REHAB-HF: A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients
Phase: NA
Conditions: Acute Decompensated Heart Failure
Sponsor: Wake Forest University Health Sciences

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 REHAB-HF: A Trial of Rehabilitation Therapy in Older Acute Heart 
Failure Patients 
 
 

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Protocol Outline 
1. Overview of the REHAB-HF Study 
2. Study Objectives 
 
2.1 Primary Objective 
 
2.2 Secondary Objective 
 
2.3 Other Objectives 
3. Background 
4. Overview of Investigational Plan 
5. Study Population 
5.1 Inclusion Criteria 
 
5.2 Exclusion Criteria 
6. Participant Enrollment 
 
6.1 Screening 
 
6.2 Baseline Testing 
 
6.3 Randomization 
7. Investigational Intervention 
 
7.1 Attention Control Group 
 
7.2 Rehabilitation Intervention Group 
 
 
7.2.1 Rehabilitation Intervention Overview 
 
 
7.2.2 Initiation of the Rehabilitation Intervention 
 
 
7.2.3 Initial Exercise Prescription 
 
 
7.2.4 Exercise Duration 
 
 
7.2.5 Exercise Intensity 
 
 
7.2.6 Exercise Progression 
 
 
7.2.7 Exercise Modality 
 
 
 
7.2.7.1 Endurance Rehabilitation 
 
 
 
7.2.7.2 Mobility Rehabilitation 
 
 
 
7.2.7.3 Strengthening Rehabilitation 
 
 
 
7.2.7.4 Balance Rehabilitation 
 
 
7.2.8 Exercise Safety 
7.2.9 Home Visit and Home Exercise Prescription 
7.2.10 Allowance of Supervised Home-Based Exercise 
 
 
7.2.11 Maintenance Phase 
 
 
7.2.12 Management of Conflicts with Physician-Ordered Care 
7.3 Intercurrent Illness and interruption to Study Intervention 
 
7.4 Monitoring Exercise and Rehabilitation 
8. Retention and Treatment Fidelity 
 
8.1 Overview 
 
8.2 Retention 
 
 
8.2.1 Adherence Screening Tool and Behavioral Agreement 
 
 
8.2.2 Retention Promotion Efforts 
 
 
8.2.3 Retention for Study Visits 
 
 
8.2.4 Monitoring Recruitment and Retention 
 
 
8.2.5 Retention and Efforts to Maintain Contact with Inactive Participants 
8.3 Treatment Fidelity: Delivering the Physical Activity Intervention as Detailed in the 
Protocol 
9. Study Participant Follow-up 
 
9.1 Follow-up Schedule 
 
9.2 Blinding 
10. Outcomes 

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10.1 Measures of Physical Performance 
 
 
10.1.1 SPPB 
 
 
10.1.2 6MWD 
 
 
10.1.3 Handgrip Strength 
 
10.2 Health Status and Quality of Life Measures 
 
 
10.2.1 Kansas City Cardiomyopathy Questionnaire (KCCQ) 
 
 
10.2.2 12-Item Short-Form Health Survey (SF-12) 
 
 
10.2.3 EuroQol (EQ5D-5L) 
 
10.3 Depression, Cognitive Status, and Optimism 
 
 
10.3.1 Geriatric Depression Scale – 15 (GDS-15) 
 
 
10.3.2 Montreal Cognitive Assessment (MoCA) 
 
 
10.3.3 Life Orientation Test (LOT-R) 
 
10.4 Accelerometry 
10.5 Biomarkers 
 
10.6 Clinical Measures 
 
 
10.6.1 Rehospitalizations 
 
 
10.6.2 Other Clinical Events 
 
10.7 Frailty 
 
10.8 Timing and Order of Outcome Measures 
11. Economic Analysis 
 
11.1 Direct Medical Costs 
 
11.2 Direct Non-Medical Costs 
 
11.3 Indirect (Patient Time) Costs 
 
11.4 Short-term Cost Analysis 
 
11.5 Long-term Cost-Effectiveness Analysis 
 
11.6 Sustainability of the Intervention 
12. Efficacy Parameters 
 
12.1 Primary Efficacy Parameter 
 
12.2 Secondary Efficacy Parameter 
 
12.3 Exploratory Efficacy Parameters 
13. Safety Monitoring and Adverse Events 
 
13.1 Adverse Events (AE) and Serious Adverse Events (SAE) 
 
13.2 Data Safety Monitoring Board (DSMB) 
 
13.3 Stopping Rules 
14. Statistical Considerations 
 
14.1 Statistical Methods 
 
14.2 Sample Size Justification 
 
14.3 Data Management 
15. Privacy protection 
16. Organizational Structure 

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Abbreviations: 
ADHF- acute decompensated heart failure 
SPPB- short physical performance battery 
6MWD- 6-minute walk distance 
KCCQ- Kansas City Cardiomyopathy Questionnaire 
SF-12- 12-item short form health survey 
HF- heart failure 
QOL- quality of life 
PND- paroxysmal nocturnal dyspnea 
BNP- B-type natriuretic peptide 
ADL- activity of daily living 
RPE- rate of perceived exertion 
EQ-5D-5L- Euroqol 5-dimension 5-level 
GDS- Geriatric Depression Scale 
MoCA- Montreal Cognitive Assessment  
DSMB- data safety monitoring board 
AE- adverse event 
SAE- serious adverse event 
REDCap- research electronic data capture 
LOT-R – Life Orientation Test

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1.   
Overview of the REHAB-HF Study 
REHAB-HF: A Trial of Rehabilitation Therapy in Older Acute Heart Failure Patients, is a 
multicenter, randomized, attention-controlled, single-blind trial designed to examine the 
hypothesis that, in addition to standard care, a novel, tailored, progressive, multi-domain 
rehabilitation intervention administered to older patients with acute decompensated heart failure 
(ADHF) beginning early during hospitalization and continuing for 12 weeks will improve physical 
function and key clinical outcomes, including the rate of rehospitalization. 
 
There will be 3 lead centers, Wake Forest Baptist Health, Duke University Medical Center, and 
Thomas Jefferson University and Hospital.  Each lead center may recruit up to 3 geographically-
close, tightly-affiliated 'satellite' sites under their direct management and budgetary control.  
Together, these sites will recruit a total of 360 consenting patients ≥ 60 years old hospitalized 
with ADHF.  Following informed consent and baseline testing, the participants will be 
randomized in a 1:1 fashion to receive a 12-week novel, progressive, multi-domain rehabilitation 
and exercise training intervention or attention control.  The multi-domain rehabilitation 
intervention will include endurance, mobility, strength, and balance training and will be tailored 
based on participant performance in each of these domains.  It will begin upon randomization 
during the hospitalization and will continue 3 times per week in an outpatient setting.  
Participants randomized to the attention control arm will receive all services ordered by their 
primary physician and will be contacted bi-weekly by study staff.  All participants will undergo 
measures of physical function and quality of life at baseline, 1 month, and 3 months.  Clinical 
events will be monitored for 6 months following the index hospitalization. 
 
By testing a novel rehabilitation intervention supported by multiple levels of evidence, this trial 
will address a critical evidence gap in the care of older patients with ADHF. The REHAB-HF 
results have the potential to shift paradigms by improving physical function and quality of life as 
well as clinical outcomes.  If successful, the results could have a major impact on the 
management of patients with ADHF, the most common Medicare discharge diagnosis. 
 
2.   
Study Objectives 
 
2.1 
Primary Objective 
To conduct a multicenter, randomized, attention-controlled, single-blind trial of a novel, tailored, 
progressive, multi-domain, 12-week physical function intervention in 360 older patients with 
ADHF in order to test the following primary specific hypothesis:  The REHAB-HF intervention 
will improve physical function, as measured by the short physical performance battery (SPPB). 
 
2.2 
Secondary Objective 
To systematically collect clinical outcomes data during the 6 months following the index 
hospitalization to test the following secondary hypothesis:  The REHAB-HF intervention will 
reduce the 6-month all-cause rehospitalization rate. 
 
2.3  
Other Objectives 
1. To assess the economic impact of the intervention by comparing medical costs between 
treatment arms, inclusive of the cost for rehabilitation therapy, relative to its associated changes 
in health outcomes. 
 
2. To estimate the proportion of the reduction in rehospitalizations explained by the 
intervention’s effect on the SPPB score.  
 
3. To examine the effect of the intervention on these exploratory endpoints: 

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1. Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) total score and 
physical component score at 3 months  
2. Change in 6-minute walk distance (6MWD) at 3 months 
 
3. Change in component scores of the SPPB at 3 months 
4. Change in the 12-item short form health survey (SF-12), depression, and cognition 
measures at 3 months 
 
5. Change in frailty status at 3 months 
 
6. All-cause rehospitalizations at 1 month and 3 months 
 
7. All-cause rehospitalizations 6 months from the date of randomization 
8. All-cause combined rehospitalization and death at 6 months 
9. Global rank endpoint of SPPB score + all-cause rehospitalization + death  
 
10. Heart failure (HF)-specific rehospitalizations 
 
11. Cardiovascular events  
 
12. All-cause rehospitalization days  
 
13. Total hospitalization days post-randomization 
 
14. Total facility-free days alive 
 
15. Deaths  
 
16. Falls  
 
17. Change in biomarkers at 3 months 
 
18. Blood-based bioenergetics profiling. 
 
3.   
Background 
ADHF is the leading cause of hospitalization in persons > 60 years in the United States.  
Hospitalized ADHF is associated with severely reduced health-related quality of life (QOL), 
persistently high rehospitalization rates,(1) markedly increased mortality, and costs over $39 
billion per year.(2)  Current HF management guidelines, even when perfectly adhered to, have 
had only modest impact on ADHF outcomes, particularly rehospitalizations in the older 
population.(1;3-5)  Furthermore, several recent trials of new interventions to improve ADHF 
outcomes, such as telemonitoring,(6;7) alternative diuretic regimens,(8-11) novel agents(11;12) 
and biomarker guidance have been negative.(9;13) This suggests outcomes in older ADHF 
patients may be driven partly by mechanisms that are not addressed by current approaches.    
 
Multiple lines of emerging evidence suggest that severely reduced physical function and frailty 
strongly contribute to adverse outcomes in older patients with hospitalized ADHF.(14)   We and 
others have shown that even when stable with compensated cardiovascular function, older 
patients with chronic HF have particularly severe impairments in physical function(14-16) due to 
the combined effects of aging, cardiovascular dysfunction, and impaired skeletal muscle 
function.(17-27)  As patients with chronic HF transition to ADHF, physical function worsens 
markedly both because of HF decompensation and accelerated physical 
deconditioning.(19;28;29) This is further exacerbated by the hospital processes, including forced 
bed rest which can markedly accelerate physical dysfunction.(30-36)  We and others have 
shown that after resolution of the acute HF symptoms and congestion, older ADHF patients 
continue to have marked impairments in physical function, including strength, balance, mobility 
and endurance, and that most patients meet formal definitions of frailty.(28;29;37-39)  
Furthermore, these deficits persist and some patients never recover baseline 
function.(14;33;40-43)  This occurs during the most vulnerable, high risk period for 
rehospitalization and adverse outcomes - up to 6 months post discharge.(44;45) We 
hypothesize that this physical frailty predisposes patients to adverse outcomes and that this 
cascade of events contributes to the persistently high rates of adverse outcomes, including 
rehospitalization, in older HF patients.(4;16;28;29;37;38;41;42;45-47)   
 

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The typical older ADHF patient has > 5 comorbidities(14;48;49) and these contribute to impaired 
physical function(50) and subsequent adverse outcomes.(4;14;28;47;49;51-56)  Impaired 
physical function and frequent non-cardiac comorbidities may explain the unexpected finding 
from multiple studies that > 50% of rehospitalizations in older ADHF patients are due to non-
cardiac events rather than recurrent ADHF.(4;14;40;48;49;57-59)   
 
In our published model,(14) we have identified 5 factors that contribute to severely impaired 
physical function and subsequent events in older ADHF patients: aging-related changes, the 
primary HF disease, deconditioning, multiple comorbidities, and iatrogenesis. Our data and 
others’ from studies in other medical conditions common in older patients support that targeted 
physical function interventions can improve impairments related to each of these factors.(21;60-
67)   
 
However, current ADHF management paradigms do not account for or address the marked 
physical dysfunction in hospitalized older patients with acute HF.(3;4;50) This may also explain 
why trials of a wide range of interventions in ADHF have been largely negative(6-8;11;12;12) 
and disease management programs have had, at most, modest impact on long-term outcomes 
and mortality.(6;37;68;69)   
 
Furthermore, the exercise training trials in HF to date (n >17) have systematically excluded 
ADHF patients in this key period of vulnerability.(70-73) The largest of these, the NIH-funded 
HF-ACTION trial, systematically excluded patients with ADHF and those within 6 weeks of 
hospital discharge.(73;74) Possibly because of recent instability, the study did not significantly 
reduce the primary endpoint of all-cause mortality or all-cause hospitalizations.(74)  HF-ACTION 
also enrolled relatively few older patients, excluded those with multiple comorbidities, and 
utilized a traditional cardiac rehabilitation exercise training intervention that would not have been 
appropriate for older patients with significant frailty.  As a result, and similar to prior trials, it likely 
missed the patients who are elderly, frail, and have multimorbidity who have the largest potential 
for improvements in outcomes.(3;3;4;75-77)   
 
Prior exercise training studies in HF have not addressed the domains of balance and strength 
which are important for preventing early injuries in frail, older hospitalized ADHF patients(78) 
and for enhancing gains in function.(79)  Prior intervention studies in older hospitalized patients 
that have included these domains have generally excluded patients with HF. (65;67;78-80)  
However, the results of such studies informed and support the primary hypothesis of the 
proposed study.(41;79-82)  For instance, Morris et al showed that an early mobility program 
improved outcomes in older hospitalized patients with acute respiratory failure.(82)  In a non-
randomized quasiexperimental study, Tinetti et al. recently showed that a restorative home care 
model that included physical function reduced rehospitalizations by one-third in older patients, 
some of whom had HF.(41) The primary hypothesis is also supported by our pilot study which 
showed that in older patients with ADHF, the proposed intervention can improve SPPB score, a 
strong predictor of hospitalization, disability, and death.(38)   
 
4.  
Overview of Investigational Plan 
The REHAB-HF study is a multicenter, randomized, attention-controlled, single-blind trial of a 
novel, progressive, multi-domain rehabilitation intervention versus attention control in 360 older 
patients hospitalized with ADHF.  The primary hypothesis is that the REHAB-HF intervention will 
improve physical function, as measured by the SPPB, the primary outcome. 
 
Patients will be screened and enrolled during the index HF hospitalization.  After completion of 
the baseline testing, participants will be randomly assigned to a novel, progressive, multi-

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domain, 12-week physical function intervention or to attention control.  Participants randomized 
to the intervention arm will begin a tailored, novel, multi-domain rehabilitation intervention in the 
hospital which will progress to the outpatient setting.  The intervention will focus on four key 
physical functional domains: endurance, mobility, strength, and balance; and will be tailored 
based on participant performance in each of these domains.  Participants randomized to the 
attention control arm will receive all services ordered by their primary physician and will be 
contacted bi-weekly by study staff.  Blinded assessments will be repeated 1 month and 3 
months following the index hospital discharge.  Data on clinical events and resource use will be 
collected for 6 months following the index hospital discharge.  
 
5. 
Study Population 
The inclusion and exclusion criteria have been developed to include a broad range of older 
patients who are hospitalized with ADHF and expected to be discharged to home.  To enhance 
the applicability of the results, the criteria are designed to be inclusive of older patients with 
multiple comorbidities, heterogeneous functional performance, and both preserved (≥ 45%) and 
reduced ejection fraction.  Specifically, the study has the goal that patients with preserved 
ejection fraction will compromise at least 30% of the total study population.   
 
5.1 
Inclusion Criteria 
 
Age ≥ 60 years old 
 
In the hospital setting >24 hours for the management of ADHF, or diagnosed with ADHF 
after being hospitalized for another reason. ADHF will be confirmed by the study 
physician, and will be defined according to the Food and Drug Administration definition 
of hospitalized heart failure as a combination of symptoms, signs, and HF-specific 
medical treatments, and requires that all 4 of the following are met: 
 
1) At least one symptom of HF which has worsened from baseline: a. dyspnea at 
rest or with exertion; b. exertional fatigue; c. orthopnea; d. paroxysmal nocturnal 
dyspnea (PND) 
 
2) At least two of the following signs of HF: a. Pulmonary congestion or edema on 
exam (rales or crackles) or by chest xray; b. Elevated jugular venous pressure or 
central venous pressure ≥ 10 mm Hg; c. peripheral edema; d. wedge or left 
ventricular end diastolic pressure ≥15 mmHg; e. rapid weight gain (≥ 5 lbs.); f. 
Increased b-type natriuretic peptide (BNP) (≥100 pg/ml) or N-terminal prohormone 
BNP (≥220pg/ml) 
 
3) Change in medical treatment specifically targeting HF defined as change in dose 
or initiation of or augmentation of at least one of the following therapies: a. diuretics; 
b. vasodilators; c. inotropes (including digoxin if for HF); d. other neurohormonal 
modulating agents, including angiotensin converting enzyme inhibitors, angiotensin II 
receptor blockers, beta-blockers, aldosterone or direct renin inhibitors 
 
4) The primary cause of symptoms and signs is judged by the investigator to be due 
to HF 
 
 
Adequate clinical stability has been achieved in the judgment of the investigator to allow 
participation in study assessments and the intervention  
 
Prior to admission and HF decompensation, patient was independent with basic 
activities of daily living (ADLs) including the ability to ambulate independently (with or 
without the use of an assistive device) 

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 
Able to walk 4 meters (with or without the use of an assistive device) at the time of 
enrollment 
 
Signed informed consent document indicating that the patient understands the purpose 
of and procedures required for the study and is willing to participate in the study 
 
5.2 
Exclusion criteria 
 
Acute myocardial infarction (Note: given that cardiac biomarkers such as troponin are 
frequently elevated in HF patients, the diagnosis of acute myocardial infarction should be 
based on clinical diagnosis, not biomarkers alone) 
 
Planned discharge other than to home or a facility where the participant will live 
independently 
 
Already actively participating in formal, facility-based cardiac rehabilitation 
 
Prior cardiac transplantation or planned within the next 6 months 
 
Severe aortic valve stenosis 
 
Ventricular assist device or anticipated within the next 6 months 
 
Already engaging in regular moderate to vigorous exercise conditioning defined as  > 30 
minutes per day, ≥ twice per week consistently during the previous 6 weeks 
 
Terminal illness other than HF with life expectancy < 1 year 
 
Impairment from stroke, injury or other medical disorder that precludes participation in 
the intervention 
 
Dementia that precludes ability to participate in rehabilitation and follow study protocols 
 
Enrollment in a clinical trial not approved for co-enrollment 
 
Expected use of continuous intravenous inotropic therapy after discharge 
 
Implantable cardioverter defibrillator with heart rate limits < expected heart rates for 
exercise and unable to be reprogrammed 
 
Advanced chronic kidney disease defined as estimated glomerular filtration rate < 20 
mL/min/1.73 m2 based upon the Modification of Diet in Renal Disease study equation, 
current ultrafiltration, or on chronic or intermittent dialysis or dialysis anticipated within 
the next 6 months 
 
High risk for non-adherence as determined by screening evaluation 
 
Inability or unwillingness to comply with the study requirements 
 
Anticipated hospital discharge before baseline study measures could be completed 
 
6. 
Participant Enrollment 
 
6.1 
Screening 
Screening for enrollment will be initiated as early as possible during the patient’s hospitalization 
for ADHF.  Patients who are eligible and agree to participate in REHAB-HF will give written, 
informed consent. 
 
Following informed consent, screening will continue with a brief assessment of walking 
capability as well as a brief adherence screening tool and behavioral agreement designed to 
identify participants at high risk of failing to adhere to the study intervention. Participants who 
are able to ambulate 4 meters independently, are not at high risk for failing to adhere to the 
intervention, and meet all other inclusion criteria will be enrolled.  A record of participants who 
provided informed consent but were not subsequently enrolled and the specific exclusion 
reasons will be maintained by the study.  In addition, a record of patients screened, but not 
consented, will be maintained by the study.   
 
6.2 
Baseline Testing 

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Baseline testing of physical function, measures of health status and QOL, and collection of 
blood samples will be completed as soon as possible after consent (see sections 9 and 10 for 
details).   
 
6.3 
Randomization  
Once a participant has been identified who satisfies all enrollment criteria, informed consent has 
been obtained, and baseline testing is complete, the participant will be randomized to a multi-
domain rehabilitation intervention group or to an attention control group.  Block randomization 
will be performed, stratified on clinical center and ejection fraction (<45, ≥45), and will be 
performed by a centralized, web-based system developed and maintained by Dr. Timothy 
Morgan.  
 
7.  
Investigational Intervention  
 
7.1 
Attention Control 
Participants randomized to the attention control arm will be notified immediately, and will follow 
standard care as ordered by their individual, treating physician.  Importantly, to reduce the 
potential for bias from greater attention and surveillance in the rehabilitation intervention group, 
participants in the attention control group will receive at least bi-weekly contact from study 
personnel during the first 3 months following the index hospitalization.  This contact will be 
provided as a combination of telephone calls and specified study visits.  Specifically, contact will 
be made with study visits at weeks 4 and 12 and with telephone calls at weeks 2, 6, 8, and 10.  
Further, in-person contact will be made within the first 2 weeks following discharge for the 
purposes of retention (section 8.2.2). Consistent with the rehabilitation intervention group, 
telephone contact will also be made at weeks 14, 16, 20, and 24. Information regarding 
symptoms, HF transitional management program use, medical compliance, activity level, 
rehabilitation received, medical resource utilization, and clinical events will be collected at each 
of these encounters. 
 
Participants in the attention control arm will not receive any specific rehabilitation 
recommendations or exercise prescription from study personnel.  They may, however, receive 
any physical or occupational therapy deemed appropriate by their usual clinical care providers, 
both during the hospitalization and as outpatients.   
 
7.2 
Rehabilitation Intervention Group 
 
7.2.1 REHAB-HF Rehabilitation Intervention Overview 
The multi-domain rehabilitation intervention for this study is a novel integration of rehabilitation 
therapies developed specifically for older heart failure patients who have been hospitalized for 
ADHF; a population characterized by heterogeneity in mobility status, multiple co-morbid 
conditions, and high rates of frailty.(48;50;83-85)  The goal of the intervention is to increase 
endurance, mobility, strength, and balance utilizing reproducible targeted exercises 
administered by a multi-disciplinary team with specific milestones for progression.   
 
This is a transitional intervention which begins during the acute hospitalization and continues for 
12 weeks after discharge in the outpatient setting.  The intervention will be administered once 
daily in the hospital and 3 days per week in the outpatient setting.  Each session will include 3 
stages: 1) warm-up (seated core exercises, 2-3 minutes light walking if able, and stretching 
exercises), 2) rehabilitation/training, and 3) cool-down (stretching exercises).  The 
rehabilitation/training portion of each session will include exercises tailored based on participant 
performance in each of 4 domains: endurance, mobility, strength, and balance. 

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7.2.2 Initiation of the Rehabilitation Intervention 
Participants randomized to the multi-domain rehabilitation intervention will begin the intervention 
in the hospital as soon as possible after randomization.  Though not required for enrollment, 
when possible the intervention will begin in the hospital.  Plans for the initiation / continuation of 
the intervention in the outpatient setting will be made prior to hospital discharge and will be 
scheduled to begin within the first week following discharge.   
 
7.2.3 Initial Exercise Prescription 
The initial rehabilitation exercise prescription will be individualized for each participant based 
upon functional performance level (1-4, from lowest to highest) in each domain using the 
objective criteria shown in Table 1.  Performance level will be assessed in the first rehabilitation 
session in both the inpatient and outpatient setting. Using a standardized approach, exercises 
specifically targeted to the participant’s functional level in each domain will be selected from the 
rehabilitation intervention protocols.  We anticipate a range of initial performance levels based 
on the REHAB-HF pilot study where 40% of participants were initially at level 1 for most 
domains, 33% were at level 2, and 27% were at level 3. 
 
Table 1.  Performance Levels for Strength, Balance, Mobility and Endurance 
 
Level 1 
Level 2 
Level 3 
Level 4 
Strength:  Rise from chair 
without hand support 
unable 
at least once 
5 times in > 15 
but <60 sec. 
5 times in ≤ 15 
sec. 
Balance: Standing 
unable with feet 
together for 10 sec. 
with feet together for 
10 sec. 
unsupported and 
reach forward 10 in. 
on 1 leg for 10 
sec. 
Endurance: Continuous 
walking 
< 2 minutes 
≥ 2 but < 10 minutes 
≥ 10 but 
< 20 minutes 
≥ 20 minutes 
Mobility: Gait speed 
≤ 0.4 m/sec. 
> 0.4 but ≤ 0.6 m/sec 
> 0.6 but ≤ 0.8 
m/sec. 
> 0.8 m/sec. 
 
7.2.4 Exercise Duration 
During the hospitalization, each rehabilitation session will last for approximately 45 minutes and 
will include warm-up (~5 minutes), cool-down (~5 minutes), and rest periods as needed.  The 
outpatient rehabilitation sessions will last for approximately 60 minutes (range 45 - 75 minutes), 
including 5 to 10 minutes each for warm-up and cool-down periods.  The relative time spent on 
each domain during the rehabilitation session will be tailored to the participant’s physical 
function impairments. Specifically, a participant with poor balance and functional mobility will 
spend a greater proportion of time performing balance and mobility exercises in the early 
portions of the intervention.  As balance and functional mobility improve, these will comprise a 
smaller portion of the session and time spent on endurance will be increased.  Alternatively, a 
participant with only modest impairments in balance and functional mobility at baseline will 
spend most of the exercise session performing endurance and strengthening exercises, even 
early in the intervention. 
 
7.2.5 Exercise Intensity 
Exercise intensity will be based upon patient-reported rate of perceived exertion (RPE) using a 
6-20 point scale.  While hospitalized and initially following discharge, target intensity will be low 
(RPE ≤ 12).  In the outpatient setting, target intensity will gradually increase over the first 2 
weeks of the intervention.  For strengthening rehabilitation, the target RPE will progress to 15-
16, as this level of intensity may be necessary to obtain significant functional improvement in 
strength, as previously shown.(67)  For the endurance exercises, the target RPE will progress to 
13 (“somewhat hard”) with a range of 11-15.  After 4 weeks of the endurance intervention, 
intensity within the RPE range will be adjusted to ensure a heart rate response of ≥ 20 beats per 

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minute above the resting heart rate, as exercise increase is needed to achieve > 60% of 
exercise reserve capacity.(86)  Using both RPE and heart rate will ensure an adequate training 
effect and minimize non-responders while maintaining safety(74;87;88)   
 
7.2.6 Exercise Progression 
A key aspect of the REHAB-HF intervention is its structured, gradual progression using specific 
small increments in each exercise.  As discussed in section 7.2.3, initial performance level 
(Table 1) will be assessed at the first inpatient and outpatient session.  Using a standardized 
approach, initial exercises specifically targeted to the participant’s functional level in each 
domain will be selected from the rehabilitation intervention protocols below.  Participants will 
then be continually challenged to safely and effectively improve physical function by advancing 
through the specified progression for each exercise based on their individual performance.  
Further, the performance level in each domain will be reassessed bi-weekly in the outpatient 
setting to re-evaluate functional abilities (i.e. to ensure no under-treatment) and to evaluate 
progression.  Exercise prescription within each domain will be adjusted accordingly.  
Importantly, as function improves, the duration of endurance-based exercise will be increased 
as tolerated by the participant.  Progression will be monitored by the intervention team under the 
direction of the site intervention supervisor and in consultation with Dr. Duncan, overall study 
intervention leader.   
 
7.2.7 Modality of Exercise 
The REHAB-HF intervention incorporates 4 exercise domains into each session: endurance, 
mobility, strength, and balance.  A brief description of the types and range of exercises in each 
of these domains is included below.  Generally, exercises range from those adapted to the 
lowest level of functioning (level 1) to the highest (level 4). A detailed description of each 
exercise and how it is to be progressed is contained in the manual of operations.    
 
7.2.7.1 Endurance Training 
For the most debilitated participants (level 1), endurance training will begin with repeated bouts 
of ambulation at usual speed with rest breaks as needed, with an initial goal of 5-10 minutes 
total duration.  The endurance training will progress to sustained walking at the target RPE for 
up to 40 minutes for the highest-functioning participants (level 4).  Walking is the preferred 
mode of endurance exercise, however, endurance exercises utilizing other equipment while still 
involving major muscle groups of the lower extremities (e.g. exercise bicycle) may be 
incorporated into the endurance training to supplement walking. 
 
7.2.7.2 Mobility Rehabilitation 
One of the primary goals of the rehabilitation intervention is to improve functional mobility, 
particularly in participants with slower gait speeds (<0.8 meter/second) and impaired dynamic 
balance.  Accomplishing this will involve rehabilitation exercises that combine balance activities 
with mobility.  Such exercises will include dynamic start and stop and changing direction while 
walking.  In addition, participants with a slow gait speed will undergo exercises involving brief 
episodes of accelerated gait.  Close supervision and guarding will be provided to prevent 
injuries and falls.   
 
7.2.7.3 Strengthening Rehabilitation 
The intervention focuses on functional strengthening exercises of the lower extremities that may 
be supplemented by general resistance exercises for major muscle groups of the upper and 
lower extremities. Functional strengthening exercises include: sit-to-stand from chair (or bed in 
the hospital setting), step-ups (front and side), calf raises, and squats.  For the most impaired 
participants (level 1), this will begin with guarded stands, assisted step-ups on a 4-inch step, 

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seated toe raises, and 0-15 degree squats with support.  These exercises will progress to (level 
4) rapidly repeated stands with platform in front of chair, unassisted step-ups on an 8-10 inch 
step, standing toe raises on one leg, and 45-90 degree squats without support. For general 
strengthening exercises, the most impaired participants (level 1) will begin with assistive or 
lightly resistive exercises.  The interventionists will match the participant’s ability to exercise 
major muscle groups of the upper and lower extremities.  As participants progress, 
strengthening exercises of the major muscle groups of the upper and lower extremities using 
resistance bands or free weights will be incorporated.  The amount of resistance will be 
progress so that the participant can perform 1 set of 10 repetitions at the target rate of RPE. 
 
7.2.7.4 Balance Rehabilitation 
Balance rehabilitation will include both static and dynamic exercises.  For the most unsteady 
participants (level 1), balance rehabilitation will begin with holding a shoulder-width stance for 
static balance and standing and reaching forward and backward 6 inches for dynamic balance.  
For static balance, these exercises will progress to holding an increasingly narrow base of 
support (feet together to semi-tandem stance to tandem stance to single leg stance) with eyes 
open and progressing to eyes closed.  Close supervision, including the use of a gait belt as 
needed, will be provided by the study personnel to prevent injuries and falls.  For dynamic 
balance, participants will be challenged to reach further beyond their base of support during 
seated progressing to standing activities.  Dynamic balance will also be integrated within 
functional strengthening exercises (e.g. step and reach).  Close supervision, including the use of 
a gait belt as needed, will be provided by the study personnel to prevent injuries and falls.  As 
patients progress to level 3 and 4, dynamic balance activities will be incorporated into 
endurance episodes, such as supervised walking and turning, walking and abrupt stops, walking 
and talking, and walking and side stepping.   
 
7.2.8 Exercise Safety  
During each exercise session, participants will sign an attendance sheet and log any health-
related problems or symptoms they are experiencing.  These sheets will be reviewed by 
intervention staff before initiating physical activity.  Should a participant report a significant 
change in health status (see safety parameters below) before or during exercise, a study 
physician onsite or the participant’s primary doctor should be consulted prior to exercise 
participation.  Vital signs, including heart rate, blood pressure and pulse oximetery will be 
recorded at the beginning and conclusion of each session.  Routine assessment of heart rate 
during the exercise session will also be used to enhance exercise safety.  Exercising blood 
pressure and pulse oximetery will be monitored on a symptom-driven basis as needed during 
the trial to ensure participant safety.   
 
For participants who meet any of the safety parameters listed below, the following steps and 
additional monitoring procedures will be conducted:  
 
Exercise training sessions will be stopped 
 
The participant will subsequently be re-evaluated for medical contraindications to 
exercise  
 
Exercise intensity levels will be re-assessed and modified as needed   
 
Safety Parameters 
 
Resting blood pressure systolic > 200 mm Hg or diastolic > 100 mm Hg 
 
Resting blood pressure systolic < 80 mm Hg 
 
Resting blood pressure systolic between 80 and 89 mm Hg with associated or 
uncertain symptoms of lightheadedness or dizziness 

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14 
 
Resting heart rate >120 beats/min or < 40 beats/min 
 
Increase in heart rate 90% of age predicted maximum during exercise 
 
Oxygen saturation < 90% on room air 
 
Unusual or severe shortness of breath 
 
Chest pain including chest discomfort or pressure, left arm pain, report of indigestion 
or stomach discomfort 
 
Palpitations 
 
Severe light headedness, dizziness or feeling about to faint 
 
A physical activity session had to be discontinued because of other symptoms 
excluding musculoskeletal symptoms (e.g. knees, ankles, hips) reported by the 
participant 
 
Decrease in diastolic blood pressure 20 mmHg during exercise 
 
Increase in systolic blood pressure to 250 mmHg or in diastolic blood pressure to 
115 mmHg during exercise 
 
Decrease in oxygen saturation to <88% on room air during exercise 
 
An automated external defibrillator (AED) will be available at the facility.  On-site staff, including 
a study interventionist, trained in basic life support, will be available to deal with medical 
emergencies.  Also, institutional and community emergency medical services will be activated if 
needed. 
 
7.2.9 Home Visit and Home Exercise Prescription 
All participants randomized to the study intervention will receive one home evaluation within one 
week following hospital discharge (preferred within 3 days).  The home visit will be utilized to:  
 
Establish patient identified goals 
 
Prescribe a customized the home exercise program based on patient goals and 
identified deficits 
 
Identify areas for safe performance of walking and functional strengthening exercises 
 
Engage the participant’s caregiver/partner to support home exercise 
 
Identify resources in the home and community (i.e. technology, exercise facilities) to 
promote adherence to home exercise and goal achievement 
 
Review use of pedometer to track progress towards goals and promote adherence  
 
Participants will be instructed in low-intensity walking at their usual pace on non-program days, 
gradually increasing toward a goal of 30 minutes daily. The functional strengthening exercises 
(sit-to-stand from chair, step-ups, if feasible, and calf raises) will be incorporated as well.  
Participants will be encouraged to wear a pedometer to both motivate and track adherence to 
the home exercise (see section 7.4). 
 
7.2.10 Allowance of Supervised Home-Based Exercise 
The preferred location of the outpatient intervention is facility-based.   However, some patients 
in the REHAB-HF target population may not be able to immediately begin the intervention in an 
outpatient facility, particularly in the first 2 weeks following hospital discharge.  At the discretion 
of the investigator, home-based training by appropriately trained personnel following the same 
intervention as described above (simply different location) is included as an option in the study 
protocol early after hospital discharge.  The investigator must have high confidence that the 
participant will be able to progress and is willing and able to transition to facility-based training.  
If a participant requires the home-based intervention, the focus will be to improve functional 
performance and to remove any barriers so that participants can subsequently transition to 
facility-based rehabilitation and exercise training.   

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15 
 
7.2.11 Maintenance Phase 
Following the completion of the outpatient intervention, participants in the intervention arm will 
be encouraged to continue with exercise training as part of a maintenance phase.  Preparations 
for the maintenance phase will begin after randomization and continue throughout the 
supervised exercise portion of the intervention.  These preparations may include  
 
Evaluation of home environment for safe and feasible participation in home exercises 
as described below (home visit section 7.2.9) 
 
Ongoing encouragement to participate in the home walking exercise as described 
above (home exercise prescription section 7.2.9) 
 
Identifying and addressing potential barriers to participation in exercise training after 
the supervised portion of the protocol is complete 
 
Discussing the importance of continued regular exercise after the supervised 
intervention is complete 
 
Identifying community resources available to the participant for ongoing physical 
activity and exercise training  
 
Engagement of spouse or caregiver, when applicable, for ongoing support of 
continued exercise training 
 
Towards the conclusion of the outpatient intervention, an individualized exercise prescription will 
be developed by the interventionist and approved by a study physician.  This exercise 
prescription will be given to the participant at the 3-month visit.  All participants will receive 
regularly scheduled phone calls (one at months 4, 5, and 6) to assess clinical status as 
described below (follow up schedule section 9.1).  For participants in the intervention arm, these 
phone calls will also be used to discuss the maintenance phase exercise prescription.   
 
7.2.12 Management of Conflicts with Physician-Ordered Care 
All participants will receive standard care as ordered by their personal, treating physician. 
Efforts will be made to integrate the REHAB-HF intervention into the standard of care ordered 
by the treating provider. In the event of conflict between standard care and the REHAB-HF 
intervention assignment, the study protocol will yield to individual, physician-ordered standard 
care.   
 
7.3  Intercurrent Illness and Interruption to Study Intervention 
Interruptions to the study intervention, including illness and hospitalization, are anticipated.  
Although this is an intention-to-treat protocol, to help ensure each participant has a reasonable 
opportunity to complete the study intervention (defined as completing at least 30 outpatient 
sessions) and that the physical performance outcome measures reflect the intended 
intervention of this study, limited extensions of the study intervention are included in the study 
protocol.  Participants who suffer an illness, hospitalization or other complications that interferes 
with participating in the study intervention will resume the intervention once medically stable.  
Participants will have up to 4 additional weeks beyond the initially planned 12 weeks to attempt 
to complete the multi-domain intervention.   
  
In addition, if a participant is acutely ill or hospitalized within 2 weeks of the anticipated date of 
the final 3-month visit, the visit will be delayed for up to 2 weeks to allow for up to 6 additional 
rehabilitation and exercise sessions.  Similarly, the final 3-month visit for those in the attention 
control arm will also be delayed for up to 2 weeks in the event of acute illness or hospitalization 
within 2 weeks of the date of the visit.     
 

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16 
7.4 Monitoring of Exercise and Rehabilitation 
The details regarding the number of rehabilitation sessions attended as well as key markers of 
adherence to the exercise prescription and progression will be recorded and entered into the 
secure database by the study personnel supervising the rehabilitation and exercise training.  In 
addition, participants in both the study intervention arm and the attention control arm will keep a 
diary of any exercise performed or any usual care rehabilitation received.   
 
Participants in the rehabilitation intervention arm will be issued a pedometer to promote 
adherence to home exercise and activity goals.   
 
Participant adherence with both exercise diary entries and wearing of a pedometer will be 
encouraged throughout the study during follow-up visits and phone calls. 
 
8. Retention and Treatment Fidelity 
 
8.1 Overview 
In order for the REHAB-HF study to be successful, we will implement proactive procedures to 
insure that we (1) retain participants in accord with the intent-to-treat principle, (2) deliver the 
REHAB-HF intervention safely and effectively as outlined in the protocol, and (3) maximize 
adherence to intervention.   
 
8.2 Retention 
 
8.2.1 Adherence Screening and Behavioral Agreement 
Retaining participants in the study will begin prior to enrollment.  Following informed consent, a 
brief adherence screening tool and behavioral agreement will be completed.  The adherence 
screening tool explains the basic commitments of the rehabilitation intervention and asks the 
participant to rate the degree of: 1) conflicts from other commitments/personal issues interfering 
with the intervention, 2) difficulty in obtaining transportation, 3) how they think their primary 
physician would feel about the study intervention, and 4) their confidence in being able to carry 
out the intervention.  The behavioral agreement is a document to be signed by the participant 
detailing the requirements of REHAB-HF and indicating the participant’s willingness to complete 
the requirements of either treatment arm of the intervention once randomized.   
 
This process will not only allow us to identify adherence risks, but along with informed consent, 
it will also be used as a mechanism to give participants an in-depth understanding of REHAB-
HF and enable us to collect information to assist in the tailoring of treatment. 
 
The study team at each site will carefully discuss the information gleaned from these 
assessments to make a final determination on behavioral suitability for REHAB-HF. 
 
8.2.2 Retention Promotion Efforts 
To promote retention, the following steps will be followed: 1) provision of a clear schedule of all 
visits, reminders, same-day phone calls for any missed visits, involvement of family and 
caregivers, and sharing of test results and intervention progress, if applicable; 2) free parking for 
study visits and intervention sessions; 3) transportation to study visits and intervention sessions 
as needed for participants of low socioeconomic status; and 4) required in-person contact within 
the first 2 weeks following discharge, achieved through intervention sessions, home visit, or 
meeting at a usual care clinic visit or if necessary, a scheduled clinic visit.  
 
8.2.3 Retention for Study Visits  

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17 
Algorithms are developed to address non-attendance to study visits. These involve procedures 
(discussed below) that facilitate documentation of these events and how best to rectify the 
problem. The following procedures will be implemented (as appropriate in each site) to carefully 
document and monitor missed study visits: 
 
Preparing for the next visit at the end of each current visit by making the 
appointment and giving instructions for the next visit 
 
Rescheduling the visit within the same window, if possible. Examinations that fall 
outside of the target window remain important and are used in all analyses. These 
examinations are assigned to whichever target visit would be the closest in time. If it 
becomes clear that a visit corresponding to a particular set of forms (e.g. a 3-month 
visit) is not completed, a Missed Visit form is filled out 
 
The following guidelines are implemented to promote adherence to study visits: 
 
Fostering personal relationships between participants and individual members of the 
staff  
 
Insuring that the clinic environment is warm and pleasant, and oriented to the 
comfort of the patient 
 
Using easily accessible clinic locations, providing transportation when necessary, 
and convenient clinic hours all serve to facilitate study adherence 
 
Keeping total clinic visit time to a minimum. If waiting is necessary, the situation is 
explained to the participant and, if possible, an offer is made for the participant to see 
another staff member, or to reschedule the visit 
 
Appointment reminders are used to prompt participants to attend clinic visits  
 
8.2.4 Monitoring Recruitment and Retention  
The study investigators, including Dr. Jack Rejeski, consultant for retention and adherence, will 
routinely monitor screening and recruitment yields, and compare these to preset gender and 
ethnic minority benchmarks for each site. If sites encounter difficulties with recruitment or 
retention, the investigators will partner with the site in question to establish specific steps to 
assist in resolving the problem encountered.  
 
8.2.5 Retention and Efforts to Maintain Contact with Inactive Participants  
Retention is promoted by:  
 
Examining and attempting to remove barriers (e.g., by addressing parking and other 
transportation issues, adjusting clinic hours). 
 
Incorporating a variety of methods to promote contact with all participants and 
provide social support for all participants. 
 
Ensuring that participants' concerns are identified and addressed before they 
express a desire to reduce their involvement in the study. 
 
REHAB-HF has the goal of maintaining some form of contact (e.g., phone, e-mail) with 
participants who are unable to continue full engagement in the study and to foster some form of 
continued involvement (e.g., even an agreement to allow future contact) with participants who 
are inactive in the study. Priority is given to attending assessment visits. 
 
8.3 Treatment Fidelity: Delivering the Physical Activity Intervention as Detailed in the 
Protocol  
Critical to the success of REHAB-HF is insuring fidelity of the intervention.  There are 3 steps 
taken to address this facet of study conduct.  
 

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1. Prior to study launch, all intervention personnel will participate in on-site training sessions.  
Training materials will include videos, handouts, and case presentations, as well as hands-on 
demonstrations for each site.  The training will be led by Dr. Pamela Duncan, overall trial 
intervention leader, who will review, critique, and provide feedback to the interventionists. 
 
2. The intervention will be carried out in a standardized manner across treatment sites.  To 
facilitate this, the intervention protocol contains a standardized protocol for guiding exercise 
prescription (section 7.3.2) and exercise progression (section 7.3.5), the two most critical pieces 
to ensure consistent implementation.   
 
3. An intervention committee will regularly review intervention adherence, progression, and 
fidelity.  This committee will comprise of Dr. Duncan and the intervention supervisors from each 
site along with Dr. Rejeski, as needed.  This committee will regularly review real-time reports 
generated from the study database to track attendance and progression on key measures in 
each domain (such as walking distance, sit-to-stand level achieved).  Bi-weekly 
teleconferences, including the interventionists, will be used to discuss the progress of individual 
participants, the performance of interventionists and sites, and to troubleshoot any potential 
barriers to attendance or progression that may arise.   
 
9. Study Participant Follow-up  
 
9.1 Follow up schedule 
 
All baseline measures (see Table 2) will be collected during the index hospitalization.  Follow up 
visits will occur 4 weeks ± 3 days and 12 weeks ± 10 days (unless intervention is extended, see 
section 7.3) from the day of discharge from the index hospitalization.  These visits will include a 
brief history and physical and collection of study measures (see Table 2).  Historical information 
will include heart failure symptoms, NYHA class, current medications, the results of any 
intervening cardiac studies (echocardiogram, stress tests, etc.), and the occurrence of any 
clinical events.  The focused physical examination will include evaluation of the lungs, heart, 
and periphery.  During these visits, the participants will also complete health status and quality 
of life measures as well as follow-up measures of physical function as detailed in Table 2 below.  
To promote retention, all participants will receive in-person contact within the first 2 weeks 
following discharge, achieved through intervention sessions, home visit, usual care clinic visit, or 
a scheduled clinic visit. In addition to the follow up visits, participants will receive a scheduled 
phone call at the end of months 2, 4, 5, and 6 to evaluate clinical status and for follow-up on 
adherence to the maintenance phase.  Additional telephone contact will be made with the 
attention control group participants (see section 7.1). Telephone contact will also be maintained 
with participants unable or unwilling to attend the clinic visits.  In some instances, participants 
unable to attend these visits may receive a home visit to collect important end points.   
 
Table 2: Collection of Outcome Measures    
 
Index 
Hospitalization 
(Baseline) 
1 Month 
(Visit) 
2 Months 
(phone 
call) 
3 Months 
(Visit) 
4, 5, & 6 
Months 
(phone call) 
6MWT 
X 
X 
 
X 
 
SPPB 
X 
X 
 
X 
 
Grip  
X 
X 
 
X 
 
Biomarkers 
X 
 
 
X 
 
Bioenergetic 
Profiling 
X 
 
 
X 
 

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KCCQ 
X 
X 
 
X 
 
SF-12 
X 
X 
 
X 
 
EQ-5D-5L 
X 
X 
 
X 
X (6M only) 
GDS-15 
X 
 
 
X 
 
LOT 
X 
 
 
X 
 
MoCA 
X 
 
 
X 
 
Clinical 
Events 
X 
X 
X 
X 
X 
Medications 
Review 
X 
X 
X 
X 
X 
Medical 
Resource 
Use 
 
X 
X 
X 
X 
 
9.2 
Blinding 
The study will use a single-blind design where the study personnel assessing outcomes will be 
blinded to the study arm to which participants are assigned.  To enhance continued blinding of 
assessors, participants will be asked not to disclose their assigned group during the assessment 
sessions. 
 
10  
Outcomes 
 
10.1  Measures of Physical Performance 
The primary efficacy outcome for this study will be the SPPB.  The 6MWD, gait speed, and 
handgrip strength are other important measure of physical function that will be assessed.   
 
10.1.1  SPPB 
The SPPB was chosen as the primary outcome because: 1) physical function is an 
independently important outcome in older persons; 2) the SPPB is a well-accepted, reliable, 
validated measure of physical function in the older population,(89) and is safe and feasible in 
clinic, home, and hospital settings,(90) including hospitalized older ADHF patients HF;(28;29;37)  
3) the  SPPB score is highly predictive of important clinical outcomes, including disability, 
hospitalization, nursing home admission, and death;(89;91-94) 4) it is sensitive to change in 
health status(95) and responsive to exercise training;(65;67;96;97)  5) interventions that 
improve SPPB also improve clinical events, providing independent confirmation of 
validity;(98;99) 6) the SPPB is a key outcome in LIFE, the largest NIA-funded physical function 
intervention trial; 7) in our pilot study, the improvement in SPPB explained 90% of the 
improvement in rehospitalizations, providing a mechanistic link; and 8) the SPPB is 
standardized, simple, and relatively brief (<10 minutes). The SPPB measures physical function 
using 3 components: usual gait speed over 4 meters, time to complete 5 chair rises, and 
standing balance with progressively narrow base of support.  Each component is scored on a 0-
4 scale and summed for an overall score range of 0-12.  Each component of the SPPB is 
independently associated with important outcomes including mortality.(100;100)  Gait speed is 
associated with survival at increments of 0.1 m/s in community-dwelling adults(101) and is 
associated with survival in hospitalized older adults with coronary disease.(102)   
 
10.1.2 6MWD 
The 6MWD test is a well-established outcome measure in HF.  It is valid and reproducible in 
patients with a wide range of physical function, predicts clinical events, and responds to 
interventions.(103-106) We showed that it is as predictive of clinical events as exercise oxygen 
consumption,(107) and improves with exercise training including in older HF patients.(74;108)  
Although most studies involved outpatients with stable HF, the 6MWD is safe, feasible and 

Protocol  Version4-2/6/2018 
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predictive of outcomes in an inpatient population(109) and was feasible, safe, and responsive to 
the intervention in the REHAB-HF pilot study.(28)  The 6MWD will be conducted in an 
unobstructed hallway, utilizing a standardized script as recommended and as previously 
reported.(106;107;110)  Total distance covered, the number of times and duration of rest, along 
with symptoms, will be recorded.   
 
10.1.3  Handgrip Strength 
Handgrip strength is a simple measure of upper extremity strength that correlates well with 
lower extremity strength and may serve as a marker of mobility.(111)  The measurement is 
obtained in only a few minutes using a handheld dynamometer.  Lower handgrip strength has 
been associated with increased risk of clinical outcomes including ADL disability (112) and 
mortality.(100)  Cut-off points of < 20 kg in women and < 30 kg in men have been 
recommended to help identify patients with sarcopenia, a geriatric syndrome characterized by 
progressive loss of muscle mass and strength (111;113) and has been used as an indicator of 
frailty.(114)  
 
10.2 
Health Status and Quality of Life Measures  
 
10.2.1  Kansas City Cardiomyopathy Questionnaire (KCCQ) 
To assess change in health status and health-related QOL, participants will complete the 
KCCQ, a 23-item self-administered questionnaire that quantifies physical function, symptoms, 
social function, self-efficacy, and QOL in patients with HF. Scores range from 0-100; higher 
scores indicate better function.  The KCCQ score is an independent predictor of clinical 
outcomes such as hospitalization and mortality in outpatients with HF,(115;116) and those 
recently hospitalized for ADHF.(117)  It is a reliable and valid measure in HF patients, more 
sensitive to change than other measures of QOL.(118;119)  The KCCQ is also reliable, valid, 
and responsive in patients with comorbidities.(120)  A change in score of as little as 5 points is 
clinically significant and is associated with changes in clinical status(119) and physical function.  
A one standard deviation change in 6-minute walk distance correlates with a 5 point change in 
KCCQ.(121;122) A 5-point change in KCCQ is associated with all-cause mortality, 
cardiovascular death and hospitalization in patients with HF complicating acute myocardial 
infarction.(123)    
 
10.2.2 12-Item Short-Form Health Survey (SF-12) 
Given the high rates of comorbidities that frequently drive events in this population and which 
may be impacted by the study intervention, participants will also complete the 12-Item Short-
Form Health Survey (SF-12).  The SF-12, a quick (2 minute)(124) 12 item health survey is valid 
and reliable in older adults (125;126) and in HF.(127)   
 
10.2.3 EuroQol (EQ-5D-5L) 
This instrument assesses patient-specific health utilities used in cost-effectiveness analyses to 
capture QOL.(128) It performed well in HF-ACTION(129) and the PROTECT trial of ADHF.(130)  
It consists of five items that measure difficulty with 1) mobility; 2) self-care; 3) usual activities; 4) 
pain/discomfort; and 5) anxiety / depression and a self-rating (0-100) "thermometer" of the 
respondent’s overall health.  We will use the 5-level version which has improved sensitivity and 
reduced ceiling effect. It takes approximately 90 sec to complete.(131) When administering the 
EQ-5D-5L we will discern if participants require assistance with any essential ADLs as identified 
with responses of ‘severe problems’ or ‘unable to’ wash or dress (i.e. the self-care domain).     
 
 
 

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21 
10.3  Depression, Cognitive Status, and Optimism 
 
10.3.1 Geriatric Depression Scale – 15 (GDS-15) 
Depression is common in patients hospitalized with heart failure and is associated with worse 
clinical outcomes (132;133) and quality of life.(134;135) The Geriatric Depression Scale is a 
depression screening questionnaire developed specifically for the elderly.  The original version 
consists of 30 ‘yes/no’ questions.  A shorter, 15 item version that was subsequently developed 
(GDS-15) has also been shown to be a valid and reliable screening instrument for depression in 
an elderly population (136) with sensitivity and specificity similar to the longer 30-item 
GDS.(137) 
 
10.3.2  Montreal Cognitive Assessment (MoCA) 
Cognitive impairment is common in HF patients(138) particularly when recently 
hospitalized,(139) and is associated with worse clinical outcomes, decreased independence 
with ADLs, and poorer functional mobility.(139;140)  The MoCA, a widely used, sensitive 
instrument for this purpose, will be used to identify participants with cognitive impairment and 
assess changes in cognitive status.(141) 
 
10.3.3 Life Orientation Test (LOT-R) 
Optimism is broadly defined as the tendency to believe that experiences will lead to good results 
rather than bad.  In other populations, optimism has been associated with decreased 
readmissions and total mortality. An objective measure of optimism, the revised Life Orientation 
Test (LOT-R), is easily administered in this population and will be used to determine its stability 
in patients with heart failure as well as the effect of physical conditioning.   
 
 
10.4 
Accelerometry 
An accelerometer (Actigraph GT3X or similar device) will be used to monitor physical activity, 
movement patterns, and sleep.  The device is worn on the wrist, is validated, and is well-
accepted (>80% compliance in NHANES).  The participant will wear the device from the time of 
enrollment through final 6-month follow-up.   
 
 
10.5 
 Biomarkers and Blood-based Bioenergetic Profiling 
To determine if the intervention alters the HF disease course, we selected two well-accepted 
biomarkers of HF disease severity and prognosis, NT-proBNP(142) and galectin-3;(142) both of 
which were responsive in HF-ACTION and ASCEND.  Tumor necrosis factor alpha, C-reactive 
protein, and interleukin-6 were selected because we found they were increased in older HF 
patients and correlated with their SPPB score(143) and are known to predict prognosis.  The 
latter two were also responsive to the physical function intervention in the LIFE study.(144)  
Twenty mL of venous blood will be drawn at the baseline visit and the 3-month follow-up visit, 
spun, and frozen at -20oC in 1 mL aliquots, stored locally at -80oC, and shipped in batches to 
Wake Forest Health on dry ice via overnight transport.  Samples will be analyzed later in paired 
fashion (baseline and follow-up) to minimize inter-batch variability and cost.   
 
Whole blood (16mL at the baseline and 3-month visit) will be drawn for bioenergetics profiling. 
PBMCs, monocytes, lymphocytes, and platelets will be separated from whole blood and 
assessed for basal respiration, maximal respiration, ATP-linked respiration, spare respiratory 
capacity, proton leak, and non-mitochondrial respiration. There may also be a blood draw for up 
to 2 rehospitalizations, if these occur during the study intervention, at the Wake Forest Clinical 
Site only. 
 

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22 
10.6 
Clinical Measures 
Clinical events will be collected prospectively from randomization until 6 months after discharge 
from the index hospitalization, the highest risk period for older ADHF patients,(44) by 
interviewing participants and family at each visit, phone calls, and medical records review. 
 
10.6.1  Rehospitalizations 
All-cause rehospitalization was chosen as the secondary outcome because: 1) it is the most 
frequent adverse outcome in ADHF; 2) it is associated with impaired physical function, reduced 
quality of life, increased mortality, and increased cost; and 3) our pilot data and others’ suggest 
that it is responsive to physical function interventions.  A rehospitalization will be defined as a 
hospital stay > 24 hours, including prolonged emergency department visits or observational unit 
stays, for any cause and categorized according to the recommendations of Horwitz et al.(145)  
Rehospitalizations will be categorized by the site investigators as primarily due to non-
cardiovascular, HF, or other cardiovascular (myocardial infarction, acute coronary syndrome 
without myocardial infarction, arrhythmia, peripheral vascular) cause, and whether they were 
related to the study intervention or assessments.   
 
10.6.2  Other Clinical Events 
The study will also capture deaths, emergency department visits < 24 hrs, stays at 
observational units < 24 hrs, unscheduled, urgent medical visits, nursing home placement, 
myocardial infarction, stroke, serious arrhythmia, syncope, and falls.  A fall will be defined as 
‘‘an unexpected event in which the participants come to rest on the ground, floor, or lower level” 
as recommended by a recent consensus statement on defining falls as an outcome.(146) 
 
10.7  Frailty 
Frailty has been described as a geriatric syndrome characterized by decreased physiologic 
reserve due to impairment in multiple interrelated systems that results in increased vulnerability 
to stressors and increased risk for adverse events (147;148).  Fried et al developed an 
operationalized definition of frailty(114)’(149) based on five characteristics:  unintentional weight 
loss; self-reported exhaustion; weakness; slow walking speed; and low physical activity.(150) 
This now widely adopted frailty phenotype is associated with multiple adverse events, disability 
and death(114;149) and in HF patients is strongly associated with increased risk of 
hospitalization.(151)  It is dynamic(152) and responds favorably to interventions.(97)  For this 
study, frailty status will be based on modification of the Fried assessment described by 
McNallan et al(153) for older HF patients using: a) slowness (gait speed by SPPB); b) low 
physical activity (physical component of SF-12); c) weakness by handgrip strength 
(dynamometer); d) unexpected weight loss by self report or body mass index <18.5; e) 
exhaustion based on KCCQ questions 5,6.  Participants meeting > 3 of these criteria will be 
classified as frail; those meeting 1 or 2 as pre-frail; and those meeting none as non-frail. 
 
10.8 
Timing and Order of Outcome Measures 
All baseline assessments are to be collected prior to hospital discharge.  Ideally, all measures at 
all visits will be performed consecutively in 1 period with short-term (~2-5 minute) rest breaks as 
needed. However, at baseline, extended rest breaks or interruptions to outcomes testing will be 
allowed to accommodate usual care procedures, visitors, or unusual fatigue. 
 
The order of testing should be kept constant for each participant at each visit.  Measures of 
health status and quality of life should be collected prior to measures of physical performance.  
Within physical performance, the SPPB should be performed first.   
 
11. 
Economic Analysis 

Protocol  Version4-2/6/2018 
23 
 
11.1 
Direct Medical Costs 
The case report form will be used to collect patient-level information on all-cause medical 
resource use (hospitalizations, emergency department and urgent care visits,  major medical 
procedures, home and skilled nursing facility care, and outpatient visits) and personnel and 
capital resources required to provide the REHAB-HF intervention. Medical resource use data 
will be ascertained by patient self-report and caregiver interviews and supplemented by their 
medical records. Intervention-related information will be documented by study personnel 
throughout the study. Direct medical costs will be valued from the societal perspective.(154) 
Professional services and costs for skilled nursing, home nursing and outpatient visits will be 
valued using Medicare fee schedules.(155) Costs for emergency department visits and 
hospitalizations will be estimated using models developed from HF-ACTION based on hospital-
level variables (length of stay, reason for admission, major procedures).(156) Cost for the 
REHAB-HF study intervention will be estimated using our recently-developed TEAM-HF Costing 
Tool.(157)   
 
11.2 
Direct Non-Medical Costs 
At 3 months and 6 months, patients will be asked to report information on direct non-medical 
costs incurred to comply with the REHAB-HF intervention including costs associated with 
transportation and/or parking and fees for health club memberships, exercise equipment or 
other services or resources that patients have chosen to purchase to help them adhere to 
exercise training. 
 
11.3 
Indirect (Patient Time) Costs 
To estimate time spent on REHAB-HF intervention, we will use information reported within the 
trial pertaining to adherence to protocol-required rehabilitation sessions and patient-reported 
information on time spent on home exercise. We will also ask patients to report the total amount 
of time they spend getting to each rehabilitation session. Indirect costs associated with patient 
time will be valued using the average hourly wage in the USA.(158)   
 
11.4 
Short-term Cost Analysis 
We will compare mean direct medical costs, indirect (patient time) costs, total costs and quality-
adjusted survival over the six-month follow-up period in the REHAB-HF intervention patients 
versus attention control. We will generate utility weights from the EQ-5D-5L collected data.  
 
11.5 
Long-term Cost-Effectiveness Analysis 
We will also perform a cost-effectiveness analysis of the REHAB-HF intervention by combining 
estimated long-term costs and quality-adjusted survival with rehabilitation versus attention 
control.  We plan to use our TEAM-HF Cost-Effectiveness Model(157) developed with NIH 
funding (R01 NR011873) to generate long-term estimates of costs, survival and quality-adjusted 
survival for patient-centered interventions in heart failure.  We will conduct sensitivity analyses 
to evaluate the impact of varying the time horizon for the study and costs associated with the 
intervention.  
 
11.6 
Sustainability of the Intervention 
To evaluate the sustainability of the intervention after the trial concludes, we will determine the 
extent to which the cost of the rehabilitation program is offset by savings from reductions in 
readmissions and other medical resources.  This information will be used to propose payment 
models for 3rd party payers (e.g. CMS) and accountable care organizations and health 
maintenance organizations who provide care to heart failure patients on a capitated basis.  If the 
intervention does not produce a net cost-savings, the cost-effectiveness analysis will assess 

Protocol  Version4-2/6/2018 
24 
gains in health outcomes vs. incremental costs of the intervention, which will provide important 
information for coverage decisions. 
 
12  
Efficacy Parameters 
 
12.1 
Primary Efficacy Parameter   
The primary outcome for assessing the efficacy of the REHAB-HF intervention will be change in 
physical function, as measured by the SPPB score, at 3 months. 
 
12.2 
Secondary Efficacy Parameter 
The secondary outcome for assessing the efficacy of the REHAB-HF intervention will be the 
total number of all-cause rehospitalizations during the 6 months following discharge from the 
index hospitalization. 
  
 
12.3  Exploratory Efficacy Parameters  
The study will explore several other possible endpoints: 
1. Change in the Kansas City Cardiomyopathy Questionnaire (KCCQ) total score and 
physical component score at 3 months  
2. Change in 6-minute walk distance (6MWD) at 3 months 
 
3. Change in component scores of the SPPB at 3 months 
4. Change in the 12-item short form health survey (SF-12), depression, and cognition 
measures at 3 months 
 
5. Change in frailty status at 3 months 
 
6. All-cause rehospitalizations at 1 month and 3 months 
 
7. All-cause rehospitalizations 6 months from the date of randomization 
8. All-cause combined rehospitalization and death at 6 months 
9. Global rank endpoint of SPPB score + all-cause rehospitalization + death  
 
10. Heart failure (HF)-specific rehospitalizations 
 
11. Cardiovascular events  
 
12. All-cause rehospitalization days  
 
13. Total hospitalization days post-randomization 
 
14. Total facility-free days alive  
 
15. Deaths  
 
16. Falls  
 
17. Change in biomarkers at 3 months 
 
 
13. 
Safety Monitoring and Adverse Events 
Safety Monitoring and Adverse Events, including falls, will be collected at all visits, recorded 
with clinical details on the case report form, discussed during the regular Operations Committee 
meetings (Section 16), and forwarded to institutional review boards and the data safety 
monitoring board (DSMB; see section 12.2).  An independent DSMB, appointed by NIH and 
governed by NIH policy, will meet semi-annually (or more frequently as indicated) and will 
monitor study-wide safety and clinical events. 
 
13.1      Adverse Events (AE) and Serious Adverse Events (SAE) 
The following standard definitions of an adverse event and a serious adverse event are based 
on NHLBI policy as follows. 
 
1. Adverse event (experience): 
Any untoward medical occurrences in participants will be captured, regardless of causal 
relationship with the intervention and procedures.  An AE can therefore be any unfavorable and 

Protocol  Version4-2/6/2018 
25 
unintended sign (including an abnormal laboratory finding), symptoms, or disease temporally 
associated with the investigational intervention, whether or not considered related to the 
investigational intervention. 
 
2. Serious adverse event (experience) (SAE): 
Any untoward medical occurrences that may result in any of the following outcomes: 
 
Death 
 
Is life-threatening 
 
Requires inpatient hospitalization or prolongation of existing hospitalization 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Important medical event that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, it may jeopardize the patient or participant and may 
require medical or surgical intervention to prevent one of the outcomes listed above   
 
Disability is defined as a substantial disruption of a person’s ability to conduct normal life’s 
functions (Federal Code of Regulations 21 CFR 312.32) 
 
For the purpose of the REHAB-HF study, the following AE’s and SAE’s will be reported to the 
DSMB: death, hospitalization, hospitalization/observation unit stay lasting less than 24 hours, 
emergency room visit, urgent clinic visits, and adverse events occurring while participant 
performing the REHAB-HF intervention (including angina, syncope/presyncope, palpitations, 
symptomatic hypoglycemia and/or falls).  All cardiovascular events (including worsening heart 
failure, acute coronary syndrome, arrhythmia, and stroke) will be collected and reported to the 
DSMB.  For the purpose of this protocol, hospitalizations will be identified as planned or not 
planned.   We will not be collecting specific information on congenital anomalies.   At the end of 
the study or at death, an attempt will be made to ascertain if any permanent disabilities occurred 
related to the intervention. 
 
All SAE’s will be coded using MedDRA.  SAE’s resulting in a death will be reported to the DSMB 
Chair and NIA program officer within 2 business days for deaths judged related in any way to 
the study and 5 business days if judged unrelated to the study.  All serious adverse events will 
be reported by a blinded treatment arm (“A” and “B”) to the DSMB Chair and the NIA Project 
Officer monthly. 
 
13.2  Data Safety Monitoring Board (DSMB)    
An independent DSMB, appointed by NIH and governed by NIH policy, will be charged with 
monitoring study-wide safety and clinical events on a regular basis (semi-annually).  In 
particular, the DSMB will review the following SAE’s and the following specific clinical and safety 
events: death, hospitalization, hospitalization/observation unit stay lasting less than 24 hours, 
emergency room visit, urgent clinic visits, and adverse events occurring while participant 
performing the REHAB-HF intervention (including angina, syncope/presyncope, palpitations, 
symptomatic hypoglycemia and/or falls), cardiovascular events (including worsening heart 
failure, acute coronary syndrome, arrhythmia, and stroke), nursing home placement, and injury 
(or fall) during rehabilitation.  
 
The protocol will guard against “unreasonable harm” by performing interim looks at DSMB 
meetings.  The events included in this analysis will be death, disabling stroke, myocardial 
infarction, resuscitated sudden cardiac death, sustained symptomatic ventricular tachycardia, 
and ED visit or hospitalization for serious fall / injury. 

Protocol  Version4-2/6/2018 
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14.  
Statistical Considerations 
 
14.1  Statistical Methods  
The primary aim of the study is to assess the efficacy of the REHAB-HF intervention on physical 
function measured by the total SPPB score. The effect of the intervention on SPPB score 
measured 3 months post-randomization will be estimated and tested for significance using 
analysis of covariance, where the randomized arm is the between-subject grouping variable and 
the pre-randomized measure of SPPB score, clinical site, age, gender, and ejection fraction 
category (preserved vs. reduced) will be covariates. Least square means will be used to 
estimate the intervention effect. Tests will be conducted at the 5% two-sided level of 
significance.   
 
The secondary aim of the study is to assess the intervention’s effect on the total number of all-
cause rehospitalizations during the 6 months following discharge from the index hospitalization. 
Since the count of all-cause rehospitalizations per participant may not be normally distributed, 
the effect of the intervention on total all-cause rehospitalizations will be estimated using a 
Poisson model for modeling count data, where the randomized arm is the between-subject 
grouping variable and clinical site, age, gender, and ejection fraction category will be covariates.  
A supplemental analysis will be performed adding the duration of the index hospitalization and 
the number of inpatient intervention sessions as additional covariates. 
 
The proportion of the intervention’s effect on total all-cause rehospitalizations that can be 
explained by its effect on 3-month SPPB score will be analyzed by multivariable regression 
between total number of all-cause rehospitalizations and the residual of the analysis of 
covariance model for 3-month SPPB omitting intervention from the model.   
 
Similar statistical methods as described above will be used for all of the exploratory efficacy 
parameters.   
 
14.2 
Sample Size Justification 
The REHAB-HF pilot study showed an estimated intervention effect of an increase of 1.13 units 
in 3-month SPPB score (the primary outcome) or a 17.9% relative increase above the least 
square mean for the attention control group, with a mean square error from the analysis of 
covariance model of 3.269. A clinically meaningful but small change in SPPB score is 0.5 units 
and a substantial change is 1.0 units.(159)  This study is designed to have 80% power to detect 
a 10% treatment difference (0.63 absolute difference) in the 3-month least square mean of 
SPPB score. This requires 258 evaluable participants. In our pilot study, the observed retention 
rate was 89%.  Conservatively assuming an 85% retention rate, the study requires randomizing 
304 participants (25.3 per site per year).  
 
In the completed pilot study, the number of all-cause rehospitalizations within 6 months was 
reduced 29.3% by the intervention (1.673+0.392 per patient in the attention control group vs. 
1.157+0.349 in the intervention group).  We performed additional work with an analysis of a 
contemporaneous sample of 239 consecutive patients aged > 65 years admitted with the 
primary diagnosis of ADHF.  This confirmatory sample yielded a 6-month rehospitalization event 
rate estimate within 0.5% of our attention control group, giving confidence in our pilot study 
estimate.  This study is designed to have 80% power to detect a 25% reduction (0.41 absolute 
difference) in the total number of all-cause rehospitalizations during the 6 months following the 
index hospitalization.  This requires 334 evaluable participants.  In the pilot study we were able 
to evaluate the number of hospitalizations within 6 months in 100% of participants. 

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Conservatively assuming up to 5% inevaluability, the study requires randomizing 352 total 
participants.  Rounding up to 30 patients per site per yr, this study will randomize a total of 360 
patients, providing > 80% power for the primary and secondary aims. 
 
14.3 
Data Management 
The REDCap (Research Electronic Data Capture) data management system developed by the 
Clinical and Translational Science Award-funded Centers (NIH) will be used.  The REDCap 
system is a secure, web-based database.  The system will be developed and maintained by the 
study Data Manager.  The REDCap system is hosted through the Bio-medical Informatics 
program of the WFU Translational Science Institute. 
 
15. 
Privacy protection 
The data analyses will pool data from all 3 sites.  Before transmission to a data center, identifier 
information will be stripped and replaced with a unique code while the code linking the specimen 
with the participant’s identity will remain in the security of the local site principal investigator.  
Data de-identification will be in full compliance with section 19.8 of the Wake Forest Office of 
Research Investigator page: http://www.wakehealth.edu/IC_Office-of-Research/IC_Investigator-
Resource-Page.htm. Only individuals trained and certified in privacy protection will have access 
to data.   
 
16. 
Organizational structure 
REHAB-HF is comprised of 3 clinical centers, their affiliated satellites, and an administrative 
center.  The Steering Committee is comprised of the directors of the 3 clinical centers (Drs. 
Kitzman, O’Connor, Whellan, Reeves, Patel), study biostatistician (Dr. Morgan), intervention 
leader (Dr. Duncan), and economic analysis leader (Dr. Reed).  All key decisions will be made 
by this group which will meet by teleconference every other week (or weekly as needed).  The 
Operations Committee will consist of the study investigators, research nurse coordinators, 
intervention supervisors, study manager and data manager from the administrative center, and 
will meet by bi-weekly teleconference. The Intervention Committee, led by Dr. Duncan, includes 
the intervention supervisors from each site and will meet every other week.  The Administrative 
Center at Wake Forest will: 1) administer subcontracts with clinical centers, matching timelines 
and deliverables; 2) maintain the Manual of Operations, protocol and intervention materials, 
questionnaires and forms; 3) coordinate training and certification of clinical center staff; 4) 
maintain the centralized web-based data management system and randomization procedures; 
5) monitor data collection, measurement and intervention reliability; 6) generate data quality 
reports for study sites, steering committee and DSMB meetings; and 7) schedule and lead all 
teleconferences.  
 
 

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