Physical rehabilitation for older patients with acute HFpEF (REHAB-HFpEF) trial: Design and rationale

ABSTRACT

Rationale

Older patients hospitalized for acute decompensated heart failure with preserved ejection fraction (HFpEF) experience persistently poor outcomes, including physical disability, cognitive impairment, depression, impaired health-related quality of life (HRQOL), rehospitalizations, loss of independence, and mortality. In our previous phase 2 REHAB-HF trial, an innovative physical rehabilitation intervention, delivered across three phases–inpatient, 12-week outpatient, and 3-month home-based maintenance–produced large improvements in physical function and HRQOL, with signals of reduced clinical events among patients with acute HFpEF. These findings provide a compelling rationale for a definitive, event-powered trial to evaluate clinical outcomes.

Hypothesis

Targeting physical frailty and multisystem functional impairments using the REHAB-HF intervention–a transitional, tailored, structured, and progressive multidomain rehabilitation program focused on balance, mobility, strength, and endurance–will reduce clinical events in older, predominantly frail patients hospitalized for acute HFpEF.

Design

REHAB-HFpEF is a multicenter, randomized, single-blind, attention-controlled phase 3 trial across 22 U.S. health system centers, enrolling 880 patients aged ≥60 years hospitalized for acute HFpEF. The primary endpoint is combined all-cause rehospitalizations and mortality at 6 months. Key secondary endpoints include major mobility disability (defined as inability to walk ≥160 meters on the 6-minute walk test) and HRQOL measured by the Kansas City Cardiomyopathy Questionnaire. Healthcare costs will also be assessed.

Conclusions

REHAB-HFpEF is designed to address care gaps for frail older adults with acute HFpEF, who currently lack an evidence-based rehabilitation pathway. If successful in meeting endpoints, this trial could establish a scalable rehabilitation intervention that improves recovery, reduces adverse events, and lowers healthcare costs. Findings may shift HF management paradigms, inform guidelines, and influence national coverage policy for this growing, high-risk population.

Current Status

Enrollment ongoing, 478 of 880 (66%) as of 24Feb2027.

Trial Registration

Clinicaltrials.gov ID NCT05525663, https://clinicaltrials.gov/study/NCT05525663?term=NCT05525663&rank=1

Key Points

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Largest physical rehabilitation trial in frail older adults with acute HFpEF.
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Tests a tailored multidomain program across hospital, outpatient, and home settings.
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Primary endpoint: 6-month all-cause rehospitalizations and mortality.
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Powered secondary endpoints: major mobility disability and HRQOL.
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Designed to inform HFpEF care guidelines and coverage policies.

Acute decompensated heart failure (ADHF) is the most frequent Medicare discharge diagnosis, accounting for over 1.2 million hospitalizations annually and more than $39 billion in healthcare expenditures. Older adults (≥60 years) hospitalized with ADHF exhibit severe functional impairments, frailty, depression, poor health-related quality of life (HRQOL), and markedly elevated risks of rehospitalizations, loss of independence, and mortality. ^, Despite substantial efforts, most pharmacologic therapies and care coordination models have failed to improve outcomes in this high-risk population. ^,^,^,^, Hospitalization itself, and the accompanying immobility, further exacerbate physical and cognitive vulnerabilities, leaving older adults especially susceptible to disability and rehospitalization.

Our research program was among the first to demonstrate that impairments in physical function are a central, modifiable, and often overlooked contributor to persistent adverse outcomes in older adults with ADHF. ^,^,^,^,^, In the phase 2 Rehabilitation Therapy in Older Acute Heart Failure Patients (REHAB-HF) ( N = 349), we tested an innovative, structured, progressive, multidomain physical rehabilitation tailored to the severe functional deficits observed in this population. The intervention—initiated during hospitalization and transitioned across outpatient and home-based settings—used an individualized sequencing strategy that prioritized strength, balance, and mobility before endurance to optimize safety and effectiveness in frail older adults. ^,^, The REHAB-HF intervention produced large, clinically meaningful improvements in physical function, frailty, depressive symptoms, and HRQOL, with the greatest benefits observed among the most impaired participants. Although the study was not powered for clinical event differences, numerically lower rates of both cardiovascular and noncardiovascular rehospitalizations were also observed in the intervention arm, suggesting that the multidomain rehabilitation may enhance overall resilience and recovery beyond cardiac mechanisms. In prespecified subgroup analyses (not adjusted for multiple comparisons), effects were consistent across age, sex, race, and multiple comorbid conditions, underscoring the intervention’s efficacy and generalizability. ^,^,^, The notable exception was heart failure phenotype.

Participants with acute heart failure with preserved ejection fraction (HFpEF)—who comprised 53% of the phase 2 cohort—had significantly worse baseline impairments yet derived ∼50% larger improvements across physical and psychosocial outcomes, along with more favorable trends in mortality, rehospitalization, and healthcare costs, compared to those with reduced ejection fraction (HFrEF). ^,^, These findings identify acute HFpEF as a uniquely vulnerable yet highly modifiable phenotype and provide strong scientific premise for a definitive, event-powered trial.

HFpEF is the most common and fastest growing HF phenotype among older adults, disproportionally affecting women and non-Hispanic Black individuals. ^,^, It is increasingly recognized as a multisystem geriatric syndrome driven by aging, inflammation, physical inactivity, and multimorbidity—factors that contribute to physical dysfunction, high frailty burden, poor HRQOL, and rising mortality. ^,^, Despite its substantial burden, patients with HFpEF and recent hospitalization have been systematically excluded from most exercise-based trials and are ineligible for cardiac rehabilitation. ^,^,^, As a result, rigorous and generalizable clinical outcomes data are urgently needed to inform clinical decision-making and guide rehabilitation policy for this high-risk group.

To address these gaps, we were funded by the National Institute of Aging (NIA) to conduct Physical Rehabilitation for Older Patients with Acute HFpEF (REHAB-HFpEF) , a phase 3, multicenter, randomized controlled trial of the multidomain REHAB-HF intervention. We hypothesize that the intervention will reduce the primary endpoint of combined all-cause rehospitalizations and mortality and improve major mobility disability (MMD) and HRQOL at 6-month follow-up, during the high-risk post-ADHF period ( Figure 1 ). This trial directly addresses national priorities articulated by the 2019 NIA workshop on HFpEF and the recent American Heart Association/American College of Cardiology scientific statement on exercise training in HFpEF, and, if successful, will provide the critical evidence needed to inform clinical guidelines, support CMS coverage decisions, and establish a scalable rehabilitation pathway for older adults with acute HFpEF.

Methods

Study design and setting

REHAB-HFpEF is a multicenter, randomized, single-blind, attention-controlled phase 3 trial aiming to enroll 880 older patients (≥60 years) with HFpEF hospitalized with ADHF. Leveraging the “hub-and-satellite” model from REHAB-HF and its predecessor, HF-ACTION, participants will be recruited across 22 U.S. health system clinical centers (hubs), each potentially linked to up to three affiliated community hospitals (satellites) to ensure broad representation ( Figure 2 , Appendix).

Study population

Inclusion and exclusion criteria are largely based on the REHAB-HF phase 2 trial, ^,^,^, but restricted to patients who appeared most responsive–those with acute HFpEF (EF ≥45%). This EF threshold matches phase 2 and facilitates implementation. Participants are screened and enrolled during the index ADHF hospitalization. ADHF is confirmed by a study physician using a standard definition: ≥1 HF symptoms, ≥2 HF signs, and a change in HF-specific medical therapy ( Table 1 ). Eligible patients are ≥60 years, able to ambulate ≥4 m independently (with or without a gait assistive device), perform basic activities of daily living independently prior to admission, and be expected to return home at discharge.

Table 1

REHAB-HFpEF inclusion and exclusion criteria

Inclusion criteria

Patients eligible for the trial must meet the following criteria at randomization:

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Age ≥60 y old
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Ejection fraction ≥45%
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In the hospital setting >24 h for the management of ADHF requires that all 4 of the following are met:
- ○
  At least one symptom of HF that has worsened from baseline:
  - ▪
    Dyspnea at rest or with exertion
  - ▪
    Exertional fatigue
  - ▪
    Orthopnea
  - ▪
    Paroxysmal nocturnal dyspnea (PND)
- ○
  At least two of the signs of HF
  - ▪
    Pulmonary congestion or edema on exam (rales) or by chest x-ray
  - ▪
    Elevated jugular venous pressure or central venous pressure ≥10 mm Hg
  - ▪
    Peripheral edema
  - ▪
    Wedge or left ventricular end diastolic pressure ≥ 15 mm Hg
  - ▪
    Rapid weight gain (≥5 lbs.)
  - ▪
    Increased b-type natriuretic peptide (BNP) (≥100 pg/mL) or N-terminal prohormone BNP (≥220 pg/mL)
- ○
  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
  - ▪
    Diuretics
  - ▪
    Vasodilators
  - ▪
    Other neurohormonal modulating agents, including angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, beta-blockers, aldosterone, direct renin inhibitors, or sodium-glucose cotransporter-2 inhibitors
- ○
  Primary cause of symptoms and signs is judged by the site physician to be due to HF

•
Clinical stability to allow participation in study assessments and the intervention
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Independent with basic activities of daily living prior to admission
•
Ambulate 4 meters independently (with or without the use of an assistive device) at the time of enrollment

Exclusion criteria

At the time of randomization, none of the following conditions may exist:

•
Acute myocardial infarction based on clinical diagnosis within the past 3 mo
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Planned coronary artery intervention (percutaneous or surgical) within the next 6 mo
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Requiring care in an intensive care unit
•
Severe aortic or mitral valve stenosis
•
Severe valvular disease with planned intervention within the next 6 mo
•
Known pericardial constriction, genetic hypertrophic cardiomyopathy, or infiltrative cardiomyopathy, including amyloid heart disease (amyloidosis)
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Advanced chronic kidney disease (eGFR < 20 mL/min/1.73 m ²) or on dialysis or expected to be within the next 6 mo
•
Terminal illness other than HF with life expectancy <1 y
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Planned discharge other than to where the participant will live independently
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Impairment from stroke, injury, or other medical disorder that precludes participation in the intervention
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Known dementia by health record documentation, or MoCA ≤ 18, and without social support, or MoCA < 10, regardless of social support
•
Already actively participating in regular moderate or vigorous exercise conditioning defines as >30 min per day, ≥twice per week consistently during the previous 6 wk
•
Anticipated hospital discharge before baseline study measures could be completed

Key exclusion criteria are acute myocardial infarction; severe valvular disease; infiltrative cardiomyopathy; advanced kidney disease (estimated glomerular filtration rate ≤20 mL/min/1.73 m ² or dialysis); regular moderate to vigorous exercise before hospitalization; or other conditions limiting safe participation. Cognitive impairment, common in older adults hospitalized with HF, ^, is assessed using the Montreal Cognitive Assessment. Patients with scores 10 to 17 are eligible for enrollment if adequate social support for adherence is confirmed by the study team.

To ensure safety and consistency across sites, eligibility is confirmed using a standardized screening process combining medical record review and clinical assessment by the site investigator in consultation with the treating team. This includes evaluation of medical stability, anticipated recovery trajectory, and ability to safely participate. Patients with noncardiovascular conditions expected to limit 1-year survival are excluded. This structured approach, used successfully in phase 2, allows clinical judgment while minimizing variability across sites. Intervention delivery is led by physical therapists experienced in geriatric multimorbidity, supporting safety throughout the trial. Oversight is provided by an NIH-appointed Data Safety Monitoring Board (DSMB) (see Appendix for trial organization).

Patients who provide informed consent and meet eligibility criteria are randomized 1:1 to the REHAB-HF intervention or attention control arm using permuted block randomization with stratification by clinical center.

The trial is conducted in accordance with the Declaration of Helsinki and was approved by the central Institutional Review Board at Wake Forest University Health Sciences, with reliance agreements from all participating institutions. The trial is registered with Clinicaltrials.gov (NCT05525663).

Usual care

Participants in both arms receive clinician-directed usual care, which may include physical therapy or occupational therapy (hospital, outpatient, and/or at home-based), and cardiac or pulmonary rehabilitation during follow-up. Disease management, including medications, device therapy, and HF management, remains entirely at the discretion of treating clinicians and are not altered by the study protocol for either arm. Any clinical concerns raised by participants or identified by study staff are referred to their clinicians. Providing full access to usual care in both arms, as in phase 2, was an intentional strategy to minimize differential exposure to nonstudy therapeutic services.

Attention control arm

To minimize differential study staff contact, attention control participants receive structured telephone and in-person contact during the 12 months following the index hospitalization, mirroring contact frequency in the intervention arm ( Table 2 and Supplementary Figure 1). Study staff conduct biweekly telephone calls at weeks 2, 4, 6, 8, and 10, followed by monthly calls at months 4, 5, and 12. Participants attend in-person reassessments at months 3 and 6 for evaluation of physical function and HRQOL. At each contact, staff collect information on symptoms, HF disease management programs, medical adherence, physical activity, rehabilitation received, healthcare utilization, HRQOL, and clinical events. Participants are encouraged to follow all usual care recommendations, but do not receive any specific rehabilitation recommendations or exercise prescription from study personnel.

Table 2

Schedule of visits and assessments

	Index hospitalization (baseline)	Phone calls (wk 2, 4, 6, 8, 10)	3 mo visit	Phone calls (mo 4 and 5)	6 mo visit	12 mo phone call
Visit window	Prior to discharge	±3 d	90 ± 10 d *	120 and 150 ± 3 d	180 ± 10 d	365 ± 10 d
Clinical events	X	X	X	X	X	X
Medications review	X	X	X	X	X	X
Medical resource use	X	X	X	X	X	X
6MWD	X		X		X
SPPB	X		X		X
Handgrip	X		X		X
Frailty phenotype	X		X		X
Biomarkers	X		X
KCCQ	X		X		X
SF-12	X		X		X
EQ-5D-5L	X		X		X	X
GDS-15	X		X		X
MoCA	X		X		X
Geriatric conditions: Falls, Urinary incontinence	X	X	X	X	X	X

6MWD , 6-minute walk distance; EQ-5D-5L , EuroQol 5-dimension 5-level; GDS , Geriatric Depression Scale; KCCQ , Kansas City Cardiomyopathy Questionnaire; MoCA , Montreal Cognitive Assessment; SF , Short Form; SPPB , Short Physical Performance Battery.

REHAB-HF intervention arm

Overview: Details of the REHAB-HF intervention have been previously published. ^,^, In brief, this multidomain physical rehabilitation intervention, developed in phase 2, is tailored for older adults with HFpEF hospitalized for ADHF, a population with heterogeneous mobility, multiple comorbidities, and high frailty. ^,^,^,^, The intervention targets physical function deficits, worsened by acute illness and hospital-associated immobility, with an initial emphasis on regaining strength, balance, and functional mobility to allow safe participation in walking-based endurance activity. The goal is to improve performance across four physical function domains essential for functional independence—strength, balance, mobility, and endurance—by utilizing standardized, targeted exercises with specific progressive milestones to prevent mobility disability. The intervention begins during hospitalization and extends through outpatient and home-built environment settings, providing a transitional dose of rehabilitation from stabilization after acute decompensation through recovery and back to chronic disease state.

Inpatient sessions occur once daily for ∼45 minutes and focus on balance, mobility, and functional strength, using exercises that can easily be administered in a hospital room with minimal equipment. Then, within 7 days after hospital discharge, 60-minute outpatient sessions are conducted 3 days/wk for a target total of 36 sessions. One-on-one (participant to interventionist), in-person delivery is the preferred mode due to the fall risk, frailty, multimorbidity, and cognitive dysfunction prevalent in this population, all of which require close supervision and frequent adaptation. For very debilitated participants, home-based sessions may be provided until they can safely attend outpatient sessions.

Outpatient sessions are complemented by independent home exercise, including strengthening exercises and low-intensity walking on nonfacility days, progressing toward 30 minutes. Home exercise begins after an extensive home-built environment assessment visit, which identifies safe and accessible areas for exercise, and highlights salient social determinants of health that the team can address to promote intervention adherence (ie, transportation needs, support person engagement).

If outpatient sessions are interrupted by rehospitalization or illness, inpatient intervention sessions resume once the participant is medically stable. The study team also maintains close contact with the participant and their providers to support retention and ensure safe, timely resumption of outpatient sessions or home sessions (as a bridge back to outpatient) following hospital discharge.

A key goal, which is addressed early and throughout the first 3 months, is preparing the participant for the independent, unsupervised home maintenance phase beginning at month 4. Near the 3-month visit, participants receive an individualized maintenance exercise prescription and recommendations for community-based exercise resources. This schedule achieved excellent retention and adherence in phase 2. ^, Flow of the intervention arm is presented in Figure 3 .

Exercise prescription: The broad range of exercises included in the study are designed to accommodate the heterogeneous capabilities of participants. Exercises are individually tailored based on functional performance (1-4, from lowest to highest) for each domain using objective criteria ( Table 3 ). Exercises are then selected to match the participant’s functional level; sample exercises are shown in Table 4 . Based on phase 2, where 14% of participants were initially at level 1 for most domains, 36% were at level 2, and 29% were at level 3, we anticipate a broad range of baseline levels in this phase 3 trial.

Table 3

Exercise stratification grid: Performance levels for exercise prescription and collaboration overlay

Table 4

Examples of exercise prescription by performance levels for each exercise domain

Exercise examples by domain	Level 1	Level 2	Level 3	Level 4
Strength:
a) Sit to stand	On edge of chair leaning forward and pushing with hands	On edge of chair leaning forward with arms reaching out	In back of chair with arms across chest	As in level 3 at faster pace or from lower surface
b) Step-ups (front and side)	4-inch step *	6-inch step *	8-inch step *	10-inch step and/or with resistance *
Balance:
Stand and reach	Stand with feet shoulder width apart; reach forward 6 inches and hold	Stand with feet shoulder width apart; reach forward 10 inches and hold	Stand with feet together; reach forward 6 inches (progressing to 10 inches) and hold	Semitandem stance; reach forward 6 inches (progressing to 10 inches) and hold
Mobility:
Gait training	Stop and start abruptly	Brief accelerations during walking	Quick change of direction	Quick change of direction while engaged in activity requiring cognitive attention (eg, conversation, questioning)
Endurance:
Continuous walking	Repeated brief bouts for a total duration of 10 min	Repeated brief bouts for a total duration of 20 min	Repeated bouts for a total duration of 30 min	Continuous for 20-30 min

Mode : Exercises appropriate to a participant’s performance level in each domain are selected as illustrated in the examples above.

Frequency and duration :

Inpatient: 30-minute sessions daily until discharge, with focus on domains to preserve functional mobility (typically 0-2 sessions). Outpatient 3×/week for approximately 60-minute sessions, integrating all domains (goal 36 sessions).

Intensity : Rate of perceived exertion (RPE) <12 initially; increasing to 13 (11-15) for endurance; 15 to 16 for strength. Balance and mobility not to exceed endurance RPE.

Progression : As performance improves, participants advance to slightly more challenging exercises through structured, small increments. Performance is assessed during one-on-one training sessions, including standardized reassessment of functional performance in each domain.

Exercise progression over time is individualized based on performance level within each domain, with the relative proportion of session time per domain tailored to the pattern of impairments ( Figure 4 ). Rate of perceived exertion guides intensity and progression. Participants are continually challenged to improve gradually in small increments from session to session. A key goal is to increase endurance (walking time); doing this safely requires first addressing deficits in balance, strength, and mobility, as standard endurance training without first addressing these deficits has reduced efficacy and increased injury risk in frail patients. ^,^,

Tags: American Heart Journal Volume 297

Jun 27, 2026 | Posted by drzezo in CARDIOLOGY | Comments Off

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