ABSTRACT

Background:

We will undertake an individual patient data (IPD) meta-analysis to assess the impact of exercise-based cardiac rehabilitation in patients with heart failure with preserved ejection fraction (HFpEF) on mortality and hospitalization and quality of life of exercise-based cardiac rehabilitation according to patient characteristics: age, sex, ethnicity, New York Heart Association functional class, ischemic etiology, ejection fraction, and exercise capacity. Despite emerging evidence supporting exercise training in HFpEF, uncertainties remain in the interpretation and understanding of this evidence base. Clinicians and health care providers seek definitive estimates of impact on mortality, hospitalization and health-related quality of life (HRQoL). This work is, therefore, important as HFpEF treatment options are evolving; however, efficacy of some medications is equivocal, so optimizing exercise rehabilitation is vital.

Methods:

We conducted a systematic search to identify randomized trials of exercise training for at least 3 weeks compared with no exercise control with 6-month follow up or longer, providing IPD time to event on mortality or hospitalization (all-cause or heart failure-specific). IPD will be combined into a single dataset. We will use Cox proportional hazards models to investigate the effect of exercise-based cardiac rehabilitation and the interactions between exercise-based cardiac rehabilitation and participant characteristics. We will use a mix of one-stage and two-stage models. Original IPD will be requested from the authors of all eligible trials; we will check original data and compile a master dataset. IPD meta-analyses will be conducted using a one-step approach where the IPD from all studies are modeled simultaneously while accounting for the clustering of participants with studies.

Results:

We expect our analyses to show improved mortality, hospitalization, cardiorespiratory fitness, and health-related quality of life.

Conclusion:

This work will clarify exercise-based rehabilitation delivery methods to optimize benefits for people with HFpEF.

BACKGROUND

Patients with chronic heart failure (HF) and preserved ejection fraction (HFpEF) (left ventricular ejection fraction [LVEF] ≥50%), experience a marked reduction in their exercise capacity, health-related quality of life (HRQoL), and life expectancy (1). Typically exercise capacity of people with HFpEF is about 4 METS, and this is comparable to people with heart failure with reduced ejection fraction (HFrEF) (2). Structured exercise training, often delivered as part of a cardiac rehabilitation program, has been shown to redress some of the deficit in physical fitness (3). Treatment options are limited for HFpEF, and the cornerstone is often lifestyle therapy, including weight loss and structured physical activity. Optimization of exercise rehabilitation is vital as people with HFpEF are traditionally more likely to be female and older than their HFrEF counterparts. Uncertainty remains about the efficacy of exercise training in people with HFpEF because of the relatively small number of published trials compared with people with HFrEF. Despite some evidence supporting exercise training in HFpEF, uncertainties remain in the interpretation and understanding of the expected magnitude of improvement and optimal exercise prescription. Clinicians and health care providers seek definitive estimates of the impact on mortality, hospitalization, HRQoL, and which HFpEF patient phenotypes derive benefits. Several group-level meta-analyses examining the effect of exercise training for HFpEF have been conducted, but an individual participant data (IPD) meta-analysis will allow a more thorough investigation.

Justification for conducting this work is derived from studies that have compared HFpEF with HFrEF which repeatedly show patients of older age, and a higher prevalence of women (4) (Table 1).

TABLE 1.

Comparison of characteristics of people with HFpEF and HFrEF who have completed exercise training trials (RCTs).

Comparison of characteristics of people with HFpEF and HFrEF who have completed exercise training trials (RCTs).
Comparison of characteristics of people with HFpEF and HFrEF who have completed exercise training trials (RCTs).

The differing characteristics of people with HFpEF may impact exercise-based cardiac rehabilitation outcomes in the following ways:

  1. Uptake rates may be different in older HFpEF patients, because of difficulty with access.

  2. Adherence rates may differ between HFpEF and HFrEF.

  3. The expected change in quality of life and physical fitness may be different to HFrEF as often HFpEF patients are older.

  4. Time to events and number of events may show differences between people with HFpEF and HFrEF.

METHODS

Search Methods for Identification of Studies

Randomized controlled trials for inclusion in the ExTra-MATCH III project have been identified from recent meta-analyses, the 2019 updated Cochrane Review (6), and the most recent database search.

Eligibility Criteria for Studies

Studies will be included if they meet the following inclusion criteria:

  1. Study design: Randomized controlled trials

  2. Population:

    • Studies that include adult patients (18 years and older) with a diagnosis of HFpEF with a LVEF ≥45%.

    • Studies with an inclusion criteria that allows for any HF patient (HFpEF and HFrEF) but provides no LVEF% inclusion or exclusion criteria, but reports a mean LVEF >40%; however only IPD for participants with LVEF ≥45% will be extracted (subanalyses will also be conducted; see subgroup analysis).

    • Studies reporting a mean LVEF >40% at baseline, but with a stated study inclusion/exclusion criterion of LVEF <45%, will be excluded

  3. Intervention: Exercise training of 4 weeks' duration or more, with no restriction on type of training

  4. Context: Patients managed in any setting, that is, home, hospital, university, community facility, supervised or unsupervised

  5. Comparator: a no-exercise group, defined as no exercise, normal daily activities, usual care, attention control, and/or education

  6. Sample size: no restriction on sample size

Tables 2 and 3 list the characteristics of the studies identified for possible inclusion in IPD meta-analysis. Table 4 outlines the status of clinical trials in HFpEF patients, previously identified in 2019 Cochrane Review.

TABLE 2.

HFpEF: possible studies for inclusion in IPD meta-analysis.

HFpEF: possible studies for inclusion in IPD meta-analysis.
HFpEF: possible studies for inclusion in IPD meta-analysis.
TABLE 3.

Heart failure studies with baseline LVEF >40%: possible studies for inclusion in IPD meta-analysis.

Heart failure studies with baseline LVEF >40%: possible studies for inclusion in IPD meta-analysis.
Heart failure studies with baseline LVEF >40%: possible studies for inclusion in IPD meta-analysis.
TABLE 4.

HFpEF clinical trials as identified from 2019 Cochrane Review.

HFpEF clinical trials as identified from 2019 Cochrane Review.
HFpEF clinical trials as identified from 2019 Cochrane Review.

MAIN VARIABLES AND OUTCOMES

This list of proposed variables and outcomes at a patient level has been generated from the ExTraMATCH II protocol (38). In accordance with the research objectives, IPD will be sought for the following variables and outcomes from eligible trials:

  1. Baseline & clinical characteristics:

    • Age

    • Gender

    • Body Mass Index

    • Ethnicity

    • LVEF and cardiac dimensions, diastology (Doppler) and HF etiology

    • New York Heart Association Class

    • Etiology and Comorbidities (e.g., hypertension, diabetes)

    • Baseline BNP and serum creatinine and hemoglobin

    • Medication class and dosage

  2. Outcomes:

    • Exercise capacity (irrespective of assessment method) (at baseline and all follow up); including peak VO2, respiratory exchange ratio, VE/VCO2 slope, resting/maximal/delta heart rate, resting/maximal blood pressure.

    • Disease-specific HRQoL, at baseline and all follow up, irrespective of assessment tool;

    • Mortality (all-cause, death due to HF); incidence and time-to-event;

    • Hospital admission/readmission (all cause, HF-specific); incidence, duration, reason for censoring, and time-to-event

Collection of Data and Data Management

Investigator Contacts

Principal investigators of included trials will be contacted via email by IPD authors to inform them of the IPD analysis and to ask if they are willing to share their original IPD. Members of the ExTraMATCH III Executive Management Group (see list of members in the Acknowledgments) have links with several study investigators, so if no response is received to the initial invitation, members of the group will be assigned to make further contact. If after this time study investigators have not responded or are unwilling to contribute their data, a final note will be sent enquiring why they are unable to participate.

Data Format

The procedure for collection and collation of data will be coordinated by the project secretariat at the University of New England, Armidale, NSW Australia. All participating study authors will be asked to provide deidentified datasets. Where possible, electronic versions of datasets will be sought together with written details of the coding of the variables. A standardized data template will be provided to all study authors; however, as primary study authors are unable to use the template, we will accept databases in all formats.

Data Transfer and Storage

Receipt of raw data from study investigators will vary depending on any concerns as to security of their host institution. In most cases, we anticipate data will be sent via an encrypted data file by email to the project secretariat. Once received data will be stored on a secure password-protected computer server managed in accordance with the data management standard operating procedures of the University of New England. Raw datasets will be stored in their original format and then converted and combined into one overall master dataset.

Data Checking

Data from each study will be evaluated and compared with the data in the original publications. We will check original data to make sure all values are reasonable and assess any missing data. Data from each trial will be checked on range, extreme values, internal consistency, missing values, and consistency with published reports. Where there is missing information, errors, or data discrepancies, the relevant study author will be contacted and asked to check their data and ensure the IPD dataset tallies with the published article. Access to data at all stages of cleaning and analysis will be restricted to core members of the research team (N.A.S., M.J.P., J.C., and R.T.).

Once all original data is checked and verified, individual study data will be combined to form a new master dataset. Data from individual datasets remain the property of the ExTraMATCH III Collaborators who have provided IPD.

Statistical Analysis

For dichotomous outcomes the number of people in each group allocation and the number of successes/failures (e.g., alive/dead) will be analyzed. For continuous variables the pre/post training mean/SD for change in these values will be calculated or imputed using standard methods (39,40). Due to the complexity of the statistical analysis the following represents the planned principal analyses; some modifications and additional analyses are likely to emerge during the project. Where there are sufficient numbers of studies using the same HrQOL tool, we will group and analyze these using the default mean difference function. Where there are a number of mixed HrQOL tools, these will be grouped and the standardized mean difference function will be used as opposed to the default mean difference function.

A detailed statistical analysis will be produced prior to the analysis. Analyses will be conducted in accordance with current recommendations for IPD meta-analyses (41).

Study and patient level characteristics of included studies will be presented. IPD meta-analyses will be conducted using a one-step approach where the IPD from all studies are modeled simultaneously while accounting for the clustering of participants with studies. All analyses will follow the principle of intention-to-treat as closely as possible. Continuous outcomes will be analyzed using linear models with adjustments for baseline values. Time-to-event endpoints will be analyses using Cox proportional hazard models.

Analyses will be undertaken using Stata v 16; Stata Statistical Software, Release 16, StataCorp LLC, College Station, TX, and study data will not be used for any other purpose without the permission of collaborators.

Subanalyses will include the following:

  1. Meta-regression: Where 8 or more studies provide relevant data, meta-regression will be performed to examine the effect of confounding variables (e.g., age, gender) on the findings.

  2. Subgroup analyses: Over the years clinical trials in HFpEF have used LVEFs of 40% to 49% to define the cut-off and inclusion of HFpEF patients. Recent European Society of Cardiology guidelines suggest that HF patients with a LVEF 40% to 49% be classified as having heart failure with mid-range ejection fraction (HFmrEF) and only HFpEF when LVEF is ≥50% (42). Initial IPD analysis will include data from all HF patients with a LVEF ≥45%. Subgroup analyses will then be conducted removing patients with a LVEF 45% to 49%.

  3. Sensitivity analysis: Where indicated sensitivity analyses will be undertaken to assess the effect of various characteristics (e.g., gender, age, renal function) on the findings.

Study Quality Assessment

Study quality assessment of included studies was undertaken using the validated TESTEX scale (43).

Publication Bias

Publication bias will be assessed for the IPD analysis will be assessed in accordance with recommended methods (44).

Project Management and Ethics

The ExTraMATCH III Executive Management Group refers to the core team of researchers who will oversee the strategic direction of the study. The Executive Management Group will act as liaison between the ExTraMATCH III Collaborators. The ExTraMATCH III Collaborators refers to all those linked to the project and includes trial teams who provide data sets for the study. The Collaborative Group will be composed of 1 representative from each of the included studies. As new eligible studies are completed, new collaborators will be invited.

The roles of the ExTraMATCH III Executive Management Group are to

  1. agree on the research questions of the collaboration and develop the initial protocol;

  2. agree on the data collection proforma;

  3. oversee arrangements for secure data handling;

  4. review the publication strategy for the collaboration;

  5. ensure that data are only used, and any additional research (including updating of the combined data sets with emerging evidence) only proceeds, following consultation and agreement with the Collaborative Group; and lead future applications for research funding.

Collaborative Group

The Executive Management Group will act as a liaison between members of the Collaborative Group. The Collaborative Group will be composed of a representative from each of the included trials. We will invite new collaborators as new eligible studies are completed.

Members of the collaborative will be given opportunities to participate in decision-making regarding the study design and analyses. We intend members of the collaborative will have opportunities to network and identify future ExTraMATCH III research questions suitable for analysis with the IPD dataset. Once the Collaborative Group and initial dataset are established, we will develop mechanisms for communication and input on methodological issues.

Data Ownership and Confidentiality

Participants in the individual trials have previously consented to participation in their respective trial. Given that the analyses proposed are simply an extension of the core analysis of the constituent trials, we do not anticipate that additional ethical permission will be required. We will ensure that datasets shared as part of the project include no patient-identifiable information (such as names and addresses), that all data storage is in accordance with the regulations governing research at the University of New England, and we will obtain a signed data sharing agreement with all authors to outline procedures for the transmission, storage, analysis, and dissemination. The collaborators remain the custodians of their own data and retain the right to withdraw their data from the analysis at any time.

Publication Policy

We will follow recommendations for authorship in IPD analyses and multicenter studies (45,46). Where possible, we will follow the policy of members of the Executive Management Group and the Collaborative Group being listed as authors and names of other participating collaborators listed in the acknowledgments. Requirements for authorship will follow those of the International Committee of Medical Journal Editors (47).

A primary publication of the results of this review will be prepared by the Executive Management Group. This and all other ExTraMATCH II manuscript drafts will be circulated to the Collaborative Group for comment, revision, and approval.

DISCUSSION

The information from ExTraMATCH III will help inform future national and international clinical and policy decision-making on the use of exercise-based interventions in HF and improve the quality, design, and reporting of future trials in this field. Despite encouraging evidence supporting exercise training in HFpEF, only data from about 20 trials have been published to date. So uncertainties remain in the interpretation and understanding of this evidence base. Providers of medical care seek more precise estimates of impact on mortality, hospitalization, cardiorespiratory fitness, and HRQoL. A pooled IPD analysis will allow predictions to be made between patient characteristics and change in the clinical outcomes, following exercise-based cardiac rehabilitation. This work is, therefore, important as HFpEF treatment options are evolving; however, efficacy of some medications is equivocal, so optimizing exercise rehabilitation is vital as people with HFpEF are traditionally more likely to be female and older than their HFrEF counterparts. The IPD analysis may reveal that some of these subtle HFpEF vs HFrEF differences in patient characteristics may have implications for optimization of exercise programming.

Acknowledgments

In addition to the authors, the following are members of the ExTraMATCH III Executive Management Group: Valentine Nijke, Yale School of Medicine, Yale University, New Haven CT, USA; Evangeline Kouidi, The School of Physical Education and Sports Science of the Aristotle University of Thessaloniki, Greece; and Peter Brubaker, Wake Forest University, Winston-Salem, NC, USA.

REFERENCES

1.
Taylor
RS,
Walker
S,
Smart
NA,
Piepoli
MF,
Warren
FC,
Ciani
O,
O'Connor
C,
Whellan
D,
Keteyian
SJ,
Coats
A,
Davos
CH,
Dalal
HM,
Dracup
K,
Evangelista
L,
Jolly
K,
Myers
J,
McKelvie
RS,
Nilsson
BB,
Passino
C,
Witham
MD,
Yeh
GY,
Zwisler
AO,
ExTra
MIIC.
Impact of exercise-based cardiac rehabilitation in patients with heart failure (ExTraMATCH II) on mortality and hospitalisation: an individual patient data meta-analysis of randomised trials
.
Eur J Heart Fail.
2018
.
20
(
12
):
1735
43
.
2.
Smart
NA,
Haluska
B,
Jeffriess
L,
Leung
D.
Exercise training in heart failure with preserved systolic function: a randomized controlled trial of the effects on cardiac function and functional capacity
.
Congest Heart Fail
.
2012
;
18
(
6
):
295
301
.
3.
Taylor
RS,
Davies
EJ,
Dalal
HM,
Davis
R,
Doherty
P,
Cooper
C,
Holland
DJ,
Jolly
K,
Smart
NA.
Effects of exercise training for heart failure with preserved ejection fraction: a systematic review and meta-analysis of comparative studies
.
Int J Cardiol
.
2012
;
162
(
1
):
6
13
.
4.
Pfeffer
MA,
Shah
AM,
Borlaug
BA.
Heart failure with preserved ejection fraction in perspective
.
Circ Res
.
2019
;
124
(
11
):
1598
617
.
5.
Taylor
RS,
Walker
S,
Smart
NA,
Piepoli
MF,
Warren
FC,
Ciani
O,
O'connor
C,
Whellan
D,
Keteyian
SJ,
Coats
A.
Impact of exercise-based cardiac rehabilitation in patients with heart failure (ExTraMATCH II) on mortality and hospitalisation: an individual patient data meta-analysis of randomised trials
.
Eur J Heart Fail
.
2018
;
20
(
12
):
1735
43
.
6.
Long
L,
Mordi
IR,
Bridges
C,
Sagar
VA,
Davies
EJ,
Coats
AJ,
Dalal
H,
Rees
K,
Singh
SJ,
Taylor
RS.
Exercise-based cardiac rehabilitation for adults with heart failure
.
Cochrane Database Syst Rev.
2019
.
Jan
29
;
1
(
1
).
doi:
7.
Alves
AJ,
Ribeiro
F,
Goldhammer
E,
Rivlin
Y,
Rosenschein
U,
Viana
JL,
Duarte
JA,
Sagiv
M,
Oliveira
J.
Exercise training improves diastolic function in heart failure patients
.
Med Sci Sports Exerc
.
2012
;
44
(
5
):
776
85
.
8.
Edelmann
F,
Gelbrich
G,
Düngen
H-D,
Fröhling
S,
Wachter
R,
Stahrenberg
R,
Binder
L,
Töpper
A,
Lashki
DJ,
Schwarz
S.
Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study
.
J Am Coll Cardiol
.
2011
;
58
(
17
):
1780
91
.
9.
Gary
RA,
Sueta
CA,
Dougherty
M,
Rosenberg
B,
Cheek
D,
Preisser
J,
Neelon
V,
McMurray
R.
Home-based exercise improves functional performance and quality of life in women with diastolic heart failure
.
Heart Lung
.
2004
;
33
(
4
):
210
8
.
10.
Karavidas
A,
Driva
M,
Parissis
JT,
Farmakis
D,
Mantzaraki
V,
Varounis
C,
Paraskevaidis
I,
Ikonomidis
I,
Pirgakis
V,
Anastasiou-Nana
M.
Functional electrical stimulation of peripheral muscles improves endothelial function and clinical and emotional status in heart failure patients with preserved left ventricular ejection fraction
.
Am Heart J
.
2013
;
166
(
4
):
760
7
.
11.
Kinusaga
Y,
Sota
T,
Ishiga
N,
Nakamura
K,
Kamitani
H,
Hirai
M,
Yanagihara
K,
Kato
M,
Yamamoto
K.
Home-based inspiratory muscle training in patients with heart failure and preserved ejection fraction: a preliminary study
.
J Card Fail
.
2020
;
26
(
11
):
1022
3
.
12.
Kitzman
DW,
Brubaker
PH,
Morgan
TM,
Stewart
KP,
Little
WC.
Exercise training in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial
.
Circ Heart Fail
.
2010
;
3
(
6
):
659
67
.
13.
Kitzman
DW,
Brubaker
PH,
Herrington
DM,
Morgan
TM,
Stewart
KP,
Hundley
WG,
Abdelhamed
A,
Haykowsky
MJ.
Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial
.
J Am Coll Cardiol
.
2013
;
62
(
7
):
584
92
.
14.
Kitzman
DW,
Brubaker
P,
Morgan
T,
Haykowsky
M,
Hundley
G,
Kraus
WE,
Eggebeen
J,
Nicklas
BJ.
Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial
.
JAMA
.
2016
;
315
(
1
):
36
46
.
15.
Lang
CC,
Smith
K,
Wingham
J,
Eyre
V,
Greaves
CJ,
Warren
FC,
Green
C,
Jolly
K,
Davis
RC,
Doherty
PJ.
A randomised controlled trial of a facilitated home-based rehabilitation intervention in patients with heart failure with preserved ejection fraction and their caregivers: the REACH-HFpEF Pilot Study
.
BMJ Open
.
2018
;
8
(
4
).
doi:
16.
Mueller
S,
Winzer
EB,
Duvinage
A,
Gevaert
AB,
Edelmann
F,
Haller
B,
Pieske-Kraigher
E,
Beckers
P,
Bobenko
A,
Hommel
J,
Van de Heyning
CM,
Esefeld
K,
von Korn
P,
Christle
JW,
Haykowsky
MJ,
Linke
A,
Wisloff
U,
Adams
V,
Pieske
B,
van Craenenbroeck
EM,
Halle
M,
OptimEx-Clin Study G.
Effect of high-intensity interval training, moderate continuous training, or guideline-based physical activity advice on peak oxygen consumption in patients with heart failure with preserved ejection fraction: a randomized clinical trial
.
JAMA
.
2021
;
325
(
6
):
542
51
.
17.
Palau
P,
Domínguez
E,
Núñez
E,
Schmid
J-P,
Vergara
P,
Ramón
JM,
Mascarell
B,
Sanchis
J,
Chorro
FJ,
Núñez
J.
Effects of inspiratory muscle training in patients with heart failure with preserved ejection fraction
.
Eur J Prev cardiol
.
2014
;
21
(
12
):
1465
73
.
18.
Palau
P,
Domínguez
E,
López
L,
Ramón
JM,
Heredia
R,
González
J,
Santas
E,
Bodí
V,
Miñana
G,
Valero
E.
Inspiratory muscle training and functional electrical stimulation for treatment of heart failure with preserved ejection fraction: the TRAINING-HF Trial
.
Rev Esp Cardiol (Engl Ed)
.
2019
;
72
(
4
):
288
97
.
19.
Smart
NA,
Haluska
B,
Jeffriess
L,
Leung
D.
Exercise training in heart failure with preserved systolic function: a randomized controlled trial of the effects on cardiac function and functional capacity
.
Congest Heart Fail
.
2012
;
18
(
6
):
295
301
.
20.
Antonicelli
R,
Spazzafumo
L,
Scalvini
S,
Olivieri
F,
Matassini
MV,
Parati
G,
Del Sindaco
D,
Gallo
R,
Lattanzio
F.
Exercise: a “new drug” for elderly patients with chronic heart failure
.
Aging (Albany NY)
.
2016
;
8
(
5
):
860
72
.
21.
Aksoy
S,
Findikoglu
G,
Ardic
F,
Rota
S,
Dursunoglu
D.
Effect of 10-week supervised moderate-intensity intermittent vs. continuous aerobic exercise programs on vascular adhesion molecules in patients with heart failure
.
Am J Phys Med Rehabil
.
2015
;
94
(
10S
):
898
911
.
22.
Chen
Y,
Funk
M,
Wen
J,
Tang
X,
He
G,
Liu
H.
Effectiveness of a multidisciplinary disease management program on outcomes in patients with heart failure in China: a randomized controlled single center study
.
Heart Lung
.
2018
;
47
(
1
):
24
31
.
23.
Chen
D-M,
Yu
W-C,
Hung
H-F,
Tsai
J-C,
Wu
H-Y,
Chiou
A-F.
The effects of Baduanjin exercise on fatigue and quality of life in patients with heart failure: a randomized controlled trial
.
Eur J Cardiovasc Nurs
.
2018
;
17
(
5
):
456
66
.
24.
Gary
RA,
Paul
S,
Corwin
E,
Butts
B,
Miller
AH,
Hepburn
K,
Williams
B,
Waldrop-Valverde
D
.
Exercise and cognitive training as a strategy to improve neurocognitive outcomes in heart failure: a pilot study
.
Am J Geriatr Psychiatry
,
2019
Aug
;
27
(
8
):
809
19
.
25.
Giallauria
F,
Cirillo
P,
Lucci
R,
Pacileo
M,
De Lorenzo
A,
D'Agostino
M,
Moschella
S,
Psaroudaki
M,
Del Forno
D,
Orio
F.
Left ventricular remodelling in patients with moderate systolic dysfunction after myocardial infarction: favourable effects of exercise training and predictive role of N-terminal pro-brain natriuretic peptide
.
Eur J Prev Cardiol
.
2008
;
15
(
1
):
113
8
.
26.
Jaarsma
T,
Klompstra
L,
Ben Gal
T,
Ben Avraham
B,
Boyne
J,
Back
M,
Chiala
O,
Dickstein
K,
Evangelista
L,
Hagenow
A,
Hoes
AW,
Hagglund
E,
Piepoli
MF,
Vellone
E,
Zuithoff
NPA,
Martensson
J,
Stromberg
A.
Effects of exergaming on exercise capacity in patients with heart failure: results of an international multicentre randomized controlled trial
.
Eur J Heart Fail
.
Forthcoming 2021.
27.
Jónsdóttir
S,
Andersen
KK,
Sigurđsson
AF,
Sigurđsson
SB.
The effect of physical training in chronic heart failure
.
Eur J Heart Fail
.
2006
;
8
(
1
):
97
101
.
28.
Kaltsatou
AC,
Kouidi
EI,
Anifanti
MA,
Douka
SI,
Deligiannis
AP.
Functional and psychosocial effects of either a traditional dancing or a formal exercising training program in patients with chronic heart failure: a comparative randomized controlled study
.
Clin Rehabil
.
2014
;
28
(
2
):
128
38
.
29.
Norman
JF,
Kupzyk
KA,
Artinian
NT,
Keteyian
SJ,
Alonso
WS,
Bills
SE,
Pozehl
BJ.
The influence of the HEART Camp intervention on physical function, health-related quality of life, depression, anxiety and fatigue in patients with heart failure
.
Eur J Cardiovasc Nurs
.
2020
;
19
(
1
):
64
73
.
30.
Redwine
LS,
Wilson
K,
Pung
MA,
Chinh
K,
Rutledge
T,
Mills
PJ,
Smith
B.
A randomized study examining the effects of mild-to-moderate group exercises on cardiovascular, physical, and psychological well-being in patients with heart failure
.
J Cardiopulm Rehabil Prev
.
2019
;
39
(
6
):
403
8
.
31.
Reeves
GR,
Whellan
DJ,
O'Connor
CM,
Duncan
P,
Eggebeen
JD,
Morgan
TM,
Hewston
LA,
Pastva
A,
Patel
MJ,
Kitzman
DW.
A novel rehabilitation intervention for older patients with acute decompensated heart failure: the REHAB-HF pilot study
.
JACC Heart Fail
.
2017
;
5
(
5
):
359
66
.
32.
Wall
HK,
Ballard
J,
Troped
P,
Njike
VY,
Katz
DL.
Impact of home-based, supervised exercise on congestive heart failure
.
Int J Cardiol
.
2010
;
145
(
2
):
267
70
.
33.
Mudge
AM,
Denaro
CP,
Scott
AC,
Meyers
D,
Adsett
JA,
Mullins
RW,
Suna
JM,
Atherton
JJ,
Marwick
TH,
Scuffham
P,
O'Rourke
P.
Addition of supervised exercise training to a post-hospital disease management program for patients recently hospitalized with acute heart failure: the EJECTION-HF randomized phase 4 trial
.
JACC Heart Fail
.
2018
;
6
(
2
):
143
42
.
34.
Exercise training in diastolic heart failure. ISRCTN registry: ISRCTN86879094
.
Updated December 8, 2020. Accessed February 25, 2021.
doi:
35.
Exercise training effect in patients with HF and PEF. ClinicalTrials.gov Identifier: NCT0269486
.
Updated January 10, 2017. Accessed February 25, 2021. https://clinicaltrials.gov/ct2/show/NCT02696486
36.
Rehabilitation program in heart failure with preserved ejection fraction
.
ClinicalTrials.gov Identifier: NCT01914315. Updated November 18, 2014. Accessed February 25, 2021. https://clinicaltrials.gov/ct2/show/NCT01914315
37.
A trial of rehabilitation therapy in older acute heart failure patients (REHAB-HF)
.
ClinicalTrials.gov Identifier: NCT02196038. Updated September 10, 2020. Accessed February 25, 2021. https://clinicaltrials.gov/ct2/show/NCT02196038
38.
Pedometer-based walking intervention in patients with chronic heart failure with preserved ejection fraction
.
ClinicalTrials. gov Identifier: NCT03041376. Updated May 17, 2018. Accessed February 25, 2021. https://clinicaltrials.gov/ct2/show/NCT03041376
39.
Taylor
RS,
Piepoli
MF,
Smart
N,
Coats
AJ,
Ellis
S,
Dalal
H,
O'Connor
CM,
Warren
FC,
Whellan
D,
Ciani
O.
Exercise training for chronic heart failure (ExTraMATCH II): protocol for an individual participant data meta-analysis
.
IntJ Cardiol
.
2014
;
174
(
3
):
683
7
.
40.
Cumpston
M,
Li
T,
Page
MJ,
Chandler
J,
Welch
VA,
Higgins
JP,
Thomas
J.
Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions
.
Cochrane Database Syst Rev
.
2019
;
10
.
doi:
41.
Riley
RD,
Lambert
PC,
Staessen
JA,
Wang
J,
Gueyffier
F,
Thijs
L,
Boutitie
F.
Meta-analysis of continuous outcomes combining individual patient data and aggregate data
.
Stat Med
.
2008
;
27
(
11
):
1870
93
.
42.
Tierney
JF,
Vale
C,
Riley
R,
Smith
CT,
Stewart
L,
Clarke
M,
Rovers
M.
Individual participant data (IPD) meta-analyses of randomised controlled trials: guidance on their use
.
PLoS Med
.
2015
;
12
(
7
).
doi:
43.
Ponikowski
P,
Voors
AA,
Anker
SD,
Bueno
H,
Cleland
JG,
Coats
AJ,
Falk
V,
González-Juanatey
JR,
Harjola
VP,
Jankowska
EA.
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC
.
Eur J Heart Fail
.
2016
;
18
(
8
):
891
975
.
44.
Smart
NA,
Waldron
M,
Ismail
H,
Giallauria
F,
Vigorito
C,
Cornelissen
V,
Dieberg
G.
Validation of a new tool for the assessment of study quality and reporting in exercise training studies: TESTEX
.
Int J Evid Based Healthc
.
2015
;
13
(
1
):
9
18
.
45.
Ahmed
I,
Sutton
AJ,
Riley
RD.
Assessment of publication bias, selection bias, and unavailable data in meta-analyses using individual participant data: a database survey
.
BMJ
.
2012
;
344
.
doi:
46.
Stewart
LA,
Tierney
JF.
To IPD or not to IPD? Advantages and disadvantages of systematic reviews using individual patient data
.
Eval Health Prof
.
2002
;
25
(
1
):
76
97
.
47.
Whellan
DJ,
Ellis
SJ,
Kraus
WE,
Hawthorne
K,
Pina
IL,
Keteyian
SJ,
Kitzman
DW,
Cooper
L,
Lee
K,
O'Connor
CM.
Method for establishing authorship in a multicenter clinical trial
.
Ann Intern Med
.
2009
;
151
(
6
):
414
20
.
48.
International Committee of Medical Journal Editors.
Updated 2021. Accessed March 19, 2021. http://www.icmje.org

Competing Interests

Conflicts of Interest: No conflicts for any author