Nejmoa 2026141

new england
The
journal of medicine
established in 1812 July 15, 2021 vol. 385 no. 3
Physical Rehabilitation for Older Patients Hospitalized

for Heart Failure
Dalane W. Kitzman, M.D., David J. Whellan, M.D., M.H.S., Pamela Duncan, P.T., Ph.D., Amy M. Pastva, P.T., Ph.D.,
Robert J. Mentz, M.D., Gordon R. Reeves, M.D., M.P.T., M. Benjamin Nelson, M.S., Haiying Chen, Ph.D.,
Bharathi Upadhya, M.D., Shelby D. Reed, Ph.D., Mark A. Espeland, Ph.D., LeighAnn Hewston, D.P.T., M.Ed.,
and Christopher M. O’Connor, M.D.
a bs t r ac t
BACKGROUND
Older patients who are hospitalized for acute decompensated heart failure have From the Department of Internal Medi-
high rates of physical frailty, poor quality of life, delayed recovery, and frequent cine, Sections of Cardiovascular Medi-
cine (D.W.K., M.B.N., B.U.) and Geron-
rehospitalizations. Interventions to address physical frailty in this population are tology and Geriatric Medicine (D.W.K.,
not well established. M.A.E.), and the Departments of Neurol-
METHODS ogy (P.D.) and Biostatistics and Data Sci-
ence (H.C., M.A.E.), Wake Forest School
We conducted a multicenter, randomized, controlled trial to evaluate a transi- of Medicine, Winston-Salem, the Depart-
tional, tailored, progressive rehabilitation intervention that included four physical- ment of Orthopedic Surgery, Doctor of
function domains (strength, balance, mobility, and endurance). The intervention Physical Therapy Division (A.M.P.), the
Department of Medicine, Division of Car-
was initiated during, or early after, hospitalization for heart failure and was con- diology (R.J.M.), and the Department of
tinued after discharge for 36 outpatient sessions. The primary outcome was the Population Health Sciences (S.D.R.),
score on the Short Physical Performance Battery (total scores range from 0 to 12, Duke University School of Medicine,
Durham, and Novant Health Heart and
with lower scores indicating more severe physical dysfunction) at 3 months. The Vascular Institute, Charlotte (G.R.R.) —
secondary outcome was the 6-month rate of rehospitalization for any cause. all in North Carolina; the Department of
RESULTS Medicine, Sidney Kimmel Medical Col-
lege at Thomas Jefferson University
A total of 349 patients underwent randomization; 175 were assigned to the reha- (D.J.W.), and the Department of Physical
bilitation intervention and 174 to usual care (control). At baseline, patients in each Therapy, Jefferson College of Rehabilita-
group had markedly impaired physical function, and 97% were frail or prefrail; tion Sciences at Thomas Jefferson Uni-
versity (L.A.H.) — both in Philadelphia;
the mean number of coexisting conditions was five in each group. Patient reten- and Inova Heart and Vascular Institute,
tion in the intervention group was 82%, and adherence to the intervention sessions Fairfax, VA (C.M.O.). Address reprint re-
was 67%. After adjustment for baseline Short Physical Performance Battery score quests to Dr. Kitzman at the Department
of Internal Medicine, Sections of Cardio-
and other baseline characteristics, the least-squares mean (±SE) score on the Short vascular Medicine and Gerontology and
Physical Performance Battery at 3 months was 8.3±0.2 in the intervention group Geriatric Medicine, Wake Forest School
and 6.9±0.2 in the control group (mean between-group difference, 1.5; 95% con- of Medicine, 1 Medical Center Blvd.,
fidence interval [CI], 0.9 to 2.0; P<0.001). At 6 months, the rates of rehospitaliza- Winston-Salem, NC 27157-1045, or at
dkitzman@wakehealth.edu.
tion for any cause were 1.18 in the intervention group and 1.28 in the control
group (rate ratio, 0.93; 95% CI, 0.66 to 1.19). There were 21 deaths (15 from car- A list of the investigators in this trial is pro-
vided in the Supplementary Appendix,
diovascular causes) in the intervention group and 16 deaths (8 from cardiovascular available at NEJM.org.
causes) in the control group. The rates of death from any cause were 0.13 and 0.10,
This article was published on May 16,
respectively (rate ratio, 1.17; 95% CI, 0.61 to 2.27). 2021, at NEJM.org.
CONCLUSIONS
N Engl J Med 2021;385:203-16.
In a diverse population of older patients who were hospitalized for acute decom- DOI: 10.1056/NEJMoa2026141
pensated heart failure, an early, transitional, tailored, progressive rehabilitation Copyright © 2021 Massachusetts Medical Society.
intervention that included multiple physical-function domains resulted in greater

improvement in physical function than usual care. (Funded by the National Insti-
tutes of Health and others; REHAB-HF ClinicalTrials.gov number, NCT02196038.)
n engl j med 385;3 nejm.org July 15, 2021 203
The New England Journal of Medicine
Downloaded from nejm.org by MATHEUS OLIVEIRA on July 24, 2021. For personal use only. No other uses without permission.
Copyright © 2021 Massachusetts Medical Society. All rights reserved.
The n e w e ng l a n d j o u r na l of m e dic i n e
A
cute decompensated heart failure tions. The protocol, which is available at NEJM.org,
is the leading cause of hospitalization was approved by the institutional review board
among older persons in the United States1 at each site. An independent data and safety mon-
and is associated with poor health-related qual- itoring committee evaluated patient safety. The
A Quick Take
ity of life, frequent rehospitalizations, high mor- authors vouch for the accuracy and completeness
is available at tality, and costs exceeding $39 billion per year.1,2 of the data and analyses and for the fidelity of
NEJM.org Most intervention trials in acute decompensated the trial to the protocol.
heart failure have had neutral results, which
suggests that outcomes may be driven in part by Patients and Randomization
mechanisms that have been overlooked.3-5 Patients were screened at the time of hospital
Among older patients with acute heart fail- admission and were enrolled before discharge.
ure, physical function is markedly impaired, and Patients were eligible for participation if they
frailty rates and the burden of coexisting condi- were 60 years of age or older, if they had been
tions are high.5-8 Even among older patients with admitted for acute decompensated heart failure
stable and well-compensated heart failure, se- regardless of ejection fraction, if they could walk
vere impairments in physical function are often at least 4 m at enrollment (with or without the
present owing to the combined effects of aging, aid of an assistive device), if they were function-
cardiovascular dysfunction, and skeletal-muscle ally independent before admission, and if they
dysfunction.9,10 As patients with chronic heart were expected to be discharged home. Full de-
failure transition to acute decompensated heart tails of the inclusion and exclusion criteria are
failure, physical function worsens further, and provided in the Supplementary Appendix.17 After
this decline is exacerbated by hospitalization eligible patients provided written informed con-
and bed rest.8 These deficits often persist. Many sent and completed baseline testing, they were
patients never recover baseline function, lose randomly assigned with equal probability to the
independence, and have high risks of rehospital- rehabilitation intervention (intervention group)
ization and death after discharge (sometimes or to usual care (control group) by a centralized,
referred to as “post-hospital syndrome”).4,5,11-14 Web-based system, with the use of block ran-
However, management guidelines do not ad- domization. Randomization was stratified ac-
dress physical dysfunction in patients hospital- cording to ejection fraction (<45% vs. ≥45%) and
ized for heart failure,15 and previous exercise clinical site. The patients in both trial groups
training trials excluded patients with heart fail- received usual care, as recommended by their
ure who had recently been hospitalized.10,16 To medical providers, which could include inpatient
address these issues, we conducted the Rehabili- or outpatient physical therapy and standard car-
tation Therapy in Older Acute Heart Failure Pa- diac rehabilitation.
tients (REHAB-HF) trial, a multicenter, random-
ized, single-blind, controlled trial of an early, Trial Procedures
transitional, tailored, progressive rehabilitation The trial intervention (for the intervention group)
intervention that included multiple physical-func- was an early, transitional, tailored, progressive
tion domains. We hypothesized that the inter- physical rehabilitation program that had been
vention would improve physical function and developed for frail, older patients with acute
reduce rates of rehospitalization for any cause at decompensated heart failure.18,19 The interven-
6 months. tion focused on four physical-function domains
(strength, balance, mobility, and endurance) and
progressed through four prespecified functional
Me thods
levels within each domain (Table S1). The pro-
Trial Design and Oversight gression of exercise intensity and the types of
Details of the trial design and intervention meth- exercises at each session were individualized on
ods have been described previously.17,18 The orga- the basis of the patient’s performance level within
nizational structure is shown in Figure S1 in the each domain.18 A key goal was to increase each
Supplementary Appendix, available with the full patient’s endurance (duration of walking); doing
text of this article at NEJM.org. The steering this safely required first addressing deficits in bal-
committee designed the trial and oversaw opera- ance, strength, and mobility.
204 n engl j med 385;3 nejm.org July 15, 2021

Physical Rehabilitation for Heart Failure
The intervention was initiated in the hospital function were assessed at baseline in the hospi-
when feasible and was subsequently transitioned tal and at 3 months.17 Clinical events were ascer-
to an outpatient facility as soon as possible after tained throughout follow-up from monthly in-
discharge. If needed, home-based sessions were terviews and from review of medical records.
provided by interventionists until the patient was The primary outcome was the score on the
physically able to attend the facility-based outpa- Short Physical Performance Battery at 3 months.
tient sessions. Outpatient sessions were 60 min- The Short Physical Performance Battery is a
utes long, occurred 3 days per week for 12 weeks standardized, reproducible measure of global
(or 36 sessions), and were conducted at a 1:1 physical function that has been validated in
interventionist–patient ratio. Outpatient sessions frail, older persons and predicts a wide range of
were complemented by home exercise (low-inten- clinical outcomes.20-22 It has three components: a
sity walking, which was gradually increased to standing balance test, a gait-speed (4-m walk)
up to 30 minutes daily, and strengthening exer- test, and a strength test (as assessed by the time
cises) on nonprogram days. The home exercise needed to rise from a chair five times). Each
component of the intervention was initiated only component is scored on a scale of 0 to 4; the
after a visit to the patient’s home by an interven- sum of the scores ranges from 0 to 12, with
tionist to evaluate the home environment.18 lower scores indicating more severe physical dys-
A key goal of the intervention during the first function.
3 months (the outpatient phase) was to prepare The secondary outcome was the rate of rehos-
the patient to transition to the independent pitalization for any cause at 6 months, with re-
maintenance phase (months 4 through 6). At the hospitalization defined as any hospital stay
3-month visit, patients were provided with indi- longer than 24 hours. The reasons for rehospi-
vidualized exercise prescriptions and were sub- talization were categorized as noncardiovascular
sequently followed every 4 weeks by telephone cause, heart failure, or another cardiovascular
contact. Patient retention in the intervention group cause by an independent adjudicator who was
and adherence to the intervention sessions were unaware of the trial-group assignments.
reviewed and discussed every 2 weeks by a dedi- Additional physical-function outcomes in-
cated committee in accordance with the recom- cluded 6-minute walk distance, frailty status
mendations of the National Institutes of Health (assessed according to modified Fried criteria6),
Behavior Change Consortium Treatment Fidelity hand-grip strength, and gait speed at 3 months.
Workgroup.18 Additional details regarding the Quality of life was assessed at 3 months with the
intervention are provided in the Supplementary use of the Kansas City Cardiomyopathy Ques-
Appendix. tionnaire (KCCQ) and the EQ-5D-5L (also known
Patients who had been randomly assigned to as the European Quality of Life 5-Dimension
the control group received a telephone call every 5-Level questionnaire) visual-analogue scale. Oth-
2 weeks and had in-person clinic visits at 1 month er outcomes included the Geriatric Depression
and 3 months after discharge from the index Scale–15 score and the Montreal Cognitive As-
hospitalization.17 Information regarding the oc- sessment score.
currence of symptoms or clinical events and the
receipt of rehabilitation therapy unrelated to the Statistical Analysis
trial was collected. Patients received no specific On the basis of the results from a pilot study,19
recommendations with respect to exercise, but we estimated that 258 patients who could be
they were encouraged to adhere to prescribed evaluated for efficacy would provide the trial with
usual-care therapy and follow-up appointments. 80% power to detect a 10% difference (equiva-
Additional details regarding the control group lent to a difference of 0.6 points) between the
are provided in the Supplementary Appendix. intervention group and the control group in the
score on the Short Physical Performance Battery
Trial Outcomes at 3 months (the primary outcome); the enroll-
Outcome measures of physical and cognitive func- ment of 334 patients who could be evaluated for
tion were assessed by personnel who were un- efficacy would be needed to detect a 25% differ-
aware of the trial-group assignments. Physical ence in the rate of rehospitalization at 6 months
function, quality of life, depression, and cognitive (the secondary outcome). We planned to enroll

27,300 Admission records were

electronically reviewed
26,890 Patients were excluded

8075 Did not meet inclusion criteria
7261 Were admitted for a reason other than ADHF
493 Were not independent with respect to activities of daily living
226 Were unable to walk 4 m
95 Did not have adequate clinical stability
18,815 Met exclusion criteria
5097 Had excessive distance that precluded travel to exercise facility
2184 Were unable to comply with trial requirements
2507 Had advanced chronic kidney disease or dialysis
1815 Had an impairment that precluded participation
1521 Were planned to be discharged to nonindependent living facility
965 Had dementia
849 Were planned to be discharged before baseline assessment
could be completed
3877 Had other reason
410 Patients were screened for eligibility
61 Were excluded
17 Did not meet inclusion criteria
11 Were unable to walk 4 m
4 Were not independent with respect to activities of daily living
2 Were admitted for a reason other than ADHF
43 Met exclusion criteria
12 Were unable or unwilling to comply with trial requirements
10 Had risk of noncompliance
6 Were planned to be discharged to nonindependent living facility
5 Had acute myocardial infarction
5 Had impairment that precluded participation, including cognition
4 Had advanced chronic kidney disease or dialysis
1 Had aortic stenosis
1 Died
349 Underwent randomization
175 Were assigned to the rehabilitation 174 Were assigned to the

intervention group control group
12 Died 6 Died
14 Were lost to follow-up and were not 13 Were lost to follow-up and were not
included in the analysis of the included in the analysis of the
primary outcome primary outcome
149 Were included in the analysis of the 155 Were included in the analysis of the
primary outcome primary outcome
360 patients in order to allow for approximately egorical variables. To account for deaths and
7% of the patients to withdraw from the trial. loss to follow-up, joint models of continuous and
Baseline characteristics are presented as survival outcomes were used to assess differ-
means and standard deviations for continuous ences between the intervention group and the
variables and as counts and percentages for cat- control group in the 3-month outcomes (includ-

Figure 1 (facing page). Screening and Randomization. R e sult s

A total of 27,300 hospital admission records were elec- Trial Population and Baseline Characteristics
tronically reviewed; these included multiple repeat ad-
missions and thus should not be construed as unique, The first patient was enrolled in September 2014,
individual patients. The most common reason for not and the last patient was enrolled in September
meeting the inclusion criteria was that heart failure 2019. A total of 27,300 hospital admission records
was not the reason for hospital admission (7261 pa-
tients). The most common exclusion criterion was an
(which included multiple repeat admissions and
excessive distance that precluded travel to the exercise thus did not represent unique patients) were
facility (5097 patients), which was generally defined as electronically reviewed. Ultimately, 410 patients
a driving time of more than 1 hour each way. Detailed were screened for eligibility, and 349 were en-
reasons for exclusion are provided in Table S2. A total rolled; 175 were randomly assigned to the inter-
of 410 patients had full, in-person screening visits, of
whom 349 were enrolled. Of these, 304 had available
vention group and 174 to the control group. Data
data for the analysis of the primary outcome. Figure S2 were available for analysis of the primary and
shows screening and randomization information for the secondary outcomes for 87% and 99% of the pa-
secondary outcome. ADHF denotes acute decompensat- tients, respectively (Fig. 1 and Fig. S2).
ed heart failure. The demographic and clinical characteristics
of the patients at baseline are shown in Table 1
ing the primary outcome), with adjustment for and in Table S3. The mean (±SD) age was
baseline measures.23 Differences between the 72.7±8.1 years, 52% of the patients were women,
two groups in the rate of rehospitalization (for and 49% were non-White (of whom 94% were
any cause and for heart failure) and in the num- Black). The cause of heart failure was ischemic
ber of days of rehospitalization were assessed heart disease in 35% of the patients, and 53% had
with the use of joint models similar to those preserved ejection fraction. Patients had high
described above, with a Poisson distribution for burdens of coexisting conditions, and the inci-
clinical events based on counts and a negative dences of previous hospitalization for any cause
binomial distribution for days of rehospitaliza- and previous hospitalization for heart failure
tion for any cause to account for overdispersion. were high (approximately 45% and 25%, respec-
Differences between the two groups in the rate tively). Most (97%) of the patients were assessed
of death and in the rate of combined rehospital- as frail or prefrail, according to the modified Fried
ization for any cause and death were assessed criteria. Urinary incontinence, falls, and depression
with the use of generalized linear models, with were common. The incidence of diabetes melli-
a Poisson distribution. Differences in proportion- tus was higher in the intervention group than in
based (binary) clinical measures were analyzed the control group (58% vs. 47%). At baseline, the
with the use of logistic regression. All the mod- patients were assessed as having severely im-
els were adjusted for clinical site, ejection fraction paired physical function, poor quality of life, and
category, age, and sex. The secondary outcome at least mild cognitive dysfunction (Table 2).
was adjusted for the baseline score on the Short
Physical Performance Battery. The potential con- Follow-up and Trial Outcomes
sistency of intervention effects among prespeci- The last follow-up visit was in March 2020.
fied subgroups for the primary outcome was ex- Among the 175 patients who had been randomly
amined with the use of forest plots. assigned to the rehabilitation intervention, 12
For the primary outcome, a two-tailed P value died before completing the intervention, 14 were
of less than 0.05 was considered to indicate sta- lost to follow-up for the analysis of the primary
tistical significance. For all other outcomes, effect- outcome, and 16 permanently discontinued the
size estimates and 95% confidence intervals are intervention but were included in the analyses of
reported without P values. The widths of the con- the primary and secondary outcomes. In an analy-
fidence intervals were not adjusted for multiple sis that excluded patients who died, patient re-
comparisons, so the intervals should not be used tention in the intervention group was 82%, and
to infer definitive treatment effects for the sec- patients completed a mean (±SE) of 24.3±1.0 out-
ondary outcome or other outcomes. Analyses were patient intervention sessions; adherence to the
performed with SAS Enterprise Guide, version 7.11, sessions was 67±3% (Fig. S3 and Table S4). After
and SAS software, version 9.4. adjustment for sessions missed because of med-

ical appointments and illness, adherence to the and 8 in the control group were from cardiovas-
intervention was 78±3%. Patients generally pro- cular causes (Table S9). Serious and nonserious
gressed to higher functional levels in each do- adverse events are summarized in Tables S10 and
main during the course of the intervention S11. Chest pain, hypertension, dizziness, hyper-
(Fig. 2). A key goal was to increase each patient’s glycemia, and hypoglycemia were more common
exercise endurance (duration of walking); among in the intervention group than in the control
patients who participated in the first and last group, and falls and heart failure were more com-
sessions, the mean (±SD) endurance doubled mon in the control group.
from 10.7±5.9 minutes in the first session to
22.0±11.1 minutes in the last session. Additional Discussion
data regarding exercise during the hospitaliza-
tion, outpatient, and maintenance phases are The REHAB-HF trial examined the effects of an
provided in Tables S5 through S7; information early, transitional, tailored, progressive rehabili-
regarding usual-care exercise therapy not associ- tation intervention that included multiple physi-
ated with the trial is provided in Table S8. cal-function domains in frail, older patients who
After adjustment for the baseline Short Physi- were hospitalized for acute decompensated heart
cal Performance Battery score and other base- failure. The intervention group had significantly
line characteristics, the least-squares mean (±SE) greater improvement in physical function, as as-
score on the Short Physical Performance Battery sessed by the score on the Short Physical Perfor-
at 3 months was 8.3±0.2 in the intervention mance Battery at 3 months, than the control
group and 6.9±0.2 in the control group (mean group. The results of the analyses of 6-minute
between-group difference, 1.5; 95% confidence walk distance, frailty status, quality of life, and
interval [CI], 0.9 to 2.0; P<0.001) (Table 2 and depression also suggested clinical benefits of
Fig. S4). This effect appeared to be relatively the intervention. Over the course of 6 months,
uniform across a wide variety of prespecified the incidence of rehospitalization for any cause,
subgroups (Fig. 3). The results for each of the rehospitalization for heart failure, and death was
three components of the Short Physical Perfor- high in both groups.
mance Battery are shown in Table 2. The benefit Our trial was designed to address several criti-
of the rehabilitation intervention persisted after cal evidence gaps regarding physical rehabilita-
post hoc adjustment for baseline imbalances in tion in patients with heart failure. Most previous
diagnoses of diabetes and peripheral vascular trials excluded patients who had been hospital-
disease; the least-squares mean score was 8.3±0.2 ized within the previous 6 weeks — a period
in the intervention group and 6.8±0.2 in the during which the severity of physical dysfunction
control group (mean between-group difference, and the risk of clinical events are highest; those
1.5; 95% CI, 0.9 to 2.1). trials also involved few older, frail patients with
The secondary outcome, the rate of rehospi- multiple coexisting conditions in whom differ-
talization for any cause at 6 months, showed no ent approaches may be appropriate.3,10 In previous
appreciable difference between the intervention early trials of rehabilitation after heart failure,
group and the control group, with rates of 1.18 enrollment of the patients and initiation of the
and 1.28, respectively (rate ratio, 0.93; 95% CI, intervention began, on average, 7 weeks after hos-
0.66 to 1.19) (Table 2). The exploratory outcomes, pital discharge; traditional endurance exercise
including 6-minute walk distance, gait speed, training was commonly used24,25; the enrolled pa-
hand-grip strength, frailty status, quality of life, tients were younger and much less frail and diverse
cognition, depression, and clinical events includ- than those in our trial25; there was no control
ing falls and rehospitalizations, are shown in group24,26; and the trials were unblinded25,27 and
Table 2 and Figure S5. often small, single-center trials.27 One of the
There were 21 deaths in the intervention largest of such trials involving recently hospital-
group and 16 deaths in the control group; the ized patients, EJECTION-HF (Exercise Joins Edu-
rates of death were 0.13 and 0.10, respectively cation: Combined Therapy to Improve Outcomes
(rate ratio, 1.17; 95% CI, 0.61 to 2.27) (Table 2). in Newly-Discharged Heart Failure), showed no
Among these deaths, 15 in the intervention group benefit of the intervention over usual care with

Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*
Intervention Control
Characteristic (N = 175) (N = 174)
Age — yr 73.1±8.5 72.2±7.7
Female sex — no. (%) 85 (49) 98 (56)
Non-White race — no. (%)† 81 (46) 91 (52)
Body-mass index‡ 32.9±8.2 33.0±8.9
Ejection fraction ≥45%, indicating preserved ejection fraction — no. (%) 93 (53) 92 (53)
Heart failure caused by ischemic heart disease — no. (%)§ 66 (38) 56 (32)
NYHA class — no. (%)
II 33 (19) 34 (20)
III 100 (57) 90 (52)
IV 41 (23) 51 (29)
Median B-type natriuretic peptide (IQR) — pg/ml¶ 595 (259–1292) 645 (381–1072)
Median N-terminal pro–B-type natriuretic peptide (IQR) — pg/ml‖ 2527 (1395–4858) 3615 (1874–8637)
Median no. of days hospitalized during index hospitalization (IQR) 4 (3–7) 5 (3–7)
Patients with ≥1 hospitalization in previous 6 mo — no. (%) 76 (43) 80 (46)
Coexisting conditions
Total no. of coexisting conditions 5.4±2.0 5.0±1.9
Hypertension — no. (%) 159 (91) 162 (93)
History of myocardial infarction — no. (%) 31 (18) 32 (18)
History of coronary revascularization, including PCI and CABG 55 (31) 47 (27)
— no. (%)
Atrial fibrillation — no. (%) 89 (51) 87 (50)
Diabetes mellitus — no. (%) 101 (58) 81 (47)
Hyperlipidemia — no. (%) 110 (63) 120 (69)
Depression, according to electronic medical record — no. (%) 29 (17) 33 (19)
Geriatric conditions
Dementia or cognitive impairment, according to electronic medical 6 (3) 4 (2)
record — no. (%)
Frail, as defined by the presence of at least three Fried criteria** 92 (53) 100 (57)
— no. (%)
Prefrail, as defined by the presence of one or two Fried criteria** 77 (44) 68 (39)
— no. (%)
Urinary incontinence — no./total no. (%) 19/144 (13) 21/142 (15)
Patients with falls in previous 3 mo — no./total no. (%) 24/143 (17) 20/146 (14)
* Plus–minus values are means ±SD. CABG denotes coronary artery bypass graft, IQR interquartile range, NYHA New
York Heart Association, and PCI percutaneous coronary intervention.
† Race was reported by the patient.
‡ The body-mass index is the weight in kilograms divided by the square of the height in meters.
§ Ischemic heart disease was determined to be the cause of heart failure if a patient had a history of myocardial infarc-
tion, coronary revascularization, or both.
¶ This analysis included data from 104 patients in the intervention group and 100 patients in the control group.
‖ This analysis included data from 58 patients in the intervention group and 59 patients in the control group.
** The five Fried criteria include weight loss, exhaustion, low physical activity, slow gait speed, and weak hand-grip
strength.

Table 2. Trial Outcomes.
Intervention Control Effect Size

Outcome (N = 175) (N = 174) (95% CI)
Outcomes at 3 mo*
SPPB score, primary outcome†
At baseline 6.0±2.8 6.1±2.6
At 3 mo 8.3±0.2 6.9±0.2 1.5 (0.9 to 2.0)‡
No. of patients assessed at 3 mo 149 155
Balance score
At baseline 2.6±1.3 2.7±1.3
At 3 mo 3.2±0.1 2.9±0.1 0.4 (0.1 to 0.6)
4-M walk score
At baseline 2.3±1.0 2.3±1.0
At 3 mo 3.0±0.1 2.5±0.1 0.5 (0.2 to 0.7)
Chair rise score
At baseline 1.1±1.2 1.2±1.2
At 3 mo 2.1±0.1 1.5±0.1 0.6 (0.4 to 0.9)
6-Min walk distance — m
At baseline 194±104 193±107
At 3 mo 293±8 260±8 34 (12 to 56)
Gait speed — m/sec
At baseline 0.60±0.23 0.61±0.22
At 3 mo 0.80±0.02 0.68±0.02 0.12 (0.07 to 0.16)
Hand-grip strength — kg
Men
At baseline 30.3±9.5 30.5±10.7
At 3 mo 30.1±0.7 30.6±0.8 −0.5 (−2.5 to 1.6)
Women
At baseline 20.7±7.3 19.6±6.6
At 3 mo 21.3±0.6 21.4±0.5 −0.2 (−1.7 to 1.4)
Frailty status — no. of modified Fried criteria met§
At baseline 2.3±1.1 2.4±1.1
At 3 mo 1.4±0.1 1.6±0.1 −0.3 (−0.5 to 0)
KCCQ overall score¶
At baseline 40±21 42±21
At 3 mo 69±2 62±2 7.1 (2.0 to 12.2)

Table 2. (Continued.)
Intervention Control Effect Size

Outcome (N = 175) (N = 174) (95% CI)
EQ-5D-5L visual-analogue scale score‖
At baseline 58±22 58±21
At 3 mo 71±2 65±2 7.0 (2.3 to 11.6)
MoCA score**
At baseline 21.9±4.2 21.8±4.5
At 3 mo 22.2±0.3 22.5±0.3 −0.2 (−1.0 to 0.6)
Geriatric Depression Scale–15 score††
At baseline 4.7±3.3 4.7±3.4
At 3 mo 3.3±0.2 4.1±0.2 −0.7 (−1.3 to −0.1)
Clinical events at 6 mo*
No. of patients 174 173
Rehospitalization for any cause, secondary outcome 194 (1.18) 213 (1.28) 0.93 (0.66 to 1.19)‡‡
— no. of events (rate)
Death — no. of events (rate) 21 (0.13) 16 (0.10) 1.17 (0.61 to 2.27)‡‡
Combined rehospitalization for any cause and death 215 (1.31) 229 (1.38) 0.93 (0.77 to 1.12)‡‡
— no. of events (rate)
Rehospitalization for heart failure — no. of events 94 (0.57) 110 (0.66) 0.89 (0.56 to 1.22)‡‡
(rate)
No. of patients with ≥2 rehospitalizations for any 47 (27) 60 (35) 0.71 (0.44 to 1.13)§§
cause (%)
No. of patients with ≥2 rehospitalizations for heart 22 (13) 27 (16) 0.78 (0.41 to 1.46)§§
failure (%)
No. of days of rehospitalization for any cause 7.2 7.6 0.92 (0.52 to 1.22)‡‡
No. of patients with ≥1 fall (%) 48 (28) 62 (36) 0.67 (0.42 to 1.06)§§
No. of patients with ≥1 fall that resulted in injury (%) 12 (7) 16 (9) 0.66 (0.30 to 1.47)§§
* Baseline data are presented as means ±SD. Follow-up data at 3 months are presented as least-squares means ±SE,
with adjustment for baseline value, clinical site, age, sex, and ejection fraction category. The effect sizes for the
3-month outcomes are shown as between-group differences in the least-squares mean change. The widths of the
confidence intervals (CIs) have not been adjusted for multiple comparisons, so the intervals should not be used to
infer definitive treatment effects for the secondary outcome and other outcomes.
† Total scores on the Short Physical Performance Battery (SPPB) range from 0 to 12, with lower scores indicating more
severe physical dysfunction; each component (the standing balance test, the gait-speed test [as assessed by a 4-m walk],
and the strength test [as assessed by the time needed to rise from a chair five times]) is scored on a scale of 0 to 4.
‡ P<0.001.
§ For the comparison of the baseline and follow-up results in this trial, the Fried criteria were modified to exclude the
weight-loss criterion owing to difficulty in ascertaining weight changes because of changes in fluid status.
¶ Scores on the Kansas City Cardiomyopathy Questionnaire (KCCQ) range from 0 to 100, with higher scores indicating
better health status.
‖ Scores on the EQ-5D-5L (also known as the European Quality of Life 5-Dimension 5-Level questionnaire) visual-
analogue scale range from 0 to 100, with higher scores indicating better health status.
** Scores on the Montreal Cognitive Assessment (MoCA) range from 0 to 30, with higher scores indicating better cogni-
tive function.
†† Scores on the Geriatric Depression Scale-15 range from 0 to 15, with higher scores indicating worse depressive symptoms.
‡‡ The effect size is shown as a rate ratio.
§§ The effect size is shown as an odds ratio.

212
A Balance B Strength
100 100
80 80
60 60
40 40
Percentage of Patients
20 20
The
0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
Intervention Session Intervention Session
C Mobility D Endurance
100 100
80 80
60 60
n e w e ng l a n d j o u r na l

of
40 40
n engl j med 385;3 nejm.org July 15, 2021

20 20

m e dic i n e
0 0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
Intervention Session Intervention Session
Figure 2. Progression of Physical Function over Time in the Intervention Group, According to Exercise Domain.
As described previously,17,18 each exercise session comprised four domains (balance, strength, mobility, and endurance) and four stratification levels (level 1, shown in red; level 2,
yellow; level 3, blue; and level 4, purple) corresponding to increasing thresholds of functional ability. For all four domains, as the number of sessions increased during the rehabili-
tation intervention, the percentage of patients who were performing at higher levels of functional ability (levels 3 and 4) generally increased, whereas the percentage of patients
who were performing at lower levels (1 and 2) generally decreased. The black, dark gray, and light gray areas indicate the percentages of patients who died, were lost to follow-up,
or discontinued the intervention, respectively.
Subgroup Intervention Control Between-Group Difference in Mean Score (95% CI)

no. of patients (mean score on SPPB) points
Overall 149 (8.3±0.2) 155 (6.9±0.2) 1.5 (0.9 to 2.0)
Age
<70 yr 63 (7.9±0.3) 74 (6.7±0.3) 1.2 (0.4 to 2.1)
≥70 yr 86 (8.0±0.3) 81 (6.3±0.3) 1.6 (0.9 to 2.4)
Sex
Male 78 (7.4±0.3) 69 (6.4±0.3) 1.0 (0.1 to 1.8)
Female 71 (8.5±0.3) 86 (6.6±0.3) 1.9 (1.1 to 2.7)
Race
Non-White 67 (7.8±0.3) 80 (6.6±0.3) 1.2 (0.4 to 2.1)
White 82 (8.1±0.3) 75 (6.4±0.3) 1.7 (0.9 to 2.5)
Ejection fraction
<45% 65 (8.1±0.3) 76 (7.0±0.3) 1.1 (0.3 to 2.0)
≥45% 84 (7.8±0.3) 79 (6.0±0.3) 1.7 (1.0 to 2.5)
NYHA class
II 31 (8.9±0.5) 28 (5.9±0.5) 3.0 (1.7 to 4.3)
III or IV 118 (7.7±0.3) 127 (6.6±0.3) 1.1 (0.4 to 1.7)
Atrial fibrillation
No 72 (8.2±0.3) 80 (6.7±0.3) 1.5 (0.6 to 2.3)
Yes 77 (7.7±0.3) 75 (6.2±0.3) 1.5 (0.7 to 2.3)
Ischemic heart disease
No 95 (8.2±0.3) 109 (6.7±0.3) 1.5 (0.8 to 2.2)
Yes 54 (7.5±0.4) 46 (6.1±0.4) 1.4 (0.4 to 2.4)
Diabetes mellitus
No 63 (8.3±0.3) 83 (6.8±0.3) 1.5 (0.7 to 2.3)
Yes 86 (7.8±0.3) 72 (6.2±0.3) 1.5 (0.7 to 2.3)
Obesity
BMI <30 59 (7.9±0.4) 62 (6.8±0.3) 1.1 (0.2 to 2.0)
BMI ≥30 90 (8.0±0.3) 93 (6.3±0.3) 1.7 (1.0 to 2.4)
Overweight or obesity
BMI <25 24 (8.0±0.5) 30 (6.3±0.5) 1.7 (0.3 to 3.1)
BMI ≥25 125 (8.0±0.3) 125 (6.6±0.3) 1.4 (0.8 to 2.0)
COPD
No 100 (8.1±0.3) 119 (6.3±0.3) 1.8 (1.1 to 2.5)
Yes 49 (7.7±0.4) 36 (7.1±0.4) 0.6 (–0.5 to 1.7)
Chronic kidney disease
No 100 (8.2±0.3) 106 (7.0±0.3) 1.2 (0.5 to 1.9)
Yes 49 (7.6±0.4) 49 (5.6±0.4) 2.0 (1.0 to 3.0)
Depression
No 125 (8.0±0.3) 125 (6.4±0.3) 1.6 (0.9 to 2.2)
Yes 24 (7.8±0.5) 30 (6.8±0.5) 1.0 (–0.4 to 2.4)
Cognitive function
MoCA score ≥26 33 (8.2±0.5) 34 (7.0±0.5) 1.2 (0 to 2.4)
MoCA score <26 114 (7.9±0.3) 119 (6.3±0.3) 1.6 (0.9 to 2.2)
Frailty status
Nonfrail or prefrail 72 (7.9±0.3) 69 (7.2±0.3) 0.7 (–0.1 to 1.5)
Frail 77 (8.1±0.3) 86 (6.0±0.3) 2.1 (1.3 to 2.8)
–2 –1 0 1 2 3 4 5
Control Intervention
Better Better
Figure 3. Prespecified Subgroup Analysis of the Primary Outcome.

Plus–minus values are least-squares mean ±SE scores on the Short Physical Performance Battery (SPPB). The primary outcome was the score
on the SPPB (total scores range from 0 to 12, with lower scores indicating more severe physical dysfunction) at 3 months. The effect size of
the intervention on the SPPB score was relatively large and uniform across a broad range of key subgroups. The widths of the confidence inter-
vals have not been adjusted for multiple comparisons, so the intervals should not be used to infer definitive treatment effects for the sub-
groups. Race was reported by the patient. An ejection fraction of at least 45% indicates preserved ejection fraction. The body-mass index
(BMI) is the weight in kilograms divided by the square of the height in meters. Cognitive function was assessed with the use of the Montreal
Cognitive Assessment (MoCA); scores range from 0 to 30, with higher scores indicating better cognitive function, and a score of 26 or higher
indicates normal cognitive function. COPD denotes chronic obstructive pulmonary disease, and NYHA New York Heart Association.

respect to 6-minute walk distance, rehospitaliza- depression in patients with heart failure have had
tion, and death, but adherence to the intervention neutral results.
was low (43%).25 The greater improvements in physical func-
Physical dysfunction, frailty, and depression tion relative to the control group were seen de-
are often unrecognized clinically in older patients spite the receipt of routine physical or occupa-
hospitalized for heart failure,8,28 are generally tional therapy or traditional cardiac or pulmonary
not addressed in clinical care pathways,10,29 and rehabilitation as part of usual care by 43% of the
probably contribute to delayed, incomplete re- patients in the control group. At 6 months, 83%
covery and high rates of rehospitalization, death, of the patients in the intervention group who
and long-term loss of independence after hospi- were alive and were being followed by telephone
tal discharge.2,11,12,14 Physical-function impairments contact reported regular home exercise, which
in the patients in the REHAB-HF trial were broad- suggested that behavioral change — a requisite
er and more severe than those observed in pa- for long-term adherence — may have occurred.
tients with chronic heart failure.28 For example, The intervention-related benefits may be re-
the mean baseline 6-minute walk distance in the lated to both the severity of the baseline deficits
REHAB-HF trial was half that observed in the and the robust, broad systemic effects of physical
HF-ACTION (Heart Failure: A Controlled Trial In- exercise, which favorably alters energy metabo-
vestigating Outcomes of Exercise Training) trial,30 lism, oxidative stress, inflammation, tissue repair,
and severe leg weakness prevented nearly one third growth-factor response, and regulatory pathways.38
of the patients from standing even once from a Older patients with heart failure can have severe
seated position without the use of their arms. skeletal-muscle myopathy that contributes to phys-
The patients in our trial also had severe deficits ical dysfunction and abates with exercise.9
in balance and mobility, and a history of falls The number of deaths, including deaths from
and other geriatric conditions was common — cardiovascular causes, was higher in the inter-
findings that are not typically seen in patients vention group than in the control group, al-
with chronic heart failure and are not addressed though the numbers and differences were small
by conventional cardiac rehabilitation. The initia- and may have been due to chance. A meta-analy-
tion of standard endurance exercise training in sis of trials of exercise-based rehabilitation for
frail, older patients without first addressing defi- heart failure showed no significant effect on
cits in balance and mobility can limit efficacy31 death from any cause during follow-up for up to
and increase the risk of injuries and falls.32,33 12 months.39 In the EJECTION-HF trial, fewer
The intervention-related benefits seen in the deaths were reported in the intervention group
REHAB-HF trial generally exceeded previously than in the control group at 12 months.25 Given
reported values for the minimal clinically impor- the wide confidence interval for the rate ratio for
tant difference. The mean difference between the death from any cause, we cannot rule out the pos-
groups in the Short Physical Performance Bat- sibility of an increase (or decrease) in risk with an
tery score (1.5 points) was three times as large early exercise regimen among some patients.
as the reported minimal clinically important Our trial has other important limitations.
difference (0.5 points).21,34 All three of the com- First, the results did not show a beneficial effect
ponents of the Short Physical Performance Bat- on clinical events. However, a study that exam-
tery — corresponding to balance, strength, and ined patient preferences in patients with heart
mobility — showed greater improvement in the failure indicated that improving physical func-
intervention group than in the control group. tion and maintaining independence are highly
The apparent benefits in 6-minute walk distance valued, independent of clinical events.40 Second,
(34 m) and KCCQ score (7.1 points) were also although the staff members who assessed the
larger than the reported minimal clinically im- primary outcome were unaware of the trial-
portant differences (30 m and 5 points, respec- group assignments, it was not possible for pa-
tively).35,36 The suggested benefit for depression tients to be unaware of the group to which they
is of interest, since depression is common among had been randomly assigned. Third, the benefits
patients with heart failure and is associated with of the intervention over usual care may have
frequent rehospitalization,37 and trials targeting been moderated owing to the usual-care exercise

therapy received by the control group. Fourth, port, paid to Wake Forest Baptist Health, and advisory board
fees from AstraZeneca and Bayer, advisory board fees from
differences between the groups in the amount of Boehringer Ingelheim and Corvia Medical, consulting fees
caregiver attention could have influenced out- from Keyto and Merck, and grant support, paid to Wake Forest
comes. Fifth, the long-term durability of the Baptist Health, and consulting fees from Novartis; Dr. Whellan,
receiving grant support, paid to Thomas Jefferson University,
benefit of the intervention is uncertain. Finally, from Amgen, end-point committee fees from CVRx and Fibro-
many patients were ineligible or unable or un- Gen, steering committee fees from Cytokinetics, and grant sup-
willing to participate, and some discontinued port, paid to Thomas Jefferson University, and advisory board
fees from Novo Nordisk; Dr. Duncan, owning stock in Care Di-
the intervention. rections; and Dr. Mentz, receiving grant support from American
Among patients who were hospitalized for Regent and Cytokinetics, consulting fees from Amgen, Boeh-
acute decompensated heart failure, a transitional, ringer Ingelheim, and Relypsa, research support and honoraria
from Abbott, American Regent, Amgen, Boehringer Ingelheim,
tailored, progressive rehabilitation intervention Eli Lilly, Boston Scientific, Cytokinetics, FAST BioMedical, Gil-
that included multiple physical-function domains ead Sciences, Innolife, Medtronic, Relypsa, Respicardia, Roche,
and that began during, or early after, hospital- Sanofi, Vifor Pharma, and Windtree Therapeutics, grant sup-
port, research support, and honoraria from AstraZeneca, and
ization and continued for 12 weeks after hospi- research support, consulting fees, and honoraria from Bayer,
tal discharge resulted in significantly greater im- Merck, and Novartis. No other potential conflict of interest
provement in physical function than usual care. relevant to this article was reported.
Disclosure forms provided by the authors are available with
Supported by research grants from the National Insti- the full text of this article at NEJM.org.
tutes of Health (R01AG045551, R01AG18915, P30AG021332, A data sharing statement provided by the authors is available
P30AG028716, and U24AG059624), the Kermit Glenn Phillips with the full text of this article at NEJM.org.
II Chair in Cardiovascular Medicine, and the Oristano Family We thank Alain Bertoni, M.D., Peter Brubaker, Ph.D., and
Fund at Wake Forest School of Medicine. Jack Rejeski, Ph.D. for their critical review and editing of an
Dr. Kitzman reports receiving steering committee fees and earlier version of the manuscript; and Timothy Morgan, Ph.D.
data and safety monitoring board fees from AbbVie, grant sup- (deceased), for his biostatistical expertise.
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new england

Physical Rehabilitation for Older Patients Hospitalized

intervention that included multiple physical-function domains resulted in greater

204 n engl j med 385;3 nejm.org July 15, 2021

The New England Journal of Medicine

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27,300 Admission records were

26,890 Patients were excluded

410 Patients were screened for eligibility

349 Underwent randomization

175 Were assigned to the rehabilitation 174 Were assigned to the

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Figure 1 (facing page). Screening and Randomization. R e sult s

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Table 1. Demographic and Clinical Characteristics of the Patients at Baseline.*

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Table 2. Trial Outcomes.

Intervention Control Effect Size

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Intervention Control Effect Size

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The New England Journal of Medicine

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Copyright © 2021 Massachusetts Medical Society. All rights reserved.

Subgroup Intervention Control Between-Group Difference in Mean Score (95% CI)

Figure 3. Prespecified Subgroup Analysis of the Primary Outcome.

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