The Improving ATTENDance to Cardiac Rehabilitation Trial
Phase: NA
Conditions: Myocardial Infarction, Heart Failure, Heart Valve Diseases, Cardiac Event, Angina Pectoris, Coronary Artery Disease
Sponsor: Henry Ford Health System

1 
 
PROTOCOL 
for The “improving ATTENDance in cardiac rehabilitation trial” = iATTEND Trial” 
 
 
 
 
 
Authors: 
Khaled Abdul-Nour, Clinton A. Brawner, Jonathan K. Ehrman, Jack Jordan, 
Steven J. Keteyian, David Lanfear, Edward Peterson, Matt Saval 
 
Document Type: 
Clinical Protocol 
 
Document Status: 
Version 04 
 
Release Date:   
June 25, 2019 
 
Funding Source:  
NIH/HLBI Grant Number 1R61HL143099 
 

2 
 
Signature Page 
 
iATTEND: The improving ATTENDance in cardiac rehabilitation Trial 
 
Protocol Version:  03 
Project Start Date: August 1, 2018 
 
Approved by the following: 
 
 
 
 
 
 
 
 
 
Steven J. Keteyian, PhD 
 
 
Date 
Principal Investigator 
 
 
 
 
 
 
 
 
 
 
 
Michael Hudson, MD  
 
 
Date 
Chair 
Data Safety Monitoring Board 
 
 
 
 
 
 
 
 
 

3 
 
Table of Contents 
Signature Page 
 
 
 
 
 
 
 
 
 
 
2 
List of Abbreviations  
 
 
 
 
 
 
 
 
 
5 
1. Overview of iATTEND 
 
 
 
 
 
 
 
 
 
6 
2. Specific Aims 
 
 
 
 
 
 
 
 
 
 
6 
 
2.1 Primary Aim 
 
2.2 Secondary Aim 
 
2.3 Exploratory Aims 
3. Background  
 
 
 
 
 
 
 
 
 
 
7 
 
3.1 Secondary prevention in vulnerable, at risk patients with cardiovascular disease 
8 
3.2 Cardiac rehabilitation as a secondary prevention therapy … role and clinical                8 
effectiveness 
3.3 Alternate delivery models … and home-based cardiac rehabilitation 
 
 
10 
3.4 Impact of changes in program operations on adherence  
 
 
 
11 
3.5 Applying hybrid cardiac rehabilitation to as vulnerable, at risk population with            12    
cardiovascular disease 
3.6 Safety of home-based cardiac rehabilitation 
 
 
 
 
 
13 
4. Investigational Plan 
 
 
 
 
 
 
 
 
 
14 
 
4.1 Overview  
 
 
 
 
 
 
 
 
 
14 
4.2 R61-Year 1- Formative or Start-up Plan  
 
 
 
 
 
14 
4.3 R33 – Years 2-5 – Clinical Trial Phase  
 
 
 
 
 
15 
 
a. Study population 
 
 
 
 
 
 
 
 
15 
 
b. Background therapies 
 
 
 
 
 
 
 
17 
 
c. Subject enrollment  
 
 
 
 
 
 
 
17 
 
d. Randomization 
 
 
 
 
 
 
 
 
19 
 
3. Study groups 
 
 
 
 
 
 
 
 
19 
4.4 Program Operations 
 
 
 
 
 
 
 
 
21 
4.5 Adherence  
 
 
 
 
 
 
 
 
 
22 
4.6 Retention  
 
 
 
 
 
 
 
 
 
23 

4 
 
4.7 Drop out  
 
 
 
 
 
 
 
 
 
24 
4.8 Subject follow-up  
 
 
 
 
 
 
 
 
25 
5. Trial Endpoints 
 
 
 
 
 
 
 
 
 
 
26 
 
5.1 Primary endpoint  
 
 
 
 
 
 
 
 
26 
 
5.2 Secondary endpoints 
 
 
 
 
 
 
 
 
26 
6. Safety 
 
 
 
 
 
 
 
 
 
 
 
27 
6.1 Safety assessment  
 
 
 
 
 
 
 
 
27 
7. Study Organization  
 
 
 
 
 
 
 
 
 
28 
 
7.1 Steering committee 
 
 
 
 
 
 
 
 
28 
 
7.2 Program management plan/team  
 
 
 
 
 
 
28 
 
7.3 Data safety monitoring plan/board 
 
 
 
 
 
 
28 
8. Data Management  
 
 
 
 
 
 
 
 
 
30 
9. Manual of Operations 
 
 
 
 
 
 
 
 
 
30 
10. Statistical Analysis Plan  
 
 
 
 
 
 
 
 
31 
 
10.1 Randomization procedure 
 
 
 
 
 
 
 
32 
10.2 Sample size and power calculation 
 
 
 
 
 
 
32 
 
10.3 Data analysis plan 
 
 
 
 
 
 
 
 
33 
11. Institutional Review Board and Ethics and Good Clinical Practice 
 
 
 
34 
12. References 
 
 
 
 
 
 
 
 
 
 
36 
Appendix A.  Data Safety Monitoring Plan  
 
 
 
 
 
 
47 
 
 
 
 
 
 
 
 

5 
 
 
List of Abbreviations. 
 
6MW =  
Six minute walk 
AE =   
Adverse event 
AHA =  
American Heart Association 
ACC =  
American College of Cardiology 
AACVPR =  American Association of Cardiovascular and Pulmonary Rehabilitation 
CPX =  
Cardiopulmonary exercise 
CBCR =  
Center based cardiac rehabilitation 
CVD =  
Cardiovascular disease 
COOP =  
Cooperative functional assessment 
DSMB/P =  
Data safety monitoring board/plan 
HYCR =  
Hybrid Cardiac rehabilitation  
iPAQ =  
International Physical Activity Questionnaire 
METs =  
Metabolic equivalents of task 
PAST =  
Past-day Adult Sedentary Time Questionnaire 
PHQ-9 =  
Patient health questionnaire 
PMT =  
Project management team 
QOL =  
Quality of life 
REDCap =  
Research Electronic Data Capture 
RPE =  
Ratings of perceived exertion 
SAE =  
Serious adverse event 
SF-12 =  
Short form health survey -12 
SC =   
Steering committee 
SRRSA =  
Subject recruitment and retention and staff adherence committee 
TM =   
Telemedicine 
VO2 =  
Oxygen uptake 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

6 
 
 

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1. Overview of iATTEND 
The benefits of cardiac rehabilitation are well known.  However, despite center based cardiac 
rehabilitation (CBCR) representing guideline-based care for patients with cardiovascular disease, 
most patients do not complete the maximum number of sessions allowed by third party insurance 
payers. As such, many patients may not be receiving the full clinical benefit ascribed to CR. 
Several studies suggest that the number of CR sessions completed is directly and independently 
associated with lower mortality (an ~1% to 2% observed decrease in risk for each additional 
session of CR completed). The barriers to attendance in CBCR include those at the patient, 
program, policy, and system-levels. Among African Americans, participation and attendance to 
CR and adoption of healthier lifestyle changes are less likely. The iATTEND (improving 
ATTENDance to cardiac rehabilitation) Trial will assess the effectiveness of an innovative 
approach to CR delivery on attendance. The intervention group combines CBCR and remote-
/home-based CR (i.e., Hybrid CR, HYCR) and is tailored to the individual needs of each patient, 
accomplished with the assistance of an easy-to-access telecommunications methodology 
(telemedicine). iATTEND is also unique because it focuses on patients residing within (or 
proximal to) Detroit, MI., representing a predominately at-risk cohort (e.g., 79% African 
American) that often cannot regularly attend CR due to social (e.g., dependent care) and 
economic challenges. In addition to being understudied and likely associated with disparity in 
CR utilization, our cohort provides an opportunity to examine the adoption and effectivenss of an 
innovative model to deliver CR, one that otherwise mimics traditional CBCR in terms of 
delivered content and expected outcomes.  During the R61 start-up phase of iATTEND (year 
one), we will prepare to operationalize a clinical trial, including finalizing protocol, developing 
and finalizing the manual of operations, establishing data safety monitoring board, confirming 
partnerships, and demonstrating the ability to screen and enroll patients in to the trial.  During the 
R33 clinical trial phase (years 2-5) we will assess the effect of a HYCR program on patient 
attendance, exercise capacity and quality of life. The design of iATTEND is a single-site, 
prospective, controlled Phase II clinical trial that will randomize 270 urban patients to CBCR 
only or HYCR. Both groups will be scheduled to attend 36 CR sessions within 6 months. Patient 
assessments will be conducted at baseline, within 10 days after completing CR, and 6 months 
after completing CR. To strengthen the generalizability of iATTEND, for both study groups we 
plan to (a) deliver the same secondary prevention elements and (b) measure the common 
program outcomes expected of traditional CBCR.  
 
2. Specific Aims 
2.1 Primary Aim 
R61 Phase (Year 1, Formative Phase): In conjunction with study investigators, 
stakeholders, and NHLBI staff, prepare and operationalize a clinical trial that evaluates the effect 
of a HYCR program on attendance to CR. This includes finalizing the protocol, obtaining any 
institutional review board approved amendments, developing the manual of operations, 

8 
 
establishing data safety monitoring board, hiring and training CR and research staff, and 
demonstrating the ability to screen and enroll patients into the trial. 
R33 Phase - Primary Aim (Years 2 – 5, Trial Phase): Assess the effect of HYCR on over-all 
patient attendance. 
Primary Hypothesis: The number of CR sessions completed within 6 months will be 
significantly greater in patients randomized to HYCR vs. patients randomized to traditional 
CBCR (usual care). 
Hypothesis 2: The percentage of patients completing 36 CR sessions within 6 months will be 
significantly greater among patients randomized to the HYCR program vs. patients randomized 
to the CBCR program. 
 
2.2 Secondary Aims 
R33 Phase: Assess the effect of HYCR on exercise capacity and quality of life. 
Hypothesis 3: The improvement in exercise capacity, as measured by distance walked during the 
six min walk (6MW) test, in patients randomized to HYCR will be equivalent (not inferior) to 
patients randomized to CBCR. 
Hypothesis 4: The improvement in exercise capacity, as measured by peak oxygen uptake (VO2), 
in patients randomized to HYCR will be equivalent (not inferior) to patients randomized to 
CBCR. 
Hypothesis 5: The improvement in quality of life (QOL), as measured by the Dartmouth COOP, 
in patients randomized to HYCR will be equivalent (not inferior) to patients randomized to 
CBCR. 
 
2.3 Exploratory Aims 
At 6 months after completing CR, explore the effect of a HYCR on (a) exercise capacity, (b) 
QOL, (c) self-engaged purposeful exercise, and (d) total physical activity habits,  Also, explore 
the cost effectiveness of a HYCR program 
 
3. Background 
Although the age-standardized death rate attributable to cardiovascular disease (CVD) has 
decreased over the past decade (1), it remains our nation’s number one killer.  In 2017, almost 
700,000 American’s will have a new coronary heart disease-related event (myocardial infarction 
[MI] or death) with another 325,000 people experiencing a recurrent coronary heart disease 
(CHD) related-event.  In addition, there are approximately 960,000 new cases of heart failure 
diagnosed annually, ~53% of which are due to reduced ejection fraction (1).  Among survivors 

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of the above cardiac-related events, most go on to experience increasing disability, a reduction in 
quality of life (QOL), and morbidity (11-13).  For example, re-hospitalization rates for patients 
that survive an MI or an index hospitalization for heart failure range from 10% to as high as 20% 
or 30% (12-15).  Finally, in addition to the burden that CVD places on health, functional 
capabilities and QOL, the recurrence of CVD-related problems carries a heavy economic burden 
as well.  The cost of re-hospitalization after an MI can exceed $19,000 (16) and if a procedure is 
required, the cost is increased further. 
There are numerous effective therapies that target secondary prevention following an 
initial CVD-related event including lipid- and blood pressure lowering-drugs, exercise training, 
after-load reduction and/or beta-adrenergic blockade agents, smoking cessation programs, and 
anti-platelet drugs (17,33).  However, despite secondary prevention guidelines advanced by the 
American Heart Association (AHA), The American College of Cardiology (ACC), and the 
American Association of Cardiovascular and Pulmonary Rehabilitation (AACVPR) (17,18), 
greater than 15% of patients still smoke cigarettes, compliance to cardioprotective drugs is not 
optimal (31% stop taking > 1 drug), regular exercise is only 40%, and obesity is common 
(1,10,19-22,91). Additionally, the simultaneous adherence to proven secondary prevention 
strategies is reported to be less than 10% (22); yet most all of these strategies are addressed 
through a comprehensive cardiac rehabilitation (CR) service and its use of disease management, 
clinical surveillance, supervised exercise, and patient education.  
3.1. Secondary Prevention in Vulnerable, at Risk Patients with Cardiovascular Disease  
Patients of lower socio-economic status (SES) experience a disparate or disproportionate 
level of morbidity and recurrent events following an initial heart problem, a portion of which can 
be explained by poorer engagement in secondary preventive strategies (e.g., cigarette cessation, 
blood pressure and lipid control, physical activity, and compliance to prescribed medication) 
(1,10,20,23,24).  Additionally, following a cardiac event annual mortality is lower among 
Caucasians versus others (4,6).   
  
Much of the research to date that pertains to CR has involved patients that were healthier 
and socially and financially better able to adhere to CR and; therefore, able to participate in CR-
related research.  Limited prior research suggests lower participation rates and fewer CR sessions 
completed among minorities and people of lower SES (3,9).  The cardiovascular health care 
needs of these patients are real (and grossly understudied).  Advancing and evaluating CR and its 
associated secondary prevention strategies (17,18) in a predominately urban, vulnerable cohort 
of at-risk patients represents an ideal opportunity to potentially impact their health care outcomes 
... and is worthy of further investigation (3). 
3.2.  Cardiac Rehabilitation as a Secondary Prevention Therapy… Role and Clinical 
Effectiveness 
Today, more so than ever before, the majority of CR programs in the US no longer 
represent an “exercise-only” intervention.  CR is now a multidisciplinary and multifaceted 
secondary prevention service that addresses the core components of CR as defined by the AHA, 
AACVPR and ACC (17,18).  Therefore, the deliverables from CR should be the same, regardless 

10 
 
if provided in center-based CBCR or a combination of CBCR and remote-/home-based CR 
(“hybrid” CR, HYCR). 
The evidence supporting the clinical effectiveness of traditional, CBCR is well-
established and as a result, CR is a class 1 recommendation following MI, coronary artery bypass 
surgery, or percutaneous coronary intervention (25-29).  Additionally, CR is recommended for 
patients who have undergone cardiac transplantation or heart valve surgery and those with 
chronic stable angina and stable chronic heart failure with reduced ejection fraction (30-33). 
Briefly, CR is associated with a 10% to 24% reduction in total mortality over 1 to 3 years and an 
~ 30% decrease in re-hospitalizations over 1 year (3,4,25,34-39).  We recently estimated that if 
CR participation was increased to 70% among eligible patients, ~25,000 lives would be saved 
and 180,000 hospitalizations would be prevented annually (25).  In addition, quality of life and 
functional capacity are improved (25,39,40,83) and much of the abnormal physiology that 
accompanies CVD is improved [e.g., coronary artery endothelial function, autonomic function, 
insulin resistance] (25,41-43).  Finally, mood is also favorably influenced (44,45).  Taken in 
sum, CR is a cost effective means to deliver and advance secondary prevention to patients with 
known CVD via a multidisciplinary and patient-centered approach. 
3.2.1.  Relationship between Number of Cardiac Rehabilitation Sessions Completed and 
Outcomes. 
Most patients attend 25 or fewer CR sessions (2-5,9), less than what is typically allowed 
by the majority of health insurers (e.g., Medicare allows 36 visits), potentially diminishing the 
functional and clinical benefits ascribed to CR.  Hammill and co-workers (6) observed that a 6 
session increase in number of CR sessions completed was associated with an ~ 6% decrease in 
risk of mortality (HR: 0.94, p < 0.001).  Martin et al (7) reported a 1% decrease in risk for each 
additional CR session attended (HR: 0.99, 99% CI: 0.98-0.99).  Finally, Doll et al. (8) reported a 
13% reduction in risk for mortality for each increase of 5 CR sessions (HR: 0.87, 95% CI: 0.83–
0.92).  We previously showed, that (a) the number of sessions completed is associated with the 
magnitude of the increase in exercise capacity (45) and (b) higher achieved MET level at 
discharge from CR is related to a reduction in risk for mortality (HR:0.60; 95% CI: 0.51–0.70) 
(46).   
Last year the Centers for Medicare and Medicaid Services (CMS) recognized the 
importance of the relationship between the number of visits completed and outcomes, when they 
proposed a model that linked level of reimbursement to the number of CR attended. Although 
that project was rescinded (47), it did indicate that CMS acknowledged the value associated with 
maximizing the number of CR sessions attended. Finally, there is biologic plausibility 
underpinning the concept that more visits in CR are related to improved outcomes. Hundreds of 
exercise trials over the past 30 years involving healthy people and patients with CVD 
demonstrate that, to an extent, the “dose” of regular exercise delivered is related to the 
magnitude of the improvement (48).   
 
 

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3.3.  Alternate Delivery Methods …. And Home-Based Cardiac Rehabilitation 
Million Hearts is a national initiative led by the Centers for Disease Control and 
Prevention and CMS (49), with an aim to improve use of evidence-based practices (e.g., aspirin 
use, blood pressure to goal), especially in priority populations. Recognizing the important role of 
CR in secondary prevention, in 2015 Million Hearts established the CR Collaborative, which set 
a target goal to increase participation in CR to 70% by 2022 and advocated that “patients 
complete all 36 sessions of the CR protocol …” (25).  Consistent with the above, two AHA 
advisories (50,51) called for the development and deployment of new delivery models to improve 
the utilization of CR services.  Both advisories recognized that the CBCR programs of today are 
insufficient to meet the needs of CR nationally. In fact, Pack et al (52) estimated that if all CBCR 
programs currently in the U.S. operated at full capacity, such an accomplishment would 
accommodate <50% of qualifying patients.   
Various types of home-based CR have been evaluated (53-75). What has not been fully 
investigated is an industry-standard, hybrid CR model, one that tailors program offerings to the 
individual needs of each patient, while at the same time demonstrating generalizability by 
operating within (not separate from) a CBCR program. Helping patients overcome barriers to 
regular attendance in CBCR is possible through a patient-centered HYCR model and; therefore, 
has the potential to increase the number of CR visits attended.   
  
Home-based CR has not flourished to date, likely for two reasons.  First, and of great 
importance, is that home-based CR is not a covered benefit by health insurers (e.g., Medicare or 
commercial payers such as Blue Cross and Blue Shield) across the U.S. Therefore, home-based 
CR is not viewed by health systems as financially favorable. That said, the technology used 
today for the remote or home delivery of telehealth (e.g., video synchronized telemedicine), 
which is insurance covered in most states in the US, has not been applied and tested on a larger 
scale as a means to secure reimbursement for remote-based CR.   
      
Second, most research studies that tested home-based CR were conducted using 
additional or assigned clinical research staff that operated independently or outside of the daily 
function of CR. This can be a source of frustration for existing CBCR programs who are unsure 
how to integrate schedules, allocate and parse limited staff, and remotely deliver patient 
education. CR programs that strive to “improve patient attendance” by offering a HYCR 
program need to be assured of not only equivalency of outcomes (between CBCR and HYCR) 
but ease of adoption within their setting as well.   
      
To help the field of CR take an evolutionary step forward, we believe it is important to 
test a HYCR model that addresses all of the industry-standard elements of contemporary CR, and 
does so by leveraging existing video telemedicine technology that (a) operates via the virtual 
private network (VPN) within the electronic medical records (EMR) that serve hospitals today 
(e.g., EPIC, Cerner, Allscripts) and (b) only requires hardware that is already accessible by most 
patient’s. This approach represents a model for CR to meet existing telemedicine (TM) statutes 
for reimbursement in most States (like Henry Ford has tested in Michigan) 

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(http://cchpca.org/state-laws-and-reimbursement-policies).  [TM is defined here-in as video 
synchronized telecommunications for the remote delivery of patient care.] 
3.3.1.  Telemedicine (TM) Today.  TM uses devices and technology to deliver patient care 
when the patient and provider are separated by distance. TM is used by many specialties 
including behavioral health and primary care to improve access to care, cost effectiveness, and 
quality of care (76). Patient satisfaction ranks high with TM, evidenced by a recent survey of 
1700 U.S. adults in which 94% reported being “very satisfied” with all aspects of their TM visit 
and only ~ 1% rated the experience confusing/complicated (77). Current estimates are that 63% 
of health care providers use some form of TM, and that 44% of health systems indicate TM is a 
“top priority” (78) in their strategic planning. Currently, 48 states provide Medicaid 
reimbursement for TM via some form of live, synchronized video (79) and 31 states have “Parity 
Laws” requiring commercial insurers (e.g., Blue Cross/Blue Shield) to reimburse for TM at the 
same rate as in-person encounters (80).    
3.3.1.a.  Within Henry Ford Health System in Detroit, TM visits are conducted with the 
patient using a mobile device (smart phone or tablet) and software integrated within their patient 
portal of our EMR [EPIC (i.e., MyChart/Vidyo, VidyoMobile, Vidyo, Inc. Hackensack, NJ)], 
ensuring a secure, two-way, real time video interaction between the patient and the provider.  
The other commercial EMR’s offer similar capabilities. 
 
3.4 Impact of Changes in Program Operations on Adherence 
To date, three studies systematically assessed the effect of changes in CR programmatic 
operations on number of CR visits completed (Table 1). Pack et al. (81) used as tailored 
welcoming video and non-monetary motivational incentives and showed that both incrementally 
increased the number of sessions completed.  Among Medicaid beneficiaries, Gaalema et al. (82) 
showed that the use of monetary incentives resulted in the completion of more CR sessions.  An 
Australian-based study is (74) particularly relevant because it employed synchronized TM, and 
reported a greater number of sessions with home CR versus CBCR.  I ATTEND is the first large, 
US-based, prospective randomized trial to use TM and assess the effect of a comprehensive, 
individualized HYCR program on the number of CR sessions attended.  If iATTEND 
successfully demonstrates the effectiveness of a HYCR program using TM on a larger scale, then 
it can be advanced as a model to CR programs in other health systems, as well as to health 
insurers in other states.  
 
Table 1: Comparison of Studies Using an Administrative or Programmatic Intervention to 
Increase Attendance in CR 
 
Design 
Sample 
Intervention 
Primary Finding 

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Pack et al 
(81) 
2013 
Retrospective 
N=1103, 
Age=64+13, 
70% men, 92% 
Caucasian 
• Policy change 
defining 
completion at ≥ 
30 sessions 
• Monetary 
motivational 
incentives for 
patients and 
staff (e.g. 
packing pass, t-
shirt) 
• Descriptive 
video 
• Overall 
completion rate 
increased 
• The addition of 
each 
intervention 
associated with 
a 3-4 visit 
increase in 
number of visits 
Gaalema et 
al (82) 
2016 
Convenience 
group compared 
to historical 
controls 
N=10 
Age=59 ± 10 yr, 
69% men, 80% 
Caucasian 
Increasing 
financial incentives 
per each session 
attended 
• 31 sessions for 
incentivized 
patients vs 13.6 
sessions for 
controls 
Hwang et al 
(74) 
2017 
Randomized 
parallel (non-
inferior), home-
based vs center-
based 
N=53, mean age 
67±12 yr, 75% 
men, 75% 
Caucasian 
Real-time video 
teleconferencing 
• 20 visits for 
home-based vs 
14 visits for 
center-based 
• Equivalent 
gains in six 
minute walk 
      
Securing insurance reimbursement for HYCR via synchronized TM has the potential to 
attenuate concerns from hospital administrators who avoid home-based CR because it is viewed 
as a negative financial endeavor. Importantly, HYCR may help overcome common attendance 
barriers by providing care in one’s home or closer to where they live, and at a mutually agreed 
upon time.   
 
3.5 Applying HYCR to a Vulnerable, at Risk Patients with Cardiovascular Disease  
Per the 2016 US census, the City of Detroit, MI is a major city in the US, with >670,000 
residents. The main demographics for Detroit are: 79% African American (AA), 8% Hispanic; 
13% age 65 yr or older; and a median annual household income < $27,000… representing a 
priority population that is vulnerable to some of the social and economic challenges that HYCR 

14 
 
is aimed at overcoming.  In 2016, ~ 80% of the patients cared for in the Henry Ford Hospital CR 
program in Detroit were AA, indicating that the patient population we serve at our Detroit site is 
indeed consistent with the population of the City.  Unfortunately, AA are less likely to use CR 
(3,9) and adopt lifestyle changes aimed at the secondary prevention of CVD (10); iATTEND will 
provide them with improved access to CR and its secondary prevention capabilities using a 
convenient approach to increase attendance. 
3.5.1  Patient access to the needed technology and home exercise equipment  
     
To test the effectiveness of our HYCR model requires that all patients studied have the 
device technology and exercise equipment needed to conduct the trial.  To minimize project 
costs, reflect “real-world” operations in CR, minimize CR staff burden, and still test effectivenss, 
iATTEND will enroll patients referred to the Hospital’s Detroit-based program that have access 
to the needed equipment; specifically, (a) a smart phone or tablet (via self or a “willing to assist” 
family member/friend) with internet access and (b) stationary exercise equipment (treadmill, 
elliptical or bike) at home, work, place of worship, or in the community; and would be willing to 
periodically use both for their CR efforts.   
3.6.  Safety of home-based CR 
It is important to emphasize that the level of incremental risk for major unexpected 
adverse events (death, events requiring hospitalization) that are probably related to a subject’s 
participation in this project will likely be extremely low.  Specifically, center-based cardiac 
rehabilitation (CR) is known to be safe for patients that participate, with reported rates of 1 major 
event per 750,000 to 900,000 patient-hours of training (88).  Concerning home-based CR, it is 
important to first emphasize that most all patients that participate in center-based programs 
today are already asked to “exercise on their own on non-rehab days”; therefore, iATTEND is 
mainly giving some structure and supervision to that recommendation.  Numerous studies have 
looked at the safety of home based CR and have shown no apparent increased risk (53-62,64,66-
68,72-74).  
 
The Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-
ACTION) Study is the largest study to assess the safety of exercise training, with the vast 
majority of the exercise training completed outside of center-based CR (38).  In HF-ACTION, 
patients with stable, chronic heart failure and NYHA class II to IV symptoms (n-2331) were 
enrolled. In that study, participants were prescribed 9 or more months of home based CR. A 
heart rate monitor (chest/wrist heart rate-watch) and daily exercise records were used to guide 
and monitor exercise intensity at home. No significant difference was reported between the 
exercise and usual care groups for the overall rate of hospitalization (1.9% vs 3.2%, respectively) 
or death (0.4% versus 0.4%, respectively) during or within 3 hours after exercise. Furthermore, 
the investigators identified 1,053 patients from the HF ACTION trial who had an implantable 
cardioverter defibrillator (ICD) at baseline and were randomized to the exercise intervention vs. 
control. Study participants had a median ejection fraction of 24% at baseline. During 2.2 years of 
follow-up, 20% of the 546 exercise patients experienced a shock vs. 22% of the 507 usual care 
patients. Exercise training was not associated with the increased occurrence of ICD shock (HR 
0.9, 95% CI, 0.7 – 1.2) (89).  
 

15 
 
 4. Investigational Plan  
4.1. Overview. 
The iATTEND Trial is a single-site, prospective, randomized controlled Phase 2 clinical trial 
that will assess the effectiveness of a patient-individualized HYCR program, one that is provided 
either remotely (home and/or in the community) and includes 1 or more sessions of CBCR. 
iATTEND tests this paradigm in a vulnerable, urban cohort that often cannot maintain 
participation in CR due to personal (e.g., dependent-care) and financial challenges. To strengthen 
the generalizability of our findings, in both study groups we plan to (a) deliver the same key 
secondary prevention elements and (b) measure the same program outcomes that are expected of 
an industry-standard CR program.  Clinical operations at the Henry Ford Detroit CR site are to 
be revised (including its staffing matrix) in a manner that allows the site to offer both CBCR 
only and HYCR, using existing CR staff (research staff will not be involved in direct patient 
care).  Therefore, the only difference between the two study groups will be the method of 
program delivery (CBCR vs. HYCR).  HYCR will be delivered with the periodic use of 
synchronous TM, which will be billed to and is covered by Blue Cross and Blue Shield of 
Michigan and Health Alliance Plan of Michigan [or billed to the project’s budget, if the patient’s 
health insurer (e.g., Medicare) has not yet agreed to cover HYCR delivered via TM.] 
 
4.2. R61 – Year 1 – Formative or Start-Up Phase. 
The first 12 mo of iATTEND will transition from starting the project and finalizing the 
protocol to subject screening and starting enrollment.  
     Month 1 of year 1.  The PI, several of the co-investigators, and the Project Manager (Matt 
Saval) will meet to discuss potential collaborations and begin to finalize the scientific aspects of 
the study protocol (e.g., recruitment, retention).  Any amendments to the protocol will be drafted 
and submitted to the institutional review board (IRB) for approval.  Hospital administration will 
be engaged to secure the approvals to post the research staff positions. 
     Months 2-4 of year 1. Constitute and conduct meetings of the Steering Committee and the 
Project Management Team (PMT), begin the development of case report forms for data 
collection, draft the manual of operations around study protocol, establish the trial’s dataset 
template using the REDCap system, and interview and hire the research staff.   
     Involving patients currently in the Detroit CR program, conduct a survey to describe access to 
a telecommunications device (smart phone, tablet) and exercise equipment, as well as ascertain 
willingness to participate in a trial like iATTEND, best hours of accessibility, and potential 
barriers with usage. Using this information, develop/test strategies aimed at preventing 
interruption in CR operations during the R33 phase. If survey data indicates potential difficulty 
recruiting subjects over the 30 month enrollment period, additional strategies aimed at boosting 
recruitment will be conceptualized and tested.  For patients who do not have the needed 
technology or equipment, develop and test messages that empowers to “think through” other 

16 
 
options for accessing the equipment (i.e. willing to assist family member, fellow church 
parishioner, friend, community center). Codify any learnings for use by the research staff. 
     Months 5-9 of year 1. Train all Detroit CR staff to work within a framework of having some 
patients in a CBCR only model and others in the HYCR model. In conjunction with feedback 
provided by the CR staff, modify program orientation materials, class sizes and format (e.g., 
open gym), computers, and staff matrixes to allow both the CBCR and HYCR program models 
to operate in an integrated manner.  Because some patients will now be receiving their CR care 
remotely, the number of sessions held at our Detroit center will decrease proportionately. This 
increased availability of staff time will be used by CR staff to conduct HYCR visits based on an 
established schedule, with the new delivery model “stress tested” within mock environments to 
ensure that all disciplines of the staff are sufficiently trained on the technology and procedures 
associated with simultaneously offering both CBCR-only and HYCB with TM. Procedures will 
be revised based on user feedback and the manual of operations near-finalized. Any forms, 
training, or procedures associated with subject testing and follow-up will be finalized and 
codified. Finally, the data safety monitoring plan will be developed, including the appointment of 
the internal data safety monitoring board (DSMB). 
     Months 8 and 10 of year 1. Interface the in-patient and out-patient processes that refer 
patients to the Detroit CR program with the screening and recruiting processes for iATTEND. 
Register the trial on clinicaltrials.gov.  Secure all approvals of the trial’s protocol. 
     Months 9-12 of year 1. Begin subject screening, recruitment, consenting, and baseline testing, 
and enroll subjects (~4% of 270 total). Hold the first of annual in-person meetings with NHLBI 
to review progress and scientific and protocol integrity; revise milestones as needed. Secure 
approval to proceed to R33 phase.  
4.2.1.  Implementation Science and Practices for the R61 Phase  
Under the guidance of co-investigator Jack Jordan, recruit several patients currently in CR to 
assist the PMT as patient stakeholders, as a means to ensure 360 degree input. Using a problem-
solving approach, identify patient markers that might be associated with discontinuing the use of 
CR, including any patients that might link their discontinuation to difficulties with the methods 
of adopting or using TM.  Also, identify what data will be regularly captured in real-time going 
forward, including but not limited to patient satisfaction, duration of patient engagements, 
language barriers, adoption/sustainability of TM in CR by patients and staff, and reliability of 
TM operations.  
 
4.3. R33 – Years 2-5 – Clinical Trial Phase. 
 
4.3.1. Study Population 
270 patients with an index event that qualifies for CR will be recruited (a) prior to 
discharge from the hospital, (b) soon after hospital discharge with documented referral to CR, or 
(c) from screening appointment schedules for physicians that will be seeing patients in an 

17 
 
ambulatory care setting.  The inclusion and exclusion criteria are not overly restrictive, such that 
we expect a sufficient number of patients eligible and enrolled in CR to consent to trial 
participation. 
 
4.3.1.a. Inclusion Criteria 
1) Has agreed to participate in CR and has experienced a cardiac event (myocardial 
infraction, coronary revascularization, heart valve surgery, or cardiac transplant in the 
past 6 months; diagnosed with chronic, stable AHA/ACC stage B or C heart failure or 
Canadian class 0-2 stable angina pectoris) 
2) Lives in or plans to remain in the greater Detroit, MI area for the next year 
3) Age 18-85 years of age 
4) Agrees to attend at least one CBCR session 
5) Agrees to scheduling at least 2, up to 3, CR sessions (either CBCR or HYCR)/wk 
6) Has demonstrated to research staff their ability to access and connect to the internet via 
smart phone or tablet and already has access to satisfactory home- or community-based 
exercise equipment 
 
4.3.1.b. Exclusion Criteria 
1) Received a left ventricular assist device, receiving continuous inotropic support (e.g., 
milrinone), or undergoing hemodialysis 
2) Angina at rest or with a low functional capacity (< 2 METs) 
3) Advanced cancer, advanced risk for falling, limiting cognitive impairment, or other 
advanced disorder that limits participation in CR 
a. Advanced risk for falling will be assessed by 5X sit-to-stand test, with a cut-off 
score of >15 seconds 
b. Cognitive assessment will be completed using the Mini-Cog instrument, with a 
cut-off score < 3 used to exclude potential subjects. 
4) Severe arrhythmia unless adequately treated (e.g., implantable cardiac defibrillator) 
5) Pregnant or plan to become pregnant in the next year. 
6) Major cardiovascular procedure or hospitalization planned in the next 6 months 
7) Exercise testing results that preclude safe exercise training, including abnormal blood 
pressure response, early ischemic changes or unexpected life-threatening arrhythmia 
8) Participation in another clinical trial that interferes with iATTEND participation, 
follow-up, data collection, exercise capacity or quality of life.  

18 
 
9) Participation in a cardiac rehabilitation program within one year.  
 
 
4.3.2. Background Therapies 
 
Guideline based medical, device and surgical care for a patient’s cardiovascular disease 
will be managed solely by their physician and any changes in therapy will remain at the 
discretion of said physicians.  While a patient is participating in the iATTEND trial we recognize 
that some patients may be or become candidates for current or new therapies that could impact 
exercise capacity or quality of life.  Patients in whom their physician considers a procedure or 
placement of a device to be probable within 6 months should be excluded from trial entry until 
after such device has been placed or procedure completed. 
 
 
4.3.3. Subject Enrollment 
 
4.3.3.a. Screening … from in-patient and EMR 
 
Using census data from the EMR for in-patient cardiology units, as well as the out-patient 
preventive cardiology unit work que in the EMR, potential subjects will be identified/screened 
by the CR and research staff that visits or calls patients.  The names of potential candidates will 
be forwarded to the research staff who will then conduct a detailed screening of eligibility using 
the EMR and a telephone call.  If the patient meets the enrollment criteria and agrees to 
participate after having discussed study purpose, procedures, risks and responsibilities, a baseline 
appointment will be made, ideally on the same day the patient will be scheduled to attend CR 
orientation; 7-14 days after discharge if hospitalized.  Patients stating interest in the research 
study will meet with the research coordinator, the project PI, or the project manager to undergo 
further screening and receive a verbal explanation of the trial and sign informed consent. 
 
 
4.3.3.b. Baseline Clinic Visit 
 
The baseline testing required in this protocol should be completed as soon as possible 
after signed consent, but may be completed up to 4 weeks after consenting, if necessary.  All 
baseline testing will be completed prior to a patient’s first session in CR.  For any study visit that 
includes a QOL assessment and a symptom-limited cardiopulmonary exercise (CPX) test, the 
quality of life (QOL) instrument(s) (Dartmouth COOP, and/or EuroQOL-5D) must be completed 
prior to the CPX test.  Also, the 6 min walk (6MW) test must be completed, per standardized 
procedures (84), 1 hour or more before the CPX test; therefore, during any clinic visit the order 
of these tests is as follows: (a) 6MW, (b) QOL tools and other assessments (PHQ-9, Rate your 
Plate, mini-cog), (c) 5x repetition sit-to-stand test, and (d) CPX test.  The 6MW and the CPX test 
will be completed per procedures as specified and overseen by the Henry Ford Clinical Exercise 
Physiology Core Laboratory (“Exercise Core Lab); and case report forms for 6MW and QOL 
surveys and data collected from the CPX test will be forwarded to the Exercise Core lab or data 
entry/management as indicated. 
 

19 
 
 
4.3.3.c.  Baseline Testing 
 
The written questionnaires (EuroQOL-5D, Dartmouth COOP, Rate Your Plate, and PHQ-
9) will be administered per the standardized instructions associated with each instrument.  
Advanced risk for falling will be assessed by the repetition 5X Sit-to-Stand test and cognitive 
status will be assessed by the Mini-Cog screening tool.  Those patients meeting the exclusion 
criteria based in advanced risk for falling or cognitive status will be excluded from participating 
in the trial, but still allowed to participate in CR. 
 
The Exercise Core Lab will oversee staff training, quality control, procedural conduct, 
and all data analysis for both the 6MW and CPX test.  The primary modality for CPX testing will 
be the motor driven treadmill; however, a stationary bike can be used if indicated.  Patients must 
use the same testing and exercises protocol for all CPX testing completed during the trial.  For 
any bike tests, a ramped protocol will be used that starts at 0 watts and work rate is increased 10 
watt/min.  For all treadmill tests, the modified Naughton protocol will be used for testing: 
Table 2. 
Stage 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Time (min) 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
Speed (mph) 
1.0 
1.5 
2.0 
2.0 
2.0 
3.0 
3.0 
3.0 
3.0 
3.5 
Grade (%) 
0 
0 
3.5 
7 
10.5 
7 
10 
12.5 
15 
14 
Estimated METs 
2.3 
3.3 
4.5 
5.5 
6.5 
7.5 
8.5 
9.5. 10.5 11.5 
 
Patients will be excluded from the study if exercise testing results preclude safe exercise training 
in CR as defined by ACC/AHA guidelines, including abnormal blood pressure response, early 
ischemic changes and unexpected life-threatening arrhythmia.  If an exercise-induced arrhythmia 
is identified as life-threatening, the exercise test will be stopped.  If the patient is performing a 
baseline exercise test, he/she will not be randomized in to the study.  If the patient is performing 
a follow-up exercise test immediately after CR or at 6 month,  he/she will be asked to stop any 
exercise training and his/her physician will be notified of the results; these patients will be 
followed per protocol for the duration of the study and no further exercise testing will be 
performed.  Patients who have a non-life-threatening arrhythmia that stops the test can re-take 
the test or re-start CR after it is treated. 
 
For patients taking a beta-adrenergic blocking agent, they should participate in exercise 
testing and training between three hours and 10 hours after taking their last dose of the drug.  All 
CPX tests will be sign- and symptom-limited, with strong encouragement to achieve a 
respiratory exchange ratio >1.10 and a Borg rating of perceived exertion >16; however, neither 
of these criteria will serve as a stopping criteria for the test.  Ventilatory threshold, peak oxygen 
uptake (VO2), and other test variables will be determined per Core lab procedures.  After the 
baseline CPX test, intentional attempts will be made to blind the person supervising all 
subsequent follow-up tests to a patient’s study group assignment through isolation of test 
materials, patient instructions, and restricted conversation with testing staff.  The exercise testing 
lab will undergo quality control testing every 6 months in accordance with Core lab procedures. 

20 
 
 
4.3.4. Randomization 
 
After a patient has satisfied all enrollment criteria, informed consent obtained, and they 
complete all of the written and exercise assessments, the patient will be randomized to usual care 
CR or Hybrid CR.  Generally, randomization should occur the same day of the final 
screening test (i.e., CPX).  A one-to-one randomization scheme will be computer generated and 
will be balanced on random accrual points and stratified by race and gender. 
 
 
4.3.5.  Study groups.  
Patients in both arms of iATTEND will receive CR.  Participation in CR will begin as 
soon as possible after randomization, with a goal of initiating training no more than 10 days after 
randomization. 
 
4.3.5.a. Usual care.  Patients in this arm of the trial will receive the following: 
 
1. Industry standard, facility-based CR, in accordance with current Henry Ford policies 
and procedures; attending CR 2-3 days per week.  Briefly, transportation issues will be resolved 
per current practices using family and community resources. Individual treatment plans (ITPs) 
will be established upon enrollment into CR; revised per patient progress; and uploaded in to the 
EMR upon entry and 30, 60, and 90 days and upon completion of CR. Current guidelines for 
prescribing exercise (type, frequency, duration, intensity) will be in accordance with Unit 
procedures, as adapted from published guidelines (85).  Any ECG telemetry or blood pressure 
measurement during exercise will be used as clinically indicated, and in accordance with 
program policies and procedures.  Health insurance coverage will be verified per Unit protocol 
and CR visits billed in accordance with a patient’s policy and per hospital practices. To avoid 
any effect that co-payments or differing co-payment amounts might have on attendance (and thus 
induce a potential source of bias between groups), all co-payments will be charged to the project. 
For those patients without health insurance, their CR sessions will charged to proposed project 
budget. CBCR subjects will be encouraged to engage in purposeful exercise ad libitum on their 
own each week.   
 
 
 
2. Upon (a) completion of 36 sessions, (b) having stopped attending CR due to medical/ 
personal reasons or non-compliance (defined per current Henry Ford polices and procedures), or 
(c) 6 months of elapsed time from their first CR session, subjects will be deemed having 
“completed” CR and follow-up visit 1 of project testing (QOL, CPX test, 6MW test, and all 
standard CR surveys) will be scheduled and completed within 10 days after such designation. 
 
3. After completing CR and then follow-up visit 1, all subjects will also be contacted by 
the research coordinator by telephone at 2 months and 4 months within the 6 month follow-up 
period. The main reason for these telephone calls at months 2 and 4 after CR is to facilitate 
continued subject retention/engagement in the trial. The coordinator will remind patients about 
their scheduled follow-up visit 2 (at 6 months). The coordinator will also equally speak with 
subjects in both groups about any barriers/issues they might be experiencing relative to proper 
self-care or disease management behaviors, and assist with resolution strategies using an open, 

21 
 
problem-solving approach.  Subjects that were administratively “dropped” from CR will still be 
contacted and scheduled to complete follow-up testing visits 1 and 2. 
 
4. Follow-up visit 2 will be completed at 6 months after completing CR, including project 
testing (QOL, CPX test, 6MW test, and all standard CR survey) will be scheduled and 
completed. 
 
4.3.5.b.  Intervention Group (HYCR) 
 
This group of iATTEND involves a hybrid design, with the frequency of CBCR visits 
and HYCR visits individualized and modified based on the subject’s personal preferences and 
their family, transportation and work constraints.  Per study eligibility criteria, patients in HYCR 
will engage in at least one CBCR visit.  For those with no preferences as to their number of TM 
visits, they will be scheduled to complete 12 of their 36 visits as HYCR-TM, with the remainder 
being home-based without TM (up to one time per week) and/or CBCR 1 or more per week.  
Immediately following CR visit 1 (which will be CBCR), patient in HYCR will have the video 
app loaded to their smart phone or tablet (or that of a “willing to assist” family member or 
friend).  HYCR patients receive a chest strap/wrist heart rate device to document HR before, 
during, and/or after exercise during the TM session.  After CBCR visit 1, if the patient opts to 
complete the remainder of the CR session as HYCR, they will be provided with a home blood 
pressure unit for the regular reporting of resting blood pressure prior to each HYCR visit.  
HYCR subjects will be encouraged to engage in purposeful exercise ad libitum on their own 
each week.  
Since both Blue Cross and Blue Shield of Michigan and Health Alliance Plan already 
cover CBCR and HYCR, only the co-payments will be covered by the project’s budget. For 
patients randomized to HYCR that have an insurer that does not yet cover CR delivered using 
TM (e.g., Medicare), their CR visits will be covered by the project’s budget.  For all patients 
randomized to CBCR, their co-payments will be covered by the project’s budget.  
Program education for patients in HYCR will be delivered using the twenty-eight, 7-15 
min audio PDF’s that are free to access from the Health System’s web site. For patients in the 
HYCR group, 1-3 of the audio PDF’s will be “assigned” (based on their ITP) for viewing before 
their next CR visit, with content discussed with the appropriate CR staff person during their next 
remote or center-based visit.   
The following table (Table 3) provides a descriptive summary of the CR protocol for 
subjects in the two study groups of iATTEND. 
Table 3.  Summary of the CR protocol for subjects in the two study groups of iATTEND. 
 
Hybrid CR 
Center-Based CR 
Staff : Subject ratio 
(contact time, setting) 
1:1 (12 to 15 min, individual 
setting) 
4:1 (60 min, group setting) 

22 
 
Programming for CR 
session 
• 2 to 3 sessions each week 
• At least 1 and no more than 12 
of the sessions will be center-
based  
• Remainder of 36 sessions will be 
remote-/home-based with TM 
All sessions will be center-based 
sessions, 2 to 3 sessions each week  
Recommended total 
number of sessions  
36 
36 
Exercise intensity 
range (85) 
60%-80% of heart rate reserve or RPE 
11-14 
60%-80% of heart rate reserve or 
RPE 11-14 
Recommendation for 
purposeful exercise 
outside of formal CR 
Encouraged, ad libitum 
Encouraged, ad libitum 
Patient monitoring 
ECG telemetry and resting and exercise 
blood pressure monitoring for 1-6 
center-based visits, with HR monitors 
provided for all home/remote 
telemedicine visits.   
ECG telemetry and resting and 
exercise blood pressure monitoring 
for 3-6 center-based visits.  
Additional monitoring based on 
clinical indications  
Patient education 
28, 7-15 min audio PDFs 
8, 45-60 min group lectures 
Completion of 
individual treatment 
plan  
At baseline; 30, 60 and 90 days; at 
discharge 
At baseline; 30, 60 and 90 days; at 
discharge 
Outcomes routinely 
assessed before and 
after CR, and used for 
iATTEND 
• Nutrition: Rate Your Plate 
• QOL: Dartmouth COOP 
• Functional Capacity: MET level* 
• Depression: PHQ-9 
• Nutrition: Rate Your Plate 
• QOL: Dartmouth COOP 
• Functional Capacity: MET level* 
• Depression: PHQ-9 
RPE = ratings of perceived exertion; COOP = cooperative functional assessment; TM=telemedicine 
*Change in MET (metabolic equivalent of task) level during training from week 1 to final week of CR 
 
4.4.  Program Operations. 
One concern with any home-based CR program that periodically incorporates some form 
of synchronized communications might be that “the use of staffing resources per patient 
encounter is less efficient”. To minimize potential inefficiencies in iATTEND, a schedule for 
HYCR at Henry Ford Main Campus will be adopted that allocates up to 4, one hour blocks of 

23 
 
time each day (up to 3 patients per block), with 1 hour blocks allotted to the early morning, late-
morning, mid-afternoon and the early evening. This approach will provide staff coverage for up 
to 20 hours (4 hours per day, 5 days per week; 0.5 FTE) of HYCR each week (or up to 60 
synchronized HYCR visits/week).  Assuming 1 to 3 TM visits per patient per week, this allows 
CR staff to comfortably care for 20 HYCR patients during any given week.  Additionally, in 
concert with the Henry Ford Virtual Care Department, technology and operational solutions will 
be sought that allow for 2 HYCR visits to occur simultaneously with a CR staff person. 
Also, since iATTEND is targeting an at-risk, urban population, another concern relative 
to program operations might be that our patients do not have at their disposal the equipment 
needed to engage in a remote synchronized video TM CR visit.  During the R61 phase of the 
trial, focus group and administrative surveys will be used to identify strategies that best facilitate 
helping patients identify confirmed and regular access (via self or a “willing to assist” family 
member or friend) to both the technology (smart phone, tablet with internet access) and exercise 
equipment (elliptical, treadmill, bike) needed to exercise while using a synchronized video.   
Regarding contingency plans for the few patients that might lose access to exercise 
equipment during the intervention period (up to 36 CR sessions), the research staff will work 
closely with these few  patients to identify and secure a nearby and safe alternate option such as 
an outdoor walking path, indoor path (mall, school hallway), school track, park, or public 
community-center for them to conduct their planned exercise (e.g., walking) sessions regardless 
of the weather; this includes the identification of a partner support person to assist with safety 
and transportation (if needed).  For the few patients for which free-walking in a community 
setting is needed for their exercise plan, maintaining a video link via the internet during free-
walking may be difficult.  For these individuals a standard audio phone call will be established 
while they walk.  Concerning the video synchronized visits, for the rare occasion where the 
video link is lost due to a poor Wi-Fi connection, we will simply rely on the audio portion or 
connected via a standard phone call. 
 
4.5. Adherence. 
Since adherence is the primary end point for this trial (defined as the number of 
scheduled CR sessions completed within 6 months after starting CR), careful instruction will be 
provided to all staff that surrounds ensuring no differential overt or covert attempts are 
undertaken to overly or unduly influence attendance in either study group.  A five person sub-
committee of the Project Management Team (called the Subject Recruitment and Retention and 
Staff Adherence [SRRSA] sub-committee) will monitor the above to ensure that only normal and 
customary program procedures that are normally used to enhance attendance are uniformly 
engaged across all patients.  These normal and customary procedures include (a) calling those 
patients who miss one or more scheduled CR appointments, (b) providing patients with a 
calendar of all future scheduled appointments, and (c) administratively discharging those patients 
that exhibit no CR appointment activity for 6 weeks. 
 

24 
 
4.5.1.  Family/Friend Involvement 
In addition to the above normal and customary, and because spouses, partners, significant 
others, or friend who support patients in an exercise program influence attendance, patients in 
both study groups will be encouraged to bring such a person(s) to the orientation session/first CR 
session and this person will be viewed and relied upon as a primary source of social support. 
4.5.2. Logistical Assistance and Incentives. 
Patients will be thoroughly interviewed and screened to identify potential barriers to 
adherence.  The study coordinator will ensure that participants have sufficient logistical 
assistance to attend the screening visits, baseline testing, CR sessions, and follow-up visits.  
Common barriers/issues that impact attendance will be addressed for resolution per standard CR 
program practices (equally in both study groups) and include the following; (a) transportation 
(countered by use of alternate transportation strategies such as Lyft, taxi,  and GoRide), (b) 
return to work conflict (countered by requesting initial part-time or temporary flexible hours), 
and (c) family care needs (countered by identifying home support person(s) to assist with such 
and offering convenient hours of operation). 
No structured system for providing patients with incentives to attend CR sessions will be 
used.  To facilitate delivery, all patients HYCR will be given a chest strap/wrist HR monitor; 
patients in HYCR that are scheduled to attend less than one CR session per week will also be 
given a home blood pressure monitoring unit.  Gas cards will be made equally available to 
patients in both study arms to facilitate retention to scheduled study baseline and follow-up 
appointments. 
 
4.6. Retention 
Retention for iATTEND is defined as compliance with scheduled testing sessions 
(baseline and follow-up visits 1 and 2), as well as compliance with scheduled follow-up 
telephone calls with the study coordinator (at months 2 and 4 after completing CR).  A main 
reason for the telephone calls at months 2 and 4 of follow-up is to facilitate continued subject 
retention/engagement in the trial. The coordinator will remind patients about their scheduled 
follow-up visit 2 (at 6 months). Also, the coordinator will equally speak with subjects in both 
groups about any barriers/issues they might be experiencing relative to proper self-care or 
disease management behaviors, and assist with resolution strategies using an open, problem-
solving approach.  Subjects that are administratively “dropped” from CR will still be contacted 
and scheduled to complete follow-up testing visits 1 and 2.  
Relying on data provided by the SRRSA, the PMT will regularly review reports detailing 
subject retention to follow-up testing and telephone calls and in conjunction with the Steering 
Committee, enact measures (telephone calls by research and clinical staff, email, and U.S. mailed 
letters) to help ensure fidelity to the specified protocol for testing.  Project budgeted gas cards 
($10 each) can be provided to help defray subjects’ travel costs associated with baseline testing 
and follow-up visit 1 and 2 testing.   

25 
 
The SRRSA sub-committee will (a) track and report on project issues that impact patient 
retention to the above testing events and follow-up telephone calls, as well as (b) staff 
compliance to protocol procedures.  The later includes the SRRSA committee periodically (every 
6 months) conducting shadow-evaluations (using video and observation) of CR staff for the 
uniform conduct of patient assessments and the uniform delivery of CR per protocol standards. 
 
4.7 Drop outs. 
 
4.7.1. Drop out recovery.   
Relative to study retention, the following definitions will be applied: 
1. Integrated subjects are those attending all appointments as scheduled, or re-
scheduling any missed appointments or cancellations 
2. Poorly compliant subjects are those who cancel, do not show and fail to reschedule 2 
of their 4 follow-up responsibilities (follow-up visit 1 or 2 and telephone encounter 1 
and 2). 
3. Refusals/drop-outs are those that state, in no uncertain terms, that they do not want to 
participate any longer in the trial, and refuse any further contact with study staff. 
iATTEND will use a systematic approach in an attempt to recover poorly compliant subjects, 
especially those that either (a) inquired about or expressed interest in dropping or (b) or appear to 
be “moving toward” dropping out based on poor compliance data.  Since most drop outs are due 
to life changes (e.g., divorce, illness of family member, change in jobs) and/or 
misunderstandings with research staff, a planned recovery approach will be used that addresses 
the following. 
1. Be sure that subjects are NOT pushed to the point that they refuse to participate/all 
contact 
2. Stay in touch with the patient though email, phone calls or being present at planned clinic 
visits they may have with their physicians.  All of this is aimed at showing support, as 
well as provides an opportunity to garner subject concerns such that problem solving and 
barrier resolution techniques can be applied to I prove participation. 
3. To foster continued, planned contact with the research staff… even if it is something as 
simple as to schedule another contact on a specific day and time. 
Engaging patients at risk for dropping out using barrier identification and problem resolution 
techniques is a dynamic endeavor that also can vary with time, especially among those subjects 
where challenging life circumstances (e.g., transportation, work, family care) change improve… 
such that it then becomes more feasible for them to re-engage in the project. 
 
4.7.2. Other important drop out recovery considerations. 
 
 
A. Attempts to re-integrate a participant should be discontinued as soon as an adamant 
refusal is communicated. 

26 
 
 
B. A patient will be considered “lost to follow-up” only after all means of contact have 
failed.  The status of the patient at the last visit or contact will be used for the final analysis.  The 
vital status of these patients will be followed by appropriate national database. 
 
C. For patients that formally withdraw consent, vital status will be followed by 
appropriate national database. 
 
4.8.  Subject Follow-Up 
 
After completing CR or a subject’s last CR visit, follow-up visits 1 and 2 will be 
scheduled, the former scheduled within 10 days of last CR visit and the latter scheduled at 6 
months + 15 days after last CR visit.  Data collected at follow-up visit one will be nearly the 
same as that gathered during baseline.  This includes both QOL instruments (Dartmouth COOP, 
EQOL), a CPX test, the 6MW, PHQ-9, Rate your Plate, and 5x sit-to-stand.  Data collected at 
follow-up visit two includes both QOL instruments (Dartmouth COOP, EQOL), a CPX test, the 
6MW, PHQ-9, Rate your Plate, and frailty assessment.   
 
Table 4.  Schedule of Trial Events and Time line 
Patient Care Event 
Screening 
and 
Baseline 
Weeks 1-
26 or CR 
visits 1-
36* 
F/up visit 1 
within 10 d 
after last CR 
visit 
2 mo 
after last 
CR visit 
4 mo 
after last 
CR visit 
F/up visit 2 
at 6 mo 
after last 
CR visit 
Testing 
 
 
 
 
 
 
  CPX 
X 
 
X 
 
 
X 
  6MW 
X 
 
X 
 
 
X 
  Dartmouth COOP 
X 
 
X 
 
 
X 
  EuroQOL-5D 
X 
 
X 
 
 
X 
  Rate your plate 
X 
 
X 
 
 
X 
  Mini-cog 
X 
 
 
 
 
 
  5x sit-to-stand 
X 
 
X 
 
 
X 
  iPAQ 
X 
 
X 
X 
X 
X 
  PAST 
X 
 
X 
X 
X 
X 
 
 
 
 
 
 
 
Training 
 
 
 
 
 
 
  Exercise sessions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Telephone calls 
 
 
 
X 
X 
 
*Patients will have 6 mo to complete 36 visits; iPAQ=International Physical Activity 
Questionnaire; PAST = Past-day Adult Sedentary Time Questionnaire 
 
5. Trial Endpoints 

27 
 
5.1. Primary endpoint 
R61 Phase.  In conjunction with study investigators, stakeholders, and NHLBI staff, prepare and 
operationalize a clinical trial that evaluates the effect of a HYCR program on attendance to CR. 
This includes finalizing the protocol, obtaining any institutional review board approved 
amendments, developing the manual of operations, establishing data safety monitoring board, 
hiring and training CR and research staff, and demonstrating the ability to screen and enroll 
patients into the trial. 
R33 Phase.  The number of CR sessions completed within 6 months 
 
5.2. Secondary Endpoints.   
R33 Phase only.   
1. Percentage of patients completing 36 CR sessions within 6 months 
2. Change in exercise capacity upon completion of CR 
 
a. Peak VO2 
 
b. Six minute walk distance 
3. Change in quality of life upon completion of CR 
4. Exploratory endpoints 
a. Change in exercise capacity at 6 mo after completion of CR 
i). Peak VO2 
 
 
ii). Six minute walk distance 
  
b. Change in quality of life at 6 mo after completion of CR 
c. Change in sedentary behavior and physical activity habits (home, work, recreation), the 
latter of which does not include exercise in CR 
d. Economics and resource utilization associated with of CR.   
Home- or hybrid approach to CR (with or without telemedicine) is often viewed as a 
“negative” financial business model due to lack or revenue (and increased patient care 
expenses and staff time).  The cost effectiveness, economics and resource utilization of 
the HYCR program will be determine and compared to the similar data for CBCR.  In 
both CR models we will collect and calculate costs associated with program 
implementation (staff time, HR monitors, and upgrading desk tops for telemedicine) as 
gathered from both administrative data within the CR unit and from the Health System’s 
Corporate Accounting/Financial Services Department.  We will also collect costs from 
participants at follow-testing, including direct nonmedical and medical costs (including 
value of time of the participants attending a program, waiting, and travel).  In a subset of 

28 
 
our his project’s full cohort, for patients insured Health Alliance Plan or Blue Cross and 
Blue Shield of Michigan, we will identify and compare  reimbursement and health care 
utilization during CR and for the 6 month period of time after CR is completed  
 
6. Safety 
Consistent with what is known today about the practice of cardiac rehabilitation, the level of 
incremental risk for major unexpected adverse events (death, events requiring hospitalization) 
that are probably related to a subject’s participation in this project is anticipated to be extremely 
low.   
6.1. Safety assessment. 
Safety assessments will consist of the recording and monitoring of all safety related 
events.  Results from patient assessments (e.g., CPX results, ECG rhythm strips [if any]) that 
include safety parameters performed as part of the patient evaluation or trial protocol will be 
maintained in the patient’s research chart and considered to be source documents. 
 
6.1.1.  Adverse and Serious Adverse Events or Experience 
An adverse event (AE) is defined as any untoward medical occurrence (new onset or 
change in disease state) in a patient that is unfavorable and unintended (e.g., new onset chest 
pain, near syncope, new onset atrial fibrillation), regardless of whether or not it is considered to 
be related to the intervention.  A serious adverse event (SAE) is defined as any untoward medical 
occurrence that results in any of the following: death; persistent or significant 
disability/incapacity; hospitalization; stroke; fall requiring medical attention; is life threatening; 
or requires or is considered serious such that the patient may require medical or surgical 
intervention to prevent any of the previously listed events.   
For the purposes of iATTEND, the project will follow all policies and procedures set 
forth by Henry Ford Hospital, its Office of Research Administration, and its Institutional Review 
Board (IRB).  SAEs and AEs of interest will be collected after randomization and through 
follow-up visit 2 and recorded on a CRF.  The project management team (PMT) will forward this 
safety data to the DSMB on a regular basis (e.g., quarterly), which will perform routine 
evaluations of such. 
Additionally, although likely very rare, unexpected SAEs that are possibly attributable to 
rehabilitation, as determined by the trial PI (e.g., occurring during or within 3 hours after 
exercising), will be reported to the IRB and DSMB within 10 days of occurrence.    
 
6.1.2.  Assessment of Actionable Events Immediately Proximal to CR 
A secondary analysis is planned of actionable events (both AE and SAE) sustained 
immediately prior to, during, or immediately after (during recovery) an exercise training session.  
These represent both major events that may require hospitalization (e.g., myocardial infarction, 
fall) or an emergency room visit, as well as events that often occur in CR and may lead to with-

29 
 
holding a patient from starting exercise, stopping a patient from continuing to exercise, or 
requiring notification of the patient’s a physician (e.g., symptomatic hypoglycemia requiring oral 
glucose supplementation, new onset or worsening angina/ischemia, falls, persistent hypotension). 
 
7. Study Organization 
7.1. Steering Committee 
The Steering Committee (SC) is responsible for overseeing and maintaining the scientific and 
operational integrity of the project. Duties include approving the final trial protocol; overseeing 
the scientific direction of the trial; review and approval of case report forms, assessment 
questionnaires and manual of operations; review and approval of main analysis plan; review and 
vote on any proposed protocol amendments; review, comment on and vote on any presentations, 
publications or recommendations of the Publications sub-committee; and act on any 
recommendations from the DSMB 
The SC will meet annually. 
 
 
7.1.1. Publications Sub-Committee 
A Publications subcommittee will be established, comprised of up to 4 individuals (two 
of which will be from the SC) who will initially meet quarterly to give direction and timelines to 
the expected writings, publications, presentations and pronouncements from this project.   The 
publications committee will be responsible to review and comment on proposals for papers made 
by investigators, review trial press releases, approve secondary databases analyses, address any 
issues pertaining to authorship of publications and presentations, and ensure that NHLBI 
publications approval procedures are followed.  It will also assist the research staff with 
registering the project with clincaltrials.gov and establish a schedule for the submission of trial 
results to clinicaltrials.gov (within 12 months after study completion). 
 
7.2. Project Management Team (Plan). 
Under the guidance and leadership of the SC, the PMT will plan and implement/conduct 
the project in a manner that adheres to the approved protocol and manual of operations.  The 
PMT will be established during month 1 or 2 of year 1 and meet in-person or via teleconference 
every 1-3 weeks.  It will be led by the Project Manager (to be determined), in concert with the 
project PI.  Any and all financial and operational issues that might require input from the full 
PMT will be added to the agenda for the next meeting of the PMT.  The agenda will follow a 
standardized format for each meeting to address on-going business (screening report, enrollment 
report, retention report, assessments, process initiatives, and financial issues), new business, and 
action items. 
Responsibilities for the PMT include, but are not limited to, telecommunication issues, 
patient education, data collection and entry, retention and adherence, maintenance of staff skills 
for testing, effective integration of both the center-based and hybrid programs, project 

30 
 
assessments, and protocol fidelity.  Other PMT members will include the PI, the project’s to-be-
hired research coordinator, the Coordinator for CR at the Detroit campus, the registered dietician 
for the Detroit CR program, the hospital’s Director of the Office of Performance Excellence and 
Quality or h/er designee, a behavioral medicine specialist, a former (recent) patient from our 
Detroit-based CR program, and a staff person from the System’s Virtual Care Unit.  To ensure 
that the objectives of the trial are being met, the PMT will adopt an approach that is both 
proactive and rapid-response reactive.  The former approach will actively survey/identify 
potential “pinch-points’ for trial operations (based on team planning discussions and experience 
gained from the years of operating CR, clinical trials in CR, and home-based CR) and design 
accordingly the study operations and schedule staff for the effective achievement of objectives.  
The latter approach (i.e., rapid-response reactive) involves both the regular review of operational 
report data (e.g., weekly enrollment reports, retention to follow-up testing, time elapsed between 
data collection and data entry) and collecting CR staff feedback on trial operations and milestone 
achievement.  If problems are identified that threaten achievement of study objectives, the PMT 
will adjust trial procedures using a rapid-cycle, data-driven methodology. 
 
 
7.2.1. Subject Recruitment and Retention and Staff Adherence [SRRSA] sub-committee  
During month 11 of the project staff will begin the real-time tracking of key indicators of 
patient engagement in the study (e.g., adherence to testing).  This will be done equally in both 
study groups to aid in identifying favorable/unfavorable implementation issues; it may include 
surveying and tracking the adoption and acceptability of changes to CR delivery by staff and 
patients, as well as assessing sustainability of the over-all model.  A sub-committee of the PMT 
(called the Subject Recruitment and Retention and Staff Adherence [SRRSA] sub-committee) will 
be convened and charged with the above duties, as well as track, report and help intervene on 
other global project issues such as: ensuring convenient hours for testing, ensuring available 
hours for delivery of both CBCR and HYCR, ensuring equivalent delivery of educational 
content, and the timely completion of the patient’s individual treatment plans. The SRRSA will 
also periodically (every 6 months) shadow-evaluate (using video and observation) CR staff for 
the uniform conduct of patient assessments and the uniform delivery of CR per protocol 
standards.  Finally, the SRRSA committee will conduct a systematic, standardized rapid-cycle 
review of any patient (from either study group) that did not complete follow-up visit 1 testing or 
follow-up visit 2 testing.  Learnings gathered from such will be applied to in a manner to 
avoiding future retention issues. 
 
7.3. Data Safety Monitoring Plan/Board (DSMB) (See also Appendix A for additional details) 
The Data Safety Monitoring Board (DSMB) for this trial will be an “internal DSMB”, 
comprised of 4 individuals that are independent of the NHLBI, trial investigators and trial 
management.  The NHLBI will approve the membership of the DSMB and the DSMB serves in 
an advisory capacity to both the NHLBI and the trial’s Steering Committee.  The DSMB will be 
comprised of two senior staff from within Henry Ford Health System, one of which will be a 
senior physician-scientist with NIH funding and the other will be a clinical cardiologist 
experienced with clinical trials from the Division of Cardiovascular Medicine (who will also 
serve as chairperson).  The third DSMB member will be an external (to HFHS) cardiac 

31 
 
rehabilitation professional (clinical exercise physiologist) that is actively working in the field of 
CR.  The fourth member will be a biostatistician (other than Dr. Peterson) from the HFHS 
Department of Public Health Sciences. It will be the responsibility of the study coordinator and 
project manager, in conjunction with the Dr. Keteyian, to ensure that unexpected SAEs 
associated with exercise training (defined as occurring during or within 3 hours after exercising) 
will be reported to the IRB and DSMB within 10 days of occurrence.   The DSMB will meet bi-
annually, of which a portion of each meeting will be with study investigators.  
The primary endpoint for this study is number of CR sessions attended (versus a clinical 
endpoint such as death or re-hospitalization); therefore, the DSMB will not have to address the 
issue of trial continuation relative to clinical endpoint futility.  All subjects will be evaluated for 
the specified duration of the trial for all primary and secondary outcomes measures.  A subject’s 
participation in the trial can also be stopped upon their formal request for withdrawal.  The 
number of subjects that withdraw consent from trial participation will be tracked and reported to 
the DSMB.   
The monitoring for unexpected major SAE’s, as well as patient withdrawals, will occur 
continuously through the study by the project manager and research coordinator.  The DSMB 
will meet every six months during the trial, and at the end of the trial, to review all trial-related 
reports and study findings.  All records of AE and SAE will be available to the DSMB chair and 
the entire DSMB at any time, upon request. 
All relevant unexpected and major SAE that occur during or within 3 hours after exercise 
will be collected, summarized and reported within 10 days to the local IRB and to the DSMB.  
Although the occurrence of these SAE’s is extremely rare in the CR setting, any such events that 
do occur will be investigated and discussed jointly between the principal investigator and the 
DSMB or its chair.  Any policy or procedural changes that arise from such discussion will be 
incorporated into a revised study protocol.  Subjects that withdraw consent from trial 
participation will also be tracked by the study coordinator and reported to the DSMB.   
The primary and secondary analyses will be conducted by Dr. Peterson (biostatistician) 
from Public Health Sciences and he will possess a copy of the treatment codes for 
randomization. 
 
8. Data Management 
8.1. The data needed to test the primary hypothesis from this proposed project will be gathered 
from 270 subjects.  The final data set will be comprised of demographic and clinical data 
gathered from questionnaire, electronic medical record, clinical CR care, and laboratory 
assessments.  The three main time points for laboratory assessments are upon entry in to the trial, 
immediately after the patient completes CR (follow-up visit 1), and at 6 months after completing 
CR (follow-up visit 2).  The primary outcome measure is attendance to CR; secondary outcome 
measures are quality of life and exercise capacity. 

32 
 
Data from the above mentioned sources will be collected on case report forms (CRFs) 
and entered in an ongoing manner (and within 2 weeks of collection) by the research assistant or 
staff from the Henry Ford Clinical Exercise Physiology Core Laboratory, and they will follow 
entry and validation processes that are consistent with the Health System’s Department of Public 
Health Sciences (Research Informatics Unit).  Study data will be collected in and then managed 
using REDCap (Research Electronic Data Capture, Vanderbilt University, Tennessee) electronic 
data capture tools (90). A thorough, study-specific data dictionary, defined by all members of the 
research team in an iterative, self-documenting process, will be compiled. The baseline data form 
and the final visit (follow-up visit 2) data forms will require the signature of Dr. Keteyian.   
The final data base will be stripped of identifiers (de-identified) and secured and hosted 
on a HIPAA-compliant server managed by the Department of Information Technology at the 
Corporate Data Center of Henry Ford Health System. REDCap will be used for generating the 
shared dataset.  It will be used to remove identifiers, export data in a format that SAS can read, 
and create the SAS code needed to read the data in SAS.  REDCap will also export PDF’s of the 
case report forms and the data dictionary (codebook).  The data base will be made available to 
the NHLBI.  It will also be made available to others (upon request), under the auspices of a data 
sharing agreement that includes a commitment to (a) use the data for research purposes only, (b) 
not attempt to identify any one individual, and c) secure the data using appropriate computer 
technology and back-up.  The dataset (and an accompanying data dictionary and other 
documentation) will be prepared to share in accordance with NHLBI data repository 
requirements, and consistent with other repository (BioLINCC) and NHLBI policy requirements. 
 
9. Manual of Operations 
A manual of operations (MOO) will be developed for all key aspects of the trial and will provide 
objectives, scope, design and operational policies and procedures beyond that spelled out in this 
clinical protocol.  The manual will detail instructions for completing CRFs (e.g., baseline 
medical history data), baseline and follow-up questionnaire and clinical assessments, retrieval of 
primary endpoint data, and exercise training in CBCR and HYCR.  The MOO will detail the 
follow-up testing/assessment schedule and survey tools, the follow-up phone calls to be 
completed at 2 and 4 months after completing CR, trial level contact information, and data 
queries.  With regards to the CPX test and the 6 min walk test, quality assurance 
assessments/training, data handling/transfer, and any variable-specific data calculations or 
manipulations will be addressed in the existing manual of operations/procedures found within the 
CPX Core lab.  
 
10. Statistical Analysis Plan 
Dr. Peterson (biostatistician) will oversee and conduct the data analysis for this trial.  He will 
also assist with the development of enrollment and retention reports sent to the NHLBI and will 
also assistant with preparing materials for the DSMB meetings that are held every 6 months.   

33 
 
 
10.1. Randomization Procedure 
 
Using computer generated randomization, the randomization process will be stratified by 
race and sex and blocked to ensure balance at random accrual points. Lists were compiled for the 
4 sex-race specific strata.  As new participants are added to the study they will be assigned the 
next available treatment assignment (CBCR, HYCR) based on the lists provided.  The project 
manager will be responsible for treatment assignment as all other staff involved in the study will 
be blinded as to the randomization lists to avoid bias. 
 
10.2. Sample size and power calculations.   
We propose to enroll a total of 270 patients evenly randomized into two groups of 135 
patients each.  To determine power for Hypothesis 1, we will use a Student’s t-test approach. 
From recent data from our administrative CR data base, we believe that the CBCR group will 
complete 21 ±13 (mean + sd) visits over the course of the study. The test, with a two-sided 0.05 
alpha level, will have 80% power to detect an increase of 4.5 visits. We believe this to be a 
clinically significant difference (5). 
      
Also, for Hypothesis 2, our recent administrative data indicates that 24% of patients in 
our CBCR program complete 36 visits. A chi-squared test with a two-sided 0.05 alpha rate and 
135 subjects per group will have 80% power to detect an increase to 39.8% or more in the 
HYCR group (effect size=15.8 percentage point increase). 
      
Hypothesis 3, 4 and 5 require longitudinal measures six months after CR is completed, 
so it is possible that some lost to follow-up will occur at follow-up testing point number 2. If we 
assume that no more than 20% will be lost, our sample size for this analysis will be at least 108. 
We anticipate a standard deviation of the change in meters walked in the 6-minute walk to be 
107 meters (based on data from the Henry Ford Core Exercise Laboratory) When the sample size 
in each group is 108, a two group 0.05 one-sided t-test will have in excess of 90% power to 
reject the null hypothesis that the CBCR and HYCR groups are not equivalent (the difference in 
means is 50 meters or farther), in favor of the alternative hypothesis that the means in the two 
groups are equivalent. 
      
The measured of peak VO2 should have a standard deviation near 6 (86).  With a sample 
size of 108 per group, a two-group one-sided t-test will have greater than 80% power to reject the 
null hypothesis that the CBCR and HYCR groups are not equivalent (the difference in means is 
2.0 mL/kg/min or farther), in favor of the alternative hypothesis that the means in the two groups 
are equivalent.  
      
Based on Campbell, et al. (87), we anticipate that the standard deviation of the Short 
Form Health Survey (SF-12) physical component summary will be 22 and the mental component 
summary will be 18. When the sample size in each group is 108, a two-group 0.05 one-sided t-
test of the physical component scale will have 80% power to reject the null hypothesis that the 

34 
 
CBCR and HYCR are not equivalent (the difference in means is 7.5 or further from zero in the 
same direction), in favor of the alternative hypothesis that the means of the two groups are 
equivalent. The power for the mental component summary will exceed 90%. 
 
10.3. Data Analysis Plan.  
Data analysis will begin with prepatory activities such as checking for complete data 
entry, identification of outliers, and other such data cleaning tasks.  Once the above tasks are 
completed, the data base will be “locked” for analyses.  The Statistical Analysis System, (SAS, 
version 9.4) will be used for data analysis. A detailed descriptive analysis of all quantitative data 
will be performed involving the summarization of data and the use of inferential and graphical 
exploratory analytic techniques. The information obtained from this preliminary investigation 
will be used to: 1) describe univariate and bivariate sample distributions of the data; 2) identify 
the interrelationships between variables (i.e., need for covariate adjustment); and 3) check for 
violations of assumptions underlying identified statistical techniques (e.g. independence, 
linearity, homoscedasticity, normality). In the event that statistical assumptions are severely 
violated, data transformations or nonparametric methods will be employed.  An intention to treat 
approach will be utilized for all analyses. For hypothesis 1 the number of visits completed before 
lost to follow up will be used and for hypothesis 2 a yes/no response will be generated based on 
the observed data. 
 
R33- Primary Aim: Assess the effect of a HYCR program on over-all patient attendance 
For the Primary Hypothesis (number of sessions completed), if the distribution of the 
number of sessions completed is normal then a Student’s t-test will be used for comparison of the 
two groups. In the likely event it is skewed a two-sample Wilcoxon with a Fligner-Policello 
correction for unequal variances will be used.   Hypothesis 2 (percentage of patients completing 
36 CR sessions) will be addressed using a Chi-squared test for comparison of proportions.  
 
     R33- Secondary Aim: Assess the effect of HYCR on exercise capacity and quality of life. 
Hypotheses 3 and 4 (both address measures of exercise capacity) and Hypothesis 5 
(QOL) all involve assessing if the two group responses are equivalent. A two one-sided test 
approach will be used to demonstrate equivalence between the two groups. 
 
There are several identified exploratory aims for this project, including but not limited to:  
(a) short-term (6 month) retention of CR-related outcomes [e.g., exercise capacity, QOL, 
and self-engaged (not CR) purposeful exercise and total physical activity habits] 
(b) program cost effectiveness.   

35 
 
 
Analyses of the exploratory aim associated with the short-term retention of CR-related 
outcomes will be analogous to the analyses described above, such that Student’s t-test, Chi-
squared tests or their nonparametric alternatives will be utilized.   
Concerning cost effectiveness, we have included it as an exploratory aim because some 
view a home- or hybrid approach to CR (with or without telemedicine) as a “negative” financial 
business model due to lack or revenue (and increased patient care expenses and staff time).  The 
cost effectiveness of the HYCR program will be explored to determine the cost differential 
between the two CR approaches.  In both CR models we will collect and calculate costs 
associated with program implementation (staff time, HR monitors, and upgrading desk tops for 
telemedicine) as gathered from both administrative data within the CR unit and from the Health 
System’s Corporate Financial Services Department.  We will also collect costs from participants 
at follow-testing, including direct nonmedical and medical costs (including value of time of the 
participants attending a program, waiting, and travel).  In collaboration with our colleagues at 
both Health Alliance Plan and Blue Cross and Blue Shield of Michigan, the two Michigan–based 
insurers that agree to cover hybrid CR for their subscribers in this project, we also have the 
unique opportunity to partially track and compare the potential impact of HYCR and CBCR on 
health care utilization and costs during the 6 months after CR is completed (and afterwards).   
Finally, the CR-outcomes and behaviors that Henry Ford normally assesses before and 
immediately after CR (e.g., Rate Your Plate, Dartmouth COPOP for QOL) will again be assessed 
at the 6 month post-program follow-up 2 visit (for short-term retention).  In addition, reasons for 
stopping program attendance before completion of the study recommended 36 visits will be 
gathered from all subjects for subsequent secondary analysis. 
 
11. Institutional Review Board and Ethics and Good Clinical Practice 
 
This study must be carried out in accordance with the approved protocol and all Henry 
Ford Health System and study operating procedures.  Compliance with such protocols and 
procedures will ensure adherence to good clinical practice.  
Before implementing the study, the final protocol, the proposed informed consent and 
other subject information documents must be reviewed and approved (initially and then 
annually) by the System’s Institutional review Board (IRB).  A signed and dated document that 
the protocol and informed consent have been approved by the IRB must be in-place before study 
initiation.  Any amendments to the protocol, other than administrative, must be approved by the 
IRB. 
 
11.1. Informed Consent (IC) 
 
The principal investigator or his designee must explain to each subject (or legally 
authorized representative) the nature of the study, its purpose, the procerus involved, the 

36 
 
expected duration, the potential risk and benefits involved and any discomforts it might entail.  
Each subject must be informed that participation is voluntary and that s/he may withdraw from 
the study at any time and that withdrawal of consent will not affect his/her subsequent treatment 
or relationship with their treating physician. 
 
The IC should be given by means of standard written statement, written in non-technical 
language.  The subject should read and consider the statement before signing and dating, and 
should be given a copy of the signed document.  If written consent is not possible, oral consent 
can be obtained if witnessed by a signed statement from one or more person not involved in the 
study that mentions why the patient was unable to sign the form.  No patient can enter the study 
before his/her IC has been obtained. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

37 
 
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Appendix A 
DATA SAFETY MONITORING PLAN 
The data safety monitoring plan will adhere to all policies and procedures set forth by Henry 
Ford Hospital, its Office of Research Administration, and its Institutional Review Board (IRB). 
Additionally, all defined unexpected adverse events and unanticipated problems will be reported 
to the system’s IRB, data safety monitoring board (DSMB), and other applicable regulatory 
agencies. 
To help ensure subject safety, the following procedures will be followed: 
a) Based on review of the System’s EMR and/or in-person interview/examination with study 
staff, potential subjects will be carefully “screened-out” during the trial’s screening processes for 
known contraindications to exercise testing and exercise training (e.g., receiving continuous 
inotropic support therapy). 
b) All study-eligible subjects will complete a symptom-limited graded cardiopulmonary exercise 
(CPX) test at baseline, prior to randomization. This test has the ability to identify and screen 
patients for rare exercise-induced contraindications to exercise training (e.g., abnormal blood 
pressure response, significant dysrhythmia).  
Concerning home-based CR, it is important to emphasize that most all patients that participate 
in center-based programs today are already asked to “exercise on their own on non-rehab 
days”; therefore, this study is mainly giving some structure and supervision to that 
recommendation.  
c) All subjects will also attend at least one exercise session in center based CR, during which 
their gait, balance and stability on their preferred exercise modality will be evaluated to ensure 
the patient will be safely able to use the equipment on their own. 
d) Published guidelines for prescribing exercise in the CR setting will be followed, such as 
progressing exercise duration and frequency before intensity, reinforcing proper warm-up and 
cool down procedures, the periodic screening for exercise-related signs or symptoms, and 
progressing and maintaining exercise training intensity to stay within prescribed levels based on 
heart rate or rating of perceived exertion. 
e) At the beginning of each remote telemedicine CR session, we will document the patient’s 
exact current street address/location (e.g. home, community fitness center, workplace), for the 
rare instance that an untoward event occurs that requires intervention by emergency medical 
services. 
 
The Data Safety Monitoring Board (DSMB).  For this trial the DSMB will be an “internal 
DSMB”, comprised of 4 individuals that are independent of the NHLBI, trial investigators, and 
trial management. The NHLBI will approve the membership of the DSMB and the DSMB is 
advisory to the NHLBI and the trial’s Steering Committee.  

48 
 
The primary endpoint for this study is number of sessions attended (not a clinical outcome such 
as mortality). However, trial safety is always a concern. Therefore, rare, untoward, unexpected 
major events related to exercise training or exercise testing (i.e., during or within three hours) 
may occur and will be monitored, such as death or events requiring hospitalization (e.g., 
myocardial infarction, syncope, arrhythmia, fall). These events will be reported to both the IRB 
and DSMB per existing institutional and protocol requirements (i.e., within 10 days) and 
documented in the subject’s study file. 
Monitoring of events.  A DSMB meeting will be held in-person (with teleconference 
capabilities) every six months, during which a comparison will be made of any excess, untoward 
events.  If needed, the DSMB will advise the NHLBI and Steering Committee accordingly.  
Minor events, such as falls not requiring emergency care, angina, and ST segment changes 
during testing that are suggestive of myocardial ischemia will be documented in the subject’s 
study file. 
Relative to suspending or discontinuing a specific subject’s participation in CR and/or the trial 
assessments due to a clinical indication (worsening symptoms, compromising arrhythmia), Dr. 
Keteyian will consult with co-investigators Drs. Lanfear or Nour to ensure that all applicable and 
relevant Henry Ford Hospital and Preventive Cardiology Unit program- and patient-level clinical 
policies and procedures are followed. With the subject’s permission, and to assist with their care, 
their own physician will be contacted regarding the relevant clinical findings. The Steering 
Committee will be informed of the above. 
Since a clinical endpoint such as death or re-hospitalization does not represent a trial endpoint or 
outcome measure for this project, the DSMB will not have to address the issue of trial 
continuation relative to endpoint futility. All subjects will be evaluated for the specified duration 
of the trial for all primary and secondary outcomes measures. The number of subjects that 
withdraw consent from trial participation will be tracked and reported. 
The monitoring for unexpected major adverse events and minor events, as well as patient 
withdrawals, will occur continuously through the study by the project manager and research 
coordinator. Major events will be discussed within the project management team.  
It will be the responsibility of the study coordinator, in conjunction with Dr. Keteyian, to ensure 
that unexpected serious/major adverse events that occur within 3 hours of exercise are collected, 
summarized and reported within 10 days to the local IRB and to the DSMB. Although the 
occurrence of an unexpected, major adverse events is not anticipated and felt to be extremely 
rare, any such events that do occur will be investigated and discussed jointly between the 
principal investigator and the DSMB or its chair. Any policy or procedural changes that arise 
from such discussion will be incorporated into a revised study protocol. Subjects that withdraw 
consent from trial participation will also be tracked by the study coordinator and reported to the 
DSMB.