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The effects of CR in HF patients with preserved EF remain undefined.
•
We studied the effects of CR across the spectrum of EF in 1784 patients.
•
Both patients with HFpEF or HFrEF achieved clinically relevant functional outcomes.
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Functional improvement was associated with improved survival, regardless of EF.
Abstract
Background
There is limited evidence regarding the effects of cardiac rehabilitation (CR) in patients with heart failure and preserved ejection fraction (HFpEF).
Methods
We studied 1784 patients admitted to inpatient CR. The patients were grouped into HFpEF (EF≥0.50), 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.
Global Burden of Disease Study 2013 Collaborators Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.
]. Functional 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 [
]. Population aging, increasing prevalence of HFpEF-related risk factors, and heightened diagnostic awareness have been implicated to explain this trend [
]. 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 [
Temporal trends of heart failure hospitalizations in cardiology versus noncardiology wards according to ejection fraction: 16-year data from the SwedeHF Registry.
]. 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 patients with HFrEF [
], 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 [
Increasing evidence indicates that cardiac rehabilitation (CR) can significantly improve symptoms, functional status and quality of life, and can reduce hospital admissions and mortality [
2021 update to the 2017 ACC expert consensus decision pathway for optimization of heart failure treatment: answers to 10 pivotal issues about heart failure with reduced ejection fraction: a report of the American College of Cardiology solution set oversight committee.
]. 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 [
]. Thus, there is lack of evidence regarding the effects of CR in patients 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 hypothesized 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 worsening 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 [
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 independent 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 assistance, 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 standardized 6 min walking test (6MWT) [
] is performed by experienced 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 resynchronization 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 [
]. 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 [
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 estimated 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. Unadjusted 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 regression 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, hemoglobin, estimated glomerular filtration rate, and 6MWD at admission [
]. 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 [
]. 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 significant. All analyses were conducted using STATA software, version 14 (Stata-Corp LP, College Station, Tex).
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.
Table 1Baseline characteristics stratified by ejection fraction.
HFpEF (LVEF ≥0.50, N. 379)
HFmrEF (LVEF 0.41–0.49, N. 237)
HFrEF (LVEF ≤0.40; N. 1168)
Number of observations
Mean (SD) or N (%)
Number of observations
Mean (SD) or N (%)
Number of observations
Mean (SD) or N (%)
p value
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 g/dL in women), N (%)
377
180 (47.7)
235
101 (43.0)
1165
450 (38.6)
.006
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 hospitalization for HF, N (%)
379
123 (32.5)
237
67 (28.3)
1168
375 (32.1)
.478
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 (18.5)
228
118.5 (17.9)
1130
109.6 (15.7)
<0.001
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 (461–2739)
148
914 (256–3214)
876
2054 (871–3973)
.354
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 <300m 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
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.
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.
Table 2Six-minute walking test data stratified by ejection fraction.
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 increase 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 increase in 6MWD to 300 m or more for HFpEF and HFmrEF was substantially 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 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 patients 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. 1Cumulative survival for patients who achieved or did not achieve the functional outcomes.
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.
Fig. 2Hazard 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.
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 capacity 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) functional 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 [
]. There is suggestive evidence that 6MWT performs better as a prognostic tool for HF patients with severely impaired functional capacity, in whom daily activity level is likely to approach maximal exercise capacity [
Six minute corridor walk test as an outcome measure for the assessment of treatment in randomized, blinded intervention trials of chronic heart failure: a systematic review.
]. Data from the HF-ACTION trial also suggest that it provides prognostic utility comparable to cardiopulmonary exercise testing in outpatients with reduced EF [
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 [
]. 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 difference was small. After adjustment, the patients with HFpEF were as likely as those with HFrEF to achieve an increase in 6MWD of more than 50 m, which represents a clinically relevant functional outcome. Among the patients with more severe functional impairment at admission (<300 m), however, those with HFpEF gained less in functional capacity and a significantly lower proportion achieved an increase in 6MWD to 300 m or more compared with those with HFrEF (30.4% vs 48.6%), most likely because of their older age and worse functional performance at presentation. Age and admission 6MWD, indeed, were by far the most important independent factors influencing the likelihood of achieving such an outcome. After adjusting for age, admission 6MWD and other covariates known to influence functional capacity, the magnitude of the decreased odds of achieving an increase in 6MWD to 300 m or more for HFpEF and HFmrEF was substantially downsized and no longer statistically significant.
After adjustment for well-established conventional and disease-focused prognostic factors, the achievement of either an increase in 6MWD >50 m or an increase to 300 m or more predicted improved survival. This significant association persisted in each EF group. In HFpEF, an increase in 6MWD greater than 50 m was associated with an approximately 40% decreased risk for all-cause mortality. Similar results were observed for the outcome of increase in 6MWD to 300 m or more in the subset of more functionally impaired patients at admission, although the wide confidence intervals of estimates leave us uncertain about the magnitude of the effect. Although an association does not prove causality, these findings suggest that HF patients derive a survival benefit from functional improvement regardless of whether the EF is preserved or reduced. This finding is particularly relevant to patients with HFpEF, given the paucity of effective treatment options. Collectively, our results suggest that the benefits of CR extend to all patients with HF, regardless of EF, and provide important background for future 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 functional capacity of patients with HFpEF. In a meta-analysis of those studies, a significant increase in peak VO2 and 6MWD of 2.08 mL kg−1 min−1 and 32 m, respectively, was observed [
]. The analysis of 6MWD, however, showed high heterogeneity. Of greater interest is an ancillary study of the REHAB-HF trial aimed to assess for differential treatment effects with a transitional, tailored, multidomain rehabilitation intervention vs control based on EF in older patients hospitalized for HF [
]. Although the interaction p value was not statistically significant, the effect size of intervention on functional outcomes appeared potentially larger in patients with HFpEF (EF ≥0.45) than with HFrEF [
]. 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 [
]. 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 retrospective in nature and a referral bias cannot be excluded. Other unmeasured or not documented factors, such as frailty, may have influenced outcomes. Frailty is common among patients with HF [
]. Data from the REHAB-HF trial suggest the rehabilitation intervention may be associated with greater improvements in physical function among frail versus non-frail patients [
], improvement in functional capacity cannot be excluded. This however, does not detract the prognostic 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 [
], 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 improvement in LVEF after CR in the short-term is negligible [
]. 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 electronic 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 compared with the included patients (36.9% vs 58.8%; Supplemental Table 2). Finally, both outpatient and inpatient CR facilities are available in Italy. According to the national regulatory rules governing admissions 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 [
]. 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” [
], 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 preserved, 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 preserved, 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.
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