European Journal of Internal Medicine 110 (2023) 86–92

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European Journal of Internal Medicine

journal homepage: www.elsevier.com/locate/ejim

Original article

Functional outcome after cardiac rehabilitation and its association with

survival in heart failure across the spectrum of ejection fraction
Domenico Scrutinio a, *, Pietro Guida a, Maria Teresa La Rovere b, Maurizio Bussotti c,
Ugo Corrà d, Giovanni Forni e, Rosa Raimondo f, Simonetta Scalvini g, Andrea Passantino a
a
Istituti Clinici Scientifici Maugeri SpA SB, IRCCS, Institute of Bari, Via Generale Nicola Bellomo 73/75, Bari, Italy
b
Istituti Clinici Scientifici Maugeri SpA SB, IRCCS, Institute of Montescano, Pavia, Italy
c
Istituti Clinici Scientifici Maugeri SpA SB, IRCCS, Institute of Milano, Milano, Italy
d
Istituti Clinici Scientifici Maugeri SpA SB, IRCCS, Institute of Veruno, Novara, Italy
e
Istituti Clinici Scientifici Maugeri SpA SB, IRCCS, Institute of Pavia, Pavia, Italy
f
Istituti Clinici Scientifici Maugeri SpA SB, IRCCS, Institute of Tradate, Varese, Italy
g
Istituti Clinici Scientifici Maugeri SpA SB, IRCCS, Institute of Lumezzane, Brescia, Italy

A R T I C L E I N F O A B S T R A C T

Keywords: Background: There is limited evidence regarding the effects of cardiac rehabilitation (CR) in patients with heart
Cardiac rehabilitation failure and preserved ejection fraction (HFpEF).
Heart failure Methods: We studied 1784 patients admitted to inpatient CR. The patients were grouped into HFpEF (EF≥0.50),
Preserved ejection fraction
HF with mildly reduced EF (HFmrEF; EF 41–49), and HF with reduced EF (HFrEF; EF≤0.40). A standardized 6-
min walking test was performed at admission and discharge. Measures of functional outcome were: (1) absolute
increase in 6-min walking distance (6MWD) from admission to discharge >50 m and (2) increase in 6MWD to
≥300 among the patients who walked <300 m at admission.
Results: After adjustment, the patients with HFpEF or HFmrEF were as likely as those with HFrEF to achieve an
increase in 6MWD >50 m (odds ratio 0.95 [95%CI 0.71-1.24; p=0.648] and 1.04 [95%CI 0.77-1.41; p=0.769],
respectively) or an increase in 6MWD to ≥300 m (odds ratio 0.79 [95%CI 0.51-1.23; p=0.299] and 0.65 [95%CI
0.38-1.12; p=0.118], respectively). The adjusted hazard ratio of 5-year mortality for patients who achieved an
increase in 6MWD >50 m was 0.60 (95%CI 0.51-0.71; p<0.001) and that for patients who achieved an increase
in 6MWD at discharge to ≥300 m 0.61 (95%CI 0.48-0.79; p<0.001). In each EF group, both outcomes remained
independently associated with improved survival.
Conclusions: Our data suggest that patients with HFpEF or HFmrEF are as likely as those with HFrEF to benefit
from CR in terms of functional improvement. Functional improvement was independently associated with
improved long-term survival, regardless of EF.

1. Introduction Approximately half of the people with chronic HF have HF with

Heart failure (HF) is an increasingly prevalent clinical syndrome and
a major cause of cardiovascular mortality and morbidity [1,2]. Func­
tional disability and loss of independence are hallmark features of HF,
with a substantial proportion of patients having moderate to severe
difficulty with basic instrumental activities of daily living [3,4]. If left
untreated, such patients are very likely to show no change or experience
progression of their functional disability over time [3]. Notably,
persistently severe or worsening disability contributes to worsen prog­
nosis [3].
preserved ejection fraction (HFpEF) [5]. Epidemiological studies have
shown an increasing relative prevalence of HFpEF over the past two
decades [5]. Population aging, increasing prevalence of HFpEF-related
risk factors, and heightened diagnostic awareness have been impli­
cated to explain this trend [5]. Moreover, hospitalized patients with
HFpEF are increasingly managed in internal medicine and geriatrics
wards; in the SwedeHF Registry, the proportion of patients with HFpEF
admitted to noncardiology wards increased by almost 50% from 2000 to
2016 [6]. Typically, patients with HFpEF are older and more likely to be
females and have higher comorbidity burden than their HFrEF

* Corresponding author.
E-mail address: domenico.scrutinio@icsmaugeri.it (D. Scrutinio).

https://doi.org/10.1016/j.ejim.2023.02.002
Received 23 November 2022; Received in revised form 31 January 2023; Accepted 2 February 2023
Available online 8 February 2023
0953-6205/© 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
D. Scrutinio et al.
counterparts [5,7]. Surprisingly, in the Get With the Guidelines–Heart
Failure registry, hospitalized patients with HFpEF were more likely to be
discharged to any kind of rehabilitation institution compared with pa­
tients with HFrEF [8], although there was no evidence to support this
practice. Impairment of functional capacity is a key manifestation of
chronic HF. In HFpEF, it is as severe and debilitating as in HFrEF and is
associated with poor quality-of-life and clinical outcomes [9].
Increasing evidence indicates that cardiac rehabilitation (CR) can
significantly improve symptoms, functional status and quality of life,
and can reduce hospital admissions and mortality [10–16]. Current
clinical guidelines consistently recommend CR referral for patients with
HFrEF [17]. Previous studies aimed at assessing the effects of CR in HF
included relatively young patients, predominantly males, with a low
burden of comorbidities, and almost exclusively, with reduced EF [18,
19]. In the ExTraMATCH II Individual Participant Meta-Analysis, only
3.2% of the patients who underwent CR had HFpEF, defined as EF >45%
[19]. Thus, there is lack of evidence regarding the effects of CR in pa­
tients with HFpEF. The underrepresentation of HFpEF has substantially
limited our understanding of the potential benefits of CR in this highly
prevalent clinical condition and recommendations for CR. We hypoth­
esized that patients with HFpEF would experience similar improvement
in functional capacity after CR as patients with HFrEF. Furthermore, we
hypothesized that the improvement in functional capacity would be
associated with improved survival. To test these hypotheses, we studied
a large cohort of HF patients admitted to inpatient CR.
2. Methods
This was a retrospective study. We studied consecutive patients
discharged with a primary diagnosis of HF (International Classification
of Diseases, Ninth Revision codes: 402.01, 402.11, 402.91, 404.01,
404.03, 404.11, 404.13, 404.91, 404.93, and 428.xx) from six inpatient
CR units of a nationwide Research Institute in the field of Rehabilitation
Medicine in Italy between January 2013 and December 2016. According
to the national regulatory rules governing admissions to inpatient CR for
HF in Italy, patients had been admitted from acute-care hospitals just
after a hospitalization for HF or from the community because of wors­
ening functional capacity and/or deteriorating clinical status. To be
eligible for study inclusion, patients had (1) to be free of adverse clinical
events during the rehabilitation period (including death, (re)admission
to acute care hospitals, or serious clinical event); (2) to be discharged
home; (3) to have paired data for 6MWT at admission to and discharge
from CR; and (4) to be able to perform a six-minute walking test (6MWT)
at admission to CR. Of the 3301 patients enrolled in the study, 1784 met
the inclusion criteria. The patients were grouped into HF with preserved
EF (HFpEF), HF with mildly reduced EF (HFmrEF), and HF with reduced
EF (HFrEF). HFpEF was defined as HF with LVEF ≥0.50, HFmrEF as HF
with LVEF >0.40 to <0.50, and HFrEF as HF with LVEF ≤0.40 [2].
All participating centers are part of a single department of CR, share
a common formal rehabilitation program, and are certified ISO9001
Quality Management Systems for activities of rehabilitation. Activities
of rehabilitation and conformity with national regulatory rules for
admission to inpatient CR are subject to periodic external audit by in­
dependent auditors of the Regional Health Agencies. Our formal
multidisciplinary program is led by cardiologists and is designed to
promote stable clinical conditions, improve physical function through a
supervised exercise training plan tailored to the individual level of
functional ability at presentation, provide specialized medical assis­
tance, and optimize medical treatment. The exercise program consists of
a supervised training program including active/passive mobilization;
assisted ambulation; respiratory, musculoskeletal flexibility, movement
coordination, and/or callisthenic exercises; and training on a (unloaded)
bedside/upright cycle ergometer. The types of exercises and exercise
intensity are gradually progressed throughout the rehabilitation period,
according to the individual functional and clinical conditions. A stan­
dardized 6 min walking test (6MWT) [20] is performed by experienced
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European Journal of Internal Medicine 110 (2023) 86–92
physiotherapists or nurses at admission and discharge, as part of our
formal rehabilitation program.
2.1. Data collection
The data were extracted from the electronic Hospital Information
System shared between the participating centers and entered into a
REDCap database. Baseline measurements were obtained at the time of
admission to inpatient CR. LVEF was determined by echocardiography
at admission to CR and recorded in the electronic Hospital Information
System. All patients provided a written consent to the use of their data in
an anonymous form for scientific purposes. Any identifying information
was removed from the database and replaced with an identification
number. The Scientific Advisory Board of our Department of Cardiac
Rehabilitation approved the study. Survival status was ascertained by
linkage to the national Health Information System. The patients were
followed-up until death or November 30, 2019.
2.2. Functional outcome
We used the 6MWT to assess functional capacity. To evaluate a
clinically relevant improvement in distance walked on 6MWT (6MWD)
from admission to discharge, two measures were used. First, we defined
an outcome of 6MWD based on absolute change from admission to
discharge >50 m. This cut-off was chosen because it is considered a
clinically significant improvement, exceeds the 95th percentile (35 m) of
the learning effect observed by Uszko–Lencer, has been used as an
outcome measure in randomized clinical trials of cardiac resynchroni­
zation therapy or exercise training in HF, is associated with significant
changes in either aerobic capacity and/or health-related quality of life,
and predicts survival in older HF patients with severe functional
impairment [21–26]. Second, we defined an outcome of improvement
based on the achievement of 6MWD values at discharge ≥300 m in
patients who walked <300 m at admission. This outcome measure was
chosen because HF patients who walk <300 m on 6MWT represent a
subgroup at high risk for death and the cutoff of 300 m is a powerful
prognostic indicator, at least in HFrEF [27,28].
2.3. Statistical analysis
Data are reported as mean and standard deviation (SD) or median
with 25th and 75th percentiles for continuous variables and as number
and percentage for categorical variables. We used ANOVA or the
Kruskal-Wallis test to compare continuous variables and the Pearson χ2
test to compare categorical variables. Cumulative survival was esti­
mated using the Kaplan–Meier method and a log-rank test was used to
compare groups. The standardized mean difference (SMD) for change in
6MWD was calculated using Hedges’ g, which provides a measure of
effect size weighted according to the relative size of each sample. Un­
adjusted and adjusted logistic regression models were used to estimate
the odds ratio (OR) with 95% confidence intervals (CI) of achieving each
measure of functional outcome. The patients with HFrEF served as
reference group. The association between functional outcomes and 5-
year mortality was assessed using unadjusted and adjusted Cox regres­
sion models. Hazard ratios (HR) with 95% CI were estimated. The
multivariable models included age, sex, obesity, diabetes, chronic
obstructive pulmonary disease, NYHA III/IV class, EF group, hemoglo­
bin, estimated glomerular filtration rate, and 6MWD at admission
[29–32]. Hyponatremia defined as a serum sodium level <136 mEq/L
was incorporated in the multivariable Cox regression model, in addition
to the above-mentioned covariates [31]. The Cox analyses were
repeated in the subgroup with available data for NT-proBNP (N. 1205).
Missing data for hemoglobin (0.4%) and eGFR (0.1%) were replaced by
the median of observed values. Values of p <0.05 were considered sig­
nificant. All analyses were conducted using STATA software, version 14
(Stata-Corp LP, College Station, Tex).
D. Scrutinio et al.
3. Results
3.1. Baseline characteristics
The flowchart of patient selection is shown in Supplemental Fig. 1.
Table 1 displays baseline characteristics of the overall cohort and the
subgroup of 781 patients who achieved only a 6MWT distance <300 m
at admission, stratified by EF. Three hundred seventy-nine patients had
HFpEF, 237 had HFmrEF and 1168 had HFrEF. Of these patients 227
(59.9%), 112 (47.5%), and 442 (37.8%), respectively, exhibited 6MWD
at admission <300 m (p <0.001). In the overall cohort, the patients with
HFpEF were older and more often females, had a higher comorbidity
burden, and more commonly had hypertension and atrial fibrillation,
compared with those with HFrEF. Similar findings were observed for the
patients who walked <300 m on admission 6MWT.
3.2. Six-minute walking test
Table 2 displays 6MWT data. Compared to patients with HFrEF,
those with HFpEF exhibited poorer functional capacity at admission, as
assessed by 6MWD. In the overall cohort, the SMD for change in 6MWD
between HFpEF and HFrEF was − 0.12 and that between HFmrEF and
HFrEF − 0.16, indicating that the magnitude of the effect was small. In
the subgroup of patients who walked <300 m on admission 6MWT, the
SMD for change in 6MWD between HFpEF and HFrEF was − 0.37 and
that between HFmrEF and HFrEF − 0.30, indicating that the magnitude
of the effect was medium.
3.3. Increase in 6MWD >50 m
One hundred sixty-nine (44.6%) patients with HFpEF, 110 (46.4%)
with HFmrEF, and 564 (48.3%) with HFrEF achieved an increase in
6MWD >50 m from admission to discharge (p=0.439). In these patients,
6MWD increased by 101±46 m, 93±42 m, and 107±50 m, respectively
(p=0.018).
Compared to patients with HFrEF, the crude OR of achieving an in­
crease in 6MWD >50 m was 0.86 (95 CI 0.68-1.09; p=0.211) for patients
with HFpEF and 0.93 (95% CI 0.70-1.23; p=0.599) for those with
HFmrEF. After full adjustment, the ORs were 0.95 (95% CI 0.71-1.24;
p=0.648) and 1.04 (95% CI 0.77-1.41; p=0.769, respectively.
3.4. Increase in 6MWD to 300 m or more
A significantly lower proportion of patients with HFpEF or HFmrEF
achieved an increase in 6MWD at discharge to 300 m or more, compared
to patients with HFrEF (30.4% and 29.5% vs 48.6%, respectively;
p<0.001). In these patients, 6MWD increased by 112±62 m, 114±66 m,
and 123±68 m (p=0.423), respectively.
Compared with patients with HFrEF, the crude OR of achieving an
increase in 6MWD to 300 m or more was 0.45 (95% CI 0.33-0,65; p
<0.001) for patients with HFpEF and 0.44 (95% 0.28-0.69; p <0.001)
for those with HFmrEF. Based on Wald statistics, 6MWD at admission
and age were by far the most important independent factors influencing
the likelihood of achieving an increase in 6MWD to 300 m or more.
Other independent factors were estimated glomerular filtration rate,
NYHA III/IV class, and female sex (Supplemental Table 1). After full
adjustment, the magnitude of the decreased odds of achieving an in­
crease in 6MWD to 300 m or more for HFpEF and HFmrEF was sub­
stantially downsized to loose statistical significance. The adjusted OR
was 0.79 (95% CI 0.51-1.23; p=0.299) for HFpEF and 0.65 (95% CI
0.38-1.12; p=0.118) for HFmrEF.
3.5. Association of functional outcome with survival
Thirty-seven (2.1%) patients (5 with HFpEF, 8 with HFmrEF, and 21
with HFrEF) were lost to follow-up, leaving 1747 available for survival
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European Journal of Internal Medicine 110 (2023) 86–92
analyses. During a mean follow-up of 1364 days, 650 patients died
within 5 years. Kaplan-Meier estimated cumulative survival was 58.8%
(95% CI 56.2-61.3). There was no between-group difference in 5-year
survival (Supplemental Fig. 2).
Fig. 1 displays Kaplan-Meier estimated survival for patients who
achieved or did not achieve the outcomes in the overall cohort. The
adjusted HR of 5-year mortality for patients who achieved an increase in
6MWD >50 m was 0.60 (95% CI 0.51-0.71; p<.001) and that for pa­
tients who achieved an increase in 6MWD at discharge to 300 m or more
0.61 (95% CI 0.48-0.79; p<.001). Further adjustment for NT-proBNP
did not modify the association between each measure of functional
outcome and 5-year mortality (HR 0.65 [95% CI 0.53-0.80; p <0.001]
and 0.62 [95% CI 0.45-0.84; p=.002], respectively).
Fig. 2 displays the adjusted HR of 5-year mortality for patients with
HFpEF, HFmrEF, or HFrEF. In each EF group, both increase in 6MWD
>50 m and increase in 6MWD to 300 m or more remained independently
associated with improved survival, albeit estimates in the subgroup of
patients who walked less than 300 m at admission had wider confidence
intervals than in the overall cohort due to the lower number of patients.
4. Discussion
There is limited evidence regarding the effects of CR in patients with
HFpEF. We hypothesized that patients with HFpEF would experience
similar improvement in functional capacity after CR as patients with
HFrEF and that the improvement in functional capacity would be
associated with improved survival. Despite the inherent limitations of
this observational, uncontrolled, retrospective study, we demonstrated
that: (1) patients with HFpEF or HFmrEF were as likely as those with
HFrEF to achieve a clinically relevant improvement in functional ca­
pacity after CR; (2) after adjustment for well-established conventional
and disease-focused prognostic factors, functional improvement was
independently associated with improved long-term survival; (3) func­
tional improvement remained significantly associated with survival
regardless of whether EF was preserved, mildly reduced, or reduced.
We used the 6MWT to assess functional capacity. The 6MWT is an
inexpensive and reproducible sub-maximal exercise tool to assess
functional capacity, to evaluate treatment efficacy, and to predict
prognosis in HF [22,23,27,33–36]. It reflects the daily activity level and
is the most widely used test to measure functional capacity in the CR
setting [37]. There is suggestive evidence that 6MWT performs better as
a prognostic tool for HF patients with severely impaired functional ca­
pacity, in whom daily activity level is likely to approach maximal ex­
ercise capacity [21,28,36,38]. Data from the HF-ACTION trial also
suggest that it provides prognostic utility comparable to cardiopulmo­
nary exercise testing in outpatients with reduced EF [35].
It is well documented that patients with HFpEF are older and more
likely to be females and have higher comorbidity burden than their
HFrEF counterparts, albeit heterogeneity in clinical phenotypes and
pathophysiological mechanisms has been suggested [5]. Our findings
are consistent with the exiting knowledge. The patients with HFpEF
were approximately 8 years older, more often females, and more likely
to be obese and to have hypertension, diabetes mellitus, chronic
obstructive pulmonary disease, anemia, and atrial fibrillation. Notably,
approximately three in ten patients with HFpEF were ≥80 years old
compared with only one in ten in HFrEF. Additionally, we showed that
the patients with HFpEF had worse functional capacity, as documented
by the significantly lower distance walked on 6MWT and the higher
proportion of patients walking less than 300 m at presentation. This
pattern persisted after CR, albeit both groups similarly benefitted in
terms of functional improvement. Indeed, no between-group difference
in absolute change in 6MWD or in the proportion of patients who gained
more than 50 m increase in 6MWD from admission to discharge was
observed; moreover, the between-group SMD for change in 6MWD
ranged from − 0.12 to − 0.16, indicating that the magnitude of the dif­
ference was small. After adjustment, the patients with HFpEF were as
D. Scrutinio et al. European Journal of Internal Medicine 110 (2023) 86–92

Table 1
Baseline characteristics stratified by ejection fraction.
HFpEF HFmrEF HFrEF
(LVEF ≥0.50, N. 379) (LVEF 0.41–0.49, N. 237) (LVEF ≤0.40; N. 1168)
Number of Mean (SD) Number of Mean (SD) Number of Mean (SD) or p value
observations or observations or observations N (%)
N (%) N (%)
ALL PATIENTS (N. 1784)

Demographics
Age (years), mean (SD) 379 73.6 (11.9) 237 69.9 (13.0) 1168 65.3 (12.3) <0.001
Age ≥80 years, N (%) 379 124 (32.7) 237 58 (24.5) 1168 136 (11.6) <0.001
Females, N (%) 379 203 (53.6) 237 87 (36.7) 1168 217 (18.6) <0.001
Comorbidities
Obesity (body mass index ≥30), N (%) 379 143 (37.7) 237 68 (28.7) 1168 261 (22.3) <0.001
Hypertension, N (%) 379 370 (97.6) 237 132 (55.7) 1168 382 (32.7) <0.001
Diabetes mellitus, N (%) 379 126 (33.2) 237 80 (33.8) 1168 313 (28.3) <0.001
Chronic obstructive pulmonary disease, N (%) 379 115 (30.3) 237 48 (20.3) 1168 209 (17.9) <0.001
Chronic kidney disease, N (%) 377 221 (58.6) 237 137 (57.8) 1168 646 (55.3) .470
Stage 3a (eGFR 45–59 mL/min/1.73 m2) 75 (19.9) 51 (21.5) 299 (25.6) .057
Stage 3b (eGFR 30–44 mL/min/1.73 m2) 98 (26.0) 58 (24.5) 244 (20.9)
Stage 4 (eGFR 15–29 mL/min/1.73 m2) 45 (11.9) 26 (11.0) 99 (8.5)
Stage 5 (eGFR <15 mL/min/1.73 m2) 3 (0.8) 2 (0.8) 4 (0.3)
Anemia (hemoglobin <13 g/dL in men and <12 377 180 (47.7) 235 101 (43.0) 1165 450 (38.6) .006
g/dL in women), N (%)
Atrial fibrillation, N (%) 379 213 (56.2) 237 82 (34.6) 1168 354 (30.3) <0.001
Clinical findings
Etiology 286 201 973
Ischemic heart disease 93 (32.5) 103 (51.2) 527 (54.2) <0.001
Hypertension 106 (37.1) 20 (10.0) 22 (2.3)
Dilated cardiomyopathy 42 (14.7) 61 (30.3) 381 (39.2)
Valve disease * 33 (11.5) 15 (7.5) 43 (4.4)
Other 12 (4.2) 2 (1.0) 0
Transferred from acute care hospitals after a 379 123 (32.5) 237 67 (28.3) 1168 375 (32.1) .478
hospitalization for HF, N (%)
NYHA III/IV class, N (%) 379 215 (56.7) 237 141 (59.5) 1168 716 (61.3) .281
ICD, N (%) 379 21 (5.5) 237 39 (16.5) 1168 510 (43.7) <0.001
Systolic blood pressure (mm Hg), mean (SD) 364 120.0 228 118.5 1130 109.6 (15.7) <0.001
(18.5) (17.9)
Diastolic blood pressure (mm Hg), mean (SD) 364 70.3 (9.1) 228 71.1 (9.4) 1130 68.5 (8.5) <0.001
Left ventricular ejection fraction, mean (SD) 379 58.2 (5.5) 237 44.5 (2.5) 1168 29.0 (6.6) <0.001
Length of stay in the IRFs (days), mean (SD) 379 20.8 (7.8) 237 19.5 (7.7) 1168 20.5 (8.8) .167
Laboratory findings
Hemoglobin (g/dL), mean (SD) 377 12.3 (1.8) 235 12.6 (1.8) 1165 13.2 (1.9) <0.001
Creatinine (mg/dL), (mean (SD) 377 1.30 (0.62) 237 1.31 (0.55) 1168 1.36 (0.53) .164
eGFR (mL/min/1.73 m2), mean (SD) 377 56.7 (25.6) 237 58.3 (25.1) 1168 58.0 (22.3) .602
Sodium <136 mEq/L, N (%) 377 43 (11.4) 237 24 (10.1) 1167 201 (17.2) .002
NT-proBNP (pg/mL), median (IQR) 181 1125 148 914 876 2054 .354
(461–2739) (256–3214) (871–3973)
Treatment at discharge
RAAS-Is, N (%) 379 282 (74.5) 237 204 (86.1) 1168 1059 (90.7) <0.001
Beta-blockers 379 279 (73.6) 237 212 (89.5) 1168 1103 (93.0) <0.001
RAAS-I plus beta-blocker 379 215 (56.7) 237 186 (78.5) 1168 1003 (85.9) <0.001

PARIENTS WHO WALKED <300 m ON ADMISSION 6MWT (N. 781)

Demographics
Age (years), mean (SD) 227 76.1 (10.4) 112 76.4 (10.0) 442 71.0 (11.2) <0.001
Age ≥80 years, N (%) 227 101 (44.5) 112 30 (26.8) 442 105 (23.7) <0.001
Females, N (%) 227 150 (66.1) 112 55 (49.1) 442 118 (26.7) <0.001
Comorbidities
Obesity (body mass index ≥30), N (%) 227 84 (37.0) 112 29 (25.9) 442 107 (24.2) .001
Hypertension, N (%) 227 221 (97.4) 112 78 (69.6) 442 209 (47.3) <0.001
Diabetes mellitus, N (%) 227 85 (37.4) 112 44 (39.3) 442 146 (33.0) .327
Chronic obstructive pulmonary disease, N (%) 227 73 (32.2) 112 29 (25.9) 442 108 (24.4) .099
Chronic kidney disease, N (%) 227 154 (67.8) 112 82 (73.2) 442 312 (70.6) .334
Stage 3a (eGFR 45–59 mL/min/1.73 m2) 227 52 (22.9) 112 26 (23.2) 442 113 (25.6) .716
Stage 3b (eGFR 30–44 mL/min/1.73 m2) 227 64 (28.2) 112 33 (29.5) 442 134 (39.3)
Stage 4 (eGFR 15–29 mL/min/1.73 m2) 227 36 (15.9) 112 22 (19.6) 442 63 (14.3)
Stage 5 (eGFR <15 mL/min/1.73 m2) 227 2 (0.9) 112 1 (0.9) 442 2 (0.5)
Anemia (hemoglobin <13 g/dL in men and <12 g/dL in women), N (%) 226 117 (51.8) 111 55 (49.5) 441 228 (51.7) .913
Atrial fibrillation, N (%) 227 132 (58.1) 112 50 (44.6) 442 173 (39.1) .001
Clinical findings
Transferred from acute care hospitals after a hospitalization for HF, N (%) 227 90 (39.6) 112 39 (34.8) 442 172 (38.9) .671
NYHA III/IV class, N (%) 227 136 (59.9) 112 72 (64.3) 442 312 (70.6) .018
ICD, N (%) 227 12 (5.3) 112 11 (9.8) 442 183 (41.4) <0.001
Systolic blood pressure (mm Hg), mean (SD) 218 118.9 (19.0) 108 119.2 (18.1) 429 110.3 (16.5) <0.001
Diastolic blood pressure (mm Hg), mean (SD) 218 69.8 (0.3) 108 70.0 (8.8) 429 68.4 (8.8) .102
(continued on next page)

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D. Scrutinio et al. European Journal of Internal Medicine 110 (2023) 86–92

Table 1 (continued )

PARIENTS WHO WALKED <300 m ON ADMISSION 6MWT (N. 781)

Left ventricular ejection fraction, mean (SD) 227 58.4 (5.5) 112 44.5 (2.6) 442 29.4 (6.3) <0.001
Length of stay in the IRFs (days), mean (SD) 227 22.8 (8.3) 112 21.5 (8.4) 442 23.6 (9.9) .039
Laboratory findings
Hemoglobin (g/dL), mean (SD) 226 12.0 (2.0) 111 12.1 (1.7) 441 12.4 (1.9) ,0001
Creatinine (mg/dL), (mean (SD) 227 1.39 (0.70) 112 1.48 (0.64) 442 1.52 (0.60) ,0416
eGFR (mL/min/1.73 m2), mean (SD) 227 51.8 (25.6) 112 49.4 (23.2) 442 49.9 (21.0) .528
Sodium <136 mEq/L, N (%) 227 28 (12.3) 112 13 (11.6) 441 88 (20.0) .013
NT-proBNP (pg/mL), median (IQR) 116 1378 (547–3058) 68 1963 (801–4626) 317 3225 (1405–6067) <0.001
Treatment at discharge
RAAS-Is, N (%) 227 164 (72.2) 112 92 (82.1) 442 384 (86.9) <0.001
Beta-blockers 227 171 (75.3) 112 95 (84.8) 442 394 (89.1) <0.001
RAAS-I plus beta-blocker 227 125 (55.1) 112 81 (72.3) 442 344 (77.8) <0.001

Abbreviations. eGFR estimated glomerular filtration rate, ICD implantable cardioverter defibrillator, IRF inpatient rehabilitation facility, LVEF left ventricular ejection
fraction, NYHA New York Heart Association, N number of patients, 6MWT six-minute walking test, RAAS-Is renin angiotensin aldosterone system inhibitors, SD
standard deviation. * Previously submitted to valve replacement.

important independent factors influencing the likelihood of achieving

Table 2
such an outcome. After adjusting for age, admission 6MWD and other
Six-minute walking test data stratified by ejection fraction.
covariates known to influence functional capacity, the magnitude of the
HFpEF HFmrEF HFrEF p value decreased odds of achieving an increase in 6MWD to 300 m or more for
All patients (N 1784)
HFpEF and HFmrEF was substantially downsized and no longer statis­
Number of patients 379 237 1168 tically significant.
6MWD at admission, mean (SD) 261 297 (120) 322 <0.001
After adjustment for well-established conventional and disease-
(112) (110)
6MWD at discharge, mean (SD) 316 348 (113) 382 <0.001
focused prognostic factors, the achievement of either an increase in
(110) (102) 6MWD >50 m or an increase to 300 m or more predicted improved
Absolute change in 6MWD 54 (56) 52 (50) 61 (59) .098 survival. This significant association persisted in each EF group. In
(meters), mean (SD) HFpEF, an increase in 6MWD greater than 50 m was associated with an
Percent change in 6MWD (%), 33.4 27.3 28.5 .305
approximately 40% decreased risk for all-cause mortality. Similar re­
mean (SD) (62.4) (55.9) (57.0)
Change in 6MWD >50 m, N (%) 169 110 564 .439 sults were observed for the outcome of increase in 6MWD to 300 m or
(44.6) (46.4) (48.3) more in the subset of more functionally impaired patients at admission,
Patients walking <300 m at admission (N. 781) although the wide confidence intervals of estimates leave us uncertain
about the magnitude of the effect. Although an association does not
Number of patients 227 112 442
6MWD at admission, mean (SD) 186 (67) 192 (64) 208 (64) <0.001
prove causality, these findings suggest that HF patients derive a survival
6MWD at discharge, mean (SD) 250 (80) 260 (78) 292 (81) <0.001 benefit from functional improvement regardless of whether the EF is
Absolute change in 6MWD 64 (61) 68 (57) 84 (70) .001 preserved or reduced. This finding is particularly relevant to patients
(meters), mean (SD) with HFpEF, given the paucity of effective treatment options. Collec­
Percent change in 6MWD (%), 48.4 46.7 54.5 .515
tively, our results suggest that the benefits of CR extend to all patients
mean (SD) (76.5) (76.2) (85.0)
Increase in 6MWD to ≥300 m, N 69 (30.4) 33 (29.5) 215 <0.001 with HF, regardless of EF, and provide important background for future
(%) (48.6) randomized clinical trials aimed at determining the impact of CR on
functional and clinical outcomes in HFpEF.
Only few, small-sized studies addressed the effects of CR on func­
likely as those with HFrEF to achieve an increase in 6MWD of more than tional capacity of patients with HFpEF. In a meta-analysis of those
50 m, which represents a clinically relevant functional outcome. Among studies, a significant increase in peak VO2 and 6MWD of 2.08 mL kg− 1
the patients with more severe functional impairment at admission min− 1 and 32 m, respectively, was observed [39]. The analysis of
(<300 m), however, those with HFpEF gained less in functional capacity 6MWD, however, showed high heterogeneity. Of greater interest is an
and a significantly lower proportion achieved an increase in 6MWD to ancillary study of the REHAB-HF trial aimed to assess for differential
300 m or more compared with those with HFrEF (30.4% vs 48.6%), most treatment effects with a transitional, tailored, multidomain rehabilita­
likely because of their older age and worse functional performance at tion intervention vs control based on EF in older patients hospitalized for
presentation. Age and admission 6MWD, indeed, were by far the most HF [40]. Although the interaction p value was not statistically

Fig. 1. Cumulative survival for patients who achieved or did not achieve the functional outcomes.

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D. Scrutinio et al.
Fig. 2. Hazard ratios of 5-year mortality for patients who achieved an increase in six-minute walking distance >50 m or an increase in 6MWD to 300 m or more in
HFpEF, HFmrEF, and HFrEF.
significant, the effect size of intervention on functional outcomes
appeared potentially larger in patients with HFpEF (EF ≥0.45) than with
HFrEF [40]. Our data are consistent with the study of Kamiya et al.
showing that CR participation is associated with prognostic benefit in
HF regardless of ejection fraction [41]. Our study adds to previous
studies by showing that patients with HFpEF are as likely as those with
HFrEF to achieve clinically relevant functional outcomes and that
functional improvement is closely associated with improved survival
regardless of whether EF is preserved, mildly reduced, or reduced.
4.1. Limitations
Some limitations must be acknowledged. The study was retrospec­
tive in nature and a referral bias cannot be excluded. Other unmeasured
or not documented factors, such as frailty, may have influenced out­
comes. Frailty is common among patients with HF [42]. It is related to
older age and increased comorbidity burden, thus being of particular
relevance to HFpEF [43], and is associated with adverse clinical and
functional outcomes [42]. Data from the REHAB-HF trial suggest the
rehabilitation intervention may be associated with greater improve­
ments in physical function among frail versus non-frail patients [44].
There was no control group; thus, a residual confounding effect resulting
from spontaneous, though unlikely [3], improvement in functional ca­
pacity cannot be excluded. This however, does not detract the prog­
nostic significance of functional improvement. Due to the retrospective
nature of the study, we could not provide granular detail on the CR
delivered; thus, we could not address potential differences in the
dose-effect relationship of CR and functional outcome across EF groups.
Although the 6MWT is the most widely used test to measure functional
capacity in the CR setting [37], adopting 6MWD as outcome measure
does not allow appreciating the effect of CR on meaningful
patient-reported outcomes. LVEF was not reassessed after CR; in patients
with HF, however, the probability of a clinically significant improve­
ment in LVEF after CR in the short-term is negligible [45]. Moreover,
589 patients had unpaired data for 6MWT because of missingness at
admission and/or discharge (Supplemental Fig. 1). For these patients, no
reason for not performing the 6MWT could be retrieved from our elec­
tronic Health Information System. The patients with unpaired data for
6MWT were older and presented with a more severe clinical profile
compared with the patients included in the study, suggesting that the
test may have been perceived as too demanding or unwarranted for
these high-risk patients by the treating cardiologist (Supplemental
Table 2). Consistent with this hypothesis, the patients with unpaired
data for 6MWT at admission had a markedly decreased 5-year survival
91
European Journal of Internal Medicine 110 (2023) 86–92
compared with the included patients (36.9% vs 58.8%; Supplemental
Table 2). Finally, both outpatient and inpatient CR facilities are avail­
able in Italy. According to the national regulatory rules governing ad­
missions to inpatient rehabilitation, patients with HF are admitted to
inpatient rehabilitation if they have serious, complex, and potentially
modifiable disability requiring specialized medical assistance or just
after a hospitalization for HF [46]. The rehabilitation intervention is
aimed at improving functional disability and achieving clinical stability.
Costs for inpatient rehabilitation care are covered by the National
Health System on a “per-day” basis. Thus, given that “CR availability,
how CR is incorporated into the health system, and CR delivery models
vary across countries” [47], the generalizability of our results may be
limited.
5. Conclusions
Our data suggest that patients with HFpEF or HFmrEF are as likely as
those with HFrEF to achieve clinically relevant functional outcomes
after CR and that functional improvement is independently associated
with improved long-term survival, regardless of whether EF is pre­
served, mildly reduced, or reduced. Since the observational design of the
study limits the inference about causality, a prospective randomized or
cohort control trial would be needed to validate our findings.
Supplementary Material
Supplemental Fig. 1. Flow-chart of patient selection.
Supplemental Fig. 2. Cumulative survival for patients with pre­
served, mildly-reduced, or reduced ejection fraction.
Declarations of Competing Interest
The authors declare they have no conflict of interest.
Funding
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
Supplementary materials
Supplementary material associated with this article can be found, in
the online version, at doi:10.1016/j.ejim.2023.02.002.
D. Scrutinio et al. European Journal of Internal Medicine 110 (2023) 86–92

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