patients were transplanted after 19-958 
(mean 363 + 250) days of support. For the patients who died over the observation period, death 
occurred after a mean of 159 + 228 days on support.  The most common adverse events were: 
 
N=254 with 252.6 Patient-Years of Support 
Complication 
Patients with 
event, n (%) 
Number of 
Events 
Event Rate 
Bleeding 
71 (28) 
101 
0.40 
Gastrointestinal Bleeding 
12 (5) 
16 
0.06 
Right Heart Failure 
24 (9) 
24 
0.10 
Stroke 
20 (8) 
20 
0.08 
Driveline Infection 
14 (6) 
18 
0.07 
Sepsis 
12 (5) 
12 
0.05 
Renal Failure 
10 (4) 
10 
0.04 
Note: Bleeding events include all post-op bleeding, tamponade, and those requiring transfusions 
and reoperation. 
One hundred and forty-five (145) patients were supported less than one year, 85 patients between 
one and two years and 24 patients were supported between two and three years. Survival post- 
transplant was excellent: of 56 patients transplanted, 2 died post-transplant, one of multiple organ 
failure and one of intracranial hemorrhage. Post-transplant survival at one month was 96% 
(54/56). The Kaplan Meier actuarial success estimate is shown. Success was defined as survival 
to transplant, recovery after explant or on continued HVAD support. The 6, 12, 24 and 36 month 
success rates were 87%, 85%, 79% and 73% respectively. 

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In addition, data collected for 40 thoracotomy patients, which is considered ‘off-label’ was not 
included in the afore-mentioned report. For the thoracotomy patients, the 6-month success rate 
was 88%. 

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4.2.3 
US Bridge to Transplant Trial 
A bridge-to-transplant trial (i.e. ADVANCE) was conducted in the US. ADVANCE was a multi- 
center, prospective, clinical trial designed to evaluate the safety and efficacy of the HeartWare® 
HVAD in heart failure patients listed for cardiac transplantation. Enrollment into the study began 
on 18 August 2008.  The trial ended on 25 February 2010 with a total enrollment of 160, 
including 140 implants at 30 sites. Subjects were predominately male (72.1%), were 53.3 (± 10.3) 
years of age and 23% were Black/African American. BMI and BSA were 28.6 (± 6.1) kg/m2 and 
2.1 (± 0.3) m2, respectively and the average LVEF was 17.8% (± 7.1%). PCWP was elevated at 
23 (± 9) mmHg and pulmonary artery pressures were also high: 49 (±15) / 25 (± 9) mmHg. The 
cardiac index was significantly reduced at 2.0 ± 0.5. The majority of subjects were classified as 
NYHA class IV (95%). The most common etiologies were ischemic disease in (40.7%) and 
idiopathic etiology (45.7%). Duration of heart failure was greater than 5 years in 48.6% (68/140) 
of subjects.  It was also observed that 17.9% and 13.6% of subjects had heart failures from 1-3 
and 4-5 years, respectively. The most common underlying risk factors for cardiovascular disease 
were smoking (64.3%) hypertension (62.9%) and hyperlipidemia (54.3%). For prior cardiac 
surgery, 6.4% (9/140) of subjects reported a prior history of coronary artery bypass grafting 
(CABG). No subject reported valve replacement, but valve repair was reported in 2.1% (3/140). 
LV reduction was reported in 7.1% (10/140) and prior sternotomy and prior thoracotomy in 
15.7% (22/140) and 3.6% (5/140) of subjects, respectively. Intra-aortic balloon pump therapy at 
baseline was reported for 25% of subjects and 85% presented with an implantable cardioverter- 
defibrillator (AICD). At Baseline 80% of subjects in the HVAD treatment group were on 
intravenous inotropic therapy and 23% were on more than one inotrope, while 82% of subjects 
received diuretics. Mean hematological and laboratory values at baseline showed an elevated 
BUN at 26 (+14) mg/dL and a depressed hematocrit of 34.0% (+ 5.8%). 
 
The median time from incision to wire closure of the sternum was 3 hours and 23 minutes and 
median time on bypass was 70 minutes. Subjects received (median) 1.5 units of packed red blood 
cells (PRBC).  The median parameters for HVAD settings were: 2700 rpm at 3.8 watts, yielding 
4.6 L/min of flow. In addition to implant, a number of additional surgical procedures were 
performed. The most common were patent foramen ovale (PFO)/atrial septal defect (ASD) 
closures (11/140) and tricuspid valve repair (11/140). 
A total of 776 events were reported during the 180 day primary analysis period. Of these 437 
(437/776, 56.3%) were INTERMACS defined specific events, and 338/776 (43.6%) events were 
recorded under the INTERMACS category of “other.” One UADE, chest wall erosion was 
reported during the 180-day primary endpoint period. 
Adverse events defined by INTERMACS criteria during the primary analysis period included the 
following: 

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1 A multiple entry (4) of one case was corrected 
2 Two cases were excluded: 1 case hemolysis < 72 hours post-implant; 1 case hemolysis occurring 
in the presence of tPA/Integrillin for VAD thrombosis 
*Events that have an onset date of 0-30 days and which reoccur in the same patient past 30 days are counted in both 
0-30 day and 31-180 day periods. 
Date of Event Onset* 
0-30 Days 
31-180 Days 
Events 
n 
Subjects 
n (%) 
Events 
n 
Subjects 
n (%) 
Bleeding 
Re-operation 
23 
20 (14.3) 
4 
4 (2.9) 
Transfusion criteria 
(>=4 within 7 days) 
10 
10 (7.1) 
0 
0 
Any units after 7 days 
31 
25 (17.9) 
46 
20 (14.3) 
Infection 
Localized Non-device 
20 
20 (14.3) 
17 
17 (12.1) 
Driveline Exit Site 
5 
5 (3.6) 
14 
11 (7.9) 
Sepsis1 
3 
3 (2.1) 
8 
7 (5) 
Neurological Event 
Ischemic CVA 
7 
7 (5) 
3 
3 (2.1) 
Hemorrhagic CVA 
2 
2 (1.4) 
2 
2 (1.4) 
TIA 
2 
2 (1.4) 
5 
4 (2.9) 
Respiratory Dysfunction 
Dysfunction 
26 
22 (15.7) 
8 
5 (3.6) 
Arrhythmia 
Ventricular 
15 
14 (10) 
14 
11 (7.9) 
Supraventricular 
25 
21 (15) 
7 
6 (4.3) 
Right Heart Failure 
Inotropes 
17 
17 (12.1) 
8 
7 (5) 
RVAD 
3 
3 (2.1) 
1 
1 (0.7) 
Device Malfunction 
Pump Failure 
3 
3 (2.1) 
4 
4 (2.9) 
Non-pump Failure 
5 
4 (2.9) 
14 
12 (8.6) 
Other 
Arterial Thromboembolism 
0 
0 
2 
2 (1.4) 
Venous Thromboembolism 
4 
4 (2.9) 
3 
3 (2.1) 
Renal Dysfunction 
8 
8 (5.7) 
6 
5 (3.6) 
Psychiatric Episode 
5 
5 (3.6) 
4 
4 (2.9) 
Myocardial Infarction 
0 
0 
1 
1 (0.7) 
Hypertension 
1 
1 (0.7) 
0 
0 
Hepatic Dysfunction 
3 
3 (2.1) 
1 
1 (0.7) 
Hemolysis event2 
1 
1 (0.7) 
1 
1 (0.7) 

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There were eight subject deaths during the 180-day study period. Six deaths occurred in subjects 
with their originally implanted device and two deaths occurred after device exchange. There were 
26 device malfunctions reported for 20 patients during the study period.  Seven (5.0%) were due 
to the LVAD component; of these 6 involved thrombosis events, necessitating exchange. 
The pre-specified primary endpoint analysis was a comparison of success rates using a non- 
inferiority margin of 15%. In the HVAD group the success rate in the Intent-To-Treat (ITT) / 
Safety Population at 180 days was 90.7% (127/140) and in the Per Protocol population 92.0% 
(126/137). The success for both Safety and Per Protocol populations in the Control group was 
90.1% (448/497). The Primary analysis found that the 95% one-sided upper confidence limit 
(UCL) on the difference in success rates between HVAD group and controls was 4.5% for the 
Safety population and 0.9% for the Per Protocol population. Each of these limits was less than the 
15% non-inferiority margin (p <0.0001). 
Survival was defined as transplanted, or alive on device support, or alive after device explant for 
recovery. The overall Kaplan-Meier survival at 180 days in the HVAD group was 93.9% in the 
Safety population and 94.2% in the Per Protocol population. The corresponding survival for the 
INTERMACS control group was 90.2%. In addition survival status at Day 180 was assessed for 
all HeartWare® HVAD patients irrespective of meeting a predefined outcome (transplant or 
explant). There were 130/140 (92.9%) of patients alive at day 180 (88/140 were alive on the 
original device, 5/140 were alive post device exchange, and 37/140 were alive post-transplant). 
The Quality of Life (QoL) determined from KCCQ Overall Summary Score for the subset of 70 
patients who had data at both baseline and Month 6 showed a 31 point improvement over the 180 
day period. In addition, as measured by the EQ-5D Visual Analog Scale, 72 subjects who had 
both baseline and 180 day data showed an improvement of 29.5 points over the 180 day period. 
Functional analyses showed similar improvements. At baseline 133/139 subjects (96%) were 
classified as NYHA class IV. A Discharge visit was conducted for 128 patients (median duration 
of hospital stays was 19 days), and data on NYHA was available for 85/128, (66.3%) of these 
patients, data on 43 was not collected. At discharge, 4/85 (4.7%) were NYHA Class I, 47/85 
(55%) of subjects were class II, 26/85 (30.6) Class III and 8/85 (9.4%) Class IV. For the 6-minute 
walk test, data collected at baseline and month 6 showed similar improvements in functional 
capacity. A total of 88 patients were still supported on the device at 6 months and of those, 74 
(84%), had 6-minute walk data at both baseline and 6 months, and they showed an average 
improvement in distance walked of 150 meters. Overall, both quality of life and functional 
capacity showed improvements following HVAD implant. 
4.3 
Name and Intended Use 
As described in the Instructions for Use, the HeartWare® HVAD is intended for use as a bridge to 
cardiac transplantation in patients who are at risk of death from refractory end-stage left 
ventricular heart failure. The HeartWare® HVAD is designed for in-hospital and out-of-hospital 
settings, including transportation via fixed wing aircraft or helicopter. 
The HeartWare® HVAD is contraindicated in patients who cannot tolerate anticoagulation 
therapy. 

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5. 
DEVICE DESCRIPTION 
5.1 
HeartWare® Ventricular Assist System 
The HeartWare® System consists of a blood pump with an integrated, partially sintered inflow 
cannula; a 10mm diameter gel impregnated polyester outflow graft, and a percutaneous driveline. 
A strain relief is used on the outflow graft to prevent kinking and secures the outflow graft to the 
pump. The driveline cable is wrapped with woven polyester fabric to encourage tissue in-growth 
at the skin exit site. The small, wearless pump has a displaced volume of 50cc and weighs 160 
grams. The pump has one moving part, an impeller, which spins blood to generate up to 10 L/min 
of flow. There are two motors in the pump housing with one motor providing redundancy. A short 
integrated inflow cannula is inserted into the left ventricle and the outflow graft connects the 
HVAD® Pump to the aorta. A sewing ring attaches to the myocardium and allows for pump 
orientation adjustments intraoperative. The device size and short inflow cannula allow for 
pericardial placement, which eliminates the need for abdominal surgery and device pockets 
(Figure 1). 
 
 
 
 
Figure 1: HVAD® Pump and left ventricular (LV) cannulation 

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5.2 
HeartWare® Controller  
The controller (Figure 2) is a microprocessor unit that controls and manages HeartWare® System 
operation. It sends power and operating signals to the blood pump and collects information from 
the pump. The percutaneous driveline is connected to the controller, which must always be 
connected to two power sources - an AC adapter or DC adapter and/or rechargeable batteries. The 
controller’s internal, non-replaceable, rechargeable battery is used to power an audible “No 
Power” alarm when both power sources are disconnected. The controller interfaces with the 
monitor through a data port. 
 
 
 
 
 
 
5.3 
HeartWare® Monitor 
Figure 2: Controller 
1. Monitor 
2. Power 
3. Driveline 
4. Power 
The monitor (Figure 3) is a touch screen tablet that uses proprietary software to display system 
performance and to permit adjustment of selected controller parameters. When connected to a 
controller, the monitor receives continuous data from the controller and displays real-time and 
historical pump information. The monitor also displays alarm conditions. 
 
 
 
Figure 3: Monitor 
1. Power Cord 
2. Monitor/Controller Connection 

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5.4 
HeartWare® Controller Power Sources 
The controller requires two power sources for safe operation: either two batteries, or one battery 
(Figure 4) and an AC adapter (Figure 5) or DC adapter (Figure 6). While active, patients will 
typically use two batteries. While relaxing or sleeping, patients should use power from an 
electrical outlet (AC adapter) because it provides power for an unlimited period of time. The 
batteries should be exchanged when their charge falls below 25% capacity. Spare, fully charged 
batteries should always be available. 
 
 
 
Figure 4: Battery 
Figure 5: AC adapter 
Figure 6: DC adapter 
 
5.5 
HeartWare® Battery Charger 
The battery charger (Figure 7) is used to simultaneously recharge up to four batteries. It takes 
approximately 4 to 5 hours to fully charge a depleted battery. 
Figure7: Battery charger 

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5.6 
Equipment for Implant 
Figure 8 shows the HeartWare® System components used at implant (provided ETO sterilized). 
• HVAD® Pump 
• Outflow graft – a 10mm diameter gel impregnated graft 
• Strain relief – to prevent outflow graft kinking 
• Sewing ring– to secure the HVAD® Pump to the left ventricle 
• Driveline cap – to protect the driveline connector when tunneling 
• Inflow cap – to cover the pump inflow cannula after the wet test and prior to implantation 
• Driveline extension cable - used during the pre-implant wet test to keep the non-sterile 
controller isolated from the sterile field 
 
Figure 8: Components used at 
implant 
1. HVAD® Pump 
2. Outflow graft 
3. Sewing ring (made of titanium 
and polyester) 
4. Driveline cap 
5. Strain relief 
6. Inflow cap 
7. Driveline extension cable 
 
A set of surgical tools (provided ETO sterilized) is also required for implantation of the device 
(Figure 9). 
Figure 9: Surgical tools 
1. Tunneler – to tunnel the pump’s 
percutaneous driveline through the 
skin to the exit site 
2. Sewing ring wrench – to tighten the 
screw on the sewing ring 
3. Driveline cover – to cover the 
driveline connection to the controller 
4. Apical coring tool – to core the LV 
apex 
5. Hex driver – to secure the strain 
relief and outflow graft to the 
HVAD® Pump 
 
All tools and accessories used during implantation are for single-use only. 

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5.7 
Principles of Operation 
Continuous flow pumps contain a rotating impeller that adds energy to the blood by converting 
the rotational kinetic energy into mechanical energy (Figure 10). Impeller blades push the fluid 
through the pump using hydrodynamic and centrifugal forces. The net effect is to build up the 
fluid pressure, sometimes referred to as pump head (i.e., related to the differential pressure across 
the device) or just head, such that the fluid is moved from the inlet to the outlet of the pump. 
Pump head is the difference between the afterload and the preload. Energy to rotate the impeller is 
provided through electromagnetic coupling between permanent magnets (rotor magnet) attached 
or enclosed within the impeller and the motor stators. The motor stators consist of coils of wire 
that are sequentially charged by electrical current, turning the coils into electromagnets. These 
electromagnets have the effect of dragging the rotor magnets around an axis of rotation. The 
HVAD® Pump is efficient at pumping moderate quantities of blood against moderate amounts of 
resistance. 
 
 
 
Figure 10: Exploded view of HVAD 
pump 
1. Inflow Cannula 
2. Front Housing Assembly 
3. Impeller 
4. Center Post 
5. Rear Housing Assembly 

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5.7.1 
Blood Flow Characteristics 
The amount of flow a rotary pump can generate is dependent upon the diameter of the impeller, 
the geometry of the impeller blades, housing design, motor capacity, rotational speed, and 
pressure differential that exists across the pump. This allows for in-vitro pump characterization for 
a specific pump and is the basis for blood flow estimation. 
The HeartWare® System estimates blood flow rate using HVAD® Pump characteristics (electrical 
current, impeller speed) and blood viscosity. Viscosity is calculated from the patient’s hematocrit. 
To obtain the most accurate estimate of blood flow, the patient’s hematocrit must be entered into 
the HeartWare® monitor.  Flow estimation should be used as a trending tool only, as it cannot 
adapt to changing fluid conditions. 
The volume of flow generated by the HVAD® Pump is determined by the rotational speed of the 
impeller and by the pressure differential across the pump. The pressure that the HVAD® Pump 
must work against is similar to the mean arterial pressure. If the pump speed (RPM) is set too low 
then the device may not generate enough forward pressure. This can lead to retrograde flow (flow 
from the aorta back through the device and into the left ventricle). The maximum rotational speed 
is determined by how much flow is available from the right heart. If the speed is set too high and 
the pump attempts to pump more blood than is available, ventricular suction may occur. 
The controller operates in “Fixed” mode, which maintains a constant motor speed. The motor 
speed range is between 1800 and 4000 RPM. The appropriate speed should be determined based 
on the patient condition. 
 
5.7.2 
Physiological Control Algorithms 
The “Fixed” mode is used for HVAD® Pump operation means the clinician sets the pump speed 
(RPM). In addition, the HVAD® Pump control algorithms provide clinicians information about 
device performance and HVAD® Pump blood flow estimation. 
5.7.3 
Flow Estimation 
Estimated HVAD® Pump blood flow is calculated using VAD power, speed parameters, and 
hematocrit, based on a blood sample from the patient. The default hematocrit setting is 30%, but 
for accurate flow estimation, the patient’s hematocrit should be entered into the monitor. 
Adjustments to the hematocrit setting on the monitor should be made for hematocrit changes of ± 
5% or greater. 
 
5.7.4 
Ventricular Suction Detection Alarm 
A suction condition may occur due to ventricular collapse or inflow occlusion. Ventricular 
collapse occurs when a continuous flow VAD attempts to pump more blood from the left ventricle 
than is available, resulting in considerable reduction in ventricular volume. Left ventricular 
collapse can be the result of clinical events affecting left ventricular preload, including 
hypovolemia (bleeding), right heart failure, arrhythmia or pulmonary embolus. An inflow 
occlusion occurs when the inflow cannula is obstructed by the interventricular septum, also 

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causing a suction condition. Temporary inflow obstruction can occur as a result of surgical 
positioning, patient position or during straining (valsalva). 
The ventricular suction detection alarm functions by monitoring the estimated flow for sudden 
decreases in flow rate. A flow baseline is established by continuously tracking the minimum flow 
values. A trigger value is established at 40% below the estimated flow baseline. An indication of 
suction is obtained when the minimum flow falls below this trigger level. The alarm will be 
triggered if this condition is maintained for 10 seconds. 
The flow minimum that triggers the suction alarm is also used to define the suction clear limit. 
The estimated flow baseline is continuously compared to this limit. The suction alarm will be 
cleared if the flow baseline is maintained above the trigger level for 20 seconds. This is an 
indication that the suction condition has cleared. 
The ventricular suction detection alarm can only be activated from the System Screen of the 
monitor. Therefore, only the clinician has access to control the state of this alarm. The default 
setting for Suction Response is off. In this mode, there will be no alarm during a ventricular 
suction condition. An “Sx Off” message will be displayed on the lower left-hand corner of the 
monitor screen below the “Fixed” mode display. When Suction Response is enabled (via the 
“Alarm” button), the “Sx On” message will be displayed on the lower left-hand corner of the 
monitor screen below the “Fixed” mode display. 
The Suction Response “Alarm” mode must not be turned on if the patient is in a suction condition. 
If the mode is turned on during a suction condition, the “Sx On” message will be displayed on the 
monitor and the ventricular suction detection alarm will be enabled but will be inaccurate due to 
the fact that normal baseline parameters could not be established during a suction condition. The 
algorithm attempts to establish a baseline detection level to distinguish abnormal conditions. This 
is not possible if the patient is experiencing ventricular suction when the algorithm is initiated. 
Once the suction condition clears, an accurate baseline will be obtained automatically and the 
suction detection will proceed. Manual changes to the speed will immediately disable the 
ventricular suction detection alarm. An “Sx Off” will be displayed on the monitor screen below 
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The ventricular suction detection function will temporarily deactivate if: 
• The estimated flow value becomes invalid. Once the flow estimation is within valid range, 
then the ventricular suction detection will resume. 
• The baseline flow value is less than 1.8 L/min – the algorithm loses sensitivity if the 
baseline and, therefore, the suction detection level gets too low. Once the baseline value is 
above 1.8 L/min, then the ventricular suction detection will resume. 
 
The clinician changes the viscosity input – the algorithm recognizes that a change in the fluid 
viscosity will cause a change in the estimated flow. The ventricular suction detection reactivates 
once a new baseline is established. 

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6. 
STUDY OBJECTIVES AND ENDPOINT MEASURES 
6.1 
Study Objectives 
The objective of this study is to evaluate the safety and effectiveness of implanting the 
HeartWare® HVAD System via thoracotomy in patients at risk of death from refractory end-stage 
left ventricular heart failure, who receive the device intended as a bridge to cardiac 
transplantation. 
This is a multi-center, prospective, single arm study that will use data from subjects enrolled in 
the InterAgency Registry for Mechanically Assisted Circulatory Support (INTERMACS®) 
protocol and database. 
All participating centers will be current enrolled INTERMACS sites in good standing. 
Participating centers will follow study subjects as they normally do for patients enrolled into 
INTERMACS®. 
Endpoints will be evaluated for subjects who receive the HeartWare® HVAD System implanted 
via thoracotomy. 
 
6.2 
Estimated Period of Study 
6.2.1 
Time Schedule 
Enrollment of subjects is expected to start in the fourth quarter of 2014 (First Implant) and each 
subject will be in the study for up to 30 months (including Screening and Follow-up phases). 
 
6.2.2 
End of Study 
Enrollment of subjects is expected to be completed in the first quarter of 2016 (Last Implant) and 
the overall end of study is defined as the day of the last visit performed on the last subject. The 
last Follow-up visit of the last subject is expected to take place by the fourth quarter of 2018. 
 
6.3 
Primary Endpoint 
The primary endpoint is success at 6 months defined as all enrolled and implanted subjects: 
• 
Alive on the originally implanted device at 6 months, and the subject has not had a stroke 
with a modified Rankin Scale ≥ 4 (assessed ≥3 months post stroke event); or 
• 
Transplanted by Month 6, and the subject has not had a stroke with a modified Rankin 
Scale ≥ 4 (assessed ≥3 months post stroke event), or 
• 
Explanted for recovery by Month 6, and the subject has not had a stroke with a modified 
Rankin Scale ≥ 4 (assessed ≥3 months post stroke event). 
All subjects with stroke events from implant to Month 6 will be required to remain in follow-up 
until the post-stroke mRS measure (≥3 months post stroke event) is obtained, even if this occurs 
after the 6-month visit. If a stroke subject is alive at 6 months, but dies before the post-stroke 
mRS is obtained, the subject will be considered a failure with regard to the primary endpoint. 

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6.4 
Secondary Endpoint 
The secondary endpoint is an improvement in the mean length of initial hospital stay (initial 
recovery and step down unit) for all enrolled and implanted subjects. The mean length of initial 
hospital stay is estimated to be 26.1 days for median sternotomy subjects. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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7. 
STUDY DESIGN 
This a prospective, single arm, multicenter study to evaluate the thoracotomy implant technique in 
up to 145 subjects implanted via thoracotomy with the HeartWare HVAD® System and enrolled 
in the InterAgency Registry for Mechanically Assisted Circulatory Support (INTERMACS®) 
protocol and database. 
 
7.1 
Number of Clinical Sites and Subjects 
This study will be conducted at up to 30 sites in the US and 1 site in Canada. All centers will be 
required to have an approved and active cardiac transplant program, have experience implanting 
the HeartWare® HVAD System, and must meet the INTERMACS® defined requirements to be 
eligible for participation: 
• All centers will be currently enrolled INTERMACS sites who are participants in good 
standing and who contribute to the INTERMACS® database. (These organizations and 
agencies have mechanisms in place to assure basic national standards and survival rates 
are maintained.) 
• All US commercial centers will have a certificate of need to perform cardiac transplants by 
the state in which they are located. 
• US centers will be United Network for Organ Sharing (UNOS) approved with a cardiac 
transplant program on active status. 
• US centers will be Centers for Medicare and Medicaid Services (CMS) and Joint 
Commission on the Accreditation of Healthcare Organizations (JCAHO) approved for 
cardiac transplantation. 
Centers will be identified by the Principal Investigators of the study in collaboration with 
HeartWare and will be based upon the center’s interest in participating in the study, their 
academic history, infrastructure, geographic location, and the number and kind of VAD implants 
per year. 
One hundred forty-five (145) subjects will be required to meet the statistical endpoints defined for 
the study. It is anticipated that each site will enroll at least 1 subject. No site will implant more 
than 20 patients into the study without prior written approval from HeartWare. 
 
7.2 
Subject Participation and Study Duration 
All subjects will be followed for the primary endpoint, and at subsequent follow-up visits, 
according to the approved INTERMACS® protocol and using data from INTERMACS®. 
Data collection for analysis and subject status for inclusion in analyses will be assessed as 
follows: 
• Subjects who have been transplanted prior to month 6 post implant will be considered 
complete at the time of the primary endpoint visit time-point. 
• Subjects, who have a device exchange prior to month 6, will be evaluated according to the 
original implant date. 

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• Subjects who remain on device support after the primary endpoint time-point, either the 
original device or exchange device, will be followed according to the INTERMACS® 
protocol until transplant, or until 2.5 years post implant of the original device. A 
subject’s study participation is considered complete at either the time of at induction of 
anesthesia for transplant, or at the 2.5 year post implant visit. 
• Subjects who have been explanted for recovery prior to month 6 will be followed until 
their next scheduled follow-up visit according to the INTERMACS® protocol, at which 
time their participation in the study is considered complete. 
• The per-protocol analysis population will include those thoracotomy subjects with the 
outflow in the ascending aorta only. As a result, enrollment may exceed sample size 
requirements. 
• The per-protocol analysis population will include those thoracotomy subjects with the 
procedure performed on-pump only. As a result, enrollment may exceed sample size 
requirements. 
Subject data will be evaluated for a maximum of 2.5 years. 

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8. 
PATIENT POPULATION, SELECTION AND WITHDRAWAL 
8.1 
Characterization of Study Population 
Subjects will be made up of those patients who are prospectively identified as candidates to 
receive a HeartWare® HVAD via a thoracotomy implant procedure and who meet the inclusion 
and exclusion criteria as defined in Sections 8.2 and 8.3 below. 
 
8.2 
Inclusion Criteria 
1. Must be ≥19 years of age at time of informed consent to participate in the INTERMACS® 
registry. 
2. Subject receives a HeartWare® VAD (The device should be the subject’s first VAD 
implant). 
3. Subject signed an INTERMACS® informed consent if required by local IRB/CREB 
policy. 
4. Subject signed a HeartWare ®informed consent 
8.3 
Exclusion Criteria 
The INTERMACS® protocol has no exclusion for age, gender, race, ethnicity, or any other 
demographic limit.  The following are exclusions currently described: 
1. Subject is incarcerated (prisoner). 
2. Subject did not sign the informed consent at sites where waiver of consent was not 
granted. 
In addition, for this study, the following additional exclusion criteria will be applied after 
enrollment into the INTERMACS® protocol: 
3. Body Surface Area (BSA) < 1.2 m2. 
4. Prior cardiac transplant or cardiomyoplasty. 
5. Subject is receiving a BiVAD. 
6. Subject is receiving the device as an RVAD. 
7. Subject data is generated from non- INTERMACS® centers. 
8. Pediatric subjects (< 19 years of age). 
9. Subjects who receive a temporary LVAD (e.g., ECMO, TandemHeart, Impella, etc.). 
10. Subjects whose device strategy is listed as “Destination Therapy” at the time of implant. 
11. Severe Right Heart failure, defined as mean central venous or right arterial pressure > 20 
mmHg on multiple inotropes, or right ventricular ejection fraction (RVEF) <15% with 
clinical signs of severe right heart failure (e.g. ascites, treatment with diuretics and two 
inotropic drugs). 
12. ≥ 2+ aortic insufficiency or mechanical aortic valve. 
13. Planned concomitant procedure (e.g. valve repair or replacement, CABG, septal defect 
repair). 
14. Known LV thrombus 

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9. 
STUDY COURSE AND PROCEDURES 
9.1 
Enrollment 
The subject data to be included in the study analyses will be recorded in the INTERMACS® 
database from enrolled subjects implanted via thoracotomy. 
9.2 
Assessments 
All study assessments will be conducted according to the approved INTERMACS® protocol and 
procedures. There are no other study specific procedures required except the consenting of 
subjects with a HeartWare Informed Consent Form (ICF). 
9.2.1 
Baseline / Pre-Implant information 
Baseline and pre-implant data recorded in the INTERMACS® database includes: 
• Patient demographic data. 
• Medical history and co-morbidities. 
• Clinical status including INTERMACS® patient profiles and NYHA Class. 
• Laboratory values including blood chemistry and hematology. 
• Cardiovascular Medications including inotropes, diuretics, anti-arrhythmics, pulmonary 
hypertensive agents, and anticoagulation therapy. 
• Hemodynamic Data. 
• Quality of Life as measured by EuroQol and KCCQ. 
• Neurocognitive Testing measured by the Trail Making Neurocognitive Test, Part B. 
• Exercise Function measured by the six minute walk test. 
9.2.2 
Implant Information 
Implant information recorded in the INTERMACS® database includes: device information and 
device tracking number, implant technique, concomitant cardiac surgical procedures, and 
cardiopulmonary bypass / surgery times. 
9.2.3 
Follow-up Assessments 
Follow-up visit time-points specified in the INTERMACS® protocol include: At discharge, 1 
week, 1 month, 3 months, 6 months and every 6 months until outcome/ 2.5 years. 
At discharge assessments recorded in the INTERMACS® database include: adverse events and 
discharge date. 
Assessments at one week and one month include: hemodynamics, laboratory values, medications, 
echocardiogram, medical condition as described by NYHA class and adverse events. 
Assessments at 3 and 6 months, and then every 6 months until outcome / 2.5 years include: 
laboratory values, medications, hemodynamics, echocardiogram, medical condition as described 
by NYHA class and INTERMACS® patient status, neurocognitive testing, quality of life testing, 
exercise function and adverse events. 

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Every attempt should be made to perform evaluations at the designated time points. Visits and 
associated visit windows will be as per the INTERMACS protocol and procedures. While per the 
INTERMACS protocol, the Month 6 visit has a ±60 day window, it is recommended that the 
Primary Endpoint visit occur at Month 6 + 60 days, whenever possible. 
9.2.4 
Re-hospitalizations 
Information on re-hospitalizations post initial discharge is recorded in the INTERMACS® 
database, including date and reason for re-admission, treatment and date of discharge. 
9.2.5 
Outcomes 
Information on the type of outcome (transplant, explant, death) is recorded in the INTERMACS® 
database, including transplant date, reason for explant, and cause of death. 
9.2.6 
Adverse Events 
Adverse events will be collected throughout the subject’s participation in the study according to 
the INTERMACS® protocol and procedures. 
INTERMACS defines 17 specific event that it considers as serious event in patients receiving a 
VAD as these specific event definitions usually encompass the traditional categorization of 
serious (i.e. considered life threatening, requires or prolongs hospitalization, results in death, if the 
event results in disability or permanent damage, or requires an intervention to prevent one of these 
outcomes). 
INTERMACS® also defines a category of “Other” adverse events and collects these as reported by 
participating centers. These will be summarized and presented in the study reports, but the 
recording of these ‘Other’ events does not capture the event seriousness or relationship to device 
(any events related to the device if applicable are captured under the INTERMACS® 
categorization of Device Malfunction). 
The events listing in the INTERMACS protocol are listed below and definitions included in 
Appendix C. 
Major infection 
Major bleeding 
Neurological dysfunction 
Device malfunction 
Cardiac arrhythmia 
Renal dysfunction 
Hemolysis 
Respiratory failure 
Hepatic dysfunction 
Right heart failure 
Hypertension 
Arterial non-CNS thromboembolism 
Myocardial infarction 
Venous thromboembolism 
Pericardial fluid collection 
Wound dehiscence 
Psychiatric episode 
Other adverse events 

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9.2.7 
Device Related Adverse Events and Device Malfunctions 
All device related adverse events and device malfunctions must be reported as complaints to 
HeartWare’s Quality group. 
All device malfunctions as defined by INTERMACS™ will be recorded in the INTERMACS™ 
database according to their Manual of Operations. 
9.2.8 
Additional data collection 
Post-Transplant 
Additional information will be collected to evaluate the effect of the lateral surgical procedure on 
the pre and post-operative requirements, length and severity of the hospitalization during the 
procedure and length of hospitalization post-transplant. 
The following parameters will be included: 
1. Total operative time 
2. Cardiopulmonary Bypass time 
3. Intraoperative blood/ coagulation products 
4. If the surgical procedure was done on a Virgin Chest 
5. If the patient had Pneumothorax 
6. Severity of pericardial/pleural adhesions 
7. Time on ventilator/inotropes 
8. Total Days on Intensive Care Unit 
9. Total Days in Hospital after transplant 
The additional data will be collected on transplanted patients only. 
The additional data will not be captured in INTERMACS database. 
Follow-Up after stroke if transplanted or explanted 
Additional information will be collected for all stroke patients who are transplanted or explanted 
in order to assess mRS (≥3 months post-stroke) to classify them for the primary endpoint. 
The following parameters will be included: 
1. Date of assessment 
2. mRS 
The additional data will be collected only on transplanted or explanted patients who had a stroke 
with mRS ≥4 less than 3 months prior to the transplant or explant. 
The additional data will not be captured in INTERMACS database. 

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10. 
SURGICAL IMPLANT PROCEDURE 
10.1 Pre-Implant Device Management 
Refer to the HeartWare® HVAD Instructions for Use for detailed equipment set-up procedures. 
10.2 Implant Procedure 
Refer to the Instructions for Use for the thoracotomy implant procedure, which describes 
HeartWare® HVAD placement in the pericardial space, cannulation techniques and tunneling of 
the percutaneous lead. 
 
10.3 Postoperative Patient Management including Blood Pressure (BP) 
Management 
Refer to the HeartWare® HVAD Instructions for Use for postoperative patient management 
guidelines. 
HeartWare strongly recommends BP Management for all implanted subjects. Since the HVAD® 
Pump provides continuous flow, resulting in narrow arterial systolic/diastolic pulse pressures, 
monitoring of the mean arterial pressure (MAP) is important. The recommended MAP target for 
subjects supported by the HeartWare® HVAD is < 85 mmHg (as tolerated). 

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11. 
STATISTICAL CONSIDERATIONS 
11.1 
Study Endpoints and Hypotheses 
11.1.1 Analysis Populations 
The Intent-to-Treat (ITT) subject population will include all enrolled subjects intended to receive 
the HVAD® pump via thoracotomy at the time of skin incision. 
The Per-Protocol (PP) subject population will include all ITT subjects who were implanted with 
the HVAD pump® via thoracotomy, on-pump, and with outflow to the ascending aorta. Sample 
size requirements reflect the minimum number of subjects needed for the PP population. 
The primary analysis population is the PP population. All endpoints will be assessed on the ITT 
and PP populations. 
 
11.1.2 Primary Endpoint 
The primary endpoint is success at 6 months defined as all enrolled and implanted subjects: 
• Alive on the originally implanted device at 6 months, and the subject has not had a stroke 
with a modified Rankin Scale ≥ 4 (assessed ≥3 months post stroke event); or 
• Transplanted by Month 6, and the subject has not had a stroke with a modified Rankin 
Scale ≥ 4 (assessed ≥3 months post stroke event), or 
• Explanted for recovery by Month 6, and the subject has not had a stroke with a modified 
Rankin Scale ≥ 4 (assessed ≥3 months post stroke event). 
 
All subjects with stroke events from implant to Month 6 will be required to remain in follow-up 
until the post-stroke mRS measure (≥3 months post stroke event) is obtained, even if this occurs 
after the 6-month visit. If a stroke subject is alive at 6 months, but dies before the post-stroke 
mRS is obtained, the subject will be considered a failure with regard to the primary endpoint. 
 
Hypothesis: 
H0: πT ≤ 77.5% 
Ha: πT > 77.5% 
πT = the expected proportion of subjects experiencing success for the Thoracotomy group 
The success prevalence in the thoracotomy group will be statistically compared to the 
performance goal (77.5%) using an exact binomial test (i.e., the lower 95% one-sided confidence 
limit will be greater than 77.5%). Success will be met if the lower bound of the one-sided exact 
95% confidence limit is greater than 77.5%. 
 
11.1.3 Secondary Endpoint 

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The secondary endpoint is an improvement in the mean length of initial hospital stay (initial 
recovery and step down unit) for all enrolled and implanted subjects, which is calculated by 
considering the number of days in acute care (ICU/CCU) plus the number of days in 
intermediate/step-down care, comprising the total number of days post-implant to discharge. The 
mean length of initial hospital stay is estimated to be 26.1 days for median sternotomy subjects. 
 
Hypothesis: 
H0: µT ≥ 26.1 
Ha: µT < 26.1 
µT = the expected mean length of initial hospital stay for the Thoracotomy group 
 
A responders’ analysis will also be assessed to help define the clinical benefit of this endpoint. 
The length of initial hospital stay will be summarized across outcomes associated with the 
primary endpoint (success at 6 months). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Strokes are those neurological events specified as an ICVA or an HCVA, as per the current 
INTERMACS event definition (See Appendix D). 

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11.2 Sample Size Justification 
Primary Endpoint: 
Success at 6 months is estimated to be 86% compared to a performance goal of 77.5%. Using an 
exact binomial test, with a one-sided alpha of 0.05, and 80% Power, a sample size of 145 
implanted subjects is required. 
The target success estimate of 86% is based on the following: 
• 
The primary endpoint observed in the final BTT IDE Report for the more recent BTT CAP 
population (N=242), resulted in a success prevalence of 85.8% (205 out of 239 eligible 
subjects) for sternotomy subjects. 
• 
Post-approval data from the INTERMACS Registry (through Q2 2014), indicates similar 
results for the sternotomy population of 88.0% (396/450) with a lower prevalence of 
success for the small subset of thoracotomy (83.3%, 55/66) and thoracotomy on-pump 
(82.6%, 38/46) subjects. 
• 
The INTERMACS Federal Partners Report (from Q1 2014) indicates an 85% Kaplan- 
Meier survival estimate at 6 months. This is not the same as “success” in that post- 
exchange survival is considered. 
• 
The INTERMACS Industry Report for HeartWare (from Q2 2014) indicates an 88% 
Kaplan-Meier survival estimate at 6 months. This is not the same as “success” in that 
post-exchange survival is considered. 
Success will be met if the lower bound of the one-sided exact 95% confidence limit is greater than 
77.5%. 
For exploratory purposes, the primary endpoint will also be assessed and observed by: 
• 
Site 
• 
CPB (on pump, off pump) 
• 
Outflow location 
Secondary Endpoint: 
The mean length of initial hospital stay is estimated to be 26.1 days with a standard deviation of 
22.8 days and a median of 20 days based on data from the BTT CAP population (N=242). Using 
a one sample t-test, with a one-sided alpha of 0.05, a sample of 145 implanted subjects with an 
average value of 21.3 days or less will result in Power greater than 80%. 
Due to the skewed nature of this data, a non-parametric test (one-sample Sign test with a one- 
sided alpha of 0.05) to assess a reduction in median days (from the estimated 20 days) will also be 
conducted for support. 
For exploratory purposes, the secondary endpoint will also be assessed and observed by: 
• Site 
• CPB (on pump, off pump) 

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• Outflow location 
The sample size calculations were performed using nQuery Advisor®. 
11.3 
Site Poolability 
The primary and secondary endpoints will be performed on pooled data, however, an Analysis 
Site poolability assessment will be incorporated into the design of the study. This will involve 
pooling sites into “Analysis Sites” with a target size of 5 subjects. Sites with at least 5 subjects 
will serve at their own Analysis Site. Those with less than 5 will be rank ordered by size and 
sorted secondarily by site identification number to break ties. Starting with the smallest 
investigative site, subjects are combined site by site until at least 5 subjects are identified, thus 
establishing an Analysis Site. The next Analysis Site is formed similarly to contain at least 5 
subjects. The process continues until all sites and subjects are accounted for. If the last Analysis 
Site has fewer than 5 subjects, it is combined with the most recently created previous Analysis 
Site. 
A Fisher’s exact test will be performed to test the homogeneity of success at 6 months across 
Analysis Sites. Analysis Site homogeneity is defined if the p-value is 0.15 or greater. If there is 
an Analysis Site effect (p-value < 0.15), an investigation of prognostic factors (i.e., baseline 
characteristics, medical history or other covariates of interest) will be reviewed to understand 
variability between Analysis Sites. As a supplemental analysis, a logistic regression model will 
be performed to estimate the probability of success controlling for Analysis Site and the selected 
prognostic factors. 
 
11.4 Handling of Missing Outcomes 
Every effort will be made to gather all data associated with the primary, secondary and additional 
endpoints. A complete case analysis, which includes all subjects with complete follow up will be 
conducted as the primary analysis of the primary endpoint. 
 
 
 
 
 
 
 
 
 
 
 
If a subject experiences a stroke and subsequently completes the 6 month follow-up, a post-stroke 
(greater than 6 months post-event) mRS is still required. If the subject dies prior to the post- 
stroke mRS but after the 6 month follow-up, the outcome will be considered a failure. 
For the secondary endpoint, imputation for missing data regarding duration of hospital stay (in 
days) will not be performed. 

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11.5 Early Submission 
Early review of the data will be performed when the first 100 subjects complete 6 months of 
follow-up. Analysis of the results will follow the Haybittle-Peto methodology7,8, where the 
interim look will involve an alpha level of 0.001, retaining an alpha level of 0.05 for the final 
analysis of 145 subjects. This is not intended to serve as a stopping rule, but rather an early 
submission indicator. A target of 92.5% of the first 100 subjects would need to experience 
success at 6 months to achieve Power greater than 80% and consideration of early submission. 

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12. 
RISK AND BENEFIT ANALYSIS 
12.1 Potential Benefits 
There is a growing trend toward the use of less invasive non-sternotomy incisions in all fields of 
cardiac surgery. While a median sternotomy provides the best access to the heart and great 
vessels, the same exposure could be accomplished with several smaller thoracotomy incisions. For 
patients who will require more than one cardiac operation (for example, VAD implantation as a 
bridge to transplantation), avoiding a median sternotomy in the first operation will reduce the 
surgical risk of a redo sternotomy in the following operations. Less-extensive mediastinal 
dissection in non-sternotomy incisions could reduce the prevalence and severity of postoperative 
bleeding. This is particularly important in VAD patients who require early anticoagulation therapy 
after implant. In addition, with a thoracotomy the pericardium remains mostly intact, which 
results in the stabilization of right heart function and possibly avoiding right heart dilatation 
during the procedure, especially when initially starting the HVAD® Pump. Many of these benefits 
also apply if the second operation is done via thoracotomy. The HVAD® Pump is designed to be 
implanted in the pericardial space. Its small design allows some versatility in placement and 
therefore does not limit the implant to a single surgical procedure. This implant versatility 
provides clinicians multiple options for implant and allows them to best match the patient with the 
procedure. There are some patients who may fare better with a thoracotomy rather than 
sternotomy. The potential benefit to the subject participating in this study is the implantation of a 
blood pump using a technique that is less obtrusive and that may be more comfortable. Morbidity 
rates and time of recovery may also be positively affected. The thoracotomy technique for implant 
may provide benefits not currently available with existing technology. The potential benefits as 
mentioned above include: 
 
 
Potential Benefit 
Thoracotomy Implant 
Less invasive implant procedure 
• Smaller incisions 
• Shorter hospitalization 
Reduced bleeding 
• Less tissue trauma 
• Virgin sternotomy at later procedure 
• Thoracotomy at second procedure/device exchange 
Reduced infection 
• Lower infection rates 
• Less severe infections 
• Virgin sternotomy at later procedure 
Reduction of right heart failure 
• Pericardium more intact 
Expand patient population 
• Include patients who may not tolerate a sternotomy 

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12.2 Risk Analysis 
There are no foreseeable, additional risks associated with the thoracotomy approach for 
implantation of the HeartWare® System beyond those historically associated with implantable, 
continuous flow LVAD systems. While no new risks have been identified, there are some events 
that can be more easily treated via a sternotomy as compared to a thoracotomy. For example, the 
LV can be examined for thrombus more thoroughly and RVAD support can be more easily 
initiated using a sternotomy. The complications (LV thrombus, right heart failure) can be 
mitigated to some degree with patient selection, however, complications are unpredictable. 
Pneumothorax is a known complication of thoracic surgery which can occur in patients who 
receive either a sternotomy or thoracotomy, however since the risk of pneumothorax may be 
higher in thoracotomy patients it was added to the potential complications list. HeartWare 
believes it has used its best efforts to foresee hardships and potential adverse events of either in- 
hospital or home use of the HeartWare® System. 
Implantation of an LVAD is an invasive operation involving a major thoracic procedure (median 
sternotomy or left thoracotomy), general anesthesia, mechanical ventilation and frequently 
cardiopulmonary bypass. These procedures are associated with numerous risks including death. 
The HeartWare® Ventricular Assist System is implanted in the hostile environment of the human 
body. This environment places severe challenges to the function of the device. Risks associated 
with the implant procedure and use of the device may include, but are not limited to, the 
following. Other than death, the adverse events are listed in alphabetical order according to 
INTERMACS categories: 
 
 
‐ 
‐ 
‐ 
‐ 
Death 
Arterial Non-CNS Thromboembolism 
Air Embolism 
Embolization of Sintered Spheres 
Embolization of tissue adherent to inflow 
at time of pump removal 
Peripheral Thromboembolism 
Bleeding 
Major Bleeding (Bleeding requiring 
transfusion) 
GI bleeding / AV malformations 
Cardiac Arrhythmias 
Supraventricular Arrhythmia 
‐ 
Driveline Wire damage 
Electrostatic Discharge (ESD) damage to 
device 
Injury from Device Exposure to 
Therapeutic ionizing Radiation 
Injury from Device Exposure to 
Therapeutic Levels of Ultrasound 
Energy 
Injury from High Electrical Power 
Sources 
Interference with/ from other devices 
Pump Stop 
Hemolysis 
Ventricular Arrhythmia 
‐ Hepatic Dysfunction 
ICD shock 
‐ Hypertension 
‐ Device Malfunction 
Battery failure 
‐ Major Infection 
Driveline Infection 
Controller failure 
Internal Pump Component, Inflow or 
Device Exchange 
Outflow Tract Infection 
Device Thrombosis 
Localized Non-device Infection 

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‐ 
Sepsis 
Myocardial Infarction 
‐ 
‐ 
Wound Dehiscence 
Other 
‐ Neurological Dysfunction 
Transient Ischemic Attack (TIA) 
Anemia 
Aortic Insufficiency 
Stroke 
Cardiopulmonary Arrest 
Ischemic Cerebral Accident (ICVA) 
Multi-organ failure 
Hemorrhagic Cerebral Accident 
Platelet Dysfunction 
(HCVA) 
Pleural Effusion 
‐ Pericardial Fluid Collection 
Pericardial Effusion 
Sensitivity to Aspirin 
Surgical Complications 
Tamponade 
Arterio-venous fistulae 
‐ 
‐ 
Psychiatric Episode 
Suicide 
Renal Dysfunction 
Organ damage during driveline 
tunneling 
Pain 
‐ 
‐ 
‐ 
Respiratory Failure 
Right Heart Failure 
Venous Thromboembolism Event 
Deep Vein Thrombosis 
Pulmonary Embolism 
Pneumothorax 
Re-operation 
Syncope 
Tissue Erosion and other tissue damage 
Worsening Heart Failure 
 
No additional risks are known for the HeartWare® System beyond those established for other 
implantable, continuous flow LVAD systems. 
The HeartWare® System should not be used in pregnant women. Any woman receiving a 
HeartWare System who is of childbearing age and sexually active should use a reliable method 
of birth control. Use of anticoagulants during pregnancy has been associated with birth defects 
and bleeding. 
This study involves only standard of care procedures and does not differ from typical LVAD 
implantation and follow-up care. Therefore, the clinical study requirements pose no additional 
risk to the patient. All investigators and clinical personnel will have previous experience with the 
HeartWare® System, surgical implant procedures and patient management. Trained and 
experienced personnel representing HeartWare will be available to support HeartWare® System 
implants, ongoing education and HeartWare® System technical support/troubleshooting. In 
addition, patients and companions will undergo an extensive hospital training program and must 
demonstrate competency prior to discharge from the hospital. 
In the event of unforeseen or increased risks to subjects, suspension or termination of the 
clinical study shall be considered. 

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13. 
INVESTIGATOR RESPONSIBILITY 
This clinical study will be performed in accordance with the Declaration of Helsinki, Good Clinical 
Practice Guidelines, and Code of Federal Regulations 21CFR Part 820, 21 CFR Part 50, 21CFR 
Part 54 and 21CFR Part 56, Health Canada Regulations and any country laws, as applicable. 
 
13.1 Institutional Review Board (IRB)/Research Ethics Board (CREB) Approval 
All enrolled INTERMACS® sites must have IRB/CREB approval as required by INTERMACS® 
procedures. In addition, each participating study center will also obtain IRB/CREB approval of the 
HeartWare IDE protocol and informed consent form. 
No subject will be consented for the study until the IRB/CREB has approved the protocol and the 
Informed Consent Forms. Documentation of approval must be sent to HeartWare or designee. At 
study termination, a Final Report must be submitted by the Investigator to the IRB/CREB and 
Sponsor. Copies of all submissions to and correspondence (approvals and disapprovals) from the 
IRB/CREB must be maintained on file at the study site. 
 
13.2 Informed Consent 
All subjects will be consented using the INTERMACS® informed consent and health privacy 
documents according to the INTERMACS procedures and local IRB/CREB policy and procedures. 
Additionally, subjects will sign a HeartWare informed consent form and health privacy document 
prior to implantation of the HeartWare® HVAD via thoracotomy. 
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent form explains the study procedures, the 
nature of the study, its objectives, potential risks and benefits, as well as the date enrollment 
informed consent is given. The informed consent form will detail the requirements of the 
participant and the fact that he or she is free to withdraw at any time without giving a reason and 
without prejudice to his or her further medical care. The subject authorization form, describe the 
planned and permitted uses, transfers, and disclosures of the subject’s personal and personal health 
information for purposes of conducting the study. 
In the event the subject is not capable of rendering an adequate written informed consent, then the 
subject’s legally acceptable representative may provide such consent for the subject in accordance 
with applicable laws and regulations. 
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the screening and (2) decide whether or not to participate in the 
screening and subsequently, if applicable, must be given ample opportunity to: (3) inquire about 
details of the study and (4) decide whether or not to participate in the study. 
If the subject, or the subject’s legally acceptable representative, determines he or she will participate 
in the study, then the informed consent form and subject authorization form must be signed and 

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dated by the subject, or the subject’s legally acceptable representative, at the time of consent and 
prior to the subject screening, or enrolling into the study and any study procedures being performed. 
Once signed, the original informed consent form and subject authorization form will be stored in the 
investigator’s site file. The investigator must document the date the subject signs the informed 
consent in the subject’s medical record. Copies of the signed informed consent form and the signed 
subject authorization form shall be given to the subject. 
 
13.3 Subject Data Protection 
Data on study subjects is collected by INTERMACS® and subject data is protected by their 
confidentiality procedures. 
All information and data sent to HeartWare or their authorized representative, concerning subjects 
or their participation in this study, will be considered confidential. Subject data provided to 
HeartWare Inc. will be identified only by a subject identification number. Data for the study will be 
de-identified data as per INTERMACS standard operating procedures. 
All data used in analysis and reports will be used without identifiable reference to the subject. At all 
times throughout the study, confidentiality shall be observed by all parties involved.  All data shall 
be secured against unauthorized access. 
All subjects consented for this study will be informed and must agree to the use and disclosure of 
their study information by the institution and investigators to HeartWare, their agents and 
representatives, the FDA, Health Canada or other government agencies or review boards, as 
applicable. This authorization is included as HIPAA Authorization: Authorization to Use and 
Disclose Health Information.  If the institution requires that an IRB or CREB specific 
Confidentiality Authorization (HIPAA) form be used, then the site must provide a copy of this form 
to HeartWare for review and approval 
 
13.4 Investigator Agreement 
Prior to study initiation, the Investigator must sign an Investigator Agreement (example Investigator 
Agreement; HeartWare or designee to provide Investigator Agreement template to sites). The 
Investigator Agreement identifies the Investigator’s legal and ethical commitments with respect to 
the conduct of the clinical study as defined in 21 CFR Part 820, Part 56, Part 50, and Part 54 or 
Health Canada Regulations, as applicable.. 
 
13.5 Financial Disclosure 
A Financial Disclosure Form must be reviewed and signed by the Investigator and sub- 
investigator(s) prior to study initiation. HeartWare or designee will provide the Financial Disclosure 
Form to sites. Updates to financial disclosure will be made during the course of the study and for 1 
year following completion of the study. The Financial Disclosure form is required to record the 
Investigator’s and Sub-Investigator’s financial interests in HeartWare, which may be a potential 
source of bias in the outcome of the clinical study. 

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13.6 Protocol Deviations and Medical Emergencies 
The Investigator will not deviate from the protocol without the prior written approval of HeartWare 
except in medical emergencies or in unforeseen, isolated instances where minor changes are made 
that will not increase the subject’s risk or affect the validity of the study. In medical emergencies, 
prior written approval for protocol deviations will not be required, but HeartWare personnel must be 
notified via telephone within 24 hours of occurrence. 
 
13.7 
Device Accountability 
As of version 7.3 of this protocol, the HeartWare® Ventricular Assist Device System is a US 
marketed device for the destination therapy indication. It is FDA approved for implantation via 
either thoracotomy or sternotomy approach. 
The disposition of all HeartWare® HVAD System components allocated to HW006 study patients 
prior to protocol version 7.3 were provided to FDA and reviewed in the Annual Report G130279. 
Under version 7.3 of this protocol, device accountability will be tracked by serial number and/or lot 
number.  

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14. 
MONITORING AND QUALITY CONTROL 
14.1 
Site Training 
The study is being conducted at experienced HeartWare implanting institutions and all participating 
study centers and relevant staff will have previously completed HeartWare® System training by 
HeartWare representatives. Training sessions will have included: HeartWare® HVAD implantation 
and management techniques, how the HeartWare® HVAD works, what to do in an emergency 
situation, procedures for troubleshooting the HeartWare® HVAD malfunctions, patient discharge 
training, regulatory requirements and general good clinical practice for the study. 
The HeartWare® HVAD Instructions for Use will be provided to assist the healthcare team on the 
proper care and operation of the HeartWare® HVAD System. 
Additional training on the Thoracotomy Implant technique will be provided to participating sites. 
Each site will be responsible for ensuring that the hospital staff directly responsible for patient care 
from the postoperative period to hospital discharge and outpatient follow-up (e.g. ICU nurses, staff 
nurses and physicians) are adequately trained in the management of these HeartWare® HVAD 
patients and emergency response procedures. 
Training related to the HW006 study protocol will be conducted through an Investigator meeting or 
through Site Initiation Visits at study start-up. All investigators and relevant staff such as study 
coordinators will be trained on the protocol. 
 
14.2 
Monitoring of the Study 
HeartWare will conduct monitoring activities as applicable and appropriate for this trial to ensure 
that it is conducted in accordance with the protocol. As required during monitoring visits for 
treatment subjects, informed consent forms and HeartWare® HVAD System accountability will be 
verified. 
HeartWare will conduct site evaluation visits to assure that potential clinical investigators are 
qualified by training and experience to participate in the trial, and site initiation visits to ensure that 
investigators and site staff have a full understanding of their obligations, are trained thoroughly, 
have the appropriate support, and have all the regulatory documentation in place to conduct the 
study. 
 
14.3 
Independent Data Review and Event Adjudication 
14.3.1 HeartWare DSMB 
To meet the trial’s ethical responsibility to its subjects, results will be monitored by a Data Safety 
Monitoring Board (DSMB). The DSMB will review the study at key points during the conduct. A 
periodic safety review of study data provided from the INTERMACS database will take place 
annually aligned with the registries reporting schedule. 

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14.3.2 INTERMACS® Observational Study Monitoring Board (OSMB 
The NHLBI-appointed independent Observational Study Monitoring Board (OSMB), which meets 
once per year, evaluates the INTERMACS® registry on an ongoing basis as to procedures, findings, 
and adverse events to assure participant safety, confidentiality of records, and registry integrity. The 
OSMB advises the NHLBI and the INTERMACS® co-investigators when and if changes should be 
made. 
 
14.4 
Progress Reports to Regulatory Agencies 
HeartWare will provide the FDA and Health Canada with progress reports as required. The 
IRBs/CREBs will be provided with copies of the progress reports. 
 
15. 
Records and Reports 
15.1 
Case Report Forms 
An Electronic Data Capture (EDC) system will be utilized to collect all subject data during the 
course of the study, and this system is provided by INTERMACS. 
 
15.2 
Data Review 
INTERMACS® is responsible for the quality control of the database and confirming the overall 
integrity of the data according to their standard operating procedures. 
 
15.3 
Record Retention 
HeartWare and all participating Investigators must establish and maintain records and reports. The 
Investigator must maintain the signed Informed Consent Forms, IRB/CREB approvals and 
communications and source documents for at least 4 years after study completion or termination. In 
accordance with the Investigator Agreement, HeartWare should be contacted if the Principal 
Investigator plans to leave or otherwise absent themselves from the investigational site. 
 
15.4 
Study Insurance 
HeartWare’s liability is underwritten by an insurance policy secured by HeartWare in accordance 
with United States laws and regulations. A copy of the insurance certificate is provided upon 
request. 

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16. 
APPENDICES 
16.1 
Appendix A – INTERMACS® Protocol 
This appendix includes the INTERMACS Protocol Version 4.0 date February 27, 2014. 

 
 
 
 
Interagency Registry for Mechanically Assisted Circulatory Support 
(INTERMACS®) 
 
Protocol 
 
Principal Investigator: James K. Kirklin, MD 
 
 
Data Coordinating Center: University of Alabama at Birmingham 
 
 
 
 
 
 
 
NHLBI Contract Number: HHSN268201100025C 

Protocol Version 4.0 
02/27/2014 
 
 
Contents 
LIST OF ABBREVIATIONS. ...................................................................................................... 5 
EXECUTIVE SUMMARY AND BACKGROUND ......................................................................... 6 
REGISTRY DESCRIPTION ........................................................................................................ 7 
REGISTRY ORGANIZATION ......................................................................................................7 
A. INTERMACS – ADULTS ....................................................................................................... 8 
A.1.0 REGISTRY DESIGN ....................................................................................................... 8 
A.1.1 
PATIENT ELIGIBILITY ........................................................................................................................ 8 
A.1.2 
DESIGN .......................................................................................................................................... 9 
A.1.3 
ADDITIONAL DATASETS .................................................................................................................... 9 
A.1.4 
MAJOR END POINTS ...................................................................................................................... 10 
A.2.0 SITE ELIGIBILITY AND ENROLLMENT ....................................................................... 11 
A.2.1 
ELIGIBILITY ................................................................................................................................... 11 
A.2.2 
REGISTRATION .............................................................................................................................. 11 
A.2.3 
IRB/EB APPROVAL ....................................................................................................................... 12 
A.2.4 
AGREEMENTS AND FEES ................................................................................................................ 12 
A.2.5 
FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST ...................................................................... 12 
A.2.6 
PRIVACY AWARENESS TRAINING..................................................................................................... 13 
A.2.7 
REGISTRY-SPECIFIC TRAINING ....................................................................................................... 13 
A.2.8 
ACTIVATION .................................................................................................................................. 13 
A.2.9 
ANNUAL RE-CERTIFICATION ........................................................................................................... 13 
A.3.0 PATIENT SAFETY........................................................................................................ 14 
A.3.1 
RISKS AND BENEFITS ..................................................................................................................... 14 
A.3.2 
INFORMED CONSENT PROCESS ...................................................................................................... 14 
A.3.3 
REGISTRY INTERVENTIONS ............................................................................................................ 15 
A.3.4 
PATIENT RECRUITMENT, COSTS, AND COMPENSATION ..................................................................... 15 
A.4.0 DATA COLLECTION .....................................................................................................15 
A.4.1 
ASSIGNMENT OF REGISTRY IDENTIFICATION NUMBER ...................................................................... 15 
A.4.2 
WEB-BASED DATA ENTRY AND SYSTEMS SECURITY ......................................................................... 15 
A.4.3 
CLINICAL DATA .............................................................................................................................. 16 
A.4.4 
QUALITY OF LIFE DATA .................................................................................................................. 17 
A.4.5 
NEUROCOGNITIVE DATA ................................................................................................................ 18 
A.4.6.  FUNCTIONAL CAPACITY DATA ......................................................................................................... 18 
A.5.0 ANALYSES OF REGISTRY DATA ............................................................................... 18 
A.5.1 
INTRODUCTION .............................................................................................................................. 18 
A.5.2 
PURPOSES ................................................................................................................................... 18 
A.5.3 
PATIENT PROFILING ....................................................................................................................... 19 
A.5.4 
PRIMARY ENDPOINTS .................................................................................................................... 19 
A.5.5 
ANALYTIC METHODS ...................................................................................................................... 20 
A.5.6 
PLANNED ANALYSES ...................................................................................................................... 23 
A.6.0 REPORTS ..................................................................................................................... 25 
A.6.1 
NATIONAL HEART, LUNG AND BLOOD INSTITUTE (NHLBI) ................................................................. 25 
A.6.2 
CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS) .............................................................. 25 
A.6.3 
FOOD AND DRUG ADMINISTRATION (FDA) ....................................................................................... 25 
A.6.4   INDUSTRY ...........................................................2 ............................................................................. 26 

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A.6.5 INDIVIDUAL SITES .......................................................................................................................... 27 
A.6.6 OBSERVATIONAL STUDY MONITORING BOARD (OSMB) ................................................................... 27 
A.7.0 QUALITY ASSURANCE ................................................................................................27 
A.7.1 
DATA QUALITY .............................................................................................................................. 27 
A.7.2 
DATA MONITORING AND CHECKS FOR INCONSISTENCIES .................................................................. 27 
A.7.3 
MEDICAL EVENT REVIEW ............................................................................................................... 28 
A.8.0 CENTERS: REQUIREMENTS, TRAINING, ASSISTANCE AND AUDITS .................... 28 
A.8.1 
REQUIREMENTS FOR CENTERS....................................................................................................... 28 
A.8.2 
TRAINING FOR CENTERS ................................................................................................................ 28 
A.8.3 
ASSISTANCE TO CENTERS .............................................................................................................. 28 
A.8.4 
AUDIT PROCESS FOR CENTERS ...................................................................................................... 29 
B. INTERMACS–PEDIATRICS (PEDIMACS) ........................................................................... 30 
B.1.0 REGISTRY DESIGN ..................................................................................................... 30 
B.1.1 PATIENT ELIGIBILITY ...................................................................................................................... 30 
B.1.2 DESIGN ........................................................................................................................................ 31 
B.1.3 ADDITIONAL DATASETS .................................................................................................................. 31 
B.1.4 MAJOR END POINTS ...................................................................................................................... 32 
B.2.0 SITE ELIGIBILITY AND ENROLLMENT ....................................................................... 33 
B.2.1 ELIGIBILITY ................................................................................................................................... 33 
B.2.2 REGISTRATION .............................................................................................................................. 33 
B.2.3 IRB/EB APPROVAL ....................................................................................................................... 33 
B.2.4 AGREEMENTS AND FEES ................................................................................................................ 34 
B.2.5 FINANCIAL DISCLOSURE AND CONFLICT OF INTEREST ...................................................................... 34 
B.2.6 PRIVACY AWARENESS TRAINING..................................................................................................... 34 
B.2.7 REGISTRY-SPECIFIC TRAINING ....................................................................................................... 35 
B.2.8 ACTIVATION .................................................................................................................................. 35 
B.2.9 ANNUAL RE-CERTIFICATION ........................................................................................................... 35 
B.3.0 PATIENT SAFETY ........................................................................................................ 35 
B.3.1 RISKS AND BENEFITS ..................................................................................................................... 35 
B.3.2 INFORMED CONSENT PROCESS ............................................................................... 36 
B.3.3 REGISTRY INTERVENTIONS ............................................................................................................ 36 
B.3.4 PATIENT RECRUITMENT, COSTS, AND COMPENSATION ..................................................................... 36 
B.4.0 DATA COLLECTION .....................................................................................................37 
B.4.1 ASSIGNMENT OF REGISTRY IDENTIFICATION NUMBER ...................................................................... 37 
B.4.2 WEB-BASED DATA ENTRY AND SYSTEMS SECURITY ......................................................................... 37 
B.4.3 CLINICAL DATA .............................................................................................................................. 38 
B.4.4 QUALITY OF LIFE DATA .................................................................................................................. 39 
B.4.5 FUNCTIONAL CAPACITY DATA ........................................................................................................... 39 
B.5.0 ANALYSES OF REGISTRY DATA ............................................................................... 40 
B.5.1 INTRODUCTION .............................................................................................................................. 40 
B.5.2 PURPOSES ................................................................................................................................... 40 
B.5.3 PATIENT PROFILING ....................................................................................................................... 40 
B.5.4 PRIMARY ENDPOINTS .................................................................................................................... 41 
B.5.5 ANALYTIC METHODS ...................................................................................................................... 41 
B.5.6 PLANNED ANALYSES ...................................................................................................................... 44 

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B.6.0 REPORTS ..................................................................................................................... 46 
B.6.1 NATIONAL HEART, LUNG AND BLOOD INSTITUTE (NHLBI) ................................................................. 46 
B.6.2 CENTERS FOR MEDICARE AND MEDICAID SERVICES (CMS) .............................................................. 46 
B.6.3 FOOD AND DRUG ADMINISTRATION (FDA) ....................................................................................... 46 
B.6.4 INDUSTRY ..................................................................................................................................... 48 
B.6.5 INDIVIDUAL SITES .......................................................................................................................... 48 
B.6.6 OBSERVATIONAL STUDY MONITORING BOARD (OSMB) ................................................................... 48 
B.7.0 QUALITY ASSURANCE ................................................................................................ 48 
B.7.1 DATA QUALITY .............................................................................................................................. 48 
B.7.2 DATA MONITORING AND CHECKS FOR INCONSISTENCIES .................................................................. 48 
B.7.3 MEDICAL EVENT REVIEW ............................................................................................................... 49 
B.8.0 CENTERS: REQUIREMENTS, TRAINING, ASSISTANCE AND AUDITS .................... 49 
B.8.1 REQUIREMENTS FOR CENTERS....................................................................................................... 49 
B.8.2 TRAINING FOR CENTERS ................................................................................................................ 49 
B.8.3 ASSISTANCE TO CENTERS .............................................................................................................. 50 
B.8.4 AUDIT PROCESS FOR CENTERS ...................................................................................................... 50 
ATTACHMENT 1: PATIENT INFORMATION FOR ADULTS ................................................... 51 
ATTACHMENT 2: PATIENT INFORMATION FOR CHILDREN ............................................. 53 

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List of Abbreviations 
 
Abbreviation 
Definition 
 
CLIA 
Clinical Laboratory Improvement Amendment(s) 
CMS 
Centers for Medicare and Medicaid Services 
DAAP 
Data Access, Analysis, and Publications Committee 
DCC 
Data and Clinical Coordinating Center 
DCR 
Data Collection Repository 
DT 
Destination Therapy 
EB 
Ethics Board 
EQ-5D-3L 
EuroQoL Questionnaire 
ET 
Eastern Time 
FDA 
United States Food and Drug Administration 
FISMA 
Federal Information System Management Act 
FWA 
HHS 
HICN 
Federal Wide Assurance 
Health and Human Services 
Health Insurance Claim Number 
IRB 
Institutional Review Board 
IDE 
Investigational Device Exemption 
INTERMACS® 
Interagency Registry for Mechanically Assisted Circulatory 
Support 
KCCQ 
Kansas City Cardiomyopathy Questionnaire 
MCSD 
Mechanical Circulatory Support Device 
MDR 
Medical Device Report 
MOP 
Manual of Operations and Procedures 
mRS 
modified Rankin Scale 
NHLBI 
National Heart, Lung, and Blood Institute 
NIST 
National Institution for Standards and Technology 
NYHA 
New York Heart Association (heart failure classification) 
OPC 
Objective Performance Criteria 
OPTN 
Organ Procurement and Transplant Network 
OSMB 
Observational Study Monitoring Board 
PediMACS 
INTERMACS® for pediatric patients 
PedsQL 
Pediatric Quality of Life Inventory 
PHI 
Protected Health Information 
PI 
Principal Investigator 
QA 
Quality Assurance 
QoL 
Quality of Life 
UAB 
University of Alabama at Birmingham 
UNOS 
United Network for Organ Sharing 
VADQoL 
Ventricular Assist Device Quality of Life instrument 
VLAN 
Virtual Local Area Networks 

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Executive Summary and Background 
The initial goal of INTERMACS® (the Interagency Registry of Mechanically Assisted 
Circulatory Support) was to establish a registry of adult and pediatric patients receiving 
a mechanical circulatory support device (MCSD) to treat heart failure. With data 
collection beginning in 2006, INTERMACS® now serves as the national quality 
improvement system to assess the characteristics, treatments, and outcomes of 
patients receiving MCSDs approved by the Food and Drug Administration (FDA). 
INTERMACS® also includes MCSD-implanting hospitals in Canada. These activities 
are supported by the INTERMACS® data and clinical coordinating center (DCC) under 
contract to the National Heart, Lung, and Blood Institute (NHLBI). 
 
The purposes of INTERMACS® include: 
1. Collecting pertinent and standardized patient demographic, clinical and device- 
related data elements from participating hospitals to measure and assess the quality 
of care and outcomes for patients receiving MCSDs; 
2. Providing confidential periodic reports to the participating hospitals, government 
agencies, and industrial partners to improve the quality of care of patients receiving 
mechanical circulatory support and to evaluate the effectiveness and optimal 
utilization and performance of these devices; 
3. Fostering collaborative research based upon the data collected by means of 
INTERMACS®; and 
4. Serving as a scalable data infrastructure for pre and post market studies. 
 
Broadly, the registry will enable evaluation of best medical practices for advancement of 
public health with respect to the use of MCSDs for the treatment of heart failure. Data 
reports from the registry are shared with the NHLBI, FDA and the Centers for Medicare 
and Medicaid Services (CMS) through a collaboration agreement. The FDA is interested 
in patient/device outcomes as a way to monitor safety, and CMS through the Joint 
Commission utilizes INTERMACS® data for site-based quality improvement 
assessments. Key performance measures are supplied to every participating hospital 
each quarter, along with a description of the benchmarking methodology used, to 
facilitate comparison of one institution’s outcomes to aggregated national data. 
Following review of a request for dissemination, data may be shared with basic and 
clinical researchers, with consideration for privacy regulations. Analytic strategies and 
data analyses are conducted resulting in publications, presentations, and potentially 
follow-up investigations. 
 
INTERMACS® collects information pertaining to patients, care providers, hospitals, and 
devices. Most of these data are collected through chart review by nurse coordinators 
and physicians at the clinical sites. Standard of care Quality of life (QoL) and functional 
capacity data are collected for adults and pediatric patients through administration of 
instruments and tests. Additionally, standard of care neurocognitive data are collected 
for adults. 
 
INTERMACS® requires that to be a member in good standing, each participating 
hospital must enter complete data on consecutively implanted patients into the 

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INTERMACS® database. To facilitate this requirement, INTERMACS® works closely 
with the member hospitals. 
 
INTERMACS® collects data on all patients receiving FDA-approved MCSDs at all 
participating sites.  Standardized data collection forms and practices are followed 
utilizing a web-based system. All Privacy Act provisions are followed in handling and 
storing patient protected health information (PHI).All participating centers are required to 
obtain Institutional Review Board (IRB)/Ethics Board (EB) approval before collecting 
registry data. 
 
An NHLBI-appointed independent Observational Study Monitoring Board (OSMB) 
evaluates the registry on an ongoing basis as to procedures, findings, and adverse 
events to assure patient safety, confidentiality of records, and registry integrity. The 
OSMB advises the NHLBI and the INTERMACS® co-investigators when and if changes 
should be made. 
 
INTERMACS® is currently supported through a Public-Private Partnership, which 
includes funding from the NHLBI and fees collected from participating hospitals and 
device companies manufacturing FDA-approved MCSDs. 
Collaborating Institutions receiving funding on this project include: 
University of Alabama at Birmingham (UAB) 
Brigham and Women’s Hospital 
University of Pittsburgh 
Cleveland Clinic 
University of Michigan 
 
Registry Description 
The INTERMACS® registry is the national quality improvement system designed to 
advance the understanding and application of mechanical circulatory support in order to 
improve the duration and quality of life in patients with advanced heart failure. These 
activities are supported by the INTERMACS® data and clinical coordinating center 
(located at UAB and hereafter referred to as the DCC) under contract to the NHLBI. 
INTERMACS® functions as a partnership between the NHLBI, FDA, CMS, participating 
hospitals, and industry with the intent of generating outcome standards for current 
clinical device application, providing a platform for the introduction of new technology, 
and acting as a vehicle for the evaluation of patient-device interactions. 
 
Registry Organization 
A university-based DCC (UAB) is responsible for administrative support, data collection 
and management, site activation and monitoring, data analysis and reporting, as well as 
registry coordination. Oversight includes an Executive Committee comprised of NHLBI 
staff and nationally-recognized investigators in advanced heart failure and MCSDs. A 
detailed description of the registry organization, its structure, and the various 

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committees responsible for ensuring the integrity of INTERMACS® can be found in the 
Manual of Operations and Procedures (MOP). 
 
A. INTERMACS – Adults 
 
A.1.0 
Registry Design 
A.1.1 
Patient Eligibility 
 
Scope 
The scope of INTERMACS® for adults encompasses those patients receiving durable 
MCSDs approved by the FDA for whom discharge from the hospital is feasible. There 
is no exclusion for gender, race, or ethnicity. 
 
Screening 
 
Each patient who receives an MCSD at an institution will be screened according to the 
eligibility criteria listed below. For patients who do not meet the inclusion criteria, the 
following information will be recorded on the screening log: gender, race, age decade, 
brand of the implanted device (left or right side of the heart), date of implant, patient in 
an MCSD clinical trial, and death should it occur within 2 days of implant. This basic 
information is necessary to assess completeness of patient capture and possible bias in 
the registry. No further information will be collected on patients who do not meet the 
inclusion criteria. 
 
Inclusion Criteria 
 
All patients ≥19 years of age who receive an FDA-approved durable MCSD* implanted 
at an INTERMACS®-activated hospital. (NOTE: Patients implanted before the hospital 
activation date are not eligible for participation in INTERMACS®.) 
*Refer to MOP Appendix K for the FDA-approved Adult Device Brands List. 
 
Exclusion Criteria 
 
1) Patients who receive a durable MCSD, which is not FDA-approved. 
 
2) Patients who are <19 years of age. 
 
3) Patients who are incarcerated persons (prisoners). 
 
Follow-up 
 
All patients will be followed as long as an MCSD is in place. If a patient has an MCSD 
removed and is not transplanted, then the patient will be followed for 1 year. Vital 

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. 
 
 
status, including transplantation and survival, will be determined during this year. If a 
patient transfers his/her care to another hospital, the patient is deactivated at the 
implanting hospital at the time of transfer and is re-activated at a new center provided 
the new center is an INTERMACS®-participating center. The patient transfer process 
can be found in the MOP, Section 4.4. 
 
If a patient has an MCSD removed and is transplanted, then the patient is no longer 
followed in INTERMACS® At that time, the patient becomes part of the Organ 
Procurement and Transplant Network (OPTN) transplant database and will be 
followed by that database. A patient undergoing transplantation more than 1 year after 
MCSD explantation with no re-implant will be followed in INTERMACS® for the first year 
after explant to determine if they have undergone transplantation or died. If the patient 
undergoes a transplant, then he/she will be followed through the OPTN database at the 
time of transplantation. 
 
A.1.2 
Design 
While INTERMACS® was intended to be primarily a prospective registry when it was first 
established, in actuality the data are collected retrospectively from existing medical 
records or concurrently in the normal course of treatment on patients who meet the 
eligibility criteria. Additional standard of care evaluations and contact with the patient 
outside of the index hospitalization are required for this registry.  Specifically, post 
implant follow up data are collected at 1 week, 1 month, 3 months, 6 months and every 
6 months after that for up to 1 year after the device is explanted. Physical examination 
and functional capacity testing is a routine portion of the care for these patients; the 
interview consists of survey questions from the EuroQOL (EQ-5D-3L), Kansas City 
Cardiomyopathy Questionnaire (KCCQ) and the Trail Making Neurocognitive Test, Part 
B assessment. These interviews are described below in Section A.4.4. 
 
A.1.3 
Additional Datasets 
With cooperation between industry and INTERMACS®, patients who were part of FDA 
device approval studies may be moved into INTERMACS®. The process for acquiring 
these data is developed on a case-by-case basis. 

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Baseline Patient 
Characteristics 
Device and 
Implant Elements 
Heart Failure 
Severity Variables 
Patient‐Device‐Disease 
Profiles 
Variables collected at implant and regular 
Intervals are entered into multivariable analysis 
Discrete 
Endpoints 
Death 
Transplant 
Explant for 
Recovery 
Complex 
Endpoints 
Improvement 
Indicators 
Adverse 
Events 
Quality 
of Life 
Functional 
Capacity 
Costs 
(Resource 
utilization) 
Hospitalizations 
 
A.1.4 
Major End Points 
 
 
INTERMACS® provides critical and contemporary data on patient outcomes, with 
additional insight into risk factors and patient-related indices. Death, transplant, and 
explant for recovery are the major discrete endpoints recorded, to provide the most 
fundamental outcome statistics. 
 
Information about re-hospitalizations is vital to address the integrated endpoint of days 
alive out of hospital, which is particularly relevant for the patient population with 
advanced heart failure receiving ventricular assist devices, as re-hospitalizations are 
common but not of the same hierarchical importance as death. In addition, the number 
of in-hospital days is closely tracked as the major resource utilized, after the initial 
implant. Any subsequent surgery or implants are also noted in addition to the in-hospital 
days. Specific attention is devoted to capturing this parameter in order to provide a 
relative estimate of cost. 
 
The complex endpoints that include the patient’s functional capacity and QoL are also 
critical to the evaluation of current MCSD therapy, for which improvements in both 
survival and function have been compelling. These indices become increasingly 
important as patient survival improves. When comparing device therapy among various 
devices, estimates of quality-adjusted survival and cost-effectiveness require 
quantification of quality and estimates of cost based on resource utilization, as 
discussed above. 
 
Defining and recording adverse events are important data collected within the Registry. 
Definitions of adverse events within the registry are fluid and reflect changing clinical 
practices and device characteristics.  The incidence and prevalence of adverse events 
 Baseline Variables And Endpoints 
 

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are made within the context of device type, management practices, patient co- 
morbidities, timing of implantation, surgical experience and technique; all are based on 
uniform adverse event definitions. For each major adverse event (device malfunction, 
bleeding, infection, neurological, and death), additional variables must be included 
which potentially allow a determination of whether an adverse event most likely resulted 
from device design failure or malfunction (device-related), patient co-morbid conditions 
(patient-related), or errors in patient management (e.g., inadequate anti-coagulation) 
(management-related). 
 
 
A.2.0 
Site Eligibility and Enrollment 
Section A.2.0 contains the steps for determining eligibility and enrollment for each 
institution. Steps A.2.1 through A.2.7 must be completed to become an active 
participant in INTERMACS®. 
 
A.2.1 
Eligibility 
Any medical center in the United States and Canada that has an active 
MCSD program is eligible to participate in INTERMACS®. In addition, the 
program must provide personnel and facilities to record and transmit 
data. 
 
A.2.2 
Registration 
INTERMACS® registration must be completed online at: 
https://www.intermacs.org/enrollment. The steps necessary for INTERMACS® 
membership are outlined in detail in the MOP. 
 
1. The medical center is registered by completing the online Hospital Information 
form. 
2. The Personnel Contact Information form, including staff roles, must also be 
completed. 
 
In order to complete the registration process, the Center must assign the following roles 
to qualified personnel: 
 
• Local Principal Investigator (PI), responsible for oversight of data submissions 
and registry compliance 
• Site Administrator, to act as “point person” for data related inquiries, receipt of 
reports and audit coordination 

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A.2.3 
IRB/EB Approval 
In preparation of materials for IRB/EB review and approval, participating sites will use 
the INTERMACS® protocol, which is a two-part registry – INTERMACS®- Adults and 
INTERMACS® - Pediatrics/pediMACS. The hospital must submit the INTERMACS® 
protocol and supporting documentation (e.g., request for waiver of consent) to the 
IRB/EB for approval. The guidelines and supporting documents for the medical center’s 
submission of an application to participate in INTERMACS® are located in the MOP. If 
the IRB/EB approves the application for participation in this registry, documentation of 
that decision along with the Federal Wide Assurance Number (FWA) and current 
Clinical Laboratory Improvement Amendments (CLIA) documentation must be 
submitted to INTERMACS® before a site can be activated. IRB/EB approval documents 
are submitted to the DCC on a yearly basis.  INTERMACS® will send annual reminders 
to the participating centers at least 30 days prior to expiration of IRB/EB approval. 
Lapse in local IRB/EB coverage will result in immediate suspension, including data entry 
capability. 
 
The facility is responsible for obtaining and maintaining all IRB/EB documentation. 
Documentation of IRB/EB status is subject to INTERMACS® audit. 
 
A.2.4 
Agreements and Fees 
The Business Associate Agreement and Participation Agreement are provided in the 
MOP, Appendix D. These agreements are between the local hospital and 
INTERMACS®. They contain the center’s and INTERMACS®’s responsibilities. The 
signed agreements must be submitted to INTERMACS®. 
 
Each site must pay a required participation fee prior to activation. INTERMACS® is 
structured to provide value to the hospitals for this fee.  For example, INTERMACS®: 
• completes and submits Medical Device Reports (MDRs)specific to MCSDs to the 
FDA in accordance with 21 CFR 803.10 on behalf of each hospital, 
• submits 21 CFR 803.10-required reports to device manufacturers for each 
hospital, 
• provides quarterly quality assurance reports to each participating hospital, 
• provides datasets for quality improvement purposes to participating hospitals 
upon request, 
• creates patient specific chronological history of the major clinical events after 
implant, and 
• encourages local physicians and coordinators to participate in the administration 
and activities within the registry. 
 
A.2.5 
Financial Disclosure and Conflict of Interest 
Site personnel participating in INTERMACS® must complete a financial disclosure and 
conflict of interest form.  The form is provided in the MOP, Appendix E.  The form must 

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be printed, signed, and submitted to INTERMACS® before a site can be activated and 
must be updated on an annual basis. 
 
A.2.6 
Privacy Awareness Training 
All staff members are required to complete Privacy Awareness training provided by their 
local site. If training is not available locally, then the NIH’s Privacy Awareness Training 
(http://irtsectraining.nih.gov/PAC/0501000.aspx) may be substituted. 
 
Copies of the Privacy Awareness Training certification must be submitted to 
INTERMACS® before a site can be activated, and training will be updated per local 
IRB/EB policy. 
 
A.2.7 
Registry-specific Training 
At least one INTERMACS® staff member at the institution must complete the 
INTERMACS® training process, which requires participation in a live web-based data 
entry training session. The DCC will schedule the training once the site has completed 
steps A.2.1 through A.2.6. 
 
A.2.8 
Activation 
After completing steps A.2.1 through A.2.7, site personnel will be notified of their 
activation (i.e., access to read or enter data in the INTERMACS® web-based data 
application). This notification will consist of a secure e-mail that will contain the 
individual’s user name and password. 
 
A.2.9 
Annual Re-Certification 
To MAINTAIN CERTIFICATION, a site must: 
 
• Maintain and provide INTERMACS® with the annual IRB/EB approval and 
current FWA Number documentation, 
• Provide current CLIA documentation, 
• Provide annual participation fee, 
• Maintain annual Conflict of Interest disclosure, 
• Maintain Privacy Awareness Training, and 
• Comply with data submission requirements outlined in this protocol and 
further detailed in the MOP. 

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A.3.0 
Patient Safety 
A.3.1 
Risks and Benefits 
 
Risks 
There is no added procedural risk to patients through involvement in INTERMACS®. No 
risk or procedures beyond those required for routine care will be imposed. The data 
collected for this Registry are from medical chart abstraction. The only exception is the 
concurrent collection of limited functional capacity data, QoL data via patient interviews, 
and neurocognitive data. The interviews and tests are standard of care for heart failure 
patients receiving MCSDs and are not considered greater than minimal risk. 
 
There is always the risk of loss of confidentiality. However, safeguards, policies and 
procedures are in place to keep PHI in each registry record confidential as required 
under the Information Security clauses of the Federal Acquisition Regulations. All 
registry information will be sent through a highly secure website to the INTERMACS® 
database. All INTERMACS® employees have passed background checks for 
government clearance to handle PHI. PHI is not available to anyone outside of 
INTERMACS®, unless required by law (e.g., to ensure safety). No published or 
unpublished report or visual or speaking presentation about the registry will include any 
material that will identify a patient in this registry. 
 
Benefits 
 
There is no direct benefit to the heart failure patients who participate in this registry. 
However, future heart failure patients may benefit from the knowledge gained through 
this registry. 
 
A.3.2 
Informed Consent Process 
INTERMACS® will not require additional consent other than the routine consent that is 
required for the MCSD surgical procedure. This is an observational data registry. In 
general, information will be retrieved from existing medical records. Minimal testing and 
contact with the patient outside of the index hospitalization is required for follow-up 
interviews and physical examination. Physical examination, functional capacity testing, 
and interviews are considered standard of care for these patients. The interview will 
consist of questions from QoL instruments and neurocognitive assessment. No data 
beyond the data gathered in the course of routine care will be collected for this 
registry. 
 
Patients will be provided with a summary statement describing the registry when 
completing the routine MCSD surgical consent form (refer to Attachment 1). 
 
Participating sites will follow their local IRB/EB policies. Refer to the MOP, Section 5.2, 
for additional guidance and Appendix C for supplementary documents that may be 
required by local IRBs/EBs. 

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A.3.3 
Registry Interventions 
No additional interventions will be performed outside of the standard course of care. 
 
A.3.4 
Patient Recruitment, Costs, and Compensation 
No recruitment specific to this registry will take place at any participating center. 
Recruitment is not applicable since the registry obtains information through a review of 
existing medical records. 
 
There are no costs or compensation to the patient or patient’s family for participation in 
this registry. 
 
 
A.4.0 
Data Collection 
A.4.1 
Assignment of Registry Identification Number 
A registry identification number will be assigned to each patient prior to entry of data 
into INTERMACS®. This identification number will be used as the primary patient 
identifier between the site, INTERMACS®, MCSD manufacturers, and government 
agencies. 
 
A.4.2 
Web-based Data Entry and Systems Security 
All data will be entered through the INTERMACS® web-based data entry system. 
Complete documentation is contained at the data entry website (www.intermacs.org), 
and the INTERMACS® Site User’s Guide can be found in the MOP, Appendix M. The 
forms should be filled out as soon as possible after the implant and at the time of follow- 
up events (within specific time windows). The data are divided into forms that 
correspond to the clinical time course of the patient. 
 
Minimal PHI [e.g., patient’s name; date of birth; last 5 digits of social security number, or 
in the event that a social security number is not available, the last 5 digits of the 
transplant wait list number; health insurance claim number (HICN), if applicable; device 
serial number; implant date; and optionally the hospital medical records number], are 
entered into the INTERMACS® database.  This information allows the patient to be 
linked to the United Network for Organ Sharing (UNOS) transplant database should 
he/she undergo transplantation, to CMS databases, and to FDA medical device safety 
databases. 
 
INTERMACS® complies with all national patient privacy regulations. All registry data 
shall be maintained on secure servers with appropriate safeguards in place. All 
INTERMACS® employees have passed federal Health and Human Services (HHS) 
background checks for government clearance. Access to the production databases 
containing PHI is on a need-to-know basis only.  INTERMACS® personnel will 

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periodically review all activities involving PHI to ensure that such safeguards, including 
standard procedures, are being followed. Any breach of confidentiality and immediate 
mitigation steps will be reported to the appropriate oversight bodies (e.g., the NHLBI 
and the IRB/EB according to their institutional policies) and these immediate mitigation 
steps will be implemented. 
 
The database and web servers reside in an environment that provides multiple layers of 
physical and systems security. INTERMACS® is compliant with the Security Act of 2002 
and the Federal Information System Management Act (FISMA). Regular audits take 
place to verify compliance. 
 
Systems security is deployed with third party software and hardware, strict adherence to 
policy, and regular verification and auditing. The servers that host the web applications 
are built within the Windows 2008R2 framework. They follow Microsoft’s best security 
practices and group policy recommendations from the National Institute for Standards 
and Technology (NIST). 
 
Each server is monitored 24x7 for both intrusion and vulnerabilities by an integrated 
third-party software package. Microsoft System Center Configuration Manager 2012R2 
is used for deploying any system patches in accordance with security policies. The 
network is also protected by an automated anti-virus retrieval and deployment system. 
 
Firewall software assists in preventing hacking, virus, and other security risks from the 
outside. Internally, the servers reside on a segmented part of the Virtual Local Area 
Networks (VLAN) that is isolated from the rest of the network protecting it from any 
adverse internal forces. All server access requires use of second level authentication for 
administrative access. Regular internal and external penetration and vulnerability tests 
are conducted by third-party contractors to determine any weaknesses in the network. 
 
A.4.3 
Clinical Data 
Clinical data are collected by medical chart review. 
 
Patient Demographics and Profile Prior to Implant 
 
The standard demographics of age, gender, and patient-described ethnicity will be 
recorded. Heart failure etiology, duration, and standard prognostic factors will be 
collected along with hemodynamic and echocardiographic parameters closest to the 
time of implant. Co-morbidities will be included, as they may affect the likelihood of 
success of MCSD therapy. A novel aspect of the data elements is the establishment of 
seven INTERMACS® patient profiles that describe the clinical severity at the time of 
implant, aid in risk stratification, improve patient selection, and refine the definition of 
future trial populations (refer to MOP Appendix O for a description of the seven patient 
profiles). INTERMACS® also seeks to transition away from the artificial distinction of 
bridge versus destination intent, by recording, before and at intervals after implant, the 
relative likelihood and limiting factors for transplant eligibility. 

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Device and Operative Details (implant) 
 
The critical elements which characterize the device and describe the implant procedure 
will be recorded within 1 week after implant. 
 
Designated Interval Follow-up 
 
A major feature of the database design is the provision of information both by event and 
by designated time interval.  In this way, the crucial events are submitted in real time, 
but there are also regularly scheduled checkpoints at which any important events during 
follow-up intervals will be captured. The first routine post-operative follow-up will be at 1 
week.  The remaining interval follow-up visits occur at 1 month, 3 months, 6 months, 
and every 6 months for the life of the device. If the device is explanted without 
transplantation, the patient will be followed for 1 year following explant for the major 
events of death or transplantation. 
 
The follow-up forms will all include information on vital signs and volume status, 
medications, basic laboratory values, and device settings. New York Heart Association 
(NYHA) functional status will be noted. At each time interval beginning with the 3-month 
follow-up, re-assessment will be documented regarding current intent as bridge to 
recovery, transplant, likelihood of eligibility for transplant, or permanent support, with a 
checklist of considerations relevant to that decision. Echocardiographic information will 
be included regarding function of both ventricles and atrioventricular valves. 
Hemodynamic measurement regarding filling pressures, pulmonary pressures, and 
cardiac output will be included when available. 
 
Adverse Events 
 
Data on specific adverse events will be collected by two mechanisms: 
(1) The occurrence of hemolysis, hypertension and right heart failure are considered 
‘triggered events’. These events are ‘triggered’ based on the relevant medical data 
collected at follow-up and re-hospitalization. 
(2) Other adverse events (see MOP Appendix A for a complete list) will be identified and 
collected through routine data acquisition at the specified follow-up intervals or at 
time of event. 
 
A.4.4 
Quality of Life Data 
QoL will be measured by the EQ-5D-3L instrument (refer to MOP Appendix F), as well 
as the KCCQ (refer to MOP Appendix H). It is anticipated that completing these 
instruments will take the patient approximately 20 minutes. Administering the 
instrument and entering the data into the registry will require approximately 30 minutes 
of coordinator time. The QoL instruments are completed pre-implant and post-implant 
(3 months, 6 months, and every 6 months thereafter for the life of the device). 

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After implantation, the EQ-5D-3L and KCCQ will be completed as scheduled, whether 
the patient is hospitalized or at a clinic visit. Missing answers will be queried by the 
coordinator at the time of form completion. Reasons for not collecting the QoL 
instruments will be recorded. 
 
A.4.5 
Neurocognitive Data 
Neurocognitive function will be measured by the Trail Making Neurocognitive Test, Part 
B (refer to MOP Appendix G). This test of general cognitive function also specifically 
assesses working memory, visual processing, visuospatial skills, selective and divided 
attention, and psychomotor coordination. It is anticipated that completing this 
assessment will take less than 5 minutes of the patient’s time. In addition, for patients 
who experience a neurological event, the modified Rankin Scale (mRS) score is 
recorded. The mRS will be administered at follow-up visits after a post-implant 
neurological event. 
 
A.4.6. 
Functional Capacity Data 
Functional capacity measures are collected pre-implantation and within follow-up 
intervals post implant at 3 months, 6 months, and every 6 months thereafter. Included 
in these functional capacity measures are: 6 minute walk test, gait speed, and 
cardiopulmonary exercise indices. Refer to the MOP, Appendix M for all functional 
capacity measures collected. 
 
 
A.5.0 
Analyses of Registry Data 
A.5.1 
Introduction 
The value of any clinical registry lies in the statistical analyses of the data and the 
clinical relevance of these analyses. The registry will collect a wide array of patient, 
device, and follow-up information. This section outlines the general analyses and the 
statistical methods. 
 
A.5.2 
Purposes 
• Summarize the characteristics of the patients who are receiving MCSDs, when (in 
relation to progression of disease) they are receiving MCSDs, and why(bridge to 
transplant, bridge to decision, bridge to recovery, destination therapy, and rescue 
therapy), as well as outcomes of the therapy 
• Summarize the characteristics of MCSDs that are being implanted 
• Describe post-implant adverse events and estimate their time-related distribution 
• Determine risk factors (both patient-related and MCSD-related) for post implant 
events 
• Contribute to evidence based management of patients with implanted MCSDs 
• Provide device specific analyses to aid in MCSD development 

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Improvement 
Indicators 
Adverse Events 
Quality of Life 
• Patient/Device/Disease 
Predictors of Favorable 
Outcome 
• Comparison of Outcome 
With Other Therapies 
• Determinants of 
post-MCSD QOL 
• Determination  of Causes     • Comparison  of QOL 
Costs 
(resource 
utilization) 
• Predictors of 
Hospitalizations 
• Repeating Event 
Analyses 
(Device-, Patient-, 
Management-Related) 
With Other Therapies 
Implant Costs 
• Cost 
Effectiveness 
Analyses 
• Days Alive out of 
Hospital 
• Risk Factors for 
Repeated 
Hospitalizations 
Death 
Transplant 
Explant for Recovery 
 
 
• Evaluate safety and efficacy of MCSD implants 
• Determine the time-related costs (resource utilization) of MCSDs and the risk factors 
associated with increased costs 
• Compare the costs (resource utilization) of MCSD therapy to other treatments for 
advanced heart failure 
• Evaluate quality of life pre- and post-MCSD implant 
• Compare alternative therapies (MCSD, transplant, medical) for patients with end 
stage heart failure 
• Produce patient-specific predictions of time-related outcomes to aid in clinical 
decision making and allocation of therapies for advanced heart failure 
 
A.5.3 
Patient Profiling 
Patients who receive MCSDs will be characterized regarding their demographic data, 
medical history, and clinical status including descriptors of heart failure, pre-implant 
laboratory values and pre-implant hemodynamic data. 
 
A.5.4 
Primary Endpoints 
The discrete endpoints are death, transplant, and explant for recovery. Other endpoints 
include patient adverse events, re-hospitalization, device related adverse events, 
change in QoL, costs (resource utilization), functional status and changes in 
hemodynamic parameters and laboratory values.  Each of the endpoints will be 
analyzed as time related events. 
 
 
Sample Endpoint Analyses 
 
Discrete Endpoints 
• Causes  of Death 
• Risk Factor Analyses 
• Competing  Outcomes     • Prediction  of Recovery 
Analyses 
• Post-transplant 
Survival Analyses 
• Post-Explant Survival 
Analyses 
Complex Endpoints 

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A.5.5 
Analytic Methods 
Statistical analysis of the MCSD will require a variety of methods including analysis of 
variance, multiple linear regression, t-tests, chi-square tests of association, correlations, 
and descriptive statistics. The group of methods generally labeled survival analysis 
techniques will be the methods most used. In general, survival analysis refers to all 
methods applicable to time-related events or outcomes. Most of the outcomes that will 
be documented in the MCSD registry will have time components. For example, time- 
until-death, time-until-transplant, time-until-infection, time-until-device-malfunction are all 
events that will have an associated interval post-implant. However, additional analytic 
methods will be necessary for issues such as costs and QoL. 
 
The Hazard Function 
 
The time-related survival methods will combine more traditional non-parametric or semi- 
parametric methods with parametric hazard function analysis. Kaplan-Meier non- 
parametric estimation provides estimates of time-related freedom from an event. While 
the depiction of these estimates is useful, parametric estimation using hazard models 
can offer more insight into the timing of an event. The hazard function is the 
instantaneous (or daily) rate of an event. This function can depict time periods of high 
risk for an event and can estimate whether the risk is increasing, decreasing or peaking. 
 
Parametric hazard estimation will employ simple to complex hazard models depending 
on the distribution of the event. Both the parametric survival function and the 
corresponding hazard function will be displayed to provide a complete description of the 
event. 
 
Competing Outcomes 
 
Depictions of a single time-related event do not take into account other events. For 
example, a depiction of death would assume that transplantation does not exist. 
Patients are censored at time of transplant. If informative censoring does not exist (i.e., 
if patients are not transplanted due to impending death but instead selected at random 
for transplant), then the depiction can be thought of as the natural history of mortality 
after device implant.  In reality, this rarely occurs, since patients are usually selected at 
a given time because of medical necessity. This informative censoring complicates the 
interpretation of this single event depiction. 
 
Alternatively, one may wish to estimate the simultaneous time-related probability of 
mutually exclusive events. Competing outcomes estimation allows the time-related 
probability of actually experiencing each of these events. At any point in time, a patient 
has either experienced one of the three events or he/she is alive and waiting for one of 
the events to occur. A probability can be assigned to each of these four possible states 
and the sum of the four probabilities will be equal to one at each point in time. The non- 
parametric estimation of these probabilities is an adaptation of the Kaplan-Meier 
method. In the standard use of the Kaplan-Meier methods, event probabilities are 
accumulated across time.  In competing outcomes analysis, the combined event is 

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analyzed and then probabilities are accumulated separately according to which event 
occurred. 
 
Multivariable Risk Factor Analysis 
 
The most common multivariable method for identifying risk factors is Cox proportional 
hazard regression. This method assumes proportional hazards for different levels of a 
potential risk factor. The p-value results from testing the null hypothesis that the 
proportionality parameter is equal to one. The method is often called a semi-parametric 
technique because it does not require or estimate the form of the underlying parametric 
hazard. It only requires (assumes) that hazards for different levels of risk factor are 
proportional across time. This assumption is often incorrect. The magnitude of the 
effects of the final risk factor model from Cox regression is not easily displayed due to 
the lack of a specified hazard model. This also prevents a simple, continuous depiction 
for a specific patient with his unique values of the risk factors. 
 
Consequently, we have pursued a parametric version of survival regression that builds 
on a framework of hazard functions. The concept is still proportional hazard regression, 
but the hazard function is estimated and decomposed into additive phases. Each phase 
is then constructed to be a function of the risk factors. The model of risk is then totally 
specified as a mathematical equation that can be “drawn” for any time period and any 
specified set of risk factors. This system also allows the identification of risk factors that 
impact different phases of risk. 
 
Predictions 
 
This ability to produce time-related expected survival for a specific patient (with his/her 
specific risk profile) is one of the strengths of parametric hazard analysis. The 
predictions are a function of the estimated hazard functions and the identified risk 
factors.  The hazard function and risk factors are derived from the actual data. 
 
Repeated Events (Adverse Events) 
 
Most adverse events can occur more than once. For example, once a patient 
experiences an infection episode, he/she remains at risk for another episode. These 
repeating events require methods that are an expansion of the previously described 
methods. 
 
First Events Analysis 
 
The first occurrence of an event can be analyzed exactly as a terminating event such as 
death (see previous discussion). While this analysis does not appear very useful 
clinically for events that recur frequently, it does provide a time-related estimate of the 
proportion of patients who have remained free of the event. 

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The FDA Approach 
 
Most of the medical device guidance documents from the FDA for analyzing events that 
can happen multiple times specify a specific analytic approach.  First, a calculation of 
the percent of patients who experience at least one event during the first 30 days post 
implant is presented. Next, a linearized rate is calculated for events that occur after the 
first 30 days. Summing all of the post 30-day events and dividing by the total patient 
follow-up intervals after 30 days calculates this. The rate is usually multiplied by 100. 
The calculation is then the number of events that are estimated to occur in 100 months 
of follow-up. This is a useful calculation but it assumes a constant hazard rate across 
time. For many events, for example device malfunction, this may be an incorrect 
assumption. 
 
Parametric Hazard Approach 
 
The parametric hazard methods can be applied to multiple events. This allows the 
estimation of the shape of the underlying hazard and specific statistical testing for an 
increasing hazard or decreasing hazard or peaking hazard. This approach will allow 
detection of device related events whose occurrence rate is rising to unacceptable 
levels at some point in time. 
 
Cumulative Event Estimation 
 
Another useful display of repeated events depicts the accumulation of events that will 
occur, on the average, for a single patient. This method of depiction illustrates the rate 
of accumulating events as a function of time. 
 
Modulated Renewal 
 
Another method of analyzing repeated events is the modulated renewal method. In this 
approach, the unit of observation is each episode of an event. A patient is tracked from 
time of device implant until he/she experiences his/her first event. The patient is then 
re-entered into the analysis, with a new starting time and is tracked until his/her next 
episode. This process is continued for event re-occurrences. The analysis of this data 
structure is then performed in the parametric hazard domain and is particularly 
amenable to risk factor analysis that incorporates the event history of a patient when 
predicting his/her next occurrence. 
 
Each of these methods for repeated adverse events contributes to the understanding of 
the time course of the event and the related risk factors.  The methods will be 
particularly helpful in calculating the time related risk of device related adverse events. 

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A.5.6 
Planned Analyses 
 
Patient Characteristics 
 
Patients who receive MCSDs will be summarized regarding their demographic data, 
medical history, and clinical status including descriptors of heart failure, pre-implant 
laboratory values and pre-implant hemodynamic data. Novel aspects of the registry 
include the seven INTERMACS® patient profiles that describe the clinical severity of 
disease at the time of implantation. The categorization of patients into INTERMACS® 
profiles will facilitate risk stratification for outcomes and advance the selection of 
patients who have sufficient severity of disease to warrant MCSDs. An additional 
component is the ongoing evaluation of patients with regard to evolving eligibility for 
transplantation and explantation in order to better understand the factors leading to 
transplantation or explantation. Subsequent tracking of patients will allow the decision 
process to be continually refined for better outcomes. 
 
Data will be summarized by frequencies, measures of central tendencies, measures of 
dispersion, cumulative distribution functions, graphical displays, cross tabulations and 
correlations. 
 
MCSD Characteristics 
 
MCSDs that are implanted will be summarized according to their physical and 
physiologic characteristics (e.g., size, weight, pulsatile or continuous flow, range of flow 
rates, etc.) and their initial flow settings. The Industry Committee, which consists of 
representatives from each participating device manufacturer, will assist in selecting 
variables for analysis that are relevant to emerging technologies. 
 
Survival 
 
The analysis of post-implant survival will utilize all of the methods outlined in the 
previous section. The emphasis will be on the time-related pattern of overall death and 
each of the causes of death. The investigation of risk factors, especially those risk 
factors which can be modified for a patient, will be a priority. 
 
Transplantation 
 
Time to transplant will be analyzed similarly to survival.  In addition to the examination 
of patient risk factors and device factors which predict survival to transplant, the 
prolonged implant duration in many “bridge” patients awaiting a suitable heart donor will 
facilitate analyses that give insight into longer-term “destination” therapy. 
 
Adverse Events: Patient- and Device-Related 
 
A key feature of the entire registry analysis will be the examination of the time course 
and risk factors for all of the possible patient-related and device-related adverse events. 
The methods listed under Analytic Methods will be used to evaluate these interactions. 

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Competing Outcomes 
 
The major events that “compete” for a patient are death, transplantation and explant for 
recovery. The simultaneous time-related estimation of the probability of these events 
will be depicted. Separate risk factor analyses will be performed for each individual 
outcome event. 
 
Quality of Life (QoL) 
 
Repeated measures methodology will test for changes in pre-implant and follow-up 
interval measures. Multiple linear regression will be used to identify patient groups who 
have the least and the greatest improvement in QoL. Analyses will focus on the impact 
of MCSD therapy on QoL indicators, comparisons with QoL after transplant and other 
therapies for advanced heart failure (through published studies or parallel patient 
cohorts). 
 
Costs 
 
Multivariate statistical techniques, most often regression analysis, are used to 
investigate relationships among the variables of interest. Analytical emphasis will be on 
resource utilization. 
 
Analysis of MCSD Efficacy 
 
In all of the analyses for death, transplant, recovery, adverse events, QoL, and costs, 
the effects of device characteristics (pulsatile flow, size, etc.) on outcome will be 
investigated. A major focus of INTERMACS® will be the identification of the strengths 
and weaknesses of the different devices for specific patient subsets and facilitation of 
the evolution of MCSD technology. 
 
Evaluation of Hospital Outcomes 
Each hospital that contributes data to INTERMACS® will be periodically evaluated for 
their outcomes. The basis of the evaluation will be risk-adjusted comparisons using the 
results of the multivariable analyses. The observed survival, depicted by a Kaplan- 
Meier, is also represented. The observed and expected deaths will then be statistically 
compared where the patient-specific risk factors and length of follow-up are explicitly 
incorporated into the comparison. 

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A.6.0 
Reports 
INTERMACS® will provide summaries to the following entities: 
 
A.6.1 
National Heart, Lung and Blood Institute (NHLBI) 
Quarterly Statistical, Semi-annual and the Final Report will include an overall summary 
of INTERMACS® patient characteristics, implant characteristics, hospital 
enrollment/activation, adverse events and significant outcomes. Manuscripts will be 
provided for review within 30 days of publication. 
 
A.6.2 
Centers for Medicare and Medicaid Services (CMS) 
CMS will receive copies of the NHLBI Quarterly Statistical Reports and a CMS-specific 
Quarterly Statistical Report. 
 
A.6.3 
Food and Drug Administration (FDA) 
In accordance with 21 CFR 803.19, sites participating in INTERMACS® (referred to as 
“user facilities” by the FDA) are exempt from the normal requirements in 21 CFR 803.30 
for adverse events reported to INTERMACS®. Instead, INTERMACS® will make the 
appropriate reports to both the manufacturer and FDA on behalf of the site. 
 
Also in accordance with 21 CFR 803.19, device manufacturers participating in 
INTERMACS® are exempt from the 30 calendar day reporting requirement in 21 CFR 
803.50.  Instead, any adverse event reported to or received from INTERMACS®, which 
meets the threshold for reporting in accordance with the MDR Regulation(21 CFR 
803.50) is due to FDA no later than 90 calendar days after the device manufacturer 
becomes aware of the event. FDA is granting this additional time so that the device 
manufacturer can do a thorough and complete analysis of the event and include their 
findings in the MDR report. All other FDA requirements concerning adverse event or 
complaint handling, investigation, retention, etc. remain unchanged. 
 
INTERMACS® (on behalf of participating sites/user facilities) and manufacturer reporting 
requirements are based on the exemptions granted by FDA under 21 CFR 803.19 as 
shown in the table below.  Refer to Section 7.3 of the MOP for additional information. 

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Summary of MDR Reporting Requirement Under 21 CFR 803.19 Exemptions 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*Per 21 CFR 803.19 Single Reporter and Time Variance Exemptions granted by FDA. 
INTERMACS® also provides reports to FDA, as requested, that inform: 
1) Objective performance criteria (OPC): Randomized trials of Investigational 
Device Exemption (IDE) MCSDs may not be practical. The FDA will often allow 
single arm studies where the results from an investigational medical device are 
compared with OPC.  These OPC are derived from the literature or existing 
databases. INTERMACS® can be used to generate OPC for the major safety 
endpoints after MCSD implant. 
2) Unexpected risks: INTERMACS® can be analyzed to identify MCSDs with 
unexpected risks for major safety events. 
 
A.6.4 
Industry 
In addition to the reports discussed in Section A.6.3, quarterly reports will be provided to 
each MCSD manufacturer summarizing data entered into INTERMACS®. A specific 
manufacturer will not receive identifiable information about any MCSDs from other 
manufacturers.  The reports will provide statistical summaries of patient demographics 
REPORTER 
WHAT TO REPORT 
WHERE 
WHEN 
Manufacturer* 
Deaths, Serious Injuries, 
Malfunction 
FDA 
Within 90 calendar 
days of becoming 
aware 
Events that require remedial 
action to prevent an 
unreasonable risk of 
substantial harm 
FDA 
Within 5 working 
days of becoming 
aware 
INTERMACS® 
(on behalf of 
User Facility)* 
Deaths 
FDA and 
Manufacturer 
Within 10 working 
days 
Serious Injury 
Manufacturer 
Within 10 working 
days 
Voluntary 
Any type of event 
FDA 
Any time 

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and clinical characteristics at the time of implant. Adverse event rates, including death 
and explant, will be calculated. 
 
A.6.5 
Individual Sites 
Quarterly reports will be provided to each participating site. A specific site will not 
receive identified information about any other site. These reports have two 
components. The first component is a quality assurance report that summarizes and 
compares the results at the individual hospital with the entire INTERMACS® registry. 
These benchmark comparisons allow the hospital to evaluate the patients and 
outcomes as compared to the aggregate data of the other participating hospitals. The 
second component focuses on patient-specific data and the quality of the site data. A 
dashboard is available for sites to view a patient’s chronological history of major 
implant-related events. The MDRs that have been submitted to the FDA, as well as 
reports provided to the device manufacturer, on behalf of the site are also included in 
this report. 
 
A.6.6 
Observational Study Monitoring Board (OSMB) 
The OSMB will receive copies of the NHLBI reports along with any specific reports that 
they may require. 
 
 
A.7.0 
Quality Assurance 
A.7.1 
Data Quality 
INTERMACS® will examine data quality and provide periodic data reports. The focus 
will be on completeness of periodic follow-up and also on identifying impossible or 
improbable combinations of variables.  Questionable data points will be verified. 
 
A.7.2 
Data Monitoring and Checks for Inconsistencies 
The database will be subject to analytical quality assurance (QA) audits following the 
completion of data entry. Depending on the types of discrepancies identified, 
INTERMACS® will contact participating centers to resolve these issues. Resolution may 
be accomplished via telephone contact, e-mail and/or hard copy mailings. The 
discrepancies and their resolutions will be tracked for future reference and further 
review.  Based on a review of the results of the analytical QA processes, additional 
items may be incorporated into the QA process at the Executive Committee’s request. 
Participating centers will be able to review and modify previously submitted data at any 
time. Additionally, summary screens and reports of patients and devices reported, 
current patient status, most recent reported event and other data will be available to the 
member institutions to assist the institution in assessing the completeness of reporting. 
INTERMACS® will employ established procedures to maintain the quality of 
INTERMACS® data.  These procedures will be used in completion of all data entry 

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activities associated with the MCSD and can be found in the MOP. Written internal 
DCC procedures will be maintained and will provide step-by-step directions for auditing 
processes involved in data entry, maintenance, and review to ensure data quality and 
completeness. 
 
A.7.3 
Medical Event Review 
Medical event review is a function of both the DCC and the Medical Event Review 
Committee.  The Committee will: 
• provide guidance on summarizing and evaluating the quality of the adverse 
event data; 
• provide strategies for electronically identifying duplicate events and questionable 
events; 
• focus on the review and categorization of device malfunction; and 
• provide guidance to the nurse monitors for auditing the correct capture of 
adverse events. All data identified as questionable are resolved via direct 
interactions between the nurse monitors and the local hospital. 
 
A.8.0 
Centers: Requirements, Training, Assistance and Audits 
A.8.1 
Requirements for Centers 
Each participating hospital shall: (1) provide dated proof of initial and annual IRB/EB 
approval, proof of FWA Number, proof of Privacy Awareness Training for the principal 
site staff (to include the Principal Investigator, Co-Investigators and Site Coordinator), 
and proof of CLIA documentation;(2) have at least one person complete training;(3) 
enter complete baseline, implant and follow-up data on all patients; (4) submit to regular 
and “for cause” data audits; and (5) correct identified errors in a timely fashion. 
 
A.8.2 
Training for Centers 
Web-based interactive software will be used to conduct training on an ongoing basis. 
This is a secure, subscription-based service that allows for meetings and their related 
documents to be conducted in a virtual electronic environment. Participants are allowed 
to view the trainer’s desktop. Attendees follow along as the trainer shows step-by-step 
instructions. 
 
A.8.3 
Assistance to Centers 
A comprehensive INTERMACS® Site User’s Guide will provide step-by-step 
instructions for using the system and will include definitions for all fields collected in the 
system. The Site User’s Guide will also identify main processes in the application and 
explain standard procedures for data collection.  Refer to MOP Appendix M. 

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The DCC is available to provide assistance with data collection and entry, regulatory 
questions, data requests and analyses, and technical support. Refer to the MOP 
Appendix L for a complete list of contacts. 
 
A.8.4 
Audit Process for Centers 
The audit process for all participating INTERMACS® sites involves interactions in the 
form of an on-site visit or a review of the documents submitted to the DCC and 
discussion with site staff via telephone and/or WebEx (remote review). Sites are notified 
up to 60 days prior to a routine on-site audit. Audited data include key data fields, as 
determined by INTERMACS®. 
The INTERMACS® monitor contacts the site by phone for a pre-audit review 
approximately 2 weeks before the scheduled audit. During the call, the monitor reviews 
site specific summaries for duplicated events, unknown sources of bleeding, unknown 
causes of death, device explants inconsistencies and any other noted discrepancies. 
The sites are requested to make corrections and to provide redacted source 
documentation (as needed for remote review), prior to the actual audit. 
 
During the audit, monitors will review data accuracy of web-based data submissions and 
information contained in source documents as well as participant performance and 
progress. “For Cause” audit visits will be made as indicated by the Hospital Standards 
Committee, which reviews hospital performance and recommends actions to reestablish 
compliance.  All audit results will be reported to the Executive Committee. 
 
The audit process will identify member institutions that perform poorly in data 
submission compliance. The INTERMACS® monitors, in collaboration with the Hospital 
Standards Committee, will identify and work with these underperformers to identify 
reasons for low rates of data collection and/or tardy data submission. These institutions 
will be retrained on proper data collection methods with the goal of identifying and 
overcoming obstacles to submission. 

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B. INTERMACS–Pediatrics (pediMACS) 
The INTERMACS® registry for pediatric patients is also referred to as 
“pediMACS”, which is used throughout the remainder of this protocol, to 
differentiate it from INTERMACS®– Adults. 
 
B.1.0 
Registry Design 
B.1.1 
Patient Eligibility 
 
Scope 
 
The scope of pediMACS encompasses pediatric patients receiving durable or temporary 
MCSDs approved by the FDA.  There is no exclusion for gender, race, or ethnicity. 
 
Screening 
 
Each patient who receives an MCSD at a pediMACS institution will be screened 
according to the eligibility criteria listed below. For patients who do not meet the 
inclusion criteria, the following information will be recorded on the screening log: 
gender, race, age decade, brand of the implanted device (left or right side of the heart), 
date of implant, patient in an MCSD clinical trial, and death should it occur within 2 days 
of implant. This basic information is necessary to assess completeness of patient 
capture and possible bias in the registry. No further information will be collected on 
patients who do not meet the eligibility criteria. 
 
Inclusion Criteria 
 
All patients <19 years of age who receive an FDA-approved durable or temporary 
MCSD* implanted at an INTERMACS®-activated hospital. (NOTE: Patients implanted 
before the hospital activation date are not eligible for participation in pediMACS.) 
 
* Refer to MOP Appendix K for the FDA-approved Pediatric Device Brands List. 
 
Exclusion Criteria 
 
1) Patients who receive an MCSD, which is not FDA-approved. 
 
2) Patients who are ≥19 years of age. 
 
3) Patients who are incarcerated persons (prisoners). 
 
Once a patient is entered as a pediatric patient, the patient will remain in pediatric status 
until the implanted device is explanted. 

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Follow-up 
 
All patients will be followed as long as an MCSD is in place. If a patient has an MCSD 
removed and is not transplanted, then the patient will be followed for 1 year.  Vital 
status, including transplantation and survival, will be determined during this year. If a 
patient transfers his/her care to another hospital then the patient is deactivated at the 
implanting hospital at the time of transfer and is re-activated at the new center provided 
the new center is a pediMACS-participating center. The patient transfer process can be 
found in the MOP, Section 4.4. 
 
If a patient has an MCSD removed and is transplanted, then the patient is no longer 
followed in pediMACS. At that time, the patient becomes part of the OPTN transplant 
database and will be followed by that database. A patient undergoing transplantation 
more than 1 year after explantation due to recovery will be followed in pediMACS for the 
first year after explant to determine if they have undergone transplantation or died.  If 
the patient undergoes a transplant, then he/she will be followed through the OPTN 
database at the time of transplantation. 
 
B.1.2 
Design 
PediMACS data are collected retrospectively from existing medical records or 
concurrently in the normal course of treatment on patients who meet the eligibility 
criteria. Additional standard of care evaluations and contact with the patient outside of 
the index hospitalization is required for this registry. Specifically, post implant follow-up 
data is collected at 1 week, 1 month, 3 months, 6 months and every 6 months after that 
for up to 1 year after the device is explanted.  Physical examination is a routine portion 
of the care for these patients. The interview will consist of survey questions from the 
Pediatric Quality of Life Inventory (PedsQL) and Ventricular Assist Device Quality of Life 
(VADQoL) instruments described in Section B.4.4. 
 
B.1.3 
Additional Datasets 
With cooperation between industry and pediMACS, patients who were part of FDA 
device approval studies may be moved into pediMACS. The process for acquiring these 
data is developed on a case-by-case basis. 

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Baseline Patient 
Characteristics 
Device and 
Implant Elements 
Heart Failure 
Severity Variables 
Patient‐Device‐Disease 
Profiles 
Variables collected at implant and regular 
Intervals are entered into multivariable analysis 
Discrete 
Endpoints 
Death 
Transplant 
Explant for 
Recovery 
Complex 
Endpoints 
Improvement 
Indicators 
Adverse 
Events 
Quality 
of Life 
Functional 
Capacity 
Costs 
Hospitalizations 
(Resource 
utilization) 
 
B.1.4 
Major End Points 
 
 
 
PediMACS provides critical and contemporary data on patient outcomes, with additional 
insight into risk factors and patient-related indices. Death, transplant, and explant for 
recovery are the major discrete endpoints recorded, to provide the most fundamental 
outcome statistics. 
 
Information about re-hospitalizations is vital to address the integrated endpoint of days 
alive out of hospital, as re-hospitalizations are common but not of the same hierarchical 
importance as death. In addition, the number of in-hospital days will be closely tracked 
as the major resource utilized, after the initial implant. Any subsequent surgery or 
implants are also noted in addition to the in-hospital days. Specific attention will be 
devoted to capturing this parameter in order to provide a relative estimate of cost. 
 
The complex endpoints that include the patient’s functional capacity and QoL are also 
critical to the evaluation of current MCSD therapy, for which improvements in both 
survival and function have been compelling. These indices become increasingly 
important as patient survival improves. When comparing device therapy among various 
devices, estimates of quality-adjusted survival and cost-effectiveness require 
quantification of quality and estimates of cost based on resource utilization, as 
discussed above. 
 
Defining and recording adverse events are important data collected within this registry. 
Definitions of adverse events within the registry are fluid and reflect changing clinical 
practices and device characteristics. The incidence and prevalence of adverse events 
are made within the context of device type, management practices, patient co- 
 Baseline Variables And Endpoints 
 

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morbidities, timing of implantation, surgical experience and technique; all based on 
uniform adverse event definitions. For each major adverse event (device malfunction, 
bleeding, infection, neurological, death), additional variables must be included which 
potentially allow a determination of whether an adverse event most likely resulted from 
device design failure or malfunction (device-related), patient co-morbid conditions 
(patient-related), or errors in patient management (e.g., inadequate anti-coagulation) 
(management-related). 
 
 
B.2.0 
Site Eligibility and Enrollment 
 
Section B.2.0 contains the steps for determining eligibility and enrollment for each 
institution. Steps B.2.1 through B.2.7 must be completed to become an active 
participant in pediMACS. 
 
B.2.1 
Eligibility 
Any medical center in the United States and Canada that has an active pediatric MCSD 
program is eligible to participate in pediMACS. In addition, the program must provide 
personnel and facilities to record and transmit data 
 
B.2.2 
Registration 
Registration must be completed online at: https://www.intermacs.org/enrollment. The 
steps necessary for pediMACS membership are outlined below and in described detail 
in the MOP. 
 
1. The medical center is registered by completing the online Hospital Information 
form. 
2. The Personnel Contact Information form, including staff roles, must also be 
completed. 
 
In order to complete the registration process, the Center must assign the following roles 
to qualified personnel: 
 
• Local PI, responsible for oversight of data submissions and registry 
compliance 
• Site Administrator, to act as “point person” for data related inquiries, receipt 
of reports and audit coordination 
 
B.2.3 
IRB/EB Approval 
In preparation of materials for IRB/EB review and approval, participating sites will use 
the INTERMACS® protocol, which is a two-part registry – INTERMACS® - Adults and 
INTERMACS® - Pediatrics/pediMACS.  The hospital must submit the protocol and 

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supporting documentation (e.g., request for waiver of consent) to their IRB/EB for 
approval. The guidelines for the medical center’s submission of an application to 
participate in pediMACS are located in the MOP. If the IRB/EB approves the application 
for participation in this registry, documentation of that decision along with the FWA 
Number and current CLIA documentation must be submitted to pediMACS before a site 
can be activated. IRB/EB approval documents are to be submitted to the DCC on a 
yearly basis. PediMACS will send annual reminders to the participating centers at least 
30 days prior to expiration of IRB/EB approval.  Lapse in local IRB/EB coverage will 
result in immediate suspension, including data entry capability. 
 
The facility is responsible for obtaining and maintaining all IRB/EB documentation. 
Documentation of IRB/EB status is subject to pediMACS audit. 
 
B.2.4 
Agreements and Fees 
The Business Associate Agreement and Participation Agreement are provided in MOP 
Appendix D. These agreements are between the local hospital and pediMACS. They 
contain the center’s and pediMACS’s responsibilities. The signed agreements must be 
submitted to pediMACS. 
 
The annual fee for participation in pediMACS is waived for the first year. After the first 
year, each site must pay a required participation fee. PediMACS is structured to 
provide value to the hospitals for this fee.  For example, pediMACS: 
• provides quarterly quality assurance reports to each participating hospital, 
• provides site-specific datasets to aid in quality improvement at that hospital on an 
as requested basis, 
• creates patient specific chronologic history of the major clinical events after 
implant, and 
• encourages local physicians and coordinators to participate in the administration 
and activities within the registry. 
 
B.2.5 
Financial Disclosure and Conflict of Interest 
Site personnel participating in pediMACS must complete a financial disclosure and 
conflict of interest form. The form is provided in MOP Appendix E. The form must be 
printed, signed, and submitted to pediMACS before a site can be activated and must be 
updated on an annual basis. 
 
B.2.6 
Privacy Awareness Training 
All staff members are required to complete Privacy Awareness Training provided by 
their local site. If training is not available locally, then the NIH’s Privacy Awareness 
Training (http://irtsectraining.nih.gov/PAC/0501000.aspx) may be substituted. 
 
Copies of the Privacy Awareness Training certification must be submitted to pediMACS 
before a site can be activated, and training will be updated per local IRB/EB policy. 

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B.2.7 
Registry-specific Training 
At least one pediMACS staff member at the institution must complete the pediMACS 
training process, which requires participation in a live web-based data entry training 
session. The DCC will schedule the training once the site has completed steps B.2.1 
through B.2.6. 
 
 
B.2.8 
Activation 
After completing steps B.2.1 through B.2.7, site personnel will be notified of their 
activation (i.e., able to read or enter data in the pediMACS web-based data application). 
This notification will consist of a secure e-mail that will contain the individual’s username 
and password. 
 
B.2.9 
Annual Re-Certification 
To MAINTAIN CERTIFICATION, a site must: 
 
• Maintain and provide pediMACS with the annual IRB/EB approval and current 
FWA Number documentation, 
• Provide current CLIA documentation, 
• Provide annual participation fee, 
• Maintain annual Conflict of Interest, 
• Maintain Privacy Awareness Training, and 
• Comply with data submission requirements outlined in this protocol and 
further detailed in the MOP. 
 
 
B.3.0 
Patient Safety 
B.3.1 
Risks and Benefits 
 
Risks 
 
There is no added procedural risk to patients through involvement in pediMACS.  No 
risk or procedures beyond those required for routine care will be imposed. The data 
collected for this Registry are from medical chart abstraction. The only exception is the 
concurrent collection of limited functional capacity data and QoL data via patient/parent 
interviews. The interviews and tests are standard of care for pediatric heart failure 
patients receiving MCSDs and are not considered greater than minimal risk. 
 
There is always the risk of loss of confidentiality. However, safeguards, policies and 
procedures are in place to keep the PHI in each registry record confidential as required 
under the Information Security clauses of the Federal Acquisition Regulations. All 
registry information will be sent through a highly secure website to the pediMACS 

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database. All employees involved in the pediMACS registry have passed background 
checks for government clearance to handle PHI. PHI is not available to anyone outside 
of pediMACS, unless required by law (e.g., to ensure safety). No published or 
unpublished report or visual or speaking presentation about the registry will include any 
material that will identify a patient in this registry. 
 
Benefits 
 
There is no direct benefit to the pediatric heart failure patients who participate in this 
registry. However, future patients with heart failure may benefit from the knowledge 
gained through this registry. 
 
 
B.3.2 
Informed Consent Process 
PediMACS will not require additional consent other than the routine consent that is 
required for the MCSD surgical procedure. This is an observational data registry. In 
general, information will be retrieved from existing medical records. Minimal testing and 
contact with the patient/parents outside of the index hospitalization is required for follow- 
up interviews and physical examination. Physical examination, functional capacity 
testing, and interviews are considered standard of care for these patients.  The 
interview will consist of questions from QoL instruments for patients and their legally 
authorized representatives. No data beyond the data gathered in the course of 
routine care will be collected for this registry. 
 
Patients/parents will be provided with a summary statement describing the registry 
when completing the routine MCSD surgical consent form (refer to Attachment 2). 
 
Participating sites will follow their local IRB/EB policies. Refer to the MOP, Section 5.2, 
for additional guidance and MOP Appendix C for supplementary documents that may be 
required by local IRBs/EBs. 
 
B.3.3 
Registry Interventions 
No additional interventions will be performed outside of the standard course of care. 
 
B.3.4 
Patient Recruitment, Costs, and Compensation 
No recruitment specific to this registry will take place at any participating center. 
Recruitment is not applicable since the registry obtains information through a review of 
existing medical records. 
 
There are no costs or compensation to the patient or patient’s family for participation in 
this registry. 

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B.4.0 
Data Collection 
B.4.1 
Assignment of Registry Identification Number 
A registry identification number will be assigned to each patient prior to entry of their 
data into pediMACS. This identification number will be used as the primary patient 
identifier between the site, pediMACS, MCSD manufacturers, and government 
agencies. 
 
B.4.2 
Web-based Data Entry and Systems Security 
All data will be entered through the pediMACS web-based data entry system. Complete 
documentation is contained at the data entry website (www.intermacs.org), and the 
pediMACS Site User’s Guide can be found in the MOP, Appendix N. The forms should 
be filled out as soon as possible after the implant and at the time of follow-up events 
(within specific time windows). The data are divided into forms that correspond to the 
clinical time course of the patient. 
 
Minimal PHI (e.g., patient’s name; date of birth; last 5 digits of social security number, or 
in the event that a social security number has not yet been issued, the last 5 digits of 
the transplant wait list number; device serial number; implant date; and optionally, the 
hospital medical records number), are entered into the pediMACS database. This 
information allows the patient to be linked to the UNOS transplant database should 
he/she undergo transplantation and to FDA medical device safety databases. 
 
PediMACS complies with all national patient privacy regulations. All registry data shall 
be maintained on secure servers with appropriate safeguards in place. All pediMACS 
employees have passed federal HHS background checks for government clearance. 
Access to the production databases containing PHI is on a need-to-know basis only. 
PediMACS personnel will periodically review all activities involving PHI to ensure that 
such safeguards, including standard procedures, are being followed. Any breach of 
confidentiality and immediate mitigation steps will be reported to the appropriate 
oversight bodies (e.g., the NHLBI and IRB/EB according to their institutional policies), 
and these immediate mitigation steps will be implemented. 
 
The database and web servers reside in an environment that provides multiple layers of 
physical and systems security. PediMACS is compliant with the Security Act of 2002 
and FISMA.  Regular audits take place to verify compliance. 
 
Systems security is deployed with third party software and hardware, strict adherence to 
policy, and regular verification and auditing. The servers that host the web applications 
are built within the Windows 2008R2 framework. They follow Microsoft’s best security 
practices and group policy recommendations from the NIST. 
 
Each server is monitored 24x7 for both intrusion and vulnerabilities by an integrated 
third-party software package.  Microsoft System Center Configuration Manager 2012R2 

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is used for deploying any system patches in accordance with security policies. The 
network is also protected by an automated anti-virus retrieval and deployment system. 
 
Firewall software prevents hacking, virus, and other security risks from the outside. 
Internally, the servers reside on a segmented part of the VLAN that is isolated from the 
rest of the network protecting it from any adverse internal forces. All server access 
requires use of second level authentication for administrative access. Regular internal 
and external penetration and vulnerability tests are conducted by third-party contractors 
to determine any weaknesses in the network. 
 
B.4.3 
Clinical Data 
Clinical data are collected by medical chart review. 
 
Patient Demographics and Profile Prior to Implant 
 
The standard demographics of age, gender, and patient-described ethnicity will be 
recorded. Heart failure etiology, duration, and standard prognostic factors will be 
collected along with hemodynamic and echocardiographic parameters closest to the 
time of implant. Co-morbidities will be included, as they may affect the likelihood of 
success of MCSD therapy. Data elements include seven patient profiles that describe 
the clinical severity at the time of implant, aid in risk stratification, improve patient 
selection, and refine the definition of future trial populations (refer to MOP Appendix O 
for a description of the seven patient profiles). PediMACS also records, pre and post 
implant (at defined intervals), the relative likelihood and limiting factors for transplant 
eligibility. 
 
Device and Operative Details (implant) 
 
The critical elements which characterize the device and describe the implant procedure 
will be recorded within 1 week after implant. 
 
Designated Interval Follow-up 
 
A major feature of the database design is the provision of information both by event and 
by designated time interval.  In this way, the crucial events are submitted in real time, 
but there are also regularly scheduled checkpoints at which any important events during 
follow-up intervals will be captured. The first routine post-operative follow-up will be at 1 
week. If the patient is in the hospital at 1 month post implant then the 1 month follow-up 
form will be completed. The remaining interval follow-up visits occur at 3 months, 6 
months, and every 6 months for the life of the device. If the device is explanted without 
transplantation, the patient will be followed for 1 year following explant for the major 
events of death or transplantation. 
 
The follow-up forms will all include information on vital signs and volume status, 
medications, basic laboratory values, and device settings.  NYHA functional status and 

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Ross Class (for children<2 years of age) will be noted. At each time interval beginning 
with the 3-month follow-up, re-assessment will be documented regarding current intent 
as bridge to recovery, transplant, likelihood of eligibility for transplant, or permanent 
support, with a checklist of considerations relevant to that decision. Echocardiographic 
information will be included regarding function of both ventricles and atrioventricular 
valves. Hemodynamic measurement regarding filling pressures, pulmonary pressures, 
and cardiac output will be included when available. 
 
Adverse Events 
 
Data on specific adverse events will be collected by two mechanisms: 
 
(1) The occurrence of hemolysis, hypertension, and right heart failure* are 
considered ‘triggered events’. These events are ‘triggered’ based on the relevant 
medical data collected at follow-up and re-hospitalization. 
(2) Other adverse events (see MOP Appendix A for a complete list) will be identified and 
collected through routine data acquisition at the specified follow-up intervals or at 
time of event. 
 
*Refer to the pediMACS User’s Guide, Appendix N, for reporting of right heart failure. 
 
B.4.4 
Quality of Life Data 
QoL will be measured by the PedsQL and VADQoL instruments (refer to MOP Appendix 
F). It is anticipated that completing these instruments will take the patient/parent 20 
minutes per instrument. Administering the instrument and entering the data into the 
registry will require approximately 30 minutes of coordinator time. The QoL instruments 
will be completed pre-implant and post-implant (3 months, 6 months, and every 6 
months thereafter for the life of the device). 
 
After implantation, the PedsQL and VADQoL instruments will be completed as 
scheduled, whether the patient is hospitalized or at a clinic visit.  Missing answers will 
be queried by the coordinator at the time of form completion. Reasons for not collecting 
the QoL instruments will be recorded. 
 
B.4.5 Functional Capacity Data 
Functional capacity measures for pediatric patients ages 10-18 years are collected pre- 
implantation and within follow-up intervals post implant at 3 months, 6 months, and 
every 6 months thereafter. Included in these functional capacity measures are:  6 
minute walk test, gait speed, and cardiopulmonary exercise indices. 
 
For pediatric patients <10 years of age, general functional capacity data is collected pre- 
implant, implant discharge, and at follow-up intervals (i.e., 3 and 6 months and every 6 
months thereafter for as long as the MCSD is in place). These data include the child’s 
functional capacity (e.g., sedated, paralyzed, intubated, ambulating), primary nutrition, 

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and if the patient has had non-medically required excursions off the unit (collected at 1 
week and 1 month post implant and at implant discharge). 
 
B.5.0 
Analyses of Registry Data 
B.5.1 
Introduction 
The value of any clinical registry lies in the statistical analyses of the data and the 
clinical relevance of these analyses. The registry will collect a wide array of patient, 
device, and follow-up information. This section outlines the general analyses and the 
statistical methods. 
 
B.5.2 
Purposes 
• Summarize the characteristics of the patients who are receiving MCSDs, when (in 
relation to progression of disease) they are receiving MCSDs and why (bridge to 
transplant, bridge to recovery, rescue therapy, or bridge to decision), and outcomes 
of the therapy 
• Summarize the characteristics of MCSDs that are being implanted 
• Describe post-implant adverse events and estimate their time-related distribution 
• Determine risk factors (both patient related and MCSD related) for post-implant 
events 
• Contribute to evidence based management of patients with implanted MCSDs 
• Provide device specific analyses to aid in MCSD development 
• Evaluate safety and efficacy of MCSD implants 
• Determine the time-related costs (resource utilization) of MCSDs and the risk factors 
associated with increased costs 
• Compare the costs (resource utilization), of MCSD therapy to other treatments for 
pediatric patients with advanced heart failure 
• Evaluate QoL pre- and post-MCSD implant 
• Compare alternative therapies (MCSD, transplant, medical) for pediatric patients 
with advanced heart failure 
• Produce patient-specific predictions of time-related outcomes to aid in clinical 
decision making and allocation of therapies for pediatric patients with advanced 
heart failure 
 
B.5.3 
Patient Profiling 
Patients who receive MCSDs will be characterized regarding their demographic data, 
medical history, and clinical status including descriptors of heart failure, pre-implant 
laboratory values and pre-implant hemodynamic data. 

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Death 
Transplant 
Explant for Recovery 
Improvement 
Indicators 
• Patient/Device/Disease 
Predictors of Favorable 
Outcome 
• Comparison of Outcome 
With Other Therapies 
Adverse Events 
• Repeating Event 
Analyses 
Quality of Life 
• Determinants of 
post-MCSD QOL 
• Determination  of Causes     • Comparison  of QOL 
Costs 
Hospitalizations 
(resource 
utilization) 
• Predictors of 
(Device-, Patient-, 
Management-Related) 
With Other Therapies 
Implant Costs 
• Cost 
Effectiveness 
Analyses 
• Days Alive out of 
Hospital 
• Risk Factors for 
Repeated 
Hospitalizations 
 
B.5.4 
Primary Endpoints 
The discrete endpoints are death, transplant, and explant for recovery. Other endpoints 
include patient adverse events, re-hospitalization, device related adverse events, 
change in QoL, costs (resource utilization), functional status, and changes in 
hemodynamic parameters and laboratory values.  Each of the endpoints will be 
analyzed as time related events. 
 
 
B.5.5 
Analytic Methods 
Statistical analysis of the MCSD will require a variety of methods including analysis of 
variance, multiple linear regression, t-tests, chi-square tests of association, correlations, 
and descriptive statistics. The group of methods generally labeled survival analysis 
techniques will be the methods most used. In general, survival analysis refers to all 
methods applicable to time-related events or outcomes. Most of the outcomes that will 
be documented in the MCSD registry will have time components. For example, time- 
until-death, time-until-transplant, time-until-infection, time-until-device-malfunction are all 
events that will have an associated interval post implant. However, additional analytic 
methods will be necessary for issues such as costs and QoL. 
 
The Hazard Function 
 
The time-related survival methods will combine more traditional non-parametric or semi- 
parametric methods with parametric hazard function analysis. Kaplan-Meier non- 
parametric estimation provides estimates of time-related freedom from an event. While 
the depiction of these estimates is useful, parametric estimation using hazard models 
 
Sample Endpoint Analyses 
 
Discrete Endpoints 
• Causes  of Death 
• Risk Factor Analyses 
• Competing  Outcomes     • Prediction  of Recovery 
Analyses 
• Post-transplant 
Survival Analyses 
• Post-Explant Survival 
Analyses 
Complex Endpoints 

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can offer more insight into the timing of an event. The hazard function is the 
instantaneous (or daily) rate of an event. This function can depict time periods of high 
risk for an event and can estimate whether the risk is increasing, decreasing or peaking. 
 
Parametric hazard estimation will employ simple to complex hazard models depending 
on the distribution of the event. Both the parametric survival function and the 
corresponding hazard function will be displayed to provide a complete description of the 
event. 
 
Competing Outcomes 
 
Depictions of a single time-related event do not take into account other events. For 
example, a depiction of death would assume that transplantation does not exist. 
Patients are censored at time of transplant. If informative censoring does not exist (i.e., 
if patients are not transplanted due to impending death but instead selected at random 
for transplant), then the depiction can be thought of as the natural history of mortality 
after device implant.  In reality, this rarely occurs, since patients are usually selected at 
a given time because of medical necessity. This informative censoring complicates the 
interpretation of this single event depiction. 
 
Alternatively, one may wish to estimate the simultaneous time-related probability of 
mutually exclusive events. Competing outcomes estimation allows the time related 
probability of actually experiencing each of these events. At any point in time, a patient 
has either experienced one of the three events or he/she is alive and waiting for one of 
the events to occur. A probability can be assigned to each of these four possible states 
and the sum of the four probabilities will be equal to one at each point in time. The non- 
parametric estimation of these probabilities is an adaptation of the Kaplan-Meier 
method. In the standard use of the Kaplan-Meier methods, event probabilities are 
accumulated across time. In competing outcomes analysis, the combined event is 
analyzed and then probabilities are accumulated separately according to which event 
occurred. 
 
Multivariable Risk Factor Analysis 
 
The most common multivariable method for identifying risk factors is Cox proportional 
hazard regression. This method assumes proportional hazards for different levels of a 
potential risk factor. The p-value results from testing the null hypothesis that the 
proportionality parameter is equal to one. The method is often called a semi-parametric 
technique because it does not require or estimate the form of the underlying parametric 
hazard. It only requires (assumes) that hazards for different levels of risk factor are 
proportional across time. This assumption is often incorrect. The magnitude of the 
effects of the final risk factor model from Cox regression is not easily displayed due to 
the lack of a specified hazard model. This also prevents a simple, continuous depiction 
for a specific patient with his unique values of the risk factors. 
 
Consequently, we have pursued a parametric version of survival regression that builds 
on a framework of hazard functions.  The concept is still proportional hazard regression, 

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but the hazard function is estimated and decomposed into additive phases. Each phase 
is then constructed to be a function of the risk factors. The model of risk is then totally 
specified as a mathematical equation that can be “drawn” for any time period and any 
specified set of risk factors. This system also allows the identification of risk factors that 
impact different phases of risk. 
 
Predictions 
 
This ability to produce time-related expected survival for a specific patient (with his/her 
specific risk profile) is one of the strengths of parametric hazard analysis. The 
predictions are a function of the estimated hazard functions and the identified risk 
factors.  The hazard function and risk factors are derived from the actual data. 
 
Repeated Events (Adverse Events) 
 
Most adverse events can occur more than once. For example, once a patient 
experiences an infection episode, he/she remains at risk for another episode. These 
repeating events require methods that are an expansion of the previously described 
methods. 
 
First Events Analysis 
 
The first occurrence of an event can be analyzed exactly as a terminating event such as 
death (see previous discussion). While this analysis does not appear very useful 
clinically for events that recur frequently, it does provide a time-related estimate of the 
proportion of patients who have remained free of the event. 
 
The FDA Approach 
 
Most of the medical device guidance documents from the FDA for analyzing events that 
can happen multiple times specify a specific analytic approach.  First, a calculation of 
the percent of patients who experience at least one event during the first 30 days post 
implant is presented. Next, a linearized rate is calculated for events that occur after the 
first 30 days. Summing all of the post 30-day events and dividing by the total patient 
follow-up intervals after 30 days calculates this. The rate is usually multiplied by 100. 
The calculation is then the number of events that are estimated to occur in 100 months 
of follow-up. This is a useful calculation but it assumes a constant hazard rate across 
time. For many events, for example device malfunction, this may be an incorrect 
assumption. 
 
Parametric Hazard Approach 
 
The parametric hazard methods can be applied to multiple events. This allows the 
estimation of the shape of the underlying hazard and specific statistical testing for an 
increasing hazard or decreasing hazard or peaking hazard. This approach will allow 
detection of device related events whose occurrence rate is rising to unacceptable 
levels at some point in time. 

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Cumulative Event Estimation 
 
Another useful display of repeated events depicts the accumulation of events that will 
occur, on the average, for a single patient. This method of depiction illustrates the rate 
of accumulating events as a function of time. 
 
Modulated Renewal 
 
Another method of analyzing repeated events is the modulated renewal method. In this 
approach, the unit of observation is each episode of an event. A patient is tracked from 
time of device implant until he/she experiences his/her first event.  The patient’s then 
re- entered into the analysis, with a new starting time and is tracked until his/her next 
episode. This process is continued for event re-occurrences. The analysis of this data 
structure is then performed in the parametric hazard domain and is particularly 
amenable to risk factor analysis that incorporates the event history of a patient when 
predicting his/her next occurrence. 
 
Each of these methods for repeated adverse events contributes to the understanding of 
the time course of the event and the related risk factors.  The methods will be 
particularly helpful in calculating the time related risk of device related adverse events. 
 
B.5.6 
Planned Analyses 
 
Patient Characteristics 
 
Pediatric patients who receive either durable or temporary MCSDs will be summarized 
regarding their demographic data, medical history, and clinical status including 
descriptors of heart failure, pre-implant laboratory values and pre-implant hemodynamic 
data. Novel aspects of the registry include the seven patient profiles that describe the 
clinical severity of disease at the time of implantation. The categorization of pediatric 
patients into these profiles will facilitate risk stratification for outcomes and advance the 
selection of pediatric patients who have sufficient severity of disease to warrant MCSDs. 
An additional component is the ongoing evaluation of pediatric patients with regard to 
evolving eligibility for transplantation and explantation in order to better understand the 
factors leading to transplantation or explantation. Subsequent tracking of patients will 
allow the decision process to be continually refined for better outcomes. 
 
Data will be summarized by frequencies, measures of central tendencies, measures of 
dispersion, cumulative distribution functions, graphical displays, cross tabulations and 
correlations. 
 
MCSD Characteristics 
 
MCSDs that are implanted will be summarized according to their physical and 
physiologic characteristics (e.g., size, weight, pulsatile or continuous flow, range of flow 
rates, etc.) and their initial flow settings.  The Industry Committee, which consists of 

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representatives from each participating device manufacturer, will assist in selecting 
variables for analysis that are relevant to emerging technologies. 
 
Survival 
 
The analysis of post implant survival will utilize all of the methods outlined in the 
previous section. The emphasis will be on the time related pattern of overall death and 
each of the causes of death. The investigation of risk factors, especially those risk 
factors which can be modified for a patient, will be a priority. 
 
Transplantation 
 
Time to transplant will be analyzed similarly to survival.  In addition to the examination 
of patient risk factors and device factors which predict survival to transplant, the 
prolonged implant duration in many “bridge” patients awaiting a suitable heart donor will 
facilitate analyses that give insight into longer-term “destination” therapy. 
 
Adverse Events: Patient- and Device-Related 
 
A key feature of the entire registry analysis will be the examination of the time course 
and risk factors for all of the possible patient related and device related adverse events. 
The methods listed under Analytic Methods will be used to evaluate these interactions. 
 
Competing Outcomes 
 
The major events that “compete” for a patient are death, transplantation and explant for 
recovery. The simultaneous time-related estimation of the probability of these events 
will be depicted. Separate risk factor analyses will be performed for each individual 
outcome event. 
 
Quality of Life (QoL) 
 
Repeated measures methodology will test for changes in pre-implant and follow-up 
interval measures. Multiple linear regression will be used to identify patient groups who 
have the least and the greatest improvement in QoL. Analyses will focus on the impact 
of MCSD therapy on QoL indicators, comparisons with QoL after transplant and other 
therapies for advanced heart failure (through published studies or parallel patient 
cohorts). 
 
Costs 
 
Multivariate statistical techniques, most often regression analysis, are used to 
investigate relationships among the variables of interest. Analytical emphasis will be on 
resource utilization. 

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Analysis of MCSD Efficacy 
 
In all of the analyses for death, transplant, recovery, adverse events, QoL, and costs, 
the effects of device characteristics (pulsatile flow, size, etc.) on outcome will be 
investigated. A major focus of pediMACS will be the identification of the strengths and 
weaknesses of the different devices for specific patient subsets and facilitation of the 
evolution of MCSD technology. 
 
Evaluation of Hospital Outcomes 
 
Each hospital that contributes data to pediMACS will be periodically evaluated for their 
outcomes. The basis of the evaluation will be risk-adjusted comparisons using the 
results of the multivariable analyses. The observed survival, depicted by a Kaplan- 
Meier, is also represented. The observed and expected deaths will then be statistically 
compared where the patient-specific risk factors and length of follow-up are explicitly 
incorporated into the comparison. 
 
 
B.6.0 
Reports 
INTERMACS will provide summaries to the following entities: 
 
B.6.1 
National Heart, Lung and Blood Institute (NHLBI) 
Quarterly Statistical, Semi-annual and the Final Report will include an overall 
summary of INTERMACS® patient characteristics, implant characteristics, hospital 
enrollment/activation, adverse events and significant outcomes. Manuscripts will be 
provided for review within 30 days of publication. 
 
B.6.2 
Centers for Medicare and Medicaid Services (CMS) 
CMS may receive pediMACS-specific reports if requested. 
 
B.6.3 
Food and Drug Administration (FDA) 
FDA requires “user facilities”, which they define as “a hospital, ambulatory surgical 
facility, nursing home, outpatient diagnostic facility, or outpatient treatment facility”, to 
report all serious injuries or deaths associated with a medical device to the FDA within 
10 working days of their occurrence through an MDR. All sites participating in 
pediMACS are required to report serious injuries and deaths where the device may 
have caused or contributed to the event according to 21 CFR 803.10and summarized in 
the following table.  Refer to Section 7.3 of the MOP for additional information. 

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Summary of MDR Reporting Requirement 21 CFR 803.10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PediMACS also provides reports to FDA, as requested, that inform: 
1) OPC: Randomized trials of IDE MCSDs may not be practical. The FDA will 
often allow single arm studies where the results from an investigational medical 
device are compared with OPC. These OPC are derived from the literature or 
existing databases. PediMACS can be used to generate OPC for the major 
safety endpoints after MCSD implant. 
2) Unexpected risks: PediMACS can be analyzed to identify MCSDs with 
unexpected risks for major safety events. 
REPORTER WHAT TO REPORT 
WHERE 
WHEN 
Manufacturer 
Deaths, Serious Injuries, 
Malfunction 
FDA 
Within 30 calendar 
days of becoming 
aware 
Events that require remedial 
action to prevent an 
unreasonable risk of 
substantial harm 
FDA 
Within 5 working 
days of becoming 
aware 
User Facility 
Deaths 
FDA and 
Manufacturer 
Within 10 working 
days 
Serious Injury 
Manufacturer 
Within 10 working 
days 
Importer 
Deaths and Serious Injuries 
FDA and 
Manufacturer 
Within 30 calendar 
days 
Malfunctions 
Manufacturer 
Within 30 calendar 
days 
Voluntary 
Any type of event 
FDA 
Any time 

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B.6.4 
Industry 
In addition to the reports discussed in Section B.6.3, quarterly reports will be provided to 
each MCSD manufacturer summarizing data entered into pediMACS. A specific 
manufacturer will not receive identifiable information about any MCSDs from other 
manufacturers. The reports will provide statistical summaries of patient demographics 
and clinical characteristics at the time of implant. Adverse event rates, including death 
and explant, will be calculated. 
 
B.6.5 
Individual Sites 
Quarterly reports will be provided to each participating site.  A specific site will not 
receive identified information about any other site.  These reports have two 
components. The first component is a quality assurance report that summarizes and 
compares the results at the individual hospital with the entire pediMACS registry. These 
benchmark comparisons allow the hospital to evaluate the patients and outcomes as 
compared to the aggregate data of the other participating hospitals. The second 
component focuses on patient-specific data and the quality of the site data. A 
dashboard is available for sites to view a patient’s chronological history of major 
implant-related events. To assist participating pediatric implanting centers in meeting 
their post-market reporting requirements, PediMACS will provide them with: 
• Deaths:  completed MDRs to submit to the FDA and the device manufacturer(s) 
• Serious Injuries:  reports to submit to the device manufacturer(s) 
 
B.6.6 
Observational Study Monitoring Board (OSMB) 
The OSMB will receive copies of the NHLBI reports along with any specific reports that 
they may require. 
 
 
B.7.0 
Quality Assurance 
B.7.1 
Data Quality 
PediMACS will examine data quality and provide periodic data reports. The focus will 
be on completeness of periodic follow-up and also on identifying impossible or 
improbable combinations of variables.  Questionable data points will be verified. 
 
B.7.2 
Data Monitoring and Checks for Inconsistencies 
The database will be subject to analytical QA audits following the completion of data 
entry. Depending on the types of discrepancies identified, pediMACS will contact 
participating centers to resolve these issues. Resolution may be accomplished via 
telephone contact, e-mail and/or hard copy mailings. The discrepancies and their 
resolutions will be tracked for future reference and further review.  Based on a review of 

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the results of the analytical QA processes, additional items may be incorporated into the 
QA process at the Executive Committee’s request. Participating centers will be able to 
review and modify previously submitted data at any time.  Additionally, summary 
screens and reports of patients and devices reported, current patient status, most 
recent reported event and other data will be available to the member institutions to 
assist the institution in assessing the completeness of reporting. PediMACS will employ 
established procedures to maintain the quality of pediMACS data.  These procedures 
will be used in completion of all data entry activities associated with the MCSD and can 
be found in the MOP. Written internal DCC procedures will be maintained and will 
provide step-by-step directions for auditing processes involved in data entry, 
maintenance, and review to ensure data quality and completeness. 
 
B.7.3 
Medical Event Review 
Medical event review is a function of both the DCC and the Medical Events Review 
Committee.  The Committee will: 
• provide guidance on summarizing and evaluating the quality of the adverse event 
data. 
• provide strategies for electronically identifying duplicate events and questionable 
events. 
• focus on the review and categorization of device malfunction. 
• provide guidance to the nurse monitors for auditing the correct capture of 
adverse events. All data identified as questionable are resolved via direct 
interactions between the nurse monitors and the local hospital. 
 
 
B.8.0 
Centers: Requirements, Training, Assistance and Audits 
B.8.1 
Requirements for Centers 
Each participating hospital shall: (1) provide dated proof of initial and annual IRB/EB 
approval, proof of FWA Number, proof of Privacy Awareness Training for the principal 
site staff (to include the Principal Investigator, Co-Investigators and Site Coordinator), 
and proof of CLIA documentation;(2) have at least one person complete training;(3) 
enter complete baseline, implant and follow-up data on all patients; (4) submit to regular 
and “for cause” data audits; and (5) correct identified errors in a timely fashion. 
 
B.8.2 
Training for Centers 
Web-based interactive software will be used to conduct training on an ongoing basis. 
This is a secure, subscription-based service that allows for meetings and their related 
documents to be conducted in a virtual electronic environment. Participants are allowed 
to view the trainer’s desktop. Attendees follow along as the trainer shows step-by-step 
instructions. 

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B.8.3 
Assistance to Centers 
A comprehensive pediMACS Site User’s Guide will provide step-by-step instructions for 
using the system and will include definitions for all fields collected in the system. The Site 
User’s Guide will also identify main processes in the application and explain standard 
procedures for data collection.  Refer to MOP Appendix N. 
 
The DCC is available to provide assistance with data collection and entry, regulatory 
questions, data requests and analyses, and technical support. Refer to the MOP, 
Appendix L, for a complete list of contacts. 
 
B.8.4 
Audit Process for Centers 
The audit process for all participating pediMACS sites involves interactions in the form of an 
on-site visit or a review of the documents submitted to the DCC and discussion with site staff 
via telephone and/or WebEx (remote review). Sites are notified up to 60 days prior to a routine 
on-site audit.  Audited data include key data fields, as determined by pediMACS. 
 
The pediMACS monitor contacts the site by phone for a pre-audit review approximately 
2 weeks before the scheduled audit.  During the call, the monitor reviews site specific 
summaries for duplicated events, unknown sources of bleeding, unknown causes of death, 
device explants inconsistencies and any other noted discrepancies. The sites are requested 
to make corrections and to provide redacted source documentation (as needed for remote 
review) prior to the actual audit. 
 
During the audit, nurse monitors will monitor data accuracy of web-based data submissions 
and information contained in source documents as well as participant performance and 
progress. “For Cause” audit visits will be made as indicated by the Hospital Standards 
Committee, which reviews hospital performance and recommends actions to reestablish 
compliance.  All audit results will be reported to the Executive Committee. 
 
The audit process will identify member institutions that perform poorly in data submission 
compliance. The pediMACS monitors, in collaboration with the Hospital Standards Committee, 
will identify and work with these underperformers to identify reasons for low rates of data 
collection and/or tardy data submission. These institutions will be retrained on proper data 
collection methods with the goal of identifying and overcoming obstacles to submission. 

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Attachment 1:  Patient Information for Adults 

 
Adult Interagency Registry for Mechanically Assisted Circulatory Support 
(INTERMACS®):  Patient Information 
As a patient receiving a durable, Food and Drug Administration (FDA)-approved mechanical 
circulatory support device (MCSD) at [insert institution name or acronym], we plan to collect 
information about your initial device implant as well as your follow-up visits. Information that 
includes your medical history, quality of life questionnaires, and information about the health 
care costs will be entered into the Interagency Registry for Mechanically Assisted 
Circulatory Support (INTERMACS®) database. INTERMACS® is the national quality 
improvement system used to collect and evaluate the characteristics, treatments, and 
outcomes of MCSD patients. This means that we will use the information entered into 
INTERMACS® to learn more about MCSDs and heart failure, which may lead 
to improvements in the devices and how we treat heart failure patients in the future. We may 
also use this information in the future to gain a better understanding of quality of life, medical 
practices, and 
other factors associated with MCSD implants. While you will not directly benefit from this 
registry, future 
heart failure patients may benefit from the knowledge gained through this registry. 
INTERMACS® data are used by the FDA to assist them in overseeing the safety and 
effectiveness of MCSDs and other agencies to measure the quality of health care at MCSD- 
implanting hospitals. In addition, INTERMACS® works closely with the National Heart, Lung, 
and Blood Institute of the National Institutes of Health, MCSD-implanting hospitals, device 
manufacturers, medical teams and scientists to evaluate the best medical practices to improve 
the treatment of advanced heart failure. 
 
Limited protected health information (e.g., your name; date of birth; last 5 digits of your social 
security number, or in the event that a social security number is not available, the last 5 digits 
of the transplant wait list number; health insurance claim number, if applicable; device serial 
number; implant date; and hospital medical record number) is collected by INTERMACS®. 
This information will allow your data to be linked to the United Network for Organ Sharing 
database if you receive a heart transplant, to the Centers for Medicare and Medicaid Services 
databases for coverage purposes, to cost databases, to FDA databases and to the 
manufacturer of your MCSD for medical device reporting.  Because INTERMACS® complies 
with all national patient privacy regulations, all registry data are transmitted from [insert 
institution name or acronym] to the INTERMACS®database through a secure website and 
maintained on secure servers with safeguards in place. All Privacy Act provisions are followed 
in handling and storing patient data, and all INTERMACS® employees have passed 
background checks for Federal Government clearance to handle protected health information. 
Protected health information is not available to any employee outside of INTERMACS®, unless 
required by law (e.g., to ensure your safety), and an INTERMACS®-assigned identification 
number is used to help maintain your 
confidentiality. No published or unpublished report or visual or speaking presentation about the 
registry will include any material that will identify you in this registry. 
If other MCSD studies begin that use INTERMACS® data, the hospital may contact you to see 
if you are interested in participating. If at that time, you are interested in participating in the 
study, you will be given information about the study and asked to sign an informed consent. 
To learn more about INTERMACS®, visit the INTERMACS® website at 
http://www.uab.edu/intermacs/ 
or www.clinicaltrials.gov. 
If you have any questions about INTERMACS®, please contact your surgeon or surgical nurse 
at [insert pager and/or telephone numbers]. 

 
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Attachment 2:  Patient Information for Children 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
53 

 
Pediatric Interagency Registry for Mechanically Assisted Circulatory 
Support 
(pediMACS): Patient 
Information 
 
Because you/your child is receiving a Food and Drug Administration (FDA)- 
approved durable or temporary mechanical circulatory support device (MCSD) at 
[insert institution name or acronym], we plan to collect information about your/your 
child’s initial device implant as well as your/your child’s 
follow-up visits. Information that includes your/your child’s medical history, quality of 
life questionnaires, and information about the health care costs will be entered into 
the Pediatric Interagency Registry for Mechanically Assisted Circulatory 
Support for Pediatric Patients (pediMACS) database. PediMACS is the national 
quality improvement system used to collect and evaluate the characteristics, 
treatments, and outcomes of pediatric MCSD patients. This means that we will use 
the information entered into pediMACS to learn more about MCSDs and heart failure, 
which may lead to improvements in the devices and how we treat heart failure 
patients in the future. We may also use this information in the future to gain a better 
understanding of quality of life, medical practices, and other factors 
associated with MCSD implants. While you/your child will not directly benefit from 
this registry, future pediatric heart failure patients may benefit from the knowledge 
gained through this registry. 
 
PediMACS data are used by the FDA to assist them in overseeing the safety and 
effectiveness of MCSDs and other agencies to measure the quality of health care at 
MCSD-implanting hospitals. In addition, pediMACS works closely with the National 
Heart, Lung, and Blood Institute of the National Institutes of Health, MCSD- 
implanting hospitals, device manufacturers, medical teams and scientists to evaluate 
the best medical practices to improve treatment of advanced heart failure. 
 
Limited protected health information (e.g., your/your child’s name; date of birth; last 5 
digits of your/your child’s social security number, or in the event that a social security 
number has not yet been issued for your child, the last 5 digits of the transplant wait 
list number; device serial number; implant date; and hospital medical record number) 
is collected by pediMACS. This information will allow your/your child’s data to be 
linked to the United Network for Organ Sharing database if you/your child receive a 
heart transplant and to FDA databases, to cost databases, and to the manufacturer 
of your/your child’s 
MCSD for medical device reporting. Because pediMACS complies with all national 
patient privacy regulations, all registry data are transmitted from [insert institution 
name or acronym] to the pediMACS 
database through a secure website and maintained on secure servers with 
safeguards in place. All 
Privacy Act provisions are followed in handling and storing patient data, and all 
pediMACS employees have passed background checks for Federal Government 
clearance to handle protected health information. Protected health information is 
not available to any employee outside of pediMACS, 
unless required by law (e.g., to ensure your/your child’s safety), and a pediMACS- 
assigned identification number is used to help maintain your confidentiality. No 

 
published or unpublished report or visual or speaking presentation about the 
registry will include any material that will identify you/your child in this registry. 
 
If other MCSD studies begin that use PediMACS data, the hospital may contact 
you to see if you/your child are interested in participating. If at that time, you/your 
child are interested in participating in the study, you/your child will be given 
information about the study and asked to sign an Informed consent/assent. 
 
To learn more about pediMACS, visit the 
pediMACS website at 
http://www.uab.edu/intermacs/pedimacs or 
www.clinicaltrials.gov. 
 
If you/your child have any questions about pediMACS, please contact your 
surgeon or surgical nurse at [insert pager and/or telephone numbers]. 

 
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16.4 
Appendix D – INTERMACS® Adverse Event Definitions 
 
Adverse event definitions continue to evolve. The adverse event definitions below may be 
revised according to the published adverse event definitions as determined by the National 
Institutes of Health (NIH) funded Mechanical Circulatory Support Database Registry 
(INTERMACS Manual of Operations Version 4.0;2014). 
The most current version of Adverse Event definitions will be used in the study. 

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Version. 7.3  
 
INTERMACS Adverse Event Definitions: 
Adult and Pediatric patients 
Approved by the INTERMACS Executive Committee:  May 15, 2013 
 
This document contains the following adverse event definitions: 
 
• Hemolysis 
•  Respiratory Failure 
• Right Heart Failure 
•  Venous Thromboembolism 
• Device Malfunction 
•  Wound Dehiscence 
• Major Bleeding 
•  Arterial Non-CNS Thromboembolism 
• Major Infection 
•  Other SAE 
• Neurological Dysfunction 
•  Hepatic Dysfunction 
• Cardiac Arrhythmias 
• Hypertension 
• Pericardial Fluid Collection 
Adult definition 
• Myocardial Infarction 
Pediatric definition 
• Psychiatric Episode 
•  Renal Dysfunction 
 
Additional Notes: 
Medical Device Reports: 
INTERMACS reports MDRs (FDA mandated Medical Device Reports) on behalf of hospitals 
that participate in INTERMACS. Each device malfunction adverse event that is reported to the 
registry generates a reportable MDR. This is the only mechanism for an MDR. Other events 
(hemolysis, death, etc.) may lead to an MDR only if the event is associated with a device 
malfunction and the device malfunction is reported to the registry. 
Triggered Adverse Events: 
The adverse events, hypertension, hemolysis and right heart failure are not directly entered into 
the registry. Each of these events is a result of direct clinical measurements. The clinical 
information collected at the specific follow-up information is used to identify these adverse 
events. For example, blood pressure is collected at each follow-up visit. If the recorded mean 
blood pressure is above 110, then the event “hypertension” is internally identified. This strategy 
allows future adjustment of the “cut points” for an adverse event depending on the evolving 
clinical understanding of the event. 
 
 
 
 
 
 
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Hemolysis: 
 
Minor Hemolysis: A plasma-free hemoglobin value greater than 20 mg/dl or a serum 
lactate dehydrogenase (LDH) level greater than two and one-half time (2.5x) the upper 
limits of the normal range at the implanting center occurring after the first 72 hours post- 
implant in the absence of clinical symptoms or findings of hemolysis or abnormal pump 
function. 
Major Hemolysis: A plasma-free hemoglobin value greater than 20 mg/dl or a serum 
lactate dehydrogenase (LDH) level greater than two and one-half times (2.5x) the upper 
limits of the normal range at the implanting center occurring after the first 72 hours post- 
implant and associated with clinical symptoms or findings of hemolysis or abnormal 
pump function. Major Hemolysis requires the presence of one or more of the following 
conditions: 
o Hemoglobinuria (“tea-colored urine”) 
o Anemia (decrease in hematocrit or hemoglobin level that is out of proportion to levels 
explainable by chronic illness or usual post-VAD state) 
o Hyperbilirubinemia (total bilirubin above 2 mg%, with predominately indirect component) 
o Pump malfunction and/or abnormal pump parameters 

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Right Heart Failure: 
 
Definition:  Symptoms or findings of persistent right ventricular failure characterized by 
both of the following: 
● Documentation of elevated central venous pressure (CVP) by: 
o Direct measurement (e.g., right heart catheterization) with evidence of a central 
venous pressure (CVP) or right atrial pressure (RAP) > 16 mmHg. 
or 
o Findings of significantly dilated inferior vena cava with absence of inspiratory 
variation by echocardiography, 
or 
o Clinical findings of elevated jugular venous distension at least half way up the 
neck in an upright patient. 
 
● Manifestations of elevated central venous pressure characterized by: 
o Clinical findings of peripheral edema (>2+ either new or unresolved), 
or 
o Presence of ascites or palpable hepatomegaly on physical examination 
(unmistakable abdominal contour) or by diagnostic imaging, 
or 
o Laboratory evidence of worsening hepatic (total bilirubin > 2.0) or renal 
dysfunction (creatinine > 2.0). 
 
IF the patient meets the definition for right heart failure, the severity of the right 
heart failure will be graded according to the following scale below. 
(NOTE: For right heart failure to meet severe or severe acute severity, direct 
measurement of central venous pressure or right atrial pressure must be one of 
the criteria) 

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Right Heart Failure Severity Grade 
Mild Right Heart Failure 
VAD Implant Admission 
Patient meets both criteria for RHF plus: 
● Post-implant inotropes, inhaled nitric oxide or intravenous vasodilators not continued 
beyond post-op day 7 following VAD implant 
AND 
● No inotropes continued beyond post-op day 7 following VAD implant 
 
Surveillance periods (3 months, 6 months, 12 months and every 6 months 
thereafter) following VAD implant 
Patient meets both criteria for RHF plus: 
● No readmissions for RHF since last surveillance period 
AND 
● No inotropes since last surveillance period. 
 
Moderate Right Heart Failure 
VAD Implant Admission 
Patient meets both criteria for RHF plus: 
● Post-implant inotropes, inhaled nitric oxide or intravenous vasodilators continued beyond 
post-op day 7 and up to post-op day 14 following VAD implant 
 
Surveillance periods (3 months, 6 months, 12 months and every 6 months 
thereafter) following VAD implant 
Patient meets both criteria for RHF plus: 
● Limited to one (1) readmission for intravenous diuretics/vasodilators to treat RHF since 
last surveillance period 
AND 
● No inotropes since last surveillance period 

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VAD Implant Admission 
Severe Right Heart Failure 
Patient meets both criteria for RHF plus: 
● Central venous pressure or right atrial pressure greater than 16mm Hg 
AND 
● Prolonged post-implant inotropes, inhaled nitric oxide or intravenous vasodilators 
continued beyond post-op day 14 following VAD implant 
 
Surveillance periods (3 months, 6 months, 12 months and every 6 months 
thereafter) following VAD implant 
Patient meets both criteria for RHF plus: 
● Need for inotropes at any time since last surveillance period 
OR 
● Two (2) or more readmissions for intravenous diuretics/vasodilators to treat RHF since 
last surveillance period 
OR 
● Requiring RVAD support at any time after hospital discharge 
OR 
● Death at any time following discharge from the VAD implant hospitalization with RHF as 
the primary cause. 
 
Severe-Acute Right Heart Failure 
VAD Implant Admission 
Patient meets both criteria for Right Heart Failure plus: 
● Central venous pressure or right atrial pressure greater than 16 mmHg 
AND 
● Need for right ventricular assist device at any time following VAD implant 
OR 
● Death during the VAD implants hospitalization with RHF as the primary cause. 

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Device Malfunction: 
 
A Device Malfunction occurs when any component of the MCSD system ceases to 
operate to its designed performance specifications or otherwise fails to perform as 
intended. Performance specifications include all claims made in the Instructions for 
Use. 
 
Device malfunctions can be further defined as major or minor: 
 
1. Major device malfunction, otherwise known as failure, occurs when of one or more of the 
components of the MCSD system either directly causes or could potentially induce a state of 
inadequate circulatory support (low cardiac output state) or death. A failure that was 
iatrogenic or recipient-induced will be classified as an Iatrogenic/Recipient-Induced Failure. 
A device malfunction or failure is considered major when one of the following conditions 
occurs: 
a. Suspected or confirmed pump  thrombus (see below) 
b. Urgent transplantation (immediate 1A listing for transplant) 
c. Pump replacement 
d. Pump explant 
e. Breach of integrity of drive line that required repair 
f. 
Death 
 
2. Minor device malfunction includes inadequately functioning external components which 
require repair or replacement but do not result in 1a-f. Device malfunction does not apply to 
“routine” maintenance which includes repair/replacement of: external controller, pneumatic 
drive unit, electric power supplies, batteries and interconnecting cables. 
 
 
Pump Thrombus represents a special case of major device malfunction and can be 
delineated as suspected pump thrombus or confirmed pump thrombus. Pump 
thrombus  will be classified as “SUSPECTED” (see definition below) based upon 
clinical, biochemical, or hemodynamic findings or “CONFIRMED” (see definition below) 
based upon device inspection or incontrovertible radiologic studies or absence of 
appropriate Doppler flow signals that confirms thrombus within the device or its conduits 
that results in or could potentially induce circulatory failure. 
 
1. Suspected pump thrombus is a pump-related malfunction in which clinical or MCSD 
parameters suggest thrombus on the blood contacting components of the pump, cannulae, 
or grafts.  Signs and symptoms should include at least 2 of the 3 following criteria: 
a. Presence of hemolysis 
b. Presence of heart failure not explained by structural heart disease 
c. Abnormal pump parameters 

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Suspected pump thrombus should be accompanied by 1 or more of the following 
events or interventions: 
i. 
treatment with intravenous anticoagulation (e.g., heparin), intravenous 
thrombolytics (e.g., tPA), or intravenous antiplatelet therapy (e.g., eptifibatide, 
tirofiban) 
ii. 
pump replacement 
iii. 
pump explantation 
iv. 
urgent transplantation (UNOS status 1A) 
v. 
stroke 
vi. 
arterial non-CNS thromboembolism 
vii. 
death 
 
2. Confirmed pump thrombus is a major pump-related malfunction in which thrombus is 
confirmed within the blood contacting surfaces of device inflow cannula or outflow conduit or 
grafts. This can be reported via direct visual inspection or by incontrovertible contrast 
radiographic evidence or by the absence of  an appropriate Doppler flow signal that results 
in or could potentially induce circulatory failure or result in thromboembolism. 
 
If a Suspected Pump Thrombus event is ultimately confirmed through visual inspection 
following pump replacement, urgent transplantation or upon autopsy following death, the 
event will be adjudicated by the CEC for reclassification to Confirmed Pump Thrombus. 

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Major Bleeding: 
 
An episode of SUSPECTED INTERNAL OR EXTERNAL BLEEDING that results in one 
or more of the following: 
a. Death, 
b. Re-operation, 
c. Hospitalization, 
d. Transfusion of red blood cells as follows: 
 
If transfusion is selected, then apply the following rules: 
During first 7 days post implant 
• ≥ 50 kg: ≥ 4U packed red blood cells (PRBC) within any 24 
hour period during first 7 days post implant. 
• < 50 kg: ≥ 20 cc/kg packed red blood cells (PRBC) within 
any 24 hour period during first 7 days post implant. 
 
After 7 days post implant 
 
• A transfusion of packed red blood cells (PRBC) after 7 days following 
implant with the investigator recording the number of units given. (record 
number of units given per 24 hour period). 
 
Note: Hemorrhagic stroke is considered a neurological event and not as a separate 
bleeding event. 

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Major Infection: 
 
A clinical infection accompanied by pain, fever, drainage and/or leukocytosis that is treated by 
anti-microbial agents (non-prophylactic). A positive culture from the infected site or organ 
should be present unless strong clinical evidence indicates the need for treatment despite 
negative cultures.  The general categories of infection are listed below: 
 
Localized Non-Device Infection 
Infection localized to any organ system or region (e.g. mediastinitis) without evidence of 
systemic involvement (see sepsis definition), ascertained by standard clinical methods and 
either associated with evidence of bacterial, viral, fungal or protozoal infection, and/or requiring 
empirical treatment. 
 
 
Percutaneous Site and/or Pocket Infection 
A positive culture from the skin and/or tissue surrounding the drive line or from the tissue 
surrounding the external housing of a pump implanted within the body, coupled with the need to 
treat with antimicrobial therapy, when there is clinical evidence of infection such as pain, fever, 
drainage, or leukocytosis. 
 
 
Internal Pump Component, Inflow or Outflow Tract Infection 
Infection of blood-contacting surfaces of the LVAD documented by positive site culture. (There 
should be a separate data field for paracorporeal pump that describes infection at the 
percutaneous cannula site, e.g. Thoratec PVAD). 
 
 
Sepsis 
Evidence of systemic involvement by infection, manifested by positive blood cultures and/or 
hypotension. 
 
Neurological Dysfunction: 
 
Any new, temporary or permanent, focal or global neurologic dysfunction ascertained by a 
standard neurological history and examination administered by a neurologist or other qualified 
physician and documented with appropriate diagnostic tests and consultation note; or an 
abnormality identified by surveillance neuroimaging. The examining physician will classify the 
event as a cerebrovascular event as defined below or as a non-vascular acute neurologic 
event. A neurologic event may be recognized by a clinically evident sign or symptom, or by 
clinically-silent electrographic seizure activity, or as a clinically silent lesion detected by 
surveillance neuroimaging. Each neurologic event should be classified by the clinical provider 
following complete neurologic assessment as one of the following event types: 

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a. Transient ischemic attack, defined as an acute transient neurologic deficit 
conforming anatomically to arterial distribution cerebral ischemia, which resolves in < 
24 hours and is associated with no infarction on brain imaging (head CT performed 
>24 hours after symptom onset; or MRI*). 
 
b. Ischemic stroke, defined as a new acute neurologic deficit (or acute encephalopathy 
or seizures in children <6 months**) of any duration associated with acute infarction 
on imaging corresponding anatomically to the clinical deficit. Ischemic stroke should 
be sub classified as due to arterial-distribution ischemia or due to venous 
thrombosis. 
 
c. Acute symptomatic intracranial hemorrhage, defined as new acute neurologic deficit 
(or acute encephalopathy or seizures in children < 6 months**) attributable to 
Intracranial hemorrhage (ICH). ICH subtype should be specified as one or a 
combination of the following types: subarachnoid, intraventricular, parenchymal, 
subdural. 
 
d. Clinically covert ischemic stroke or ICH: infarction or ICH seen by surveillance 
imaging, without clinical findings of stroke or ICH at the time of event recognition. 
 
e. Hypoxic-Ischemic Encephalopathy: Acute new encephalopathy*** due to hypoxic- 
ischemic injury (HIE), manifest as clinically- evident signs or symptoms, or subclinical 
electrographic seizures found by complete neurological diagnostic evaluation to be 
attributable to acute global or focal hypoxic or ischemic brain injury not meeting one 
of ischemic stroke or ICH events as defined above. 
 
f. 
Acute new encephalopathy*** due to other causes, manifest as clinically-evident 
signs or symptoms or subclinical electrographic seizures found by complete 
neurological diagnostic evaluation to be attributable causes other than stroke, ICH or 
HIE, as defined above. This category of "other" acute encephalopathy includes 
neurologic signs or symptoms or subclinical seizures found to be attributable to other 
conditions such as meningitis, toxic-metabolic or drug-related processes. 
 
 
*** Acute encephalopathy is a sign or symptom of some underlying cerebral disorder, 
and is manifest as depressed consciousness with or without any associated new global 
or multifocal neurologic deficits in cranial nerve, motor, sensory, reflexes and cerebellar 
function. 
 
Cardiac Arrhythmias: 
 
Any documented arrhythmia that results in clinical compromise (e.g., abnormal VAD function 
[e.g., diminished VAD flow or suction events], oliguria, pre-syncope or syncope, angina, 

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dyspnea), or requires hospitalization or treatment (drug therapy, defibrillation, cardioversion, 
ICD therapy (e.g., shock or anti-tachycardia pacing) or arrhythmia ablation procedure). Cardiac 
arrhythmias are classified as 1 of 2 types: 
1) Sustained ventricular arrhythmia resulting in clinical compromise, or requiring 
hospitalization or drug treatment, defibrillation, cardioversion, ICD therapy, or 
arrhythmia ablation procedure. 
2) Sustained supraventricular arrhythmia resulting in clinical compromise, or 
requiring hospitalization or drug treatment, cardioversion, ICD therapy, or 
arrhythmia ablation procedure. 
 
 
Pericardial Fluid Collection: 
 
Accumulation of fluid or clot in the pericardial space that requires surgical intervention or 
percutaneous catheter drainage. This event will be subdivided into those with clinical signs of 
tamponade (e.g. increased central venous pressure and decreased cardiac/VAD output) and 
those without signs of tamponade. 
 
 
 
Myocardial Infarction: 
 
Two categories of myocardial infarction will be identified: 
 
 
Peri-Operative Myocardial Infarction 
 
The clinical suspicion of myocardial infarction together with CK-MB or Troponin > 10 
times the local hospital upper limits of normal, found within 7 days following VAD implant 
together with ECG findings consistent with acute myocardial infarction. (This definition 
uses the higher suggested limit for serum markers due to apical coring at the time of 
VAD placement, and does not use wall motion changes because the apical sewing ring 
inherently creates new wall motion abnormalities.) 
 
 
Non-Perioperative Myocardial Infarction 
The presence at > 7 days post-implant of two of the following three criteria: 
 
 
a) Chest pain which is characteristic of myocardial ischemia, 
b) ECG with a pattern or changes consistent with a myocardial infarction, and 
c) Troponin or CK (measured by standard clinical pathology/laboratory medicine 
methods) greater than the normal range for the local hospital with positive MB 

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fraction (≥ 3% total CK). This should be accompanied by a new regional LV or 
RV wall motion abnormality on a myocardial imaging study. 
 
Psychiatric Episode: 
 
Disturbance in thinking, emotion or behavior that causes substantial impairment in functioning or 
marked subjective distress and requires intervention. Intervention is the addition of new 
psychiatric medication, hospitalization, or referral to a mental health professional for treatment. 
Suicide is included in this definition. 
 
Respiratory Failure: 
 
Impairment of respiratory function requiring reintubation, tracheostomy or the inability to 
discontinue ventilatory support within six days (144 hours) post-VAD implant. This 
excludes intubation for re-operation or temporary intubation for diagnostic or therapeutic 
procedures. 
 
Venous Thromboembolism: 
 
Evidence of venous thromboembolic event (e.g. deep vein thrombosis, pulmonary 
embolism) by standard clinical and laboratory testing. 
 
Wound Dehiscence 
 
Disruption of the apposed surfaces of a surgical incision, excluding infectious etiology, 
and requiring surgical repair. 
 
Arterial Non-CNS Thromboembolism: 
An acute systemic arterial perfusion deficit in any non-cerebrovascular organ system 
due to thromboembolism confirmed by one or more of the following: 
 
1) standard clinical and laboratory testing 
2) operative findings 
3) autopsy findings 
 
This definition excludes neurological events. 
 
Other SAE: 
 
An event that causes clinically relevant changes in the patient’s health (e.g. cancer). 

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Hepatic Dysfunction: 
 
An increase in any two of the following hepatic laboratory values (total bilirubin, 
aspartate aminotransferase/AST and alanine aminotranferease/ALT) to a level greater 
than three times the upper limit of normal for the hospital, beyond 14 days post-implant 
(or if hepatic dysfunction is the primary cause of death). 
 
 
Hypertension: 
 
New onset blood pressure elevation greater than or equal to 140 mm Hg systolic or 90 
mm Hg diastolic (pulsatile pump) or 110 mm Hg mean pressure (rotary pump). 
 
PediMACS: Hypertension is defined as systolic, diastolic, or mean blood pressure 
greater than the 95th percentile for age which requires the addition of a new IV or 
oral therapy for management. The event shall be considered resolved upon the 
discontinuation of the treatment. 
 
 
Renal Dysfunction: 
 
Two categories of renal dysfunction will be identified: 
 
 
Acute Renal Dysfunction 
Abnormal kidney function requiring dialysis (including hemofiltration) in patients who did 
not require this procedure prior to implant, or a rise in serum creatinine of greater than 3 
times baseline or greater than 5 mg/dL (in children, creatinine greater than 3 times 
upper limit of normal for age) sustained for over 48 hours. 
 
 
Chronic Renal Dysfunction 
An increase in serum creatinine of 2 mg/dl or greater above baseline, or requirement for 
hemodialysis sustained for at least 90 days. 

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17. REFERENCES 
 
1. United States Department of Health and Human Services - Organ Procurement and 
Transplantation Network website. http://optn.transplant.hrsa.gov/latestData/rptData.asp. 
February 24, 2013. 
2. Rose EA, Gelijns AC, Moskowitz AJ, Heitjan DF, Stevenson LW, Dembitsky W, Long 
JW, Ascheim DD, Tierney AR, Levitan RG, Watson JT, Meier P, Ronan NS, Shapiro 
PA, Lazar RM, Miller LW, Gupta L, Frazier OH, Desvigne-Nickens P, Oz MC, Poirier 
VL; Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive 
Heart Failure (REMATCH) Study Group. Long-term use of a left ventricular assist 
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PMID: 11794191 
3. Rogers JG, Aaronson KD, Boyle AJ, Russell SD, Milano CA, Pagani FD, Edwards BS, 
Park S, John R, Conte JV, Farrar DJ, Slaughter, MS; HeartMate II Investigators. 
Continuous flow left ventricular assist device improves functional capacity and quality of 
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4. Lund LH, Edwards LB, Kucheryavaya AY, Dipchand AI, Benden C, Christie JD, 
Dobbels F, Kirk R, Rahmel AO, Yusen RD, Stehlik J; International Society for heart and 
Lung Transplantation. The Registry of the International Society for Heart and Lung 
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Heart lung Transplant. 2013 Oct;32(10):95164doi:10.1016/j.healun.2013.08.006. 
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5. Aaronson KD, Slaughter MS, Miller LW, McGee EC, Cotts WG, Acker MA, Jessup ML, 
Gregoric ID, Loyalka P, Frazier OH, Jeevanandam V, Anderson AS, Kormos RL, 
Teuteberg JJ, Levy WC, Naftel DC, Bittman RM, Pagani FD, Hathaway DR, Boyce SW; 
for the HeartWare Ventricular Assist Device (HVAD) Bridge to Transplant ADVANCE 
Trial Investigators. Use of an Intrapericardial, Continuous-Flow, Centrifugal Pump in 
Patients Awaiting Heart Transplantation. Circulation. 2012 Jun 26;125(25):3191-3200. 
Epub 2012 May 22. PubMed PMID: 22619284. 
6. Mehrotra, DV and Railkar, R: 2000; Statistics in Medicine, 19, 811-825 
7. Haybittle, J. L. (1971), “Repeated Assessment of Results in Clinical Trials of Cancer 
Treatment,” British Journal of Radiology, 44, 793–797. 
8. Peto, R., Pike, M. C., Armitage, P., Breslow, N. E., Cox, D. R., Howard, S. V., Mantel, 
N., McPherson, K., Peto, J., and Smith, P. G. (1976), “Design and Analysis of 
Randomized Clinical Trials Requiring Prolonged Observation of Each Patient: I. 
Introduction and Design,” British Journal of Cancer, 34, 585–612. 
 
 
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