CSP #592 - Efficacy and Safety of ICD Implantation in the Elderly
Phase: NA
Conditions: Cardiomyopathy, Coronary Artery Disease, Congestive Heart Failure, Myocardial Infarction
Sponsor: VA Office of Research and Development

Official Title: Efficacy and Safety of Implantable Cardioverter-Defibrillator (ICD) Implantation in 
the Elderly (I-70) 
ClinicalTrials.gov Identifier: NCT02121158 
Document Type: Protocol 
Document Date: 6/17/2016 

 
 
 
 
 
 
 
    VA Cooperative Studies Program #592 
 
    Efficacy and Safety of ICD  
    Implantation in the Elderly 
 
 
 
 
 
 
Study Protocol 
Version 2.3.2 
 June 15, 2016 
Principal Investigator: Steven Singh, M.D. 
Biostatisticians: Michael Wininger, Ph.D.,  
Jane Zhang, Ph.D. 
 
 
 
 
 
 
PRIVILEGED AND CONFIDENTIAL 
Not For Distribution Beyond the 
Official Committee Function and Use 

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LETTERS OF SUBMITTAL ................................................................................................................i 
Principal Proponent ........................................................................................................................................................... i 
Principal Proponent (Revision).....................................................................................................................................iii 
Director: Cooperative Studies Program Coordinating Center .............................................................................. v 
Director: Cooperative Studies Program Clinical Research Pharmacy Coordinating Center .................... vii 
EXECUTIVE SUMMARY/ABSTRACT ............................................................................................ix 
PLANNING COMMITTEE .............................................................................................................xiii 
I. 
INTRODUCTION AND BACKGROUND...............................................................................1 
A. 
Background on Sudden Cardiac Death (SCD) .......................................................................................... 1 
B. 
ICD as Interventional Therapy...................................................................................................................... 3 
C. 
Study Rationale: ICD Implantation Among the Elderly ...................................................................... 11 
D. 
ICD Efficacy and General Health Status .................................................................................................. 17 
E. 
Summary of Study Goals ............................................................................................................................... 17 
II. 
STUDY OBJECTIVES AND HYPOTHESES .......................................................................19 
A. 
Primary Objective ........................................................................................................................................... 19 
B. 
Primary Hypothesis......................................................................................................................................... 19 
C. 
Secondary Objectives...................................................................................................................................... 19 
D. 
Exploratory Analyses...................................................................................................................................... 20 
III. 
SUMMARY OF STUDY DESIGN.........................................................................................21 
A. 
Overview ............................................................................................................................................................ 21 
B. 
Study Population and Rationale .................................................................................................................. 23 
C. 
Treatments and Rationale ............................................................................................................................. 23 
D. 
Outcome Measures and Rationale .............................................................................................................. 25 
E. 
Sample Size........................................................................................................................................................ 26 
F. 
Data Collection and Assessments ................................................................................................................ 26 
G. 
Alternate Design Considerations ................................................................................................................. 26 
IV. 
IMPORTANCE TO THE VETERANS ADMINISTRATION ...............................................31 
V. 
STUDY POPULATION .........................................................................................................33 
A. 
Inclusion Criteria............................................................................................................................................. 33 
B. 
Exclusion Criteria............................................................................................................................................ 34 
C. 
Inclusion of Women and Minorities ........................................................................................................... 35 
D. 
Justification of Age Cutoff at 70 years....................................................................................................... 35 
E. 
Projected Health Status of the Study Population.................................................................................... 36 
F. 
Implantation Rates by Disease Category .................................................................................................. 37 
G. 
Age versus Health Status as a Determinant in Implantation............................................................... 39 
H. 
Justification of Stratification at Charlson Index 3  ................................................................................. 40 
VI. 
OUTCOME MEASURES ......................................................................................................41 
A. 
Primary Outcome ............................................................................................................................................ 41 
B. 
Secondary Outcomes and Exploratory Analyses .................................................................................... 41 
C. 
Device Data........................................................................................................................................................ 44 
VII. 
HUMAN RIGHTS ISSUES AND INFORMED CONSENT PROCEDURES.........................47 
A. 
Risks and Benefits............................................................................................................................................ 47 
B. 
Informed Consent Process............................................................................................................................. 48 
C. 
Capacity to Consent ........................................................................................................................................ 49 

D. 
Surrogate Consent ........................................................................................................................................... 50 
E. 
Withdrawal........................................................................................................................................................ 51 
VIII. 
BASELINE ASSESSMENTS AND PROCEDURES ..............................................................53 
A. 
Recruitment and Screening........................................................................................................................... 53 
B. 
Baseline Data Collection ................................................................................................................................ 56 
IX. 
STRATIFICATION AND RANDOMIZATION ....................................................................59 
A. 
Randomization Procedure............................................................................................................................. 59 
B. 
Blinding .............................................................................................................................................................. 60 
X. 
TREATMENT REGIMENS ..................................................................................................61 
A. 
Overview ............................................................................................................................................................ 61 
B. 
ICD....................................................................................................................................................................... 61 
C. 
Optimal Medical Therapy ............................................................................................................................. 67 
XI. 
FOLLOW-UP ........................................................................................................................71 
A. 
Time Table......................................................................................................................................................... 71 
B. 
Follow-up Procedures..................................................................................................................................... 73 
C. 
Study Withdrawal and Crossover............................................................................................................... 75 
D. 
Study Termination and Closeout................................................................................................................. 75 
XII. 
STUDY MONITORING AND QUALITY CONTROL PROCEDURES ...............................77 
A. 
Overview ............................................................................................................................................................ 77 
B. 
Monitoring Bodies and CSP Monitoring................................................................................................... 77 
C. 
GCP Monitoring Visits................................................................................................................................... 81 
D. 
Monitoring Participant Intake and Probation or Termination of Participating Sites ................. 83 
E. 
Monitoring Medical Center Performance................................................................................................. 84 
F. 
Monitoring Participant Safety ..................................................................................................................... 84 
G. 
Adverse Event Definition and Monitoring ................................................................................................ 86 
H. 
Serious Adverse Event Definition and Reporting ................................................................................... 87 
I. 
Minimizing Attrition....................................................................................................................................... 87 
J. 
Remote Monitoring ......................................................................................................................................... 88 
XIII. 
QUALITY CONTROL AND DATA MANAGEMENT PROCEDURES ...............................89 
A. 
Data Collection Methods  ............................................................................................................................... 89 
B. 
Data Quality Control ...................................................................................................................................... 91 
C. 
Electronic Study File....................................................................................................................................... 93 
D. 
Quality Control of the Process ..................................................................................................................... 93 
E. 
Data Security..................................................................................................................................................... 94 
F. 
Data Management and Access Plan (DMAP) .......................................................................................... 97 
XIV. 
ADVERSE EVENT ASSESSMENT AND REPORTING ......................................................99 
A. 
Role of the Local Site Investigator in Event Monitoring ...................................................................... 99 
B. 
Definitions .......................................................................................................................................................... 99 
C. 
AE/UADE and SAE Monitoring and Reporting  ...................................................................................103 
XV. 
BIOSTATISTICAL CONSIDERATIONS ...........................................................................105 
A. 
Sample Size......................................................................................................................................................105 
B. 
Interim Monitoring and Analysis..............................................................................................................110 
C. 
Final Statistical Analysis of the Data........................................................................................................114 
XVI. 
FEASIBILITY .....................................................................................................................119 
A. 
Estimating the Patient Population ............................................................................................................119 

XVII. GOOD CLINICAL PRACTICES ........................................................................................127 
A. 
Role of Good Clinical Practices .................................................................................................................127 
B. 
Summary of Monitoring and Auditing Plans.........................................................................................127 
XVIII. PUBLICATIONS.................................................................................................................129 
A. 
Publication Policy ..........................................................................................................................................129 
B. 
Planned Publications.....................................................................................................................................130 
REFERENCES ................................................................................................................................131 
 

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LETTERS OF SUBMITTAL  
Principal Proponent 
 
DEPARTMENT OF VETERANS AFFAIRS 
VA Connecticut Healthcare System 
950 Campbell Avenue 
West Haven, CT 06516 
 
 
October 15, 2013 
Timothy J. O'Leary, MD, PhD 
Acting Chief Research and Development Officer 
VA Central Office 
810 Vermont Avenue, NW 
Washington, DC 20420 
 
Dear Dr. O'Leary: 
 
We hereby submit CSP-592 for review by the Cooperative Studies Scientific Evaluation Committee. The 
study is intended to determine the survival benefit of the internal cardioverter defibrillator (ICD), as 
compared to the Optimum Standard of Care (OSC) in patients greater than or equal to 70 years old with 
systolic heart failure and reduced ejection fraction. 
Sudden Cardiac Death (SCD) is a major public health issue affecting over 500,000 Americans each year. 
While the ICD has been shown to improve survival in patients with heart failure, its use in the ‘elderly’ 
has been questioned, since such patients were either excluded from or under-represented in trials. Thus 
the use of the ICD in this population is being individualized, and therapy is empiric. 
We hypothesize that the ICD will reduce all cause mortality compared to Standard of Care. The study will 
last 5 years with 3 years of intake and a minimum of 2 years of follow-up. Seeking a 25% reduction in the 
hazard ratio (23.5% relative risk reduction) and a 2-sided alpha of p<0.05, a sample of 1,488 patients is 
needed. We have identified 40 potential sites, and expect to operate with a full complement of 30 sites.  
The study is very important not only to our Veterans but to the public as well. The results of this study 
whether positive or negative will undoubtedly change the practice of medicine. After numerous meetings 
and lengthy discussions, we believe that our protocol is ready for review.  
 
Thanks for your consideration,  
 
Sincerely 
 
 
 
Steven Singh, M.D. 
Study Proponent 
 

 
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Principal Proponent (Revision) 
 
DEPARTMENT OF VETERANS AFFAIRS 
VA Connecticut Healthcare System 
950 Campbell Avenue 
West Haven, CT 06516 
 
 
February 20, 2015 
Timothy J. O'Leary, MD, PhD 
Acting Chief Research and Development Officer 
VA Central Office 
810 Vermont Avenue, NW 
Washington, DC 20420 
 
Dear Dr. O'Leary: 
 
We hereby submit this revised protocol for CSP-592 following review by the Central Institutional Review 
Board (CIRB), and the convening of our Pre-Kick Off meeting; both occurring last month. Following 
extensive collaboration on the part of the Executive Committee and the staff at the Coordinating Center, 
we have refined our study and Protocol. The objective of the full study phase is to determine the survival 
benefit of the internal cardioverter defibrillator (ICD), as an additive therapy on top of Optimal Medical 
Therapy (OMT) in patients greater than or equal to 70 years old with systolic heart failure and reduced 
ejection fraction. We hypothesize that the OMT + ICD will reduce all-cause mortality compared to OMT 
without device. The objective of the Pilot study is to determine the feasibility of recruitment for the full 
study phase. We summarize the changes in greater detail in an accompanying Impact Statement, and 
submit to you at this time two copies of this Protocol: 1) a tracked-changes version, and 2) a “clean” copy 
of the latest version. 
The Pilot phase will operate at 6 sites for 1 year; with a target of recruitment of 102 participants. If the 
study proves feasible during the Pilot, and is approved by CSP to continue, Phase 2 would expand to a 
five-year study with a full complement of 27 sites, with 3 years of intake and a minimum of 2 years of 
follow-up. Seeking a 25% reduction in the hazard ratio (23.5% relative risk reduction) and a 2-sided alpha 
of p<0.05, a sample of 1,462 patients is needed.  
The study is very important not only to our Veterans but to the public as well. The results of this study 
whether positive or negative will undoubtedly change the practice of medicine.  
 
Thank you for your support of this study, 
 
 
Sincerely 
 
 
 
Steven Singh, M.D. 
Study Proponent 
 

 
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Director: Cooperative Studies Program Coordinating Center 
 
 
DEPARTMENT OF VETERANS AFFAIRS 
VA Connecticut Healthcare System 
950 Campbell Avenue 
West Haven, CT 06516 
COOPERATIVE STUDIES PROGRAM COORDINATING CENTER 
 
April 30, 2010 
In Reply Refer To: 689/151A 
 
 
February 20, 2015 
Timothy J. O'Leary, MD, PhD 
Acting Chief Research and Development Officer 
VA Central Office 
810 Vermont Avenue, NW 
Washington, DC 20420 
 
Dear Dr. O’Leary: 
 
Attached is a revision of CSP #592, “Efficacy and Safety of ICD Implantation in the Elderly” 
from the Principal Proponent, Steven Singh, MD and the Study Biostatisticians, Michael 
Wininger, PhD, and Jane Zhang, PhD.  
 
The ICD (implantable cardioverter defibrillator) has a single, but powerful action: prevention of 
sudden cardiac death by restoring normal rhythm in the event of a life-threatening ventricular 
tachyarrhythmia. While ICD therapy is proven to be effective at preventing death in younger 
patients, its impact on all-cause mortality in those with advanced age is unclear.  
 
Study Design  
CSP #592 is a multi-center, randomized trial of two treatment strategies for prevention of sudden 
cardiac death, the second largest cause of death in the United States.  
 
The study will operate in two stages: a Pilot study to determine feasibility of recruitment, and a 
full-scope study to assess the main study hypotheses. The Pilot study will operate for 1 year at 6 
sites. The study in its full-scale implementation will recruit for an additional 3 years at 27 sites, 
and is designed to answers the question: does an ICD provide a mortality benefit in older heart 
failure patients? The primary objective is to compare the effect on all-cause mortality of two 
different treatment strategies: 1) optimal medical therapy including management with 
appropriate heart failure medications, and education in lifestyle modification and disease 
management, vs. 2) optimal medical therapy plus implantation of an ICD device. Secondary 
objectives are to compare the effect of the two treatment strategies on quality of life and whether 
there is a differential benefit under the conditions of high versus low co-morbid burden.  

 
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The target study population is Veterans over the age of 70 years and meeting Central Medicare 
and Medicaid Services guidelines for primary prevention of sudden cardiac death, including low 
ejection fraction, and New York Heart Association Class I, II, or III. The eligibility criteria are 
relatively simple to maximize the study’s generalizability and to recruit a broad representative 
sample of older Veterans with heart failure. Seventy years of age was selected as the minimum 
age for eligibility for the trial because it is evident from VA databases that utilization of ICD 
therapy declines rapidly after age 70 and there have been few individuals over the age of 70 
years that have been included in previous ICD clinical trials. 
 
Sample Size  
The target sample size is 1,462 total participants (731 per treatment group) enrolled from 27 VA 
medical centers. This sample size will provide 90% power to detect a 25% reduction in the 
hazard from all-cause mortality, and will provide ample power to identify clinically meaningful 
differences in treatment effect across co-morbidity levels.  
 
Analytic Plans  
The statistical analysis plans are straightforward and appropriate. The primary outcome of all-
cause mortality will be analyzed as time to event and tested by the stratified log rank statistic 
(stratified by site and Charlson score <3 versus ≥3) with a type I error of 0.05 (2-sided). Patients 
who are lost or withdraw prior to an outcome assessment, or who do not experience an event will 
be right-censored at date of last contact, date withdrawn, or date of study exit. VA Vital Status 
File will be used to determine the vital status of all study participants who are lost to follow-up at 
study exit.  
 
Budget  
The total estimated study budget is $12.5 million. The budget is based on 3 years of participant 
intake and minimum follow-up of 2 years, with follow-up completed centrally after completion 
of post-implantation clinic visit, and accounts for both the Pilot and Full-scope stages of the 
study.  
 
 
Peter Guarino, MPH, PhD  
Director, WH-CSPCC  

 
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Director: Cooperative Studies Program Clinical Research Pharmacy Coordinating 
Center 
 
DEPARTMENT OF VETERANS AFFAIRS 
VA Cooperative Studies Program 
Clinical Research Pharmacy Coordinating Center (151-I) 
2401 Centre Avenue SE 
Albuquerque NM 87106-4180 
 
 
February 20, 2015 
501/151-1 
In Reply Refer To: CSP #95/CSP #592 
File: STD_DOC 
 
Timothy J. O'Leary, MD, PhD 
Acting Chief Research and Development Officer 
VA Central Office 
810 Vermont Avenue, NW 
Washington, DC 20420 
 
 
Dear Dr. O'Leary: 
SUBJ: CSPCRPCC Issues Letter for CSP #592 / “Efficacy and Safety of ICD Implantation in the 
Elderly" 
 
There are no PCC issues related to this study.  The PCC will provide safety monitoring and MedDRA 
coding for the duration of the study.  The study does not require either an Investigational New Drug 
(IND) or Investigational Device Exemption (IDE) application.   
 
A CSP policy decision was made to require (i) Good Clinical Practices (GCP) training for study 
personnel (nurse coordinators and site investigators) at study initiation meetings, and (ii) in addition to 
central monitoring, periodic site monitoring/auditing of all CSP studies regardless of whether the study is 
to be conducted under an IND or IDE.  A site initiation visit, annual site monitoring, and closeout visits 
were used in formulating the outline of the GCP training and monitoring/auditing plan included in the 
submission.  The personnel and travel costs for providing GCP training and for the monitoring/auditing of 
sites are in the Site Monitoring, Auditing and Resource Team (SMART), portion of the PCC budget. 
 
Should you have any questions or need additional information, contact me at (505) 248-3203. 
 
Sincerely yours, 
 
ALEXANDRA A. SCRYMGEOUR, Pharm. D. 
Clinical Research Pharmacist 
Regulatory and Clinical Compliance 

 
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EXECUTIVE SUMMARY/ABSTRACT 
Background: Sudden cardiac death (SCD) is the second greatest cause of death in the United 
States, after all cancers combined. The implantable cardioverter defibrillator (ICD) has shown 
great efficacy in reducing all-cause mortality, and specifically SCD, by continuously monitoring 
the electrophysiological signatures of the heart, and intervening with a therapeutic shock in case 
of a detected arrhythmia. However, whereas the landmark clinical trials demonstrating ICD 
efficacy have included primarily middle-aged patients, there is little known of the impact of the 
ICD on older patients; clinicians often treat the elderly based on empiric judgments, rather than 
robust clinical evidence.  There is an emergent need to study both efficacy and safety of the ICD 
in patients with advanced age.  
Objectives: The overall aim of CSP #592 is to study the safety and efficacy of ICD implantation 
as a primary prevention strategy of SCD in patients 70 years and older. In particular, this study is 
designed to determine the comparative effectiveness of ICD, in addition to optimal medical 
therapy (OMT), in reducing all-cause mortality, versus OMT alone; OMT includes standard 
intervention 
for chronic heart failure patients, i.e. maintenance of proper heart-failure 
medications, lifestyle modification, disease management, adoption of healthy diet and exercise 
practices, etcetera. One particularly important secondary objective is to assess treatment efficacy 
under the conditions of high versus low co-morbidity burden. 
Research Plan: This study will be conducted in two stages. The first phase will be a one-year 
Pilot study with 6 participating sites. If the study proves feasible during the Pilot phase, Phase 2 
would expand to a five-year study in its full scope with the number of sites expanded to 27. The 
objective of the full study phase is to assess the safety and efficacy of implantable cardioverter 

 
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defibrillator (ICD) therapy in the elderly; the objective of the Pilot study is to determine 
feasibility of recruitment for the full study phase. The Pilot and main study are designed to 
recruit an average of 17 patients per site per year, of both genders and all ethnic/racial and 
socioeconomic backgrounds.  All participants will meet CMS criteria for ICD implantation, and 
be stable on optimal medical therapy.  Otherwise, the inclusion criteria are broad and the 
exclusion criteria are few; participants with most co-morbid general medical conditions are 
generally included to provide a broadly representative sample.   
Participants will be randomized (1:1 ratio) to ICD + OMT (n=731), or OMT alone (n=731) 
stratified by participating site and co-morbidity level (Charlson score <3 versus ≥3). The sole 
acute treatment visit will occur on day of implantation (ICD arm); central follow-up will occur at 
1-4 months post-randomization, and at every 6 months thereafter, until study close. Neither the 
participant nor the treating clinician will be masked to treatment. 
We postulate that ICD + OMT will result in a 25% reduction in the hazard for all-cause mortality 
(42.0% versus 34.1% cumulative mortality after accounting for administrative losses). Using a 
log-rank test with a 2-sided test of significance, α = 0.05, a sample size of 1,462 participants will 
be required to test the primary hypothesis with 90% power, adjusted for crossovers and losses. 
The plan study duration is six years in total: 1 year of Pilot phase + 5 years of full-scale phase; 
participants will be recruited through year 3 of the full-study phase, and followed for up to 5 
years.  
 
Public Health Significance:  The impact of ICD implantation on the elderly has never before 
been studied as a primary objective in a clinical trial. This study will therefore have a major 

 
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impact on public health, whatever its outcome. There are many competing factors involved with 
primary prevention of SCD in the elderly via ICD, including 1) the impact on mortality, 
especially in the context of a declining rate of sudden death with advanced age, and 2) the impact 
on quality of life. Whereas the ICD implantation is an expensive and invasive procedure, patients 
and practitioners alike will look to CSP #592 as the first instance of highest-level clinical 
evidence as to the effect of ICD implantation on older patients. 
 

 
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PLANNING COMMITTEE 
  
Steven Singh, M.D. – Principal Proponent 
Assoc Chief of Staff for Education and Academic 
Affairs 
Washington DC VAMC (688/151-D) 
50 Irving Street, NW 
Washington, DC 20422 
Steven.Singh@va.gov 
 
Pamela A. Karasik, M.D. 
Acting Chief, Cardiology (4A-105) 
Washington DC VAMC (688/151-D) 
50 Irving Street, NW 
Washington, DC 20422 
Pamela.Karasik@va.gov 
 
Merritt H. Raitt, M.D. 
Director of EP Cardiology 
Portland VAMC (648) 
3710 SW US Veterans Road 
Portland, OR 97239-2999 
Merritt.Raitt@va.gov 
Peter Guarino, M.P.H., Ph.D. 
Director, CSPCC (151A) 
VA Connecticut Healthcare System 
950 Campbell Ave 
 
West Haven, CT 06516 
Peter.Guarino@va.gov 
 
Jeffrey Rottman, M.D. 
Chief of Cardiology 
Tennessee Valley Healthcare System (626/111H) 
1310 24th Avenue, South 
Nashville, TN 37212 
Jeff.Rottman@vanderbilt.edu 
Michael Wininger, Ph.D. 
Biostatistician, CSPCC (151A) 
VA Conneticut Healthcare System 
950 Campbell Ave 
West Haven, CT 06516 
Michael.Wininger@va.gov 
 
Melissa J. West, M.D. 
Co-Director of Community Living Center 
Minneapolis VA Medical Center 
One Veterans Drive 
Minneapolis, MN 55417 
Melissa.West@va.gov 
Jane Zhang, Ph.D. 
Senior Biostatistician, CSPCC (151A) 
VA Conneticut Healthcare System 
950 Campbell Ave 
West Haven, CT 06516 
Jane.Zhang@va.gov 
 
Cynthia L. Colling, R.Ph., M.S. 
Clinical Research Pharmacist, CSPCRPCC (151-I) 
New Mexico VA Healthcare System 
2401 Centre Avenue, SE 
Albuquerque, NM 87106 
Cynthia.Colling@va.gov 
 
 
 

 
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I. 
INTRODUCTION AND BACKGROUND 
A. 
Background on Sudden Cardiac Death (SCD) 
1. 
Overview of SCD 
Sudden cardiac death (SCD) describes the unexpected natural death from a cardiac cause within 
a short window of time after the onset of symptoms, typically within one hour 1,2. While the 
pathophysiology of cardiac arrest may be either mechanical or arrhythmic 3, the rapid death of 
SCD is usually attributed to a cardiac arrhythmia, although accurate classification of cause of 
death can be confounded since many sudden deaths are un-witnessed 2,4. 
Risk factors for SCD include coronary artery disease, cardiomyopathy, cardiac rhythm 
disturbances including long QT syndrome and other ion channel diseases, hypertensive heart 
disease, as well as family history of cardiac disease 3,5,6. Up to 80% of individuals who suffer 
from SCD have coronary heart disease2  and anatomic findings at autopsy include acute changes 
in coronary plaque morphology, e.g., thrombus or plaque disruption, and active coronary lesions.  
Plaque rupture and apoptosis may participate in the genesis of some cardiac arrhythmias or 
conduction disturbances responsible for SCD 2,7. Heart failure is also commonly associated with 
SCD and afflicts approximately 5 million people in the United States, with over 550,000 new 
cases diagnosed each year 8.  
2. 
Incidence of SCD in the United States 
SCD accounts for 300,000 – 450,000 deaths per year, with estimated incidence rates  ranging 
from 150-250 events per hundred thousand individuals a year in the United States, depending on 
the definition used 9–12 (Table 1). Since coronary artery disease is a risk factor for SCD, the 

 
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incidence of SCD is highest amongst subgroups at risk for coronary artery disease, e.g., men and 
adults between 45 and 75 years of age 2.  
Table 1. Incidence of sudden cardiac death (SCD) in the United States. 
Demographic Group 
Incidence (per year) 
Study 
Men, 35-74 years 
191 per 100,000 men 
Gillum, 1989 139 
Women, 35-74 years 
57 per 100,000 women 
Adults (undefined) 
100-200 per 100,000 adults 
Zipes, 1998 2 
 
3. 
SCD Prevention: Primary versus Secondary 
The strategies for reducing mortality among patients at high risk for SCD are categorized as 
primary or secondary. Candidates for primary prevention have not yet had the clinical expression 
of a potentially fatal arrhythmia, but are identified by pre-existing disease indicating high risk for 
one 14. Secondary prevention refers to interventions in patients who have survived a cardiac 
arrest due to ventricular tachyarrhythmia 
14,15. Thus, the distinction between primary and 
secondary prevention is whether a potentially fatal arrhythmia has already been experienced. The 
guidelines and data for primary versus secondary prevention are different. 
4. 
SCD Prevention Options 
There is a wide variety of anti-arrhythmic drugs that shape the cardiac action potential by 
interacting with either the beta-adrenoreceptor (“beta blockers”) or a specific type of ion channel. 
However, except for studies of beta blockers, no placebo-controlled anti-arrhythmic drug trials 
have reported a benefit in reduction of all-cause mortality 16,17. Beta blockers are widely accepted 

 
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as a highly effective therapy that can significantly reduce morbidity and mortality in patients 
with heart failure associated with left ventricular systolic dysfunction 18,19. 
 
The mechanism by which beta blockers are thought to decrease the risk of SCD may be related 
to its elevation of ventricular fibrillation threshold. This effect is in addition to beta blockers’ 
suppression of premature ventricular contractions (PVCs) or ventricular tachycardia (VT) events, 
which in themselves carry a potential risk. By contrast, the mechanism of the single-lead shock-
only implantable cardioverter defibrillator (ICD) is to continually monitor the electrophysiology 
of the heart for sustained ventricular tachycardia or ventricular fibrillation, delivering an 
electrical shock if either are detected to reset the pace-making activity of the heart and return it to 
sinus rhythm. There are several different types of ICDs, produced by a handful of manufacturers. 
Each ICD is programmable to deliver therapy within a specific range of heart rate, heart rhythm, 
and ventricular beat morphology. There is now broad clinical evidence of the efficacy of ICDs 
beyond that of beta blockers in reducing SCD mortality in heart failure patients. 
B. 
ICD as Interventional Therapy 
1. 
Rationale for Use of ICD 
There exists broad evidence of ICD efficacy for reducing mortality for adult patients with left 
ventricular systolic dysfunction, especially those with a history of myocardial infarction 20,21. 
Also, because half of all deaths from heart failure are sudden events thought to be attributable 
primarily to lethal arrhythmias, ICD can be a highly effective treatment strategy in adults with 
heart failure 22,23. Furthermore, there are few external impediments to ICD implantation: Central 
Medicare and Medicaid Services (CMS) expanded its ICD coverage, thus reducing the financial 

 
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burden associated with ICD implantation 24. In addition, both device efficacy (99%) and rate of 
success of ICD implantation (99%) are excellent 21,25.  
2. 
Early Case Studies  
The ICD was first described for its ability to achieve ventricular defibrillation in active conscious 
dogs 26, and subsequently piloted in a 57-year-old woman, a 16-year-old boy, and a 43-year-old-
man, yielding satisfactory discharges in all three cases 27. However, while the ICD has 
demonstrated termination of tachy-arrhythmias 28, successful shock therapy does not necessarily 
translate into improved survival 10. Primary prevention of sudden cardiac death and reduction of 
overall mortality in patients with left ventricular dysfunction was subsequently proven via 
randomized controlled clinical trials 29,30. 
3. 
ICDs in Clinical Trials 
Several landmark studies have demonstrated clinical efficacy in reducing all-cause mortality 
with ICD therapy. The primary findings of a selection of randomized clinical trials (RCTs), of 
primary- prevention type are shown in Table 2. 
 
Table 2. Efficacy of ICD in reducing all-cause mortality in randomized clinical trials (RCT). †=  
hazard ratio (95% Confidence Interval); ‡=log-rank of cumulative survival versus anti-
arrhythmic medication, placebo, or conventional therapy. CB=Coronary bypass, DC=Dilated 
cardiomyopathy, MI=Myocardial infarction. 
Outcome 
Study 
Summary (Sample size, median follow-up, patient pool) 
0.46 (0.26 – 0.82)† 
MADIT-I 31 
N=196, 27 months;  NYHA class I-III, with prior MI 
1.07 (0.81 – 1.42)† 
CABG-Patch 32 
N=1055, 32 months; CB patients <80 years old 
10% (P=0.554) ‡ 
CAT  33 
N=104, 22.8 months; idiopathic DC 
0.69 (0.51 – 0.93)† 
MADIT-II 34 
N=1232, 20 months; NYHA class I-III, with prior MI 

 
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1% (P=0.800) ‡ 
AMIOVIRT 35 
N=103, 36 months; non-ischemic DC 
0.65 (0.40 – 1.06)† 
DEFINITE 30 
N=458, 29 months; non-ischemic DC 
0. 77 (0.62 – 0.96)† SCD-HeFT 29 
N=2521, 45.5 months; NYHA class II or III 
 
From this evidence, the reproducibility of the apparent therapeutic benefit of ICD implantation at 
23-35% supports the current guidelines that recommend that physicians should carefully 
consider the potential benefit of ICD therapy in eligible patients 23.  
4. 
Guidelines and Support for ICD Implantation 
On the basis of favorable outcomes reported among ICD recipients in RCTs, the American 
College of Cardiology and American Heart Association in 1995 established guidelines for heart 
failure to include ICD therapy for primary prevention of sudden cardiac death in patients with 
ischemic (class I, evidence A) and non-ischemic (class I, evidence B) heart disease and left 
ventricular ejection fraction (LVEF) of 30% or less who are receiving long-term optimal medical 
therapy and have a reasonable expectation of survival with good functional status for greater than 
1 year 8. Later that same year, after SCD-HeFT was published, the Centers for Medicare & 
Medicaid Services (CMS) approved reimbursement for ICD implantation in patients with 
ischemic or non-ischemic heart disease, LVEF of 35% or less, and New York Heart Association 
(NYHA) class II or III heart failure 24. Subsequently the 2008 American College of Cardiology 
and American Heart Association guidelines extended the class one indication for ICD implant to 
the same population with an EF of 35% or less covered by the CMS criteria. ICD therapy is thus 
generally accepted as a safe and efficacious therapy.  

 
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5. 
Under-Utilization of ICD  
Despite widely recognized record of safety and efficacy, ICD therapy is considered to be an 
under-utilized treatment option. Observational studies that have examined ICD implantation 
rates among potentially eligible patients with heart failure and low LVEF discharged from 
hospitals  show several trends (Table 3). First, ICD utilization appears to be low in general: 
typically less than 40% of eligible patients have, or plan to receive, an ICD implant. Second, 
there are prominent sex and ethnic differences, with higher rates of ICD implantation among 
men than women, and whites versus blacks.  Furthermore, there appears to be an age effect in the 
use of ICDs 36. These findings on the under-utilization of ICD persist even after accounting for 
presence of severe co-morbid conditions that might make an otherwise eligible patient an 
unsuitable candidate for implantation. 
Table 3. Utilization of Implantable Cardioverter Defibrillator (ICD) in the United States. 
Demographic Group 
Utilization 
Source 
Eligible patients 
36.5 to 56.5% 
Ruskin, 2002 37 
Eligible patients 
35.4% 
Hernandez, 2007 23 
Eligible patients 
38.4% 
Saba, 2009 38 
Eligible patients 
43.3% 
Lakshmanadoss, 2011 39 
Black women 
28.2% 
Hernandez, 2007 23 
White women 
29.8% 
Black men 
33.4% 
White men 
43.6% 
Women 
35% 
Lakshmanadoss, 2011 39 
Men 
48% 
 

 
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It is noted that these estimates of ICD utilization must be interpreted with some caution as the 
rate of ICD utilization is difficult to estimate among potentially eligible patients. LVEF 
measurement is an important quality metric among patients with heart failure because it helps to 
inform many treatment decisions, including ICD therapy. However, up to 20% of patients with 
heart failure do not have LVEF recorded in their medical records and non-conformity rates 
increase substantially when patients with no documentation of LVEF are including. Furthermore, 
patients with no plans to receive ICD at the time of the survey, but later elect to receive an ICD 
would inflate estimated non-conformity rates 23. For these reasons, ICD utilization rates can be 
difficult to estimate with precision. 
6. 
Reasons for Non-Utilization of ICD 
a) 
Contraindications 
There are several specific contraindications to ICD therapy: NYHA class IV heart failure, 
cardiogenic shock or symptomatic hypotension while in a stable rhythm, coronary artery bypass 
graft (CABG) or percutaneous transluminal coronary angioplasty (PTCA) in the past 3 months, 
acute myocardial infarction in the past 30 days, candidacy for coronary revascularization, 
irreversible brain damage from cardiovascular disease, or disease with life expectancy less than 1 
year 8. While the ICD is a powerful corrector of tachyarrhythmia, not all SCDs are due to 
ventricular arrhythmia 21.  Concurrent myocardial infarction represents a potentially reversible 
cause for aborted sudden death, and constitutes a major contra-indication for cardioverter 
defibrillator implantation 40. 

 
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b) 
Watchful Waiting 
Analyses of baseline mortality risk scores amongst participants receiving an ICD have found that 
individuals with a low risk of death or a high risk of non-sudden death experience minimal 
benefit from ICD therapy 41–43. There is modest evidence that the proportion of patients matching 
the criteria for ICD implantation drops significantly after 6 months on optimal medical treatment, 
with a low rate of total mortality and especially SCD 44. This may predispose some clinicians to a 
more conservative response to patient presentation with candidacy for ICD implantation and 
instead opt for watchful waiting while continuing optimal medical treatment. 
c) 
Perceived Impact on Life and Lifestyle 
An important consideration in the decision-making process prior to ICD election is whether the 
device will extend life without maintaining or improving Quality of Life (QoL). There is mixed 
evidence about the QoL following ICD implantation. For instance, anxiety, depression and fear 
are common psychosocial responses after implantation of an ICD; mood disturbance is especially 
high at the time of hospitalization for implantation, and recurs after resuscitation 45. However, 
single-lead ICD therapy has shown little association with detectable adverse QoL effects in long-
term follow-up 46. 
The mechanism of action of an ICD is singular and instantaneous, whereas most anti-arrhythmic 
medications and cardio-therapeutics are ongoing and multifaceted and in addition to their effect 
on mortality they may also improve symptoms and disability 21. In contrast, the ICD reduces the 
probability of SCD, which for some individuals may be a preferred mode of death 21.  

 
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d) 
Cultural Barriers 
For reasons not apparently related to clinical need or device effectiveness, significant sex and 
ethnic differences persist in ICD utilization rates. For example, women are 16-32% less likely to 
have an ICD than men, and black patients are 5-24% less likely to have an ICD than white 
patients despite a higher risk for SCD 47 (Table 3). The reason for these disparities cannot be 
explained by practice guidelines or treatment evidence. The ACC/AHA guidelines recommend 
equal treatment, regardless of sex, race or ethnicity 8, and no major interaction effects between 
sex, race or ethnicity and ICD efficacy have emerged from RCTs 23.  
Two possible explanations for lower ICD implantation rates in black individuals are: 1) a 
reduced preference for adoption of a “technological innovation,” such as the implantable device; 
and 2) socio-economic drivers, e.g. reduced access to medical care or receiving treatment at a 
facility that does not provide quality ICD care 23. However, these factors were not found to have 
an impact in several other studies 23,46,48. While it is possible that demographic factors impact an 
individual’s predilection for compliance with a physician’s recommendation, in actuality little is 
known regarding the characteristics of patients who refuse ICD implantation 49,50. 
e) 
Clinician Bias & Infrastructure 
Historically, new technologies, such as the ICD, are expensive and thus their accessibility is 
limited. The consequent limit on number of procedures that can be performed in a given period 
results in a rationing behavior among clinicians 21. In addition to patient preference and supply 
constraint, it has been suggested that low utilization of ICD among candidate patients could 
reflect referral bias. There is a direct relation between utilization of services, particularly 
invasive procedures, and in-hospital availability of specialists 51. 

 
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Age bias is a particularly prominent theory in the effort to explain under-utilization of ICD. 
While age is not an explicit contraindication for implantation, age compounds the clinician’s 
perception of risks associated with ICD implantation 52–54. There is some evidence that 
intervention using an ICD is best suited for patients of an intermediate risk category 41, and while 
age and co-morbidity are strongly associated with immediate risk, clinicians may be reluctant to 
implant due to a perception of increased risks associated with implantation from these factors 43. 
From a published analysis of data obtained from the National Cardiovascular Data Registry, the 
authors concluded that physicians are conservatively selecting older adults for ICD implantation 
and deferring referral of older adults with high co-morbid burden 43. Thus, without strong 
objective evidence, it appears that age is an important factor whether a patient is referred for ICD 
implantation or whether or not to implant a device. 
7. 
Erroneous ICD Implantation 
In contrast to the putative under-utilization of ICD among qualified patients, is the circumstance 
of implantation into individuals not meeting the evidence-based criteria of ICD. One recent 
survey of a registry of 111,707 patients revealed 25,145 (22.5%) receiving non–evidenced-based 
ICD implants 55. If implantations are taken into account that are performed as a result of over-
diagnosis of conditions for which ICD therapy is warranted, the rate of inappropriate 
implantation may be even higher 56. Of note, some implantations found in registries not meeting 
evidence-based guidelines were not necessarily “inappropriate,” since some variables in the 
registry may not be accurate 57.  

 
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C. 
Study Rationale: ICD Implantation Among the Elderly 
1. 
ICD Prevention of SCD in Aged Patients   
One of the interests of the clinical community with regard to ICD implantation is to better 
understand which patients groups will benefit and which will not 58,59, especially since the 
benefit of ICD therapy to prevent SCD and reduce overall mortality appears to be different 
across some patient subgroups 20,29,30,34,60. For heart failure patients, age is a particularly 
important consideration, as the proportion of patients dying due to sudden cardiac death 
decreases steadily with age 61. It is reasonable to expect that elderly patients with severe left 
ventricular dysfunction would not gain the same overall survival benefit from prophylactic ICD 
therapy as would younger patients because the survival benefit of ICD therapy is directly 
dependent on its effect on SCD –the only preventable outcome with ICDs– and not on overall 
mortality 62. On the other hand, there is evidence suggesting that a population with higher 
baseline all-cause mortality risk does not preclude it from receiving substantial benefit from ICD 
therapy 53.  
2. 
Age Demographics in Previous ICD Studies 
The age ranges of patients receiving ICDs in major clinical trials over the past 15 to 20 years are 
summarized in Table 4 below. The mean and median age of study populations of these past trials 
range between 50 and 65 years of age.  
 
 
 
 
 

 
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Table 4. Statistics on age of patients receiving ICD in previously published clinical trials. *= 
mean ± std; †= median: range; ‡= median: inter-quartile range. 
Age in Years 
Size of ICD Group 
Study 
62 ± 9* 
95 
MADIT-I 31 
64 ± 9* 
446 
CABG-Patch 32 
65 ± 11* 
507 
AVID 63 
58 ± 11* 
99 
CASH 64 
63 ± 10* 
328 
CIDS 65 
52 ± 12* 
50 
CAT 33 
64 ± 10* 
742 
MADIT-II 34 
58 ± 11* 
51 
AMIOVIRT 35 
58.4 : 20.3 – 83.9 † 
229 
DEFINITE 30 
60.1 : 51.9 – 69.2 ‡ 
829 
SCD-HeFT 29 
 
Among the studies with a mean and standard deviation listed, the age of the 75th percentile is 
likely to be at or near 70 years of age. In the SCD-HeFT trial, which is noteworthy for its size 
(N=2,521); 70 years was the approximate threshold for the upper-quartile of participant age 
range. 
3. 
Age as a Sub-Analysis in Previous Studies 
Previous prominent clinical trials have analyzed the efficacy of ICD therapy in older participants 
via subgroup analysis. Table 5 displays the effect of subgroup analyses across different age 
groups in three major clinical trials of ICD for primary prevention patients.  
 
 
 

 
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Table 5. Sub-group analyses of ICD efficacy vs. anti-arrhythmic drug therapy in reducing all-
cause mortality in aged cohorts in previously published clinical trials.  
Sub-Group Age 
HR (95% CI) 
Study 
60 – 69 
>70 
0.80 (0.45 – 1.28) 
0.64 (0.36 – 0.96) 
MADIT-II 34 
<65 
>65 
0.67 (0.27 – 1.37) 
0.64 (0.24 – 1.28) 
DEFINITE 30 
<65 
>65 
0.68 (0.50 – 0.93) 
0.86 (0.62 – 1.18) 
SCD-HeFT 29 
 
The summarized results in Table 5 show a benefit of ICD in older populations but no consistent 
trend between age and ICD efficacy in reducing the risk of death from any cause.  
4. 
Correlation of ICD Implantation and Age 
In order to better understand the correlation of age and ICD usage, we reviewed the VA patient 
electronic medical records. Patient records from the National Data Service were assessed for 
match to systolic heart failure (SHF) and ICD within any of their diagnostic codes. Age of ICD 
implantation was estimated for those patients with both SHF and ICD codes. For those patients 
with only SHF codes, their age was noted at the time of their visit; if a given patient was 
observed on multiple visit occasions, a representative age was selected randomly from among 
their visit profile. In this way, a “snapshot” is generated of the potentially implant-eligible patient 
population at a given time, i.e. SHF patients in FY 2009, and a separate snapshot is generated of 
the age distribution of patients at the time of device receipt. Due to the comparatively low 
proportion of patients with both SHF and ICD diagnosis codes, age-at-implantation data were 
aggregated over 5 years (2008-2012), and the histogram data normalized this time period in 
order to scale it to the single-year snapshot of the SHF data.  

 
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A scatter plot is shown representing the ICD implantation rate among potential candidates by age 
(Figure 1). A constant scatter plot would indicate uniform implantation rate across age; positive 
or negative slopes indicate increasing or decreasing ratio with age. 
 
 
 
 
Figure 1: Scatter plot of ICD implantation rate with age. 
 
As can be seen in Figure 1, the proportion of potentially eligible VA patients implanted with an 
ICD peaks at approximately 67 years of age and declines continuously thereafter. This data-
driven assessment of the potentially available patient pool within the VA Healthcare System 
shows that there is a non-monotonic decrease in ICD implantation starting just before the 70th 
year.  

 
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5. 
Focused Study of Aged Cohorts 
Despite the attention paid to age in subgroup analyses in major clinical trials, no randomized 
clinical trials have focused solely on an older population. Moreover, in the few recent non-
randomized studies that have examined the efficacy of ICD therapy in older patients, the results 
are inconclusive. In one recent prospective cohort study of 965 patients with ischemic and non-
ischemic cardiomyopathies (ejection fraction ≤35%), found that the efficacy of ICD therapy was 
consistent across age subgroups 53. The hazard ratio and 95% confidence intervals for the sub-
group analysis by age in this study were: <65 years (N=383): 0.74 (0.43, 1.28), 65-74 years 
(N=313): 0.76 (0.45, 1.29), and ≥75 years (N=269), 0.59 (0.39, 0.90).  
In contrast, a meta-analysis of several primary prevention studies (MADIT-II, DINAMIT, 
DEFINITE, SCD-HeFT and IRIS) concluded that prophylactic ICD therapy may be less 
beneficial for elderly patients 62, defined as over 60 and over 65 years. However, the study’s 
analytical approach of pooling data from subgroup analyses is susceptible to type I error. In 
addition, as with any meta-analysis, the results are subject to bias due to the choice of studies 
that are included and the heterogeneity of methodology used in each study. The authors 
acknowledged the limitations of their study due to the substantial qualitative heterogeneity 
among included trials and the fact that four important trials (MADIT-I, CABG-Patch, CAT, and 
AMIOVIRT) were not included because mortality data by age group were not available, and 
further concluded that the results of their meta-analysis demonstrated the need for a properly 
designed randomized trial of prophylactic device therapy in elderly patients 62.  

 
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6. 
Clinicians’ Call for Study of ICD in Aged Populations 
The community of practitioners has repeatedly called for a study focused on the impact of ICD 
on all-cause mortality in elderly patients.  
Table 6. Appeals for a study of ICD in aged populations 
Pull-out quote 
Publication 
“I 
would 
recommend 
that 
the 
Medicare 
Coverage 
Advisory 
Committee … advise CMS to issue a national coverage determination 
for ICDs only for the populations where evidence is strong that they 
actually gain desired outcomes, which may mean that only a small part 
of the Medicare population should be covered now, and certainly does 
not now include elderly...” 
Phurrough, 2003 66 
“The validity of this observation [that ICDs may be less effective in 
older 
patients] 
requires 
confirmation 
in 
prospective 
trials with 
adequate enrollment of patients with a wide range in age including the 
elderly...” 
Krahn, 2004 61 
“… a randomized controlled trial is the only proper way to address 
this question [of the effectiveness of ICD among elderly patients].”  
Healey, 2007 67 
“Future studies should help to further define the category of eligible 
heart failure patients who will derive a significant benefit from ICD 
therapy.” 
Hernandez, 2007 23 
“Although retrospective analyses of the elderly in clinical trials have 
suggested that ICD and CRT therapy afford benefit, inclusion biases 
may have been present. Given that more than 40% of ICDs implanted 
are for primary prevention in patients older than 70 years and that only 
approximately 1,000 patients in this age range were included in 
randomized controlled clinical trials with ICDs, clinical trials of 
device efficacy in the elderly are needed.” 
Epstein, 2009 68 
“Is there an age limit beyond which there is a poor value from an 
ICD? Yes, but we still need additional well-designed study outcome 
studies… to determine what age this might be and to fill in the many 
other knowledge gaps not addressed by clinical trials.” 
Heidenreich, 2009 69 
“Our findings call for a properly designed randomized trial of 
prophylactic device therapy in elderly patients.…. Because of the 
overall increase in life expectancy of the population and the fact that 
elderly patients benefit from medical therapies that were not always 
used in the older ICD trials, … we suggest that future trials consider 
enrolling elderly patients….”  
Santangeli, 2010 62 
“Primary prevention may be beneficial in older patients, but our 
findings need to be validated by future studies.” 
Kong, 2011 70 

 
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 It is clear that there is an identified need for a study that tests as its primary objective the safety 
and efficacy of ICD therapy in an aged cohort. To provide the most convincing evidence of 
whether ICD therapy is effective on top of optimal medical therapy in the elderly, a prospective 
randomized controlled clinical trial is needed. 
D. 
ICD Efficacy and General Health Status 
Despite the guidelines for referral for implantation based on prognosis, age appears to 
predominate all other factors in referral for ICD 14. However, decisions regarding ICD therapy 
should not be based on age alone, but rather should consider key factors that predispose to 
mortality without defibrillator implantation 71. Nevertheless, following the completion of the 
landmark randomized clinical trials of ICD efficacy, it is evident that general health status is not 
typically measured, and rarely included as a variable of stratification 52,72. Consequently, the 
therapeutic effect of ICDs in patients with high co-morbid burden remains an open question 
(Chan et al. 2009). To provide the most convincing evidence of whether ICD therapy is effective 
on top of optimal medical therapy in the elderly, a prospective randomized controlled clinical 
trial is needed. 
E. 
Summary of Study Goals 
The implantable cardioverter defibrillator has a single, but powerful action: to prevent sudden 
cardiac death by restoring normal rhythm in the event of a life-threatening ventricular 
tachyarrhythmia. While ICD therapy is proven as an effective preventer of SCD in younger 
patients, its ability to reduce all-cause mortality in those with advanced age is unclear. To answer 
this important question, we propose here a randomized controlled clinical trial of the safety and 
efficacy of ICDs in persons age 70 or older. At the same time, we will provide the most 

 
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convincing evidence of whether ICD therapy is effective on top of optimal medical therapy in 
the elderly with high- and low co-morbidity burden. 
 
 
 

 
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II. 
STUDY OBJECTIVES AND HYPOTHESES 
A. 
Primary Objective 
The primary objective of CSP #592 is to determine if a primary prevention strategy with ICD 
implantation in addition to optimal medical therapy (OMT) is effective in reducing all-cause 
mortality compared to OMT alone in patients ≥70 years of age who are eligible for ICD therapy 
according to current Centers for Medicare & Medicaid Services (CMS) criteria.  
B. 
Primary Hypothesis 
The primary hypothesis of CSP #592 is that implantation of an ICD plus optimal medical therapy 
will reduce all-cause mortality in patients ≥70 years of age versus OMT alone.   
C. 
Secondary Objectives 
1. 
Co-morbidity Burden 
A secondary objective of this study is to ascertain whether age, co-morbidity burden, or age and 
burden together, are determinants in mortality outcomes in the OMT versus ICD + OMT group. 
2. 
Quality of Life 
An additional secondary objective of the study is to determine the effect of ICD implantation 
plus optimal medical therapy on QoL among elderly patients compared with optimal medical 
therapy without ICD.  

 
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D. 
Exploratory Analyses 
1. 
Prevention of Sudden Cardiac Death 
This study will also ascertain whether –irrespective of the effect of ICD on all-cause mortality– 
the ICD is effective in its designed mechanism of action, i.e. preventing sudden cardiac death. 
2. 
Reduction in All-Cause Hospitalization 
As an additional exploratory analysis, CSP #592 decreases the number of hospitalizations versus 
those with optimal medical therapy alone. 
 

 
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III. 
SUMMARY OF STUDY DESIGN  
A. 
Overview 
This aim of this study is to test the safety and efficacy of ICD therapy as a strategy for the 
primary prevention of sudden cardiac death (SCD) in elderly patients meeting the standard ICD 
implantation criteria. CSP #592 is a two-arm study, with participants randomizing either to 1) 
ICD therapy plus optimal medical therapy, or 2) optimal medical therapy alone. The primary 
hypothesis is that ICD therapy + optimal medical therapy reduces all-cause mortality compared 
to optimal medical therapy alone. The secondary objectives of the study are to examine the 
influence of co-morbidity burden on the effect of ICD therapy, and to establish the impact of 
ICD therapy on QoL, sudden cardiac death, and all-cause hospitalization. This study will operate 
in a two-stage format: a one-year Pilot to assess feasibility of recruitment, followed by a five-
year study wherein the main study objectives will be accomplished. The Pilot study will operate 
at 6 sites; the study in its full scope will operate at 27 sites, pending outcome of the Pilot stage. 

 
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e 
 
 
 
 
 
 
 
 
 
 
 
Figure 2: CSP #592, multi-site, prospective, randomized clinical trial comparing ICD therapy 
against optimal medical therapy (OMT). 
  Signed Informed Consent and HIPAA 
Baseline assessments and 
Randomization 
(N=1,462) 
ICD + OMT 
(N=731) 
OMT 
(N=731) 
Follow through Study Close 
– Initial Follow-Up contact@ 1-4 months 
– Follow-up contacts at 6-month intervals through exit or study close 
– Quality of Life at 6, 12, and 24 months 
Inclusion criteria (must meet all) 
1. 70 years of age or older 
2. Eligible for ICD according to the CMS criteria for  primary Prevention 
3. Stable condition on Optimal Medical Therapy 
4. Able and willing to provide informed consent to participate in this study 
Excluded 
No to any. 
Yes to all. 
No to all. 
Exclusion criteria (must avoid all) 
1. Enrolled in or planning to enroll in a competing trial  
2. Receiving a bi-ventricular ICD device 
3. New York Heart Association class IV heart failure 
4. Cardiogenic shock or symptomatic hypotension  in stable baseline rhythm,  
5. Coronary artery bypass graft (CABG) or percutaneous  
  
transluminal coronary angioplasty (PTCA) within the past 3 months 
6. An MI within the past 40 days 
7. Clinical symptoms or findings that would make them a candidate for coronary  
 
revascularization 
8. Irreversible brain damage from pre-existing cerebral disease 
9. Any disease other than cardiac disease (e.g. cancer, uremia, liver failure),  
 
associated with a likelihood of survival less than 1 year 
10. Circumstance that would prevent completion of the trial and follow-up 
activities, including medical condition 
Excluded 
Yes to any. 

 
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B. 
Study Population and Rationale 
CSP #592 will enroll 1,462 total participants (an average of approximately 55 participants from 
each of the 27 participating sites). Patients who meet the standard profile of a candidate for ICD 
therapy according to current Centers for Medicare & Medicaid Services criteria for primary 
prevention and are at least 70 years of age will be screened for eligibility. CMS criteria primarily 
include patients with an established diagnosis of chronic heart failure, a qualifying ejection 
fraction, and survivability beyond 12 months. The primary exclusion criteria for the study are: 1) 
contemporaneous participation in an ongoing interventional clinical trial, 2) inability to complete 
study protocol, or 3) election into receiving a bi-ventricular ICD device. Details of the eligibility 
criteria are provided in Chapter V. The inclusion criteria were designed to include a broad 
sample of elderly patients eligible for an ICD with few exclusions, in order to maximize 
generalizability.  
C. 
Treatments and Rationale 
1. 
Overview 
The primary goal of this study is to compare ICD on top of optimal medical therapy against 
optimal medical therapy alone in reducing overall mortality in the patients with advanced age. 
For those participants randomized to the ICD group, implantation will occur as soon as possible 
after enrollment, with a target of 1 week post-randomization. A thorough medical history will be 
recorded prior to randomization for all participants, and stability on optimal medical stability will 
be established before participant can be randomized. After randomization, all participants will be 
returned to clinical care for continuation of their optimal medical therapy, according to local 
standard care for heart failure patients. Study follow-up phone callswill be scheduled for months 

 
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1 to 4, and at 6-month intervals post-randomization (6 months, 12 months, 18 months, etc.), all 
conducted by the study Central Follow-Up office; maximum follow-up will be 5 years.  
2. 
Prior to Randomization 
Recommendations for consideration of ICD therapy, particularly those for primary prevention, 
apply only to patients who are already receiving optimal medical therapy 68. To ensure that the 
participants are truly in need of an ICD, they must be at least 40-days post-MI, and have a 
NYHA functional Class of II or III, and have recorded a qualifying ejection fraction in the past 6 
months while being “clinically stable”. Referring clinicians will be advised to treat patients 
beyond this minimal duration if they feel more time on medical therapy is warranted. They will 
be encouraged to refer patients to the study once they believe a patient is eligible after 
consistently receiving optimal medical therapy. 
3. 
ICD Implantation 
Patients interested and eligible to receive single- or dual-chamber ICD devices for primary 
prevention will be screened for study eligibility by the site investigator. Those patients who are 
eligible and provide written informed consent will be enrolled and randomized. Participants 
randomized to ICD therapy will be implanted as soon as possible, with a recommendation of less 
than 1 week following randomization.   
4. 
Optimal Medical Therapy 
All participants in CSP #592 will continue to receive optimal medical therapy designed to meet 
the Guidelines of the American Heart Association for primary prevention of cardiovascular 
disease and stroke 73. This includes: 

 
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 Monitoring of clinical findings and therapies, both for suitability and compliance, e.g. 
blood pressure, blood lipids, and the use of medications such as angiotensin 
converting 
enzyme 
(ACE) 
inhibitors, 
angiotensin 
receptor 
blockers 
(ARB), 
aldosterone receptor blockers, beta blockers, aspirin, and statins, as specified in 
standard therapy guidelines and as applicable to the participant; 
 Recommendation to engage in regular physical activity, if appropriate; 
 Heart healthy diet counseling; and 
 Healthy lifestyle management and counseling, including smoking cessation, alcohol 
consumption limits, weight management, and care of co-morbid conditions. 
While these lifestyle modifications cannot be mandated, participant compliance with these 
conventions will be strongly encouraged. Per clinical trial evidence linking outcome to dose, all 
participants will be strongly recommended to be on maximum tolerated doses of a beta blocker 
and an ACE inhibitor or ARB74 to be eligible for entry into the study. Optimal medical therapy 
was chosen to explicitly test the efficacy and safety of the ICD on top of guideline-driven 
medical care.  
D. 
Outcome Measures and Rationale 
This study is designed to compare the efficacy and safety of ICD implantation in an aged 
population in reducing all-cause mortality. The primary outcome is measured by survival time. 
The study is designed to detect 25% reduction in the hazard of all-cause mortality among 
participants randomized to ICD with an estimated average follow-up of 3.6 years. Key secondary 
analyses will be quality of life and the effect of ICD in high- versus low co-morbidity burden. 
Quality of life (QoL) will be measured by the Minnesota Living with Heart Failure 

 
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questionnaire, a cardiac disease-specific QoL instrument. Quality of Life will be measured at 
baseline, six months, twelve months, and twenty-four months.  
E. 
Sample Size  
The target sample size for CSP #592 is 1,462 total participants (731 per treatment group to 
achieve a total of 565 primary outcome events). This sample size will provide 90% power to 
detect a 25% reduction in hazard from all-cause mortality between ICD + OMT and OMT alone, 
and will provide ample power to identify clinically meaningful differences between treatments in 
longer-term safety and Quality of Life measures, as well as significance in the treatment 
interaction based on co-morbidity burden. 
F. 
Data Collection and Assessments 
Study participants will be assessed at baseline via in-person clinic visit and at month 1 to 4  
following randomization and every 6 months thereafter via phone-based centralized follow-up; 
information related to the device will be collected on the day of implantation. The maximum 
follow-up is 5 years, the average participant follow-up across all participants (recruited in the 
pilot and full-scale stages) is 3.6 years. Chapter VIII provides details of the baseline assessments 
and procedures and Chapter 0 describes details of the follow-up schedule and procedures. 
G. 
Alternate Design Considerations 
1. 
Age Eligibility Criterion 
Several different age cut-offs ranging between 65 and 80 years of age were considered for the 
primary inclusion criterion for this study. The age cutoff of 70 years was selected on the basis 
that it would yield a population that has not been previously studied well. Importantly, 70 years 

 
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is just above the age boundary of the upper quartile of enrollment of many previous clinical trials 
(See Table 4). Moreover, based on data queries performed within the National Data Service 
(NDS), and direct communications with investigators from one of these previous trials (SCD-
HeFT), a cutoff of 70 years of age is likely to capture the patients for whom the steady decline in 
utilization of ICD is incipient. An older age cutoff was decided against because it would limit the 
study’s generalizability and could compromise its feasibility due to the increased restriction of 
the eligible patient pool; whereas, a younger age cutoff, would include many patients where the 
evidence in support of the efficacy of an ICD is stronger and limit the study’s ability to answer 
the study’s primary question, i.e., is ICD implantation safe and effective on top of OMT in 
reducing mortality in the elderly. We believe that a minimum age of 70 years provides maximum 
opportunity to extend the extant literature; lowering the minimum enrollment age would dilute 
the study sample (limiting the study’s value in extending the knowledge base), while raising the 
minimum enrollment age might exclude patients for whom the question of efficacy still appears 
to exist.  
2. 
Co-morbidities and Functional Status 
In addition to age as the primary entry criterion of the study, co-morbidity level and functional 
status was were considered as an eligibility criterion. It is clear that age is an imperfect predictor 
of mortality risk: a young person with more co-morbid conditions can have a greater mortality 
risk than an otherwise healthy aged person. Extensive consideration was given to the possibility 
of including younger patients with co-morbid conditions, but composing a list of conditions or 
risk level that was clinically meaningful was considered impractical, particularly because of the 
need to specify for each condition, or combination of conditions, a severity range that would 
constitute “moderate” risk. A general health status index, e.g., the Charlson Index, was 

 
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determined to be the most practical measure of disease burden as a complement to age. The 
Charlson score will be calculated upon study entry, and will be used as a stratification criterion, 
but will not be used explicitly as part of the eligibility criteria: entry to the study is based strictly 
on candidacy as determined through the CMS guidelines for implantation, which doesn’t exclude 
an exclusion for co-morbidity but does list survivability beyond 1 year as a criterion. In addition, 
the general function level of participants will be measured at baseline using a six-minute walk 
test for exploratory analysis but not as an eligibility criterion. Therefore, to maximize the 
simplicity, generalizability and impact of the study, CSP #592 will select patients based solely on 
their age, without regard to their functional status per AHA/ACC guidelines 73. 
3. 
Stratification Schema 
This study is designed to stratify the randomization on two levels: site, and co-morbidity burden 
(Charlson score <3 and Charlson score ≥3). An alternative schema was considered that did not 
include stratification by site, but the variability of geography, demography, and local clinical 
approaches makes site an important co-variate that should be accounted for in the final analysis. 
Co-morbidity burden was chosen instead of age, because stratification by co-morbidity will 
allow for direct testing of the possible treatment interactions by co-morbidity level. A 
stratification involving all three variables (i.e. site, age, and co-morbidity) was determined to not 
be feasible given the sample size and number of sites involved in this study. 
4. 
Generator Changes 
Consideration was given to including patients 70 years of age or older in need of an ICD 
generator replacement.  The ICD generator requires replacement every 5-7 years depending on 
use with a relatively less invasive surgical procedure compared to a new ICD implantation. The 

 
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decision on whether to include elderly patients due for a generator change involved consideration 
of several aspects of high relevance to this study including implications of ethics,  study design, 
and the impact of the trial. It was ultimately decided that patients in need of a generator 
replacement are too dissimilar from patients requiring a new implantation to include both patient 
groups in the trial. Patients in need of a generator replacement who have experienced shocks vs. 
those that have not would also introduce increased study population heterogeneity. In addition, 
the inclusion of 5-year survivors of heart failure with an ICD could skew mortality risk, 
introduce a survivorship bias, or risk introducing uncontrolled devices, device elements, or 
implantation variables into CSP #592. Therefore, patients with an ICD due for a generator 
change will not be eligible for this study. 
5. 
Additional Considerations 
Conventional ICDs are implanted under the skin with the generator positioned beneath the 
collarbone; the defibrillation lead is inserted through the veins that enter the heart, allowing for 
direct attachment to the inside of the right ventricle. Sub-cutaneous ICD implantation provides 
patients with the same protection against sudden cardiac death as conventional ICDs, but leaves 
the heart and vasculature untouched: the lead does not course through the central veins of the 
chest, and does not attach within the chambers of the heart.  This reduces complications 
associated with transvenous lead removal as might be indicated for lead infections, fractures, or 
mechanical blockage that prevents effective action of the ICD. Whereas the sub-cutaneous ICD 
has the same mechanism of action as conventional ICD, and is among the treatment options 
available in general practice, CSP#592 will allow for use of sub-cutaneous implants.  

 
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6. 
Aggregation to Registry 
CSP #592 presents a unique opportunity to collect data during recruitment and enrollment, such 
that some advancement may be made against the question “Why do some eligible candidates 
elect into ICD therapy, versus not.” This is an interesting question for its relevance both to the 
low ICD utilization rate (Section I.B.5) as well as the propensity for erroneous implantation 
(Section I.B.7). We will collect this data and review it both for interim evaluation of study 
entrance criteria, and for post facto reporting on recruitment statistics. This registry will be used 
locally to facilitate recruitment at each site, and may contain PHI; the local study team will be 
the only team members with access to this PHI. A de-identified version of this registry will be 
uploaded to the Coordinating Center on a regular basis, containing information about all 
screened patients, stripped of PHI, but retaining variables salient to understanding who is being 
screened, who becomes randomized, and their pathway to study entry, including: date screened, 
referral source, gender, age, race, ethnicity, and either date of enrollment or reasons for non-
enrollment. These data will be considered a registry, and not a repository: the data will be used 
only for the purposes of CSP#592, and not for use beyond the completion of the study’s aims. 
We note in particular that one of this study’s aims is to assess feasibility of a study like 
CSP#592, with a 50-50 chance of randomization to OMT versus ICD + OMT; accordingly it is 
expected that this study will produce manuscripts for publication related to the screening and 
consent into CSP#592. 
 

 
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IV. 
IMPORTANCE TO THE VETERANS ADMINISTRATION 
The Department of Veterans Affairs has anticipated the need to provide health care for an aging 
patient population since the return of soldiers following WWII, and along with the need to care 
for an aging population the VA has recognized the need for the inclusion of elderly participants 
in clinical trials 75. CSP #592 is specifically designed to target this population and a condition 
that has one of the greatest impacts on the elderly. Sudden cardiac death accounts for 300,000 – 
450,000 deaths per year, with an incidence rate of approximately 1.5-2.5 events per thousand 
individuals, depending on the definition used 9–12. SCD is the second largest cause of death after 
all cancers combined, and more than twice the rate of the next-most common cause of death, 
chronic lower respiratory diseases 76. Ventricular fibrillation, the most common cause of SCD, 
was once a uniformly fatal condition, but is now highly survivable with proper intervention 77, 
including a strategy of anti-arrhythmic medication and ICD implantation in patients meeting a 
small set of objective criteria.  
The standard guidelines for ICD implantation, disseminated by the American Heart Association, 
the American College of Cardiology, and the Heart Rhythm Society, and adopted by the CMS in 
indicating Medicare coverage, are unambiguous and easily practiced. Despite the clarity of these 
Guidelines, it is speculated that ICD utilization among those eligible for implantation is less than 
30% in some groups 23,37–39. One major contributing factor to this gross under-utilization of ICD 
among the elderly is a lack of data related to the safety and efficacy associated with implantation 
in the elderly, as evidenced by the many appeals for a focused clinical study of implantation 
outcomes 23,61,62,67,69,70, and a knowledge gap recognized in the ICD implementation Guidelines: 
“Unfortunately, few clinical trials of device-based therapy have enrolled enough elderly patients 
… to reliably estimate the benefits of device-based therapy in this group” 68.  

 
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Heart failure, the major eligibility criteria for ICD implementation,  is the number one reason for 
hospital admission in the VA 78: we estimate that there are 13,882 patients over 70 years of age 
in a single calendar year within 40 potential VAMC study sites who meet the criteria for ICD 
implantation, of whom at maximum 4,505 (32.5%) have received ICD therapy based on a search 
of records within the National Data Service (NDS) and the VA Cardiac Device Surveillance 
Database (See Chapter XVI for details). Furthermore, while the number of elderly patients 
receiving ICD implants is relatively small (approximately 2,000-2,500 patients per year 2005-
2010), the number of VA patients whose dual enrollment in Medicare allows them to receive 
ICD at a non-VA provider is large (approximately 20,000) 79. Thus, this study has implications 
for a large number of Veterans, whether they are receiving treatment at the VA or not. By 
addressing impact on both mortality and Quality of Life, CSP #592 will have direct and major 
implications, not only for a rapidly growing segment of the VA patient base, but for the standard 
of care provided by the VA.  
CSP #592 is a prospective randomized controlled clinical trial to compare the effect of ICD 
implantation plus optimal medical therapy vs. optimal medical therapy alone in the elderly. 
Whatever the results of this trial, it will have a major impact on clinical practice and will provide 
definitive evidence to inform ICD implantation guidelines and change clinical practice in the VA 
and throughout the world.  

 
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V. 
STUDY POPULATION 
A. 
Inclusion Criteria 
All patients with documented heart failure will be included if they meet all of the following 
eligibility criteria 68: 
1) 70 years of age or older 
2) Eligible for ICD implementation according to the CMS criteria for primary 
prevention by one of the following conditions: 
(a) Documented prior MI and a measured LVEF ≤30% (includes NYHA class I, 
II, or III) 
(b) Coronary artery disease with a documented prior MI, a measured left 
ventricular ejection fraction ≤35%, and inducible, sustained VT or VF at EP 
study  
(c) Ischemic dilated cardiomyopathy (IDCM), documented prior MI, NYHA class 
II and III heart failure, and measured LVEF ≤35% 
(d) Non-ischemic dilated cardiomyopathy (NIDCM) > 3 months, NYHA Class II 
and III heart failure, and measured LVEF ≤35% 
3) Stable condition on Optimal Medical Therapy 
4) Able and willing to provide informed consent to participate in this study 
As evaluation of above inclusion criteria, the ejection fractions must be measured by 
angiography, radionuclide scanning, or echocardiography, and MI’s must be documented and 
defined 
according 
to 
the 
consensus 
document 
of 
the 
Joint 
European 
Society 
of 
Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial 

 
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Infarction Ejection fraction must be measured within 6 months of consenting to be considered 
eligible for entry. This study will allow the recruitment of inpatients. 
B. 
Exclusion Criteria  
All patients satisfying the inclusion criteria will be excluded for any of the following criteria 68: 
1) Enrolled in or planning to enroll in a conflicting trial 
2) Receiving a bi-ventricular ICD device 
3) New York Heart Association class IV heart failure 
4) Cardiogenic shock or symptomatic hypotension while in stable baseline rhythm,  
5) Coronary artery bypass graft (CABG) or percutaneous transluminal coronary 
angioplasty (PTCA) within the past 3 months 
6) An MI within the past 40 days 
7) Clinical symptoms or findings that would make them a candidate for coronary 
revascularization 
8) Irreversible brain damage from pre-existing cerebral disease 
9) Any disease other than cardiac disease (e.g. cancer, uremia, liver failure), associated 
with a likelihood of survival less than 1 year 
10) Circumstance that would prevent completion of the trial and follow-up activities, 
including medical condition 
 
Regarding co-enrollment in CSP#592 and another trial: in order both study chairs must 
concur on the dual-enrollment. Both chairs must agree that the co-enrollment does not adversely 
effect the rights or well-being of the participant, and by either the sponsor (CSPCO) or by one or 
more of the studies. It is the responsibility of the Principal Investigator or Local Site Investigator 

 
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to determine if it is appropriate for a participant to be in more than one study concurrently.  This 
may 
require, 
contacting 
the 
Principal 
Investigator 
of 
the 
other 
study 
to 
determine 
appropriateness. Where practicable, the LSI is encouraged to discuss with the Study Chair and 
the Executive Committee.    
 
C. 
Inclusion of Women and Minorities 
Because female Veterans comprise such a small proportion of the VA population, participating 
VA medical centers will be requested to make a special effort to recruit female veterans. No 
special recruitment of minorities is planned because they are well-represented among the VA 
population. Demographics, including race/ethnicity and sex, will be monitored for randomized, 
as well as excluded patients. All adult patients fulfilling the inclusion and exclusion criteria will 
considered for enrollment into the study.  No patients will be excluded on the basis of gender, 
race or ethnicity. 
D. 
Justification of Age Cutoff at 70 years 
From inspection of the NDS database, it is evident that utilization of ICD therapy begins a steady 
and unceasing decline between age 65 and 70. Furthermore, there have been few individuals over 
the age of 70 years that have been included in ICD clinical trials. For these reasons, 70 years of 
age was selected as the minimum age of eligibility for CSP #592 as it represents both an 
incremental advance on the age profile of the previously studied population (while also 
maintaining adequate comparability to the existing literature), and targets with high precision the 
age at which there appears to be a turning point in the utilization of ICD in prevention of sudden 
cardiac death in high-risk patients. 

 
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E. 
  Projected Health Status of the Study Population 
Pursuant towards a full understanding of the potentially available study population, the general 
health status was assessed from the electronic medical records of systolic heart failure patients 
utilizing the VA Healthcare System in FY2009. For all patients with SHF codes, a Charlson co-
morbidity index score was calculated using an algorithm according to the original Charlson 
framework 80, but using updated coding paradigms reflecting the Enhanced ICD-9-CM database 
81,82.  
Patients with SHF codes were categorized as a) having no ICD, or b) having ICD, based on the 
appearance of ICD-9 device code V45.02 anywhere in their medical record. For those with no 
record of ICD possession, a ‘benchmark’ visit date was taken from the FY2009 medical record; 
if a patient made multiple visits in FY2009, a representative visit was selected at random from all 
FY2009 visits (see Section I.C.4). For those with ICD, a surrogate “date of implantation” was 
estimated according to the date at which the device code first appeared in the medical record 
following at least one visit with SHF code but no device code. Charlson co-morbidity index 
score was calculated following interrogation of all medical records in the two years preceding the 
benchmark (SHF) and surrogate implantation (SHF + ICD) dates. 
By computing the Charlson score for both SHF patients without ICD as well as ICD-implanted 
patients, it is possible to both: ascertain the general health status of the potentially eligible patient 
pool, as well as to make preliminary inferences as to whether there is a systematic difference 
between those who are eligible to receive versus those who receive ICD, in terms of co-
morbidity burden. Summary results are presented in Table 7. 
 

 
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Table 7. General health status of CSP #592 potentially eligible patient population: Co-morbidity 
burden of SHF patients (top series), mirror that of patients already in receipt of ICD (bottom 
series); Source: National Data Service. 
Charlson Score 
1 
2 
3 
4 
5+ 
Total 
SHF Patients without ICD 
N 
316 
511 
561 
616 
2,066 
4,070 
Percentage 
7.8% 
12.6% 
13.8% 
15.1% 
50.8% 
100% 
SHF recipients with ICD (on day of ICD receipt) 
N 
86 
195 
264 
268 
820 
1,633 
Percentage 
5.2% 
11.9% 
16.2% 
16.4% 
50.2% 
100% 
 
Here, two inferences are made: Firstly, the potentially eligible patient population is, –in general– 
heavily burdened: All patients have Charlson ≥1; the majority of patients have Charlson ≥5; 
Charlson scores in this higher range are associated with a greatly elevated mortality risk. 
Secondly, it is evident that there is high concordance between the Charlson score distribution 
across SHF patients with- and without ICDs: there does not appear to be a systematic difference 
in general health status between those who receive and those who do not receive and ICD. 
F. 
Implantation Rates by Disease Category 
Following the calculation of aggregate Charlson scores, ICD implantation rate by disease 
category was assessed. For each of the seventeen disease states comprising the Charlson co-
morbidity index, the proportion of SHF patients without ICD was compared against the 
proportion of SHF patients with ICD 
 

 
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June 15, 2016 
 
 
 
Figure 3: Forest plots of ICD implantation rate (versus non-implantation) for SHF patients in 
possession of diagnostic codes from among each of the seventeen Charlson co-morbidity index 
disease categories. (Not shown: Charlson category 2, i.e. congestive heart failure). 
 
From Figure 3 it is seen that there is only one condition for which there is a significantly greater 
likelihood of ICD implantation (history of Myocardial Infarction; Odds Ratio = 1.44, 95% CI = 
1.27 – 1.62, P<0.001). There are three conditions where the ICD is utilized less: Dementia (OR = 
0.75, 95% CI = 0.57 – 0.99, P=0.045), Hemi- or Paraplegia (OR = 0.62, 95% CI = 0.41 – 0.94, 
P=0.024), and Malignancies (OR = 0.85, 95% CI = 0.73 – 0.98, P=0.022). Otherwise, the 
proportion of ICD patients with a given condition is similar to the proportion of SHF patients 

 
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without ICD; the aggregate Charlson score is similar across the SHF and SHF + ICD groups: 
3.93 versus 3.88, OR = 1.01, 95% CI = 0.98 – 1.05 (cf. Figure 3 and Table 7). 
G. 
Age versus Health Status as a Determinant in Implantation 
As a final assessment of factors associated with ICD implantation within the potentially eligible 
patient pool, implantation status was regressed against three factors: age (as a continuous 
predictor), history of myocardial infarction (per Figure 3) and a modified Charlson score (as a 
continuous variable excluding MI). Results are shown in Table 8. 
Table 8. Logistic regression of ICD implantation against age, general health status without 
considering history of myocardial infarction (charlsonNonMI, i.e. aggregate Charlson score not 
accounting for MI), and separate predictor of MI history.  
 
Estimate 
Std. Error 
z 
Pr(|z|) 
Intercept 
6.01 
1.04 
5.78 
<0.001 
age 
–0.09 
0.01 
–6.75 
<0.001 
charlsonNonMI 
–0.26 
0.20 
–1.26 
0.21 
historyMI 
3.72 
1.78 
2.09 
0.04 
Interactions 
No significant interaction terms 
 
Here it is seen that age and history of MI are significant predictors in receipt of ICD; the 
modified Charlson score (i.e. Charlson that accounts for all non-MI co-morbidities) does not 
otherwise predict ICD receipt. 
 

 
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H. 
Justification of Stratification at Charlson Index 3 
Though general health status does not appear to be associated with the rate of ICD implantation, 
whether there exists an interaction between co-morbid burden and treatment effect remains to be 
seen. Accordingly, this study will stratify on the basis disease burden, specifically participants 
will be stratified into “fair” and “poor” health status, on the basis of their Charlson score being 
lesser versus greater than/equal to 3. This threshold was established following the database 
review, and in consideration of the general criteria for implantation. Because those patients with 
the highest co-morbidity score would likely be determined to be ineligible for study (on the basis 
of 1-year survivability) we estimated the median Charlson score of study-eligible patients would 
be closer to Charlson score of 3. In this context, a classification of “fair” health status as 
corresponding to Charlson score of <3 is well-suited in terms of study feasibility, and would 
commensurate with the existing body of literature to which this study will ultimately be 
compared. This stratification is in addition to stratification by site. 
 

 
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VI. 
OUTCOME MEASURES 
A. 
Primary Outcome 
The primary outcome measure for this study will be death from any cause analyzed as time to 
event. The date of randomization will be used as the time origin. VA Vital Status File will be 
used to determine the vital status of all study participants who are lost to follow-up at study exit.  
The VA Vital Status File has been shown to be highly accurate compared to the National Death 
Index (NDI) 83. As cause of death is not available from the VA Vital Status File, a NDI Plus 
database search will be performed for all participants who are found to have died through the 
database search in order to adjudicate the cause of death for secondary outcomes.   
B. 
Secondary Outcomes and Exploratory Analyses 
1. 
Quality of Life 
Among the cardiac-specific quality of life (QoL) instruments, the Minnesota Living with Heart 
Failure questionnaire (MLHF) is considered to be among the best 84. It has been widely validated 
85–87, and it is more sensitive than the generic QoL measures in detecting clinically important 
changes over time in patients with heart failure 88,89. The MLHF was also chosen as the QoL 
measure for this study because it is simple, inexpensive, short, easily understood by ill and 
elderly individuals, self-administered, and easy to score 90–97. 
The MLHF questionnaire is designed to specifically assess the impact of heart failure on QoL. It 
consists of 21 questions that measure the effect of symptoms specifically related to heart failure 
and its treatment in adults 98,99. The response to each question is scored on a 6-point Likert scale 

 
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(0-5). There are two subscales to MLHF: physical and emotional. The effect size outcomes of 
several studies employing QoL are summarized in the following table. 
Table 9: Effect sizes reported using Minnesota Living with Heart Failure survey. MLHF on 105-
point scale, including their calculated significance. Original references listed. 
Effect Size 
Interpretation 
Source 
1 
Not significant 
Rector, 1992 97 
1.6 
Not significant (P=0.33) 
Kasper, 2002 96 
4 
P<0.001 
Rector, 1992 97 
5 
Not significant 
Owen, 2000 94 
6.6 
P=0.0006 
Kasper, 2002 96 
6.7 
Not significant (P=0.41) 
Curiati, 2005 99 
9.6 
P=0.01 
Kasper, 2002 96 
11.6 
P=0.02 
Curiati, 2005 99 
 
A disease-specific instrument was chosen in favor of a broader (“generic”) QoL assessment for 
the reason that questionnaires with greater emphasis on ICD-specific and arrhythmia-specific 
measures may be more sensitive to changes in outcome, and would be more impactful in 
addressing ICD as a treatment choice for life threatening arrhythmias 100.  The Minnesota Living 
with Heart Failure is designed to capture both physical and emotional (anxiety or distress) 
dimensions of patient well-being and is considered an effective and efficient instrument 101. The 
MLHF is a proprietary instrument; its use requires procurement of a one-time licensing contract 
through the University of Minnesota. 
2. 
Co-morbidity Burden 
One of the primary reasons for doing a study like CSP #592 is to determine whether there are 
differential risk-benefit issues in the elderly: in patients with declined health status, the 

 
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likelihood of surviving long enough to derive benefit from device implantation is decreased. This 
study will test whether poor general health status shifts the risk-benefit profile. In this way, the 
Charlson Co-Morbidity Index is the most practical tool for incorporation into CSP #592, as it is 
an extensively validated method of measuring the prognostic impact of co-morbid disease 80,102.  
3. 
Sudden Cardiac Death 
Sudden cardiac death will include deaths that occur unexpectedly that is not preceded by an 
acute myocardial infarction. SCD will include the following events 103: 
o Death witnessed and instantaneous without new or worsening symptoms; 
o Death witnessed within 60 minutes of the onset of new or worsening cardiac 
symptoms, unless the symptoms suggest an acute myocardial infarction; 
o Death witnessed and attributed to an identified arrhythmia, e.g., captured on an 
electrocardiographic (ECG) recording, witnessed on a monitor, or unwitnessed 
but found on implantable cardioverter-defibrillator review; 
o Death after unsuccessful resuscitation from cardiac arrest; 
o Death after successful resuscitation from cardiac arrest and without identification 
of a non-cardiac etiology (Post-Cardiac Arrest Syndrome); and 
o Unwitnessed death without other cause of death (information regarding the 
participant’s clinical status preceding death should be provided, if available). 
General considerations for SCD are that a subject seen alive and clinically stable 12-24 hours 
prior to being found dead without any evidence or information of a specific cause of death 
should be classified as SCD. Deaths for which there is no information beyond “Patient found 

 
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dead at home” may be classified as “death due to other cardiovascular causes” or “undetermined 
cause of death” 103. A strategy for dealing with such deaths will be decided on by the Executive 
Committee prior to study initiation. Cause of death determination will be National Death Index 
(National Center for Health Statistics); the NDI Plus database has been shown to be highly 
accurate in resolving cause of death 104; an Adjudication Committee may be assembled if deemed 
necessary by the Executive Committee. 
4. 
All-cause Hospitalization 
Hospitalization information will be captured by participant self-report and medical record 
review. Self-report is valid and reliable, especially with inpatient care and recall periods less than 
one year 105; however, hospitalization data will also be collected from VA electronic medical 
records, and –where feasible– from non-VA providers. The study’s case report forms will 
contain detailed information about the index hospitalization and will note re-hospitalizations, 
rehabilitation unit admissions, and long-term care facility admissions. Specifically, the case 
report forms will record the total number of days of hospitalization. Hospitalizations of any type 
will be considered: there is no minimum time-frame for hospitalization and both admissions and 
observations will be considered as countable. In this study, hospitalizations associated with index 
implantation, re-implantation, or generator changes will not be considered as countable all-cause 
hospitalizations.  
C. 
Device Data 
ICDs monitor and store data on a wide range of parameters including battery and lead function, 
patient activity, heart rate, frequency of pacing, and most importantly tachyarrhythmia events. 
The ICD stores extensive data on all tachycardia events that trigger therapy including beat to 

 
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beat intervals that met the programmed criteria for ICD therapy, electrograms from before, 
during, and after ICD therapy, the types of ICD therapy employed including shocks and anti-
tachycardia pacing (ATP), the results of each therapy attempt, and the final results of ICD 
treatment. This data can be accessed in clinic using a device called a programmer which 
interrogates the defibrillator and then displays the results and allows the results to be saved as a 
PDF file. This data can also be retrieved “remotely” in the patient’s home using a home 
monitoring device that is available to all newly implanted ICD patients. These home monitoring 
systems interrogate the ICD on a programmable schedule and transmit the data to secure servers 
via either land line or cell phone systems on a routine usually every 3 month basis and when 
certain 
programmable 
criteria 
for 
unscheduled 
transmissions 
are 
met. 
“On 
demand” 
transmissions can also be initiated by patients if they feel they are having a problem or are 
instructed to do so by their provider. The VA National Cardiac Device Surveillance Center 
manages the data flow from this remote monitoring and posts PDF files of all transmissions on 
their web site and alerts providers if there are urgent findings on a transmission. Remote 
monitoring provides significant benefits to the Study Team, as it 1) provides accurate, objective, 
and timely record of therapeutic events, and 2) provides a platform for assessing protocol 
adherence with regard to device programming, and 3) reduces loss to follow-up. CSP#592 study 
participants should be registered for remote follow-up with the VA National Cardiac Device 
Surveillance Center. Failureto register within 30 days of implantation will be considered a 
protocol deviation. 
Files documenting all in clinic interrogations will be accessed by the Study Team in a separate 
and independent transaction from that conducted by the care provider as part of routine clinical 
practice. by investigators who see patients in clinic and by the VA National Cardiac Device 

 
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Surveillance Center. These files will be used most importantly as source documentation for 
exploratory analyses of ICD therapy events including the frequency of ICD therapy, the 
appropriateness of ICD therapy, the rhythms that trigger ICD therapy and the overall number of 
shocks experience by participants with ICDs. These files could also be used for other exploratory 
analyses focusing on other aspects of ICD function. The data contained within these files may be 
the result of direct interrogation of the device, or a filtered dataset exported from a larger 
database used in order to increase the efficiency of data analysis.  
Lastly, every effort will be made to interrogate the device upon death. This is standard clinical 
practice and is often impactful in facilitating determination of the cause of death. 
 

 
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VII. 
HUMAN RIGHTS ISSUES AND INFORMED CONSENT PROCEDURES 
A. 
Risks and Benefits 
The ICD delivers electric shocks when necessary and stops most arrhythmias with weak 
electrical stimulation that cannot be felt. In the delivery of a strong shock, it is possible to feel a 
short pain, much like a punch to the chest. Known risks of ICD and implantation include  
 swelling and/or bruising;  
 bleeding (particularly around the heart, which can be life-threatening); 
 cardiac perforation with and without pericardial tamponade, requiring pericardiocentesis or 
other surgical intervention; 
 pneumothorax or hemothorax, requiring prolong hospitalization or chest tube placement; 
 infection at the site of the implant, requiring intravenous antibiotics or system removal; 
 damage to the vein where the ICD leads are placed; 
 generator or lead malfunction requiring reoperation; 
 pocket hematoma requiring evacuation, drainage, blood transfusion, hospitalization or 
extension of hospitalization; 
 deep vein thrombosis; 
 arterial embolus; 
 drug reaction or hemodynamic instability resulting in abortion of the implant procedure; 
 ICD shock or cardiac arrest within 24 hours of the procedure; and 

 
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 Other medical complications requiring a prolonged hospital stay (e.g. respiratory arrest, 
drug reaction, or re-hospitalization that is attributable to the implant procedure). 
Further risks include those associated with diagnostic x-rays, sedation, and other complications 
during the implantation procedure. Participants may also receive inappropriate or unnecessary 
shocks. These shocks can be treated by changing the ICD settings, or by adding an anti-
arrhythmic medication. However, because of complications and discomfort that may arise due to 
implantation and shocks, there is a risk of psychological distress for participants who receive an 
ICD. 
Risks of Optimal Medical Therapy may arise due to changes in diet, exercise, and medication. 
During a blood draw or placement of intravenous fluid delivery, it is possible to experience some 
momentary discomfort, bruising, bleeding or pain at the site of needle entry into the vein. There 
is a very small risk of fainting. There is also a very small risk that infection could occur at the 
place where the needle goes into the arm.  
 
Those participants receiving an ICD and/or OMT may potentially receive life-saving 
therapy that would prevent sudden cardiac death. Also close monitoring will occur throughout 
your participation in the study. Additionally, information we get from this study might help us 
treat patients in the future 
B. 
Informed Consent Process 
When patient eligibility has been confirmed, the study coordinator or site investigator will 
determine if the patient is willing and able to provide informed consent. The site investigator or 
designee will review and discuss the study with the potential study participant and answer any 

 
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questions that he/she might have. The general purpose of the study, along with detailed 
information about comparisons between therapy arms, the randomization process, the study 
timeline, including what is expected of the participant, and the rights of study participants will be 
clearly described. The risks associated with study therapy and procedures will also be addressed. 
The importance of patient confidentiality will be stressed, and the process for maintaining 
confidentiality will be described. Informed consent will be documented in this trial by the use of 
a standard consent form approved by the Institutional Review Board(s) of record. The consent 
form will be read verbatim to potential participants who are unable to read the document due to 
literacy or vision issues. 
It must be ensured that the patient understands every aspect of the trial, including its risks and 
benefits, prior to signing the informed consent. Informed consent requires that the patient 
understand the details of the study and agrees, without coercion, to participation in the study. 
Merely obtaining a signature on a consent document does not constitute informed consent.  
C. 
Capacity to Consent 
To help ensure that potential study participants understand the study’s purpose, procedures, risks, 
and benefits and his/her rights as a research participant, a standardized set of questions will be 
developed to assess a patient’s actual and perceived understanding of the information presented, 
i.e. i.e. Informed Consent Questionnaire). The primary purpose of the Informed Consent 
Questionnaire is to help ensure that participants receive and understand the critical aspects of the 
study and their rights as a research study participant. 

 
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The Informed Consent Questionnaire will be presented to the potential participant after 
completion of the informed consent discussion. Incorrect answers will be discussed with the 
patient and the site investigator or coordinator and will emphasize the areas of the consent 
document where the correct information is stated and will further clarify the information to be 
certain the participant understands. The results from the informed consent quiz will be recorded 
on the data form and submitted to WH-CSPCC. Documentation (e.g., a progress note) of the 
consent process, the administration of the questionnaire, the questionnaire review and the 
determination of adequate understanding will be retained in the participant’s study files. If it is 
determined that the patient is not able to adequately understand the study or their rights, the 
patient will be excluded from participating in the trial. 
While there is no consensus on how to reliably assess autonomy or decision-making capacity, the 
use of a standardized questions and information aids can assure that participants receive adequate 
and consistent information about the trial. While the Informed Consent Questionnaire can assist 
the investigator in the determination of a patient’s decision-making capacity, the final 
determination is the responsibility of the site investigator and must be carried out in compliance 
with all applicable local laws and regulations.  
D. 
Surrogate Consent 
No surrogate/proxy consent will be allowed to enroll into CSP #592. For patients who are 
competent to give informed consent and judged not able to carefully read the consent form 
because of either literacy issues or impaired vision, the informed consent will be read to the 
patient and his/her written consent will be obtained if he/she is willing to participate. Surrogate 
consent will be permitted for re-consent or for Release of Information (Form 3). 

 
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E. 
Withdrawal  
Participants may withdraw at any time during the study. A withdrawal form (see Appendix E) 
will be provided to participants who wish to withdrawal. On the withdrawal form, participants 
will be asked whether they wish to:     
 Revoke permission for the study to collect clinical data through VA medical records; or 
 Revoke permission for the study coordinator or local site investigator to contact the 
participant. 
 
 

 
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VIII. BASELINE ASSESSMENTS AND PROCEDURES 
A. 
Recruitment and Screening 
1. 
Recruitment Strategies 
Several approaches will be used to identify potential participants. Veterans will be recruited for 
the study directly from each VA heart failure clinic participating in the study as well as 
cardiology and primary care clinics. Additional recruitment methods will include direct mailings, 
VA heart attack survivor support groups presentations, and advertisements and in the VA 
Community newsletter. 
The study will also seek a waiver from the IRB for identifying potentially eligible participants 
through local database searches. In this case, the site investigators will work with primary care 
physicians and cardiology doctors in order to send letters to potential participants, inviting them 
to be screened to assess eligibility for the study. To facilitate study recruitment, CSP#592 will 
employ a Screening Tracker Log to capture patient-level data that will carry relevant information 
regarding age and source of referral for potentially eligible participants, as well as reasons for 
non-entry into this study, if applicable. A de-identified version of this Tracker will be passed to 
the Coordinating Center on a regular basis. 
2. 
Remote VAMCs 
Due to the limited number of electrophysiologists within the VA, it is common practice to refer 
patients to an implanting center from a distant facility; patients referred into CSP592 in this way 
shall be allowed to enter into the recruitment and collection of baseline data by either by remote 
methods or by study team member visit to the remote facility. All study-related activities will be 

 
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performed by Study Team members. Patients whose primary care is delivered at a VAMC that 
does not provide implantation may also be recruited for study as is done in standard clinical 
practice for ICD implementation.  Face-to-face consent may be transacted either centrally, e.g. if 
the patient travels to the implanting center, or locally, e.g. if a qualified Study Team member 
travels to the local clinic. Remote consent can also be accomplished either through fax or 
through postal delivery, following delivery by a qualified team member via telephone or video 
teleconference. Consenting patients who cannot or prefer not to travel to their implanting VA 
may elect to be randomized during a teleconference where feasible, and will be informed of the 
outcome of their randomization. Distant participants being randomized to ICD therapy will be 
prepared to travel to the implanting Center under standard compensation arrangements per local 
site convention, and will not be specially compensated for this expense. In concurrence with 
common practice in VA facilities (VAMCs, CBOCs, etcetera) without staff electrophysiologists, 
recruitment at affiliated facilities will be facilitated by encouraging referrals for ICD consult at 
the study site.  
 
Engagement of patients at remote VA facilities is meant to ensure broad recruitment into 
CSP#592 that is representative of the diverse patient pool normally serviced by the implanters 
within the VA system. Whereas ICD implantation is practiced by a small number of specialists, 
the implantation procedure is only performed at select VAMCs. Patients from more distant 
locales routinely consult with the electrophysiology staff at a regional VAMC via telemedicine 
from a remote VA facility; if implantation is decided, the patient will travel to the implanting 
center for the procedure. This “remote ICD consult” occurs across the VA, and may occur for 
any patients for whom ICD implantation may be clinically indicated, regardless of their apparent 
eligibility for CSP-592.  

 
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In many cases, e.g. distant CBOCs, these patients will already be in the implanting 
center’s CPRS; for patients not already in the implanting center’s CPRS (e.g. smaller referring 
hospital), however, once a consult referral is requested of the clinicians at the implanting site, the 
patient will appear in the local CPRS, and can be contacted in the same way as any patient in the 
local VAMC system. All recruiting and study activities, possibly including the first research 
contact, will be performed remotely by a Study Team member via Telemedicine. Essential 
baseline data in this study can be collected from the medical record, so there is no reason for 
clinicians at the remote site to be involved in study interventions or study data collection; remote 
clinicians will, of course, still be responsible for performing standard exams typical of any 
implantation candidate, but these will occur based purely on clinical indication and without 
regard to whether the patient has entered into CSP592. 
 
Without this approach, the Study’s recruitment will be compromised and may be biased 
by including only those patients receiving care from major VAMCs; the feasibility and 
generalizability of this study warrants recruitment at remote VA facilities. 
 
3. 
Screening 
All referred patients who have a diagnosis of heart failure, with low LVEF verified by 
echocardiogram, multi-gated acquisition scan or cardiac catheterization will be further screened 
for eligibility. If a patient is determined to be ineligible during the initial screening process, a 
screening instrument, which will include no patient identifying information, will be completed 
and submitted to the Coordinating Center. If the patient appears to be eligible based on an initial 
screening, the patient will be approached for participation in the trial. If the patient is willing to 
participate, an informed consent document and HIPAA authorization must be signed before 

 
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enrollment. For those patients who enroll, complete screening procedures and baseline 
assessments will be completed including a clinical history, a physical exam and assessment of 
cardiovascular health. After completion of the screening visit, the site will submit all screening 
forms and the signed informed consent documents to the WH-CSPCC. Source documentation for 
the inclusion and exclusion criteria will remain at the site.   
B. 
Baseline Data Collection 
When feasible, screening, consenting, baseline data collection and randomization will be 
completed on the same day. However, in order to provide potential participants time to consider 
enrollment, minimize participant burden and fatigue, and to provide time to complete all 
screening and baseline assessments, enrollment activities can be completed after screening and 
consent and divided into 2 or more sessions if needed. However, all baseline assessments must 
be completed within one month prior to randomization. If not, then the baseline assessments will 
be re-assessed or repeated. The results of the baseline assessments will also alert the Study 
Investigator 
to 
any 
pre-existing 
problems 
or 
medical 
conditions 
that 
might preclude 
randomization. Only patients meeting the inclusion and exclusion criteria (See Chapter V) after 
the completion of all baseline assessments will be randomized; patients not meeting these criteria 
will be excluded and will continue to receive care from by their regular VA physicians.  
Listed below are all required baseline assessments. The data forms are provided in Appendix E. 
Baseline assessments cannot be administered without written informed consent and must be 
completed prior to randomization.  
 Demographics and Military History 
 Clinical History 
 Laboratory Measurements 

 
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 EKG 
 Physical Examination 
 Six-minute walk test 
 Medication Use 
 Minnesota Living with Heart Failure Questionnaire 
 
 
 

 
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IX. 
STRATIFICATION AND RANDOMIZATION 
A. 
Randomization Procedure 
Veterans who satisfy all of the study eligibility criteria, provide written informed consent and 
complete the necessary baseline assessments will be randomized to one of two treatment 
strategies: ICD therapy + optimal medical therapy, or optimal medical therapy alone. The 
treatment assignment will be provided through a web-based randomization platform or over the 
telephone to the site investigator or coordinator. The treatment allocation ratio for the two 
treatment regimens will be 1:1 within each stratum; participants will be stratified both by 
medical center and by Charlson score (Charlson <3, and Charlson ≥3), using a random permuted 
block scheme with randomly varying block size. Charlson score will be calculated using the 
method described in Section V. E. The random treatment scheme will be generated by the West 
Haven CSP Coordinating Center (WH-CSPCC). When a subject is to be randomized, the Study  
Coordinator or Local Site Investigator will complete the eligibility and baseline forms. If all 
eligibility criteria are satisfied and informed consent has been obtained, a new randomization 
will be assigned. This procedure will be tested and validated before enrollment begins.  
The WH-CSPCC will review the overall and by-site randomization at least weekly during the 
enrollment phase of the study, and will be monitoring the randomization transactions with equal 
or greater frequency. The participant’s unique study ID number will be linked in the 
randomization file to the treatment assignment for each individual. The randomization file data 
will remain separate from the rest of the study data on the central database. 
Randomization will occur in most cases on the same day the patient has completed the necessary 
portions of the Screening and Baseline assessments and is judged eligible for randomization. 

 
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Delay in randomization due to participant or medical circumstances are permitted up to a 
maximum of 30 days past baseline data collection. When a new participant has been enrolled, 
his/her electronic medical record will be updated indicating participation in the study. Source 
documentation for eligibility criteria and randomization will be kept at the site with the 
participant’s study folder.  
B. 
Blinding 
Neither the participant nor the study personnel at the site will be blinded to the treatment 
assignment. The variable block sizes included in the randomization scheme will be designed to 
help conceal the next treatment assignment for each site to reduce the chance of selection bias. 
The Study Biostatistician and the Data Monitoring Committee will operate with a blinded 
treatment coding (Treatment A versus Treatment B) for the analysis and review of the data, until 
such time that the DMC requests removal of the blind. As far as is feasible, decision-making 
within the study will be performed without removing this treatment code. 
 
 
 

 
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X. 
TREATMENT REGIMENS 
A. 
Overview  
Eligible patients who consent for the study will be randomized to ICD implant plus optimal 
medical therapy vs. optimal medical therapy alone. Standards for optimal medical therapy in the 
study will be defined by current practice guidelines, but will generally comprise medical 
therapies and lifestyle modifications. Optimal medical therapy will be closely monitored prior to 
enrollment, in order to be certain Veterans are receiving the best evidence-based care possible. In 
addition to optimal medical therapy, participants randomized to the ICD arm will have regular 
consultation with their Device Technician per standard clinical practice. 
B. 
ICD 
1. 
Overview 
Participants randomized to the ICD group will be implanted as soon as possible, with a target 
window of one week or less between randomization and implantation; this time frame is sought 
in order to minimize the opportunity for SAEs to accrue before study treatment can be delivered, 
and to create maximum compatibility between the AE collection window on OMT arm (first 30 
days post-randomization) and the OMT + ICD arm (30 days post-implantation). ICD therapy 
will be standardized with respect to rate cut off zone for defibrillation and anti-tachycardic 
pacing.  
2. 
Device Specifications 
This study will enroll patients eligible for standard single- and dual-chamber ICD devices. A 
dual-chamber device includes a pacing lead in the right atrium, plus a defibrillator lead in the 

 
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right ventricle. The atrial lead provides theoretical advantages to the pacing modality and 
diagnostics, particularly in the elderly 106, who are at higher risk for both sinus and AV nodal 
dysfunction. However, the clinical superiority of dual-chamber devices has not yet been shown 
conclusively and recent guidelines do not specifically address single- versus dual-chamber 
device selection. Dual-chamber devices may also carry a higher risk of adverse events 68,106,107. 
While the prevalence of dual-chamber devices is low or non-existent in the studies that are 
comparable to CSP #592, i.e. AVID, MADIT and SCD-HeFT 29,34,63, it has been reported that the 
number of dual-chamber devices in clinical practice are somewhat higher than those studied in 
clinical trials 108.  
CSP #592 will specifically exclude patients who meet the criteria of ICD implantation as 
secondary prevention, require a generator change on an existing ICD device, or who receive a bi-
ventricular ICD device. A bi-ventricular cardioverter-defibrillator (BiV ICD) provides cardiac 
resynchronization therapy for patients with congestive heart failure and left bundle branch block 
on EKG.  BiV ICD devices require left ventricular epicardial lead placement through the 
coronary 
sinus 
that 
may extend and complicate the implantation procedure. Cardiac 
resynchronization therapy is a distinct and dissimilar therapy from that delivered by the ICD, and 
the patients qualifying for BiV ICD implantation depart from those targeted for enrollment in 
CSP #592 and historically important clinical trials.  
Inclusion of patients due for generator change involves consideration of several aspects of high 
relevance to this study including implications on ethical treatment and study design. For 
instance, whether the patient has experienced shocks or not could make stratification intractably 
complex (or, if pooled with de novo implantations: make the patient pool untenably 

 
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heterogeneous), and inclusion of 5-year survivors of heart failure could skew mortality risk, 
introduce a survivorship bias, or risk introducing uncontrolled devices, device elements, or 
implantation variables into CSP #592. 
In summary, participants requiring single- and dual-chamber devices are eligible to enroll in CSP 
#592; any participants who are due for an ICD generator change, or are receiving a BiV ICD 
device will not be eligible for this study. 
3. 
Testing 
Defibrillation-threshold testing (DFT) involves inducing ventricular fibrillation to ensure reliable 
sensing, detection, and defibrillation from a recently-implanted device. DFT was considered 
prudent practice when failure of defibrillation was common, recipients had a high risk of 
ventricular tachycardia or ventricular fibrillation, and the only therapy for rapid VT or VF was 
shock 109. DFT incurs a small, but non-negligible risk of mortality (0.016%) and stroke (0.026%) 
110, but may be ineffective in extending one- or five-year mortality 111. There are currently no 
guidelines for when DFT should be implemented, and the benefits are thought to outweigh the 
risks in only a small number of patients 112,113. Therefore, the decision to carry out DFT will be 
left to the discretion of Study Investigator, with any such testing being noted in the study data 
base for possible adjustment in the statistical analyses. The Investigators of CSP #592 will be 
offered the following guidance: the decision of whether and how to conduct DFT is left to the 
discretion of the Study Investigator, with the expectation that the frequency of device testing 
commensurate with the usual practice of the Local Site Investigator. 

 
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4. 
Programming 
One potentially deleterious outcome that this study shall seek to avoid is that of inappropriate 
shocks. Strategically chosen device programming parameters have been shown in a clinical trial 
setting to significantly reduce the rate of morbidity index events in primary prevention patients 
when compared with the rate of events for patients in the historical physician-tailored control 
cohort 114–116. Specifically, programming strategies that prolong detection duration, increase the 
heart rate threshold of tachycardia detection, use supraventricular detection discrimination 
algorithms and ATP, and encourage first shock termination of tachyarrhythmias can safely and 
substantially reduce the number of tachyarrhythmias subjected to shock therapy 117.  
 
Moreover, it is recommended that single-chamber devices be programmed to back up VVI 
pacing 29. The parameters specified below have been shown to provide significant benefit over 
“discretionary programming” at the time of implant. In particular, brady pacing parameters and 
tachycardia detection and treatment parameters will be programmed to minimize ventricular 
pacing and minimize inappropriate therapy. Brady pacing will be set to VVI 40 BPM and 
tachycardia detection and therapy will be programmed based on parameters shown in 
randomized controlled trials to reduce the risk of inappropriate ICD therapy, as described in the 
following tables:  

 
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Table 10: Tachycardia Detection 
Make 
detection 
Rate/cycle length 
detection  
Delay or NID 
Monitor 
Rate/cycle 
length 
Monitor 
duration/NI
D 
Discriminators 
Medtron
ic 
VF: 
188 BPM /320 ms 
30/40 intervals 
171 
BPM 
350 ms 
32 intervals 
Stability 
50, 
Wavelet On, 
SVT limit 300 
ms 
Boston 
Scientific 
VF: 
200 BPM/300 ms 
2.5 seconds 
170 BPM 
350 ms 
2.5 seconds 
Onset 
On, 
stability On 
St. Jude 
VF: 
250 BPM/240 ms 
VT-2: 
214 BPM/280 ms 
VT-1: 
181 BPM/330 ms 
VF: 12 intervals 
 
VT2: 
18 
intervals 
 
VT-1: 
25 
intervals 
171 BPM 
350 ms 
20 intervals 
Onset 
On 
Stability ON 
Morphology 
ON 
“if all” in VT-1 
zone only 
Biotroni
k 
200 BPM/300 ms 
18 out of 24 
171 BPM 
350 ms 
26 intervals 
Stability 
with 
SMART 12% 
 
and 
 
Table 11: Tachycardia Therapy 
Make 
ATP 
shocks 
Medtronic 
ATP during charging 
1 Burst, 88%, 8 pulses 
Maximum 
Boston Scientific 
Quick Convert ATP ON 
Maximum 
St. Jude 
VF: none 
VT-2: 1 Burst, 85%, 8 stimuli 
VT-1: 2 Burst, 85%, 8 stimuli 
Maximum 
Biotronik 
ATP One Shot ON 
1 Burst, 85%, S1 number 8 
Maximum 
 
If during follow-up a clinical situation arises such that a modification of this 
programming is in the best interest of the patient programming changes are allowed and will not 
be a protocol violation. However, while the implanting clinician is very strongly advised to 
adhere to these programming parameters, it is possible that clinician judgment may call for 
change to some of these parameters. Deviation from this programming at the time of 

 
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implantation is allowed, but is considered a Protocol Deviation; in this case, Form 23 should be 
submitted to notify the study that a change in programming has been made.  
 
Thus, CSP#592 will expect all devices to be so programmed at time of implant. 
Programming changes that depart from these parameters at time of implant (whether 
intentionally or unintentionally) will be considered protocol deviation. After day of implantation, 
programming changes will be allowed based on clinical indications, such as development of 
heart block, development of slow VT, and syncope with VT/VF. Ultimately, the programming 
parameters will be left to the discretion of the investigator.  
5. 
Re-implantation 
Patients who have previously had an ICD or pacemaker explanted will not be eligible for entry 
into this study. For patients receiving an ICD as part of CSP592, and then being explanted and 
re-implanted, e.g. if the study implantation becomes infected and the device is removed and then 
re-implanted, then no new ICD Implantation Case Report Form (Form 12) is to be completed; 
the second implantation procedure is to be documented via a Process Note and Site Data Edit 
Form (Form 22) when the device or procedure information needs to be updated (as well as SAE 
and Hospitalization Forms, as appropriate). Adverse Events will be collected after any implant 
procedure; AEs will be assessed in two different analyses: 1) ‘index AEs’, occurring in the 30 
days following the first implantation procedure, and 2) ‘all AEs’, occurring in the 30 days after 
any implantation procedure.  

 
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C. 
Optimal Medical Therapy 
1. 
Overview 
Optimal Medical Therapy must be established prior to entry into the study, and will be 
documented at the time of Randomization. Notwithstanding this condition for entry, Study team 
members will be available to provide guidance on where to learn more about lifestyle 
modification, exercise training, and disease management as needed, so that every participant will 
be exposed to the basic skills required to sustain improved health and well-being. Participants 
will also be encouraged to discuss lifestyle modifications with their regular treating clinician; 
however, the instructions and –as applicable– educational materials provided by the Study Team 
will be the same as those that would be provided by the clinical care team outside of the study; 
there will be no study-wide materials provided. These activities comprise the field guidelines for 
primary prevention of cardiovascular disease and stroke. Details on these lifestyle principles 
follow.   
2. 
Physical Activity 
AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke, suggest 
moderate-intensity physical activity for 4-7 days of the week, at 40-60% maximum capacity, 
equivalent to a brisk walk (15-20 min per mile), at a duration greater than 30 minutes. Flexibility 
and resistance training are also recommended, with additional benefits gained from vigorous-
intensity activity (>60% maximum capacity) at a reduced frequency 73. Where it is anticipated 
that rigorous physical activity may not be appropriate for every participant in CSP#592, clinician 
discretion will be urged here. 

 
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3. 
Diet 
Participants will be encouraged to adopt a diet that includes a variety of fruits, vegetables, grains, 
low-fat or non-fat dairy products, fish, legumes, poultry, and lean meats. Energy intake should 
commensurate with energy needs, and changes should be made to achieve weight loss when 
indicated. Food choices should reflect a reduction in saturated fats (<10% of calories), 
cholesterol (<300 mg/day), and trans-fatty acids by substituting grains and unsaturated fatty 
acids from fish, vegetables, legumes, and nuts. Salt intake should be minimized, and alcohol 
should be limited: ≤2 drinks per day in men and ≤1 drink per day in women 73.  
4. 
Lifestyle Management 
Where appropriate, a management of concomitant risk factors and co-morbidities should be 
undertaken, in order to mitigate risk of cardiovascular events. Smoking cessation, weight 
management, and diabetes management are considered essential to a complete risk intervention 
in cardiovascular disease. Compliance with medications that regulate blood pressure, blood 
lipids, and normal sinus rhythm should be maintained 73. All patients will receive guidance on 
stress management techniques and –as appropriate– technical explanations about their device, as 
is recommended for best practices in patient education 100,118; this guidance will come from their 
regular treating clinicians de rigueur, but will made available upon request by the local Study 
Team, using whatever educational materials (pamphlets, etcetera) may be available locally.. 
5. 
Therapy Delivery 
All study participants will engage in an information session with the Local Site Investigator or 
Study Coordinator prior to randomization. During this session, participants will be advised of the 
AHA Guidelines for Primary Prevention of Cardiovascular Disease and Stroke, and provided 

 
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recommendations on how to implement the Guidelines. Participants will be invited to ask 
questions to their satisfaction, and a Study Team member will provide clinical referrals and/or 
provide printed materials as needed.  

 
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XI. 
FOLLOW-UP 
A. 
Time Table 
All randomized participants will be followed at 1 to 4 months post-randomization, and at 6-
month intervals starting from their randomization date, through study closeout (maximum 
follow-up 5 years). Most measurements will be collected at every 6-month visit. The schedule of 
baseline and follow-up assessments is given in Table 12 below. The estimated time to complete 
the follow-up is 15-30 minutes. All follow-ups will be performed by Central Follow-Up staff or 
the Chair’s Office. Every effort must be made to ensure equal study follow-up for both study 
arms. For this reason, participants randomized to OMT will also receive the 1-4 month follow-
up. This is an important and purposeful facet of the study design.  

 
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Table 12: Schedule of Baseline and Follow-up Assessments  
Evaluation/Form 
Approx. 
Time to 
Complete: 
Screening1 
Baseline1 
Day of Imp-
lantation1 
Initial  
Follow-up2 
Every 6 
Months2 
End of 
Study2 
As 
Needed1,2 
Informed Consent Form 
120 min 
X 
 
 
 
 
 
 
ICF Questionnaire 
5 min 
X 
 
 
 
 
 
 
HIPAA Authorization Form 
5 min 
X 
 
 
 
 
 
 
Form 01: Screening 
10 min 
X 
 
 
 
 
 
 
Form 02: Participant Contact Information 
5 min 
X 
 
 
 
 
 
 
Form 03: Release of Information 
10 min 
X 
 
 
 
 
 
 
Form 04: Baseline Demographics and Military History 
10 min 
 
X 
 
 
 
 
 
Form 05: Baseline Clinical History 
20 min 
 
X 
 
 
 
 
 
Form 06: Baseline EKG 
30 min 
 
X 
 
 
 
 
 
Form 07: Baseline Laboratory Measurements 
15 min 
 
X 
 
 
 
 
 
Form 08: Physical Examination 
30 min 
 
X 
 
 
 
 
 
Form 09: Baseline 6-Minute Walking Test 
20 min 
 
X 
 
 
 
 
 
Form 10: Medication Use 
15 min 
 
X 
 
X 
X 
 
 
Form 11: Quality of Life 
10 min 
 
X 
 
 
X[a] 
 
 
Form 12: ICD Implantation  
20 min 
 
 
X 
 
 
 
 
Form 13: Follow-Up 
5 min 
 
 
 
X 
X 
 
 
Form 14: ICD Follow-Up 
10 min 
 
 
 
X 
X 
 
X 
Form 15: Therapy Event Report 
10 min 
 
 
 
 
 
 
X 
Form 16: Therapy Event Adjudication Form 
20 min 
 
 
 
 
 
 
X3 
Form 17: Adverse Event 
30 min 
 
 
 
 
 
 
X 
Form 18: Serious Adverse Event 
15 min 
 
 
 
 
 
 
X 
Form 19: Hospitalization 
20 min 
 
 
 
 
 
 
X 
Form 20: Adjudication (Death Review) 
30 min 
 
 
 
 
 
 
X3 
Form 21: Note-to-File 
5 min 
 
 
 
 
 
 
X 
Form 22: Site Data Edit 
5 min 
 
 
 
 
 
 
X 
Form 23: Protocol Deviation 
20 min 
 
 
 
 
 
 
X 
Form 24: Withdrawal Form 
5 min 
X 
 
 
 
 
 
X 
Form 25: Exit Form 
10 min 
 
 
 
 
 
X 
 
[a] Form 11: Quality of Life is only collected at months 6 and 12 and 24 of follow-up., 2Completed by Central Follow-Up Personnel or Chair’s Office, 3Completed by a 
designated adjudication committee 
 
 

 
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B. 
Follow-up Procedures 
1. 
Measurement of Outcome Variables 
Quality of Life will be measured in-person during baseline observation, and over the phone at 
months 6, 12 and 24.  
Additionally, ICD interrogation records will be reviewed for device-related complications, such 
as lead failure; the device itself will be interrogated to confirm proper functioning, and to 
determine if any episodes of ICD therapy have occurred. The results of ICD interrogation will be 
saved in .PDF format, and transmitted to the study center.  
2. 
Remote Monitoring 
In addition to regularly scheduled follow-up, participants randomized to the ICD implantation 
arm will be monitored where possible using standard device interrogation performed either in 
association with their follow-up phone calls, or whenever device reports are generated, usually 
following therapy delivery. All therapeutic activities will be recorded via the device’s remote 
monitoring capabilities, which capture salient physiological data prior to a device-delivered 
therapy, as well as information about the intervention itself and information about device 
programming changes. As part of routine clinical practice, these data are transmitted from the 
device to the manufacturer, placed in a VA-sponsored database accessible to the central follow-
up office , and communicated to the treating clinician. The CSP#592 Study Team will access this 
record in parallel, obtaining either from the device manufacturer or the National Registry; the 
Study Team’s access of the record will not interfere with the treating clinician’s ability to receive 
and act on this information. Data are taken from the device in a completely non-invasive way, 

 
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i.e. the participant is uninvolved and unaware of the transmission: no participant contact or 
interaction is necessary for data exchange. 
In addition to device interrogation during clinic visits participants in the ICD arm will also be 
followed via remote monitoring where possible, which is now part of the standard of care for 
ICD patients in the VA system. Participants may be provided with a home monitoring device that 
can communicate wirelessly with their ICD and will download and transmit a complete 
interrogation of the ICD on a regular schedule (usually every 6 months). In addition, 
unscheduled transmissions can be initiated by the ICD if preprogrammed criteria such as lead or 
battery failure are met. Finally, the participants can initiate a manual transmission if they are 
instructed to do so by a member of the Study Team, or if they feel like they may be having an 
issue with their ICD. PDF files documenting all remote transmissions will be forwarded to the 
national study center and the site investigators by a VA-sponsored device database .  
 
Data obtained from these transmissions will contain PHI including name and SSN. These 
reports will be protected in the same way as all other case report forms: their access will be 
granted to Study Team members on a need-to-know basis, and will be stored behind the VA 
firewall. Besides the Study Team (Chair’s Office, Central Follow-Up Office, and WH-CSPCC), 
a given report will only be viewable by select members of the Events Adjudication Committee 
(see Section XII. B.). Permission for the Study Team to access this record is granted by the 
patient in their consent into the study and through registration for the National Database; there is 
no need for a separate Data Use Agreement with an external agency or manufacturer.   

 
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C. 
Study Withdrawal and Crossover 
A participant may choose to withdraw from the study at any time. If a participant withdraws or is 
permanently lost to follow-up, a Study Exit Form will be completed. The study will employ an 
intention-to-treat analysis, i.e. participants will be analyzed as randomized whether or not they 
receive their protocol-assigned treatment. Patients who wish to withdraw from treatment, e.g., 
decide against the ICD implant after randomization, request that ICD implant be explanted or 
disabled, or for those enrolled to the OMT who receive an ICD implant in the follow-up period,  
will be asked to still complete all follow-up contacts. If a participant withdraws consent to be 
followed, the person will be withdrawn from further study except for the collection of publicly 
available data, e.g. survival data. When participants consent to enroll they will be informed that 
the collection of survival data from public record sources will continue even if they withdraw 
from follow-up. All other data collected up to the point of withdrawal will be used in the 
analyses; study follows an “intention-to-treat” design: in the case of ‘cross-over,’ any patient will 
be included in the group to which they were assigned. 
D. 
Study Termination and Closeout 
The VA Cooperative Studies Program, as the sponsor of the trial, may stop the study at any time 
based on funding issues or internal or external evidence that the study is no longer feasible or 
ethical to continue. The Data Monitoring Committee will be the only group that can review 
unblinded outcome data and can at any time recommend to the sponsor that the trial be 
terminated because of efficacy, safety, or futility. The DMC will also make a recommendation to 
Central Office whether to expand the study from Pilot stage to its planned Full-Scope. The 
Executive Committee, in consultation with the Data Monitoring Committee and the CSP 

 
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Director, can also terminate individual sites from participation in the trial. If a site or the entire 
trial is terminated, participating sites will be notified and given a closeout plan and a schedule at 
that time.  
At the final study follow-up contact, participants will be withdrawn from the trial. Participant 
exit will be scheduled over the final 3 months of the trial.  In most cases, site personnel will be 
funded for 30 days following the termination of the study or site to clean and store data. After 
publication of the primary study results, site investigators, if requested, will inform participants 
of the study’s results. The Executive Committee will also consider providing each site 
investigator with a lay summary of the trial that can be used to be mailed to all participants. 

 
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XII. 
STUDY MONITORING AND QUALITY CONTROL PROCEDURES 
A. 
Overview  
The VA Cooperative Studies Program establishes overall policies and procedures that are applied 
to all VA cooperative studies through the Principal Proponent’s office, and the West Haven 
Cooperative Studies Coordinating Center (WH-CSPCC). The Cooperative Studies Scientific 
Evaluation Committee (CSSEC) reviews the scientific merit of all new cooperative study 
proposals. The CSSEC is composed of both VA and non-VA clinical research scientists and 
biostatisticians. The organizational and administrative structure of this cooperative study is 
similar to others in the Cooperative Studies Program and includes the components described 
below. 
B. 
Monitoring Bodies and CSP Monitoring 
The Executive Committee is chaired by the Principal Investigator and consists of the study 
Biostatisticians, study Research Pharmacist, selected participating investigators, and expert 
consultants.  The Executive Committee is concerned with overall study management and is the 
decision-making body for the operational aspects of the study. The Executive Committee 
monitors the performance of participating medical centers and quality of data collected, plans the 
publications, and oversees the publication and presentation of all data from the study.  The 
Executive Committee must grant permission before any study data may be used for presentation 
or publication. This committee meets by conference call typically on a monthly basis to review 
the study progress and meets every 12 months to review blinded study data, decide upon changes 
in the study, determine the fate of sites whose performance is substandard, initiate any sub-
protocols, and discuss publication of the study results. 

 
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The West Haven Cooperative Studies Program Coordinating Center (CSPCC) and the Principal 
Investigator administer the trial, oversee its organization, and perform the day-to-day scientific 
and administrative coordination of the study. These duties include developing the study protocol, 
operations manual, and case report forms; ensuring the appropriate support for the participating 
centers; scheduling meetings and conference calls; responding to site queries about the protocol; 
conducting site visits; publishing newsletters; preparing interim and final progress reports; and 
archiving study data. Participant accrual and data quality are monitored closely to ensure that the 
study is progressing satisfactorily. 
Local IRBs or the VA Central IRB (CIRB) serves as the oversight body for the protection of 
human subjects. The study is reviewed and approved by the IRB of record at the initiation and 
continuing review. If the IRB of record is the VA CIRB, each site's local R&D must also review 
and approve the local site’s involvement in the study. 
The CSP Clinical Research Pharmacy Coordinating Center (CSPCRPCC) is responsible for 
monitoring and reporting the safety of trial participants through the review, assessment, and 
communication of adverse events and serious adverse events reported by study personnel. The 
CSPCRPCC’s responsibilities occur through ongoing communication with the Study Chair, 
Executive Committee, West Haven CSPCC, and CSP Central Office. The reporting activities 
include the filing of regulatory documents involving adverse events to meet applicable federal 
regulations and CSP policies. In conjunction with the West Haven CSPCC, the CSPCRPCC 
prepares reports safety data for various committees including the Data Monitoring Committee, 
the IRB, Executive Committee, and the study group.   

 
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The Data Monitoring Committee (DMC) provides interim, independent, and unbiased reviews of 
the study's ongoing progress. The DMC is composed of clinical and statistical members who 
have expertise in clinical trials and/or the subject area(s) of the study. These experts are not 
participants in the trial and have not participated in the planning of the protocol.  The Principal 
Proponent, study Biostatisticians, Clinical Research Pharmacist, and the Director of the CSPCC 
are ex officio (liaison, non-voting) members of the DMC. The DMC meets at least annually to 
review the progress of the study and monitor participant intake, outcomes, adverse events, 
serious adverse events, and other issues related to participant safety.  At its meetings, the DMC 
reviews the randomization rates and assess the difference between the actual and the projected 
rates, as well as the impact of these assessments on overall trial size.  If the study enrollment is 
inadequate, impediments to enrollment will be discussed and the reasons for patient exclusion 
may be scrutinized and actions may be suggested.  The DMC’s primary responsibilities are to 
review safety and the progress of the study and to decide whether or not the study should 
continue. To help the Committee make its assessment, the Principal Proponent and Study 
Biostatisticians will provide the DMC with appropriate monitoring data before each meeting. 
The DMC makes recommendations to the Director, VA CSR&D about whether the study should 
continue or be stopped.   
A member of the Human Rights Committee (HRC) at the Coordinating Center conducts a site 
visit to at least one participating center during the course of the study to determine if 
participants’ rights and safety are being properly protected. The HRC member may interview 
study participants during the site visit. 

 
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The Adjudication Committee will consist of 3 to 5 members nominated by the Executive 
Committee and chosen for their clinical and technical expertise. Committee members will 
establish a standard adjudication procedure. The Committee will periodically review endpoint 
reports and relevant clinical information and vote as to whether or not reported endpoints satisfy 
the protocol-defined criteria for cardiovascular or sudden cardiac death.  
The ICD Events Committee will comprise qualified members of the Study Team, including 
Local Site Investigators and Executive Committee members, as well as staff in the Central 
Follow-Up office; the Committee Chair will be a member of the Executive Committee. Device 
interrogation reports will be circulated to Committee members who will review and categorize 
each report. Each report will be read by two Committee members; if the reviewers agree, the 
classification will be noted, if there is disagreement, the report will be reviewed either by a third 
Committee member, or the Committee Chair; once the third vote is cast, the classification will be 
determined by the majority vote. Reviews will be performed ad hoc, but the Committee will 
assure “clearance” of reviews every 6 months in the main study, to ensure timely review and to 
prevent data backlog.  
The Local Site Investigator (LSI) at each participating VA medical center is responsible 
administratively and scientifically for the conduct of the study at the center. The LSI is expected 
to attend all annual Study Group meetings, as well as to hire and supervise local study personnel. 
By agreeing to participate in the study, the VAMC delegates responsibility for global monitoring 
of the ongoing study to the DMC, the CSPCC Human Rights Committee, the IRB of record, and 
CSSEC. However, the Research and Development Committee (R&D) of the medical center may 
require the participating investigator to submit annual reports concerning the status of the study 

 
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at the medical center for local monitoring purposes. The LSI will be assisted by the Study 
Coordinator; it is recommended that the Study Coordinator having a background in nursing, 
however this is not a strict requirement: hiring of non-nurse Coordinators is allowed. 
The Study Group consists of the Principal Proponent, the CSP staff (Biostatisticians, Project 
Manager, Clinical Research Pharmacist, and others), all participating local site investigators, and 
research coordinators. The Principal Proponent leads the Study Group, which typically meets 
monthly by teleconference and once per year in face-to-face meeting to discuss the progress of 
the study, any problems that the investigators have encountered, and any suggestions for 
improving the study. No endpoint data are presented to this group while the study is ongoing.  
The Site Monitoring, Auditing and Review Team (SMART), located at the CSP Clinical 
Research Pharmacy Coordinating Center (CSPCRPCC) in Albuquerque, will provide Good 
Clinical Practices (GCP) training at the kick-off meeting and will conduct monitoring visits at all 
sites.  A SMART member visits participating sites shortly after enrollment is initiated and 
annually thereafter to monitor investigator regulatory compliance, protocol adherence, and 
overall research practices.  In addition to the regularly scheduled GCP review visits, an 
independent comprehensive GCP site audit may be conducted at any time at the request of CSP 
study management. 
C. 
GCP Monitoring Visits 
A member of the Site Monitoring and Review Team conducts at least one site visit to each site 
during the enrollment period for monitoring GCP and study protocol adherence (see Section 
XIV).  The purpose of these visits is to encourage and assess compliance with GCP 

 
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requirements.  Additional monitoring visits may be conducted as deemed necessary by study 
leadership or SMART.  The investigator is contacted prior to the visit to arrange a mutually 
agreeable time for the visit.  The SMART reviewer is on site for approximately two days to 
review study records and discuss the conduct of the trial.  The SMART reviewer examines 
participant study files, including source documents held electronically, in clinic files and 
participants’ official medical records and reviews regulatory and essential documents, such as 
IRB correspondence.  Areas of particular concern are informed consent issues, protocol 
adherence, safety monitoring, IRB reviews and approvals, regulatory documents, participant 
records, site operations, and investigator involvement. The local site is required to document 
protocol breaches and any medical center with repeated protocol violations is reported to the 
Executive Committee and the Director, VA CSR&D.  If a participating site investigator feels that 
adherence to the protocol will be detrimental to a particular participant’s health or well-being, 
the interest of the participant must take precedence.  Monitoring may include but is not limited to 
the informed consent process, data validation, source verification, and safety reporting. The 
Executive Committee will consider recommending additional SMART site visits for any 
participating centers with repeated protocol violations to evaluate a sites’ need for additional 
training to remedy compliance concerns. Additional site-specific monitoring may be conducted if 
triggered by study performance metrics. For-cause audits may be conducted at any time if 
requested by the study leadership or CSP Central Office. For-cause audits can be announced or 
unannounced. In addition to SMART visits, WH-CSPCC, the Executive Committee, and DMC 
will 
monitor 
protocol 
adherence centrally through periodic reports, data queries and 
coordinator/PI conference calls. 

 
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D. 
Monitoring Participant Intake and Probation or Termination of 
Participating Sites 
The Study’s Executive Committee, Principal Proponent and the Study Biostatisticians will 
monitor the intake rate and operational aspects of the study.  The Executive Committee may take 
action leading to the discontinuation of enrollment at a center with the concurrence of the 
Director, VA CSR&D. Participating medical centers may continue in the study only if adequate 
participant intake is maintained.   
The target enrollment for the study is 1,462 Veterans. If recruitment is not proceeding at an 
appropriate rate, the Principal Investigator and the Study Biostatisticians will scrutinize the 
reasons for participant exclusions and other barriers to recruitment.  Based on this information, 
the Executive Committee may choose, with the approval the Director, VA CSR&D, to drop 
centers or add additional centers, or with the concurrence of the DMC, and the Director CSR&D 
make modifications to the inclusion/exclusion criteria, or extend the recruitment period in some 
or all centers and/or to extend the total length of the study.  
Medical centers will only be allowed to continue in the study if adequate participant intake is 
maintained. The target recruitment for each VA site is 17 participants per year (approximately 1 
every 3 weeks). Because there is usually a ramp-up in recruitment early on, during the main 
study phase, sites that do not enroll at least four participants during their first six months, or 
twelve participants within the first year, will be considered for probation or reduction in funding.  
Since the Pilot study will be operating at six sites selected on the basis of projected high 
recruitment, all sites within the Pilot study must meet at least 90% of the target enrollment of 17 
patients within the first year; satisfaction of this recruitment criteria by these “vanguard” sites 

 
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will provide evidence of study feasibility in full-scale operation over a wider range of sites. If a 
medical center is placed on probation, the Principal Investigator and Study Biostatistician confer 
with the site personnel and, if necessary, visit the site to help improve the rate of recruitment. If 
there is no improvement in accrual after the probation period, the site may be subject to reduced 
funding or possible termination as a study site. The Executive Committee only takes actions 
leading to discontinuation of a center with the concurrence of the Director, VA CSR&D.  If a 
center is terminated from the trial, resources are reallocated to other centers or used to start up a 
backup site.  
E. 
Monitoring Medical Center Performance 
Strict adherence to the protocol is expected of every participating center and monitored by the 
DMC, the Executive Committee and the Study Group.  Data quality and the completeness of data 
retrieval, including the Screening Tracker, are closely monitored on an ongoing basis by the 
WH-CSPCC.  The Study Biostatistician presents interim monitoring reports, overall and by site, 
to the Executive Committee and DMC that include the following types of information: 
recruitment of participants, characteristics of the population, completeness of data retrieval, and 
data quality.  If a site is identified as an outlier in terms of data quality, a site conference call or 
site visit is initiated to assess the reasons that problems are occurring and how they can be 
corrected.  If the problems continue, the site may be placed on probation or terminated from the 
study if the problems cannot be corrected.  
F. 
Monitoring Participant Safety 
The local site investigator is responsible for following adverse event reporting requirements as 
outlined below in the Protocol. These responsibilities include: 1) reviewing the accuracy and 

 
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completeness of all adverse events reported, 2) compliance with IRB policies for reporting 
adverse events and/or serious adverse events, and 3) closely monitoring research participants at 
for Adverse Events (AEs) or Serious Adverse Events (SAEs).  All AEs and SAEs are recorded 
on the appropriate event form(s).  Active monitoring of SAEs begin as soon as the study 
participant provides consent and continue until the participant completes follow-up. In this study, 
we will only monitor AEs for 30 days post-randomization (OMT arm) or 30 days post-
implantation (OMT + ICD arm). We identify several SAEs that will not require immediate 
reporting to CIRB, in order to enable detection of clinically meaningful safety information. 
These SAEs include  
 
Bleeding/Hematoma 
 
Incisional pain 
 
Infection: ICD pocket or lead; requiring antibiotic treatment or explant 
 
Infection: Other, requiring antibiotic treatment 
 
Lead dislodgement 
 
Lead fracture 
 
Pacing parameters require lead replacement or revision 
 
Pneumothorax 
 
Myocardial infarction (MI) 
 
Stroke 
 
Tachyarrhythmia/atrial fibrillation 
Unexpected SAEs will follow regulations for timely reporting to CIRB: All Serious 
Unanticipated 
Problems 
involving 
risks 
to 
subjects or others and all Serious 

 
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Unanticipated SAEs as defined by VHA Handbook 1058.01 will be reported to the CIRB 
within 5 business days of becoming aware of the problem or event. 
Sites will be responsible for safety surveillance in order to capture serious adverse events 
in a timely manner, e.g. through alerts in the local medical record or periodic searches of 
the medical record for hospitalizations. Whomever encounters news of an event must 
report that event via the proper reporting pathways (SAE case report form, and when 
appropriate for unexpected and related problems: Form 119 to Central IRB). The sites 
and Central Follow-Up office are asked to notify each other of event discovery for 
maximum efficiency. Once the initial event report has been processed, its 30-day follow-
up will be the responsibility of the Central Follow-Up Office.  
G. 
Adverse Event Definition and Monitoring 
While an AE does not necessarily have to have a causal relationship with the research, in CSP 
#592 only non-serious AEs will be collected, related to the treatment of heart failure. Adverse 
Events will be collected for 30 days after implantation (OMT + ICD arm) or 30 days post-
randomization (OMT arm). Relatedness involves an assessment of the degree of causality 
(attributability) between the study intervention and the event. Site investigators are asked to 
provide an assessment of relatedness. All AEs with a reasonable causal relationship to the 
investigative treatment should be considered “related” and will be collected. A definite 
relationship does not need to be established. AEs are defined in Section XIV. 

 
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H. 
Serious Adverse Event Definition and Reporting 
Serious Adverse Events (SAEs) are defined in Section XIV. All SAEs whether or not they are 
considered related will be collected in CSP #592. Site investigators will still be asked to provide 
an assessment of relatedness as the assessment provided by the site investigator is part of the 
information used by the sponsor to determine if the SAE presents a participant safety concern.  
Any SAE that originally started as a non-serious AE that was not reported at the time of the 
event because it was considered unrelated will be reported within 72 hours of becoming an SAE 
as defined above regardless of relatedness.  
I. 
Minimizing Attrition 
As a primary way to minimize drop-out from the study, the investigators provide thorough pre-
enrollment education for all prospective participants about the study objectives and procedures in 
order to assess and confirm the participants’ commitment to and feasibility for long-term follow-
up.  The investigators also provide ongoing education during the study to reinforce the 
participants’ commitment to long-term follow-up.  As an alternative to telemedicine, members of 
the Study Team will be allowed to travel to a location in the community in order to make more 
convenient contact with the participants for assessments.   
To contend with the challenge of getting participants to participate in baseline data collection, 
attendance at these visits will result in patient compensation; all subsequent follow-ups will be 
conducted centrally, via telephone, minimizing participant burden, and will therefore not 
generate participant compensation.  All participants would be compensated for each completed 
in-person visit regardless of whether they continued in the study or exited the study at the 
completion of the visit.   To minimize the risk of financial coercion, the payment will be 

 
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relatively modest. In addition, there are minimal risks involved in these assessments (i.e. no 
invasive procedures, physical demands, or medications interventions are required in order to 
receive payment). Distant participants will receive this same reimbursement for all compensable 
study visits; travel to-and-from the implanting Center will not be compensated by the study. 
These travel costs will be managed per regular VA clinical reimbursement regulations.  
J. 
Remote Monitoring 
ICDs are capable of delivering information related to a wide range of parameters including 
activity level, heart rate variability and battery and lead status. In general clinical practice, the 
remote monitoring feature may increase quality of care by providing a platform for information-
driven decision making and timely event reporting, and may reduce anxiety of a device 
implantation if the device functionality can be ascertained by trained clinicians or technicians. 
Remote ICD monitoring reduces emergency department/urgent in-office visits, and in general, 
total healthcare utilization in patients with ICDs, and in the clinical trial setting, has shown the 
capacity to increase efficiency for healthcare providers, and improve the quality of care for 
patients 119. Remote monitoring also provides benefits to the Study Team, as it 1) provides 
accurate, objective, and timely record of events, 2) provides a platform for assessing protocol 
adherence with regard to device programming, and 3) reduce losses to follow-up. 
The analysis of remotely acquired data will be limited in scope to Routine assessment of ICD 
therapy events, and Device interrogation upon death (where feasible).  

 
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XIII. QUALITY CONTROL AND DATA MANAGEMENT PROCEDURES 
A. 
Data Collection Methods 
1. 
Data Capture 
The data for CSP #592 will be managed by the WH-CSPCC using a web-based data capture 
system and/or paper / fax based optical character recognition software system. The Cooperative 
Studies Program may implement a new web-based data capture system prior to the launch of 
CSP #592 in its full scope. The system will meet or exceed all VA data security requirements 
and will be fully described in the study’s Operations Manual. The system will allow approved 
site investigators and personnel to enter study participant data directly into web-based forms and 
thus track and manage their patients, complete randomization, record data in electronic case 
report forms (CRFs), receive data clarifications, and correct participant data online.  Data 
collected on source documents at the site (paper and/or electronic medical records) will be 
entered in the data capture system and be submitted to a central study database.  Paper versions 
of the CRFs will be supplied to the sites for recording of source clinical data if needed.  This data 
capture system may be tested for viability during the Pilot phase of CSP#592. 
If an electronic data capture system cannot be validated or made accessible by study initiation, 
the backup data collection system for the study will be a paper based system.  If paper forms are 
used, they will be submitted via tracked overnight mail or fax to the WH-CSPCC fax server (see 
Section XVIII.A.2.). The PDF forms will be accessed and completed on-line or by copies 
provided to the sites on their local PC. These forms will be easy to navigate and have data edit 
checks (e.g. min/max ranges, allowable values, must-enter fields) programmed into the forms 

 
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and will be reviewed regularly so that data errors will be reduced and corrections can be made as 
data are collected.  All study data will be transferred into SAS datasets for reporting and analysis. 
Updates to the electronic forms and database can be generated during the study without affecting 
collected data.  Study reports will be generated from exported data in order to track the study 
progress and to monitor adverse events, particularly Serious Adverse Events.  Study reports will 
be circulated to appropriate personnel including the Study Chairman, the Site Investigators, CSP 
program sites, the Executive Committee, and the Data Monitoring Committee. 
2. 
Paper CRF and Source Document Tools 
Although a web-based data capture system is expected to be used to collect study data for the 
study central database in the study’s full-scale implementation, paper data collection tools will 
still be needed at the sites.  Any information that is not recorded in the study participant’s VA 
electronic medical record will need to be recorded on a source document tool or paper study 
CRF.  Paper CRF will be required for two reasons:  1) Collection of participant self-reported 
responses to study questionnaires, and 2) as a backup in the event that the data collection system 
is not accessible due to system/network failure or downtime.  The paper CRF will be readable by 
optical character recognition software (e.g. Teleform ® Elite v. 10.0 or higher, by Cardiff, Inc.).  
Electronic scanner-readable e-PDF versions of the data collection forms will be sent to the sites.  
The e-PDF versions may be completed on a personal computer at the study site.  If a form is 
completed on a personal computer or terminal, a completed copy of the form must be printed.  
The printed copy will be faxed to the WH-CSPCC fax data server or mailed via tracked 
overnight mail to the WH-CSPCC.  The printed copy kept at the site will be filed in the 
participant study folder.  Once the forms are received at WH-CSPCC, they will be processed 

 
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through the Teleform form reader and verifier software where a research assistant at the WH-
CSPCC will review the forms for consistency and completeness.  CRFs processed by the 
Teleform Verifier will be exported to an image file folder, and the extracted data items will be 
exported to a comma-delimited file in a data capture folder, both on a secure WH-CSPCC file 
server.  In case of persistent fax transmission problems, sites may be asked to post e-versions of 
the CRFs to their secure study-site sub-page on the CSP592 SharePoint site. All changes or 
corrections to data entered on paper CRF forms will be dated and initialed by site personnel on 
the original CRF and the associated data edit sheet if applicable. 
B. 
Data Quality Control 
After the study is approved, the Case Report Forms (CRFs) will be field-tested using the data 
capture or paper-based system.  Communication between WH-CSPCC, CSPCRPCC, the Study 
Sites and the central database will be tested.   
On a weekly basis, or more frequently, programmers at WH-CSPCC will transfer the cumulative 
data in the central database to SAS datasets on the CSPCC UNIX server.  SAS programs will be 
run to generate reports that summarize the accumulated study data and data exceptions (e.g., 
missing forms or data, any out of range values). These notices may request completion, 
correction, or verification of specific data items.  A computerized record will be kept of the 
number and types of errors to ensure a high level of data integrity.  Interim progress reports of 
cumulative errors and overall data quality will be sent to the investigators, the Executive 
Committee, and the DMC.  Unresolved data queries will be included in the datasets that will be 
used in interim reports.  However, every effort will be made to resolve all outstanding Data 
Correction Forms (DCFs) prior to a DMC report. 

 
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Data files on the central study database containing the accumulated participant information will 
be examined for completeness and consistency at regular intervals.  Tested and validated 
computer programs will check newly entered forms for missing or out-of-range values.  
Computer-generated notices will be mailed to the participating investigators requesting 
completion for forms and follow-up on DCFs for correction or verification of specific data items.  
A computerized record of the types of errors will be kept in order to ensure a high level of data 
integrity. 
At periodic intervals, a cumulative record of errors and data quality progress reports will be sent 
to investigators and the Study Chairman.  Data edits and removal of duplicate records will be 
applied to the data files on a regular basis, and cleaned (final) files through the time of the most 
recent running of data edits will be created.  These final files will be used to run monitoring 
reports on a regular basis. The progress of data collection will be monitored with computerized 
data form inventory programs that will produce a profile of all forms expected and received for 
each study participant.  Missing-forms reports will be generated and sent to the sites periodically 
during the enrollment phase of the study. 
Data quality will be monitored on an ongoing basis by the WH-CSPCC.  The Study 
Biostatistician will present interim monitoring reports to the Executive Committee at least 
monthly and to the DMC at least annually.  Interim reports will include recruitment of 
participants, characteristics of the population, completeness of data retrieval, and data quality.  
Prototype tables are given in Appendix D and serve as an example of the statistical reports that 
will be generated for study monitoring by the Executive Committee and the DMC. 

 
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C. 
Electronic Study File 
CSP has established a Clinical Trials Management System (CTMS).  This system is hosted on a 
server at a secure VA regional data facility and is based in a MS SharePoint platform.  An MS 
SharePoint site or similar CTMS will be used for maintaining an electronic version of the Central 
Study File for this study.  Participating medical centers will be able to access current and past 
versions of the Study Protocol, Operations Manual, Operations Memoranda and other work 
instructions, CRFs, and other study-related documentation, as well as meeting announcements, 
conference call notices, and study newsletters using the CTMS.   
D. 
Quality Control of the Process 
The Study Chairman and the WH-CSPCC will prepare an Operations Manual that will be 
provided to the local site investigators as a guide to the operation and management of the study 
as well as a technical reference manual.  A training session will be held at the study kick-off 
meeting(s) for all study personnel in order to: (1) assure uniformity in participant management 
and data collection procedures, and (2) train the personnel in study procedures and criteria. 
Study procedures will be reinforced by the use of regular conference calls, particularly in the first 
few months of the study and by the periodic distribution of a study newsletter.  All study 
personnel will attend group meetings during the enrollment period when study procedures again 
will be discussed in detail.  The Study Chairman’s Office and the WH-CSPCC study personnel 
will be available to clarify study procedures by telephone, fax and e-mail. 
If the Executive Committee determines that a procedure must be changed, the participating sites 
will be informed by conference call and/or newsletter, and an updated section of the Operations 

 
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Manual pertinent to the changed procedure will be provided to all sites. The trial will be 
conducted in compliance with Good Clinical Practices (see Section XVII). 
E. 
Data Security 
CSP has a commitment to maintaining data security and patient privacy.  Standard practices and 
policies as part of the responsible conduct of clinical research studies are implemented and 
reviewed periodically.  CSP Center Directors are responsible for ensuring that all CSP Data 
Security Policies are enforced within their Centers.  All study data collected will be handled, 
maintained and stored according to CSP standard practices and policies. This includes but is not 
limited to the following:   
 Protected Health Information (PHI) as defined by HIPAA will not be used for any 
purpose that is not related to the activities of this study. 
 Records are identified only by a participant identification number.  
 Patient identification numbers are not derived from or related to information 
about an individual. 
 All electronic PHI are stored on secure servers and may not be moved to a PC or 
other external device. 
 Paper CRFs, if any, are stored in locked file cabinets and rooms. 
 When necessary, PHI (exclusive of HCPHI) may be transported between secure servers.  
PHI must be encrypted and password protected while being transferred using a FIPS 140-
2 certified program.  Any removable storage device used to transfer PHI (e.g., hard-copy 
printouts, data tapes, encrypted CDs, encrypted USB drives, etc.) should either be 
destroyed after transfer is complete or given to the Data Security Administrator to be 

 
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secured in a secure, fireproof safe.  A trackable mail system must be used for the physical 
data transfers. 
 Data from studies are utilized at CSPCC and are not removed from the Center.  
 No PHI may be sent via MS Outlook or Exchange unless the message is secured utilizing 
encryption and VA-authorized security protocol. 
 Documents sent for medical evaluation purposes (e.g., endpoint adjudication) are sent via 
trackable express mail.  Personal information is redacted by the VAMC or CSPCC if not 
determined to be necessary for completing the evaluation. 
 Only VA-owned equipment or equipment configured to VA security standards is 
permitted to directly connect to the CSP networks in accordance with VA Directive 6504.  
Non-VA sites will submit data through a secure Demilitarized Zone (DMZ). 
 Training, reminders, and signed data security statements are used to ensure CSP 
personnel understand VA policies. 
 Sharing of CSP study data outside of CSP requires the approval of the Director, CSR&D, 
and data use agreements.  In addition, sharing of data outside of the VA requires local 
ISO, PO, and ACOS-R approvals. 
Any data capture system used for data collection in this study will be fully compliant with US 
Federal regulations regarding electronic web-based data capture systems established by the FDA 
under 21 CFR 11.  Data entered directly into the central database provides the official clinical 
record for data collection.  Source documentation is handled in the same manner as a paper based 
system.  All paper-based records will be kept under lock and key.  

 
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The electronic data capture system will utilize state-of-the-art technologies that meet or exceed 
the current VA standards for transport in order to protect the data during transmission. In brief, 
electronic systems will employ secure socket layer technology and FIPS 140-2 compliant 
encryption algorithms to ensure that data is not vulnerable during transport. Hard copy data will 
be sent via a traceable mail system (i.e., UPS), via a courier, or via secure fax. 
Access to the study data will be afforded the same level of security as all forms of VA protected 
and/or highly sensitive information. Access is heavily restricted to individuals with CSP 
approval to access the data. Individuals must be properly credentialed research staff and must be 
compliant with VA security trainings (i.e., Research Data Security, HIPAA and VA Privacy 
Training, Cyber-Security, and Good Clinical Practices).  In addition, research data will be stored 
on VA secure servers with restricted permissions for copying and exporting data. Only properly 
approved Coordinating Center personnel will have the ability to copy and export data. These 
individuals have received training on the local SOPs governing their permissions and will not 
access or export data without written approval from the Coordinating Center Director. 
Furthermore, the permissions of the electronic systems are structured such that individual sites 
can only see the data for their study participants, and they cannot see or access the data for 
another clinical site or for another participant. 
Backup copies of the database will be transferred to the WH-CSPCC behind the VA firewall on a 
frequent basis depending on the study need.  These backup copies will be transferred and stored 
across secure connections according to VA regulations and WH-CSPCC operating procedures. 
Periodic off-site back-ups will be made as part of a comprehensive disaster recovery plan.  

 
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F. 
Data Management and Access Plan (DMAP) 
Upon final analyses of the stated objectives in this proposal, the study plans to submit results for 
publication 
in 
scientific 
peer-reviewed 
journals 
and 
provide 
summary 
results 
on 
clinicaltrials.gov. After acceptance of the primary and other stated analyses by a journal, CSP 
will make these publication(s) available via the National Library of Medicine’s PubMed Central 
within a year of the date of publication. 
Digital data underlying primary scientific publications from this study will be held as part of a 
data sharing resource maintained by the Cooperative Studies Program (CSP). Study data held for 
this purpose may include data, data content, format, and organization. The data may contain but 
are not limited to individually identifiable information, other protected health information, and 
study codes. The data may be available to the public and other VA and non-VA researchers 
under certain conditions and consistent with the informed consent and CSP policy which 
prioritize protecting subjects’ privacy and confidentiality ot the fullest extent possible. A detailed 
plan for data sharing will be developed in accordance with current technology, infrastructure, 
best practices, and policies and procedures in place at the time of oversight committee reviews 
(e.g. Privacy Board, IRB, Information Security and IT standards). The plan will include how data 
will be discovered, retrieved, and analyzed, managed and will note the materials that are 
available in machine readable formats. This plan may be revised to ensure consistency with VA, 
including CSP, policies and standards for overall management and sharing.  

 
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XIV. ADVERSE EVENT ASSESSMENT AND REPORTING 
A. 
Role of the Local Site Investigator in Event Monitoring 
The Local Site Investigator is responsible for the following adverse medical event reporting 
requirements: 
 Reviewing the accuracy and completeness of all adverse events reported 
 Complying with study policies as well as IRB policies for reporting adverse events, 
serious adverse events, and unanticipated adverse device effects 
 Report to CSP all SAEs within 72 hours of becoming aware of the event 
 Reporting to the IRB safety issues reported to the site by the Sponsor 
 Closely monitoring research subjects for any new AEs, UADEs, and SAEs 
 Maintaining clinic lists to facilitate near-real time event discovery 
 Provide updates to Central Follow-Up Office upon event discovery and upon their 
request during event follow-up 
B. 
Definitions 
1. 
Adverse Event (AE) 
An Adverse Event (AE) is defined as “any untoward physical or psychological occurrence in a 
human subject participating in research.” An AE can be any unfavorable and unintended event, 
including an abnormal laboratory finding, symptom, or disease associated with the research or 
the use of a medical investigational test article.  While an AE does not necessarily have to have a 

 
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causal relationship with the research 120, in CSP #592 AEs will be collected, and only for 30 days 
after implantation (within the ICD + OMT arm), or 30 days after randomization (OMT arm). We 
will also collect AEs for 30 days after any re-implantation procedure. For the purposes of this 
study,  we are primarily interested in the following AEs: 
 Discomfort at the implant site 
 Cosmetic issues (e.g. scars, etc.) 
 Psychological issues (e.g. apprehension of an activation, etc.) 
 Technical issues related to the device (e.g. actions that may require re-implantation or a 
generator change) 
 Delay angioedema with cough 
 Rise in creatinine 
 Fatigue 
 Slow heart rate 
  
Other adverse events –including those that may not necessarily have to have a causal 
relationship with this treatment– may also be collected.  
2. 
Unanticipated (or Unexpected) Adverse Event (UAE) 
An Unanticipated (or Unexpected) Adverse Event (UAE) is an AE that is new or greater than 
previously known, in terms of nature, severity, or frequency of occurrence, as documented in the 
protocol or other materials approved by IRB. Such materials may include, but are not limited to: 
the informed consent form, clinical investigator’s brochure, and product labeling 120. 

 
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3. 
Unanticipated Adverse Device Effect (UADE) 
An Unanticipated Adverse Device Effect (UADE) means any serious adverse effect on health or 
safety or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem or death was not previously identified in nature, severity, or degree of incidence 
in the investigational plan or application, or any other unanticipated serious problem associated 
with a device that relates to the rights, safety, or welfare of subjects 121. 
All AEs and UADEs with a reasonable causal relationship to the investigative treatment should 
be considered at least “possibly related.”  A definite relationship does not need to be established.   
4. 
Serious Adverse Event (SAE) 
An adverse event is considered a Serious Adverse Events (SAE) if, in the view of either the 
investigator or Sponsor, it results in any of the following outcomes: 
 
Death 
 
A life-threatening adverse event 
 
Inpatient hospitalization or prolongation of existing hospitalization 
 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 
A congenital anomaly/birth defect 
 
Any other condition that, based upon medical judgment, may jeopardize the subject 
and require medical or surgical treatment to prevent one of the above outcomes.  

 
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In particular, this study will not consider any of the following as either an SAE or a 
hospitalization: index implantation of an ICD device, re-implantation of an ICD after 
explantation, or generator change.  
All serious adverse events are collected, including those related and not related to the study 
intervention. All serious adverse events with a reasonable causal relationship to the 
investigative treatment should be considered “related”.  All SAEs will be promptly reported by 
submission of the event into the CSP #592data capture system within 72 hours of the site 
investigator being made aware of the event. Email notification of the submission will 
immediately be relayed by the CSP #592 data capture system to the Study Biostatistician, 
Clinical Research Pharmacist, and Study Chair. The CSPCRPCC will be responsible for 
evaluating all serious adverse events for participant safety concerns. Serious adverse events (as 
defined by CRF 312.32) that are unanticipated and related to the investigational treatment 
are expeditiously reported to the CSPCRPCC Director, CSPCC, CIRB, DMC, and all regulatory 
agencies.  
The Clinical Research Pharmacist and Study Biostatistician generate tabulations of adverse 
events and present a summary of all AEs and SAEs to the DMC on a schedule set by the DMC. 
The DMC also determines when they should be unblinded to treatment assignment in reviewing 
adverse event data. The Study Biostatisticians provides the appropriate data to the DMC at 
specified intervals for this purpose. Serious adverse events are reported on a regular basis to the 
DMC for their review.  Unanticipated serious adverse events are reported to the DMC as soon as 
they become known based upon the consensus of the Principal Proponent, the Study 
Biostatisticians, the Director of the West Haven CSPCC, and the Study Pharmacist.   

 
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C. 
AE/UADE and SAE Monitoring and Reporting 
AEs, UADEs and SAEs will be monitored at the study sites throughout the period of the study, 
beginning as soon the research subject signs the Informed Consent and continuing through end-
of-study for each participant.  Reportable AEs will be collected and recorded on the appropriate 
case report form; though we note that while AEs will be continually monitored for closure, new 
AEs will only be collected for the relevant 30-day window.  All UADE and SAEs, including 
both those related to the study intervention and those not related to the study intervention will be 
collected and recorded on the appropriate case report form; new UADEs and SAEs will be 
collected throughout the study.  For the purpose of safety monitoring, the study intervention is 
defined as “ICD implantation” or  “Optimal Medical Therapy”.  
All UADEs/SAEs require expedited reporting.  An SAE case report form will be completed and 
submitted via the data capture system within 72 -hours of the Site Investigator initially becoming 
aware of the event.  The Study Pharmacist at CSPCPRCC will be responsible for evaluating all 
SAEs/UADEs for participant safety concerns in a timely manner.   
UADEs/SAEs that suggest evidence of a causal relationship between one of the study 
interventions and the adverse medical event and is unexpected will be reviewed by the Study 
Leadership Team (i.e., Study Chairperson, Study Biostatistician, Study Project Manager, and the 
Study Pharmacist) prior to notifying VA Central Office.  
 

 
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XV. 
BIOSTATISTICAL CONSIDERATIONS 
A. 
Sample Size 
The primary outcome of CSP #592 is all-cause mortality analyzed as time to event. The sample 
size required for this outcome was calculated using the log-rank test to compare survival, where 
the null hypothesis is that the average risk of death between the two treatment arms are equal 122. 
The primary hypothesis is that the ICD arm will have a 25% reduction in the hazard ratio 
(HR=0.75) (23.5% relative risk reduction in the annual mortality rate). The sample size 
calculation assumes a 15% annual mortality rate in the control arm. The cumulative event rate by 
the end of the 5-year trial (3.6 years average follow-up1), taking into account administrative 
censoring, loss, drop-in, and drop-out, is projected to be 42.0% in the control arm versus 34.1% 
in the ICD arm. The following sections describe the rationale behind these assumptions and the 
details of the sample size calculations.  
1. 
Hypothesized Event Rates and Treatment Effect Size 
Table 13 presents annual mortality rates from the control arms of prior interventional studies of 
ICD-based therapy.  
                                                 
1 Five years follow-up for Pilot Study participants (N=102), plus 3.5 years average follow-up for participants in 
Stage II (N=1360): (6×102 + 3.5×1360) ÷ (102+1360) = 3.60 average years of follow-up. 

 
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Table13. Annual mortality rates from control arm in studies of ICD usage in primary prevention. 
Study 
ICD Age Subgroup 
Annual Mortality Rate 
Heidenreich 2009 69 
Age 71-80 
22% 
Age >80 
25% 
Chan 2009 53 
Age ≥75 
15% 
Goldenberg 2008 41 
>70 years 
27% 
Groeneveld 2008 123 
Age > 66 
23% 
 
Based on these results, this study’s sample size calculation uses an annual event rate of 15% for 
the control arm. Given that the participant population enrolled in CSP #592 will be very similar 
to those in the studies shown in Table 13, a 15% annual event rate for the control group can be 
considered a conservative assumption. This translates into a 42.0% cumulative mortality rate 
after 3.6 years average follow-up, taking into account administrative censoring, drop-in, and 
drop-out.  
Expected effect size for the sample size calculation was selected based on review of prior studies 
shown in Table 14.  

 
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Table14. Hazard Ratios in Comparable Patient Populations (ICD vs. Conventional Therapy). 
Study 
Comparison 
Hazard Ratio (95% CI) 
Moss 2002 34 
All patients 
0.69 (0.51 – 0.93) 
>70 years 
0.66 (0.48 – 0.98) 
Kadish 2004 30 
All patients 
0.66 (0.40 – 1.08) 
NYHA Class II 
1.02 (0.51 – 2.09) 
NYHA Class III 
0.37 (0.15 – 0.90) 
Bardy 2005 29 
All patients 
0.77 (0.62 – 0.96) 
Ischemic Chronic Heart Failure 
0.79 (0.60 – 1.04) 
Non-Ischemic Chronic Heart Failure 
0.73 (0.50 – 1.07) 
NYHA Class II 
0.54 (0.40 – 0.74) 
NYHA Class III 
1.16 (0.84 – 1.61) 
Chan 2009 53 
>75 years 
0.59 (0.39 – 0.90) 
Santangeli 2010 62 
>60-65 years (meta-analysis) 
0.75 (0.61 – 0.91) 
Kong 2011 70 
>75 years (meta-analysis) 
0.73 (0.51 – 0.97) 
 
The hazard ratio for effect of ICD therapy on all-cause mortality varies widely, primarily 
because of the differences in the populations analyzed in the various clinical trials. For this 
reason, it is a challenge to identify specific clinical trials on which to base our effect size 
assumption. However, two meta-analyses have been published that assess the impact of ICD on 
the elderly. In the assessment of the MADIT-II, DEFINITE, DINAMIT, SCD-HeFT and IRIS 
studies, a Hazard Ratio of 0.75 (95% CI 0.61 to 0.91) was found 62; and in a separate analysis of 
MADIT-I, MUSTT, MADIT-II, DEFINITE, and SCD-HeFT, a Hazard Ratio of 0.73 (95% CI 

 
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0.51 to 0.97) was found 70. These Hazard Ratios are similar, and based on a sufficiently broad 
literature basis that they are the best point estimates of expectation for CSP #592. This study will 
adopt the more conservative of the two estimates, i.e. Hazard Ratio of 0.75.  
2. 
Projected Sample Size 
The following assumptions were used for the sample size calculation: 
 Two-sided Type I error of 0.05 
 Pilot stage with uniform recruitment over 1 year, with uniform follow-up of 5 years for 
all participants; 17 participants per site at 5 sites, i.e. 102 × 5 = 510 patient follow-up 
years 
 Full-scale stage with uniform recruitment over 3 years (minimum follow-up = 2 years, 
maximum follow-up = 5 years, median follow-up = 3.5 years) 
 Annual event rate of 15% in the control arm 
 Hazard ratio of 0.75 (relative risk reduction =23.5%) 
 Allocation ratio of 1:1 for the treatment groups 
 Annual drop in rate of 2.5% from the control group to the ICD group 
 Drop-out rate of 1% from the ICD group to the control group in year 1 only. 
 Annual loss-to-follow-up of 1% 

 
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Table15. Total Sample Size Under Different Control Rate and Effect Size Assumptions. 
Annual Event Rate in the 
Control Arm 
Hazard Ratio 
0.70 
0.75 
0.80 
12% 
1,177 
1,771 
2,881 
15% 
971 
1,462 
2,384 
18% 
834 
1,258 
2,057 
 
Because the VA Vital Status File will be searched for all deaths, loss-to-follow-up for the 
primary endpoint is considered to be very negligible and was therefore not accounted for in the 
sample size calculation.  Based on a 15% annual event rate in the control arm and a hazard ratio 
of 0.75, and the other assumptions listed above, a sample size of  1,462 (565 total primary 
outcome events) will be needed in order to achieve 90% power with a 2-sided Type I error rate 
of 0.05. 
Using the target sample size of 1,462, the following scenarios were considered as sensitivity 
analyses: 
 If the recruitment rate is less than anticipated, the study will still maintain 80% power to 
detect a hazard ratio of 0.75 with 1,084 participants (422 events).  
 If the control group annual event rate was 3% lower than anticipated (i.e. 12% annual 
mortality rate) the study would still maintain 81.0% power to detect a hazard ratio of 
0.75. 
 If the effect size is smaller than hypothesized, the study would still maintain 80% power 
to detect a hazard ratio of 0.78.  

 
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3. 
Power for Secondary Analyses 
The secondary objectives for this trial are to test the treatment interactions by co-morbidity level, 
and to test the change from baseline in the Minnesota Living with Heart Failure score.  Neither 
secondary analysis will require adjustment for type I error, i.e. no “multiple testing” corrections:  
adjustments for multiple comparisons are required in confirmatory whenever results from 
multiple tests have to be combined in one final conclusion and decision; in studies with a single 
primary endpoint, all other endpoints are considered subsidiary and their results can only have an 
exploratory rather than a confirmatory interpretation – multiplicity corrections are not required 
124. A sample size of 1,462 participants will yield the following power for secondary endpoints:  
 Assuming equal enrollment across high- and low-burden groups, this study will reach 
statistical significance for an increased in therapeutic effect by 50% in the low-burden 
group (Charlson <3) and decrease in efficacy of 50% in the high-burden group (Charlson 
≥3).Assuming a pooled standard deviation of 5 for change from baseline in Minnesota 
Living with heart failure score, the study will have 80% power to detect a 0.73 difference 
between groups in mean change from baseline at 12 months. 
B. 
Interim Monitoring and Analysis 
Interim monitoring will be performed by the WH-CSPCC and focuses on recruitment (overall 
and by site), baseline comparability of treatment groups, protocol adherence, completeness of 
data, accrual of primary endpoint events (i.e., information accrual), safety, and treatment 
efficacy. Recruitment and completeness of data will also be monitored for purposes of daily trial 
operations and quality assurance. The WH-CSPCC monitoring provides the basis for reporting to 

 
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the Data Monitoring Committee (DMC). A prototype set of tables and figures for presentation to 
the DMC is given in the Appendix D. 
1. 
Monitoring Recruitment 
The WH-CSPCC will monitor all steps in the recruitment process to assure early recognition of 
inadequate performance and to identify reasons for inadequate performance at each recruitment 
site and for the trial overall. To assist in this process, the WH-CSPCC will produce weekly data 
monitoring reports. These reports will include number of screening forms completed, reasons for 
non-matriculation into study, number of informed consent documents signed, and number of 
randomizations overall and by medical center. The same reports will be made available to the 
DMC at each of its meetings.  The data gives the DMC a regular opportunity to compare the trial 
assumptions with the observed data to make early judgments about the merits of continuing the 
study.  
2. 
Monitoring Protocol Adherence 
Protocol adherence will be monitored to assure early identification of poor performance at 
individual sites and in the trial overall. Periodic reports will be provided to the Executive 
Committee and to the DMC at each of its meetings. Specific parameters to be monitored include: 
• Randomization of ineligible participants 
• Treatment allocation errors 
• Failure to complete required follow-up assessments on time 
• Timely registration with the National Registry 
• Loss and withdrawal rates 

 
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• Treatment adherence  
3. 
Monitoring Efficacy and Futility 
Two interim analyses of the treatment effect on the primary endpoint of all-cause mortality will 
be performed when approximately half and three quarters of the events are accumulated (~280 
and 420, estimated at approximately 3 and 4 years).  However, the DMC will have discretion to 
request additional or different timing of interim analyses. A Haybittle-Peto type stopping 
boundary (p<0.001) will be used for monitoring the study for early efficacy 125.  
A futility analysis for the primary endpoint is also planned at the time of the interim analysis. If 
the analysis shows that the primary endpoint crosses the internal boundary for futility, it would 
indicate that the observed effect size is much smaller than anticipated and that the trial has very 
low conditional power to detect the estimated treatment effect for the primary outcome. The 
proposed stopping boundary for futility is a hazard ratio of between 1.02 and 0.98 (approximate 
p-value of 0.80).   
In addition to these futility analyses, the observed primary outcome event rate and rate of 
information accrual (number of events) is monitored from the initiation of the trial and compared 
with the expected rates. Based on these rates, an estimated time for study completion (i.e. time to 
reach 565 events) and the estimated number of events that will be reached by the scheduled end 
of the trial will be presented to the DMC. When considering the futility analyses and rate of 
information accrual, the DMC may also consider other internal or external evidence of futility 
(i.e., secondary outcomes) and has the option of recommending early termination of the trial for 
futility, or continuing with a possible adjustment to sample size.  

 
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4. 
Sample Size Re-estimation  
CSP #592 is designed as an event driven trial. Therefore, the sample size assumptions regarding 
the control group event rate and the crossover rate will be re-evaluated at between 6 and 12 
months after initiation of the Pilot study, and again approximately six months prior to the end of 
Full study recruitment to determine whether the estimated sample size and projected follow-up 
time are sufficient to achieve the target number of events. This will be done blinded to the 
treatment effect. If necessary, the sample size will be re-estimated based on the accumulated data 
but under the original hypothesized treatment effect to preserve the Type I error. This 
information will be presented to the DMC who will make a recommendation to the CSP on 
whether the sample size for the trial and/or the length of follow-up should be increased to 
achieve the study objectives.  Efficacy and futility analyses, as described above will not be 
performed until the sample size re-estimation has been completed.    
5. 
Interim Safety Monitoring 
Trial safety will be monitored by CSPCC and the CSPCRPCC, and the Study Chair’s Office 
throughout the study. Safety reports will be submitted to the DMC approximately every 6 
months after enrollment begins, or more frequently, if requested by the DMC. For reports to the 
DMC closed session, serious adverse events will be summarized by treatment groups, and 
relatedness to the assigned interventions.  
The proportion of participants experiencing an SAE in each treatment group will be calculated. If 
the DMC finds the proportion of SAE unacceptably higher in one treatment group compared to 
another, the DMC may consider recommending that the trial be stopped or that the protocol be 
modified.  

 
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C. 
Final Statistical Analysis of the Data 
All primary analyses will be according to the principle of intent-to-treat; i.e., subjects will be 
analyzed according to their original treatment assignment regardless of adherence to protocol. 
1. 
Baseline Comparability 
Because of the size of this study, we expect that the randomization process will produce 
reasonably comparable groups of participants.  However, the adequacy of the randomization will 
be assessed by comparing the distribution of baseline demographics, medical history, and clinical 
characteristics among the treatment groups.  Comparability for continuous variables will be 
examined graphically and by summary statistics (means, medians, quartiles, etc.).  Categorical 
variables will be examined by calculating frequency distributions.  Adjustment for significant 
treatment imbalances in baseline covariates will not be done in the primary analysis because this 
approach can be biased 126,127. Instead, sensitivity analyses examining the treatment effect will be 
conducted using a model adjusted for a predefined set of important clinical covariates known to 
moderate or mitigate outcomes. They will include age at randomization, number of previous 
myocardial infarctions (MI), and baseline left ventricular ejection fraction.   
2. 
Analysis of the Primary Outcome  
The analysis of the primary outcome, all-cause mortality, will be analyzed as time to event and 
tested by the stratified log rank statistic (stratified on site and Charlson score <3 versus ≥3), with 
a type I error of 0.05 (2-sided). Cumulative survival rates will be calculated using the method of 
Kaplan-Meier. The treatment effect will be estimated from a stratified Cox proportional hazards 
model and summarized as a hazard ratio (ICD versus optimal medical therapy) with a 95% 
confidence interval. The assumption of proportionality will be tested by treatment by time 

 
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interaction term prior to fitting the model.  The start time for all time-to-event analyses will be 
defined as the date of randomization and participants who do not experience an event will be 
right-censored at the date of last contact, date withdrawn, or date of study exit. VA Vital Status 
File will be used to determine the vital status of all study participants who are lost to follow-up at 
study exit.   
3. 
Secondary Analyses 
The overall type I error for the secondary outcomes will be of 0.05 (2-sided) without adjustment 
for multiple comparisons. 
a) 
Treatment Interactions by Co-Morbidity 
 The primary analysis of the treatment interaction with co-morbidity will take the form of a time 
to event, and will be analyzed using the same methodology described for the primary outcome at 
a 0.05 2-sided significance level. A test of treatment interaction by Charlson score <3 versus ≥3 
(alternative subgroups will also be explored) and by Charlson score as a continuous measure. In 
addition, a forest plot and treatment interaction will be examined for each type of comorbidity. 
b) 
Quality of Life 
The primary analysis of QoL will be a comparison between treatment groups of the change in the 
Minnesota Living with Heart Failure questionnaire scores at 12 months post-randomization 
relative to baseline using a two-sample t-test if the data appear sufficiently normal and a non-
parametric method if the normality assumption looks like it does not hold.  

 
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4. 
Exploratory Analyses 
a) 
Quality of Life 
Early effects (QoL at 6 months), late effects (QoL at 24 months), and longitudinal effects (effect 
over 24 months) for the Minnesota Living with Heart Failure QoL data will also be assessed by a 
longitudinal repeated measures mixed effects analysis. All mixed models will be adjusted for the 
baseline Minnesota Living with Heart Failure score, and for the randomization design (site and 
co-morbidity burden). Site will be included in the model as a random effect and general health 
status (Charlson <3 versus ≥3) as a fixed effect. The outcome variable in the model will be the 
change in the Minnesota Living with Heart Failure Quality of Life Score at each follow-up 
contact relative to baseline.  Model building methods will be used to first determine the best 
mean structure of the outcome (e.g., time as linear or categorical) and then to determine the best 
fitting and most parsimonious covariance structure for the data. 
b) 
All-cause Hospitalization 
Total hospitalizations, total number of days of hospitalization, and the proportion of participants 
who require at least one hospitalization during the follow-up period will be compared between 
treatment groups at a 0.05 significance level. No adjustment will be made for multiple testing for 
tertiary outcomes because they are considered exploratory in nature. The total hospitalizations 
and total days of hospitalization will be analyzed using generalized Poisson or negative binomial 
regression models. Proportion of participants requiring at least one hospitalization will be 
analyzed using a chi-square test statistic. 

 
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c) 
Sudden Cardiac Death 
Time to event for sudden cardiac death will be analyzed using the same methodology described 
for the primary outcome at a 0.05 2-sided significance level. VA Vital Status File will be used to 
determine the vital status of all study participants who are lost to follow-up at study exit.  VA 
Vital Status File search plus a NDI Plus database search for all participants who are found to 
have died through the VA database search in order to adjudicate the cause of death. 
5. 
Analysis of Safety Data 
The total number of SAE will be summarized by treatment. The proportion of participants 
experiencing an SAE will be calculated for each treatment group. A chi-square test for the 
difference in the proportion of SAEs will be used to compare treatment groups over all at the 
0.05 level, and with subgroupings of SAEs and non-serious AEs at the 0.01 significance level. 
Treatment comparisons will be made for the number of participants experiencing SAE, the 
number of treatment-related SAE, and for the number of non-serious adverse events.  
6. 
Exploratory Analyses 
Additionally, data from the Informed Consent Questionnaire will be used for exploratory 
analysis of the association between perceived and actual participant understanding of the study. 
ICDs are capable of delivering information related to a wide range of parameters including 
activity level, heart rate variability and battery and lead status. Descriptive analysis will be used 
to summarize the ICD device data. The analysis will be limited in scope to three activities:  
 Routine assessment of device activations to assess shock events;  
 Device interrogation upon death; and 

 
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 Analysis of device data at follow-up appointments as is done in standard clinical 
practice.  
These activities contribute substantially to optimal medical therapy.  
7. 
Consenting Rates 
Whereas there are no known published data on the willingness of elderly patients to consent into 
a study of this nature, it is incumbent on CSP#592 to measure and report the rates of consent 
among patients deemed so eligible. Data collected from patients found eligible for entry into the 
study will be analyzed for rate of consenting into the study, as well as rationale for non-
matriculation. This activity contributes substantially to the knowledge base for the design of 
future clinical trials both in the study of the elderly, and in device-based trials. 
 
 

 
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XVI. FEASIBILITY 
A. 
Estimating the Patient Population 
1. 
ICD Candidacy among VA Patients 
a) 
Candidacy Criteria 
The American College of Cardiology and American Heart Association have established 
guidelines for device based therapy to include a class I indication of ICD therapy for primary 
prevention of sudden cardiac death in patients with New York Heart Association class II or III 
symptoms, ischemic and non-ischemic heart disease and left ventricular ejection fraction (LVEF) 
of 30% or less, who are receiving long-term optimal medical therapy and have a reasonable 
expectation of survival with good functional status for greater that 1 year 8. While it is difficult to 
determine “long-term optimal medical therapy” and “expectation of survival” from the electronic 
patient records database, it is possible to identify heart failure patients who may qualify for ICD 
implantation. 
b) 
Estimating Candidacy from the Patient Records Database 
Based on the stated criteria for implantation of an ICD, the primary diagnosis by which study-
eligible patients can be identified is that of Systolic Heart Failure (SHF). Additionally, a large 
segment of patients with a Congestive Heart Failure (CHF) diagnosis may also be eligible, 
however due to the inconsistencies in diagnostic and coding practices within heart failure 
patients 128,129, it may be difficult to estimate the exact proportion of CHF patients who meet the 
implantation criteria. Several surveys report the proportion of CHF patients with low ejection 
fraction (LVEF ≤ 30%) at 22-47% of the CHF population (Table 16). 

 
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Table 16. Proportion of non-systolic heart failure patients with suppressed ejection fraction. 
Ejection Fraction 
Proportion of CHF patients 
Source 
≤ 30% 
47% 
Hallstrom, 1995 130 
< 30% 
30% 
Nieminen, 2006 131 
< 30% 
29% 
Tavazzi, 2006 132 
< 30% 
22% 
Cohen-Solal, 2000 133 
 
For the purposes of estimating the volume of potential candidates for this study, we shall adopt 
the assumption of eligibility for 100% of SHF patients and 30% of all CHF patients (a 
conservative estimate based on Table 16).  
An attempt was made to corroborate these statistics against the VA medical record. Select 
members of the CSP #592 Planning Committee were asked to provide estimates of the 
proportion of CHF patients with true candidacy for ICD; this search was to include inspection of 
the clinic record of ejection fraction estimation, restriction to patients ≥70 years of age, without 
clearly 
disqualifying 
conditions 
(including 
contraindication 
of 
1-year 
survivability). 
The 
minimum projected estimates of ICD-eligible patients was 26%; therefore we concluded that an 
estimate of 30% of CHF patients as candidates for ICD implantation was implantation was 
conservative. We note that these estimates do not account for the proportion of candidate patients 
already in receipt of ICD, which varies substantially by VAMC (see Table 18). 
c) 
Patient Eligibility Analysis via National Data Service 
An assessment of study participant availability was performed by searching within the National 
SSN Security Database (NSSD) for unique patients with diagnostic codes of the International 

 
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Statistical Classification of Diseases and Related Health Problems, Ninth Revision (ICD-9), 
associated with congestive heart failure or systolic heart failure and also for possession of a 
defibrillator device (Table 17). 
Table17. Heart Failure Patients Across 40 Select VAMCs (Patients ≥70 years). 
Congestive Heart Failure 
Systolic Heart Failure 
402.01, 402.11, 402.91,  
404.01, 404.03,  
404.11, 404.13, 404.91, 404.93 
428.0, 428.1,  
428.40, 428.41, 428.42, 428.43 
428.9 
428.20, 428.21, 428.22, 428.23 
Implantable Cardioverter Defibrillator 
V45.02 
 
Search criteria involved: 
 Six separate databases 
a. Inpatient Encounters (DSN = MDPPRD.MDP.SAS.IE09) 
b. Outpatient Events (DSN = MDPPRD.MDP.SAS.SE09) 
c. Inpatient Acute Care (DSN = MDPPRD.MDP.SAS.PM09) 
d. Inpatient Extended Care (DSN = MDPPRD.MDP.SAS.XM09) 
e. Inpatient Observation Care (DSN = MDPPRD.MDP.SAS.PMO09) 
f. Non-VA Care (DSN = MDPPRD.MDP.SAS.NM09) 
 Fiscal Year 2009 
 Unique patients (as opposed to assessment of visits) 

 
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Furthermore, this search was refined to consider only the 40 sites known to perform ICD 
implantation, i.e. only those sites that might be eligible for involvement in CSP #592. The total 
patient pool estimation is given in Table 18:  
Table 18. Heart Failure Patients Within Select VAMCs, FY2009 (Patients ≥70 years). 
 
VAMC 
CHF+  ICD– 
CHF+  ICD+ 
SHF+  ICD– 
SHF+  ICD+ 
1. 
Albuquerque 
431 
27 
14 
1 
2. 
Ann Arbor 
469 
29 
12 
1 
3. 
Bay Pines 
977 
77 
22 
4 
4. 
Birmingham 
523 
32 
11 
1 
5. 
Buffalo 
1499 
95 
55 
7 
6. 
Cincinnati 
388 
31 
26 
1 
7. 
Cleveland 
1015 
88 
18 
2 
8. 
Columbia 
625 
45 
21 
4 
9. 
Dallas 
1127 
150 
32 
3 
10. 
Atlanta 
700 
69 
17 
4 
11. 
Durham 
415 
45 
13 
0 
12. 
Gainesville 
1081 
91 
31 
5 
13. 
Hines 
577 
68 
3 
1 
14. 
Houston 
760 
88 
6 
3 
15. 
Indianapolis 
524 
44 
15 
2 
16. 
Kansas City 
1626 
99 
39 
6 
17. 
Little Rock 
612 
73 
5 
2 
18. 
Lexington 
454 
39 
3 
1 
19. 
Louisville 
424 
56 
13 
3 
20. 
Milwaukee 
589 
35 
21 
0 
21. 
Minneapolis 
850 
72 
54 
10 
22. 
Nashville 
739 
87 
34 
8 
23. 
New York 
424 
66 
29 
10 

 
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24. 
Oklahoma 
673 
67 
1 
0 
25. 
Omaha 
1308 
111 
11 
1 
26. 
Palo Alto 
536 
39 
21 
1 
27. 
Philadelphia 
675 
46 
14 
3 
28. 
Pittsburgh 
577 
68 
12 
3 
29. 
Portland 
735 
42 
61 
6 
30. 
Richmond 
395 
47 
35 
3 
31. 
St. Louis 
1411 
78 
26 
4 
32. 
Salt Lake City 
660 
32 
18 
3 
33. 
San Diego 
529 
50 
4 
3 
34. 
San Francisco 
335 
20 
8 
1 
35. 
Tampa 
652 
71 
57 
12 
36. 
Tucson 
518 
28 
24 
3 
37. 
Washington, DC. 
292 
15 
2 
0 
38. 
West Los Angeles 
628 
33 
15 
1 
39. 
West Palm Beach 
609 
59 
3 
2 
40. 
West Roxbury 
594 
40 
22 
4 
 
Total (Top-20) 
18,353 
1,514 
537 
84 
 
Total (Top-27) 
22,364 
1,873 
623 
102 
 
Total (Top-30) 
23,929 
1,977 
673 
104 
 
Total (Top-40) 
27,956 
2,352 
828 
125 
FY2009 data summary: 44,713 records across 130 sites. Top sites selected by # CHF+ ICD–. 
 
  
 

 
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Thus, assuming that among congestive heart failure patients, 30% qualify by sufficiently low 
ejection fraction, then there are over 6,000 heart failure patients meeting the minimum criteria 
for ICD eligibility in the 30 largest candidate sites (as given by the number of CHF patients 
without ICD), without accounting for adequate medical therapy and survivability. This is likely a 
moderate underestimate of the total number of available patients, as this number reflects patient 
visits in FY2009, i.e. there may be many eligible patients who did not appear in the patient 
registry in FY2009 
d) 
Not-previously-seen Patients 
It is likely that eligible patients will continually present to the study centers over the three years 
of enrollment. We estimate the number of newly presenting patients at the 27 enrolling sites 
throughout the enrollment period. Table 19 displays the number of unique patients in FY2009 
with SHF (top row) and CHF (but not SHF, bottom row), as found in FY 2009 (left column), 
followed by patients not seen at all in before FY2010 (next column). 
Table 19. Newly presenting patients in 2008-2010. Recruitment pools summed over years. 
DX Code 
2008 
2009 
2010 
3 years 
CHF+, ICD– 
123,580 
57,872 
48,379 
229,831 
CHF+, ICD– (× 30%) 
37,074 
17,362 
14,514 
68,950 
SHF+, ICD– 
2,125 
1,657 
1,941 
5,723 
Subtotal  (i.e. Across VA) 
39,199 
19,019 
16,455 
74,673 
Subtotal (30% adj. top-27) 
19,600 
9,510 
8.228 
37.337 
Top-N adjustments: Proportion of Across-VA patient pool within the top-N sites (ref. previous 
table): Top-27: 22,364 ÷ 44,713=50.0%.  
 

 
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Using these data we estimate that there will be approximately 37,000 unique Veterans eligible 
for the trial at the 27 participating sites. This was estimated based on a 3-year running total of 
5,723 patients with documented systolic heart failure without an ICD (SHF+, ICD–) and a total 
population of chronic heart failure patients without ICD (and not double-counting those with 
SHF) of 229,831, of which there are an estimated 30% (=68,950) truly eligible for this study, we 
project a patient pool of 74,673 patients across all VAMCs. We estimate that a study comprising 
27 of the top-implanting sites would avail this study to approximately 50% of the VA heart 
failure population (37,337).  
e) 
Summary 
The available pool of patients ≥ 70 years was estimated by two independent methods: 1) pulling 
of patient records from the National Data Service for all in- and outpatient visits made in 2010, 
identifying patients with heart failure + ICD, and 2) extraction of the total number of ICD 
procedures performed in the VA from the Cardiac Surveillance Database. From these data 
sources, we estimate there to be nearly 37,000 patients available for study across 27 sites in a 3-
year recruitment period. The average number of heart failure patients being seen at each of the 
27 selected participating sites is estimated to be more than 440 Veterans per year. Whereas we 
target a sample size of N=1,462, this equates to an enrollment rate of approximately 3.7% of the 
potentially eligible patient pool.   
 

 
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XVII. GOOD CLINICAL PRACTICES 
A. 
Role of Good Clinical Practices  
This trial is conducted in compliance with the Good Clinical Practice (GCP) regulations.  All 
investigators and clinical research coordinators are properly trained in Good Clinical Practices 
and the Protection of Human Subjects in Research.  The Site Monitoring, Auditing and Review 
Team (SMART) is responsible for assessing and promoting compliance with Good Clinical 
Practices at participating sites throughout the trial.  This training is conducted at study start-up by 
the CSP SMART team.  During the start-up phase, SMART develops study specific GCP 
guidance and tools for the sites, and provides training in the use of these materials and in the 
principles of GCP both at the study organizational meeting and during subsequent site visits.  
Monitoring of sites participating in the trial is executed according to the VA Cooperative Studies 
Program Guidelines.   
B. 
Summary of Monitoring and Auditing Plans 
 
Monitoring Visits 
 Initiation visits at each site soon after study start-up. 
 Additional monitoring visits may be conducted as deemed necessary by study 
leadership or SMART. 
 
Audits  
 Routine audits – independent site visits to one or more sites during the Pilot, 
and each year during the first three years of the full-scale trial (site selection 
as determined by SMART).  

 
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 For-Cause audits – an independent audit of any participating site as requested 
by study leadership or CSP Central Office.  For-cause audits may be 
announced or unannounced. 

 
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XVIII. PUBLICATIONS 
A. 
Publication Policy 
According to the policy of the Cooperative Studies Program, outcome data will not be revealed 
to the Study Chair or participating site investigators until data collection is completed and the 
study database is locked.  This policy safeguards against possible biases affecting the data 
collection. 
All presentations and publications from this study will follow CSP policy as stated in the CSP 
Guidelines.  The presentation or publication of any or all data collected by site investigators on 
participants of CSP #592 is under the direct control of the Executive Committee.  No individual 
site investigator has the right to perform analyses, make interpretations, make public 
presentations, or seek publication of any or all of the data without the approval of the Executive 
Committee. This is true whether the publication or presentation is concerned with the results of 
the principal undertaking or is associated with the study in some other way. 
The Executive Committee has the authority to establish one or more publication committees 
(usually comprised of subgroups of site investigators and some members of the Executive 
Committee) for the purpose of producing manuscripts for presentation and publication.  A 
presentation or publication, formulated by the Executive Committee or its authorized 
representatives, should be circulated to all members of the Executive Committee for review, 
comments, and suggestions prior to submission of the manuscript to the presenting or publishing 
body. 
All publications must give proper recognition to the Department of Veterans Affairs Cooperative 
Studies Program and should list or reference all principal and site investigators in the study.  Any 
manuscript, abstract, or letter to the editor submitted for publication or presentation must be sent 

 
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to the CSP Director for approval prior to submission for publication. Primary manuscripts will 
also be presented to the members of the study’s DMC for information purposes.   
B. 
Planned Publications 
An intended plan of the main publications is given below: 
Table 20. Intended study publication plan 
Manuscript 
Projected time of submission 
Study design and baseline patient characteristics 
6 months after enrollment is completed 
Primary efficacy analysis 
6-12 months after end of study 
Secondary and exploratory outcomes, including 
safety outcomes 
12-18 months after end of study 
Effect of atrial fibrillation on the elderly 
   –with or without ICD 
   –with respect to shocks, survival, QoL, etc. 
12-18 months after end of study 
Density of ICD shocks and hospital admissions 
for HF, or deterioration of LV function (if 
follow-up echo data is available) 
12-18 months after end of study 
Comparison of survival curve: OMT versus 
ICD without shocks versus ICD with shocks 
12-18 months after end of study 
Pacing in ICD (33% versus 66% versus 100%) 
relating to HF or death 
12-18 months after end of study 
Analysis of race and survival across secondary 
end-points 
12-18 months after end of study 
Analysis of beta blocker and survival 
12-18 months after end of study 
Analysis of enrollment and participation 
12-24 months after end of study 
 

 
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Official Title: Efficacy and Safety of Implantable Cardioverter-Defibrillator (ICD) Implantation in 
the Elderly (I-70) 
ClinicalTrials.gov Identifier: NCT02121158 
Document Type: Informed Consent Form 
Document Date: 6/17/2016 

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 1 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
You are being invited to take part in a research study that is being funded by the Department of
Veterans Affairs. Before you decide to take part, it is important for you to know why the research
is being done and what it will involve. This includes any potential risks to you, as well as any
potential benefits you might receive.
Read the information below closely, and discuss it with family and friends if you wish. Ask one of
the study staff if there is anything that is not clear or if you would like more details. Take your
time to decide. If you do decide to take part, your signature on this consent form will show that
you received all of the information below, and that you were able to discuss any questions and
concerns you had with a member of the study team.
BACKGROUND AND PURPOSE
Patients with heart failure are more likely to die from electrical problems of the heart, like
arrhythmia, than those without heart failure. An arrhythmia is an abnormal heart beat that could
potentially cause death. These can be prevented with medications, but can also be treated with
the use of an ICD. Certain medications and a device, the implantable cardioverter defibrillator
(ICD), all approved by the Food and Drug Administration (FDA), have been shown to extend the
lives of patients younger than 70 years old with heart failure. Most patients with heart failure will
not have a sudden death episode and will eventually die from a progressive weakening of the
heart. In clinical studies on younger patients with heart failure, the ICD has proven to be more
effective than medication in extending life. However, in older patients, the cause of death is
more commonly of a non-cardiac reason. The ability of an ICD in extending life in patients with
advanced age has never before been studied directly; we hope to answer this question in this
study.
An ICD is an implantable heart device about the size of a pocket watch. It is implanted under the
skin typically just below the collarbone on the left or right side of the chest. Wires are attached
and then inserted into the heart through a vein. Nothing can be seen from the outside except a
lump under the skin. The ICD continuously monitors the heart rhythm. If a dangerous arrhythmia
(irregularity of heart beats) is detected, an electrical shock is sent to correct it.

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 2 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
While the ICD is approved for implantation in adults with heart failure, regardless of age, older
patients tend to receive ICD therapy much less frequently than younger patients. The ICD is not
an experimental device: this study will test the ICD in an application and a patient population
that has already received FDA-approval, and complies with national guidelines for ICD
implantation.
On the other hand, it has been shown that all patients with the same type of heart condition you
have who receive certain medications, adopt a healthy lifestyle with diet and exercise, and have
close follow-up with their health care providers have a lower risk of sudden cardiac death. This
is called optimal medical therapy (or OMT). It has been shown that when an ICD is also used
with OMT, there is an added benefit of reducing the risk of sudden cardiac death even further in
those under the age of 70 years. This benefit from the ICD is also possible those 70 years and
older however research is needed to make sure this is true.
Both OMT alone and OMT with the ICD are considered standard of care clinically. Because of
the uncertainty of the benefit with ICD in those 70 years and older and the known possible risks
(as described later in this consent), the decision is usually made between the doctor and patient
as to whether to have the ICD placed in addition to OMT. By participating in this research study,
you and your doctor will not be making this decision. Instead, you will be randomly assigned to
either continue with OMT alone or to receive an ICD while continuing with OMT. To participate
in this study, you should be willing to receive either OMT alone or OMT plus the ICD added.
With this study we hope to learn whether using an ICD together with OMT is more effective than
using optimal medical therapy alone in improving survival in older adults with heart failure.
This research is sponsored by VA Cooperative Studies Program, a branch of VA Office of
Research & Development which conducts large multiple site clinical trials.
This phase of the research study will include approximately 100 Veterans at 6 different VA
Medical Centers. Approximately 17 Veterans will participate at each VA Medical Center. There
is the possibility this study will grow to include a total of approximately 1,462 Veterans at about
27 VA Medical Centers. If so, approximately 68 Veterans will participate from each VA Medical
Center. This potential increase in enrollment will not affect your participation in any way.
You are invited to participate in this research because you are at least 70 years old, have heart
failure, and may be eligible to receive an ICD. You must be willing to potentially receive an ICD
if you wish to take part in this study.

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 3 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
DURATION OF THE RESEARCH
This research study is expected to take approximately 6 years. If you continue with this study
until its conclusion, your participation will last up to 5 years.
STUDY PROCEDURES
If you decide to take part in this study and sign this informed consent form, this is what will
happen:
During your Baseline Research Visit, a member of the research study team will review your
medical record and ask you questions about your medical history, current state of health, and
which medications you are taking. You may have an electrocardiogram (also known as an
EKG), blood drawn for laboratory analysis, and/or a routine physical exam. We will administer a
questionnaire (the Minnesota Living with Heart Failure Questionnaire) to understand how your
life is affected by your health status. If you would rather not answer certain questions, you may
skip them. We will also ask you to perform a 6 minute walk test. We will monitor you closely as
we see how far you can walk during this time frame. We estimate this visit to take
approximately 4 hours or less.
When it is determined you are eligible for this study you will be randomized either to the group
receiving an ICD, or to the group not receiving an ICD. You may be randomized during this visit
or a later date. Randomization means that you will be assigned to one group or the other by
chance, as in the flip of a coin. You will have an equal chance (50/50) of being assigned to
either group. Neither you nor the research study staff will be able to choose which group you will
be assigned. Following randomization, your clinical care team (i.e. your primary care physician,
cardiologist, and other clinical providers) will determine how often and what type of visits you
need for your clinical care. These clinical appointments are not part of the research study.
All participants will receive Optimal Medical Therapy: All participants entering into this
study will be receiving optimal medical therapy (OMT). All participants will continue to receive
OMT throughout the study, regardless of their randomization. OMT will be provided by their
regular clinicians.
OMT includes education on healthy lifestyle maintenance, changes in diet
and exercise, keeping follow-up appointments, and monitoring compliance with medications. It
is important that you take medications as prescribed. While we outline the risks and benefits of
OMT here, you are strongly encouraged to discuss them with your regular health care provider.

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 4 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
The clinician providing your follow-up care may or may not be a member of the research study
team. If the study team, in consultation with your doctor, cannot establish that you are fully
stable on OMT, we will delay your entry into the study until it can be determined that OMT has
been reached, and that you are ready to be entered into the study. In this case, your regular
treating clinician will work with you to reach Optimal Medical Therapy. You may be reconsidered
for entry into the study at any time.
If You Are Randomized to receive an ICD:
You may have already received, or you will receive, education about this device, how it works,
potential risks of the procedure, pre-procedure preparation, post-procedure care, and
restrictions you will need to follow after receiving an ICD. You will be asked to sign a clinical
consent for implantation of the ICD which will explain the procedure and associated risks. The
following information gives you an overview of the ICD procedure that will be covered in more
detail by your doctor who will do the procedure. However, you are also encouraged to ask
questions and discuss anything you do not understand with the study team or your doctor.
Day of the Procedure:
If necessary, upper chest hair (if applicable) may be shaved or clipped. Based on your medical
condition and history, you may need to have other specific preparations done. An intravenous
(IV) line will be started in your hand or arm prior to the procedure for injection of medication and
to give you fluids.
During the Procedure:
The procedure usually takes up to one or two hours, but may take longer. You will lie on your
back on a procedure table. A local anesthetic will be injected into the skin at the insertion site.
Once this anesthetic has taken effect, the doctor will make a small incision (cut).
A small plastic tube containing wires will be inserted into a blood vessel usually under the
collarbone and advanced into the heart. It will be very important for you to remain still during the
procedure.
There may be one or two wires inserted, depending on the type of device your doctor has
chosen for your condition. Once the wire(s) is inside the heart, it may be tested to verify proper
location and that it works. Fluoroscopy (a special type of x-ray that will be displayed on a TV
monitor) may be used to help your doctor guide the wire to the right location. The ICD will then
be slipped into a pocket under the skin.

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 5 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
Generally, the ICD will be placed on the non-dominant side. (If you are right-handed, the device
will be placed in your upper left chest. If you are left-handed, the device will be placed in your
upper right chest).
The skin incision will be closed with stitches, adhesive strips, or special glue. A bandage will
cover the incision.
After the Procedure:
After the procedure, you will be taken to the recovery room or to your hospital room. Your blood
pressure, breathing, and alertness will be checked often. You will be placed on a heart monitor
(like a continuous EKG). The ICD insertion site may be sore or painful. You will be given pain
medication if needed. Prior to discharge, you will have a chest x-ray. The ICD will also be
tested. If there are any medical problems or concerns following the procedure, you may need to
remain in the hospital for more than one night.
You will not be able to drive until your doctor gives you approval. You will also be given
instructions about your medications and wound care. You will be instructed about what to do if
your ICD discharges a shock.
You will be given written instructions on what to watch for, what to report to your doctor, and
precautions to take to ensure your safety. You may be asked to keep a diary in order to record
any shocks you receive or symptoms you may experience.
You will receive an ICD patient card upon leaving the hospital. It contains information about
your ICD. You should carry this card with you at all times. It is important to share this
information with any medical staff prior to having any medical treatment anywhere, including
dental procedures.
Remote Monitoring:
In addition to monitoring your heart for dangerous heart beats, the ICD records important
information about the device itself, such as battery status, wire information, and programming of
the device. This data will be monitored by your regular treating doctor, as part of routine care of
patients with an ICD. This may provide a benefit to you by regular monitoring of the activity of
your heart and the ICD. The collection of this information is called “remote monitoring” or “home
monitoring”. As part of this study, if you are randomized to receive an ICD, you will be enrolled

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 6 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
in the Remote Monitoring program within 30 days of receiving your ICD. You will be given
instructions on how to participate in this program and set up your equipment.
You will be given a small “base unit” that will allow for your ICD to be monitored. Either a land
line telephone or being within range of a cell phone tower is needed for remote monitoring. If
you don’t have either a land line or live close to a cell phone tower, your ICD monitoring will be
done during a clinic visit.
Information collected from remote monitoring is part of routine clinical care for patients with
ICDs. As part of this study, data collected from the remote monitoring seen by your doctor will
also be seen by the research study team. Any information collected by the research study team
will be stored in a protected study database.
If at any time, you or your doctor would like to have the device turned off, this option is available
to you.
Research Study Follow-Up for All Participants:
The first research study related follow-up visit will occur one to four months after you are
randomized. We will review your medications and ask if you have had any hospitalizations, ER
visits, or other medical events. If you received an ICD, we will collect ICD information from your
clinical records.
Research study follow-ups will occur i) at 1-4 months after randomization, and ii) every six
months after randomization; all follow-ups will occur by phone. During the phone calls, we will
ask you the same questions about how your life is affected by your health status (Minnesota
Quality of Life Questionnaire). We will review your medications and ask if you have had any
hospitalizations, ER visits, or other medical events. We estimate these follow-up phone calls will
last less than 30 minutes. These “centralized follow-up visits” will be performed for all study
participants by the same staff persons from Central Follow-Up staff or the Chair’s Office.
As part of optimal medical therapy, you may have additional clinical appointments which are not
described in this consent. These appointments are not part of the research study.
Participant Responsibilities:

Follow the plan of care you and your doctor agree on

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 7 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A

Keep your study appointments

Complete your questionnaires as requested

Ask questions as you think of them

Tell the study team if you change your mind about staying in the study.
While participating in this study, please do not take part in any other research study without
discussing it with this study team. This is for your protection and the integrity of this study.
Members of the Human Rights Committee (HRC) at the VA Cooperative Studies Program
Coordinating Center conduct site visits and interviews during the course of the study to
determine if participants’ rights and safety are being properly protected. An HRC member, or a
member of the research study team, may contact you to set up an interview.
POSSIBLE RISKS OR DISCOMFORTS
Optimal Medical Therapy
Risks of optimal medical therapy may arise due to changes in diet, exercise, and medication.
These are not risks of the research. Your clinical care team will discuss risks as they relate to
you.
6 Minute Walk Test
There are a few risks with this test. You will decide how fast you walk depending on your ability
and how you are feeling. Changes in breathing, blood pressure, and/or heart rate may occur.
You may sweat, fall, have chest pain, and/or develop leg cramps. You can ask to stop this test
at any time.
Blood Draw and IV Placement
During a blood draw or placement of an IV, you may experience some discomfort, bruising,
and/or bleeding at the site where the needle goes into the arm as you might during any blood
draw or IV procedure. There is also a very small risk that infection could occur or that you may
faint.
Psychological Risk
There is a risk of psychological distress from answering the Minnesota Living with Heart Failure
Questionnaire throughout the study as some questions may make you sad or upset. You are
free to skip any questions you choose not to answer.

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 8 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
ICD
The ICD delivers electric shocks when necessary and stops most arrhythmias with a weak
shock that cannot be felt. If you ever experience a strong shock, you will feel a short pain, much
like a hard blow to the chest.
Any procedure has possible risks and discomforts. The ICD procedures in this study may cause
all, some or none of the risks or side effects listed below. Known risks of ICD implantation
include but are not limited to:

Swelling, bruising, and/or discomfort at the incision site

Bleeding (particularly around the heart, which can be life-threatening) or pocket
hematoma (blood collection around the ICD) requiring drainage, blood transfusion,
hospitalization, and/or extension of hospitalization

Cardiac perforation possibly requiring additional surgical intervention

Pneumothorax (lung collapse) or hemothorax (collection of blood in the space between
the lung and chest wall) requiring prolonged hospitalization and/or chest tube placement

Infection at the site of the implant, requiring intravenous antibiotics, debridement
(removal of damaged tissue), and/or removal of the ICD

Damage to the vein where the ICD wires are placed

ICD or wire malfunction requiring additional surgical procedures

Blood clots in arteries and/or veins

Drug reaction or other serious complication during the procedure resulting in inability to
implant the ICD

ICD shock or cardiac arrest within 24 hours of the procedure

Other serious medical complications related to the implant procedure requiring a
prolonged hospital stay such as sepsis (bacteria in the bloodstream), pulmonary edema
(buildup of fluid in the lungs), myocardial infarction (heart attack), cardiogenic shock
(heart cannot pump enough blood to meet the body’s needs), and electrical storm
(sustained irregular heart beats resulting in multiple shocks in a 24 hr. period).

Further risks include those associated with diagnostic x-rays, sedation, and other
complications during the procedure

Unnecessary shocks which can be treated by changing the ICD settings or adding
medication

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 9 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A

Psychological distress from complications and/or discomfort which may arise due to ICD
implantation and possible shocks.
Rare, unknown, or unforeseeable (unexpected) risks also may occur. We summarize some of
the most well-known risks of ICD implantation in the following table:
POTENTIAL BENEFITS
We cannot promise that you will get any benefits from taking part in this research study.
However, all participants receiving an ICD and/or optimal medical therapy potentially receive
life-saving therapy that could prevent sudden cardiac death. Additionally, information we get
from this study might help us treat patients in the future.
Complication
Percentage of
patients
experiencing
Complication
Percentage of
patients
experiencing
MAJOR COMPLICATIONS
Lead replacement
2.7
Pulmonary edema
0.6
Lead repositioning
2.0
Myocardial perforation
0.4
Infection requiring
debridement
1.0
Pneumothorax/hemothorax
0.4
Electrical Storm
0.9
Post-implant myocardial
infarction
0.2
Lead dislodgement
with re-positioning
0.8
Sepsis
0.2
Lead extraction
0.7
Cardiogenic shock
0.2
MINOR COMPLICATIONS
Incisional infection
1.1
Lead dislodgement not
repositioned
0.8
Pocket hematoma
1.0
Subclavian vein
thrombosis
0.2
List of known risk frequencies for major and minor complications in new ICD implantation.

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 10 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
ALTERNATIVES TO PARTICIPATING IN THIS RESEARCH
You may choose not to participate in this study. If this is your choice, you may receive an ICD or
OMT alone outside of the study. You may discuss this and other possible options with your
clinical providers.
CONFIDENTIALITY
Taking part in this study will involve collecting private information about you, including health
information, name, address, telephone number, and social security number. We will ask you to
provide us the name of one or more persons we can contact in case we are not able to contact
you for follow-up visits. All data collected as part of this research study will be protected in the
following ways:
All research data will be stored on password protected computers or in locked file cabinets. Only
approved research staff will have access to this data. Information about you will be combined
with information from other people taking part in the study. We will write about the combined
data we have gathered. Any talks or papers about this study will not identify you.
We will not share your records or identify you unless we have to by law. There are times when
we might have to show your records to other people. For example, someone from the Office of
Human Research Protections, the Government Accountability Office, the FDA, the Office of the
Inspector General, the VA Office of Research Oversight, the VA Central IRB, our local Research
and Development Committee, and other study monitors may look at or copy portions of records
that identify you.
If you are a VA patient, you already have a VA medical record. We will put information about
your participation in this study into your medical record. This electronic record will be kept in
accordance with the VA Records Control schedule and is accessed only by authorized users
within the VA Healthcare System. All authorized users in the VA Health Administration can have
access to your medical record.
A description of this clinical trial will be available on http://www.ClinicalTrials.gov as required by
U.S. Law. This website will not include information that can identify you. At most, the website
will include a summary of the results. You can search this website at any time.

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 11 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
Your SSN will only be used for three purposes: 1) for safety monitoring and auditing purposes,
2) to assess your survival, and 3) to process your payment for participating study visits.
The West Haven VA Cooperative Studies Program Coordinating Center will be the statistical
and data coordinating center for this study. The Albuquerque VA Cooperative Studies Program
Research Pharmacy Coordinating Center (PCC) will be the central study pharmacy center and
safety monitor during the study. The Cooperative Studies Program Site Monitoring, Auditing
and Resource Team (SMART) will access your VA medical record using your social security
number (SSN) to monitor your participation and safety during the study.
The data that we gather as part of this study will be analyzed and published, as is typical in
studies like ours. We may in the future contribute data from this study to a central database
where similar studies will also contribute data. While there is currently no database like this, it is
possible that one would be created in compliance with national mandates for Federal agencies
to share data from sponsored researches. If so, we will comply with any Federal requirements in
supplying de-identified data from this study.
COSTS TO PARTICIPANTS AND PAYMENT
You will not be charged co-pays for the implantation procedure (as applicable) and the first
research study follow-up visit. If you usually pay co-payments for VA care, you will continue to
pay them for all clinical care visits and medications, which may include any future procedures
related to your implanted device. There may also be costs associated with transportation to
your healthcare facility or time away from work that will not be covered by participation in this
study.
Payment Offered for Participation:
For your time, you will be paid $25 for the baseline visit. Payment will be in the form of a debit
card or by electronic transfer of funds, or according to local medical center procedures. An
Internal Revenue Service (IRS) Form 1099, which documents that you received income, will be
generated using your Social Security Number. Because participant compensation for
involvement in this study is disbursed through the Bureau of the Fiscal Service, it is possible
that your compensation may be reduced (an “offset”), via the Treasury Offset Program (TOP), if
the Bureau’s Debt Management Services identifies outstanding debt owed to a Federal agency.
MEDICAL TREATMENT AND COMPENSATION FOR INJURY

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 12 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
Every reasonable safety measure will be used to protect your well-being. If you are injured as a
result of taking part in this study, the VA will provide necessary medical treatment at no cost to
you unless the injury was due to your not following the study procedures.
If you should have a medical concern or get hurt or sick as a result of taking part in this study,
call:
DURING THE DAY:
Dr./Mr./Ms.
at
and
AFTER HOURS:
Dr. /Mr./Ms. _____
at ________________________.
Emergency and ongoing medical treatment will be provided as needed.
You do not give up any of your legal rights and you do not release the VA from any liability by
signing this form.
PARTICIPATION IS VOLUNTARY
It is up to you to decide whether or not to take part in this study. You are giving us permission to
use your personal health information until the goals of this study are met. If you decide to take
part, you may still withdraw at any time. You must withdraw in writing in order to withdraw your
permission for us to continue to collect and use further information (except from public records,
such as survival data). However, the information we already collected before your withdrawal
will be used by investigators to complete the study and to record any information that is required
by oversight agencies concerning safety of participants.
If you do not wish to be in this study, or leave the study early, or if the study closes at any time,
for any reason, you will not lose any of the benefits to which you are entitled. If you don’t take
part or withdraw, you can still receive all the usual care that is available to you. Your decision
not to take part will not affect the relationship you have with your doctor or other staff, and it will
not affect the usual care that you receive as a patient.

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 13 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
You may be asked whether you are willing to continue limited participation in the study. This
means if you consent to provide information on a less active level such as allowing study
personnel to review your medical record to determine your medical status or by agreeing to
limited phone contact.
If you wish to withdraw from this study, you may do so by submitting your request in writing to:
CSPCC (151-A), VA Connecticut Healthcare System, 950 Campbell Avenue, West Haven, CT
06516; ATTN: CSP#592. The study team at this site can provide you with a Withdrawal Form as
a convenience.
RIGHT OF INVESTIGATOR TO TERMINATE PARTICIPATION
The investigator reserves the right to terminate your participation if, in the judgment of the
investigator, your continued participation represents a potential for harm. Reasons for this may
include your inability to comply with the study, or early stoppage of the study due to safety
concerns, benefit or insufficient number of participants.
PERSONS TO CONTACT ABOUT THIS STUDY
If you have questions, complaints, or concerns about this research, you can call the National
Study Coordinator at 1-202-745-8000 x 54087 or your VA medical center patient advocate(s):
_________________________________at ________________________________.
If you have questions about your rights as a study participant, or you want to make sure this is a
valid VA study, you may contact the VA Central Institutional Review Board (IRB). This is the
Board that is responsible for overseeing the safety of human participants in this study. You may
call the VA Central IRB toll free at 1-877-254-3130 if you have questions, complaints or
concerns about the study or if you would like to obtain information or offer input.
SIGNIFICANT NEW FINDINGS
Sometimes during a research study, new information becomes available about the treatments
that are being studied that might change a person’s decision to stay in the study. If this
happens, your research study team will tell you about it and discuss with you whether you want
to continue in the study. If you decide to continue in the study, you might be asked to sign an
updated informed consent form. Your research study team may also decide it to be in your best
interests to withdraw you from the study. If so, the reasons will be explained and your usual
clinical care will not be affected.

RESEARCH CONSENT FORM
Version Date: 6/17/2016
Participant Name:
Date: _________
Title of Study: VA Cooperative Studies Program #592: Efficacy and Safety of Implantable Cardioverter
Defibrillator (ICD) Implantation in the Elderly
Local Site Investigator: _____________________________________ VA Facility: _________________
Principal Investigator for Multisite Study: Steven Singh, MD
Site #
ID #
Alpha Code
VA Form
10-10-86
Page 14 of 14
MAR 2006
FOR VA CENTRAL IRB USE ONLY
PI/SC Approval Date:
07/11/2016
LSI Approval Date: N/A
LSI Verification Date:
N/A
AGREEMENT TO PARTICIPATE IN THE RESEARCH STUDY
A study team member has explained the research study to you. You have been told of the risks
or discomforts and possible benefits of the study. You have been told of other choices of
treatment available to you. You have been given the chance to ask questions and obtain
answers.
You voluntarily consent to participate in this study. You also confirm that you have read this
consent, or it has been read to you. You will receive a copy of this consent after you sign it. A
copy of this signed consent will also be put in your medical record if applicable.
I agree to participate in this research study as has been explained in this document.
_________________________
Participant’s Name
____________________________
Participant’s Signature
___________
Signature Date
___________________________
Name of person obtaining consent
______________________________
Signature of person obtaining consent
____________
Signature Date
FOR RESEARCH STAFF
In-person
Telemedicine
Telephone

Official Title: Efficacy and Safety of Implantable Cardioverter-Defibrillator (ICD) Implantation in 
the Elderly (I-70) 
ClinicalTrials.gov Identifier: NCT02121158 
Document Type: Statistical Analysis Plan 
Document Date: 2/19/2016 

CSP592 - Statistical Analysis Plan 
CSP592 Statistical Analysis Plan, v1.2                                            2/19/16 
1 
 
 
 
 
VA Cooperative Study No. 592 
 
Efficacy and Safety of ICD Implantation in the Elderly 
(the “I-70 Study”) 
  
 
 
Statistical Analysis Plan 
 
 
 
 
 
February 19, 2016 
v1.2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRIVILEGED AND CONFIDENTIAL 
Not for Dissemination Beyond the Official Study Function and Use 

CSP592 - Statistical Analysis Plan 
CSP592 Statistical Analysis Plan, v1.2                                            2/19/16 
2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
 
Definition 
AR1 
 
Autoregressive Covariance Structure 
ATP 
 
Antitachycardia Pacing 
BMI 
 
Body Mass Index 
CI 
 
Confidence Interval 
CMS  
Center for Medicare and Medicaid Services 
CSP 
 
Cooperative Studies Program 
CS 
 
Compound Symmetry 
CSPCC 
Cooperative Studies Program Coordinating Center 
CSPCRPCC Cooperative Studies Program Clinical Research Pharmacy Coordinating Center 
DMC  
Data Monitoring Committee 
ECG (EKG) Electrocardiogram 
ICD 
 
Implantable Cardioverter Defibrillator 
LRT 
 
Likelihood Ratio Test 
LVEF  
Left Ventricular Ejection Fraction 
MI 
 
Myocardial Infarction 
MITT  
Modified Intention to Treat 
MLHF  
Minnesota Living with Heart Failure 
NDI 
 
National Death Index 
OMT  
Optimal Medical Therapy 
PDF 
 
Portable Document Format 
SAP 
 
Statistical Analysis Plan 
SAS 
 
Statistical Analysis Software 
SCD  
Sudden Cardiac Death 
QOL  
Quality of Life 
VA 
 
Department of Veterans Affairs 
 
 

CSP592 - Statistical Analysis Plan  
20160219_CSP592_SAP_v1-2_Clean.docx2,                                            2/9/16 
3 
Table of Contents 
PAGE 
List of Figures 
7 
1. Introduction 
9 
1.1 Overview 
9 
1.1.1 Motivation of the Statistical Analysis Plan 
9 
1.1.2 Motivation of CSP#592 
9 
1.2 Study Objectives and Hypotheses 
10 
1.2.1 Primary Objectives 
10 
1.2.3 Secondary Objectives 
10 
1.2.3.1 Co-morbidity Burden 
10 
1.2.3.2 Quality of Life 
10 
1.2.4 Exploratory Analyses 
10 
1.2.4.1 Prevention of Sudden Cardiac Death 
11 
1.2.4.2 Reduction in All-Cause Hospitalization 
11 
1.3 Outcome Measures 
11 
1.3.1 Primary Outcome Measure 
11 
1.3.2 Secondary Outcome Measures 
11 
1.3.2.1 Quality of Life 
11 
1.3.2.2 Co-Morbidity Burden 
13 
1.3.2.3 Sudden Cardiac Death 
13 
1.3.2.4 All-Cause Hospitalization 
14 
1.3.2.5 ICD Device Data 
14 
1.4 Patient Characteristics 
16 
1.4.1 Screened Population 
16 
1.4.2 Enrolled Population 
17 
1.4.3 Randomized Participants 
17 
2. Statistical Approaches 
19 
2.1  Study Design Summary 
19 
2.2  Statistical and Analytical Plans 
21 
2.2.1 Randomization Scheme 
21 
2.2.2 Baseline Comparability 
22 
2.2.3 Analysis of the Primary Outcome 
23 
2.2.4 Exploration of a Modified Intention to Treat 
Approach 
24 
2.2.5 Supportive Co-Variate-Adjusted Analysis 
25 
2.2.6 Analysis of the Secondary Outcomes 
25 
2.2.6.1 Treatment Interactions by Co-Morbidity 
25 
2.2.6.2 Quality of Life 
26 
2.2.7 Exploratory Analysis 
26 
2.2.7.1 Quality of Life 
26 
2.2.7.2 All-cause Hospitalization 
28 
2.2.7.3 Sudden Cardiac Death 
29 
2.2.7.4 Informed Consent Questionnaire 
29 
2.2.8 Device Data 
30 

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2.2.9 Analysis of Safety Data 
32 
2.2.10 Consenting Rates 
32 
2.3 Interim Monitoring and Analysis 
33 
2.3.1 Overview 
33 
2.3.2 Monitoring Recruitment 
33 
2.3.3 Monitoring Safety 
34 
2.3.4 Monitoring Outcomes 
35 
2.3.5 
Monitoring Protocol Adherence 
36 
2.3.6 
Sample Size Re-estimation 
36 
3. Ground Rules and Data Handling Conventions 
39 
3.1 Baseline Definitions or Conventions 
39 
3.2 Time Points, Day Ranges, and Phasing of Study 
Periods 
39 
3.3 Handling of Missing Data 
40 
3.4 Description of Protocol Violations 
40 
3.5 Datasets/Programs/Variables 
40 
3.6  Programming Specifications and Software 
42 
4. References 
43 
5. Reporting Tables 
49 
  
 
 

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List of Tables 
 
Table 1: Cumulative Number of Subjects Pre-screened, Enrolled, and Randomized by month  
Table 2: Total Number of Subjects Pre-screened, Enrolled and Randomized by Site 
Table 3: Summary of Inclusion and Exclusion Criteria and Pre-Screening Status – All Pre-
Screened Subjects with Age ≥70, eligible for implantation and with OMT 
Table 4: Summary of Inclusion and Exclusion Criteria and Reasons for Non-Randomization – All 
Enrolled Participants 
Table 5: Summary of Stratification – All randomized participants 
Table 6: Frequency of Total Charlson Score among Randomized Participants 
Table 7: Frequency Table by Charlson Item  
Table 8: Completeness of Data Forms by Site-All Enrolled Participants  
Table 9: Reason for Exit for before and after Randomization – All Enrolled Participants 
Table 10: Baseline Demographic Characteristics - All Randomized Participants 
Table 11: Military Service History-All Randomized Participants 
Table 12: Baseline Clinical History - All Randomized Participants 
Table 13: Baseline Laboratory Assessments – All Randomized Participants 
Table 14: Baseline Physical Examination – All Randomized Participants  
Table 15: Summary of Adverse Events occurring 30 days of Randomization (OMT) or 
Implantation (OMT+ICD)* – All Randomized Subjects after Randomization 
Table 16: Summary of Adverse Events– All randomized subjects after randomization 
Table 17: Summary of Adverse Events after Randomization by System Organ Class and 
Preferred Term – All Randomized Participants 
Table 18: Summary of Serious Adverse Events occurring 30 days of Randomization (OMT) or 
Implantation (OMT + ICD) – All randomized subjects after randomization 
Table 19: Summary of Serious Adverse Events – All randomized subjects after randomization 
Table 20: Summary of Serious Adverse Events after Randomization by System Organ Class and 
Preferred Term – All Randomized Participants 
Table 21: Listing of Serious Adverse Events after Randomization – All Randomized Participants 
Table 22: Summary of Mortality by Preferred Term-All Randomized Participants after 
Randomization 
Table 23: Summary of the Cause of Mortality -All Deaths Occurring after Randomization 
Table 24: Primary Outcome: All-cause Mortality by Treatment Assigned 
Table 25: Secondary Outcome: Cardiovascular Death by Treatment Assigned 
Table 26: QoL MLHF Score by Time Point and Treatment Assigned – All randomized 
participants 
Table 27: Sudden Cardiac Death by Treatment Assigned  

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Table 28: Summary of ICD reports 
Table 29: ICD Therapy Event Frequency Table 
Table 30: Summary Rhythm at Time of Detection  
Table 31: Summary of Rhythm at end of episode 
 
 
 
 

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List of Figures 
 
Figure 1: CSP #592, multi-site, prospective, randomized clinical trial comparing ICD therapy 
against optimal medical therapy (OMT). 
Figure 2: Observed and Expected Intake by Month 
Figure 3: Kaplan Meier Survival plot for primary outcome all-cause mortality   
Figure 4: Kaplan Meier Survival plot for exploratory analysis - Sudden Cardiac Death 
 
 
 
 

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1. 
Introduction 
1.1 
Overview  
1.1.1 
Motivation of the Statistical Analysis Plan 
This Statistical Analysis Plan (SAP) is intended to be a comprehensive and detailed 
description of the strategy, rationale, and statistical techniques that will be used in the 
monitoring and analysis of the data collected in this study. 
1.1.2 Motivation of CSP#592 
 
Sudden cardiac death (SCD) is the second greatest cause of death in the United States, 
after all cancers combined. The implantable cardioverter defibrillator (ICD) has shown 
great efficacy in reducing all-cause mortality, and specifically SCD, by continuously 
monitoring the electrophysiological signatures of the heart, and intervening with a 
therapeutic shock in case of a detected arrhythmia. However, whereas the landmark 
clinical trials demonstrating ICD efficacy have included primarily middle-aged patients, 
there is little known of the impact of the ICD on older patients; clinicians often treat the 
elderly based on empiric judgments, rather than robust clinical evidence.  There is an 
emergent need to study both efficacy and safety of the ICD in patients with advanced age.  
The overall aim of CSP#592 is to study the safety and efficacy of ICD implantation as a 
primary prevention strategy of SCD in patients 70 years and older. In particular, this 
study is designed to determine the comparative effectiveness of ICD, in addition to 
optimal medical therapy (OMT), in reducing all-cause mortality, versus OMT alone. 
OMT includes standard intervention for chronic heart failure patients, i.e. lifestyle 
modification, disease management, adoption of healthy diet and exercise practices, 

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etcetera. One particularly important secondary objective is to assess treatment efficacy 
under the conditions of high versus low co-morbidity burden. 
1.2 Study Objectives and Hypotheses 
 
1.2.1 Primary Objectives  
The primary objective of CSP#592 is to determine whether a primary prevention strategy 
with ICD implantation in addition to optimal medical therapy (OMT) is effective in 
reducing all-cause mortality compared to OMT alone in patients ≥70 years of age who 
are eligible for ICD therapy according to current Centers for Medicare & Medicaid 
Services (CMS) criteria. The primary hypothesis of CSP#592 is that implantation of an 
ICD plus optimal medical therapy will reduce all-cause mortality in patients ≥70 years of 
age versus optimal medical therapy alone.   
1.2.3 Secondary Objectives 
 
1.2.3.1 Co-morbidity Burden 
A secondary objective of this study is to ascertain whether age, co-morbidity burden, or 
age and burden together, are determinants in mortality outcomes in the OMT versus ICD 
+ OMT group. 
1.2.3.2 Quality of Life 
An additional secondary objective of the study is to determine the effect of ICD 
implantation plus optimal medical therapy on QoL among elderly patients compared with 
optimal medical therapy.  
1.2.4 Exploratory Analyses 
 

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1.2.4.1 Prevention of Sudden Cardiac Death 
This study will also ascertain whether –irrespective of the effect of ICD on all-cause 
mortality– the ICD is effective in its designed mechanism of action, i.e. preventing 
sudden cardiac death. 
1.2.4.2 Reduction in All-Cause Hospitalization 
As an additional exploratory analysis, CSP#592 will test whether there is a significant 
difference in the number of hospitalizations among participants randomized to ICD + 
OMT versus those randomized to optimal medical therapy alone. 
1.3 Outcome Measures 
1.3.1 Primary Outcome Measure 
The primary outcome measure for this study will be death from any cause analyzed as 
time to event. The date of randomization will be used as the time origin. VA Vital Status 
File will be used to determine the vital status of all study participants who are lost to 
follow-up at study exit.  The VA Vital Status File has been shown to be highly accurate 
compared to the National Death Index (NDI)1. As cause of death is not available from the 
VA Vital Status File, a NDI Plus database search will be performed for all participants 
who are found to have died through the database search in order to adjudicate the cause 
of death for secondary outcomes.   
1.3.2 Secondary Outcome Measures 
1.3.2.1 Quality of Life 
Among the cardiac-specific quality of life (QoL) instruments, the Minnesota Living with 
Heart Failure questionnaire (MLHF) is considered to be among the best2. It has been 
widely validated3–5, and it is more sensitive than the generic QoL measures in detecting 
clinically important changes over time in patients with heart failure6,7. The MLHF was 

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also chosen as the QoL measure for this study because it is simple, inexpensive, short, 
easily understood by ill and elderly individuals,  and easy to score 8–15. 
The MLHF questionnaire is designed to specifically assess the impact of heart failure on 
QoL. It consists of 21 questions that measure the effect of symptoms specifically related 
to heart failure and its treatment in adults16-17 The response to each question is scored on 
a 6-point Likert scale (0-5). There are two subscales to MLHF: physical and emotional. 
The effect size outcomes of several studies employing QoL are summarized in the 
following table. 
Table 1 Effect sizes reported using Minnesota Living with Heart Failure survey *.  
Effect Size 
Interpretation 
Source 
1 
Not significant 
Rector, 1992 15 
1.6 
Not significant (P=0.33) 
Kasper, 2002 14 
4 
P<0.001 
Rector, 1992 15 
5 
Not significant 
Owen, 2000 12 
6.6 
P=0.0006 
Kasper, 2002 14 
6.7 
Not significant (P=0.41) 
Curiati, 2005 18 
9.6 
P=0.01 
Kasper, 2002 14 
11.6 
P=0.02 
Curiati, 2005 18 
MLHF on 105-point scale, including their calculated significance. Original references 
listed. 
 
A disease-specific instrument was chosen in favor of a broader (“generic”) QoL 
assessment for the reason that questionnaires with greater emphasis on ICD-specific and 
arrhythmia-specific measures may be more sensitive to changes in outcome, and would 
be more impactful in addressing ICD as a treatment choice for life threatening 

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arrhythmias19. The Minnesota Living with Heart Failure is designed to capture both 
physical and emotional (anxiety or distress) dimensions of patient well-being and is 
considered an effective and efficient instrument 20. 
1.3.2.2 Co-Morbidity Burden 
 
One of the primary reasons for doing a study like CSP#592 is to determine whether there 
are differential risk-benefit issues in the elderly: in patients with declined health status, 
the likelihood of surviving long enough to derive benefit from device implantation may 
be decreased. This study will test whether poor general health status shifts the risk-benefit 
profile. In this way, the Charlson Co-Morbidity Index is the most practical tool for 
incorporation into CSP#592, as it is an extensively validated method of measuring the 
prognostic impact of co-morbid disease 20,21 
1.3.2.3 Sudden Cardiac Death  
 
Sudden cardiac death will include deaths that occur unexpectedly that are not preceded 
by an acute myocardial infarction. SCD will include the following events 22: 
o Death witnessed and instantaneous without new or worsening symptoms; 
o Death witnessed within 60 minutes of the onset of new or worsening cardiac 
symptoms, unless the symptoms suggest an acute myocardial infarction; 
o Death witnessed and attributed to an identified arrhythmia, e.g., captured on an 
electrocardiographic (ECG) recording, witnessed on a monitor, or unwitnessed but 
found on implantable cardioverter-defibrillator review; 
o Death after unsuccessful resuscitation from cardiac arrest; 

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o Death after successful resuscitation from cardiac arrest and without identification of 
a non-cardiac etiology (Post-Cardiac Arrest Syndrome); and 
o Unwitnessed death without other cause of death (information regarding the 
participant’s clinical status preceding death should be provided, if available). 
General considerations for SCD are that a subject seen alive and clinically stable 12-24 
hours prior to being found dead without any evidence or information of a specific cause 
of death should be classified as SCD. Deaths for which there is no information beyond 
“Patient found dead at home” may be classified as “death due to other cardiovascular 
causes” or “undetermined cause of death” 22. Cause of death determination will be 
National Death Index (National Center for Health Statistics); the NDI Plus database has 
been shown to be highly accurate in resolving cause of death 21; an Adjudication 
Committee may be assembled if deemed necessary by the Executive Committee. 
1.3.2.4 All-Cause Hospitalization 
 
Hospitalization information will be captured by participant self-report and medical record 
review. Self-report is valid and reliable, especially with inpatient care and recall periods 
less than one year23; however, hospitalization data will also be collected from VA 
electronic medical records, and where feasible: access of non-VA medical records. 
Specifically, this study will test whether the total number of days of hospitalization are 
different between the two treatment arms. 
1.3.2.5 ICD Device Data 
 

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ICDs monitor and store data on a wide range of parameters including battery and lead 
function, patient activity, heart rate, frequency of pacing, and most importantly 
tachyarrhythmia events. The ICD stores extensive data on all tachycardia events that 
trigger therapy including beat to beat intervals that met the programmed criteria for ICD 
therapy, electrograms from before, during, and after ICD therapy, the types of ICD 
therapy employed including shocks and anti-tachycardia pacing (ATP), the results of 
each therapy attempt, and the final results of ICD treatment. This data can be accessed in 
clinic using a device called a programmer which interrogates the defibrillator and then 
displays the results and allows the results to be saved as a PDF file. This data can also be 
retrieved “remotely” in the patient’s home using a home monitoring device that is 
available to all newly implanted ICD patients. These home monitoring systems 
interrogate the ICD on a programmable schedule and transmit the data to secure servers 
via either land line or cell phone systems on a routine usually every 3 month basis and 
when certain programmable criteria for unscheduled transmissions are met. “On demand” 
transmissions can also be initiated by patients if they feel they are having a problem or 
are instructed to do so by their provider. The VA National Cardiac Device Surveillance 
Center manages the data flow from this remote monitoring and posts PDF files of all 
transmissions on their web site and alerts providers if there are urgent findings on a 
transmission. Remote monitoring provides significant benefits to the Study Team, as it 1) 
provides accurate, objective, and timely record of therapeutic events, and 2) provides a 
platform for assessing protocol adherence with regard to device programming, and 3) 
reduces loss to follow-up. Registration for this database is expected of all CSP#592 study 

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participants; failure to register within 30 days of implantation will be considered a 
protocol deviation. 
Files documenting all in clinic interrogations will be accessed by the Study Team in a 
separate and independent transaction from that conducted by the care provider as part of 
routine clinical practice. These files will be used most importantly as source 
documentation for exploratory analyses of ICD therapy events including the frequency of 
ICD therapy, the appropriateness of ICD therapy, the rhythms that trigger ICD therapy 
and the overall number of shocks experienced by participants with ICDs. These files 
could also be used for other exploratory analyses focusing on other aspects of ICD 
function. The data contained within these files may be the result of direct interrogation of 
the device, or a filtered dataset exported from a larger database used in order to increase 
the efficiency of data analysis.  
Lastly, every effort will be made to interrogate the device upon death. This is standard 
clinical practice and is often impactful in facilitating determination of the cause of death. 
 
1.4 Patient Characteristics 
1.4.1 Screened Population 
 
This study will recruit within the electrophysiology service, heart failure clinics, 
gerontology, and general practice. A broad outreach effort will be undertaken in an effort 
to ensure adequate enrollment and from a diverse patient pool. All individuals identified 
in the site screening logs as potential participants who referred to the study for screening, 
or for whom referral was sought through a treating clinician, or for whom there appeared 
to be evidence of study eligibility will be noted. De-identified data from these screening 
logs will be transmitted from the sites to the centralized members of the Study Team 

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(Chair’s Office and Coordinating Center). This population may include many patients 
who are ineligible for the study; Eligibility criteria will be clearly noted within this 
screening log 
1.4.2 Enrolled Population 
 
Participants enrolled in CSP#592 will have been introduced to the study and its 
risk and benefits, and provided informed consent to be randomized to either study arm 
(OMT + ICD, or OMT without implantation). Provision of informed consent permits the 
collection of baseline data, which will be useful in confirming eligibility to be 
randomized. This population may still include patients who are ineligible for the study.  
1.4.3 Randomized Participants 
 
Participants qualified to be randomized within CSP#592 must meet all eligibility 
criteria, and may not meet any of the exclusion criteria. The Inclusion and Exclusion 
criteria are exhaustively detailed in the Study Protocol and Operations Manual, and are 
summarized as follows (Figure 1). 
 
 

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Figure 1: CSP #592, multi-site, prospective, randomized clinical trial comparing ICD 
therapy against optimal medical therapy (OMT). 
  Signed Informed Consent and HIPAA 
Baseline assessments and 
Randomization (N=1,462) 
ICD + OMT 
(N=731) 
OMT 
(N=731) 
Follow through Study Close 
– Clinical Follow-Up visit @ 1-4 months 
– Follow-up at 6-month intervals from Randomization Date 
– Quality of Life at 6, 12, and 24 months 
Inclusion criteria (must meet all) 
1.
70 years of age or older 
2.
Eligible for ICD according to the CMS criteria for primary Prevention 
3.
Stable condition on Optimal Medical Therapy 
4.
Able and willing to provide informed consent to participate in this study 
Excluded 
No to any. 
Yes to all. 
No to all. 
Exclusion criteria (must avoid all) 
1.
Enrolled in or planning to enroll in a conflicting interventional trial 
2.
Receiving a bi-ventricular ICD device 
3.
New York Heart Association class IV heart failure 
4.
Cardiogenic shock or symptomatic hypotension while in stable baseline 
Rhythm 
5.
Coronary artery bypass graft (CABG) or percutaneous 
transluminal coronary angioplasty (PTCA) within the past 3 months 
6.
An MI within the past 40 days 
7.
Clinical symptoms or findings that would make them a candidate for coronary 
revascularization 
8.
Irreversible brain damage from pre-existing cerebral disease 
9.
Any disease other than cardiac disease (e.g. cancer, uremia, liver failure), 
associated with a likelihood of survival less than 1 year 
10. Circumstance that would prevent completion of the trial and follow-up 
activities, including medical condition 
Excluded 
Yes to any. 

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2. 
Statistical Approaches 
2.1  Study Design Summary 
The primary outcome of CSP#592 is all-cause mortality analyzed as time to event. The 
primary hypothesis is that the ICD arm will have a 25% reduction in the hazard ratio 
(HR=0.75) (23.5% relative risk reduction in the annual mortality rate). The sample size 
calculation assumes a 15% annual mortality rate in the control arm. The cumulative event 
rate by the end of the 5-year trial (3.6 years average follow-up1), taking into account 
administrative censoring, loss, drop-in, and drop-out, is projected to be 42.0% in the 
control arm versus 34.1% in the ICD arm. The following assumptions were used for the 
sample size calculation: 
 Two-sided Type I error of 0.05 
 Pilot stage with uniform recruitment over 1 year, with uniform follow-up of 5 
years for all participants; 17 participants per site at 6 sites, i.e. 102 × 5 = 510 
patient follow-up years 
 Full-scale stage with uniform recruitment over 3 years (minimum follow-up = 2 
years, maximum follow-up = 5 years, median follow-up = 3.5 years) 
 Annual event rate of 15% in the control arm 
 Hazard ratio of 0.75 (relative risk reduction =23.5%) 
 Allocation ratio of 1:1 for the treatment groups 
 Annual drop-in rate of 2.5% from the control group to the ICD group 
                                                 
1 Five years follow-up for Pilot Study participants (N=102), plus 3.5 years average follow-up for 
participants in Stage II (N=1360): (5×102 + 3.5×1360) ÷ (102+1360) = 3.6 average years of follow-up. 

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 Drop-out rate of 1% from the ICD group to the control group in year 1 only. 
 Annual loss-to-follow-up of 1% 
Because the VA Vital Status File will be searched for all deaths, loss-to-follow-up for the 
primary endpoint is considered to be very negligible and was therefore not accounted for 
in the sample size calculation.  Based on a 15% annual event rate in the control arm and a 
hazard ratio of 0.75, and the other assumptions listed above, a sample size of  1,462 (565 
total primary outcome events) will be needed in order to achieve 90% power with a 2-
sided Type I error rate of 0.05. 
The secondary objectives for this trial are to test the treatment interactions by co-
morbidity level, and to test the change from baseline in the Minnesota Living with Heart 
Failure score.  Neither secondary analysis will require adjustment for type I error, i.e. no 
“multiple testing” corrections:  adjustments for multiple comparisons are required in 
confirmatory whenever results from multiple tests have to be combined in one final 
conclusion and decision; in studies with a single primary endpoint, all other endpoints are 
considered subsidiary and their results can only have an exploratory rather than a 
confirmatory interpretation – multiplicity corrections are not required24.  
 
 

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2.2  Statistical and Analytical Plans 
2.2.1 Randomization Scheme 
Veterans who satisfy all of the study eligibility criteria, provide written informed consent 
and complete the necessary baseline assessments will be randomized to one of two 
treatment strategies: ICD therapy + optimal medical therapy, or optimal medical therapy 
alone. The treatment assignment will be provided through a web-based randomization 
platform or over the telephone to the site investigator or coordinator. The treatment 
allocation ratio for the two treatment regimens will be 1:1 within each stratum; 
participants will be stratified both by medical center and by Charlson score (Charlson <3, 
and Charlson ≥3), using a random permuted block scheme with randomly varying block 
size. The random treatment scheme has been generated by CSPCC. When a subject is to 
be randomized, the Study Coordinator or Local Site Investigator will complete the 
eligibility and baseline forms. If all eligibility criteria are satisfied and informed consent 
has been obtained, a new randomization will be assigned. This procedure has been tested 
and validated before enrollment began.  
The CSPCC will review the overall and by-site randomization at least weekly during the 
enrollment phase of the study, and will be monitoring the randomization transactions 
with equal or greater frequency. The participant’s unique study ID number will be linked 
in the randomization file to the treatment assignment for each individual. The 
randomization file data will remain separate from the rest of the study data on the central 
database. 
Randomization may occur on the same day the patient has completed the necessary 
portions of the Screening and Baseline assessments and is judged eligible for 

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randomization. Delay in randomization due to participant or medical circumstances are 
permitted up to a maximum of 30 days past baseline data collection; if randomization is 
delayed further, baseline data must be collected anew. When a new participant has been 
enrolled, his/her electronic medical record will be updated indicating participation in the 
study. Source documentation for eligibility criteria and randomization will be kept at the 
site with the participant’s study folder. 
2.2.2 Baseline Comparability 
Because of the size of this study, we expect that the randomization process will produce 
reasonably comparable groups of participants. However, the adequacy of the 
randomization will be assessed by comparing the distribution of baseline assessment. The 
baseline assessment includes demographics and military history, clinical history, 
laboratory measurements, EKG, physical examination, six-minute walk test, medication 
use, and Minnesota Living with Heart Failure Questionnaire score. Specifically, 
continuous variable (e.g. age and BMI) will be examined for skewness and outliers , both 
quantitatively and by graphical means such as side-by-side histograms, boxplots, and 
normal quartile plots. The summary statistics will also be calculated including means, 
medians, quartiles, etc. The difference in the means for continuous variable will be tested 
through two-sample t test. F tests for equality of variances will be used to guide the 
selection of the appropriate statistical tests for continuous measures.  For the variables 
that are not normally distributed, a nonparametric method, such as Wilcoxon rank-sum 
test will be used to test the difference between the two groups. Categorical variables will 
be examined by calculating frequency distributions. Chi-square test or Fisher’s exact test 

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(when expected cell counts are less than 5) will be used for comparing the distribution 
between treatment groups.  
2.2.3 Analysis of the Primary Outcome 
For all the endpoints (primary, secondary, and exploratory) we will present summary 
information, as well as estimated result with p-value from an appropriately selected 
hypothesis test. The number of participants reaching the primary endpoint will be 
summarized in terms of total number participants as well as percent by treatment arm and 
treatment stratified by health stratum. 
Treatment effect on the primary outcome, all-cause mortality, will be analyzed as time to 
event and tested by the stratified log rank statistic (stratified by  Charlson score <3 versus 
≥3), with a type I error of 0.05 (2-sided). Cumulative survival rates will be calculated 
using the method of Kaplan-Meier. The treatment effect will be estimated from a Cox 
proportional hazards model, adjusted by Charlson score and provided as a hazard ratio 
(ICD versus optimal standard of care) with a 95% confidence interval. The start time for 
all time-to-event analyses will be defined as the date of randomization and participants 
who do not experience an event will be right-censored at the date of last contact, date 
withdrawn, or date of study exit. VA Vital Status File will be used to determine the vital 
status of all study participants who are lost to follow-up at study exit.   
Prior to Cox model fitting, the assumption of proportionality will be tested via treatment 
by time interaction term. If the assumptions of proportionality are not fulfilled, there will 
be no impact on the primary hypothesis test since we apply log-rank test on the primary 

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hypothesis test. We may estimate the hazard ratio by introducing interactions of treatment 
with function of time in the model. In addition, we will also test the treatment and 
Charlson stratum interaction in the Cox proportional hazards model25. Breslow’s 
approximation, which is the default in PROC PHREG in SAS, will be used to handle tied 
event times when ties are relatively few26. If data are moderately- or heavily tied, we will 
use Efron’s method, which gives closer results to the exact results than Breslow’s 
approximation27,28.  
2.2.4 Exploration of a Modified Intention to Treat Approach 
The primary analysis uses an intention to treat approach, with time to event according to 
time from randomization to exit/death. As we anticipate that there will be some delay 
between randomization and ICD implantation, we will perform a sensitivity analysis on 
the primary outcome using a modified intention to treat (MITT) approach without 
adjusting the type I error. In the MITT sensitivity analysis, we will first calculate the 
average time from randomization to implantation τ. Then, the start time for participants in 
the OMT arm will be adjusted by τ, in order to calibrate the time of treatment; the time 
for participants randomized to ICD will be taken from time of implantation. In a situation 
where a participant dies before implantation (OMT+ICD arm) or τ (OMT arm), he/she 
will be excluded from the MITT analysis29. The survival analysis for MITT will be the 
same as the primary analysis.   
Similar sensitivity analysis will be applied to other mortality endpoints, such as sudden 
cardiac death.  
 

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2.2.5 Supportive Co-Variate-Adjusted Analysis 
Adjustment for significant treatment imbalances in baseline covariates will not be done in 
the primary analysis because this approach can be biased 30,31. Instead, exploratory 
analyses examining the treatment effect will be conducted using a model adjusted for a 
predefined set of important clinical covariates known to moderate or mitigate outcomes. 
The model will include factors that are known to increase risk in ICD patients, such as 
age at randomization, number of previous myocardial infarctions (MI), and baseline left 
ventricular ejection fraction (LVEF).   
2.2.6 Analysis of the Secondary Outcomes 
The overall type I error for the secondary outcomes will be 0.05 (2-sided) without 
adjustment for multiple comparisons. We will apply the same analysis to the secondary 
outcome as the primary outcome. 
2.2.6.1 Treatment Interactions by Co-Morbidity 
The primary analysis of the treatment interaction with co-morbidity will take the form of 
a time to event, and will be analyzed using the same methodology (log-rank test) 
described for the primary outcome at a 0.05 2-sided significance level. The treatment 
effect will be summarized as a hazard ratio with 95% confidence interval. A test of 
treatment interaction by Charlson score <3 versus ≥3 (alternative subgroups) will also be 
performed.  

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In the study, the original Charlson score is a continuous variable. It is known that 
dichotomizing a continuous outcome into low or high values leads to a loss of 
information32,33. Therefore, to keep the statistical power of the analysis, the testing of 
interaction will also be conducted by treating Charlson score as a continuous measure, via 
the Cox model, cf. the log-rank rest for dichotomous formulation. The results from the 
above two methods will be compared, and they should be similar. In addition, a forest 
plot and treatment effects will be examined for each type of co-morbidity. 
2.2.6.2 Quality of Life 
The QoL will be measured by the Minnesota Living with Heart Failure questionnaire 
(MLHF), which contains 21 items that evaluate patients' perception of the effects of heart 
failure on their daily lives. In the questionnaire, each question is rated on a scale of 0 to 5, 
producing a total score between 0 and 105. The higher the score, the worse the quality of 
life. The total score will be treated as a continuous variable. The change in MLHF score 
at 12 months post-randomization relative to baseline will be calculated and tested for 
normality. If the distribution appears sufficiently normal, two sample t-test will be used 
to compare the difference between the two treatment groups. If not, a non-parametric 
method, such as the Wilcoxon rank-sum test will be used.  
2.2.7 Exploratory Analysis 
2.2.7.1 Quality of Life 
The QoL score at each time point will be summarized in terms of mean and standard 
deviation by treatment arm and treatment by stratified health status. 

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Early effects (QoL at 6 months), late effects (QoL at 24 months), and longitudinal effects 
(effect over 24 months) for the Minnesota Living with Heart Failure QoL data will also 
be assessed by a longitudinal repeated measures mixed effects analysis.  
The outcome variable in the mixed models will be the change in the MLHF QoL score at 
each follow-up visit relative to baseline, which is a continuous variable. Model building 
methods will be used to first determine the most parsimonious covariance structure for 
the data. The model will first be fit with an unstructured covariance matrix with time 
treated as a categorical variable. The mixed model will include the following covariate: 
baseline MLHF score (continuous variable), site as a random effect, and general health 
status (Charlson co-morbidity index) as a fixed effect and time, along with a time and 
treatment interaction term. A second model will be fit with an unstructured covariance 
matrix with time treated as a linear trend. The model will include treatment, time, and the 
treatment by linear time interaction plus the pre-determined covariates. A likelihood ratio 
test (LRT) will then be performed to determine if the linear trend (plus its interaction 
with treatment) is consistent with the data. If the simpler model with time as linear is 
sufficient, time will be treated continuously. If the fit is significantly improved with time 
as a categorical effect, then time will be included in the model as a categorical variable.  
Once the mean structure of the model is determined, a LRT will be performed to 
determine whether a more parsimonious covariance structure e.g. autoregressive 
covariance structure 1 (AR1) or AR1 or compound symmetry (CS), will fit better. Once 
the mean and covariance structure are identified for this model, a treatment by time 
interaction will be examined. If the interaction term is not significant, it will be removed 

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from the model. If the treatment by time interaction is significant, then pairwise treatment 
comparisons will be performed at each time point separately.  
As discussed previously, the Charlson score is originally a continuous variable. We will 
also perform the mixed model analysis without dichotomizing general health status. In 
addition, graphical methods will used to summarize the estimates of least square means 
and standard deviation, with pairwise comparisons at each time point.  
2.2.7.2 All-cause Hospitalization 
Total hospitalizations, total number of days of hospitalization, and the proportion of 
participants who require at least one hospitalization during the follow-up period will be 
summarized by treatment and compared between treatment groups at a 0.05 significance 
level. No adjustment will be made for multiple testing for tertiary outcomes because they 
are considered exploratory in nature.  
The total hospitalizations and total days of hospitalization will be analyzed using 
generalized Poisson or negative binomial regression models. If extra zero counts are 
observed in the above, a zero inflated Poisson model will be used34. In the generalized 
mixed model, covariates will include site as a random effect, and general health status 
(Charlson <3 versus ≥3, or as continuous variable) as a fixed effect. Proportion of 
participants requiring at least one hospitalization will be analyzed using a chi-square test 
statistic. 

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Considering informative censoring due to death if there is a treatment effect, we will also 
summarize hospitalization rate and days of hospitalization based on total active follow-up 
time. Similar tests as described above will be processed. 
2.2.7.3 Sudden Cardiac Death 
Time to event for sudden cardiac death will be analyzed using the same methodology 
described for the primary outcome at a 0.05 2-sided significance level. VA Vital Status 
File will be used to determine the vital status of all study participants who are lost to 
follow-up at study exit.  VA Vital Status File search plus a NDI Plus database search for 
all participants who are found to have died through the VA database search will be 
performed in order to adjudicate the cause of death (Table 23). 
2.2.7.4 Informed Consent Questionnaire 
Additionally, data from the Informed Consent Questionnaire will be used for exploratory 
analysis of the association between perceived and actual participant understanding of the 
study. The goal of this analysis is to measure which study nuances are most easily 
understood. The first part (Items 1-11) of Informed Consent Questionnaire measures the 
patients’ perception/knowledge of the study. The total number and proportion of correct 
responses per each item will be calculated for each subject. Mean and standard deviation 
will be calculated for each group.    
The second part (Question 12-15) comprises validated items that measures patients’ 
perceived understanding of the study35, which are subjective patients’ reports of their 
own understanding. The perceived understanding is scored on 0 to 3 scales with total 

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score of 0 to 9. Higher scores indicate greater perceived understanding. The association 
between perceived and actual participant understanding of the study can be measured by 
agreement analysis between part 1 and part 2. In addition, the association between 
patients’ perceived understanding and the probability of patients’ withdrawal and other 
factors in baseline, such as patients’ age will also be studied. We note that because these 
data are collected during the consenting procedure, there is no plan to analyze by 
treatment group. 
2.2.8 Device Data 
 
ICDs are capable of delivering information related to a wide range of parameters 
including activity level, heart rate variability, as well as data related to the delivery and 
cessation of arrhythmic therapy. The device data will be collected during study follow-up 
visits for participants in the ICD arm and followed by remote monitoring where possible. 
Descriptive analysis will be used to summarize the ICD device data. The analysis will be 
focused on three activities in particular:  
(1) Routine assessment of device activations to assess shock events. The shock events 
will be summarized and grouped in relevant categories, e.g. by year, by age, by 
health status, by cause, and by resolution/outcome, and whether appropriate or 
inappropriate shock36. Subjects with no recorded events will also be noted.   
(2) The risk of death after shock will be analyzed for both appropriate shock and 
inappropriate shock 
(3) Analysis of device data at follow-up appointments as is done in standard clinical 
practice.  

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ICD therapy will be defined as either antitachycardia pacing (ATP) or ICD shock. Any 
ICD therapy not delivered for VT or VF will be deemed inappropriate, and the rhythm 
triggering therapy categorized as: atrial fibrillation or atrial flutter (AF), supraventricular 
including sinus tachycardia (SVT), or inappropriate sensing using published criteria. An 
episode’s termination will be defined by the ICD re-detecting sinus rhythm and thus 
could include more than 1 shock (and/or ATP bursts). As done previously in the AVID 
(Antiarrhythmics Versus Implantable Defibrillators) study, a subsequent episode 
beginning <5 min after episode termination will be ignored for this analysis. Thus, an 
inappropriate shock episode will be defined as an episode during which one or more 
inappropriate shocks occurred; a separate ICD episode of the same type (inappropriate or 
appropriate) occurring <5 min later will not be counted. 
Descriptive statistics will be used to summarize all clinical characteristics.  The Kaplan-
Meier life-table method will be used to graphically display the time to first shock event 
and calculate the cumulative event rates for each group. The results will be compared 
using the log-rank statistic.  
Among the patients who have an active ICD, we will use a Cox regression to evaluate 
what factors are associated with time to inappropriate shock where time to the first 
inappropriate shock will serve as the dependent variable, and subjects who never 
experience a shock or experience only appropriate shocks will be censored at the last time 
of follow-up. In a similar way, we will evaluate the association of inappropriate, 
appropriate shock with mortality where time to death will serve as dependent variable 
and inappropriate shocks, appropriate shocks and other related clinical variables will be 

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included as time-dependent co-variates. These analyses may provide insights in 
understanding how the device shock therapies are utilized and affect the study outcomes.  
2.2.9 Analysis of Safety Data 
New Adverse Events (AEs) will be collected for only 30 days post-randomization (OMT 
arm) or 30 days post-implantation (ICD arm); these events will be followed throughout 
the study until study close or AE resolution, but new AEs will not be collected after this 
period. All reportable non-serious and serious adverse events will be coded by one or 
more AE specialist. The total number of AE/SAE, and total number of participants 
experiencing an event will be summarized by treatment. The proportion of participants 
experiencing an AE/SAE will be calculated for each treatment group. A chi-square test 
for the difference in the proportion of SAEs will be used to compare treatment groups 
over all at the 0.05 level. Treatment comparisons will be made for the number of 
participants experiencing SAE, the number of treatment-related SAE, and for the number 
of non-serious adverse events.  
In addition, the adverse events will be summarized according to the Medical dictionary 
for Regulatory Activities (MedDRA)37, in terms of system organ class and preferred 
terms, by treatment and as overall (Tables 17 and 20).  
2.2.10 Consenting Rates 
Whereas there are no known published data on the willingness of elderly patients to 
consent into a study of this nature, it is incumbent on CSP#592 to measure and report the 
rates of consent among patients deemed so eligible. Data collected from patients found 

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eligible for entry into the study will be analyzed. The total number of patients meeting 
ICD eligibility criteria, and the total number and percent of patients meeting each 
exclusion criterion will be calculated. Among the eligible patients, we will summarize the 
percentage of those enrolled and –as applicable– reasons for non-enrollment. Both the 
raw percentage and exclusive percent (pick the first exclusion for each subject) will be 
reported (Tables 3 and 4). This activity contributes substantially to the knowledge base 
for the design of future clinical trials both in the study of the elderly, and in device-based 
trials. 
2.3 Interim Monitoring and Analysis 
2.3.1 Overview 
Interim monitoring of both the pilot study and the full scope study will be performed by 
the CSPCC. The first phase of the study will be a one-year Pilot study with six 
participating sites. The objective of the Pilot study is to determine feasibility of 
recruitment for the full study phase. The interim monitoring within the Pilot study will 
focus on recruitment and safety. The interim monitoring within the whole study will 
focus on recruitment (overall and by site), baseline comparability of treatment groups, 
protocol adherence, completeness of data, accrual of primary endpoint events (i.e., 
information accrual), safety, and treatment efficacy. Recruitment and completeness of 
data will also be monitored for purposes of daily trial operations and quality assurance. 
The CSPCC monitoring provides the basis for reporting to the Data Monitoring 
Committee (DMC).  
2.3.2 Monitoring Recruitment 

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The CSPCC will monitor all steps in the recruitment process to assure early recognition 
of inadequate performance and to identify reasons for inadequate performance at each 
recruitment site and for the trial overall. To assist in this process, the CSPCC will 
produce weekly data monitoring reports (Table 1 and 2). These reports will include 
number of screening forms completed, reasons for non-matriculation into study, number 
of informed consent documents signed, and number of randomizations overall and by 
medical center. The same reports will be made available to the DMC at each of its 
meetings.  Predicted total patient accrual for the full study will be calculated using both 
direct extrapolation. 
In CSP#592 we may test an alternative accrual assessment approach via multicenter 
Bayesian method38 , using the recruitment goal of 17 patients per site per year as prior 
and the data from the Pilot study. The Bayesian prediction methods will extend the direct 
extrapolation method by providing a credible interval for the prediction of the recruitment 
which considers the uncertainty and variation during the process. The purpose of this 
analysis is to pursue new and different techniques for projecting study enrollment rates. 
2.3.3 Monitoring Safety 
 
Trial safety will be monitored by CSPCC and the CSPCRPCC, throughout the study, 
both in Pilot and full study. Safety reports will be submitted to the DMC approximately 
every 6 months after enrollment begins, or more frequently, if requested by the DMC. 
For reports to the DMC closed session, serious adverse events will be summarized by 
treatment groups, and relatedness to the assigned interventions.  
The proportion of participants experiencing an SAE in each treatment group will be 
calculated. If the DMC finds the proportion of SAEs unacceptably higher in one 

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treatment group compared to another, the DMC may consider recommending that the 
trial be stopped or that the protocol be modified. 
2.3.4 Monitoring Outcomes  
Two interim analyses of the treatment effect on the primary endpoint of all-cause 
mortality will be performed when approximately half and three quarters of the events are 
accumulated (~280 and 420, anticipated at approximately years 3 and 4).  However, the 
DMC will have discretion to request additional or different timing of interim analyses. A 
Haybittle-Peto type stopping boundary (p<0.001) will be used for monitoring the study 
for early efficacy39.  
A futility analysis for the primary endpoint is also planned at the time of the interim 
analysis. If the analysis shows that the primary endpoint crosses the internal boundary for 
futility, it would indicate that the observed effect size is much smaller than anticipated 
and that the trial has very low conditional power to detect the estimated treatment effect 
for the primary outcome. The proposed stopping boundary for futility is a hazard ratio of 
between 1.02 and 0.98 (approximate p-value of 0.80).   
In addition to these futility analyses, the observed primary outcome event rate and rate of 
information accrual (number of events) is monitored from the initiation of the trial and 
compared with the expected rates. Based on these rates, an estimated time for study 
completion (i.e. time to reach 565 events) and the estimated number of events that will be 
reached by the scheduled end of the trial will be presented to the DMC. When 
considering the futility analyses and rate of information accrual, the DMC may also 
consider other internal or external evidence of futility (i.e., secondary outcomes) and has 
the option of recommending early termination of the trial for futility, or continuing with a 

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possible adjustment to sample size. As there will not be enough events for analysis of 
efficacy, we will not monitor outcomes in a meaningful way in the Pilot study.   
2.3.5 Monitoring Protocol Adherence 
Protocol adherence will be monitored to assure early identification of poor performance 
at individual sites and in the trial overall. Periodic reports will be provided to the 
Executive Committee and to the DMC at each of its meetings. Specific parameters to be 
monitored include: 
• Randomization of ineligible participants 
• Treatment allocation errors 
• Failure to complete required follow-up assessments on time 
• Loss and withdrawal rates 
• Treatment adherence  
2.3.6 
Sample Size Re-estimation  
CSP#592 is designed as an event-driven trial. Therefore, the sample size assumptions 
regarding the control group event rate and the crossover rate will be re-evaluated at 
between 6 and 12 months after initiation of the Pilot study, and again approximately six 
months prior to the end of Full study recruitment to determine whether the estimated 
sample size and projected follow-up time are sufficient to achieve the target number of 
events. This will be done blinded to the treatment effect. If necessary, the sample size 
will be re-estimated based on the accumulated data but under the original hypothesized 
treatment effect to preserve the Type I error. This information will be presented to the 
DMC who will make a recommendation to the CSP on whether the sample size for the 
trial and/or the length of follow-up should be increased to achieve the study objectives.  

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Efficacy and futility analyses, as described above will not be performed until the sample 
size re-estimation has been completed.    
 
 
 

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3. 
Ground Rules and Data Handling Conventions 
3.1 
Baseline Definitions or Conventions 
Baseline will be defined as the last assessment taken prior to randomization and the 
assignment of study treatment. These assessments could have been taken at either the 
screening visit or the baseline visit, or at a later visit meant to recapture baseline data 
(e.g. if the extant baseline data are older than the limit specified in the Protocol).  
3.2 
Time Points, Day Ranges, and Phasing of Study Periods 
The time points for analysis will follow the visit schedule presented in the Protocol. Visit 
windows are defined in the operations manual and the patient scheduling program and 
shown below.  Follow-up visits are to be scheduled within the visit window based on the 
days from date of randomization.  If the visit occurred early or late outside of the visit 
window, the visit is still identified as targeted for that month and included in the analyses 
for that time point, but study team members are strongly encouraged to adhere to the ± 30 
days window. The number of days the actual follow-up visit occurred from the scheduled 
visit date will be tracked and the number of times and number of days the visits occurred 
outside the allowable window will be reported.  
If a follow-up visit is missed, then the assessments from the next completed follow-up 
visit will be used as the next consecutive visit.  A missed visit will also be reported as a 
protocol deviation, so long as proper contacting procedures were followed per the 
Operations Manual.  
In this study, the 1-4 month follow-up  cannot be sooner than 30 days since day of 
randomization, or later than 120 days following randomization (both treatment groups). 

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Additionally, so as to mirror clinical practice, among the ICD group, this visit cannot be 
sooner than 30 days following implantation and cannot be later than 120 days post 
implantation. 
3.3 
Handling of Missing Data  
For data summaries, descriptive statistics will be calculated based on available data.  The 
number of missing data values will be reported for major data items and be made 
apparent by reporting the number of values that were available and/or the number of 
missing responses. Missing data can occur through loss to follow-up, or missed visit, etc. 
For the survival outcome, such as all cause mortality, sudden cardiac death, 
cardiovascular death, there should be no missing data since we perform a time to event 
analysis.  Quality of life will be measured at four different time points. A longitudinal 
mixed model will be used for the analysis. For this analysis, missing data can be handled 
through a slope analysis or some imputation method. Overall, missing data is not a big 
concern in the current study.  
3.4 
Description of Protocol Violations  
The frequency of protocol deviations will be tabulated by protocol deviation category and 
treatment group.  The number and category of protocol deviations will also be 
summarized by site.  
3.5 
Datasets/Programs/Variables  
Raw Datasets:   Raw datasets will be created for each study case report form.  CRFs are 
transmitted to CSPCC via a fax server and will be processed through the Teleform 
Reader optical character recognition (OCR) program.  Each CRF is then exported to our 

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local server as a CSV file.  CSV files will be read by SAS programs to create SAS 
datasets for each CRF.  The CSPCC data management utility tools are used to create and 
manage the updating and checking of these datasets.   
Analysis Datasets:  Programs will be developed to create analysis datasets that will 
facilitate production of tables and figures for interim reports and final analyses. These 
files include:  
• 
Pre-screening Activities 
 
 
PreScreening.sas7bdat 
• 
Demographic, Baseline and Subject Status  Demo.sas7bdat 
• 
Regular Follow-up  
 
 
 
RegFollowUp.sas7bdat 
• 
ICD Follow-up 
 
 
 
ICDFollowUp.sas7bdat 
• 
Safety  (Adverse Events) 
 
 
safety.sas7bdat 
• 
Consent and HIPAA   
 
 
hipaavsicf.sas7bdat 
• 
Accrual  
 
 
 
 
intakebymonthbysite.sas7bdat 
DEMO:  Demographic, Baseline Data and Subject Status dataset – One record per 
enrolled participant.  Includes screening data (Form 1 Screening) for all enrolled 
participants, and baseline data (Baseline Forms 4 – 9, Form 11 QoL (at baseline only), 
randomization (Randomization Report from Albuquerque and Form 12 ICD 
Implantation) and termination data (Form 25 Exit) for all randomized patients.    
REGULAR FOLLOW-UP:  Data collected at regular follow-up visit – One record per 
regular follow-up visit for each randomized participant, therefore, multiple records per 
randomized participant.  Follow-up data includes Form 10 Medication Use, Form 11 QoL 
(all except baseline), and Form 13 Follow-Up.   

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ICD FOLLOW-UP:  ICD Therapy Events Analysis File – Multiple records per 
randomized participant.  ICD follow-up data includes Form 12 ICD Implantation, Form 
14 ICD Follow-up, and Form 15 ICD Therapy Event. 
SAFETY:  Adverse Event dataset that includes all reported adverse events.   There is one 
record per adverse event record including the initial report and all follow-ups (Forms 17 
and 18).  Value added fields include time from randomization/implantation to onset of the 
event, and MedDRA coding terms. ACCRUAL:  Intake by month and by site.  Targeted 
randomization versus actual randomization. 
3.6 
 Programming Specifications and Software  
 
Programming for data summaries and analyses will be primarily performed using SAS 
v9.1 or v9.3 on the UNIX AIX platform.  Programming specifications and documentation 
will be completed according to the study data management plan and the Center work 
instructions. 
 
 
 

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26. Breslow, N. Covariance analysis of censored survival data. Biometrics 30, 89–99 
(1974). 
27. Hertz-Picciotto, I. & Rockhill, B. Validity and efficiency of approximation methods 
for tied survival times in Cox regression. Biometrics 53, 1151–1156 (1997). 
28. Efron, B. The Efficiency of Cox’s Likelihood Function for Censored Data. J. Am. 
Stat. Assoc. 72, 557–565 (1977). 
29. Montedori, A. et al. Modified versus standard intention-to-treat reporting: Are there 
differences in methodological quality, sponsorship, and findings in randomized 
trials? A cross-sectional study. Trials 12, 58 (2011). 
30. Senn, S. Testing for baseline balance in clinical trials. Stat. Med. 13, 1715–1726 
(1994). 
31. Senn, S. J. Covariate imbalance and random allocation in clinical trials. Stat. Med. 8, 
467–475 (1989). 
32. Cohen, J. The Cost of Dichotomization. Appl. Psychol. Meas. 7, 249–253 (1983). 
33. MacCallum, R. C., Zhang, S., Preacher, K. J. & Rucker, D. D. On the practice of 
dichotomization of quantitative variables. Psychol. Methods 7, 19–40 (2002). 
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hospitalization data: potential limitations of Poisson regression. Nephrol. Dial. 
Transplant. Off. Publ. Eur. Dial. Transpl. Assoc. - Eur. Ren. Assoc. (2015). 
doi:10.1093/ndt/gfv071 

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35. Guarino, P., Lamping, D. L., Elbourne, D., Carpenter, J. & Peduzzi, P. A brief 
measure of perceived understanding of informed consent in a clinical trial was 
validated. J. Clin. Epidemiol. 59, 608–614 (2006). 
36. Saxon, L. A. et al. Long-Term Outcome After ICD and CRT Implantation and 
Influence of Remote Device Follow-Up The ALTITUDE Survival Study. Circulation 
122, 2359–2367 (2010). 
37. Schroll, J. B., Maund, E. & Gøtzsche, P. C. Challenges in Coding Adverse Events in 
Clinical Trials: A Systematic Review. PLoS ONE 7, e41174 (2012). 
38. Gajewski, B. J., Simon, S. D. & Carlson, S. E. Predicting accrual in clinical trials 
with Bayesian posterior predictive distributions. Stat. Med. 27, 2328–2340 (2008). 
39. Peto, R. et al. Design and analysis of randomized clinical trials requiring prolonged 
observation of each patient. I. Introduction and design. Br. J. Cancer 34, 585–612 
(1976). 
 
 
 
 
 

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5. 
Reporting Tables 
 
 
Table 1: Cumulative Number of Subjects Pre-screened, Enrolled, and Randomized by 
month 
 
Date 
Number of 
Patients pre-
screened 
Number of 
Participants 
Enrolled 
Number of 
Participants 
Randomized 
Expected 
Number of 
Randomizations 
05/2015 
 
 
 
 
06/2015 
 
 
 
 
07/2015 
 
 
 
 
08/2015 
 
 
 
 
⁞ 
 
 
 
 

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Table 2: Total Number of Subjects Pre-screened, Enrolled and Randomized by Site 
 
 
 
 
 
 
 
Site 
Number of 
Patients Pre-
screened 
Number of 
Participants 
Enrolled 
Number of 
Participants 
Randomized 
Expected 
Number of 
Randomizations 
Gainesville, FL(573) 
 
 
 
 
Minneapolis, MN (618) 
 
 
 
 
Nashville, TN (626)  
 
 
 
 
Palo Alto, CA (640) 
 
 
 
 
Portland, OR (648) 
 
 
 
 
Washington, DC (688) 
 
 
 
 

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Table 3: Summary of Inclusion and Exclusion Criteria and Pre-Screening Status – All 
Pre-Screened Subjects with Age ≥70, eligible for implantation and with OMT 
 
 
N (%) 
No. of Pre-Screened Subj who meet Inclusion Criteria and Eligibility 
determined 
 
 
 
No. of Pre-Screened Subj. who meet Inclusion Criteria but not eligible 
 
Enrolled in or planning to enroll in a conflicting trial 
 
Receiving a bi-ventricular ICD device 
 
NYHA class IV heart failure 
 
Cardiogenic shock or symptomatic hypotension while in stable baseline 
rhythm 
 
Coronary artery bypass graft (CABG) or percutaneous transluminal 
coronary angioplasty (PTCA) within the past 3 months 
 
An MI within the past 40 days 
 
Clinical symptoms or findings that would make them a candidate for 
coronary revascularization 
 
Irreversible brain damage from pre-existing cerebral disease 
 
Any disease other than cardiac disease (e.g. cancer, uremia, liver failure), 
associated with a likelihood of survival less than 1 year 
 
Circumstance that would prevent completion of the trial and follow-up 
activities, including medical condition 
 
 
 
No. of Pre-Screened Subj who meet Inclusion Criteria and are Eligible 
 
Final: Enrolled in study 
 
Final: Eligible but will not enroll 
 
Ongoing: Eligible & planning to enroll; 
 
Ongoing: Eligible & contacted but not final 
 
Ongoing: Eligible but not yet contacted 
 
Other 
 
Missing 
 
 
 
 
 

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Table 4: Summary of Inclusion and Exclusion Criteria and Reasons for Non-
Randomization – All Enrolled Participants 
 
 
N (%) 
No. of Enrolled Participants 
 
    No. of Randomized Participants 
 
 
 
Inclusion Criteria 
 
    Veteran Aged 70 Years or Older 
 
    Eligible for ICD per CMS Criteria for Primary Prevention 
 
    Stable Condition on Optimal Medical Therapy 
 
    Able and Willing to provide ICF 
 
 
 
Exclusion Criteria 
 
Enrolled in a Conflicting Trial 
 
Candidate for bi-ventricular ICD device 
 
NYHA class IV heart failure 
 
Cardiogenic shock or symptomatic hypotension 
 
CABG/PTCA within past 3 months 
 
I within the past 40 days 
 
Candidate for coronary revascularization 
 
Irreversible brain damage  
 
Likelihood of survival less than 1 year 
 
Inability to complete follow-up 
 
 
 
No. of Enrolled Participants who exited prior to Randomization 
 
Physician refused entry 
 
Participant wants to choose his/her own therapy 
 
Participant died 
 
Participant lost to follow-up 
 
Other reason for non-randomization 
 
 
 
 

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Table 5: Summary of Stratification – All randomized participants 
  
 
Treatment 1 
Treatment 2 
All 
N (%) 
N (%) 
N (%) 
Charlson Score <3 
 
 
 
Charlson Score ≥3 
 
 
 
 

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Table 6: Frequency of Total Charlson Score among Randomized Participants 
  
 
Treatment 1 
Treatment 2 
All 
 
N (%) 
N (%) 
N (%) 
No. of Randomized Participants 
 
 
 
 
 
 
 
Charlson Score 
 
 
 
1 
 
 
 
2 
 
 
 
3 
 
 
 
4 
 
 
 
5 
 
 
 
6 
 
 
 
7 
 
 
 
8 
 
 
 
9 
 
 
 
10+ 
 
 
 
 
 
 
 
N 
 
 
 
Median 
 
 
 
Mean 
 
 
 
Std 
 
 
 
 
 
 
 
Subtotal Charlson <3 
 
 
 
Subtotal Charlson ≥3 
 
 
 
 
 
 

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Table 7: Frequency Table by Charlson Item  
 
 
Treatment 1 
(N = ##) 
Treatment 2 
(N = ##) 
All 
(N = ##) 
No. of Randomized Participants 
 
 
 
 
 
 
 
Charlson Score Items 
 
 
 
1. Myocardial Infarction 
 
 
 
2. Congestive Heart Failure 
 
 
 
3. Peripheral Vascular Disease 
 
 
 
4. Cerebrovascular Disease 
 
 
 
a. Stroke 
 
 
 
b. TIA 
 
 
 
c. Other 
 
 
 
5. Dementia 
 
 
 
6. Chronic Pulmonary Disease 
 
 
 
7. Rheumatologic Disease 
 
 
 
8. Peptic Ulcer Disease 
 
 
 
9. Mild Liver Disease 
 
 
 
10. Diabetes without Complications 
 
 
 
11. Diabetes with Complications 
 
 
 
12. Hemiplegia or Paraplegia 
 
 
 
13. Renal Disease 
 
 
 
14. Any Malignancy 
 
 
 
15. Moderate/Severe Liver Disease 
 
 
 
16. Metastatic Solid Tumor 
 
 
 
17. AIDS 
 
 
 
 
 

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Table 8: Completeness of Data Forms by Site-All Enrolled Participants  
 
 
Form ** 
Form ** 
Form ** 
Rec* 
Exp** 
% 
Rec* 
Exp** 
% 
Rec* 
Exp** 
% 
Gainesville, FL (573)  
 
 
 
 
 
 
 
 
 
Minneapolis, MN (618)  
 
 
 
 
 
 
 
 
 
Nashville, TN (626) 
 
 
 
 
 
 
 
 
 
Palo Alto, CA (640) 
 
 
 
 
 
 
 
 
 
Portland, OR (648) 
 
 
 
 
 
 
 
 
 
Washington, DC (688) 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 9: Reason for Exit for before and after Randomization – All Enrolled Participants 
 
 
 
 
 
All 
 
 
 
 
N (%) 
No. Enrolled Participants 
  
  
  
No. of Enrolled but not yet Randomized Participants 
  
  
  
No. Exit Study Before Randomization 
  
  
  
Reason for Exit During  
  
  
  
   Death 
  
  
  
  Participant voluntarily withdrew 
  
  
  
  Lost to follow up 
  
  
  
  Due to AE/SAE 
  
  
  
  Withdrew consent 
  
  
  
  Unknown 
  
  
  
  Other 
  
  
  
   LSI withdrew participant 
  
  
  
         Withdrew for safety reasons 
  
  
  
          Participant lost capacity to consent 
  
  
  
           Other 
  
  
  
 
  
  
  
 
Treatment 1 
Treatment 2 
  
 
N (%) 
N (%) 
  
No. of Randomized Participants 
  
  
  
No. of Randomized Participants who exited study 
  
  
  
Reason for Exit After Randomization 
  
  
  
Study Ended 
  
  
  
Death 
  
  
  
  Participant voluntarily withdrew 
  
  
  
  Lost to follow up 
  
  
  
  Due to AE/SAE 
  
  
  
  Withdrew consent 
  
  
  
  Unknown 
  
  
  
  Other 
  
  
  
   LSI withdrew participant 
  
  
  
         Withdrew for safety reasons 
  
  
  
         Participant lost capacity to consent 
  
  
  
         Other 
  
  
  
 
 
 

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Table 10: Baseline Demographic Characteristics - All Randomized Participants 
 
 
Treatment 1 
Treatment 2 
All 
N 
% 
N 
% 
N 
% 
No. of Randomized Participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
Age 
 
 
 
 
 
 
N 
 
 
 
 
 
 
Mean  
 
 
 
 
 
 
Median 
 
 
 
 
 
 
Std 
 
 
 
 
 
 
Min 
 
 
 
 
 
 
Max 
 
 
 
 
 
 
 
 
 
 
 
 
 
Gender 
 
 
 
 
 
 
Male 
 
 
 
 
 
 
Female 
 
 
 
 
 
 
 
 
 
 
 
 
 
Race 
 
 
 
 
 
 
   White 
 
 
 
 
 
 
   Black or African-American or Negro 
 
 
 
 
 
 
   American Indian or Alaskan Native 
 
 
 
 
 
 
Asian Indian 
 
 
 
 
 
 
Chinese 
 
 
 
 
 
 
Japanese 
 
 
 
 
 
 
   Filipino 
 
 
 
 
 
 
   Korean 
 
 
 
 
 
 
   Vietnamese 
 
 
 
 
 
 
   Other Asian 
 
 
 
 
 
 
   Native Hawaiian 
 
 
 
 
 
 
   Gaumanian or Chamorro 
 
 
 
 
 
 
   Samoan 
 
 
 
 
 
 
   Other Pacific Islander 
 
 
 
 
 
 
   Other 
 
 
 
 
 
 
   Refused to Answer 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ethnicity 
 
 
 
 
 
 
Not Hispanic 
 
 
 
 
 
 
Mexican, Mexican American, 
 
 
 
 
 
 
Puerto Rican 
 
 
 
 
 
 
Cuban 
 
 
 
 
 
 
Other Spanish, Hispanic or Latino 
 
 
 
 
 
 
Refused to Answer 
 
 
 
 
 
 
 
 

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Table 11: Military Service History-All Randomized Participants 
 
 
 
Treatment 1 
Treatment 2 
All 
N(%) 
N(%) 
N(%) 
No. Participants Randomized 
  
  
  
  
  
  
  
Service U.S. Military 
  
  
  
Yes, Active Duty 
  
  
  
Yes, Reserves Only 
  
  
  
No 
  
  
  
  
  
  
  
Time Served 
  
  
  
Prior to December 1941 
  
  
  
World War II 
  
  
  
January 1947 – June 1950 
  
  
  
Korean Conflict (July 1950 – January 1955) 
  
  
  
February 1955 – July 1964 
  
  
  
Vietnam Conflict (Aug 1964 – April 1975) 
  
  
  
May 1975 – July 1990 
  
  
  
Persian Gulf War (August 1990 – February 
  
  
  
February 1991 – September 2001 
  
  
  
Afghanistan/Iraq Conflict (October-present)  
  
  
  
  
  
  
  
Served Outside U.S. 
  
  
  
Yes 
  
  
  
No 
  
  
  
  
  
  
  
Branch of Service 
  
  
  
Army 
  
  
  
Navy 
  
  
  
Marine Corps 
  
  
  
Coast Guard 
  
  
  
Air Force 
  
  
  
National Guard 
  
  
  
Merchant Marines 
  
  
  
National Oceanic and Atmospheric Adm. 
  
  
  
Public Health Services 
  
  
  
 

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Table 12: Baseline Clinical History - All Randomized Participants 
 
 
Treatment 1 
Treatment 2 
All 
N 
Mean 
(SD) 
Or % 
N 
Mean 
(SD) 
Or % 
N 
Mean 
(SD) 
Or % 
No. Of Randomized Participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
Qualifying Ejection Fraction 
 
 
 
 
 
 
N 
 
 
 
 
 
 
Mean 
 
 
 
 
 
 
Std 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cardiomyopathy (N %) 
 
 
 
 
 
 
        No 
 
 
 
 
 
 
    Ischemic (N %) 
 
 
 
 
 
 
    Non-ischemic (N %) 
 
 
 
 
 
 
Arrhythmias (N %) 
 
 
 
 
 
 
  Atrial fibrillation/atrial flutter (N %) 
 
 
 
 
 
 
        Paroxysmal 
 
 
 
 
 
 
        Persistent 
 
 
 
 
 
 
        Permanent 
 
 
 
 
 
 
 Clinically significant SVT (N %) 
 
 
 
 
 
 
Sick Sinus Syndrome 
 
 
 
 
 
 
Ablation 
 
 
 
 
 
 
Syncope 
 
 
 
 
 
 
Shortness of Breath 
 
 
 
 
 
 
Paroxysmal Nocturnal Dyspnea 
 
 
 
 
 
 
Dizziness 
 
 
 
 
 
 
Palpatations 
 
 
 
 
 
 
Hypertension 
 
 
 
 
 
 
Smoking Status  
 
 
 
 
 
 
Current Smoker 
 
 
 
 
 
 
Former Smoker 
 
 
 
 
 
 
Non-Smoker 
 
 
 
 
 
 
Alcohol Consumption 
 
 
 
 
 
 
More than moderate drinker 
 
 
 
 
 
 
Moderate Drinker 
 
 
 
 
 
 
Non-drinker 
 
 
 
 
 
 
NYHA Functional Class 
 
 
 
 
 
 
I 
 
 
 
 
 
 
II 
 
 
 
 
 
 
III 
 
 
 
 
 
 
 

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Table 13: Baseline Laboratory Assessments – All Randomized Participants 
 
 
Treatment 1 
Treatment 2 
All 
N 
Mean 
(SD) 
Or % 
N 
Mean 
(SD) 
Or % 
N 
Mean 
(SD) 
Or % 
No. of Randomized Participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
BUN (mg/dL) 
 
 
 
 
 
 
Serum Creatinine (mg/dL) 
 
 
 
 
 
 
Glucose (mg/dL) 
 
 
 
 
 
 
Total Cholesterol (mg/dL) 
 
 
 
 
 
 
Hemoglobin (g/dL) 
 
 
 
 
 
 
Hematocrit (%) 
 
 
 
 
 
 
Platelet Count (K/mm3) 
 
 
 
 
 
 
BNP (pg/mL) 
 
 
 
 
 
 
NT-proBNP (pg/mL) 
 
 
 
 
 
 
 
 
 
 

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Table 14: Baseline Physical Examination – All Randomized Participants  
 
 
Treatment 1 
Treatment 2 
All 
N 
Mean 
(SD) 
Or % 
N 
Mean 
(SD) 
Or % 
N 
Mean 
(SD) 
Or % 
No. of Randomized Participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight (lbs) 
 
 
 
 
 
 
Height (inches) 
 
 
 
 
 
 
SBP (mmHg) 
 
 
 
 
 
 
DBP (mmHg) 
 
 
 
 
 
 
Heart Rate (beats/min) 
 
 
 
 
 
 
Respiration Rate (breaths/min) 
 
 
 
 
 
 
 
 

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Table 15: Summary of Adverse Events occurring 30 days of Randomization (OMT) or 
Implantation (OMT+ICD)* – All Randomized Subjects after Randomization 
 
 
 
Treatment 1 
Treatment 2 
All 
N(%) 
N(%) 
N(%) 
No. Subjects Randomized 
  
  
  
Subject-Months of Treatment Exposure 
  
  
  
  
  
  
  
No. Adverse Events within 30 days 
  
  
  
No. Subjects with Adverse Events 
  
  
  
  
  
  
  
AE Criteria  
  
  
  
Emergency room or unscheduled clinic visit 
for heart failure 
  
  
  
Persistent painful implant site  
  
  
  
New symptomatic dizziness 
  
  
  
New symptomatic fatigue 
  
  
  
Psychological distress 
  
  
  
Other   
  
  
  
 
  
  
  
Severity of this AE 
  
  
  
Mild 
  
  
  
Moderate 
  
  
  
Severe 
  
  
  
  
  
  
  
AE Attribution to ICD device 
  
  
  
Not Attributed 
  
  
  
Possibly Attributed 
  
  
  
Yes, Attributed 
  
  
  
 
  
  
  
AE Attribution to OMT 
  
  
  
Not Attributed 
  
  
  
Possibly Attributed 
  
  
  
Yes, Attributed 
  
  
  
 
  
  
  
Outcome of AE 
  
  
  
Ongoing, Recovering/Resolving 
  
  
  
Recovered/resolved 
  
  
  
Recovered/resolved with sequelae 
  
  
  
Ongoing, not recovered/not resolved 
  
  
  
Unknown 
  
  
  
 
* For the control arm, it is within 30 days of randomization. 

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Table 16: Summary of Adverse Events– All randomized subjects after randomization 
 
 
Treatment 1 
Treatment 2 
All 
N(%) 
N(%) 
N(%) 
No. Subjects Randomized 
  
  
  
Subject-Months of Treatment Exposure 
  
  
  
  
  
  
  
No. Adverse Events 
  
  
  
No. Subjects with Adverse Events 
  
  
  
  
  
  
  
AE Criteria  
  
  
  
Emergency room or unscheduled clinic visit 
for heart failure 
  
  
  
Persistent painful implant site  
  
  
  
New symptomatic dizziness 
  
  
  
New symptomatic fatigue 
  
  
  
Psychological distress 
  
  
  
Other   
  
  
  
 
  
  
  
Severity of this AE 
  
  
  
Mild 
  
  
  
Moderate 
  
  
  
Severe 
  
  
  
  
  
  
  
AE Attribution to ICD device 
  
  
  
Not Attributed 
  
  
  
Possibly Attributed 
  
  
  
Yes, Attributed 
  
  
  
 
  
  
  
AE Attribution to OMT 
  
  
  
Not Attributed 
  
  
  
Possibly Attributed 
  
  
  
Yes, Attributed 
  
  
  
 
  
  
  
Outcome of AE 
  
  
  
Ongoing, Recovering/Resolving 
  
  
  
Recovered/resolved 
  
  
  
Recovered/resolved with sequelae 
  
  
  
Ongoing, not recovered/not resolved 
  
  
  
Unknown 
  
  
  
 
 
 

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Table 17: Summary of Adverse Events after Randomization by System Organ Class and 
Preferred Term – All Randomized Participants 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
Treatment 1 
Treatment 2 
All 
N 
% 
N 
% 
N 
% 
System Code 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 18: Summary of Serious Adverse Events occurring 30 days of Randomization 
(OMT) or Implantation (OMT + ICD) – All randomized subjects after randomization 
 
 
 
Treatment 1 
Treatment 2 
All 
N(%) 
N(%) 
N(%) 
No. Subjects Randomized 
  
  
  
Subject-Months of Treatment Exposure 
  
  
  
  
  
  
  
No. Serious Adverse Events within 30 days 
  
  
  
No. Subjects with Serious Adverse Events 
within 30 days 
  
  
  
  
  
  
  
SAE Criteria * 
  
  
  
Death 
  
  
  
Life Threatening 
  
  
  
Congenital anomaly/birth defect 
  
  
  
Disability-incapacity 
  
  
  
Hosp/Prolongation of Hosp 
  
  
  
Other 
  
  
  
 
  
  
  
SAE being reported 
  
  
  
Bleeding/Hematoma 
  
  
  
Infection: ICD pocket or lead 
  
  
  
Infection: other 
  
  
  
Pacing parameters required lead 
replacement or revision 
  
  
  
Pnuemothorax 
  
  
  
Myocardial infarction (MI) 
  
  
  
New onset Atrial Fibrillation/Atrial Flutter 
  
  
  
Stroke 
  
  
  
Other 
  
  
  
 
  
  
  
SAE Attribution to ICD device 
  
  
  
Not Attributed 
  
  
  
Possibly Attributed 
  
  
  
Yes, Attributed 
  
  
  
 
  
  
  
SAE Attribution to OMT 
  
  
  
Not Attributed 
  
  
  
Possibly Attributed 
  
  
  
Yes, Attributed 
  
  
  
 
  
  
  
Outcome of SAE 
  
  
  

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Fatal 
  
  
  
Ongoing, Recovering/Resolving 
  
  
  
Recovered/resolved 
  
  
  
Recovered/resolved with sequelae 
  
  
  
Ongoing, not recovered/not resolved 
  
  
  
Unknown 
  
  
  
 
 

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Table 19: Summary of Serious Adverse Events – All randomized subjects after 
randomization 
 
 
 
Treatment 1 
Treatment 2 
All 
N(%) 
N(%) 
N(%) 
No. Subjects Randomized 
  
  
  
Subject-Months of Treatment Exposure 
  
  
  
  
  
  
  
No. Serious Adverse Events 
  
  
  
No. Subjects with Serious Adverse Events 
  
  
  
  
  
  
  
SAE Criteria * 
  
  
  
Death 
  
  
  
Life Threatening 
  
  
  
Congenital anomaly/birth defect 
  
  
  
Disability-incapacity 
  
  
  
Hosp/Prolongation of Hosp 
  
  
  
Other 
  
  
  
 
  
  
  
SAE being reported 
  
  
  
Bleeding/Hematoma 
  
  
  
Infection: ICD pocket or lead 
  
  
  
Infection: other 
  
  
  
Pacing parameters required lead replacement 
or revision 
  
  
  
Pneumothorax 
  
  
  
Myocardial infarction (MI) 
  
  
  
New onset Atrial Fibrillation/Atrial Flutter 
  
  
  
Stroke 
  
  
  
Other 
  
  
  
 
  
  
  
SAE Attribution to ICD device 
  
  
  
Not Attributed 
  
  
  
Possibly Attributed 
  
  
  
Yes, Attributed 
  
  
  
 
  
  
  
SAE Attribution to OMT 
  
  
  
Not Attributed 
  
  
  
Possibly Attributed 
  
  
  
Yes, Attributed 
  
  
  
 
  
  
  
Outcome of SAE 
  
  
  
Fatal 
  
  
  

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Ongoing, Recovering/Resolving 
  
  
  
Recovered/resolved 
  
  
  
Recovered/resolved with sequelae 
  
  
  
Ongoing, not recovered/not resolved 
  
  
  
Unknown 
  
  
  
 
 

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Table 20: Summary of Serious Adverse Events after Randomization by System Organ 
Class and Preferred Term – All Randomized Participants 
 
 
 
 
 
 
 
 
 
 
Treatment 1 
Treatment 2 
All 
N 
% 
N 
% 
N 
% 
System Code 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 21: Listing of Serious Adverse Events after Randomization – All Randomized 
Participants 
 
 
 
Rand. 
Date 
SAE 
Preferred 
Term 
SAE 
Onset 
Date 
SAE 
Event 
No. 
SAE 
Report 
Type 
SAE 
Criteria 
Attribution 
SAE 
Outcome 
OMT 
ICD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 22: Summary of Mortality by Preferred Term-All Randomized Participants after 
Randomization 
 
Treatment 1 
Treatment 2 
All 
No. Subjects Randomized 
 
 
 
 
   
No. of Deaths 
 
 
  
   
  
  
  
  
  
  
  
Preferred Term 
N (%) 
N (%) 
N (%) 
 
  
  
  
 
  
  
  
 
  
  
  
 
  
  
  
 
 
 
 
 
 
 
Note: After Randomization - From the date of randomization to the end or exit from the study. 
 
 
 
 

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Table 23: Summary of the Cause of Mortality -All Deaths Occurring after Randomization 
 
Treatment 1 
Treatment 2 
All 
No. Subjects Randomized 
 
 
 
 
   
No. of Deaths 
 
 
  
   
  
  
  
  
  
  
  
Primary cause of death on the 
available documentation 
N (%) 
N (%) 
N (%) 
Sudden Death 
  
  
  
Other factors 
  
  
  
Cardiovascular death 
  
  
  
   Due to an arrhythmic event 
  
  
  
   Due to congestive heart failure 
  
  
  
   Due to stroke 
  
  
  
   Other 
  
  
  
Death due to complications from 
implantation 
  
  
  
Death due to infection 
  
  
  
Death due to trauma 
  
  
  
Death due to cancer 
  
  
  
Death due to another cause 
  
  
  
 
  
  
  
 
 
 
 
 
 
 
 
 

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Table 24: Primary Outcome: All-cause Mortality by Treatment Assigned 
 
Primary Outcome 
(No. of Death) 
Treatment 1 
Treatment 2 
Overall 
R/N 
% 
R/N 
% 
R/N 
% 
No. of Randomization 
 
 
 
 
 
 
No. of Death (all-cause) 
 
 
 
 
 
 
Hazard Ratio (95% CI) 
NA 
NA 
NA 
NA 
x.xx 
(x.xx, x.xx) 
 
 

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Table 25: Secondary Outcome: Cardiovascular Death by Treatment Assigned 
 
Secondary Outcome 
(No. of Death) 
Treatment 1 
Treatment 2 
Overall 
R/N 
% 
R/N 
% 
R/N 
% 
No. of Randomization 
 
 
 
 
 
 
No. of Death (all-cause) 
 
 
 
 
 
 
Hazard Ratio (95% CI) 
NA 
NA 
NA 
NA 
x.xx 
(x.xx, x.xx) 
 
 
 

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Table 26: QoL MLHF Score by Time Point and Treatment Assigned – All randomized 
participants 
 
QoL 
MLHF Score 
Treatment 1 
Treatment 2 
Overall 
Mean 
Std 
Mean 
Std 
Mean 
Std 
No. of Randomized Participants 
 
 
 
 
 
 
 
 
 
 
 
 
 
Baseline 
 
 
 
 
 
 
6 Months 
 
 
 
 
 
 
12 Months 
 
 
 
 
 
 
24 Months 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 27: Sudden Cardiac Death by Treatment Assigned  
 
Secondary Outcome (No. 
of Sudden Cardiac Death) 
Treatment 1 
Treatment 2 
Overall 
R/N 
% 
R/N 
% 
R/N 
% 
No. of Randomization 
 
 
 
 
 
 
No. of Death (all-cause) 
 
 
 
 
 
 
Hazard Ratio (95% CI) 
NA 
NA 
NA 
NA 
x.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 

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Table 28: Summary of ICD reports 
 
 
Total 
Median (IQR) 
per 
participant 
Mean (SD) 
per 
participant 
N Participants yielding at least  1 report 
 
– 
– 
N Reports 
 
 
 
N Days between implantation and first report 
 
 
 
N Missed Days  
 
– 
– 
    Interval between implantation and 1st report 
 
 
 
    Intervals between reports 
 
 
 
N Reports containing at least 1 therapy 
 
– 
– 
N Events 
 
 
 
    Median (IQR) per subject 
 
 
 
    Mean (SD) per subject 
 
 
 
Programming status 
 
 
 
    Not changed 
 
 
 
    Changed to return to protocol settings 
 
 
 
    Changed to accommodate SVT 
 
 
 
    Changed to accommodate Syncope 
 
 
 
    Changed to accommodate Near-Syncope 
 
 
 
    Changed to accommodate Heart Block 
 
 
 
    Changed to accommodate Sick Sinus 
 
 
 
    Changed for unknown reasons 
 
 
 
    Changed for other reason 
 
 
 
TOTAL Programming Status Change 
 
 
 
 
 
 
 

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CSP592 Statistical Analysis Plan, v1.2                                            2/19/16 
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Table 29: ICD Therapy Event Frequency Table 
 
N Participants randomized to ICD 
 
N Participants yielding at least one report 
 
N Events 
 
 
 
 
 
 
Number of 
participants 
with at least 1 
event 
Per-
cent 
Total 
Number 
of events 
Per-
cent 
ATP Pacing Events 
 
 
 
 
No Change 
 
 
 
 
Acceleration without termination 
 
 
 
 
Acceleration, termination into additional 
therapy 
 
 
 
 
Termination, with tachycardia restart into 
additional therapy 
 
 
 
 
Termination 
 
 
 
 
     NA 
 
 
 
 
     Unknown 
 
 
 
 
TOTAL 
 
 
 
 
 
 
 
 
 
Shock Events 
 
 
 
 
    No Change 
 
 
 
 
    Acceleration without termination 
 
 
 
 
    Acceleration, termination into additional 
therapy 
 
 
 
 
    Termination, with tachycardia restart into 
additional therapy 
 
 
 
 
    Termination 
 
 
 
 
     NA 
 
 
 
 
     Unknown 
 
 
 
 
TOTAL 
 
 
 
 
 
 
 
 

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Table 30: Summary Rhythm at Time of Detection  
 
N Participants randomized to ICD 
 
N Participants yielding at least one report 
 
N Events 
 
 
 
 
Number of 
participants 
with at least 1 
event 
Per-
cent 
Total 
Number of 
events 
Per-
cent 
Oversensing 
 
 
 
 
EMI 
 
 
 
 
T-wave over-sensing 
 
 
 
 
Lead Fracture 
 
 
 
 
Myopotentials 
 
 
 
 
Other 
 
 
 
 
Atrial Fibrillation 
 
 
 
 
Supraventricular Tachycardia 
 
 
 
 
Ventricular Tachycardia 
 
 
 
 
Non-sustained Ventricular Tachycardia 
 
 
 
 
Ventricular Fibrillation 
 
 
 
 
Non-sustained Ventricular Fibrillation 
 
 
 
 
Unknown 
 
 
 
 
      No egram available 
 
 
 
 
      No RR data 
 
 
 
 
      Conflicting data 
 
 
 
 
TOTAL 
 
 
 
 
 
 
 
 
 

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Table 31: Summary of Rhythm at end of episode 
 
N Participants randomized to ICD 
 
N Participants yielding at least one report 
 
N Events 
 
 
 
 
Number of 
participants 
with at least 1 
event 
Per-
cent 
Total 
Number 
of events 
Per-
cent 
Normal Sinus Rhythym/Sinus 
Tachycardia/Atrial pacing 
 
 
 
 
Atrial Firbillation 
 
 
 
 
New 
 
 
 
 
Pre-Existing 
 
 
 
 
Unknown 
 
 
 
 
Ventricular Pacing 
 
 
 
 
Supraventricular Tachycardia (other than AF) 
 
 
 
 
Ventricular Tachycardia 
 
 
 
 
Ventricular Fibrillation 
 
 
 
 
Accelerated Idioventricular Rhythm 
 
 
 
 
Unknown 
 
 
 
 
      No egram available 
 
 
 
 
      No RR data 
 
 
 
 
      Conflicting data 
 
 
 
 
Other 
 
 
 
 
TOTAL